Slide 1

Pathophysiology of DM
Topics:
Aetiology
Pathophys of hyperglycaemia complications


I talk more on the pathophys of hyperglycaemic complications than the pathogenesis of DM
itself (because its boring and not much is known, read Kumar if you really want to know)



Slide 2

Causes/Types of DM
Type 1 (IDDM):
5-10% of diabetics
Characterised by pancreatic -cell destruction and absolute deficiency of insulin
Caused by combo of genetic, immunological and environmental stimuli causing
auto-immune destruction of -cells
Auto-antigens responsible arent necessarily always -cell specific?
Type 2 (NIDDM):
90-95% of diabetics
Combination of peripheral resistance to insulin and inadequate insulin secretion
Caused by insulin resistance which is initially compensated by increased insulin
secretion, but eventually becomes uncompensated
Has a stronger genetic component, but is polygenic/multifactorial
Gestational
Others


Type 1 DM is an autoimmune disease characterized by pancreatic -cell destruction and an
absolute deficiency of insulin. It accounts for approximately 5% to 10% of all cases, and is the
most common subtype diagnosed in patients younger than 20 years of age. Polymorphisms in
the HLA complex account for 4050% of the genetic risk of developing type 1 DM and primarily
involve the DR3/4 and some of the DQ phenotypes.

Type 2 DM is caused by a combination of peripheral resistance to insulin action and an
inadequate secretory response by the pancreatic cells (relative insulin deficiency).
Approximately 90% to 95% of diabetic patients have type 2 diabetes, and the vast majority of
such individuals are overweight/obese. Although classically considered adult-onset, the
prevalence of type 2 diabetes in children and adolescents is increasing at an alarming pace.

A more in-depth pathophys analysis of NIDDM aetiology: Type 2 DM is characterized by
impaired insulin secretion, insulin resistance, excessive hepatic glucose production, and
abnormal fat metabolism. Obesity, particularly visceral or central (as evidenced by the hip-waist
ratio), is very common in type 2 DM (80% or more are obese). In the early stages of the
disorder, glucose tolerance remains near-normal, despite insulin resistance, because the
pancreatic beta cells compensate by increasing insulin output. As insulin resistance and
compensatory hyperinsulinemia progress, the pancreatic islets in certain individuals are unable
to sustain the hyperinsulinemic state. IGT, characterized by elevations in postprandial glucose,
then develops. A further decline in insulin secretion and an increase in hepatic glucose
production lead to overt diabetes with fasting hyperglycemia. Ultimately, beta cell failure
ensues.




Slide 3

Causes/Types of DM
American Diabetes Association:
Position statement from the American
Diabetes Association on the diagnosis
and classification of diabetes mellitus.


A variety of monogenic and secondary causes are responsible for the non-Type I/II cases. It
should be stressed that while the major types of diabetes have different pathogenic
mechanisms, the long-term complications affecting the kidneys, eyes, nerves, and blood vessels
are the same, as are the principal causes of morbidity and death. The pathogenesis of the two
major types is discussed separately, but first we briefly review normal insulin secretion and the
mechanism of insulin signaling, since these aspects are critical to understanding the
pathogenesis of diabetes.

Note MODY mentioned in lecture



Slide 4

Pathophys of Hyperglycaemia
Complications
Chronic:
Advanced Glycation End-Products
Activation of PKC
Polyol Pathway Disturbance
Hexosamine Pathway
Acute:
Diabetic Ketoacidosis
Hyperglycaemic Hyperosmolar State
Crash Course!


The morbidity associated with long-standing diabetes of either type results from several serious
complications, caused mainly by lesions involving both large- and medium-sized muscular
arteries (macrovascular disease) and capillary dysfunction in target organs (microvascular
disease). Macrovascular disease causes accelerated atherosclerosis among diabetics, resulting
in increased risk of myocardial infarction, stroke, and lower extremity gangrene. The effects of
microvascular disease are most profound in the retina, kidneys, and peripheral nerves, resulting
in diabetic retinopathy, nephropathy, and neuropathy, respectively.

At least three distinct metabolic pathways have been implicated in the deleterious effects of
persistent hyperglycemia on peripheral tissues, although the primacy of any one over the others
is unclear. The pathways are discussed below.



Slide 5

Diabetic Ketoacidosis (DKA)


Someone else



Slide 6

Hyperglycaemic Hyperosmolar State
Typical HHS:
elderly individual with type 2 DM
Several-week history of polyuria, weight loss, and diminished oral
intake
Culminates in mental confusion, lethargy, or coma.
Ex: profound dehydration and hyperosmolality and reveals
hypotension, tachycardia, and altered mental status.
High BGL Glycosuria
High Blood
Osmolarity
Dehydration
of Cells
CNS Failure


Coma in diabetes can be due to acidosis and dehydration. However, the plasma glucose can be
elevated to such a degree that independent of plasma pH, the hyperosmolarity of the plasma
causes unconsciousness (hyperosmolar coma). Accumulation of lactate in the blood (lactic
acidosis) may also complicate diabetic ketoacidosis if the tissues become hypoxic, and lactic
acidosis may itself cause coma. --- CNS sensitive to osmolarity

Cause:
When a person with a very high (usually considered to be above 300 mg/dl (16 mmol/L)) BGL,
water is osmotically drawn out of cells into the blood and there is glycosuria. This results in loss
of water and an increase in blood osmolarity. If fluid is not replaced, the osmotic effect of high
glucose levels, combined with the loss of water, will eventually lead to dehydration. The body's
cells become progressively dehydrated as water is taken from them and excreted and
electrolyte imbalances are also common.



Slide 7

Advanced Glycosylation End-Products
Elevated intracellular levels of glucose cause a non-enzymatic covalent
bonding with proteins, which alters their structure and inhibits their function.
AGE cause:
Bind to AGE receptors (RAGE) on leukocytes, endothelium and
vascular smooth muscle
Cross-link proteins (esp ECM)
Effects:
Cytokines from intimal macrophages
ROS in endothelium
Procoagulant activity
Proliferation of SM and ECM synthesis
Decreased vessel elasticity
Proteolytic resistance and protein
deposition enhancement
Reduce NO synthesis
Endothelial Dysfunction
Glomerular dysfunction
Contribution to microangiopathy
and hence neuropathy


Increased intracellular glucose leads to the formation of advanced glycosylation end products
(AGEs), which bind to a cell surface receptor, via the nonenzymatic glycosylation of intra- and
extracellular proteins. Nonenzymatic glycosylation results from the interaction of glucose with
amino groups on proteins.



Slide 8

Activation of PKC
Hyperglycaemia stimulates synthesis of DAG from glycolytic
intermediates (DAG required for PKC activation)
Abnormal PKC activity causes:
Production of proangiogenic vascular endothelial growth factor (VEGF),
implicated in the neovascularization characterizing diabetic retinopathy

Elevated levels of endothelin-1 and decreased levels of NO, due to
decreased expression of endothelial nitric oxide synthase

Production of profibrogenic factors like TGF-, leading to increased
deposition of extracellular matrix and basement membrane material

Production of PAI-1, leading to reduced fibrinolysis and possible
vascular occlusion

Production of pro-inflammatory cytokines by the vascular endothelium


Activation of intracellular protein kinase C (PKC) by Ca
*2+
+ ions and the second messenger diacyl
glycerol (DAG) is an important signal transduction pathway in many cellular systems.
Intracellular hyperglycemia stimulates the de novo synthesis of DAG from glycolytic
intermediates, and hence causes activation of PKC. The downstream effects of PKC activation
are numerous.

It should be evident that some effects of AGEs and activated PKC are overlapping, and both
contribute to the long-term complications of diabetic microangiopathy.




Slide 9

Polyol Pathway Disturbance
Some tissues dont require insulin for glucose
transport nerves, lenses, kidneys, blood vessels
ICF Glucose
Glycolysis etc
Sorbitol
Aldose Reductase
Effects:
Redox potential -> ROS generation
Inc cellular osmolality
NADPH NAD
NADPH required for reduced
glutathione regeneration (antioxidant)


In some tissues that do not require insulin for glucose transport (e.g., nerves, lenses, kidneys,
blood vessels), persistent hyperglycemia in the extracellular milieu leads to an increase in
intracellular glucose. Hyperglycemia increases glucose metabolism via the sorbitol pathway.
Intracellular glucose is predominantly metabolized by phosphorylation and subsequent
glycolysis, but when increased, some glucose is converted to sorbitol by the enzyme aldose
reductase. Increased sorbitol concentration alters redox potential, increases cellular osmolality,
generates reactive oxygen species. Minimal effect though?



Slide 10

Hexosamine Pathway
ICF hyperglycaemia increases flux through the hexosamine
pathway via F6P synthesis (glycolysis intermediate).
-> O-linked glycosylation and proteoglycan production
Effects:
Glycosylation of endothelial NO synthase
Changes in gene expression of TGF and PAI-1


A fourth theory proposes that hyperglycemia increases the flux through the hexosamine
pathway, which generates fructose-6-phosphate, a substrate for O-linked glycosylation and
proteoglycan production that alters signalling pathways and TF inductino. The hexosamine
pathway may alter function by glycosylation of proteins such as endothelial nitric oxide synthase
or by changes in gene expression of transforming growth factor (TGF-) or plasminogen activator
inhibitor-1 (PAI-1).



Slide 11

Synthesis of Everything
= everything goes wrong


I was going to go through an example (e.g. Diabetic retinopathy) that went through it all, but it
would have taken all day. Wikipedia is actually quite accurate on each topic



Slide 12

Lecture material, 2012
Harrison's Online
Boron: Medical Physiology, Updated Edition, 2nd ed.
Kumar: Robbins and Cotran Pathologic Basis of Disease, Professional
Edition, 8th ed.
Hall: Guyton and Hall Textbook of Medical Physiology, 12th ed.
Something else I forgot to write down
References




Endocr i ne Phy si ol og y, 3e > Chapt er 7. Endocrine Pancreas >
OBJECTI VES
I dent ify t he principal hormones secret ed from t he endocrine pancreas, t heir cells of or igin, and t heir chemical nat ure.
Underst and t he nut rient , neural, and hormonal mechanisms t hat r egulat e pancreat ic hormone r elease.
List t he pr inci pal t arget organs for insulin and glucagon act ion and t hei r maj or physiologic effect s.
I dent ify t he t ime course for t he onset and durat ion of t he biologic act ions of insulin and glucagon.
I dent i f y t he disease st at es caused by oversecret i on, undersecret i on, or decreased sensi t i vit y t o i nsul in, and descr ibe t he
pri ncipal manif est at i ons of each.
ENDOCRI NE PANCREAS: I NTRODUCTI ON
The pancreas is a mixed exocrine and endocr ine gland t hat plays a cent r al rol e in digest ion and in t he met abol ism, ut ili zat ion,
and st or age of energy subst rat es. Normal pancreat ic funct ion involving t he product ion and release of t he hormones insulin and
glucagon is essent ial for t he physiol ogic cont rol of glucose homeost asis. This chapt er focuses on t he endocrine funct ion of t he
pancr eas t hrough t he r elease of insulin and glucagon and t he mechanisms by which t hese hormones regulat e event s cent ral t o
mai nt aining glucose homeost asi s. Mai nt enance of gl ucose homeost asi s is similar t o t he mai nt enance of calcium balance
discussed in Chapt er 6, in which several t issues and hor mones int er act in t he r egulat ory process. I n t he case of glucose, t he
process i nvolves a regulat ed bal ance among hepat i c gl ucose rel ease ( f rom glycogen breakdown and gl uconeogenesi s) , diet ary
glucose absorpt ion, and glucose upt ake and disposal from skel et al muscl e and adi pose t issue. The pancreat ic hormones insulin
and glucagon play cent r al roles i n r egulat ing each of t hese processes and t hei r overall effect s are in part modified by ot her
hormones such as growt h hormone, cort isol, and epinephr ine. I n addit ion t o secret ing insulin and glucagon, t he endocr ine
pancr eas also secr et es somat ost at in, amyli n, and pancr eat i c pol ypept ide.
FUNCTI ONAL ANATOMY
The pancreas is a ret roperit oneal gland divided i nt o a head, body, and t ail and is l ocat ed near t he duodenum. Most of t he
pancr eat i c mass i s composed of exocr ine cel ls t hat are cl ust er ed i n lobul es ( aci ni) divided by connect ive t i ssue and connect ed
t o a duct t hat drains i nt o t he pancreat ic duct and int o t he duodenum. The product of t he pancreat ic exocrine cells is an
al kaline fluid rich wit h digest ive enzymes, which is secret ed int o t he small int est ine t o aid in t he digest ive process. Embedded
wit hi n t he acini ar e ri chly vasculari zed, small clust ers of endocri ne cell s cal led t he i sl et s of Langer hans, in which 2 endocrine
cell t ypes ( and ) predominat e. The - cells const it ut e about 7375% of t he t ot al mass of endocrine cells, and t heir principal
secr et or y pr oduct is i n sul i n . The - cells account for about 1820% of t he endocrine cells and ar e responsible for gl ucagon
secret ion. A small number of - cells ( 46%) secret e somat ost at i n, and an even smaller number of cells ( 1%) secret e
pancr eat i c pol ypept i de. The localizat ion of t hese cell t ypes wit hin t he islet s has a part icular pat t er n, wit h t he - cell s locat ed
cent rally, surrounded by - and - cel ls. This arrangement plays a r ole in t he cell- t o- cel l paracr ine r egulat ion of hor mone
r el ease.
The ar t er ial blood suppl y t o t he pancr eas i s deri ved f rom t he spleni c art ery and t he super ior and i nf eri or pancreat icoduodenal
art eri es. Al t hough i sl et s r epresent only 12% of t he mass of t he pancr eas, t hey receive about 1015% of t he pancreat ic blood
flow. The rich vascularizat ion by fenest rat ed capillaries al lows ready access t o t he cir culat ion for t he hormones secret ed by t he
isl et cells. The direct ion of blood flow is prefer ent iall y from t he cent er of t he isl et t o t he periphery. Therefor e, - and - cells
are exposed t o high concent rat ions of hormones produced by t he - cel ls ( ie, i nsulin) , cont r ibut ing t o t he inhibit i on of glucagon
r elease by hi gh local insulin concent rat ions. Venous blood from t he pancreas drains int o t he hepat ic port al vein. Ther efore, t he
liver , a principal t arget organ for t he physiologic effect s of pancreat ic hormones, is exposed t o t he hi ghest concent rat ions of
pancr eat i c hor mones. Fol lowing fi rst - pass hepat ic met abolism, t he pancreat ic endocrine hormones are dist r ibut ed t o t he
syst emi c ci rculat i on.
Parasympat het ic, sympat het i c, and sensory nerves ri chly innervat e t he pancr eat i c i slet s, and t he respect i ve neurot ransmi t t ers
and neuropept ides released from t heir nerve t erminals exert import ant r egulat ory effect s on pancreat ic endocrine hor mone
r el ease. Acet ylchol ine, vasoact i ve i nt est i nal polypept i de, pi t uit ar y adenylat e cyclaseact ivat i ng pol ypept ide, and gast ri n-
r el easi ng pept i de ar e rel eased f rom t he parasympat het ic ner ve t er mi nals. Norepi nephri ne, galanin, and neuropept i de Y are
r el eased f rom sympat het i c nerve t erminals. Vagal ner ve act ivat ion st i mulat es t he secr et i on of i nsulin, glucagon, somat ost at in,
and pancreat ic polypept i de. Sympat het ic nerve st imul at ion inhibit s basal and gl ucose- st imulat ed insuli n secret ion and
somat ost at i n rel ease and st imulat es glucagon and pancreat i c pol ypept ide secr et i on.
PANCREATI C HORMONES
I nsul i n
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I NSULI N SYNTHESI S
The process involved in t he synt hesis and release of insul in, a polypept ide hormone, by t he - cell s of t he pancreas is similar t o
t hat of ot her pept ide hormones, as discussed in Chapt er 1 ( Figure 15) . Preproi nsuli n undergoes cl eavage of it s signal pept i de
dur ing i nser t ion int o t he endoplasmi c ret i culum, generat ing proinsul in ( Figur e 71) . Proinsul in consist s of an amino- t erminal -
chain, a carboxy- t er minal - chain, and a connect ing pept ide in t he middle known as t he C- pept i de. C- pept i de l i nks t he - and
- chains, allowing proper folding of t he molecule and t he format ion of disulfide bonds bet ween t he 2 chains. I n t he
endopl asmi c ret icul um, pr oinsuli n i s processed by specif i c endopept i dases known as prohormone conver t ases, which cleave
t he C- pept ide t o generat e t he mat ure form of insul in. Removal of t he C- pept ide exposes t he end of t he insulin chai n t hat
int er act s wit h t he insulin recept or . I nsulin and t he fr ee C- pept ide are packaged int o secret ory granules in t he Golgi apparat us
and are released t oget her. These secret or y gr anules accumulat e in t he cyt oplasm. About 5% of t he granules ar e st or ed in a
r eadily releasable pool. Most of t he granul es ( more t han 95%) belong t o a reserve pool and need t o be chemicall y modified, or
even physi call y t r ansl ocat ed, t o become i mmedi at el y avail able f or release. Thi s rel ease of i nsul in granules f rom dif ferent pools
leads t o a biphasic pat t ern of insul in release in r esponse t o st imulat ion of t he - cell by glucose. Only a small pr oport ion of t he
cel lular st ores of insuli n are released even under maximal st i mulat ory condit ions.
St imulat ion of t he pancreat i c - cell leads t o exocyt osis of t he cont ent s of t he secret or y gr anules, wit h t he result ing release of
equal amount s of insulin and C- pept ide int o t he port al circulat ion. I nsuli n circulat es in it s fr ee form and has a half - life of 38
minut es. I nsuli n l evel s i n t he cir culat i on average 43186 pmol/ L ( 626 U/ mL) i n t he f ast i ng st at e. I nsul i n i s degr aded
Fi gu r e 71.
A. I nsulin synt hesis st art s wit h t he t ranslat ion of insulin mRNA int o an inact ive prot ein called preproinsulin. Preproinsulin under goes
post - t ranslat ional modificat ion in t he endoplasmic ret iculum ( ER) t o for m proinsulin. The act ive for m of insulin is produced by
modificat ion of proinsulin by cleavage of t he C- pept ide st ruct ur e linking t he and chains. I nsulin is composed of 2 chains; an chain
of 21 amino acids and a chain of 30 amino acids. The chains are held t oget her by 2 disulfi de ( S- S) bonds. A t hird disulfide bond is
pr esent wit hin t he chain. Bot h insulin and t he cleaved C- pept ide ar e packaged in secret ory granules, which accumulat e in t he - cell
cyt osol and are coreleased in response t o glucose st imulat ion. B. I nsulin release occurs in a biphasic mode and is derived from secret ory
gr anules t hat ar e immediat ely available for release ( < 5%) , from granules t hat must undergo a series of preparat ory react ions including
mobilizat ion t o t he plasma membrane ( > 95%) . These gr anule pr eparat ory or mat urat ion processes are modulat ed by int racellular levels
of ATP, ADP and, Ca
+ +
. C. I nsulin release in response t o a meal is charact erized by increased frequency and amplit ude of pulsat ile
release. Shown are port al insulin concent rat ions dur ing basal st at e (left ) and aft er ingest ion of a mixed meal ( right ) in normal pat ient s.
( Reproduced, wit h permission, from: Porksen N, Groft e T, Gr eisen J, Mengel A, Juhl C, Veldhuis JD, Schmit z O, Rossle M, Vilst rup H.
Human insuli n release pr ocesses measured by int raport al sampling. Am J Physiol Endocrinol Met ab. 2002; 282( 3) : E695E702. Figur e 4
of art icle.)
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predominant ly by t he liver dur ing it s first pass, which ext ract s about 4080% of insulin delivered. Addit ional degradat ion of
insulin occurs in t he kidneys as well as at t arget t issues by insul in prot eases following endocyt osis of t he recept or - bound
hormone. C- pept ide, which was pr eviously t hought t o be biologically inert , appears t o have some biol ogical act ion as recent
evidence indicat es t hat replacement of C- pept ide improves renal funct ion and nerve dysfunct ion in pat ient s wit h t ype 1
diabet es. The recept or and signal ing mechani sms invol ved i n medi at ing t hese responses ar e st il l under invest i gat i on. The
impor t ance of C- pept i de is t hat unli ke insuli n, it is not readi ly degraded i n t he li ver. Thus, t he relat i vely l ong hal f- li f e of t he
pept ide ( 35 minut es) al lows it s release t o be used as an index of t he secret ory capacit y of t he endocrine pancreas.
The amino acid sequence of i nsulin i s highl y conserved among species. I n t he past , porcine and bovine insulin wer e used t o
t reat pat ient s wi t h di abet es. Curr ent l y, human r ecombi nant insul in is avai labl e and has replaced animal - der ived insulin,
avoiding pr oblems such as t he development of ant ibodies t o nonhuman i nsulin.
REGULATI ON OF I NSULI N RELEASE
The rel ease of i nsulin t hroughout t he day is pulsat ile and rhyt hmic in nat ur e; 2 i dent ifiable rhyt hms occur wit h per iods
of 510 and 60120 minut es ( Figur e 71) . The pulsat ile release of insulin is impor t ant for achieving maximal physiologic
effect s. I n part icul ar , it appear s t o be crit ical in t he suppr ession of li ver glucose product ion and in insulin- mediat ed gl ucose
disposal by adipose t issue. I nsul in release rises aft er a meal in response t o t he increases in plasma levels of glucose and
amino acids. Secret ion is t he result of a combinat ion of an i ncrease in t he t ot al amount of insulin released in each secret ory
bur st ( by about 50%) and an i ncreased pulse fr equency of a similar magnit ude Figure 71) . The synchronized increase in
insulin r elease is t hought t o be t he r esult of recruit ment of - cells t o release insuli n. Alt hough it is not clear how t he - cell s
communicat e wit h each ot her t o synchronize t he r elease of insuli n, some of t he proposed mechanisms incl ude gap j unct ions
bet ween t he pancreat ic - cel ls, all owi ng t he passage of ions and smal l mol ecules; membrane depolari zat ion, aiding t he
pr opagat ion of t he synchronizat ion bet ween t he cells; and glucose- induced changes in t he ext r acellular pot assium
concent rat ion and in nit ric oxide. I n addit ion, int rapancreat ic neural, hor monal , and subst rat e fact ors have been shown t o play
an import ant role in t he pulsat ile pat t er n of i nsul in release.
The pancreat ic - cell funct ions as a fuel sensor t hat r esponds t o changes in plasma levels of energy subst r at es
r el easi ng insuli n in response t o int egrat ed si gnals f r om nut r ient s ( gl ucose and ami no aci ds) , hor mones ( i nsul in, glucagon- l ike
pept ide- 1 ( GLP- 1) , somat ost at in, and epinephrine) , and neurot r ansmit t er s ( norepinephr ine and acet ylcholine) ( Figur e 72) .
Gl ucose is t he pri ncipal st i mulus f or i nsuli n r el ease fr om t he pancr eat i c - cell s, and in addit ion exert s a permissive effect for
t he ot her modulat ors of i nsul i n secret i on.
Fi gu r e 72.
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The gl ucose- induced st imulat ion of insulin release is t he result of glucose met abolism by t he - cell , t he gener at ion of
met abolic int ermediat es, an i ncrease in t he ATP/ ADP rat io i n t he cyt osol, and a ri se in int racellular Ca
2+
( Figure 73) . Glucose
ent er s t he - cell t hrough a membrane- bound glucose t ransport er ( GLUT- 2) . Once inside t he - cel l, t he enzyme gl ucokinase
phosphorylat es glucose in t he init ial st ep of glycolysis, leading event ually t o t he generat i on of acet yl- coenzyme A ( CoA) and
adenosine t ri phosphat e ( ATP) by t he Krebs cycle. The r esul t i ng increase i n i nt racell ul ar ATP l evel s inhibit s ( cl oses) t he ATP-
sensi t ive K
+
channels ( K
ATP
) i n t he - cell, reduci ng t he efflux of K
+
. This process r esult s in membrane depolari zat i on,
act ivat ion ( openi ng) of volt age- dependent Ca
2+
channels, and increased Ca
2+
influx. The ri se in int racellular Ca
2+
concent rat ions t riggers t he exocyt osis of insul in secret ory granules and t he release of insulin int o t he ext racellul ar space and
int o t he circulat ion. I t is i mport ant t o not e t hat t he regulat ion of K
+
channels by ATP is mediat ed by t he sulfonylurea recept or.
This is t he basis for t he t herapeut ic use of sulfonylur ea dr ugs in t he t reat ment of diabet es.
Regulat ion of insulin release. Glucose is t he principal st imulus for insulin release from t he pancreat ic - cell. Glucose ent er s t he - cell by
a specific glucose- t ransport er pr ot ein ( GLUT- 2) and is immediat ely phosphorylat ed by glucokinase. Format ion of glucose- 6- phosphat e in
t he first st ep of glycolysis init iat es t he glycolyt ic met abolism of glucose f ollowed by t he Krebs cycle leading t o generat ion of adenosine
t riphosphat e ( ATP) . The increased concent r at ions of ATP and result ing gr eat er ATP/ adenosine diphosphat e ( ADP) rat io leads t o inhibit ion
and closure of t he ATP- sensit ive K
+
channels ( t he t arget of sulfonylurea drugs), result ing in depolar izat ion of t he plasma membrane and
opening of t he vol t age- dependent Ca
2+
channels. As a result , t her e is an increased influx of ext racellular Ca
2+
as well as mobilizat ion of
Ca
2+
f rom int racellular st ores leading t o t he fusion of insulin- cont aining secr et ory granules wit h t he plasma membrane and t he r elease
of insulin ( and C- pept ide) int o t he circulat ion. Addit ion fact ors can also st imulat e insulin release from t he - cell, including hormones
( glucagon- like pept ide- 1) and neur ot ransmit t er s ( acet ylcholine) . Glucose syner gizes wit h t hese mediat ors and enhances t he secret ory
response of t he - cell t o t hese fact ors. AC, adenylat e cyclase; CCK, cholecyst okinin; GLP- 1, glucagon- like pept ide- 1; PLC, phospholipase
C. ( Modified, wit h permission, from Faj ans SS et al. Mechanisms of disease: Molecular mechanisms and clinical pat hophysiology of
mat urit y- onset diabet es of t he young. NEJM. 2001; 345: 971. Copyright Massachuset t s Medical Societ y. All right s reserved.)
Fi gu r e 73.
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The - cel l Ca
2+
concent rat ions can also be elevat ed by amino acids t hrough t heir met abol ism and ATP generat ion, or by direct
I nsulin- recept or signaling. I nsulin binding t o t he recept or act ivat es t he int rinsic kinase act ivit y of t he int racellular domain of t he
recept or. This result s in downst ream act ivat ion of cellular event s mediat ed t hrough t he phosphorylat ion of insulin recept or subst r at es.
Signaling pat hways including t he phosphat idyli nosit ol- 3- kinase ( PI
3
- K) and t he mit ogen- act ivat ed prot ein kinase ( MAPK) cascades
cont ribut e t o t he over all effect s of insulin. As shown in t he insert , one of t he immediat e effect s of insulin is t he act ive recruit ment of
GLUT- 4, st ored in int racellular vesicles t o t he cell sur face. I nsulin binds t o it s recept or in t he plasma membrane, result ing in
phosphorylat ion of t he recept or and insulin- recept or subst rat es such as t he I RS molecules. These subst r at es form complexes wit h
docking prot eins such as phosphoinosit ide- 3- kinase at it s 85-kDa subunit ( p85) by means of SH2 ( Scr homology region 2) domains.
Then p85 is const it ut ively bound t o t he cat alyt ic subunit ( p110) . Act ivat ion of phosphoinosit ide- 3- kinase is a maj or pat hway in t he
mediat ion of insulin- st imulat ed glucose t ranspor t and met abolism. Exercise can also st imulat e glucose t r ansport by pat hways t hat are
independent of phosphoinosi t ide- 3- kinase and t hought t o involve 5' - AMP- act ivat ed kinase. ( Reproduced, wit h permission, from
Shepherd PR, Kahn BB. Glucose t r ansport ers and insulin act ion: I mplicat ions for insulin r esist ance and diabet es mellit us. NEJM.
1999; 341( 4) : 248257. Copyright Massachuset t s Medical Societ y. All right s reserved.)
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depolarizat ion of t he plasma membrane. Ot her fact ors ( shown in Figur e 72) t hat amplify t he glucose- i nduced rel ease of
insulin f rom t he - cell incl ude acet yl choli ne, chol ecyst okinin, gast roi nt est inal pept ide, and GLP- 1. These subst ances all bind t o
cell surface recept ors and act ivat e adenylat e cycl ase and phospholipase C. Acet ylcholine and cholecyst okinin promot e
phosphoinosit ide breakdown, wit h a consequent mobilizat ion of Ca
2+
from int racellular st or es, Ca
2+
influx acr oss t he cel l
membrane, and act ivat ion of prot ein kinase C. GLP- 1 raises l evels of cycli c adenosi ne monophosphat e ( cAMP) and act ivat es
cAMP- dependent prot ein kinase A. The subsequent generat ion of cAMP, inosit ol 1, 4, 5- t r isphosphat e, diacylglycer ol, and
arachidonic acid and t he act ivat ion of prot ein kinase C amplify t he Ca
2+
signal by decreasing Ca
2+
upt ake by cel lul ar st ores
and pr omot ing bot h t he phosphor ylat ion and act ivat ion of prot eins t hat t rigger t he exocyt osis of insulin. Cat echolamines and
somat ost at in inhibit insulin secr et ion t hrough G prot eincoupl ed recept or ( GPCR) mechanisms, i nhi bi t ion of adenylat e cycl ase,
and modificat ion of Ca
2+
and K
+
channel gat ing.
The short - t erm regulat ion of insulin release is mediat ed t hrough modificat ion of proi nsulin mRNA t ranslat ion. Over longer
per iods, glucose also increases pr oinsulin mRNA cont ent by bot h st imulat ing pr oinsulin gene t r anscript ion and st abilizing t he
mRNA. As ment ioned above, t he release of i nsul in in response t o glucose is biphasi c, wit h an init i al rapid r elease of prefor med
insulin followed by a more sust ained release of newly synt hesized insulin. An elevat ion in plasma glucose concent rat ions is
fol lowed by a t ransi ent st imulat ion of i nsulin secr et ion known as " f i r st - phase secr et i on, " which consist s of a rapid burst of
r elease t o a high peak and t hen a st eep decline t o a low secret ion rat e. This is fol lowed by " secon d- phase secr et i on," which
consi st s of a gradual ly increasing rat e of secret ion t o a plat eau level. Thi s biphasic response t o glucose is a maj or
charact eri st i c of gl ucose- st imulat ed insulin secret ion. The first phase occurs over a period of minut es, t he second over an hour
or more. Several hypot heses have been proposed t o explain t he biphasic nat ure of insul in secret ion. The mechanism may
involve insuli n r elease fr om 2 separ at e pool s of granules, wit h t he first phase repr esent ing t he readily r eleasable pool of -
granul es al ready docked at t he - cell pl asma membrane t hat does not require addi t i onal movement al ong micr ot ubules. The
second phase would require mobil izat ion of - granules from a st or age pool t o repleni sh t he readily r eleasable pool of -
granul es bef ore - granule docking and exocyt osis.
PHYSI OLOGI C EFFECTS OF I NSULI N
I nsul in produces a wide variet y of effect s t hat range from immediat e ( wit hin seconds) , such as t he modulat ion of ion ( K
+
) and
glucose t ranspor t int o t he cell; early ( wit hin minut es) , such as t he regulat ion of met abolic enzyme act ivit y; moderat e ( wit hin
minut es t o hours) , such as t he modul at ion of enzyme synt hesis; t o delayed ( wit hin hours t o days) , such as t he effect s on
growt h and cellular differ ent iat ion. Overall , t he act ions of insulin at t ar get organs ar e anabolic and promot e t he synt hesis of
car bohydr at e, fat , and prot ein, and t hese effect s ar e mediat ed t hrough binding t o t he insulin recept or ( Table 71) .
I NSULI N RECEPTOR
The insulin recept or is part of t he insulin- r ecept or f amil y, which i ncludes t he i nsul i n recept or , t he i nsul i n- l ike growt h- fact or
r ecept or , and t he i nsulin- r el at ed r ecept or, all of which are invol ved i n cel l di vi si on, met aboli sm, and devel opment ( Figure 73) .
The insuli n recept or is a het er ot et ramer ic glycoprot ei n membrane recept or composed of 2 - and 2 - subunit s, linked by
disulfide bonds. The - chain i s t he ext r acellular port ion and is t he sit e for insulin binding. The - chai n consist s of a short
ext racel lul ar region, a t ransmembr ane segment , and an int r acel lular segment t hat has int ri nsic t yrosine kinase act ivit y
cont r oll ed by i nsul i n bindi ng t o t he ext racel lul ar - subuni t .
I nsul in bi nding t o t he recept or t riggers recept or aut ophosphorylat i on on t yrosi ne residues in t he cyt opl asmic domain ( - chain) .
The act ivat ed recept or phosphorylat es t yrosine residues of several prot eins known as i nsul i n- r ecept or su st r at es ( I RS- 1, -
2, - 3, - 4) . These I RS prot eins facilit at e t he int er act ion of t he insulin recept or wit h int racellular subst rat es by serving as a
Ta l e 7 1. I nsul i n Ef f ect s on Car ohy dr at e, Fat , and Pr ot ei n Met a ol i sm
Met a ol i c ef f ect s I nsu l i n st i mul at es I nsu l i n i n hi i t s
Carbohydr at e
met abol ism
Gl ucose t r anspor t in adipose t issue and muscl e
Rat e of gl ycol ysi s i n muscle and adi pose t i ssue
Glycogen synt hesis in adipose t issue, muscle, and
li ver
Gl ycogen breakdown i n muscle and li ver
Rat e of gl ycogenolysis gluconeogenesis in t he
li ver
Li pi d met abol ism Fat t y aci d and t ri acyl gl ycerol synt hesis i n t issues
Upt ake of t ri gl yceri des f rom t he bl ood int o adi pose
t issue and muscl e
Rat e of cholest erol synt hesi s i n t he li ver
Li pol ysi s in adi pose t issue, l oweri ng t he plasma
fat t y acid l evel
Fat t y aci d oxi dat i on i n muscle and li ver
Ket ogenesi s
Prot ein met abol ism Ami no aci d t ransport i nt o t issues
Prot ein synt hesis in muscl e, adipose t i ssue, li ver,
and ot her t i ssues
Prot ein degradat i on i n muscl e
Ur ea for mat ion
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scaffol d for recr uit ment of prot eins involved in si gnal t ransduct ion t o downst ream pat hways. The result is coupling of insulin
r ecept or act ivat ion t o si gnali ng pat hways, mainly t he phosphat idyli nosit ol - 3- kinase ( PI
3
- ki nase) and t he mi t ogen- act i vat ed
prot ein kinase ( MAPK) pat hways ( Figur e 73) .
The PI
3
- ki nase pat hway i nvolves phosphoryl at ion of inosi t ol phospholi pids and t he gener at ion of phosphat idyl inosit ol -
3,4, 5- t r isphosphat e and phosphat idylinosit ol - 3,4- bisphosphat e. These product s, i n t urn, at t ract serine kinases t o t he plasma
membr ane, including t he phosphoinosit ide- dependent kinase and different isoforms of prot ein kinase B, which, when
act ivat ed, cat alyze some of t he cellular effect s of insulin. The Pl
3
- kinase pat hway is invol ved pr edominant ly in mediat i ng t he
met abolic effect s of t he hormone, i ncluding glucose t ransport , glycolysis, and glycogen synt hesis, and plays a crucial role in
t he regulat ion of prot ein synt hesis by insulin. Mor eover, t his pat hway is involved in cell gr owt h and t ransmit s a st rong
ant i apopt ot i c si gnal, promot i ng cell survi val . The ot her main si gnal i ng pat hway t hat i s act ivat ed by i nsuli n bindi ng t o i t s
r ecept or is t he MAPK pat hway. Alt hough si gnali ng cascades in t his pat hway do not appear t o play a significant role in t he
met abolic effect s of insul in, t hey are involved in mediat ing t he pr oliferat ive and different iat ion effect s elicit ed by insul in.
Signal t ransduct ion by t he insulin recept or is not limit ed t o i t s act ivat ion at t he cell sur face. The act ivat ed ligand- recept or
complex is int er nal ized int o endosomes. Endocyt osis of act ivat ed recept ors is t hought t o enhance t he insuli n r ecept or t yr osine
kinase act ivit y on subst rat es t hat are dist ant fr om t hose readily accessible at t he plasma membrane. Following acidificat ion of
t he endosomal lumen, insul in di ssoci at es f r om it s recept or, endi ng t he i nsul in recept ormedi at ed phosphorylat i on event s and
promot ing t he degradat ion of insul in by prot eases such as t he acidic i nsulinase. The insulin recept or can t hen be recycled i nt o
t he cell sur f ace, where it becomes avai l able f or insuli n bi nding agai n.
The number of avai lable insuli n recept ors is modulat ed by exercise, diet , insulin, and ot her hormones. Chroni c exposure t o
hi gh insulin levels, obesit y, and excess gr owt h hor mone all lead t o a downregul at ion of i nsuli n recept ors. I n cont rast , exercise
and st ar vat ion upregulat e t he number of recept ors. The affinit y of t he r ecept or for insul in is increased fol lowing a peri od of
decr eased i nsul in l evel s and during adr enal i nsuf fi ci ency.
I NSULI N EFFECTS AT TARGET ORGANS
Ear l y ef f ect s Alt hough t he expression of insulin recept ors is widespread, t he specific effect s of insulin on skelet al
muscle glucose ut ilizat ion dominat e insulin act ion. I nsulin mediat es about 40% of glucose disposal by t he body, t he great
maj ori t y ( 8090%) of whi ch occur s in skelet al muscle. The movement of glucose int o t he cell is mediat ed by a family of carr ier
pr ot eins, or glucose t r anspor t ers, wit h t heir own unique t issue dist ribut ion. The main t ranspor t er s and t heir pr edominant
t issue di st ri but i ons ar e summar ized i n Table 72.
I nsulin- st imulat ed glucose t ransport is mediat ed t hrough GLUT- . Appr oxmat ely 90% of GLUT- 4 is sequest er ed int racell ularl y
in t he absence of i nsul in or ot her st imuli such as exercise. I nsulin binding t o it s recept or result s in recrui t ment of GLUT- 4 from
Ta l e 7 2. Mai n Feat ur es of Gl ucose Tr anspor t er s
Tr anspor t er E pr essi on Funct i on
GLUT- 1 Ubi quit ous, wi t h part i cularl y high l evel s i n human eryt hr ocyt es
and in t he endot hel ial cel ls li ning t he blood vessel s of t he brain.
Expr essed in skelet al muscle and fat .
Glucose upt ake by skelet al muscle and fat
under basal condit ions
GLUT- 2 Low- affinit y glucose t r ansport er present in pancreat ic - cel ls,
l iver, int est i ne, and ki dney
Funct ions in t he glucose sensor syst em
and ensures t hat glucose upt ake by
pancreat ic - cells and hepat ocyt es occurs
only when cir culat i ng gl ucose l evel s are
high
GLUT- 3 Pri maril y i n neur ons Toget her , GLUT- 1 and GLUT- 3 are cruci al
in allowing glucose t o cr oss t he blood- brai n
barri er and ent er neurons
GLUT- 4 Predominant ly in st riat ed muscle and adipose t issue. I n cont rast
t o t he ot her GLUT isoforms, which are pr imaril y localized on t he
cell membr ane, GLUT- 4 t r anspor t er prot ei ns are sequest er ed in
speci ali zed st or age vesi cl es t hat remain wit hi n t he cel l ' s i nt eri or
under basal condit ions.
The maj or i nsul in- responsi ve t ransport er
GLUT- 5 Spermat ozoa and small i nt est ine Predomi nant ly a fr uct ose t ransport er
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cyt osolic vesicular compart ment s t o t he plasma membrane. Accumul at ion of GLUT- 4 at t he membrane is t he net resul t of
increased t ranslocat ion t hrough t arget ed exocyt osis and decreased rat e of GLUT- 4 endocyt osis. This i s t he underl yi ng
mechani sm by whi ch insulin st imulat es glucose t ransport i nt o fat and muscl e cells.
I nt er medi at e ef f ect s The int ermediat e effect s of insulin are mediat ed by modulat ion of prot ein phosphorylat ion of
enzymes involved in met abolic processes in muscle, fat , and li ver ( Figur e 74) . I n fat , insul in inhibit s li polysi s and ket ogenesi s
by t riggering t he dephosphorylat ion of hormone- sensi t ive l ipase and st i mulat es l ipogenesis by act i vat i ng acet yl - CoA
car boxylase. I n t he adipocyt es, dephosphorylat ion of hormone- sensi t ive li pase inhibit s t he breakdown of t r iglycer ides t o fat t y
acids and glycerol , t he rat e- limit ing st ep in t he release of fr ee fat t y acids mediat ed by li polysis. This process t hereby r educes
t he amount of subst rat e t hat is available for ket ogenesis. I nsulin ant agonizes cat echolamine- i nduced l ipolysis t hrough t he
phosphoryl at ion and act ivat ion of phosphodi est erase, l eadi ng t o a decrease i n i nt racel lul ar cAMP l evel s and a concomi t ant
decrease in pr ot ei n kinase A act ivit y.
Fi gu r e 7 .
Glucagon and insulin effect s on hepat ic glucose met abolism. Binding of glucagon and insulin t o t heir respect ive recept ors st imulat es a
cascade of pr ot ein phosphorylat ion st eps t hat act ivat e ( or inhibit ) key enzymes i nvolved in t he regulat ion of glycogenolysis,
gluconeogenesis, and glycolysi s. The principal t arget enzymes for insulin- and glucagon- mediat ed effect s are present ed. The overall
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I n t he li ver, i nsul in st i mul at es t he gene expressi on of enzymes i nvolved in gl ucose ut i li zat i on ( eg, glucokinase, pyr uvat e
kinase, and l i pogeni c enzymes) and i nhibit s t he gene expressi on of enzymes invol ved i n glucose product ion ( eg,
phosphoenolpyruvat e carboxykinase and glucose- 6- phosphat ase) ( Figure 75) . I nsul in st i mulat es glycogen synt hesi s by
increasing phosphat ase act ivit y, leading t o t he dephosphorylat ion of glycogen phosphorylase and glycogen synt hase. I n
addit ion, i nsul in- medi at ed dephosphoryl at i on of inhibit or y si t es on hepat ic acet yl- CoA carboxylase increases t he product ion of
mal onyl- CoA and simult aneousl y reduces t he rat e at which fat t y acids can ent er hepat ic mit ochondr ia for oxidat ion and ket one
body pr oduct ion.
result is an increase in hepat ic glucose out put . ADP, adenosine diphosphat e; ATP, adenosine t riphosphat e; G, glucagon; I , insulin; PEP,
phosphoenolpyruvat e.
Fi gu r e 7 .
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Process of ket ogenesis in insulin deficiency. I nsulin def iciency and high levels of count erregulat or y hormones glucagon, epinephrine, and
cort isol combine t o increase t he act ivit y of hormone- sensit ive lipase, incr ease t he release of fr ee fat t y acids, and decrease t he act ivit y of
acet yl- coenzyme A ( CoA) carboxylase, t hereby impairing t he r eest erificat ion of free fat t y acids and promot ing fat t y acid conversion int o
ket one bodies. The excess supply of fat t y acet yl- CoA and t he deficiency in oxaloacet at e increase t he oxidat ion t o ket one bodies, wit h t he
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I n muscle, insul in st imulat es glucose upt ake and favors prot ein synt hesi s t hough phosphor ylat ion of a serine/ t hreonine prot ein
kinase known as mammalian t arget of rapamyci n. I n addit ion, i nsul in favors lipid st orage in muscle as well as in adipose
t issue. As discussed lat er, i nsuli n def i ci ency l eads t o gl ucose accumul at i on in bl ood, a decrease i n l ipid st orage, and pr ot ei n
l oss, r esul t i ng in negat i ve nit r ogen bal ance and muscle wast ing.
Long- t er m ef f ect s Sust ai ned insuli n st imulat ion enhances t he synt hesis of lipogenic enzymes and t he repression of
gluconeogenic enzymes. The growt h- promot ing and mit ogenic effect s of insuli n are long- t erm responses mediat ed t hrough t he
MAP pat h ay. Bot h MAPK and part icularly t he chronic act ivat ion of ext r acellular r ecept or kinase by insulin recept or binding
lead t o excessive cell growt h. Alt hough t his pat hway of insulin act ion is not as well elucidat ed as t he effect s t hat are mediat ed
t hr ough t he act ivat ion of I RS, evidence is now sur facing on t he pat hophysiol ogic effect s of chronic el evat ions of insulin on
specif i c cell popul at ions.
I nsul in levels ar e high dur ing t he development and earl y st ages of t ype 2 diabet es. Chronic hyper insuli nemi a has been linked
t o increased risk of cancers i ncluding endomet rium, post - menopausal breast , colon, and kidney. Condit ions t hat cause
elevat ed i nsul in l evel s incl ude hi gh waist ci rcumf erence, excess visceral fat , hi gh wai st - t o- hip rat io, high body mass index,
sedent ary lifest yle, and high energy i nt ake. I n addit ion, t he prolifer at ive effect s of chr onic hyperi nsulinemia influence vascular
smoot h muscle cells, which are r esponsible for t he maint enance of vascular t one. These cells play an impor t ant role in t he
pat hogenesis of several diseases, incl udi ng hypert ension, at her osclerosi s, car diovascular di sease, and dysl ipidemi a, all of
which are closely associat ed wit h insulin resist ance and hyperi nsuli nemi a. The mol ecul ar basis of insuli n' s effect on vascular
smoot h muscle cell growt h and it s associat ion wit h hypert ension are current ly unclear.
Gl ucagon
GLUCAGON SYNTHESI S
Glucagon, is a 29amino acid polypept ide hor mone secret ed by t he - cells of t he islet s of Langerhans, which plays an
impor t ant role in t he r egulat ion of glucose homeost asis by produci ng ant agoni st ic effect s on insul in act ion. The primary
sequence of glucagon is almost perfect ly conserved among vert ebrat es, and it is st ruct urall y relat ed t o t he secret in family of
pept ide hormones. Glucagon is synt hesi zed as proglucagon and t hen prot eolyt ically processed t o yield glucagon. The
prohormone progl ucagon i s expressed i n t he pancreas, and al so i n ot her t i ssues, such as ent er oendocr ine cel ls i n t he int est i nal
t ract and in t he brain. However , t he processing of t he pr ohormone differs among t issues. The 2 main product s of proglucagon
processi ng ar e glucagon in t he - cells of t he pancr eas and GLP- 1 in t he i nt est i nal cel ls. GLP- 1 is produced i n t he int est i ne i n
r esponse t o a high concent rat ion of glucose in t he int est inal lumen. GLP- 1 is known as an incr et i n, a mediat or t hat ampli fies
i nsulin r el ease fr om t he - cell i n response t o a glucose load. Glucagon has a short half- li fe ( 510 minut es) and is degraded
most ly in t he liver. Plasma glucagon concent rat ions aver age 50100 ng/ L ( 50100 pg/ mL) .
REGULATI ON OF GLUCAGON RELEASE
The mechanisms i nvolved i n t he regulat i on and st imul us- secret ion coupling of glucagon r elease are not as well under st ood as
t hose f or i nsul in. Gl ucagon r el ease is i nhi bi t ed by hypergl ycemi a ( hi gh bl ood gl ucose l evel s) and st imul at ed by hypoglycemia
( low blood glucose levels) . A meal rich in carbohydrat es suppresses glucagon release and st imulat es insuli n rel ease fr om t he
- cel ls t hrough i nt est inal release of GLP- 1. Somat ost at in al so inhibit s glucagon release. High amino acid levels fol lowing an
amino acidri ch meal st i mulat e gl ucagon release. Epinephri ne st i mulat es release of gl ucagon t hr ough a
2
- adr ener gi c
mechani sm ( whil e i t suppresses insuli n rel ease f rom - cells t hrough an
2
- adrenergi c mechani sm) . Vagal ( par asympat het i c)
st imulat ion incr eases gl ucagon r el ease.
PHYSI OLOGI C EFFECTS OF GLUCAGON
The principal t arget t issues for glucagon are t he liver and adipose t issue. The rol e of glucagon recept ors in t he rest of t he
t issues i s st ill unclear. Glucagon' s main physiologic effect is t o increase plasma glucose concent rat ions by st imulat ing de novo
hepat ic glucose product ion t hr ough gluconeogenesis and glycogen br eakdown; overall, t hese act ions count eract t he effect s of
i nsuli n ( Fi gure 75) . Glucagon mediat es it s effect s by binding t o t he glucagon G
s
prot eincoupl ed recept or.
GLUCAGON RECEPTOR
The gl ucagon and GLP- 1 pept ide recept ors belong t o a family of GPCRs t hat include t hose for secret in, calcit onin, vasoact ive
int est inal polypept ide, parat hyroid hormone, and growt h hormonerel easi ng f act or. The gl ucagon r ecept or is expressed in
l iver , pancreat ic - cells, kidney, adipose t issue, heart , and vascular t issues, as well as in some regions of t he br ain, st omach,
and adrenal glands. Glucagon binding act ivat es adenylat e cyclase and result s in int racel lular accumul at ion of cAMP,
mobil i zat ion of int racell ular Ca
2+
, prot ein kinase A act ivat ion, and phosphorylat ion of effect or prot eins. The glucagon- r ecept or
compl ex undergoes endocyt osis i nt o int r acel lular vesi cl es, wher e glucagon is degraded.
result ing release of ket one bodies int o t he blood. The plus sign ( + ) denot es st eps t hat are favor ed by insulin defici ency. FA, fat t y acid;
HMG, 3- hydroxy- 3- met hylglut aryl; HSL, hormone- sensit ive lipase.
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GLUCAGON EFFECTS AT TARGET ORGANS
The princi pal physiologic effect s of glucagon are mediat ed i n t he liver. Glucagon st imulat es hepat ic glucose out put by
st imul at ing glycogen breakdown and gl uconeogenesi s and decreasi ng gl ycol ysis Fi gure 76) . The key enzymat ic st eps
r egulat ed by glucagon t hat mediat e t he st imulat ion of hepat ic glucose out put ar e summarized in Table 73. The effect s of
glucagon on adi pose t i ssue are relevant pri mari ly duri ng periods of st ress or f ood depri vat i on, par t i cul arl y when i nsul in release
i s suppressed.
Fi gu r e 7 .
Glucagon recept ormediat ed cellular effect s. Glucagon binds t o G prot eincoupled recept or ( GPCR) on t arget cells. The principal eff ect s
of glucagon are mediat ed in hepat ocyt es wher e glucagon t hrough act ivat ion of adenylat e cyclase, elevat ion in cAMP leads t o incr eased
pr ot ein kinase A act ivit y leading t o phosphor ylat ion of enzymes responsible for cont rol of glucose met abolism. The ult imat e result is an
incr ease in hepat ic glucose product ion t hrough increased gluconeogenesis and glycogenolysis. G- 6- Pase, glucose- 6- phosphat ase; PEPCK,
phosphoenolpyruvat e carboxykinase; PGC- 1, per oxisome prolifer at oract ivat ed recept or- coact ivat or- 1; PI P2, phosphat idylinosit ol 4,5-
biphosphat e. ( Repr oduced, wit h permission, from Guoqiang Jiang, Bei B. Zhang. Glucagon and regulat ion of glucose met abolism. Am J
Physiol Endocrinol Met ab. 2003; 284: E671E678. Figure 1 of art icle.)
Ta l e 7 3 . Ef f ect s of Gl u cagon on Hepat i c Gl u cose Met a ol i sm
Ef f ect on t ar get en yme Met a ol i c r espon se
I ncreased expressi on of glucose- 6- phosphat ase Frees gl ucose t o ent er
t he cir culat i on
Suppressi on of gl ucoki nase Decreases glucose ent r y
i nt o t he gl ycol yt ic
cascade
Phosphor ylat ion ( act ivat ion) of glycogen phosphor ylase St imulat es glycogenolysis
I nhibit ion of glycogen synt hase I nhibit s glycogen
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I n t he adipocyt e, glucagon st imulat es prot ein kinase Amediat ed phosphor ylat ion ( act ivat ion) of hor mone- sensit ive l ipase, t he
enzyme t hat br eaks down t ri gl yceri des ( st or ed f at ) int o di acyl gl ycerol and f ree fat t y acids, r el easi ng t hem i nt o t he ci rcul at ion.
Gl ycerol released int o t he circul at ion can be ut i li zed i n t he li ver f or gl uconeogenesi s or f or reest erif i cat i on. Fr ee f at t y aci ds are
used as fuel by most t issues, pr edominant ly skelet al muscle and liver . I n t he liver, free fat t y acids are used for reest erificat ion
or t hey can undergo - oxidat ion and conver sion int o ket one bodies. Thus, ket ogenesis is regulat ed by t he balance bet ween
t he effect s of glucagon and insulin at t heir t ar get organs. The import ance of t his balance is evident during insulin deficiency
and gl ucagon excess, as seen in uncont r oll ed diabet es ( discussed lat er) .
Somat ost at i n
Somat ost at in is a 14amino acid pept ide hor mone pr oduced by t he - cells of t he pancr eas. I t s release is st imulat ed by high-
fat , high- carbohydrat e, and part i cularl y prot ein- ri ch meal s, and is inhibi t ed by insul in. Somat ost at in has a gener alized
i nhi bi t ory ef fect on vir t ual ly all gast roi nt est inal and pancreat ic exocr ine and endocri ne f unct ions. The regulat i on of i t s release i s
not well st udied because of t he difficult y in analyzing t he small number of isl et cells t hat produce t his hormone. Furt her, t he
impor t ance of endogenous paracrine inhibit ion of insulin and glucagon release is not well est ablished. Because - cell s are
l ocat ed in t he per iphery of t he - cells and because blood flows from t he cent er of t he islet s of Langerhans t oward t he
per iphery, pancreat ic somat ost at in may have a limit ed cont r ibut ion t oward physiologic cont r ol of insulin and glucagon release.
However, exogenous admini st rat ion of somat ost at in does suppress t he r elease of bot h insulin and glucose and is used in t he
cli ni cal set t ing f or t he management of i nsuli n- or glucagon- produci ng t umors.
Pancr eat i c Pol ypept i de
Pancreat ic pol ypept i de i s a 36amino acid pept ide hormone t hat bel ongs t o a pept ide family including neur opept ide Y and
pept ide YY. I t is pr oduced in t he endocrine t ype F cells locat ed in t he per iphery of pancr eat ic islet s and is released int o t he
circulat ion aft er ingest ion of food, exercise, and vagal st imulat ion. The effect s of pancreat ic polypept ide incl ude inhibit i on of
pancr eat i c exocri ne secret i on, gal l bladder cont ract i on, modulat i on of gast ri c acid secr et ion, and gast r oi nt est i nal mot il it y.
Pancreat ic pol ypept ide crosses t he blood- brai n bar rier and has been post ul at ed t o play a r ol e i n r egul at ing f eeding behavi or.
Amyl i n
Amyl in, or i sl et amyloi d polypept i de, is a 37ami no aci d pept ide hormone t hat bel ongs t o t he cal ci t onin famil y, which i ncl udes
calcit onin, calcit onin gene- r el at ed pept i de, and adrenomedul li n. Amyli n i s synt hesi zed as a small precursor, undergoes post -
t ranslat ional modificat i on ( ami dat ion) , is st ored in - gr anules, and i s released al ong wi t h i nsuli n and C- pept ide. Pl asma amyli n
concent rat ions increase aft er a meal or glucose infusion. Amylin appears t o work wit h insuli n t o r egulat e plasma glucose
concent rat ions in t he bloodst ream, suppr essing t he post prandial secret ion of glucagon and slowing gast ric empt ying. I n
muscle, amyl i n opposes gl ycogen synt hesis and act i vat es gl ycogenol ysi s and gl ycol ysi s, t hereby i ncreasi ng l act at e product i on.
Ci rculat i ng amyl in i s increased in obesi t y, hypert ension, and gest at i onal diabet es; i t is l ow or absent i n t ype 1 di abet es
mellit us. I n t ype 2 diabet es, t he secret ion of amylin is impaired before t hat of i nsul in. Amylin is t he main component of
pancr eat ic islet amyloid, found in t he vast maj orit y of pat ient s wit h noni nsulin- dependent ( t ype 2) diabet es mell it us, and i s
t hought t o cont r ibut e t o dest ruct ion of t he pancreat ic - cell. Amylin binds t o a var iant of t he cal cit oni n GPCR. The modified
calci t onin recept or has hi gher affinit y for amylin, an effect mediat ed by t r ansmembrane prot eins known as recept or act ivit y
modifying prot eins ( RAMPs) .
synt hesi s
St imul at ion of phosphoenolpyruvat e carboxykinase expressi on St imulat es
gluconeogenesi s
I nact ivat ion of phosphofruct okinase- 2 ( PFK- 2) and act ivat ion of fr uct ose- 6- phosphat ase. PFK- 2 is
t he kinase act ivit y and fruct ose- 2,6- bisphosphat ase ( F- 2,6- BPase) is t he phosphat ase act ivit y of
t he bifunct ional regulat ory enzyme, phosphofruct okinase- 2/ fr uct ose- 2, 6- bisphosphat ase ( PFK- 2/ F-
2,6- BPase) .
I nhibit s glycol ysi s
St imulat es
gluconeogenesi s
Suppression of act ivit y of t he pyr uvat e kinase Decreases glycolysi s
DI SEASES ASSOCI ATED I TH PANCREATI C HORMONES
Hor mone- Pr oduci n g Tumor s
Excess pancreat ic hormone pr oduct ion and release are usually due t o hormone- producing t umor s, wit h insulinoma being t he
most frequent . I nsulinomas pr oduce excessive amount s of insulin, and pat ient s present wit h episodes of hypoglycemia,
confusi on, aggressi veness, palpit at i ons, sweat i ng, convul sions, and even unconsciousness. These sympt oms are most l y
obser ved before breakfast and foll owing physical exercise. The compensat ory or count erregulat ory r esponse of t he body
i ncludes t he rel ease of cat echol amines, gl ucagon, cort i sol , and growt h hormone.
Glucagonomas ar e unusual t umor s t hat may produce sympt oms of diabet es. Excessive glucagon pr oduct ion by t he t umor may
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al so result i n an over all cat abolic effect on fat and muscle, l eading t o severe weight l oss and anorexia. Somat ost at inoma is a
r ar e t umor t hat may cause moderat e di abet es.
Di a et es Mel l i t us
The most common disease result i ng from impaired pancreat ic hormone r elease is diabet es mellit us. The 2 forms of diabet es,
t ype 1 and t ype 2, are charact erized by impair ed insulin release. Type 1 diabet es, also known as i nsulin- dependent di abet es
mellit us, is t he r esul t of - cell dest ruct ion. I t account s for 25% of cases and it occurs mor e frequent ly in younger people,
hence i t s ot her name, j uveni le- onset diabet es. Type 1 diabet es i s char act er ized by t he development of ket oacidosis in t he
absence of insulin t herapy. Type 2 diabet es result s from a loss of nor mal regulat ion of insulin secret ion and account s for more
t han 90% of diabet es cases. I t is usually associat ed wit h obesit y in adult s and is charact erized by mild hyperglycemia. I t rarely
leads t o ket oacidosis. Type 2 diabet es is oft en part of "syndrome X" or " insul in resist ance syndrome, " a met abolic syndrome
charact eri zed by hypert ension, at her oscl erosi s, and cent ral obesi t y.
The diagnosis of diabet es is based on plasma glucose levels obt ai ned i n t he fast ing st at e ( great er t han 126 mg/ dL) . Diabet es
can also present as random plasma glucose levels higher t han 200 mg/ dL in associat ion wit h sympt oms of diabet es ( polyuria,
polydipsia, and polyphagia) or as persist ent elevat ions i n plasma glucose levels fol lowing an or al glucose load ( gr eat er t han
200 mg/ dL, 2 hours aft er glucose ingest ion) . The pat hophysiology of t he disease involves impaired ent r y of glucose int o t he
cells and accumulat ion of glucose in t he blood. This process result s in increased plasma osmolarit y and urinary loss of glucose,
accompanied by excess loss of wat er and sodium ( pol yur i a) . The result ing dehydrat ion t r igger s compensat ory mechanisms
such as t hir st ( pol ydi psi a) . The i nabi l it y of t he cell s t o ut i li ze glucose resembl es a st at e of cel l ul ar st arvat ion, st i mulat i ng
hunger ( pol y phagi a) and t riggeri ng t he act ivat ion of compensat ory responses t o increase t he release and availabilit y of fuel
subst rat es t hough act ivat ion of lipol ysis and prot eolysi s. Lack of insulin result s in increased circul at ing levels of free fat t y acids
and gluconeogenic amino aci ds. These exceed t he liver' s capacit y for t heir met abolic ut ilizat ion, leading t o t he buildup of
ket one bodi es in t he blood ( diabet i c ket oacidosi s) and t hei r ur inary excret ion.
Di a et i c et oaci dosi s
Diabet i c ket oacidosi s is an acut e pat hol ogic event charact erized by elevat ed blood glucose levels and ket one bodi es
and met abol ic aci dosi s, r esul t ing dir ect ly from decreased insuli n availabil it y and simult aneous el evat ions of t he
count erregulat or y hor mones glucagon, cat echolami nes, cor t i sol, and growt h hormone. Diabet i c ket oacidosis is precipit at ed by
inf ect ions, discont inuat ion of or inadequat e insulin use, new- onset ( unt r eat ed) diabet es, and ot her event s such as t he st ress
associat ed wi t h surgery.
The insulin defici ency causes glucose t o accumulat e in t he blood. As ment ioned earlier, insuli n mediat es t he maj orit y of t he
body' s gl ucose disposal t hrough i t s ef fect s on skel et al muscl e. I n diabet i c ket oacidosi s, gl uconeogenesi s in t he li ver pr oceeds
unopposed by t he physi ologic presence of i nsuli n. The excess bl ood glucose increases osmolari t y, which, if severe, can r esul t
in diabet ic coma. The lack of insuli n and t he high levels of count er regulat ory hormones glucagon, epinephrine, and cort isol
combine t o increase t he act ivit y of hormone- sensi t i ve l i pase, increase t he release of f ree f at t y acids, and decrease t he act ivit y
of acet yl - CoA carboxylase, t hereby impairi ng t he reest erificat i on of free fat t y acids and promot ing fat t y acid conversion int o
ket one bodi es ( Figur e 76) . Fat t y acids r eleased int o t he circulat ion undergo - oxi dat i on t o acet yl - CoA in t he li ver. Act el y- CoA
condenses wit h oxaloacet at e t o form cit rat e in t he ent ry st ep t o t he Krebs cycle ( cit ric acid cycle or t ricarboxylic cycle) . Dur ing
i nsuli n def i ciency and excess gl ucagon, oxaloacet at e i s pr ef erent iall y used f or gluconeogenesi s, t hus decr easi ng it s avai l abil it y
for condensat ion wit h acet yl- CoA. As a result , acet yl- CoA is divert ed fr om ent eri ng t he Krebs cycl e and is used pref erent iall y
for ket one body format ion or ket ogenesis, t he process by which fat t y acids ar e t ransfor med int o acet oacet at e and 3-
hydroxybut yrat e i n hepat ocyt e mit ochondr ia. The st eps i nvolved i n ket ogenesi s ar e - oxidat ion of fat t y acids t o acet yl- CoA,
format ion of acet oacet yl - CoA, and conversion of acet oacet yl- CoA t o 3- hydroxy- 3- met hylglut aryl- CoA and t hen t o
acet oacet at e, which i s t hen reduced t o 3- hydr oxybut yrat e. The enzymes invol ved in ket ogenesis are summari zed i n Tabl e 74.
Acet oacet at e can be spont aneousl y decarboxylat ed t o acet one, a highl y fat - soluble compound t hat is excret ed slowly by t he
lungs and is r esponsible for t he fruit y odor of t he breat h of i ndividual s wit h diabet ic ket oacidosis.
Ta l e 7 . Thr ee Pr i nci p al En y mes I n ol ed i n et ogenesi s
En yme Ti ssue Funct i on
Hor mone- sensit ive
l ipase
Adi pocyt es Breaks down t ri gl yceri des, releasing f at t y acids i nt o t he ci rculat i on
Acet yl- CoA
carboxylase
Liver Cat al yzes t he conver sion of acet yl- CoA t o malonyl - CoA, t he primar y subst rat e of fat t y
acid bi osynt hesi s
HMG- CoA synt hase Liver I nvolved in t he conversion of acet yl- CoA t o acet oacet at e
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During diabet ic ket oacidosis, high amount s of ket one bodies are released int o t he blood, and a high r at io ( 3: 1 or higher) of 3-
hydroxybut yrat e t o acet oacet at e i s generat ed because of t he hi ghl y reduced st at e of hepat i c mi t ochondri a. These ket one
bodies can freely diffuse across cell membranes and serve as an energy source for ext rahepat ic t issues i ncluding t he brain,
skelet al muscl e, and kidneys. Ket one bodi es are f il t ered and reabsorbed i n t he ki dney. At physi ologi c pH, ket one bodi es, wi t h
t he except i on of acet one, dissociat e compl et el y. The result i ng li berat i on of H
+
from ket one body met abolism exceeds t he
blood' s buffer ing capacit y, leading t o met abolic acidosis wit h an increased anion gap. I f severe, t hi s condit ion can lead t o
coma.
Type 2 Di a et es
Type 2 diabet es i s t he r esul t of i nadequat e responsi veness of t he - cells t o glucose, which is lat er followed by a net reduct ion
in - cel l mass and a decreased responsiveness of peri pheral t issues t o insuli n act i on. Pat ient s wi t h t ype 2 di abet es secr et e
normal amount s of insulin during fast ing, but in response t o a glucose load ( or a meal ) , t hey secret e considerably less insulin
( 70%) t han nondiabet ic pat ient s. I n addit ion t o a r educt ion in i nsulin release, t he pat t ern of insul in release is also alt ered
fol lowing a meal, wit h pulses t hat are si gnificant ly smaller, sluggish, and errat ic, part icularly aft er dinner. Thi s abnormalit y
r esul t s in signi ficant ly higher level s of fast ing glucose in t hese pat ient s.
Regardl ess of t he et iol ogy ( eg, abnor mali t i es i n glucose t ranspor t ; abnormal i nsul i n synt hesi s, processi ng, st or age, or
secr et i on) , t he earli est physiol ogic indi cat i on of - cel l dysfunct i on i s a delay i n t he acut e i nsul in response t o gl ucose. The
defect in t he ini t ial response t o a glucose load leads t o an excessive r ise in plasma glucose, which i n t urn produces a
compensat or y and exaggerat ed second- phase hyperinsuli nemic r esponse. Thi s ini t ial period of sust ai ned hyperinsul inemia
downregulat es t he insulin r ecept or s, decreasing t he sensit ivit y of t issues t o insulin act ion and pr oducing a st at e of insulin
r esi st ance. The mai n pat hol ogi c def ect s in di abet es ar e excessi ve hepat i c gl ucose product i on, def ect ive - cell secret ory
f unct i on, and per ipheral i nsul in resi st ance.
I nsul i n Resi st ance
I nsul in resist ance is t he i nabi li t y of per ipheral t ar get t issues t o r espond proper ly t o normal ci rculat i ng concent r at ions of insuli n.
To maint ain euglycemia, t he pancr eas compensat es by secret ing increased amount s of insulin. I n pat ient s wit h t ype 2
diabet es, insulin resi st ance precedes t he onset of t he disease by several years. Compensat ing for insuli n resist ance by an
i ncrease i n i nsul in release i s ef fect ive only t emporari ly. As i nsul i n resi st ance i ncreases, impai red glucose t olerance devel ops.
Ul t imat el y, f ai lure or exhaust i on of t he pancr eat i c - cell resul t s i n decreased i nsuli n secr et i on. The combinat i on of insul in
r esi st ance and i mpai red - cel l f unct i on charact eri zes cl inical t ype 2 di abet es. Exerci se has been demonst r at ed t o i ncrease
glucose t ranspor t in skel et al muscl e and t o decrease i nsul in resi st ance i n pat ient s wi t h t ype 2 diabet es. The i ncrease i n glucose
t ransport r esul t ing f r om exer cise i s not mediat ed t hrough t he i nsuli n r ecept or . The si gnali ng pat hways invol ve increased
cyt osol ic Ca
2+
and t he enzyme AMP- act i vat ed pr ot ei n kinase. AMP- act i vat ed prot ein ki nase is act ivat ed during exerci se and
has been t ermed a mast er met abol ic swit ch because it phosphorylat es key t arget prot eins t hat cont rol flux t hrough met abolic
pat hways.
Cl i ni cal E al uat i on of Di a et es
According t o t he American Diabet es Associat ion, hyperglycemia ( fast ing glucose at least 126 mg/ dL or random glucose at least
200 mg/ dL) is t he diagnost ic crit eri on and a main pr ognost ic paramet er in diabet es. The sl ow post - t ransl at ional and
nonenzymat ic glycat ion of hemoglobin provides a measur e of chronic glycemia. Values of glycosylat ed hemoglobin are st r ongly
cor relat ed wi t h t he average bl ood gl ucose l evel over t he preceding 13 mont hs and can be obt ained in t he nonfast ed st at e.
The measurement of glycosylat ed hemoglobin is used t o moni t or gl ycemi c cont r ol in pat i ent s wi t h known di abet es.
Tr eat ment of t h e Di a et i c Pat i ent
The goal of t herapy is t ight glycemic cont rol , which has been shown t o delay t he development of microvascul ar complicat ions
associat ed wi t h di abet es. Glucose homeost asis r esul t s f rom t he regulat ed bal ance among hepat i c gl ucose r el ease, di et ar y
glucose absorpt ion, and skelet al muscle and adipose t issue glucose upt ake and disposal. All 3 of t hese component s have been
t ar get ed for pharmacologic t reat ment of diabet ic pat ient s. Some of t he approaches used, in addit ion t o convent ional insulin,
warrant ment ion because t hey affect t he physiologic mechanisms of pancr eat ic hor mone release and t arget or gan effect s on
t he cont rol of glucose.
Su l f onyl ur eas Sulfonyl ur eas incr ease insuli n r el ease by closi ng K
+
ATP channels i n t he pancreat ic - cell membr ane. This
act ion is mediat ed by binding of t he drug t o t he sulfonylurea recept or subunit of t he channel. Because t ype 1 diabet es i s
charact eri zed by - cell dest ruct ion, t his approach is ineffect ive in t hose pat ient s.
Bi gu an i des Biguanides such as met f ormi n reduce hepat ic glucose out put ( primar il y t hrough inhibit ion of gluconeogenesis
and, t o a l esser ext ent , glycogenol ysis) and i ncrease insuli n- st i mulat ed glucose upt ake in skel et al muscle and adipocyt es. I n
CoA, coenzyme A, HMG, 3- hydroxy- 3- met hyl gl ut aryl.
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insulin- sensi t ive t issues ( such as skelet al muscle) , met for min facilit at es glucose t ranspor t by increasing t yrosi ne kinase act i vit y
in insulin r ecept ors and enhanci ng glucose t ransport er t r afficking t o t he cell membrane.
Al pha- gl ucosi dase i nhi i t or s Alpha- glucosidase inhibit ors delay t he int est inal absor pt ion of carbohydrat es t hrough
inhibit ion of t he br ush- border enzymes t hat hydrol yze pol ysacchari des t o gl ucose.
Th i a ol i di nedi on es Thiazol idinediones reduce i nsul i n resi st ance i n skelet al muscle by act ivat i on of t he - isoform of t he
per oxisome proli fer at or act ivat ed recept or in t he nucl eus, t hereby affect ing t he t ranscript ion of several genes involved in
glucose and lipid met abolism and energy bal ance. Among t he genes t hat are affect ed are t hose t hat code for lipoprot ein
lipase, fat t y acid t ranspor t er prot ei n, adipocyt e fat t y acidbinding prot ein, fat t y acet yl- CoA synt hase, malic enzyme,
glucokinase, and t he GLUT- 4 glucose t ransport er.
Gl ucagon- l i e pept i de GLP- 1 ampl ifi es glucose- i nduced insuli n r el ease. I n addi t i on, GLP- 1 increases insulin biosynt hesi s
and insulin gene expression and has t ropic and ant iapopt ot ic effect s on t he pancreat ic - cells.
EY CONCEPTS
I nsulin release is under nut r ient , neur al, and hor monal regulat ion.
The pancr eat i c - cell funct ions as a glucose sensor in t he process of insulin release.
The PI
3
- kinase pat hway mediat es most of insuli n' s met abolic effect s, and t he MAPK pat hway is most ly involved in
mediat i ng t he proli fer at ive responses.
The pri ncipal met aboli c eff ect s of i nsuli n are t o incr ease glucose ut il i zat ion in skel et al muscl e, suppress hepat i c
gl ucose pr oduct i on, and i nhi bi t li pol ysi s.
Gl ucagon ant agonizes i nsulin' s ef fect s by st imul at ing hepat ic glucose release.
A disr upt ion in t he balance of insuli n and glucagon leads t o ket ogenesis and hyperosmol ar coma.
SUGGESTED READI NGS
Bergst en P. Pat hophysi ol ogy of i mpai red pul sat il e i nsuli n r el ease. iabet es Met ab es ev. 2000; 16: 179. [ PMI D: 10867718]
Cefalu WT. Evaluat ion of alt ernat ive st rat egies for opt imizing glycemia: progress t o dat e. Am J Med. 2002; 113( suppl 6A) : 23S.
Ger ich JE. Mat ching t reat ment t o pat hophysiology in t ype 2 diabet es. l in her . 2001; 23: 646. [ PMI D: 11394726]
Hauner H. The mode of act ion of t hiazolidinediones. iabet es Met ab es ev. 2002; 18( suppl 2) : S10.
Kirpichnikov D, McFarlane SI , Sowers JR. Met formin: an updat e. Ann I nt er n Med. 2002; 137: 25. [ PMI D: 12093242]
Laffel L. Ket one bodies: A review of physiology, pat hophysiology and applicat ion of monit oring t o diabet es. iabet es Met ab es
ev. 1999; 15: 412. [ PMI D: 10634967]
Lang J. Molecular mechanisms and regulat ion of i nsulin exocyt osis as a paradigm of endocrine secret i on. Eur J iochem.
1999; 259: 3. [ PMI D: 9914469]
LeRoi t h D. Bet a- cell dysf unct i on and i nsul in resi st ance i n t ype 2 di abet es: r ole of met abol i c and genet ic abnormal i t ies. Am J
Med. 2002; 113( suppl 6A) : 3S.
Por ksen N et al. Human insuli n rel ease pr ocesses measured by int rapor t al sampli ng. Am J Physiol Endocrinol Met ab.
2002; 282: E695.
Ri cht er EA, Derave W, Woj t aszewski JFP. Glucose, exerci se and i nsul in: emergi ng concept s. J Physiol . 2001; 535( Pt 2) : 313.
Ryder JW, Chibal in AV, Zi erat h JR. I nt racell ular mechani sms underl yi ng increases i n gl ucose upt ake i n r esponse t o i nsul in or
exer cise i n skel et al muscl e. Act a Physi ol cand. 2001; 171: 249. [ PMI D: 11412137]
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Salt iel AR, Pessin JE. I nsulin signaling pat hways in t ime and space. rends ell iol . 2002; 12: 65. [ PMI D: 11849969]
St r aub SG, Sharp GWG. Glucose- st imulat ed signaling pat hways in biphasic insulin secr et ion. iabet es Met ab es ev.
2002; 18: 451. [ PMI D: 12469359]
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