Integracin metablica de diabetes

Tema: Integracin metablica en la diabetes y mecanismo de accin, biotransformacin y sntesis de dos medicamentos de accin antidiabtica: glibenclamida (secretagogo tipo sulfonilurea/hipoglucemiante) y metformina (biguanidina/antihiperglucemiante)

Diabetes La diabetes es una enfermedad metablica que se caracteriza por la resistencia a la accin de la secrecin de insulina, a una secrecin insuficiente o a ambas. La manifestacin clnica de estos desrdenes es la hiperglucemia y se clasifica en: 1) Diabetes mellitus tipo 1: en que la diabetes resulta de una destruccin autoinmune de las clulas del pncreas. Los marcadores de la destruccin autoinmune de clulas estn presentes al momento del diagnstico en 90% de los individuos e incluyen anticuerpos en las clulas del islote, anticuerpos del cido glutmico descarboxilasa y anticuerpos a insulina. Esta forma de diabetes puede ocurrir en cualquier etapa de la vida. Los individuos jvenes tienen un ritmo rpido de destruccin de clulas que se presenta con cetoacidosis, mientras que los adultos mantienen suficiente secrecin de insulina para prevenir la cetoacidosis por muchos aos, lo que se conoce como LADA. 2) Diabetes mellitus tipo 2: esta forma se caracteriza por la resistencia a la insulina y la relativamente poca secrecin de insulina, con la progresivamente reduccin de la produccin de insulina con el tiempo. La mayora de estos individuos tambin presentan obesidad abdominal, lo que causa por si misma resistencia a la insulina. Adems, hipertensin, dislipidemia (niveles altos de triglicridos y bajos niveles de HDL) y un elevado plasmingeno activador del inhibidor tipo 1 (PAI-1, plasminogen activator inhibitor type 1), estn comnmente presentes en estos individuos. Este agrupamiento de anormalidades se refiere como el sndrome de la resistencia a insulina o sndrome metablico. Tiene una predisposicin gentica muy fuerte. 3) Diabetes mellitus gestacional: se define como la intolerancia a la glucosa que se reconoce durante el embarazo. Una deteccin oportuna evita morbilidad perinatal y mortalidad. 4) Otros tipos de diabetes mellitus: como a. Defectos genticos de: clulas del pncreas y funcin en la accin de la insulina. b. Desrdenes del pncreas excrino. c. Endocrinopatas. d. Formas poco comunes de diabetes mediada por el sistema inmune.

e. Otros sndromes genticos asociados algunas veces con diabetes.

PATOGNESIS Diabetes mellitus tipo 1 Se caracteriza por una deficiencia absoluta de la funcin de las clulas del pncreas. A menudo es el resultado de una destruccin de las clulas pancreticas mediada por el sistema inmune, pero raramente es un proceso por causas idiopticas o desconocidas. Tiene 4 caractersticas principales: o Un periodo preclnico marcado por la presencia de marcadores inmunes cuando ocurre la destruccin de las clulas . o Hiperglicemia, cuando 80 90% de las clulas est destruida. o Remisin transitoria (la llamada fase de luna de miel o honeymoon phase). o Enfermedad establecida con riesgos asociados a complicaciones y muertes. Desconocida es cuando hay factores incitantes (por ejemplo: leche de vaca, virales, dietas o exposicin ambiental) que inician el proceso inmune. El proceso autoinmune es mediado por macrfagos y linfocitos T con anticuerpos circulantes a varios antgenos de clulas . El anticuerpo ms comnmente detectado, asociado con DM1, es el anticuerpo de las clulas del islote. Otros anticuerpos circulantes ms fcilmente medidos incluyen a los anticuerpos de insulina, anticuerpos dirigidos contra cido glutmico descarboxilasa, anticuerpos de insulina contra la tirosina fosfatasa de los islotes y varios otros. La autoinmunidad preclnica de las clulas , procede del diagnstico de DB1 por ms de 9 a 13 aos. La autoinmunidad puede remitirse quiz un poco menos en personas susceptibles o puede progresar en falla a clulas en otros. Estos anticuerpos son generalmente considerados marcadores de la enfermedad ms que mediadores de destruccin de clulas . Otros desrdenes autoinmunes no pancreticos estn asociados con la DM1, ms la tiroiditis de Hashimoto, pero se extienden en el rgano envuelto, puede tener rango de otros rganos con ninguna otra falla glandular.

 La destruccin de la funcin de las clulas del pncreas causan hiperglicemia debido a la deficiencia absoluta de insulina y amilina. La insulina baja los niveles de glucosa sanguneos por una variedad de mecanismos que incluyen: o Estimulacin de la captacin de glucosa en tejido. o Supresin de la produccin de la glucosa por parte del hgado. o Supresin de cidos grasos libres liberados de las clulas adiposas. La supresin de los cidos grasos libres juegan un papel importante en la homeostasis de la glucosa. Los niveles aumentados de cidos grasos libres inhiben la captacin fe glucosa en msculos y estimula la gluconeognesis heptica. La amilina, una hormona pptica glucoregulatoria, co-secretada con la insulina, juega un rol importante en la regulacin de la glucosa sangunea al reducir el vaciamiento, suprimiendo el rendimiento del glucagn de las clulas del pncreas y aumentando la saciedad. En la DM1, la produccin de amilina causada por la destruccin de las clulas es muy baja.

Diabetes mellitus tipo 2

Accin normal de la insulina. En el estado de ayuno, 75% del total de la glucosa dispuesta toma lugar en los tejidos no dependientes de insulina: el cerebro y tejidos esplcnicos o viscerales (tejidos de hgado y gastrointestinales GI ). De hecho, la captacin de glucosa del cerebro ocurre al mismo ndice durante periodos de alimentacin y ayuno y no est alterado en la DM2. El 25% que queda del metabolismo de la glucosa tiene lugar en el msculo, que es dependiente de insulina. En el estado de ayuno, aproximadamente el 85% de la produccin de glucosa derivan del hgado y la cantidad restante es producida por el rin. Glucagn, producido por las clulas del pncreas, es secretado en el estado de ayuno oponindose a la accin de la insulina y estimulando la produccin de glucosa. Hasta aqu, el glucacn previene la hipoglucemia o restaura (restablece) la normoglucemia si la hipoglucemia ha ocurrido. En el estado de ayuno, la ingesta de carbohidratos incrementa la concentracin de glucosa en plasma y estimula la liberacin de insulina de las clulas pancreticas, la hiperinsulinemia resultante: Suprime la produccin de glucosa heptica. Estimula la captacin de glucosa por parte de los tejidos perifricos.

La mayor parte de la glucosa (alrededor de 80-85%) que es tomada por los tejidos perifricos es aprovechada en los msculos, con solo una pequea cantidad (aproximadamente entre 4-5%) siendo metabolizada por adipocitos. En el estado de ayuno, el glucacn es suprimido. Aunque el tejido adiposo es el responsable por solo una pequea cantidad de la disposicin total de glucosa en el cuerpo, juega un papel importante en el mantenimiento de la homeostasis de la glucosa total del cuerpo. Los pequeos incrementos en la concentracin de insulina en el plasma ejercen un efecto antilipoltico potente, llevando a una reduccin marcada de los niveles de cidos grasos libres (free fat acids -FFA-) en el plasma. El descenso en el plasma de la concentracin de FFA resulta en el aumento de la captacin de glucosa en el msculo y reduce la produccin de glucosa heptica. De ste modo, una reduccin de la concentracin en plasma de FFA reduce la glucosa plasmtica por la reduccin de la produccin aumentando la captacin en msculo. Los individuos con DM2 se caracterizan por: Defecto en la secrecin de insulina. Resistencia a la insulina que involucra al msculo, hgado y al adipocito. La resistencia a la insulina est presente an en aquellos individuos con DM2 delgados. En los pacientes con DM2, la reduccin de la secrecin de insulina postpandrial es causada por dao en la funcin de las clulas del pncreas y a un reducido estmulo de la secrecin de las hormonas intestinales. El papel que las hormonas intestinales juegan en la secrecin de insulina es mostrado mejor comparando la respuesta de la insulina a una carga oral de glucosa versus una infusin intravenosa de glucosa isoglicmica. En individuos no diabticos controlados, se libera 73% ms insulina en respuesta a una carga oral de glucosa en comparacin con la misma cantidad de glucosa dada intravenosamente. Este incremento de secrecin de insulina en respuesta a un estmulo oral de glucosa es conocido (referido) como el efecto incretina y sugiere que las hormonas derivadas del intestino, cuando son estimuladas por glucosa, llevan a un incremento en la secrecin de insulina pancretica. En pacientes con DM2 este efecto de incretina se despunta con el incremento de la secrecin de insulina a solo 50% del visto en pacientes no diabticos controlados. Es bien conocido qie dos hormonas, la glucacon-like peptide-1 (GLP-1) y la glucosedependent insulin-releasing peptide (GIP) glucagn parecido a pptido 1 y pptido liberador de insulina dependiente de glucosa-, son responsables de ms del 90% del aumento de la secrecin de insulina visto en respuesta a una carga de glucosa. En pacientes con DM2, los niveles de GLP-1 se reducen, mientras que los de GIP se incrementan. GLP-1 es secretada desde las clulas L en la mucosa intestinal distal en respuesta de la alimentacin mixta. Debido a que se incrementan los niveles de GLP-1 con el aumento del

tiempo desde la ingesta de alimentos, las seales neuronales inician con la entrada de alimentos en el tracto gastrointestinal proximal debe simular la secrecin de GLP-1. La accin insulinotrpica de GLP-1 es dependiente de glucosay, para que la GLP-1 incremente la secrecin de insulina, la concentracin de glucosa debe ser mayor a 90 mg/dL. Adems, para estimular la secrecin de insulina, la GLP-1 suprime la secrecin de glucagn, retrasa el vaciado gstrico y reduce la ingesta de alimentos incrementando la saciedad. Estos efectos de la GLp-1 combinan los lmites de las excursiones pospandriales de glucosa. GIP es secretada por las clulas K en el intestino y GLP similar (like GLP), incrementan la secrecin de insulina. Sin embargo, GIP no tiene efecto en la secrecin de insulina, en la motilidad gstrica o en la saciedad. El tiempo medio de la GLP-1 y de GIP es corto (<10 minutos). Ambas hormonas se inactivan rpido al remover los nitrgenos terminales de los aminocidos de la enzima, dipeptidil peptidasa tipo IV (DPP-IV).

Sitios de Resistencia a la Insulina en la Diabetes Tipo 2. Hgado: En sujetos con diabetes tipo 2 con baja a moderada hiperglicemia por ayuno (140 a 200 mg/dL, 7.8 a 11.1 mmol/L), la produccin de glucosa heptica basal se incrementa en ~0.5 mg/kg/min. Consecuentemente, durante las horas en el sueo de noche el hgado en un individuo diabtico de 80 kg con hiperglicemia por ayuno moderada, aade 35 gramos de glucosa adicionales a la circulacin sistmica. Este incremento en la produccin de glucosa heptica por ayuno en el caso de hiperglicemia por ayuno. Despus de la ingesta de glucosa, la insulina es secretada en la vena portal y llevada al hgado, donde suprime la secrecin de insulina y reduce el rendimiento de la glucosa. Pacientes con DM2 fracasan al suprimir el glucagn en respuesta al alimento y pueden incluso tener elevacin paradjica en los niveles de glucosa. De este modo, la resistencia heptica a la insulina y la hiperglucagonemia resultan en una produccin continua de glucosa en el hgado. Por tanto, los pacientes con DM2 tienen dos fuentes de glucosa en el estado postpandrial, uno proveniente de la dieta y otro de la produccin continua de glucosa del hgado. Estas fuentes de glucosa, en combinacin con el reducido tiempo del vaciamiento gstrico puede resultar en una marcada hiperglucemia.

Msculo (perifrico): El msculo es el mayor sitio de la disposicin (disposal) de la glucosa en el humano, y aproximadamente el 80% de la captacin de glucosa del cuerpo ocurre en el msculo esqueltico. En respuesta al incremento fisiolgico en la concentracin de

insulina plasmtica, la captacin de glucosa por el msculo es lineal, alcanzando niveles mximos en plasma de 10 mg/km/min. En contraste, en sujetos con DM2 delgados (con poca grasa), el comienzo de la accin de la insulina es retrasado por alrededor de 40 minutos y la habilidad de la insulina de estimular la captacin de la glucosa de las piernas, se reduce en un 50%. Es por esto que el sitio primario de la resistencia a la insulina en sujetos con DM2 reside en el tejido muscular. Adipocitos (perifrico): En humanos no diabticos obesos, los niveles de plasma basal FFA estn aumentados y fallan al suprimirla normalmente despus de la ingesta de glucosa. FFA esta almacenada como triglicridos en forma de adipocitos y sirven como una fuente importante de energa durante condiciones de ayuno. La insulina es un potente inhibidor de liplisis y restringe la liberacin de FFA desde los adipocitos al inhibir la hormona sensible a enzima lipasa (hormone-sensitive lipase enzyme). Ahora se sabe que la concentracin elevada de FFA en plasma puede llevar a resistencia de insulina en msculo e hgado y a dao en la secrecin de insulina. Adems de que la cantidad de FFA que est en el plasma circulantes esta aumentada, los individuos con DM2 y los no diabticos han incrementado sus reservas de triglicridos en el msculo, hgado y el alto contenido de grasa se correlaciona estrechamente con la presencia de la resistencia a insulina en estos tejidos. En resumen, la resistencia a la insulina que involucra al msculo e hgado son rasgos caractersticos de la intolerancia a la glucosa en individuos con DM2. En el estado basal, el hgado representa el mayor sitio de resistencia a la insulina y se refleja en la sobreproduccin de glucosa. Este ritmo acelerado de produccin de glucosa heptica es el determinante primario de la elevada concentracin de FPG en individuos con DM2. En el estado de ayuno, la baja captacin de glucosa muscular y la supresin daada de la produccin heptica de glucosa contribuyen a la resistencia a insulina. En individuos obesos y en la mayora de los sujetos con DM2 (80%), hay una masa clulas de grasa expandida y los adipocitos son resistentes a los efectos antilipolticos de la insulina. La mayora de los individuos obesos y diabticos se caracterizan por la adiposidad visceral expandida, la que es especialmente refractoria a los efectos de insulina y resultan en un alto ritmo lipoltico. Individuos con DM2 y obesidad se caracterizan por la elevacin en la concentracin de plasma de FFA de significancia de 24 horas. Niveles elevados de FFA en plasma, as como el contenido elevado d acilcoenzima A (CoA) de triglicridos y grasas en msculo, hgado y clulas , conducen al desarrollo de la resistencia a insulina de msculo e hgado y al dao en la secrecin de insulina. Mecanismo Celular de Resistencia a la Insulina La resistencia a insulina y los componentes del sndrome de la resistencia a insulina se describe como: Obesidad y Resistencia a Insulina. La ganancia de peso lleva a una resistencia a insulina y los individuos obesos no diabticos, tienen el mismo grado de resistencia a insulina como los pacientes moderados con DM2.

El incremento en la resistencia a insulina con ganancia de peso, est relacionada directamente a la cantidad de tejido adiposo visceral. El trmino de (visceral adipose tisue VAT) se refiere a las clulas de grasa localizadas dentro de la cavidad abdominal e incluye el tejido adiposo omental (peritoneo gastroclico), mesentrico (membrana serosa que constituye un repliegue plano del peritoneo, principalmente de tejido conjuntivo, que contiene numerosos vasos sanguneos y linfticos con destino a las vsceras abdominales, y que une al estmago y el intestino con las paredes posteriores del abdomen, dando as posicionamiento a estos rganos digestivos), retroperitoneal (s la regin anatmica abdominoplvica, localizada por detrs del peritoneo, que contiene, entre otros rganos, los grandes vasos abdominales, los riones y las glndulas suprarrenales) y perirrenal. VAT se ha mostrado correlacin con la resistencia a insulina y explica mucha de la variacin en la resistencia de la insulina vista en la poblacin de afroamericanos. El tejido adiposo visceral representa20% de la grasa en hombres y 6% en mujeres. Este tejido adiposo ha demostrado tener un mayor ndice de liplisis que la grasa subcutnea, lo que resulta en un incremento en la produccin de FFA (free fat acids).Estos cidos grasos son liberados a la circulacin portal y drenado al hgado, donde estos estimulan la produccin de lipoprotenas de muy baja densidad y reduce la sensibilidad a la insulina en tejidos perifricos. VAT tambin produce un nmero de citoquinas que causan resistencia a la insulina. Estos factores drenan a la circulacin portal y reduce la sensibilidad en tejidos perifricos. Las clulas de grasa tambin tienen la capacidad de producir por lo menos una hormona que mejora la sensibilidad a la insulina, la adiponectina. Este factor se forma en cantidades reducidas mientras que el individuo se torna ms obeso. En modelos animales, la adiponectina reduce la produccin de glucosa heptica y aumenta la oxidacin de cidos grasos en msculo. El Sndrome Metablico. La asociacin de la resistencia a insulina con el agrupamiento de los factores de riesgo cardiovasculares, que incluyen hiperinsulinemia, hipertensin, obesidad abdominal, dislipidemia y anormalidades en la coagulacin, ha sido referido con una variedad de nombres, como: sndrome de resistencia a la insulina, el sndrome metablico, el sndrome desmetablico y el cuarteto de la muerte, entre otros. Desde la descripcin del sndrome de la resistencia a la insulina, Raven, 1988. Definicin reciente segn la Federacin Internacional de Diabetes (International Diabetes Federation IDF), 2005: Para que una persona sea definida por tener el sndrome metablico, debe tener: obesidad central (definida como una circunferencia de cintura 94 cm en hombres y 80 cm para mujeres, personas de origen europeo, con valores de especificidades tnicas en otros grupos), adems de cualquiera de los siguientes factores: Nivel de triglicridos aumentado: 150 mg/dL (1.7 mmol/L) o tratamiento especfico para esta anormalidad.

Colesterol HDL reducido: <40 mg/dL (1.03 mmol/L) en hombres y <50 mg/dL (1.29 mmol/L) en mujeres, o tratamiento especfico para esta anormalidad en los lpidos. Presin arterial aumentada: PA sistlica 130 o PA diastlica 85, o tratamiento previo a este padecimiento de diagnstico de hipertensin. En la definicin de IDF del sndrome metablico, la obesidad es reconocida como un factor importante causante y como prerrequisito para el diagnstico. La obesidad central puede calcularse fcilmente usando la circunferencia de la cintura. Terapia No Farmacolgica. Se centra principalmente en: Dieta. Con alimentacin baja en grasas saturadas y carbohidratos. Actividad fsica. Principalmente el aerbico. Meta. Por lo menos 150 minutos semanales de ejercicio intenso moderado (50-70% de rango mximo de hear) .

Terapia Farmacolgica. Existen diversos agentes orales antidiabticos para DM2: inhibidores de la glucosidasa, biguanidinas, meglitinidas, proliferadores activados por receptores de agonistas (peroxisome proliferator-activated receptor - agonists) o tiazolidinedionas (TZD o glitazonas), inhibidores de DPPIV y sulfonilureas Biguanidinas y TZD se incluyen en sensibilizadores debido a su capacidad de reducir la resistencia a insulina. Sulfonilureas y meglitinidas estn en los secretagogos porque elevan la liberacin de insulina endgena. Sulfonilureas (SU, hipoglicmicos). Mecanismo de accin principal: mejorar la secrecin de insulina. Las SU se unen a un receptor especfico de SU (SUR) en las clulas pancreticas. La unin cierra un canal adensin trifosfato dependiente de ion potasio (K+), llevando a una reduccin del eflujo de potasio y a la subsecuente despolarizacin de la membrana. Los canales del ion de calcio (Ca2+) dependientes de voltaje se abren y permite un flujo hacia adentro. Los aumentos en el Ca2+ intracelular causan la translocacin de los grnulos secretorios de insulina a la superficie de la clula y a la exocitosis resultante del grnulo de insulina. La secrecin elevada de insulina del pncreas viaja por la va de la vena portal y subsecuentemente suprime la produccin de glucosa heptica. Ejemplos: 1 generacin: tolazamida, acetohexamida, clorpropamida. 2 generacin: glibenclamida, glimepirida, gliburida, glizipida. Farmacocintica. Se metabolizan en el hgado en metabolitos activos o inactivos. El citocromo P450 (CYP) 2C9 est involucrado con el metabolismo heptico de la

mayora de las sulfonilureas. Los agentes con metabolitos activos o droga madre, que es excretada renalmente requiere de un ajuste de dosis o utilizarse con precaucin en pacientes con funcin renal comprometida. La vida media de una SU se relaciona directamente con el riesgo de hipoglicemia . Biguanidinas (antihiperglicmicos). Su principal representante es la metformina. La metformina mejora y/o aumenta la sensibilidad a la insulina en tejidos hepticos y perifricos (msculo). Esto permite el incremento de la captacin de glucosa en tejidos sensibles a insulina. El mecanismo exacto de cmo la metformina consigue la sensibilizacin de insulina se sigue investigando, aunque se sabe que toman parte en el mecanismo la actividad de la adenosin- 5-monofosfato, una protena quinasa activada, aumento en la actividad de la tirosin-quinasa y el transportador 4 de glucosa. La metformina no tiene un efecto directo en las clulas , aunque los niveles de insulina son reducidos, reflejando un incremento en la sensibilizacin a la insulina. Farmacocintica de la metformina. Tiene una biodisponibilidad de 50-60%, baja solubilidad en lpidos y un volumen de distribucin de aproximadamente el agua del cuerpo. No se metaboliza y no se une a las protenas del plasma. Se elimina por la secrecin del tbulo renal y filtracin glomerular. El tiempo de vida media es de 6 horas, aunque farmacodinmicamente, los efectos antihiperglicmicos de la metformina duran 24 horas. .

http://www.encuentros.uma.es/encuentros105/metabolismo.htm Integracin del metabolismo III: adaptacin del organismo a la disponibilidad de los nutrientes Maria Jess Mir Obradors* y Evangelina Palacios Alaiz *Profesora Contratada Doctora y Profesora Titular del departamento de Bioqumica y Biologa Molecular, Facultad de Farmacia, Universidad Complutense de Madrid. La alteracin de los valores normales de la concentracin plasmtica de la glucosa se asocia a una serie de manifestaciones patolgicas: la hipoglucemia puede motivar la prdida de la conciencia y, en situaciones crticas, la muerte a causa de la dependencia del cerebro de la glucosa como fuente energtica. Por el contrario, la hiperglucemia sostenida, como ocurre en la diabetes, origina desequilibrios metablicos e induce daos en los tejidos, a travs de la glucosilacin de las protenas, ocasionando insuficiencia renal, ceguera y lesiones cardiovasculares, entre otras enfermedades. Para adaptarse a las distintas situaciones fisiopato-lgicas que alteran la glucemia, el organismo ha desarrollado una serie de mecanismos homeostticos intrnsecos que le permiten mantener los valores de la concentracin de glucosa en la sangre en el margen fisiolgico que asegura nuestra salud. Para la coordinacin de esos mecanismos, el metabolismo de cada rgano y tejido debe estar estrictamente regulado e integrado con el del resto del organismo. En el ciclo alimentacin-ayuno (estados: postabsortivo, ayuno y realimentacin) las hormonas pancreticas insulina y glucagn son las principales seales que alertan a las clulas del estado de la glucemia, para que, mediante un metabolismo integrado, se mantengan disponibles las fuentes energticas y los precursores biosintticos que el organismo necesita para sobrevivir. Integracin metablica en el estado postabsortivo Los glcidos, los lpidos y las protenas que se ingieren sufren la digestin, a travs de hidrlisis enzimticas, en el tubo digestivo. En el enterocito se resintetizan los triglicridos, que se transportan incluidos en los quilomicrones, a travs de la va linftica, a la sangre, desde donde se distribuyen a los tejidos extrahepticos.

La mayor parte de los azcares y los aminocidos acceden al hgado a travs de la vena porta: los hepatocitos captan estos nutrientes, en mayor o menor cantidad, dependiendo de factores como el tipo de dieta y el intervalo de tiempo entre cada ingesta. Estas clulas transforman dichos nutrientes en los combustibles y precursores biosintticos necesarios para otros tejidos, cuyas necesidades varan con la actividad del organismo. En este sentido, el hgado tiene gran flexibilidad metablica para adaptarse a las distintas circunstancias y mantener la homeostasia de la glucosa. La glucosa que no captan los hepatocitos se distribuye a otros tejidos u rganos que utilizan este azcar como fuente de energa, como el cerebro, y al tejido adiposo y al muscular, donde se almacena en forma de triacilgliceroles y de glucgeno, respectivamente. Los tejidos extrahepticos captan la mayor parte de los aminocidos y el excedente se utiliza en el hgado para la sntesis de protenas o se degrada en este rgano. La elevacin de la concentracin de la glucosa en el plasma y la consiguiente liberacin de la insulina por el pncreas motiva, en el hgado, la activacin de: la sntesis de glucgeno, la gluclisis y la transformacin del piruvato generado en acetilCoA, molcula, esta ltima, que se utiliza como sustrato para la sntesis de los cidos grasos, cuyo destino inmediato es su oxidacin mitocondrial y la consiguiente generacin de energa. Los cidos grasos excedentes se esterifican y, en forma de triacilgliceroles, se incluyen en las VLDL (lipoprotenas de muy baja densidad) que hacen posible su distribucin desde el hgado a los tejidos extrahepticos. En definitiva, la insulina favorece la captacin de la glucosa por las clulas y el almacenamiento de su exceso en forma de glucgeno. As mismo, estimula los procesos que hacen posible la transformacin del azcar en lpidos de reserva (triacilgliceroles). Integracin metablica en el estado de ayuno

Tras la ingesta, y como consecuencia de la rpida captacin de la glucosa por las clulas de diferentes tejidos, la concentracin plasmtica del monosacrido desciende y se restablece el valor normal de la glucemia, lo que frena la tasa de liberacin de la insulina por el pncreas. Cuando el organismo entra en fase de ayuno, el descenso adicional de la concentracin de la glucosa plasmtica motiva que las clulas de esta glndula secreten glucagn. La cada del cociente insulina/glucagon dirige el metabolismo celular de los distintos rganos y tejidos, as como su perfecta interconexin e integracin, asegurando el suministro continuo de glucosa al cerebro.

En el estado de ayuno, la glucogenlisis heptica es la va principal que mantiene la glucemia. La glucosa heptica liberada a la sangre constituye la fuente energtica que captan las clulas del cerebro y del msculo. En este ltimo, el piruvato y el lactato originados en la degradacin glucoltica del monosacrido se transportan al hgado, donde se utilizan como precursores de la glucosa en la va gluconeognica, completndose as el denominado ciclo de Cori (glucosalactato). Tambin la alanina, generada por la transaminacin del piruvato, se puede convertir en glucosa en el hgado, cerrando el ciclo glucosa-alanina. A medida que el ayuno se prolonga, las reservas hepticas de glucgeno se agotan. La gluconeognesis a partir de lactato y alanina contina, si bien este proceso nicamente recupera la glucosa que previamente se haba convertido en lactato y alanina en los tejidos perifricos. Como el cerebro consume glucosa continuamente, es necesaria su sntesis a partir de otras fuentes carbonadas. Uno de los sustratos que aporta carbonos es el glicerol liberado en la liplisis en el tejido adiposo; los aminocidos glutamina y alanina, cuyo origen se encuentra en la protelisis

muscular tambin son sustratos gluconeognicos. Los cidos grasos que se movilizan del tejido adiposo constituyen una buena fuente energtica que se utilizar con preferencia a la glucosa en la mayora de los tejidos. En el hgado, la oxidacin de los cidos grasos aporta la mayor parte del ATP necesario para la gluconeognesis. Sin embargo, en el estado de ayuno, slo una pequea parte del acetilCoA que se libera en la oxidacin entra en el ciclo del cido ctrico para su completa oxidacin. El destino principal de esta molcula es la formacin heptica de cuerpos cetnicos que se liberan a la sangre y que se captan en los tejidos que pueden utilizarlos como fuente energtica. En el cerebro, aunque constituyen el combustible alternativo a la glucosa, los cuerpos cetnicos no satisfacen por completo las necesidades energticas de sus clulas, para las cuales es siempre necesario el suministro del monosacrido. En el msculo esqueltico, los cuerpos cetnicos evitan que se produzca la hidrlisis de las protenas, ya que, a medida que los cidos grasos se oxidan en el hgado, aumenta la concentracin de los cuerpos cetnicos en el plasma y, en consecuencia, las clulas demandan menos glucosa y menos aminocidos gluconeognicos. En estas condiciones, no se activa la protelisis ni tiene lugar, por tanto, la destruccin del fundamental tejido muscular. Estas interrelaciones estn coordinadas a travs del glucagn, cuyo efecto es, en definitiva, la estimulacin de la glucogenlisis y la liberacin de la glucosa desde el hgado, as como la movilizacin de los cidos grasos en el tejido adiposo. Integracin metablica en el estado de realimentacin Con la realimentacin, los triacligliceroles se metabolizan inmediatamente en la forma habitual propia del estado nutricional (postabsortivo), pero la glucosa requiere, en cambio, un tiempo de adaptacin: inicialmente debido a la baja concentracin de este azcar en la sangre las clulas hepticas apenas captan glucosa, por lo que la mayor parte de la que recibe el hgado a travs de la vena porta se distribuye al cerebro y a otros tejidos perifricos que necesitan este combustible energtico. Realmente, el hgado permanece en estado gluconeognico durante algunas horas despus de la ingesta con el fin principal, no de liberar glucosa a la sangre, sino de proporcionar glucosa fosforilada para restablecer las reservas del glucgeno heptico.

Pero, a medida que la concentracin plasmtica de la glucosa se eleva, tambin aumenta la velocidad de captacin de este azcar por el hgado que lo se utiliza para obtener energa mediante la gluclisis; su exceso, queda disponible para la sntesis de glucgeno y, seguidamente, los metabolitos procedentes de la degradacin oxidativa de la glucosa se destinarn a la sntesis de cidos grasos y de triacilgliceroles. Estos ajustes metablicos desencadenados por la insulina y el glucagn tienen lugar en cortos intervalos de tiempo. A ms largo plazo actan otros mecanismos reguladores para mantener en equilibrio la ingesta de nutrientes y el gasto energtico, de manera que el organismo de los mamferos se mantenga en una homeostasia perfectamente controlada

http://chemicrobia.blogspot.com/2011/05/tema-27-integracion-metabolica-ayuno-y.html

jueves 5 de mayo de 2011 Tema 27: Integracin metablica: Ayuno y diabetes Va sobre: 2 Cuatrimestre, Bioqumica, BQ: Temas 26-27

1) El Ciclo Ayuno-Alimentacin Interrelaciones de tejidos en estado de nutricin buena El Hgado

Es el mayor rgano productor de cidos grasos en humanos. En los pases desarrolados la mayora de cidos grasos vienen de la dieta.

En estado de nutricin buena, el hgado est sometido a control por Insulina (por las clulas -pancreticas). La Glucosa y los Aminocidos de la dieta pasan del intestino a sangre, llegando al va vena porta heptica. En el hgado estn activadas varias rutas:

Glucolisis Degradacin de glucosa y obtencin de energa para el higado. Este estado se conoce como Hgado Glucoltico. Glucogenognesis Sntesis de glucogeno heptico. Este estado se denomina Hgado Glucogenognico. Lipognesis Sntesis de triglicridos, usando los esqueletos carbonados de los aminocidos, para exportacin como VLDL: Hgado Lipognico. Proteognesis Sntesis heptica de protenas: Hgado proteognico. Ureognesis Los aminocidos de la dieta son desaminados, y el NH3 entra en el ciclo de la urea: Hgado ureognico. Tejidos perifricos

La glucosa y los aminocidos se suministran desde hgado a tejidos perfricos(va sangunea), siendo empleados para el cerebro, el msculo esquelticos o el msculo cardiaco. Cerebro

Emplea la glucolisis para obtener energa en condiciones normales. Requiere aporte continua de conbustible (pues no tiene reservas). Consume el 60% de la glucosa diaria del organismo en reposo (120g/da, unas 420 Kcal). Gasta el 60-70% del ATP producido en mantener activa la Bomba K+/Na+ (potencial de membrana de las neuronas). Su transportador mayoritario de Glucosa (GLUT-3; KM=1,6mM), trabaja rpidamente a la concentracin normal de glucosa (5 mM), haciendo que la concentracin de glucosa normal en cerebro sea 1mM. De esta forma se consigue que la Hexoquinasa trabaje a Vmax.

Si la concentracin de glucosa en sangre baja de 2,2 mM, GLUT-3 trabaja ms lento. Si la concentracin de glucosa en el cerebro baja al valor de la KM de la hexoquinasa, se bloquea la glucolisis. Msculo esqueltico

Secuestra Glucosa y la dirige a glucogenognesis para crear reservas de glucgeno muscular. Tambin es importante en este tejido la proteognesis (para la sntesis de protenas musculares). En reposo consume en un 85% cidos grasos (predomina la lipolisis). En actividad es inicialmente glucogenoltico y glucoltico (fase anaerbica), y luego se vuelve lipoltico de nuevo (fase aerbica). Msculo cardiaco

No tiene prcticamente reservas de glucgeno y trabaja siempre de modo aerobio consumiendo grasas. Grasas y tejido adiposo

Las de la dieta (son exgenas) pasan del intestino a la linfa y de ah a la sangre por los Quilomicrones, distribuyndose a los dems tejidos y acumulndose en el tejido adiposo y/o gastndose en el tejido muscular. Las grasas sintetizadas en hgado (endgenas), se distribuyen a los tejidos como VLDL acumulndose en el tejido adiposo y/o gastndose en el tejido muscular. El tejido adiposo, bajo control de Insulina est en estado:

Lipognico La LPL est activada y esto estimula la entrada de cidos grasos desde quilomicrones de la dieta y VLDL hepticas para la sntesis de grasas para almacenaje energtico. Glucoltico Activa transportadores GLUT-4, activando la glucolisis de la glucosa hasta DHAP para obtener Glicerol-3-P (glicerina), necesaria para la sntesis de triglicridos.

Interrelaciones de tejidos en el ayuno a corto y largo plazo

El ayuno temprano (16-28 horas) supone los siguientes cambios respecto al estado de nutricin buena: las clulas -pancreticas secretan glucagn a sangre (Va Porta heptica), induciendo los siguientes cambios: Hgado

Glucogenolisis Degradacin de glucgeno para dar Glucosa: Hgado Glucogenoltico. Gluconeognesis Sntesis de glucosa desde lactato: Hgado Gluconeognico.

Lo anterior se destina a incrementar la salida a sangre de glucosa heptica, a fin de mantener estable los niveles de glucosa (Homeostasis de glucosa), con destino a aquellos tejidos perifricos consumidores exclusivos de glucosa.

Si el ayuno es prolongado (hasta 40 das) el glucagn induce las siguientes adaptaciones. Hgado

Gluconeognesis Se crea glucosa para distribuirla al cerebro y tejidos que lo precisan (homeostasis de glucosa). La gluconeognesis se realiza a partir de protenas hepticas y musculares cuyos aminocidos llegan al hgado va Glutamina o va ciclo de la Alanina. Por ello tambin se activa la ureognesis. A partir de grasas (del glicerol) tambin se puede rendir glucosa. ste rgano se comporta como Hgado Gluconeognico, proteoltico y ureognico. Cetognesis Sntesis de cuerpos cetnicos a partir de grasas del tejido adiposo, para consumo en Cerebro y Msculo: Hgado Cetognico. Lipolisis La -oxidacin est activada: Hgado Lipoltico.

Tejido Adiposo

Lipolisis Se movilizan grasas, obteniendo cidos grasos que se dirigen al hgado para la sntesis de cuerpos cetnicos o al msculo como fuente de energa. El glicerol se dirige al hgado para la gluconeognesis.

Msculo Esqueltico

Proteolisis Degradacin de protenas musculares hasta sus aminocidos, y transformacin en Glutamina. La Glutamina se dirige por el torrente sanguneo hasta los Enterocitos donde se convierte en Alanina, que se dirige a hgado para gluconeognesis. Cerebro

En el ayuno prolongado el cerebro gasta como combustible cuerpos cetnicosy glucosa: cerebro glucoltico y cetoltico.

En el caso lmite de ayuno prolongado, casos de nutricin insufiente de lactantes, o adultos con enfermedades que previenen la deglucin, puede producirse un marasmo nutricional: La movilizacin de grasas del tejido adiposo para sntesis heptica de cuerpos cetnicos, unida a la movilizacin de aminocidos musculares para gluconeognesis heptica, conducen al agotamiento de las reservas de grasa y protenas. Si no se renutre a tiempo para evitar este marasmo se produce de modo irreversible la muerte por inanicin. En el caso de nios el fallecimiento sobreviene mayoritariamente por neumona (el nio pierde la capacidad de toser y as eliminar a posibles patgenos de las vas respiratorias). Renutricin tras el ayuno

Hgado

La Glucosa de la dieta no resulta retenida por el hgado y se distribuye directamente a los tejidos junto con algunos aminocidos. El hgado tiene activadas varias rutas:

Gluconeognesis y Glucogenognesis A partir de aminocidos de la dieta, se produce Glucgeno, no hay produccin neta de Glucosa. Proteognesis A partir de aminocidos de la dieta. Ureognesis A partir de NH3 liberado de los aminocidos de la dieta usados en gluconeognesis y glucogenognesis.

Tejido Adiposo

Los quilomicrones de la dieta se dirigen al tejido adiposo.

Lipognesisy glucolisis (hasta DHAP) Se acumulan grasas, a partir de cidos grasos de los quilomicrones, y Glicerol sintetizado desde Glucosa de la dieta. Msculo esqueltico

Lipoltico Usa cidos grasos (quilomicrones de la dieta) como fuente de energa. Glucogenognico Sintetiza Glucgeno a partir de glucosa de la dieta. Proteognico Sintetiza protenas musculares a partir de aminocidos de la dieta. El Efecto Rebote

En la renutricin es comn el llamado que se de el efecto rebote: acumulacin excesiva de grasas a nivel del tejido adiposo y, adicionalmente, incremento de acumulacin de glucgeno muscular.

En los momentos iniciales de la renutricin, los niveles de Glucosa sangunea aumentan por encima de lo normal. Esto es debido a que el hgado no consume la glucosa y esta es solo consumida, entre otros, por el Tejido Adiposo (sntesis de triglicridos), y el msculo esqueltico (sntesis de glucgeno muscular).

En estas circustancias, el organismo se haya bajo control de insulina, activndose un ms la incorporacin de Grasas al Tejido adiposo. Si en la renutricin empleamos una dieta compuesta solo por glcidos y protenas (aminocidos) evitando las grasas, podemos conseguir que el msculo emplee la glucosa para aumentar la

cantidad acumulada de glucgeno muscular (mayor resistencia muscular), incrementado adems la sntesis de protenas musculares (aumento de la masa muscular). De este modo, el Efecto Rebote puede emplearse en ciertos tipos de dietas deportivas. Otras interrelaciones del metabolismo Sntesis de Arginina y Creatina

A nivel de los enterocitos, la glutamina de la sangre, puede convertirse en Citrulina que pasara a sangre. A nivel renal, la citrulina puede emplearse para la sntesis neta de Arginina, que se dirigira al Hgado (ciclo de la urea) y otros tejidos (sntesis proteica). Parte de esa Arginina puede emplearse para la sntesis renal de Creatina. A nivel del msculo esqueletico, la Creatina es fosforilada con gasto de ATP a Creatina-P (que constituye una forma de almacenamiento energtico del msculo). Sntesis de Glutatin

A nivel heptico, la Metionina se convierte en cistena (familia catablica de aminocidos sulfurados), que junto con Glutamato y Glicina daran lugar al Glutatin. El Glutatin tiene dos posibles vas de distribucin:

Sangunea Se transportara en forma reducida (GSH) en los eritrocitos hacia los diferentes tejidos. Biliar Se transportara tambin forma reducida (GSH) a travs de los conductos biliares hasta el intestino. Una vez all sera absorbido por los enterocitos. Sntesis de Carnitina

A nivel heptico, renal y del msculo esqueltico la degradacin de protenas produce Trimetil-lisina (TML). La TML es hidroxilada y partida liberando glicina y otro producto cuya oxidacin (-butirobetana) e hidroxilacin dara lugar a Carnitina que se distribuira por va sangunea a los tejidos.

2) Mecanismos de conmutacin heptica entre estados de Nutricin-Inanicin Control alostrico de enzimas En estado nutrido

La presencia de glucosa estimula la glucogenognesis. La fructosa-2,6-BP y la fructosa-1,6-BP promueven la glucolisis. El piruvato motiva la formacin de Acetil-CoA. El Citrato promueve la conversin de Acetil-CoA a Malonil-CoA y, consecuentemente, la formacin de triglicridos. En el ayuno

La presencia de citrato inhibe la glucolisis y la glucogenognesis. Los Acil-CoA promueven la sntesis de grasas a partir de Acetil-CoA. El Acetil-CoA estimula la conversin de piruvato en oxalacetato para la gluconeognesis. El NADH inhibe el ciclo de los cidos tricarboxlicos.

Modificacin covalente de enzimas Estado nutrido: Insulina

Los siguientes enzimas se encuentran defosforilados:

Glucgeno fosforilasa Glucgeno sintasa Enzima bifuncional Piruvato quinasa Piruvato deshidrogenasa Acetil-CoA carboxilasa

Por tanto, se encuentran activados estos procesos:

Glucolisis Glucogenosntesis Conversin de piruvato a Acetil-CoA y Ciclo de Krebs Sntesis de cidos grasos Ayuno: Glucagn

Los siguientes enzimas se encuentran fosforilados:

Glucgeno fosforilasa Glucgeno sintasa Enzima bifuncional

Piruvato quinasa Piruvato deshidrogenasa Acetil-CoA carboxilasa

Por tanto, se encuentran activos estos procesos:

Gluconeognesis Glucogenolisis Sntesis de cuerpos cetnicos Ciclo de Cori Catabolismo de grasas (-oxidacin). 3) Interrelaciones metablicas entre tejidos: Ayuno y Diabetes Obesidad

La Obesidad puede producirse por: Fallo en el control neurolgico de la ingesta (mayoritario). Desrdenes hormonales. Eg: Hipotiroidismo, Sndrome de Cushing (casos raros).

Los individuos obesos no tienen un ciclo normal de nutricin/ayuno. El organismo se halla en un estado bien nutrido casi permanente: las grasas del tejido adiposo no se movilizan entre comidas. En este estado, el metabolismo se halla bajo control de la insulina.

Hgado Estado Lipognico (sntesis de grasas y VLDL que se dirigen al tejido Adiposo. Tejido Adiposo Estado Lipognico: acumulacin de grasas de los Quilomicrones y las VLDL.

La obesidad pre-puberal, suele acompaarse de hiperplasia (aumento del nmero de adipocitos) del tejido adiposo. La obesidad post-puberal, suele acompaarse de hipertrofia (aumento del volumen del adipocito y no del nmero de clulas). En ambos casos: los adipocitos expresan el factor de necrosis tumoral (TNF-), produciendo cierta resistencia a la insulina. Estos individuos tendrn propensin a desarrollar diabetes tipo II (no insulina dependiente).

La obesidad por fallo en el control de ingesta puede solucionarse. Las dietas deben ser dirigidas y controladas por el especialista. Las dietas rpidas no son aconsejables. Cuanto ms rpido se pierde peso ms rpido se gana y en mayor medida que antes: ralentizacin del metabolismo basal seguido de efecto rebote. El ejercicio es recomendable pero nunca debe exceder las capacidades fsicas del individuo (se debe empezar suavemente y entrenar antes de pasar a ejercicios con ms fondo). Diabetes Mellitus No Insulina Dependiente (Tipo II)

Supone el 80-90% de los casos de diabetes y aparece en individuos adultos. Las clulas- pancreticas pueden expresar insulina, sin embargo, los adipocitos de estos individuos presentan una expresin elevada el factor- de necrosis tumoral (TNF-), afectando a la actividad de los receptores y produciendo resistencia a la insulina. Cuadro resultante en estado nutrido

Hgado glucogenoltico, glucoltico y lipognico Los hepatocitos son resistentes a la seal de insulina y actan como si la glucemia fuera baja. Aumentan los niveles sanguneos de glucosa dando hiperglucemia y usan glucosa y aminocidos para sintetizar grasas y vertiendolas en sangre como VLDL. Tambin se movilizan las reservas de glucgeno. Tejido Adiposo Los adipocitos son resistentes a la seal de insulina y la ruta de incorporacin de grasas (VLDL y QM) est bloqueada. En este caso se produce la hipertriacilgliceridemia. Msculo esqueltico Resistente a insulina y por lo tanto la ruta de incorporacin de glucosa est bloqueada. Aumenta la hiperglucemia.

En ancianos con esta enfermedad en las situaciones de estrs metablico pueden aparecer cuadros muy graves:

Prdida de agua, glucosa y electrolitos en la orina. Aumento de la hiperglucemiay de la resistencia a la insulina. En ltima instancia: deshidratacin y coma hiperosmolar hiperglucmico. Diabetes Mellitus Insulina Dependiente (Tipo I)

Se la denomina juvenil, pues se manifiesta en edad temprana. Requiere tratamiento mediante inyecciones de insulina. Estos individuos no presentan clulas- y no pueden expresar insulina, sin embargo, s expresan glucagn. Cuadro resultante en estado nutrido

Hgado glucogenoltico, gluconeognico, ureognico, lipognico y cetognico Los hepatocitos actan como en estado de ayuno. Movilizando glucgeno hacia glucosa y sintetizando glucosa a partir de aminocidos y lactato. Esto produce hiperglucemia. Sintetizan grasas (VLDL) y cuerpos cetnicos a partir de cidos grasos induciendo hipertriacilgliceridemia y cetosis. Tejido Adiposo lipoltico Los adipocitos liberan cidos grasos a sangre y se acumulan. Por otra parte la ruta de incorporacin de grasas (VLDL y QM) est bloqueada. Se aumenta la hipertriacilgliceridemia. Msculo esqueltico proteoltico Est activada la degradacin de protenas musculares, destinando los aminocidos a gluconeognesis heptica. Se produce una prdida de masa muscular a largo plazo. Por otra parte, la ruta de incorporacin de glucosa est bloqueada. Aumenta la hiperglucemia. Ejercicio muscular anaerbico y aerbico

Ejercicio anaerbico Aparece al inicio del ejercicio o en ejercicio rpido y extenuante. Se gasta glucgeno (en forma de glucosa) hasta Lactato (que se reutiliza va ciclo de Cori). Ejercicio aerbico Se da en el ejercicio continuado o de fondo. Aunque puede gastar algo de glucosa hasta Alanina

(ciclo de la Alanina), mayoritariamente se consumen cidos grasos y en casos de hipoglucemia cuerpos cetnicos. El embarazo

Durante el embarazo se desarrolla un nuevo rgano que asume el papel de alimentar al feto: La Placenta. Este gano sintetiza hormonas (Progesterona, estradiol y Lactgeno placentario) que redirigen el metabolismo de la embarazada hacia el Feto. En estado nutrido: Insulina

Hgado glucogenolco, gluconeognico, ureognico y cetognico La progesterona y el estradiol inducen en la embarazada cierta resistencia a la insulina. Se moviliza el glucgeno hacia glucosa y sintetiza glucosa a partir de aminocidos y lactato. Toda la glucosa se dirige a la placenta y el feto. La hiperglucemia en la madre, sera patolgica. Adems, se sintezan cuerpos cetnicos a partir de cidos grasos. Los cuerpos cetnicos se dirigen al msculo y a la placenta y el feto (pero no llega a producirse cetosis). Tejido Adiposo lipoltico Los adipocitos liberan cidos grasos a la sangre que se dirigen al hgado, a la placenta y el feto. Msculo esqueltico proteoltico Est activada la degradacin de protenas musculares, que se dirigen al hgado, a la placenta y el feto.

En ayuno, entre comidas, existe una tendencia hacia la hipoglucemia.

La lactancia En estado nutrido: Insulina

Hgado Lipognico Parte de la glucosa de la dieta se emplea para sintetizar grasas (VLDL), que se dirigen a la glndula mamaria.

Tejido Adiposo lipoltico Los adipocitos liberan cidos grasos a sangre que se dirigen al hgado. Glandula mamaria lactognica, proteognica y lipognica La glucosa de la dieta se emplea para sintetizar lactosa. Los aminocidos de la dieta se emplean para sintetizar las protenas de la leche. Las grasas de la dieta (QM) y las de sntesis heptica (VLDL), se emplean para sintetizar las grasas de la leche.

Otras situaciones que influyen en el metabolismo Estrs

Se produce por heridas, traumas quirrgicos, quemaduras, etc. Se activa la sntesis glucagn y catecolaminas. Hay una movilizacin de grasas del tejido adiposo y de glucgeno heptico, aumentando los niveles de glucosa y cidos grasos en sangre. Los linfocitos y monocitos sintetizan interleuquinas (1 y 6) y Factor de necrosis tumoral (TNF), estimulando la sntesis heptica de reactivos de fase aguda (factores de coagulacin y fibringeno). Se promueve la degradacin de protenas musculares, potenciando la acumulacin de lpidos en sangre (inhibe incorporacin VLDL a adiposo y potencia la lipolisis) y se produce fiebre. Enfermedades hepticas

Las enfermedades hepticas tienen tres fases:

1. Fase Inicial. Se bloquea el ciclo de la urea aumentando los niveles sanguneos de NH4+ (neurotxicidad: coma). 2.Fase Avanzada. Aumenta la secrecin de aminocidos aromticos que se acumulan en sangre junto con el NH4+. Esto aumenta el efecto neurotxico del NH4+. Adems, los aminocidos aromticos afectan a la funcin de la Serotonina dando ms problemas neurolgicos. 3.Fase Terminal. Se produce la proteolisis muscular (caquexia), inhibicin de la gluconeognesis heptica y por tanto, la hipoglucemia (causa comn de muerte). Enfermedades renales

La enfermedad renal se caracteriza porque el rin no es capaz de dializar la sangre y los productos de degradacin se acumulan. Solo es solucionable mediante dilisis cclica y/o el transplante. La ingestin de Etanol

La ingestin de Etanol aumenta el NADH heptico produciendo:

Liberacin de acetaldehido y acetato a la sangre, que producen efectos txicos sobre los tejidos. Inhibicin de la gluconeognesis heptica dando hipoglucemia. Inhibicin de la sstesis de cuerpos cetnicos y de la -oxidacin, y activacin de la sntesis heptica de triglicridos. Estas grasas pueden ir acumulndose con el paso del tiempo y haciendo que este rgano se convierta en un hgado graso. Se acumula el lactato en sangre. Esta molcula tiene un efecto txico y produce cambios en el pH sanguneo (al bajar el pH, el individuo hiperventila, pudiendo llegar a la alcalosis y perder el conocimiento, a parte del coma por hipoglucemia). Acidosis metablica crnica

En el rin produce: Incremento de la gluconeognesis renal a partir de aminocidos. Incremento de la excrecin urinaria de iones amonio. La metabolizacin de la glutamina a iones amonio permite excretar el nitrgeno, pero conlleva un gasto de hidrogeniones que baja el pH sanguneo.

En el hgado ocurre: Inhibicin de la ureognesis (sntesis de urea por su ciclo). Esto aumenta la va alternativa del ciclo intracelular de Glutamina con destino al rin. Escrito por Saturnosring Enviar por correo electrnicoEscribe un blogCompartir con TwitterCompartir con Facebook 0 comentarios: Publicar un comentario en la entrada Entrada ms reciente Entrada antigua Pgina principal

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http://themedicalbiochemistrypage.org/spanish/diabetes-sp.html

Return to Medical Biochemistry Page 19962011 themedicalbiochemistrypage.org, LLC | info @ themedicalbiochemistrypage.org

Definition of Diabetes Diabetes is any disorder characterized by excessive urine excretion. The most common form of diabetes is diabetes mellitus, a metabolic disorder in which there is an inability to oxidize carbohydrate due to disturbances in insulin function. Diabetes mellitus is characterized by elevated glucose in the plasma and episodic ketoacidosis. Additional symptoms of diabetes mellitus include excessive thirst, glucosuria, polyuria, lipemia and hunger. If left untreated the disease can lead to fatal ketoacidosis. Other forms of diabetes include diabetes insipidus and brittle diabetes. Diabetes insipidus is the result of a deficiency of antidiuretic hormone (ADH, also referred to as vasopressin or arginine vasopressin, AVP). The major symptom of diabetes insipidus (excessive output of dilute urine) results from an inability of the kidneys to resorb water. Brittle diabetes is a form that is very difficult to control. It is characterized by unexplained oscillations between hypoglycemia and acidosis. Criteria, which clinically establish an individual as suffering from diabetes mellitus, include: 1. having a fasting plasma glucose level in excess of 126mg/dL (7mmol/L). Normal levels should be less than 100mg/dL (5.6mmol/L) or:

2. having plasma glucose levels in excess of 200mg/dL (11mmol/L) at two times points during an oral glucose tolerance test, OGTT, one of which must be within 2 hrs of ingestion of glucose. The earlier a person is diagnosed with diabetes (principally type 2) the better chance the person has of staving off the primary negative consequences which are renal failure, blindness and limb amputations due to circulatory problems. The American Diabetes Association is planning to recommend that physicians consider patients to be pre-diabetic if their fasting blood glucose level is above 100mg/dL but less than 125mg/dL and whose glucose levels are at least 140mg/dL but less than 200mg/dL following an oral glucose tolerance test (OGTT).

Glucose tolerance curve for a normal person and one with non-insulin-dependent diabetes mellitus (NIDDM, Type 2 diabetes). The dotted lines indicate the range of glucose concentration expected in a normal individual.

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Types of Diabetes Mellitus Diabetes mellitus is a heterogeneous clinical disorder with numerous causes. Two main classifications of diabetes mellitus exist, idiopathic and secondary.

Idiopathic diabetes is divided into two main types; insulin dependent and non-insulin-dependent. Insulin-dependent diabetes mellitus, IDDM (more commonly referred to as type 1 diabetes) is defined by the development of ketoacidosis in the absence of insulin therapy. See the Diabetic Ketoacidosis diagnosis and treatment page. Type 1 diabetes most often manifests in childhood (hence, also called juvenile onset diabetes) and is the result of an autoimmune destruction of the -cells of the pancreas. Non-insulin-dependent diabetes mellitus, NIDDM (more commonly referred to as type 2 diabetes) is characterized by persistent hyperglycemia but rarely leads to ketoacidosis. Type 2 diabetes generally manifests after age 40 and therefore has the obsolete name of adult onset-type diabetes. Type 2 diabetes can result from genetics defects that cause both insulin resistance and insulin deficiency. There are two main forms of type 2 diabetes: 1. Late onset associated with obesity. 2. Late onset not associated with obesity. There is a strong correlation between obesity and the onset of type 2 diabetes with its associated insulin resistance. It should be pointed out that in the United States the proportion of the population under 40 that can be clinically defined as obese now exceeds 25%. Many children are obese and are developing type 2 diabetes at an alarming epidemic rate. The dramatic rise in obesity in the US has lead to an equally alarming increase in the percentage of the population who suffer from the metabolic syndrome. The metabolic syndrome (see below as well) is a clustering of atherosclerotic cardiovascular disease risk factors, one of which involves insulin resistance characteristic in type 2 diabetes. It should be pointed out that obesity alone does not always lead to insulin resistance as some individuals who are obese do not experience insulin resistance and conversely, some individuals who manifest insulin resistance are not obese. These latter observations point to the added role of genetics in the acquisition of insulin resistance. Secondary, or other specific types of diabetes mellitus are the result of many causes including: 1. Maturity onset type diabetes of the young (MODY) was previously considered to be a third form of type 2 diabetes. However, with the discovery of specific mutations leading to MODY, it is now classified under secondary or other specific types of diabetes. MODY is characterized by onset prior to age 25. All cases to date have shown impaired -cell function. Patients may also exhibit insulin resistance and late -cell failure. Evidence indicates that mutations in 10-12 different genes have been correlated with the development of MODY. Mutations in the 8 genes described here are all clearly correlated to MODY: MODY1: the transcription factor identified as hepatic nuclear factor-4 (HNF-4; gene symbol = HNF4A). This gene is also called transcription factor-14 (TCF14). Expression of HNF-4 is associated with the growth and normal functioning of the pancreas. Many genes are known to be regulated by HNF-4 including those encoding HNF-1, PPAR, insulin, glucose-6-phosphatase, GLUT2, the liver pyruvate kinase isoform (L-PK) which is also expressed in the pancreas, glyceraldehyde-3-phosphate dehydrogenase (G3PDH), aldolase B and uncoupling protein 2, UCP2. MODY2: pancreatic glucokinase

MODY3: the transcription factor HNF-1 (gene symbol = HNF1A). This gene is also called hepatocyte transcription factor-1 (TCF1). HNF-1 is involved in a regulatory loop with HNF-4 controlling many genes involved in liver function such as the GLUT2 and L-PK genes. MODY4: the homeodomain transcription factor insulin promoter factor-1 (IPF-1). This gene is more commonly called PDX1 which is derived from pancreas duodenum homeobox-1. MODY5: the transcription factor HNF-1. This gene is also called hepatocyte transcription factor2 (TCF2). HNF-1 is a critical regulator of a transcriptional network that controls the specification, growth, and differentiation of the embryonic pancreas. In humans, mutations in the HNF-1 gene (symbol = HNF1B) are associated with pancreatic hypoplasia, defective kidney development and genital malformations. MODY6: the bHLH transcription factor NeuroD1. NeuroD1 was first identified as a neural fateinducing gene. The hamster 2 gene, shown to regulate insulin transcription is identical to NeuroD1 so the gene is often called NeuroD/2. MODY6 is a rare form of MODY MODY7: the Krupple-like factor 11 (KLF11) protein is a zinc-finger transcription factor that is involved in activation of the insulin promoter. KLF11 is a TGF--inducible transcription factor. MODY8: the carboxyl-ester lipase gene (CEL) which is involved in lipid metabolism. Frameshift deletions in the variable number tandem repeats (VNTR) of the CEL gene are associated with MODY8 which is characterized by pancreatic exocrine and -cell dysfunction. MODY8 is a rare form of MODY. 2. Pancreatic disease: Pancreatectomy leads to the clearest example of secondary diabetes. Cystic fibrosis and pancreatitis can also lead to destruction of the pancreas. 3. Endocrine disease: Some tumors can produce counter-regulatory hormones that oppose the action of insulin or inhibit insulin secretion. These counter-regulatory hormones are glucagon, epinephrine, growth hormone and cortisol. a. Glucagonomas are pancreatic cancers that secrete glucagon. b. Pheochromocytomas secrete epinephrine. c. Cushing syndrome results in excess cortisol secretion. d. Acromegaly results in excess growth hormone production. 4. Drug-induced diabetes; treatment with glucocorticoids and diuretics can interfere with insulin function. 5. Anti-insulin receptor autoantibodies (Type B insulin resistance). 6. Mutations in the insulin gene.

7. Mutations in insulin receptor gene which lead to the syndromes listed below. Two clinical features are common in all syndromes that result from mutations in the insulin receptor gene: acanthosis nigricans and hyperandrogenism (the latter being observed only in females). a. Donohue syndrome (also referred to as Leprachaunism) b. Rabson-Mendenhall syndrome c. Type A insulin resistance 8. Gestational diabetes; this syndrome sets in during pregnancy and usually resolves itself following childbirth. 9. Many other genetic syndromes have either diabetes or impaired glucose tolerance associated with them; lipoatrophic diabetes, Wolfram syndrome, Down syndrome, Klinefelter syndrome (XXY males), Turner syndrome, myotonic dystrophy, muscular dystrophy, Huntington disease, Friedreich ataxia, Prader-Willi syndrome, Werner syndrome, Cockayne syndrome, and others such as those indicated above. back to the top

Insulin-Dependent Diabetes Mellitus (IDDM) Type 1 Etiology of Type 1 Diabetes Type 1 diabetes has been shown to be the result of an autoimmune reaction to antigens of the islet cells of the pancreas. There is a strong association between IDDM and other endocrine autoimmunities (e.g. Addison disease). Additionally, there is an increased prevalence of autoimmune disease in family members of IDDM patients. Types of Autoantibodies 1. Islet cell cytoplasmic antibodies: The primary antibodies found in 90% of type 1 diabetics are against islet cell cytoplasmic proteins (termed ICCA, islet cell cytoplasmic antibodies). In nondiabetics ICCA frequency is only 0.5%4%. The presence of ICCA is a highly accurate predictor of future development of IDDM. ICCA are not specific for the -cells and recognize antigens in other cell types in the islet. However, the autoimmune attack appears to selectively destroy -cells. Therefore, the antibodies may play a primary role in the destruction of islet cells. It is an equally likely possibility that the production of anti-islet antibodies occurs as a result of the destruction of -cells. Whether a direct cause or an effect of islet cell destruction, the titer of the ICCA tends to decline over time. 2. Islet cell surface antibodies: Autoantibodies directed against cell-surface antigens (ICSA) have also been described in as many as 80% of type 1 diabetics. Similar to ICCA, the titer of ICSA

declines over time. Some patients with type 2 diabetes have been identified that are ICSA positive. 3. Specific antigenic targets of islet cells: Antibodies to glutamic acid decarboxylase (GAD) have been identified in over 80% of patients newly diagnosed with IDDM. Like ICCA, anti-GAD antibodies decline over time in type 1 diabetics. The presence of anti-GAD antibodies is a strong predictor of the future development of IDDM in high-risk populations. Anti-insulin antibodies (IAA) have been identified in IDDM patients and in relatives at risk to develop IDDM. These IAA are detectable even before the onset of insulin therapy in type 1 diabetics. IAA are detectable in around 40% of young children with IDDM. Pathophysiology of Type 1 Diabetes The autoimmune destruction of pancreatic -cells leads to a deficiency of insulin secretion. It is this loss of insulin secretion that leads to the metabolic derangements associated with IDDM. In addition to the loss of insulin secretion, the function of pancreatic -cells is also abnormal. There is excessive secretion of glucagon in IDDM patients. Normally, hyperglycemia leads to reduced glucagon secretion. However, in patients with IDDM, glucagon secretion is not suppressed by hyperglycemia. The resultant inappropriately elevated glucagon levels exacerbates the metabolic defects due to insulin deficiency (see below). The most pronounced example of this metabolic disruption is that patients with IDDM rapidly develop diabetic ketoacidosis in the absence of insulin administration. If somatostatin is administered to suppress glucagon secretion, there is a concomitant suppression in the rise of glucose and ketone bodies. Particularly problematic for long term IDDM patients is an impaired ability to secrete glucagon in response to hypoglycemia. This leads to potentially fatal hypoglycemia in response to insulin treatment in these patients. Although insulin deficiency is the primary defect in IDDM, in patients with poorly controlled IDDM there is also a defect in the ability of target tissues to respond to the administration of insulin. There are multiple biochemical mechanisms that account for this impairment of tissues to respond to insulin. Deficiency in insulin leads to elevated levels of free fatty acids in the plasma as a result of uncontrolled lipolysis in adipose tissue. Free fatty acids suppress glucose metabolism in peripheral tissues such as skeletal muscle. This impairs the action of insulin in these tissues, i.e. the promotion of glucose utilization. Additionally, insulin deficiency decreases the expression of a number of genes necessary for target tissues to respond normally to insulin such as glucokinase in liver and the GLUT 4 class of glucose transporters in adipose tissue. The major metabolic derangements which result from insulin deficiency in IDDM are impaired glucose, lipid and protein metabolism. Glucose Metabolism: Uncontrolled IDDM leads to increased hepatic glucose output. First, liver glycogen stores are mobilized then hepatic gluconeogenesis is used to produce glucose. Insulin deficiency also impairs non-hepatic tissue utilization of glucose. In particular in adipose tissue and skeletal muscle, insulin stimulates glucose uptake. This is accomplished by insulin-mediated movement of glucose transporter proteins to the plasma membrane of these tissues. Reduced glucose uptake by peripheral tissues in turn leads to a reduced rate of glucose metabolism. In addition, the level of hepatic glucokinase is regulated by insulin. Therefore, a reduced rate of glucose phosphorylation in hepatocytes leads to increased delivery to the blood. Other enzymes involved in anabolic metabolism of glucose are affected by insulin (primarily through covalent modifications). The combination of increased hepatic glucose production and reduced peripheral

tissues metabolism leads to elevated plasma glucose levels. When the capacity of the kidneys to absorb glucose is surpassed, glucosuria ensues. Glucose is an osmotic diuretic and an increase in renal loss of glucose is accompanied by loss of water and electrolytes, termed polyuria. The result of the loss of water (and overall volume) leads to the activation of the thirst mechanism (polydipsia). The negative caloric balance which results from the glucosuria and tissue catabolism leads to an increase in appetite and food intake (polyphagia). Lipid Metabolism: One major role of insulin is to stimulate the storage of food energy following the consumption of a meal. This energy storage is in the form of glycogen in hepatocytes and skeletal muscle. Additionally, insulin stimulates hepatocytes to synthesize triglycerides and storage of triglycerides in adipose tissue. In opposition to increased adipocyte storage of triglycerides is insulin-mediated inhibition of lipolysis. In uncontrolled IDDM there is a rapid mobilization of triglycerides leading to increased levels of plasma free fatty acids. The free fatty acids are taken up by numerous tissues (however, not the brain) and metabolized to provide energy. Free fatty acids are also taken up by the liver. Normally, the levels of malonyl-CoA are high in the presence of insulin. These high levels of malonyl-CoA inhibit carnitine palmitoyltransferase I, the enzyme required for the transport of fatty acyl-CoA's into the mitochondria where they are subject to oxidation for energy production. Thus, in the absence of insulin, malonyl-CoA levels fall and transport of fatty acyl-CoA's into the mitochondria increases. Mitochondrial oxidation of fatty acids generates acetyl-CoA which can be further oxidized in the TCA cycle. However, in hepatocytes the majority of the acetyl-CoA is not oxidized by the TCA cycle but is metabolized into the ketone bodies, acetoacetate and hydroxybutyrate. These ketone bodies leave the liver and are used for energy production by the brain, heart and skeletal muscle. In IDDM, the increased availability of free fatty acids and ketone bodies exacerbates the reduced utilization of glucose furthering the ensuing hyperglycemia. Production of ketone bodies, in excess of the organisms ability to utilize them leads to ketoacidosis. In diabetics, this can be easily diagnosed by smelling the breath. A spontaneous breakdown product of acetoacetate is acetone which is volatilized by the lungs producing a distinctive odor. Normally, plasma triglycerides are acted upon by lipoprotein lipase (LPL), an enzyme on the surface of the endothelial cells lining the vessels. In particular, LPL activity allows fatty acids to be taken from circulating triglycerides for storage in adipocytes. The activity of LPL requires insulin and in its absence a hypertriglyceridemia results. Protein Metabolism: Insulin regulates the synthesis of many genes, either positively or negatively that then affect overall metabolism. Insulin has a global effect on protein metabolism, increasing the rate of protein synthesis and decreasing the rate of protein degradation. Thus, insulin deficiency will lead to increased catabolism of protein. The increased rate of proteolysis leads to elevated concentrations in plasma amino acids. These amino acids serve as precursors for hepatic and renal gluconeogensis. In liver, the increased gluconeogenesis further contributes to the hyperglycemia seen in IDDM. back to the top

Genetics of Type 1 Diabetes The majority of genetic loci associated with the development of type 1 diabetes (T1D) map to the human leukocyte antigen (HLA) class II proteins which are encoded for by genes in the major histocompatibility complex (MHC) which is located on chromosome 6p21. The Figure below diagrams a simplified view of the MHC cluster which spans 3.5 megabases of chromosome 6 and encompasses over 200 genes divided into three subregions termed class I, class II and class III.

Simplified view of the MHC cluster genes. The class I genes encode peptide chains, which associate with 2 microglobulin to form the class I molecules. Class I molecules are expressed on the surface of all nucleated cells where they are involved in the restriction of cytotoxic T cell activity. The class II (HLA-D) loci are subdivided into at least one A and one B gene which encode the and peptide chains, respectively. The class II proteins combine to form heterodimeric molecules that are expressed on antigen presenting cells, B cells, and activated T cells. The HLADP, HLA-DQ, and HLA-DR molecules are involved in the activation of helper T cells. There are nine B genes in the DR cluster identified as DRB1DRB9. There are five distinct DR haplotypes in humans identified as DR1 (composed of the DRB1, DRB6, and DRB9 genes), DR51 (composed of the DRB1, DRB6, DRB5, and DRB9 genes), DR52 (composed of the DRB1, DRB2, DRB3, and DRB9 genes), DR8 (composed of the DRB1 and DRB9 genes), and DR53 (composed of the DRB1, DRB7, DRB8, DRB4, and DRB9 genes). The current MHC nomenclature arranges the DR sequences into different allelic groups. DRB1 sequences are arranged into 13 different allelic groups that through phylogenetic analyses cluster within the five haplotypes outlined above. These allelic groups are denoted: *01 and *10 (the DR1 group), *08 (the DR8 group), *15 and *16 (the DR51 group), *03, *11, *12, *13, and *14 (the DR52 group), and *04, *07, and *09 (the DR53 group). The second expressed DRB loci (DRB3, DRB4, and DRB5) exhibit limited polymorphisms in the human genome. The class III genes encode a range of molecules with a variety of functions, including complement components, tumor necrosis factor (TNF), and heat shock protein, Hsp70. This is not to say that all genetic associations in T1D are due to mutations in HLA genes as more than 40 additional T1D susceptibility loci have been identified that are not HLA genes. The most frequently observed non-HLA genes associated with T1D are the insulin (INS), protein tyrosine phosphatase, non-receptor type 22 (PTPN22), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), interleukin-2 receptor alpha (IL2RA), and interferon-induced with helicase C domain 1 (IFIH1) genes. The INS gene is on chromosome 11p15.5, the PTPN22 gene is on chromosome

1p13, the CTLA4 gene is on chromosome 2q33, the IL2RA gene is on chromosome 10p15.1, and the IFIH1 gene is on chromosome 2q24. Polymorphisms in the INS gene account for approximately 10% of genetic susceptibilities to T1D. All of the INS gene polymorphisms reside outside the coding region of the gene indicating that susceptibility to T1D is related to modulation of expression of the INS gene. The PTPN22 gene encodes a protein identified as lymphoid-specific phosphatase (LYP) which is involved in the prevention of spontaneous T cell activation. One of the polymorphisms in the PTPN22 gene that is associated with T1D susceptibility is also associated with other autoimmune diseases such as systemic lupus erythematosus (SLE), Graves disease, and rheumatoid arthritis (RA). The protein encoded by the CTLA4 gene is also involved in regulating T cell activation and like polymorphisms in the PTPN22 gene, polymorphisms in CTLA4 are associated with other autoimmune disorders such as Addison disease and Graves disease. The highest risk population for the development of T1D are children born with the HLA DR3/4 DQ8 serotype allele which accounts for almost 50% of all children who develop antibodies against pancreatic islet cells and thus develop T1D by the age of 5. HLA DR serotype alleles are molecules that recognize different DR gene products. The DR3 serotype recognizes the DRB1*03 gene products and the DR4 serotype recognizes the DRB1*04 gene products. Children with the high risk HLA alleles DR3/4DRQ or DR4/DR4 and who have a family history of T1D have a nearly 1 in 5 chance of developing islet cell autoantibodies resulting in T1D. These same children born into a family with no history of T1D still have a 1 in 20 chance of developing T1D. It should be pointed out that although there are these strong genetic associations to T1D over 85% of all children who develop the disease do not have a family history associated with T1D. The class II HLA molecules that are associated with increased risk of T1D have been shown to bind peptides derived from the currently identified autoantigens described above and present these peptides to CD4+ T cells which then activate CD8+ cytotoxic T cells resulting in killing of islet cells. back to the top

Non-Insulin-Dependent Diabetes Mellitus (NIDDM): Type 2 Etiology of Type 2 Diabetes Type 2 diabetes is characterized by a lack of the need for insulin to prevent ketoacidosis. Type 2 diabetes refers to the common form of idiopathic NIDDM. Type 2 diabetes is not an autoimmune disorder, however, there is a strong genetic correlation to the susceptibility to this form of diabetes. The susceptibility genes that predispose one to NIDDM have not been identified in most patients. This is due in part to the heterogeneity of the genes responsible for the susceptibility to type 2 diabetes. Obesity is a major risk factor that predisposes one to type 2 diabetes. Genetic studies in mice and rats have demonstrated a link between genes responsible for obesity and those that cause diabetes mellitus. Pathophysiology of Type 2 Diabetes

Unlike patients with type 1 diabetes, those with type 2 diabetes have detectable levels of circulating insulin. On the basis of oral glucose tolerance testing the essential elements of type 2 diabetes can be divided into 4 distinct groups; those with normal glucose tolerance, chemical diabetes (called impaired glucose tolerance), diabetes with minimal fasting hyperglycemia (fasting plasma glucose <140 mg/dL), and diabetes mellitus in association with overt fasting hyperglycemia (fasting plasma glucose >140 mg/dL). In patients with the highest levels of plasma insulin (impaired glucose tolerance group) there was also elevated plasma glucose. This indicates that these individuals are resistant to the action of insulin. In the progression from impaired glucose tolerance to diabetes mellitus the level of insulin declines indicating that patients with type 2 diabetes have decreased insulin secretion. Additional studies have subsequently demonstrated that both insulin resistance and insulin deficiency is common in the average type 2 diabetic patient. Many experts conclude that insulin resistance is the primary cause of type 2 diabetes, however, others contend that insulin deficiency is the primary cause because a moderate degree of insulin resistance is not sufficient to cause type 2 diabetes. As indicated above, most patients with the common form of type 2 diabetes have both defects. The major clinical complications of type 2 diabetes are the result of persistent hyperglycemia which leads to numerous pathophysiological consequences. As the glucose level rises in the blood the blood becomes more viscous which makes circulation of the blood in the small capillaries difficult. The reduced circulation results in progressive vascular complications leading to diabetic retinopathy (referred to as diabetic blindness), peripheral neuropathy (resulting in numbness in the extremities and tingling in fingers and toes), poor wound healing, and erectile dysfunction. In addition to these major clinical complications, the body reacts by increasing the level of glucose excretion by the kidneys leading to frequent urination which is called polyuria. As the glucose is excreted there is a concomitant loss of water to maintain normal osmolarity of the urine. The water loss leads to excessive thirst called polydypsia. back to the top

Measurement of HbA1c Levels The development of hypoglycemia inducing drugs is the major pharmacological focus of type 2 diabetes therapies. Assessment of therapeutic efficacy in the treatment of the hyperglycemia in type 2 diabetes is accomplished by routine measurement of the circulating levels of glycosylated hemoglobin, designated as the level of HbA1c, often designated as just A1C. HbA1 is the major form of adult hemoglobin in the blood and the "c" refers to the glycosylated form of the protein. Since hemoglobin is present in red blood cells and these cells have a limited life span of 120 days in the circulation, measurement of HbA1c levels is a relatively accurate measure of the amount of glucose in the blood and the length of time the level has been elevated. Typical values for HbA1c measurement (using the previous standard Diabetes Control and Complications Trial, DCCT units of %) are shown in the Table below. Beginning in 2011 a new international standard (International Federation of Clinical Chemistry, IFCC units) for the measurement of HbA1c levels will be utilized. This new standard equates the mmole of HbA1c per mole of total measured hemoglobin, Hb

(mmol/mol). The method for calculating the relationship between these two measurement values is to use the following formula: IFCC-HbA1c (mmol/mol) = [DCCT-HbA1c (%) - 2.15] 10.929. To calculate the estimated average glucose (eAG) level in the blood using the DCCT (%) values one would use the following formula: eAG(mg/dl) = 28.7 A1C 46.7 (for glucose level in mM use: eAG(mM) = 1.59 A1C 2.59 With new IFCC standard the target range of HbA1c for healthy levels is 4859mmol/mol.

HbA1c 4% 5% 6% 7% 8% 9% 10% 11% 12% 13% 14%

HbA1c/Hb eAG (mg/dl) eAG (mM) mmol/mol 20 31 42 53 64 75 86 97 108 119 130 68 97 125 154 183 212 240 270 298 326 355 3.8 5.4 7 8.5 10 11.7 13.3 15 16.5 18 19.7

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Genetics of Type 2 Diabetes Development of type 2 diabetes is the result of multifactorial influences that include lifestyle, environment and genetics. The disease arises when insulin resistance-induced compensatory insulin secretion is exhausted. A high-caloric diet coupled with a sedentary lifestyle are the major contributing factors in the development of the insulin resistance and pancreatic -cell dysfunction. However, a predisposing genetic background has long been suspected in playing a contributing role in the development of type 2 diabetes. By using whole-genome linkage analysis the entire genome of affected family members can be scanned and the family members monitored over several generations. In addition, large numbers of affected sibling-pairs can also be studied. Using these genome-wide linkage methods the first major susceptibility locus for type 2 diabetes was located on chromosome 2 in 1996. This locus was designated NIDDM1. The first gene identified in the NIDDM1 locus with polymorphisms correlated to type 2 diabetes susceptibility was calpain 10 (CAPN10). CAPN10 is a calcium-activated neutral protease that is a member of the calpain-like cysteine protease family. The CAPN10 gene is located on chromosome 2q37.3 and spans 31 kb composed of 15 exons encoding a 672 amino acid protein. Variation in the non-coding region of the CAPN10 gene is associated with a threefold increased risk of type 2 diabetes in Mexican Americans. However, in European populations polymorphisms in CAPN10 are less contributory to type 2 diabetes than other recently discovered genes. Genetic variants in CAPN10 may alter insulin secretion or insulin action as well as the production of glucose by the liver. Recent studies indicate that CAPN10 may have a critical role in the survival of pancreatic -cells. Another early genetic marker for type 2 diabetes was hepatocyte nuclear factor 4- (HNF4A). Note that HNF4A is also known to be associated with the development of MODY1 (see above). The hepatocyte nuclear factor family of proteins was first identified as an abundant class of transcription factors in the liver. In addition to the liver, HNF4A is expressed in pancreatic -cells, kidneys and intestines. As indicated above, mutations in HNF4A can cause MODY1 which is characterized by a normal response to insulin but an impaired insulin secretory response in the presence of glucose. The HNF4A gene maps to a region of chromosome 20 that has been linked to type 2 diabetes. Specifically the HNF4A gene is located at 20q12q13.1 and is encoded in 12 exons. Single nucleotide polymorphisms (SNPs) in the HNF4A gene have an impact on pancreatic -cell function leading to altered insulin secretion and result in the development of MODY1. The SNPs in the HNF4A gene that are related to development of type 2 diabetes lie in a promoter element called P2. The P2 promoter is used primarily in pancreatic -cells, whereas, both the P1 and P2 promoters are used in liver cells. The P2 promoter is a binding site for the transcription factors HNF-1 (HNF1A), HNF-1 (HNF1B), and insulin promoter factor-1 (IPF1). As described above, alteration in the function of each of these latter three transcription factors is associated with various forms of MODY. Recent evidence has demonstrated a role for a member of the nuclear hormone receptor superfamily of proteins in the etiology of type 2 diabetes. The thiazolidinedione (TZD) class of drugs, used to increase the sensitivity of the body to insulin (see below), bind to and alter the function of the peroxisome proliferator-activated receptor-, PPAR. PPAR is also a transcription factor and, when activated, binds to another transcription factor known as the retinoid X receptor, RXR. When these two proteins interact they bind to specific PPAR response elements (termed PPREs) in target genes thereby regulating their expression. PPAR is a key

regulator of adipocyte differentiation; it can induce the differentiation of fibroblasts or other undifferentiated cells into mature fat cells. PPAR is also involved in the synthesis of biologically active compounds from vascular endothelial cells and immune cells. Mutations in the gene for PPAR (gene symbol = PPARG) have been correlated with insulin resistance. More recent genome-wide screens for polymorphisms (in particular single nucleotide polymorphisms, SNPs) in type 2 diabetes have identified several new candidate genes. The Table below lists several genes that either, reside within chromosomal loci that are highly correlated to the development of type 2 diabetes, or that have had polymorphisms identified in the gene itself that correlate to development of type 2 diabetes. Included in the Table are PPARG and CAPN10 described above as well as the gene potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11) which is described in the Insulin Function page. The transcription factor TCF7L2 (transcription factor 7-like 2, T-cell specific HMG-box) is one of four TCF proteins involved in the signaling pathways initiated by the Wnt family of secreted growth factors. Two SNPs identified in the TCF7L2 gene are the most highly correlated polymorphisms with type 2 diabetes. Given that evidence is accumulating that Wnt and insulin signaling pathways exhibit cross-talk at the level of both the gut and the pancreas, it is likely that new targets in the treatment of type 2 diabetes will involve the interrelationships between these two factors. In addition to the genes described in the following Table, and those described for permanent neonatal diabetes mellitus (next section), at least 25 additional genes have been shown by genome wide association studies (GWAS) to be associated with type 2 diabetes and/or elevated fasting plasma glucose levels.

Genes Associated with Type 2 Diabetes Susceptibility Gene Name a disintegrin-like and metalloproteinase (ADAM) with thrombospondin type 1 motif, 9 Gene Symbol Gene Function, Comments Disease Mechanism

demonstrated to proteolytically cleaved bovine versican (a large extracellular ADAMTS9 matrix proteoglycan) and aggrecan (large aggregated proteoglycan)

unknown

Ca2+/calmodulinleads to activation of extracellular signaldependent protein kinase CAMK1D regulated protein kinase 1 (ERK1) activity 1- calpain 10 CAPN10 calcium-activated neutral protease, member of the calpain-like cysteine

-cell dysfunction

glucose

protease family cell division cycle 123 homolog cyclin-dependent kinase5 regulatory subunit associated protein 1-like 1 CDC123 CDC123 is in the same chromosomal region as the CAMK1D gene

transport -cell dysfunction -cell dysfunction, impaired insulin secretion

CDKAL1

inhibitor of cyclin-dependent kinase 5 (CDK5)

cyclin-dependent kinase inhibitor 2A

the CDKN2A gene produces 2 major proteins: p16(INK4), which is a cyclinCDKN2A/B dependent kinase inhibitor, and p14(ARF), which binds the p53-stabilizing protein MDM2, p14 is also called CDKN2B catalyzes the iron- and 2-oxoglutaratedependent demethylation of 3methylthymine in single-stranded DNA, with concomitant production of succinate, formaldehyde, and CO2 is a transcriptional repressor in liver cells, may be involved in the differentiation and/or maintenance of the differentiated state in hepatocytes, is a target of the Wnt signaling pathway

-cell dysfunction

fat mass- and obesityassociated gene

FTO

obesity

hematopoietically expressed homeobox

HHEX

-cell dysfunction, impaired insulin secretion

hepatocyte nuclear factor-1: hepatocyte transcription factor-2

HNF1B mutations in gene associated with also called MODY5 TCF2 is an extracellular thiol metalloprotease with preference for insulin, also degrades amyloid- protein; the IDE gene resides within the same chromosomal locus as HHEX

unknown

insulin degrading enzyme

IDE

-cell dysfunction

insulin-like growth factor-2 mRNA binding

IGF2BP2 binds to the IGF2 mRNA

-cell dysfunction

protein 2 juxtaposed with another zinc-finger gene 1: TAK1(TGF-activated kinase-1)-interacting protein 27 potassium inwardlyrectifying channel, subfamily J, member 11

JAZF1 functions as a transcriptional repressor, also called exhibits antiapoptotic activity TIP27

-cell dysfunction

KCNJ11

forms the core of the ATP-sensitive potassium (KATP) channel involved in insulin secretion, protein is also called Kir6.2 pore-forming -subunit of a cardiac delayed rectifier potassium channel; also referred to as KvLQT because the gene resides in a critical region for the cardiac long QT syndrome-1 disorder which is a region that is also in the imprinted locus associated with Beckwith-Weidemann syndrome; gene also expressed in epithelial cells of the exocrine and endocrine pancreas Krppel-like transcription factors all related to Drosophila Krppel gene; are a family of zinc-finger transcription factors; KLF14 is a master trans regulator of adipose gene expression gene is expressed exclusively in the cycling crypt base of the columnar cells of the gut and hair follicle, protein is a glycoprotein that associates with integrins, the gene is a marker for intestinal stem cells, expression is regulated by Wnt signaling is a single exon (intronless) gene, mutations in this gene are the most frequent genetic cause of severe obesity, receptor binds -melanocyte stimulating

-cell dysfunction

potassium channel, voltage-gated, KQT-like subfamily, member 1

KCNQ1

-cell dysfunction

Krppel-like factor 14

KLF14

leucine-rich repeat containing G-protein coupled receptor 5

LGR5

-cell dysfunction

melanocortin 4 receptor

MC4R

obesity

hormone (-MSH) -cell dysfunction, impaired insulin secretion

melatonin receptor 1B

MTNR1B

high affinity G-protein coupled receptor, expressed primarily in pancreatic -cells

Notch homolog 2

one of three mammalian homologues of NOTCH2 the Notch gene of fruit flies which regulates cellular differentiation transcriptional co-activator with retinoid X receptors (RXRs), master regulator of adipogenesis, activation of adipocytes leads to increased fat storage and secretion of insulin-sensitizing adipocytokines such as adiponectin

unknown

peroxisome proliferatoractivated receptor- (PPAR)

PPARG

insulin sensitivity

solute carrier family 30 (zinc transporter), member 8

SCL30A8 permits cellular efflux of zinc

-cell dysfunction

transcription factor 7-like 2 (T-cell specific HMGbox)

TCF7L2

one of four TCF transcription factor proteins involved in the signaling pathways initiated by the Wnt family of secreted growth factors, polymorphisms in this gene have the highest correlation to type 2 diabetes protein contains an ARM repeat (ARM = armadillo which is a fruit fly gene involved in segment polarity), the ARM repeat is involved in protein-protein interactions tetraspanins are proteins that contain 4 transmembrane domains, this gene and LGR5 are found in the same chromosomal region is an integral ER membrane glycoprotein, associates with the C-terminal domain of

-cell dysfunction, impaired insulin secretion

thyroid adenomaassociated gene

THADA

unknown

tetraspanin 8

TSPAN8

-cell dysfunction

Wolfram syndrome gene; also called diabetes

WFS1

-cell

insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD)

the ER-localized Na+/K+ATPase -1 subunit (ATP1B1)

dysfunction

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Neonatal Diabetes Neonatal diabetes refers to a circumstance in which hyperglycemia results from dysfunction in insulin action within the first 6 months of life. This form of diabetes is not typical type 1 diabetes (T1D, or juvenile onset diabetes) since T1D involves immune destruction of the pancreatic -cells and thus, requires several years to fully develop. Neonatal diabetes can be transient or permanent. If an infant suffers from the transient form they are at increased risk for developing full-blown later in life. The advent of genetic studies to identify HLA haplotypes associated with the risk of development of T1D as well as the description of several T1D-associated autoantibodies provided the foundation for characterization of the clinical features of the disease in newborns. Evidence is clear that the etiology of diabetes in the first year of life is different from that of the autoimmune forms of T1D more classically diagnosed when children are older. As indicated, the presentation of diabetes in infants prior to 6-months of age can be transient or permanent. The permanent form of the disease is termed Permanent Neonatal Diabetes Mellitus (PNDM). PNDM is a rare event occurring with a frequency of approximately 2 cases per 100,000 births. Definitive determination of PNDM requires early gene screening as soon as symptoms manifest. This allows for a differential diagnosis to be made as to whether or not the symptoms can be expected to be transient or permanent. Very low birth weight is highly correlated to PNDM and is associated with fetal lack of insulin. The most prominent of symptoms is the onset of hyperglycemia within the first 6 months after birth. Affected infants do not secrete insulin in response to glucose or glucagon but will secrete insulin in response to tolbutamide administration. Tolbutamide is a drug of the sulfonylurea class used to treat type 2 diabetes. Many infants will exhibit similar neurologic abnormalities, including developmental delay, muscle weakness, and epilepsy. In patients manifesting with neurologic abnormalities there are often associated dysmorphic features, including prominent metopic suture (persistence of the space between the frontal bones of the skull), a downturned mouth, bilateral ptosis (drooping eyelid), and limb contractures. Early on it was thought that the underlying defect resulting in neonatal diabetes was pancreatic -cell dysfunction or a defect in -cell maturation. However, genetic evidence now indicates that neonatal diabetes, in particular PNDM, is the result of single-gene defects. This make PNDM a monogenic disorder. The disorder can be inherited although it is most often the result of a sporadic mutation in one of the parental gametes. Over the past decade at least 12 genes have been identified as being associated with the development of PNDM. The most commonly

mutated genes are the potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11), ATP-binding cassette transporter, subfamily C, member 8 (ABCC8), and insulin (INS) genes. The proteins of the KCNJ11 and ABCC8 genes form the ATP-sensitive potassium channel (KATP channel) that is involved in insulin secretion (see the Insulin Function page). Mutations in the KCNJ11 gene are also associated with an increased risk for the development of T2D as described in the Genetics of Type 2 Diabetes section above. The insulin gene is one of the non-HLA genes that is mutated in T1D as indicated above in the Genetics of Type 1 Diabetes section.

Genes Associated with Permanent Neonatal Diabetes Mellitus Gene Name Gene Symbol Comments

ATP-binding cassette transporter, subfamily C, member 8

along with KCNJ11 encoded proteins ABCC8 forms the ATP-sensitive potassium (KATP) channel involved in insulin ABCC8 secretion; gene is also known as the sulfonylurea receptor: SUR; mutations in the ABCC8 gene found in 13% of PNDM cases also associated with skeletal dysplasia, mental retardation, and hepatic failure; gene also known as RNA-dependent EIF2AK3 protein kinase-like endoplasmic reticulum kinase, PERK; this particular form of PNDM is also known as WolcottRallinson syndrome (WRS) is a member of the fork-winged helix family of transcription factors,; plays an important role in development and function of CD4-positive/CD25-positive regulatory T cells (Tregs); Tregs are involved in active suppression of inappropriate immune responses same gene found associated with MODY2 also associated with severe congenital hypothyroidism, cholestasis, congenital glaucoma, and polycystic kidneys mutations in the INS gene represent 16% of PNDM cases

eukaryotic translation initiation factor 2- kinase 3

forkhead box family member P3

FOXP3

pancreatic glucokinase Gli similar (GLIS family) Krppel-like zinc finger transcription 3 insulin potassium inwardlyrectifying channel,

GCK

GLIS3

INS

KCNJ11 forms the core of the ATP-sensitive potassium (KATP) channel involved in insulin secretion, protein is also called

subfamily J, member 11

Kir6.2; mutations in this gene found in 30%50% of PNDM cases regulates transcription of the insulin gene; also is a key regulator of the development of the pancreas, most probably by determining maturation and differentiation of common pancreatic precursor cells in the developing gut gene is essential to normal pancreas formation; mutations in gene also associated with cerebellar hypoplasia/agenesis, and dysmorphism; similar phenotypes to those resulting from PDX1 mutations

pancreatic and duodenal homeobox 1

PDX1

pancreas transcription factor 1A

PTF1A

regulatory factor x-box binding family transcription factor member 6 solute carrier family, facilitated glucose (GLUT) transporter subfamily, member 2

RFX6

involved in pancreatic islet cell differentiation; also associated with intestinal atresia and gall bladder hyoplasia

SLC2A2

also associated with Fanconi-Bickel syndrome (glycogen storage disease XI, GSD11)

solute carrier family, folate/thiamine transporters subfamily, member 2

mutations in gene result in thiamine-responsive megaloblastic anemia syndrome (also known as Rogers syndrome), defined by the occurrence of megaloblastic SLC19A2 anemia, diabetes mellitus, and sensorineural deafness; thiamine treatment results in varying degrees of positive response

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Diabetes and the Metabolic Syndrome: MetS Although the metabolic syndrome (also called syndrome X) is not exclusively associated with type 2 diabetes and the associated insulin resistance, the increasing prevalence of obesity and associated development of type 2 diabetes places insulin resistance as a major contributor to the syndrome. The metabolic syndrome is defined as a clustering of atherosclerotic cardiovascular disease risk factors that include visceral adiposity (obesity), insulin resistance, low levels of HDLs and a systemic proinflammatory state. There are key components to the metabolic syndrome

which include in addition to insulin resistance (the hallmark feature of the syndrome), hypertension, dyslipidemia, chronic inflammation, impaired fibrinolysis, procoagulation and most telling central obesity. For more information on the biochemical and clinical aspects of MetS visit the Metabolic Syndrome page. Given the complexities of the factors contributing to the metabolic syndrome numerous health groups in various countries have defined the disorder with slightly different criteria. Some health organizations believe that insulin resistance is the signal most important predictor for future development of type 2 diabetes and cardiovascular disease that the disorder is defined as the insulin resistance syndrome. In addition, there are significant differences in ethnic predisposition to the effects of the dysfunctions of the metabolic syndrome that some criteria must be assessed with this in mind. Of particular note is the use of waist circumference as an indicator of obesity. The following Table lists the criteria set forth by the American Heart Association and the National Heart, Lung and Blood Institute as defining the metabolic syndrome. Defining Criteria elevated fasting blood glucose elevated waist circumference elevated triglycerides reduced HDL cholesterol (HDLc) Parameters of Criteria 100 mg/dL ( 5.6mmol/L) 102 cm ( 40 inches) in men 88cm ( 35 inches) in women 150mg/dL ( 1.7mmol/L) < 40mg/dL (< 1.03mmol/L) in men < 50mg/dL (< 1.3mmol/L) in women 130mm Hg systolic or 85mm Hg diastolic

elevated blood pressure

The role of adipose tissue (fat) stems from the fact that the organ is active at secretion of cytokines, termed adipocytokines. These include tumor necrosis factor- (TNF), interleukin-6 (IL-6), leptin, adiponectin and resistin. Leptin has received particular attention of late due to its role in obesity in addition to the fact that recent data indicates that plasma leptin levels are found to be predictive of the potential for cardiovascular pathology. Many clinicians and researchers believe that insulin resistance underlies the cardiovascular pathologies of the metabolic syndrome. One primary reason for this is the role of insulin in fat homeostasis. As indicated above, the major role of insulin is to induce the storage of fuel. This can be as fat (triacylglycerides, TGs) in adipose tissue or as carbohydrate in the form of glycogen in liver and skeletal muscle. The effect of insulin resistance at the level of fat homeostasis is an increase in circulating TGs, referred to as dyslipidemia. Due to insulin resistance there is an increase in the delivery of peripheral fatty acids to the liver which in turn drives hepatic TG

synthesis. These TGs are then packaged into lipoprotein particles termed VLDLs (very low density lipoproteins) which are returned to the circulation. An additional role of insulin resistance in the overall cardiac pathology associated with the metabolic syndrome relates to the normal role of insulin in platelet function. In platelets, insulin action leads to an increase in endothelial nitric oxide synthase (eNOS) activity that is due to its phosphorylation by AMPK. Activation of NO production in platelets leads to a decrease in thrombin-induced aggregation, thereby, limiting the pro-coagulant effects of platelet activation. This response of platelets to insulin function clearly indicates why disruption in insulin action is a major contributing factor in the development of the metabolic syndrome. Taken together, the insulin resistance and its associated negative effects on metabolism, the increased levels of circulating TGs, the reduced levels of HDLs and hypertension, all contribute to the progression of atherosclerosis. With associated coagulation and fibrinolysis pathologies, the cardiovascular events of the metabolic syndrome can be devastating. Since many of these pathologies can be reversed with proper diet and exercise, it is in a persons best interest to take responsibility for the role their life style choices play in the development of the metabolic syndrome. back to the top

Mitochondrial Dysfunction in Type 2 Diabetes and Obesity Well established data demonstrate that mitochondrial dysfunction, particularly as it relates to the processes of oxidative phosphorylation (oxphos), is contributory to the development of encephalomyopathy, mitochondrial myopathy, and several age-related disorders that include neurodegenerative diseases, the metabolic syndrome, and diabetes. Indeed, with respect to diabetes, several mitochondrial diseases manifest with diabetic complications such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and maternally inherited diabetes and deafness (MIDD). Normal biogenesis of mitochondria is triggered in response to changes in the ATP/ADP ratio and to activation of AMPK which in turn results in increased expression of PPAR co-activator 1 (PGC-1) and nuclear respiratory factor-1 (NRF1). PGC-1 is a master transcriptional co-activator of numerous genes involved in mitochondrial biogenesis. NRF1 is a transcription factor that regulates the expression of mitochondrial transcription factor A (TFAM, for transcription factor A, mitochondrial; also designated mtTFA) which is a nuclear transcription factor essential for replication, maintenance, and transcription of mitochondrial DNA. NRF1 also controls the expression of nuclear genes required for mitochondrial respiration and heme biosynthesis. Evidence has shown that both PGC-1 and NRF1 expression levels are lower in diabetic patients as well as in non-diabetic subjects from families with type 2 diabetes. The expression of NRF1 is highest in skeletal muscle which is also the tissue that accounts for the largest percentage of glucose disposal in the body and, therefore, is the tissue that is most responsible for the hyperglycemia resulting from impaired insulin signaling.

Mitochondrial dysfunction results in increased production of ROS which activates stress responses leading to increased activity of MAPK and JNK. Both of these serine/threonine kinases phosphorylate IRS1 and IRS2 resulting in decreased signaling downstream of the insulin receptor. Inhibited IRS1 and IRS2 activity results in decreased activation of PI3K. PI3K activation is involved in the translocation of GLUT4 to the plasma membrane resulting in increased glucose uptake. Therefore, inhibition of PI3K results in reduced glucose uptake in skeletal muscle and adipose tissue. Mitochondrial dysfunction results in a reduction in the level of enzymes involved in oxidation leading to increases in intramyocellular lipid content. Indeed, skeletal muscle metabolism of lipids has been shown to be impaired in type 2 diabetics. An increased delivery of fatty acids to skeletal muscle, as well as diminished mitochondrial oxidation, results in increased intracellular content of fatty acid metabolites such as diacylglycerol (DAG), fatty acyl-CoAs, and ceramides. These metabolites of fatty acids are all known to induce the activity of protein kinase C isoforms (PKC and PKC) that phosphorylate IRS1 and IRS2 on serine residues resulting in impaired insulin signaling downstream of the insulin receptor. Because skeletal muscle consumes the largest amount of serum glucose, mitochondrial dysfunction in this tissue will have the greatest impact on glucose disposal. However, adipose tissue also plays an important role in glucose homeostasis and mitochondrial dysfunction in this tissue has been shown to result in impaired glucose homeostasis resulting in diabetes. For example, when animals are treated with inhibitors of mitochondrial oxidation insulin-stimulated glucose uptake in adipose tissue is significantly impaired. Adipose tissue secretes a number of proteins classified as adipokines. Adiponectin is an adipokine that promotes insulin-sensitivity in insulin-responsive tissues, such as skeletal muscle. When plasma levels of adiponectin are measured in obese or type 2 diabetic subjects it is found to be significantly lower than in age and sex matched control subjects that are of normal weight or that do not have diabetes. In animal studies, the enhancement of adipocyte mitochondrial biogenesis results in increased adiponectin release from adipose tissue. Conversely, expression of adiponectin expression is decreased in adipocytes with mitochondrial dysfunction. Given that impaired mitochondrial function is clearly associated with obesity and type 2 diabetes, it is not surprising that there is great interest in the use of pharmacology to augment mitochondrial function in the treatment of these disorders. Of significance is the fact that the thiazolidinedione (TZD) class of drugs used to treat the hyperglycemia of type 2 diabetes (see the next section) activate PPAR which in turn increases the level of activity of PGC-1. Although the TZDs were first marketed due to their ability to improve insulin sensitivity, they have since been shown to increase mitochondrial functions both in vitro and in vivo. Antioxidants have also been shown to enhance mitochondrial function by reducing the production of ROS. Resveratrol (found in grape skins and red wine) is a potent antioxidant whose activity is, in part, due to its ability to activate the deacetylase SIRT1 (see below). Activated SIRT1 deacetylates PGC-1 resulting in increased transcriptional activity and thus, enhanced mitochondrial biogenesis. back to the top

Therapeutic Intervention for Hyperglycemia

Many, if not all, of the vascular consequences of insulin resistance are due to the persistent hyperglycemia seen in type 2 diabetes. For this reason a major goal of therapeutic intervention in type 2 diabetes is to reduce circulating glucose levels. There are many pharmacologic strategies to accomplish these goals. 1. The Thiazolidinediones (TZDs): The TZDs, such as rosiglitazone (Avandia) and pioglitazone (Actos) have proven useful in treating the hyperglycemia associated with insulin-resistance in both type 2 diabetes and non-diabetic conditions. The TZDs function as agonists for the transcription factor, PPAR. PPAR is a member of the superfamily of nuclear receptor transcription factors. In addition to PPAR there are the closely related members, PPAR and PPAR/. PPAR exists as a heterodimer with the nuclear retinoid X receptors, RXRs. The heterodimer binds to PPAR response elements (PPREs) in a number of target genes. Without ligand bound the heterodimer is associated with a co-repressor complex that includes a histone deacetylase. Deacetylated histone keeps DNA in a transcriptionally repressed state. When ligand binds to PPAR the co-repressor complex dissociates and a co-activator complex containing histone acetylase associates resulting in chromatin structural changes and transcriptional activation. The net effect of the TZDs is a potentiation of the actions of insulin in liver, adipose tissue and skeletal muscle, increased peripheral glucose disposal and a decrease in glucose output by the liver. Genes shown to be affected by PPAR action include those encoding glucokinase, GLUT4, malic enzyme, lipoprotein lipase, fatty acyl-CoA synthase and adipocyte fatty acid binding protein. PPAR is primarily expressed in adipose tissue and thus it was at first difficult to reconcile how a drug that was apparently acting only in adipose tissue could lead to improved insulin sensitivity of other tissues. The answer to this question came when it was discovered that the TZDs stimulated the expression and release of the adipocyte hormone (adipokine), adiponectin. Adiponectin stimulates glucose uptake and fatty acid oxidation in skeletal muscle. In addition, adiponectin stimulates fatty acid oxidation in liver while inhibiting expression of gluconeogenic enzymes in this tissue. These responses to adiponectin are exerted via activation of AMPK. The significance of PPAR as a diabetes target is apparent not only from the observed effects of drugs that activate the receptor but also from genome wide screens showing that mutations in the PPAR gene are correlated to familial insulin resistance. Recent studies have identified a critical role for an enzyme (phosphatidic acid phosphatase, PAP1) involved in overall triacyglyceride and phospholipid homeostasis as a critical target of the PPAR signaling pathway. In the yeast Saccharomyces cerevisiae, the PAP1 gene was identified as Smp2p and the encoded protein was shown to be the yeast ortholog of the mammalian protein called lipin-1. The fission yeast lipin-1 ortholog is identified as Ned1p. Lipin-1 is only one of four lipin proteins identified in mammals. The lipin-1 gene (symbol = LPIN1) was originally identified in a mutant mouse called the fatty liver dystrophy (fld) mouse. The mutation causing this disorder was found to reside in the LPIN1 gene. There are three lipin genes with the LPIN1 gene encoding two isoforms derived through alternative splicing. These two lipin-1 isoforms are identified as lipin-1A and lipin-1B. Mutations in the LPIN2 gene have recently been associated with Majeed syndrome which is characterized by chronic recurrent osteomyelitis, cutaneous inflammation, recurrent fever, and congenital dyserythropoietic anemia. In addition to the obvious role of lipin-1 in TAG synthesis, evidence indicates that the protein is also required for the development of mature adipocytes, coordination of peripheral tissue glucose and fatty acid storage and utilization, and serves as a transcriptional co-activator. The latter function has significance to diabetes as it has been shown that some of the effects of the TZDs are exerted via the effects of lipin-1. Lipin-1 has been shown to interact with PPAR co-activator 1 (PGC-1) and PPAR. The

interactions of lipin-1 with these other transcription factors leads to increased expression of fatty acid oxidizing genes such as carnitine palmitoyl transferase-1, acyl CoA oxidase, and mediumchain acylCoA dehydrogenase (MCAD). 2. Targeting glucagon-like peptide-1 (GLP-1): The synthesis and activities associated with GLP-1 are described in detail in the Insulin Function page as well as on the Peptide Hormones page. As review, the primary metabolic responses to GLP-1 release from the enteroendocrine L-cells of the gut are inhibition of glucagon secretion and enhancement of glucose-dependent insulin release from the pancreas, both effects lead to decreased glycemic excursion. As discussed in the Insulin Function page, the hormonal action of GLP-1 is rapidly terminated as a consequence of enzymatic cleavage by dipeptidylpeptidase IV (DPP IV or DPP4). Recent clinical evidence has shown that either infusion of GLP-1 or inhibition of DPP4 can result in dramatic reductions in plasma glucose concentrations, reductions in HbA1c and improvement in pancreatic -cell function. Thus, both represent potential targets for the prevention of the hyperglycemia associated with diabetes and impaired insulin function. For more information on the activities of DPP4 go to the DPP4 page. There are advantages and disadvantages with the current therapeutic approaches to targeting GLP-1 action in diabetic patients. Current use of GLP-1 mimetics and/or GLP-1 receptor (GLP-1R) agonists focus on peptides or modified peptides and these must be injected. The need for chronic injection as a means of therapy always runs into the problem of patient compliance. One of the most promising GLP-1R agonists that has recently been approved for use is YETTA (also written as BYETTA) developed by Amylin Pharmaceuticals and Eli Lilly and Co. BYETTA is composed of exenatide which is the lizard salivary peptide called exendin-4. Exenatide is 53% identical to GLP-1 at the level of amino acids and binds to and activates the GLP-1R. The advantage of exenatide as a therapeutic is that it is resistant to cleavage and inactivation by DPP4. In a recent trial in patients with type 2 diabetes, BYETTA was shown not only to lower blood glucose levels and HbA1c, but patients also had an associated weight loss. Another GLP-1R agonist is Victoza (liraglutide) which was developed by Novo Nordisk. Victoza is a once-a-day injectable recombinant DNA produced modified GLP-1 protein complex. The protein is a fatty acid-linked derivative of human GLP-1 that is resistant to DPP4 cleavage. The 16carbon fatty acyl-chain (palmitic acid) addition to the protein allows liraglutide to bind to albumin in the blood which prevents its excretion via the kidneys. Liraglutide has been shown to have a half-life of 11-13 hours making it ideal for once-a-day injection. Results of clinical studies demonstrated significant reductions in HbA1c levels in liraglutide treated patients. Victoza was approved for use in the United States in January 2010. One problematic side effect of Victoza treatment is pancreatitis which occurs in patients with a higher frequency than with other diabetes treatments. Although targeting compounds that can inhibit the enzymatic action of DPP4 would seem like ideal candidates for treating the hyperglycemia of uncontrolled diabetes, there are several unknowns associated with DPP4 inhibition. One of these issues is the fact that GLP-1 and GIP are only two of the many known substrates for DPP4 cleavage. Thus, prolonged inhibition of DPP4 enzymatic activity may have unexpected consequences unrelated to control of hyperglycemia. Despite the potential for as yet unknown effects, the DDP4 inhibitor developed by Merck, Januvia (sitagliptin), has recently been approved for use alone or in combination with either metformin or the thiazolidinediones. Treatment of patients with Januvia as the only therapeutic

agent for 18 weeks produced significant reductions of HbA1c, along with an improvement of -cell function and no change in body weight. A second generation DPP4 inhibitor developed by Novartis called Glavus (vildagliptin) has recently received approvable status from the US FDA. Glavus administration is associated with significantly increased pancreatic -cell function and reduced HbA1c levels without hypoglycemia or other adverse events. Another drug in the DPP4 inhibitor class to receive US FDA approval is Onglyza (saxagliptin) made by AstraZeneca and Bristol-Myers Squibb. Onglyza is designed as a once-daily orally administered tablet. DPP4 was originally identified as the lymphocyte cell surface antigen CD26. In humans CD26 functions in many pathways that are not directly related to its peptidase activity. It harbors adenosine deaminase-binding (ADA-binding) properties and is involved in extracellular matrix binding. Of importance to the immune system, CD26 expression and activity are enhanced upon T-cell activation. CD26 interacts with other lymphocyte cell surface antigens including ADA, CD45 and the chemokine receptor CXCR4 (notable is the fact that CXCR4 is a T-cell attachment site for HIV). Currently available data indicates that the peptidase activity of DPP4 is independent of the T-cell activating and co-stimulatory functions assigned to CD26. Of significance, however, is that in gene knock-out mice lacking CD26 there is enhanced insulin secretion and improved glucose tolerance. The major clinical advantages to the use of DPP4 inhibitors is that the ones in use or in current trials are orally delivered. Compliance in patients is much higher with orally delivered drugs than with those that require injection. 3. The Biguanides: The biguanides are a class of drugs that function to lower serum glucose levels by enhancing insulin-mediated suppression of hepatic glucose production and enhancing insulinstimulated glucose uptake by skeletal muscle. Metformin (Glucophage) is a member of this class and is currently the most widely prescribed insulin-sensitizing drug in current clinical use. Metformin administration does not lead to increased insulin release from the pancreas and as such the risk of hypoglycemia is minimal. Because the major site of action for metformin is the liver its use can be contraindicated in patients with liver dysfunction. The drug is ideal for obese patients and for younger type 2 diabetics. Evidence on the mode of action of metformin shows that it improves insulin sensitivity by increasing insulin receptor tyrosine kinase activity, enhancing glycogen synthesis and increasing recruitment and transport of GLUT4 transporters to the plasma membrane. Additionally, it has been shown that metformin affects mitochondrial activities dependent upon the model system studied. Metformin has a mild inhibitory effect on complex I of oxidative phosphorylation, has antioxidant properties, and activates both glucose 6-phosphate dehydrogenase, G6PDH and AMP-activated protein kinase, AMPK. The importance of AMPK in the actions of metformin stems from the role of AMPK in the regulation of both lipid and carbohydrate metabolism (see AMPK: Master Metabolic Regulator for more details). In adipose tissue, metformin inhibits lipolysis while enhancing re-esterification of fatty acids. The activation of AMPK by metformin is likely related to the inhibitory effects of the drug on complex I of oxidative phosphorylation. This would lead to a reduction in ATP production and, therefore, an increase in the level of AMP and as a result activation of AMPK. In fact, since the cells of the gut will see the highest doses of metformin they will experience the greatest level of inhibited complex I which may explain the

gastrointestinal side effects (nausea, diarrhea, anorexia) of the drug that limit its utility in many patients. In adolescent females with type 2 diabetes, the use of metformin is highly recommended to reduce the incidence as well as the potential for polycystic ovarian syndrome, PCOS. PCOS is brought on by the hyperinsulinemia of type 2 diabetes. Insulin effects on the ovary drive conversion of progesterone to testosterone and a reduction in serum hormone binding globulin (SHBG). Taken together, the effects of hyperinsulinemia lead to a hyperandrogenic state in the ovary resulting in follicular atresis and ovulatory dysfunction. 4. The Sulfonylureas: The sulfonylurea and meglitinide classes of oral hypoglycemic drugs are referred to as endogenous insulin secretagogues because they induce the pancreatic release of endogenous insulin. The sulfonylureas have been used in the US for nearly 50 years. The first generation sulfonylureas (tolbutamide, acetohexamide, chlorpropramide and tolazamide) are not routinely prescribed any longer in the US. The second generation sulfonylureas include glipizide (Glucotrol), glimepiride (Amaryl) and glyburide (DiaBeta, Micronase, Glynase). Because all of these drugs can induce pronounced hypoglycemia, treatment is initiated with the lowest possible dose and carefully monitored until the dose is found that results in a FPG of 110-140mg/dL. Sulfonylureas function by binding to and inhibiting the pancreatic ATP-dependent potassium channel that is normally involved in glucose-mediated insulin secretion (see above under insulin function). Sulfonylureas have no significant effects on circulating triglycerides, lipoproteins or cholesterol. 5. The Meglitinides: As indicated, the meglitinides repaglinide (Prandin) and nateglinide (Starlix) are non-sulfonylurea insulin secretagogues that are both fast acting and of short duration. Like the sulfonylureas, meglitinides therapy results in significant reduction in FPG as well as HbA1c. The mechanism of action of the meglitinides is initiated by binding to a receptor on the pancreatic -cell that is distinct from the receptors for the sulfonylureas. However, meglitinides do exert effects on potassium conductance. Like the sulfonylureas, the meglitinides have no direct effects on the circulating levels of plasma lipids. 6. The -Glucosidase inhibitors: -glucosidase inhibitors such as acarbose (Precose) and miglitol (Glyset) function by interfering with the action of the -glucosidases present in the small intestinal brush border. The consequence of this inhibition is a reduction in digestion and the consequent absorption of glucose into the systemic circulation. The reduction in glucose uptake allows the pancreatic -cells to more effectively regulate insulin secretion. The advantage to the use of the -glucosidase inhibitors is that they function locally in the intestine and have no major systemic action. Hypoglycemia does not usually occur with the use of -glucosidase inhibitors but they are effective at reducing fasting plasma glucose (FPG) levels and levels of glycosylated hemoglobin (HbA1c). The common adverse side effects of these inhibitors are abdominal bloating and discomfort, diarrhea and flatulence. back to the top

New Frontiers in Diabetes Therapy

Several new approaches are being taken in the search for treatments for diabetes. These include the development of newer drugs that target the same pathways as described in the sections above including, but not limited to, new classes of DPP IV antagonists and GLP-1 receptor agonists. Additional, potentially exciting targets, include the hepatic-derived fibroblast growth factor 21 (FGF21), the renal sodium-glucose transporter-2 (SGLT2), the NAD+-dependent deacetylase SIRT1 or sirtuin 1, and the lipid binding G-protein coupled receptor GPR119. FGF21 Agonists: Hepatic lipid homeostasis is tightly controlled through the influences of insulin, free fatty acids, sterol regulatory element-binding protein (SREBP), and nuclear receptors and associated regulatory molecules such as the liver X receptors (LXRs) and peroxisome proliferatoractivated receptor (PPAR), respectively. The LXRs are members of the steroid/thyroid hormone superfamily of cytosolic ligand binding receptors that migrate to the nucleus upon ligand binding and regulate gene expression by binding to specific target sequences. There are two forms of the LXRs, LXR and LXR. The LXRs form heterodimers with the retinoid X receptors (RXRs) and as such can regulate gene expression either upon binding oxysterols (e.g. 22R-hydroxycholesterol) or 9-cis-retinoic acid. Recent evidence demonstrated that expression of the fibroblast growth factor family member, FGF21, was significantly elevated in mice fed a high-fat, low-carbohydrate ketogenic diet. Additionally, in mice with experimentally induced reduction in FGF21 expression there was an associated lipemia, reduced ketogenesis and a resultant fatty liver. Conversely, administration of FGF21 to diabetic animals resulted in reductions in the levels of fasting glucose and serum lipids. These results indicate that FGF21 plays a key role in regulating the expression of genes involved in hepatic lipid homeostasis and that activation of FGF21 activity could prove to be a significant tool in the treatment of the disrupted metabolic status in diabetic individuals. SGLT2 Antagonists: A new class of orally administered compounds that targets renal glucose transport and inducers of glucosuria are currently being tested for efficacy in type 2 diabetes treatment. In the kidney, glucose is filtered at the glomerulus and then reabsorbed via active transport in the proximal convoluted tubule. Two sodium-glucose co-transporters (SGLT1 and SGLT2) have been identified as responsible for this renal glucose reabsorption. The SGLT proteins are members of the solute carrier 5 family of membrane transporters, and thus, SGLT1 is SLC5A1 and SGLT2 is SLC5A2. SGLT1 is found in other tissues and accounts for approximately 10% of the renal glucose reabsorption. SGLT2 is expressed exclusively in the S1 segment of the proximal tubule and is responsible for 90% of the renal glucose reabsorption (see Figure below). Therefore, it is postulated that selective inhibition of the renal SGLT2 activity should result in greatly enhanced glucose release in the urine. Several approaches to inhibition of SGLT2 are currently under investigation. The most promising drug at this time is the Bristol-Myers-Squibb compound called dapagliflozin. Dapagliflozin exhibits a high degree of selectivity for SGLT2 inhibition (1000 times greater than on SGLT1). Clinical trials showed a dose-dependent reduction in serum glucose and hemoglobin A1c levels in patients taking the drug compared to placebo controls.

Diagrammatic representation of the re-uptake of glucose in the S1 segment of the proximal tubule of the kidney by the Na+-glucose co-transporter SGLT2. Following re-uptake the glucose is transported back into the blood via the action of GLUT2 transporters. The Na+ that is reabsorbed with the glucose is transported into the blood via a (Na+-K+)-ATPase. SIRT1 Activators: SIRT1 or sirtuin 1 is the homolog of the yeast (S. cerevisiae) Sir2 gene (Sir refers to Silent mating type Information Regulator). SIRT1 is a member of the sirtuin family of proteins (seven members; SIRT1 through SIRT7) that are characterized by a sirtuin core domain and grouped into four classes. The yeast sirtuin proteins are known to regulate life-span extension, epigenetic gene silencing and suppress recombination of ribosomal DNA (rDNA). SIRT1 is an NAD+-dependent deacetylase that modulates the activities of proteins that are in pathways downstream of the beneficial effects of calorie restriction. SIRT1 catalyzes a reaction where hydrolysis of NAD+ is coupled to the deacetylation of acetylated lysines in target proteins. These target proteins include histones, transcription factors and transcription factor co-regulators. The NAD+ is hydrolyzed to nicotinamide (which is a strong inhibitor of SIRT1 activity) and O-acetylADP ribose. Principal pathways involved in glucose homeostasis and insulin sensitivity are affected by SIRT1 activity. In skeletal muscle, a major site of insulin-induced glucose uptake, SIRT1 and AMPK work in concert to increase the rate of fatty acid oxidation in periods of decreased nutrient availability. The plant-derived compound, resveratrol (a polyphenolic compound), is a known activator of SIRT1 function. The effects of resveratrol have been shown to increase mitochondrial content, ameliorate insulin resistance and prolong survival in laboratory mice fed a high-fat diet. Recent studies on the action of SIRT1 agonists have demonstrated that compounds that activate SIRT1, but that are structurally unrelated to resveratrol, also improve insulin sensitivity in adipose tissue, liver and skeletal muscle resulting in lower plasma glucose. The actions of these compounds in laboratory studies indicate the potential efficacy of a therapeutic approach to type 2 diabetes that includes activators of SIRT1 activity.

GPR119 Agonists: The fatty acid-sensing receptor, GPR119, is a Gs G-protein coupled receptor. GPR119 is expressed at the highest levels in the pancreas and fetal liver with expression also seen in the gastrointestinal tract, specifically the ileum and colon. GPR119 is a member of the class A family (rhodopsin-type) of GPCRs. GPR119 binds long-chain fatty acids including oleoylethanolamide (OEA), lysophosphatidylcholine (LPC), various lipid amides, and retinoic acid. OEA is the most potent ligand and likely represents the endogenous ligand for GPR119. The demonstration that OEA is the most active endogenous ligand for GPR119 is of particular interest since previous work has demonstrated that OEA, when administered to laboratory animals, causes a significant reduction in food intake and body weight gain. These effects of OEA are the result of the activation of the nuclear receptor PPAR, increased expression of fatty acid translocase, and modification of feeding behavior and motor activity. In addition, activation of GPR119 in the pancreas is correlated with enhanced glucose-stimulated insulin secretion (GSIS) and activation of the receptor in the gut results in increased secretion of the incretin hormones GLP-1 and GIP. These observations indicate that GPR119 activation is associated with a dual mechanism of reducing blood glucose: acting directly through pancreatic -cells to promote GSIS and in the gut via the stimulation of the incretins GLP1 and GIP both of which increase insulin release from the pancreas in response to food intake. Currently there are several small molecule agonists of GPR119 in clinical trials being tested for their efficacy in treating the hyperglycemia of type 2 diabetes as well as for their efficacy in treating obesity. back to the top

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BIOQUMICA METABLICA II

PROGRAMA

I.- Introduccin al metabolismo Tema 1.- Vias metablicas. Aproximaciones experimentales al estudio del metabolismo. Termodinmica de los compuestos de fosfato. Reacciones de oxidacin-reduccin biolgicas. II.- Metabolismo de los Hidratos de Carbono Tema 2.- Catabolismo anaerobio de las hexosas. Utilizacin de los glcidos de la dieta: digestin y absorcin intestinal. Fases de la glucolisis. Destino anaerobio del piruvato: Fermentaciones. Incorporacin de otras hexosas a la via glucoltica. Fosforilaciones a nivel de sustrato. Control del flujo metablico. Tema 3.- Catabolismo aerobio de las hexosas Descarboxilacin oxidativa del piruvato. Secuencia de reacciones del ciclo del cido ctrico. Regulacin del ciclo. Naturaleza anfiblica del ciclo. Tema 4.- Transporte electrnico y fosforilacin oxidativa. Flujo electrnico mitocondrial. Sntesis de ATP acoplada al transporte de electrones. Oxidacin mitocondrial

del NAD+ citoslico: Sistema de lanzaderas. Nivel energtico celular y regulacin de la fosforilacin oxidativa. Inhibidores y desacoplantes. El gradiente de protones impulsa muchos procesos celulares. Tema 5.- Otras vias de oxidacin de la glucosa. Ruta de las pentosas-fosfato. Fases oxidativa y de isomerizaciones. Regulacin de la fase oxidativa. Relacin entre glucolisisis y la ruta de las pentosas-fosfato.Conversin de glucosa en cido urnico y ascrbico. Tema 6.- Gluconeognesis. Formacin de glucosa a partir de precursores no glucdicos. Ciclos futiles. Regulacin coordinada de glucolisis y gluconeognesis. Gluconeognesis a partir de Acetil-CoA en plantas y microorganismos. Regulacin del ciclo del Glioxilato. Biosntesis de disacridos. Tema 7.- Metabolismo del glucgeno. Papel fisiolgico del glucgeno en los animales. Sntesis y degradacin del glucgeno: Cascada enzimtica de regulacin. Papel del AMPcclico. Tema 8.- Regulacin del metabolismo glucdico. Metabolismo de la glucosa y el glucgeno en el hgado y en el msculo. Niveles de glucosa en sangre y curvas de tolerancia a la glucosa. Regulacin hormonal. Defectos patolgicos en la absorcin de los glcidos de la dieta y en su metabolismo. Tema 9.- Fotosntesis. Importancia biolgica. Fase luminosa de la fotosntesis: pigmentos fotosintticos, complejo antena, sistemas de transporte de electrones, fotosistemas I y II, fotofosforilacin y rendimiento energtico. Fase oscura: fijacin del C02. Biosntesis de sacarosa y almidn. Regulacin del metabolismo glucdico en las plantas. La fotorrespiracin y su significado biolgico. III.- Metabolismo de los Lpidos Tema 10.- Origen y transporte de los lpidos en el organismo. Digestin y absorcin de los lpidos de la dieta. Movilizacin de los lpidos de reserva. Lipoprotenas plasmticas: tipos, estructura, propiedades y funciones. Lipoproteinemias Tema 11.- Catabolismo de los cidos grasos y cetognesis. Activacin de los cidos grasos y transporte a la mitocondria. Papel de la carnitina. Mecanismo de la b-oxidacin. Oxidacin de los cidos grasos de cadena impar. Degradacin de los cidos grasos insaturados. Regulacin de la oxidacin de los cidos grasos. Metabolismo de los cuerpos cetnicos. Regulacin de la cetognesis. Tema 12.- Biosntesis de cidos grasos. Diferencias entre b-oxi- dacin y biosntesis de los cidos grasos. Biosntesis de cidos grasos saturados: fuentes de carbono y NADPH. Complejo de la cido graso-sintetasa. Acidos grasos esenciales Desaturacin y elongacin de los cidos grasos. Regulacin de la biosntesis de los cidos grasos. Tema 13.- Biosntesis de Lpidos. Biosntesis de triacilglicridos. Biosntesis de lpidos de membrana:Fosfoacilglicridos. Fosfoesfingo-lpidos. Glucolpidos. Esfingolipidosis.

Icosanoides e Isoprenoides. Tema 14.- Metabolismo del colesterol. Acetil-CoA como precursor del colesterol. Encrucijada metablica del HMG-CoA. Biosntesis del colesterol. Regulacin del metabolismo del colesterol. El Colesterol como precursor de hormonas y cidos biliares. Colesterinemias. Tema 15.- Regulacin del metabolismo lipdico. Regulacin de la sntesis y almacenamiento. Movilizacin de lpidos de reserva y hormonas movilizadoras. Movilizacin de lpidos hepticos. Interrelaciones del metabolismo lipdico. Ciclo glucosacidos grasos e influencia hormonal. Defectos genticos y alteraciones patolgicas del metabolismo lipdico. IV.- Metabolismo de los compuestos nitrogenados Tema 16- Degradacin de los aminocidos. Utilizacin de las protenas de la dieta: digestin y absorcin intestinal de aminocidos y oligopptidos. Proteolisis intracelular. Ciclo de la urea. Regulacin del ciclo de la urea. Energtica del ciclo de la urea. Defectos genticos del ciclo. Tema 17.- Destino metablico del esqueleto carbonado de los aminocidos. Aminocidos glucognicos y cetognicos. Aminocidos que producen Acetil-CoA. Aminocidos que conectan con el ciclo de Krebs. Principales errores congnitos en el metabolismo de los aminocidos. Tema 18.- Aspectos generales del metabolismo del nitrgeno. Procedencia del nitrgeno orgnico. Procesos de nitrificacin y desnitrificacin: ciclo del nitrgeno. Fijacin biolgica del nitrgeno: la nitrogenasa. Asimilacin del nitrato y nitrito. Incorporacin del amoniaco a los esqueletos carbonados: enzimas implicadas. Regulacin del metabolismo nitrogenado. Tema 19.- Biosntesis de aminocidos y procesos biosintticos relacionados. Aminocidos esenciales y no esenciales. Precursores y rutas de la sntesis de aminocidos. Los aminocidos como precursores de otras biomolculas. Biosntesis y degradacin de porfirinas: etapas principales, regulacin y defectos genticos. Tema 20.- Regulacin del metabolismo de los aminocidos. Principios de la regulacin de la sntesis de aminocidos. Relacin entre el metabolismo glucdico y proteico: ciclo glucosa-alanina. Conversin muscular de valina en alanina. Regulacin hormonal del metabolismo de aminocidos: insulina y glucagn. Tema 21.- Metabolismo de los nucletidos. Biosntesis de purinas y pirimidinas: etapas principales y regulacin. Degradacin de purinas y pirimidinas. Aspectos patolgicos del metabolismo de los nucletidos. V.- Integracin del Metabolismo

Tema 22.- Integracin del metabolismo I. Estrategias generales del metabolismo. Mecanismos frecuentes en la regulacin metablica. Principales vas metablicas y centros de control. Perfiles metablicos de los rganos ms importantes: cerebro, msculo, tejido adiposo e hgado. Tema 23.- Integracin del metabolismo II. Principales mecanismos de regulacin hormonal del metabolismo. Adaptaciones metablicas durante el ejercicio, ayuno, estrs, gestacin y lactancia. Diabetes. Obesidad.

SEMINARIOS 2006:
HIF Insulina UCPs P53 Glucobiologa cidos Grasos Supercomplejos Leptinas

BIBLIOGRAFIA: Herrera, E., "Bioqumica", 2 ed., (1991), Ed. Interamericana-MacGraw-Hill. Horton, R., Moran, L. Och, R., Rawn, D. and Scrimgeour, G., "Principles of Biochemistry", 2th ed., (1996), Ed. Prentice-Hall. Lehninger, A., Nelson, D. y Cox, M., "Principios de Bioqumica", 2 ed., (1993), Ed. Omega. Moran, L. and Scrimgeour, G., "Biochemistry", 2th ed., (1994), Ed. Prentice-Hall. Stryer, L., "Bioqumica", 4 ed., (1995), Ed. Revert. Zubay, G., "Biochemistry", 4th ed., (1998), Ed.

http://www.lumosity.com/personal-training-plan

HORMONA
Un compuesto orgnico sintetizado en pequeas cantidades en un tejido endocrino (glndula o clula endcrina) y transportado por va sangunea a otro tejido (blanco) en el cual acta como un mensajero para regular la funcin de ese tejido u rgano. Para que la hormona pueda actuar sobre los tejidos blancos, debe existir en ellos un receptor especfico para la hormona. Por ejemplo, el calcitriol para actuar en el enterocito debe haber en este un receptor especfico para el calcitriol.

Clasificacin de las hormonas

1. Peptdicas o protenicas: insulina, glucagn. 2. Catecolaminas (derivadas de aminocidos): adrenalina y noradrenalina que son derivadas de la tisorina. 3. Eicosanoides: prostaglandinas, tromboxanos y leucotrienos. 4. Esteroides: testosterona, progesterona y estrgenos. 5. Vitamina D: origina calitriol. 6. Retinoide: cido retinoico derivado de la vitamina A, acta en la diferenciacin celular. 7. Tiroideas: triyodotironina (T3). 8. xido Ntrico: xido ntrico.

Tipos de receptores de Hormonas

Receptores de la membrana plasmtica (para insulina y glucagn por ejemplo y para todas las hormonas que no pueden difundir a travs de la membrana, y actan entonces a travs de mensajeros secundarios como el AMPc). Receptores nucleares: Por ejemplo para calcitriol y cido retinoico y para todos los que pueden difundir a travs de la membrana.

Receptores que se encuentran en el citoplasma: Ocurre lo mismo que en el caso anterior.

La insulina tiene un peso de 5000 Da y se define entre polipptido y protena; se forma por dos cadenas (A y B), que estn unidas por puentes S2 e incluso la cadena A presenta un puente S2 en ella misma. La insulina se sintetiza como una preprohormona, al igual que el Glucagn. Las hormonas polipeptdicas y proticas se sintetizan primero en los ribosomas como una preprohormona, formadas por una sola cadena polipeptdica que se caracteriza en que, al ser una protena que va a ser exportada, es sintetizada por los ribosomas adosados al retculo endoplsmico rugoso (REr) por ser una protena de la va secretoria. Una pre-prohormona tiene en el extremo amino terminal una secuencia seal, formada por un grupo de aminocidos hidrofbicos que tiene como fin pegarse a la membrana del RE para empujar a la protena en formacin hacia dentro del RE, liberndo el pptido seal y la proinsulina queda en el RE y ah, esta cadena de proinsulina viajaa en vesculas a Golgi que lo va a exportar. En el aparato de Golgi, la proinsulina va a sufrir ahora una transformacin ms, que consiste en cortarle el pptido C que es un segmento proteico que se encuentra entre las cadenas A y B de modo que estas quedan separadas, pero se forman los caractersticos puentes S2 entre las cadenas A y B. El pptido C tambin se exporta fuera de la clula. El glucagn se sintetiza en esencia del mismo modo, pero no est constituido por dos cadenas con puentes S2.

Secrecin de insulina por las clulas Beta del pncreas

La clula beta () del pncreas en respuesta a una hiperglicemia, va a tener inducida la glucoquinasa y se realiza la respiracin celular en respuesta al metabolismo de la glucosa y en consecuencia, aumentan las concentraciones de ATP que van a cerrar un canal de K+ que es sensible al ATP y por lo tanto, no se exportar ms con la despolarizacin de la membrana y la entrada de Ca2+ que induce la liberacin del contenido de los grnulos que contienen la insulina en la clula Beta del pncreas. La insulina, adems de participar en el metabolismo va a hacer que los GLUT4 del msculo esqueltico y tejido adiposo se adhieran a la membrana en las clulas de stos

tejidos, favoreciendo la entrada de glucosa a los mismos. Estos GLUT4 se encuentran secuestrados en vesculas que se originaron por fisin de la membrana celular en respuesta a una hipoglicemia anterior. Una vez que se une la insulina a su receptor, va a haber toda una transduccin de seales que hace que la reserva intracelular de GLUT4 en vesculas, se exprese en la membrana por la fusin de las vesculas con la membrana celular. Cuando se presenta una hipoglicemia nuevamente, los GLUT4 se introducen a la clula en los endosomas o vesculas. Expresin de genes, regulacin del crecimiento, utilizacin de glucosa, sntesis de glucgeno, de lpidos, de protenas, son todas funciones consecuentes de la unin de la insulina a su receptor. Se le conoce a la insulina por algunos de sus efectos metablicos, una hormona anablica o anabolizante. Efectos de la insulina sobre la glucosa sangunea, es capturar glucosa por las clulas y almacenamiento como triglicridos y glucgeno. 1. En hgado, el transportador de glucosa no es dependiente de insulina. Las tres enzimas que catalizan las reacciones reguladoras de gliclisis en hgado son estimuladas por glucosa. 2. Afecta la sntesis de Glucgeno porque favorece la defosforilacin de la glucgeno sintasa que se activa por defosforilacin. 3. Disminuye la glucogenlisis al favorecer la defosforilacin y consecuente inactivacin de la glucgeno fosforilasa. 4. La insulina va a favorecer la gliclisis y la produccin de Acetil-CoA en msculo, y esto lo hace activando a la PFK-1 porque activa a la PFK-2 que produce fructosa2,6-bifosfato que activa a la PFK-1. En hgado, por medio de la gliclisis es producir acetil-CoA para formar cidos grasos. 5. Activando a la acetil-CoA carboxilasa por defosforilacin activa la sntesis de lpidos (la insulina es lipognica). 6. Favorece la sntesis de triglicridos en el tejido adiposo porque va a favorecer la lipoproteinlipasa y por otro lado va a inhibir la lipasa sensible a hormonas que se activa por fosforilacin. El tejido adiposo depende de la gliclisis que se lleve a cabo en l mismo para la obtencin del glicerol-3-P.