Classification

Diabetes is classified by underlying cause. The categories are: type 1 diabetes an autoimmune disease in which the body's own immune system attacks the pancreas, rendering it unable to produce insulin; type 2 diabetes in which a resistance to the effects of insulin or a defect in insulin secretion may be seen; gestational diabetes; and other types . Table 1 compares the presentation !phenotype" of type 1 and type 2 diabetes. Type 2 diabetes commonly occurs in adults who are obese. There are many underlying factors that contribute to the high blood glucose le#els in these indi#iduals. $n important factor is the body's resistance to insulin in the body, essentially ignoring its insulin secretions. $ second factor is the falling production of insulin by the beta cells of the pancreas. Therefore, an indi#idual with type 2 diabetes may ha#e a combination of deficient secretion and deficient action of insulin. %n contrast to type 2, type 1 diabetes most commonly occurs in children and is a result of the body's immune system attacking and destroying the beta cells. The trigger for this autoimmune attack is not clear, but the result is the end of insulin production. References 1. &'pert (ommittee on the Diagnosis and (lassification of Diabetes )ellitus. *eport of the e'pert committee on the diagnosis and classification of diabetes mellitus. Diabetes (are 2+:,-.,2/; 2//0. !1ub)ed"

History of Diabetes
1hysicians ha#e obser#ed the effects of diabetes for thousands of years. 2or much of this time, little was known about this fatal disease that caused wasting away of the body, e'treme thirst, and fre3uent urination. %t wasn't until 1422 that the first patient was successfully treated with insulin. 5ne of the effects of diabetes is the presence of glucose in the urine !glucosuria". $ncient 6indu writings, many thousands of years old, document how black ants and flies were attracted to the urine of diabetics. The %ndian physician ,ushruta in 7// 8.(. described the sweet taste of urine from affected indi#iduals, and for many centuries to come, the sweet taste of urine was key to diagnosis. $round 2-/ 8.(., the name diabetes was first used. %t is a 9reek word that means to syphon , reflecting how diabetes seemed to rapidly drain fluid from the affected indi#idual. The 9reek physician $retaeus noted that as affected indi#iduals wasted away, they passed increasing amounts of urine as if there was li3uefaction of flesh and bones into urine . The complete term diabetes mellitus was coined in 1+:7 by Thomas ;illis, personal physician to <ing (harles %%. )ellitus is =atin for honey, which is how ;illis described the urine of diabetics ! as if imbued with honey and sugar ".

>p until the mid.1?//s, the treatments offered for diabetes #aried tremendously. @arious fad diets were prescribed, and the use of opium was suggested, as were bleeding and other therapies. The most successful treatments were star#ation diets in which calorie intake was se#erely restricted. Aaturally, this was intolerable for the patient and at best e'tended life e'pectancy for a few years. $ breakthrough in the puBBle of diabetes came in 1??4. 9erman physicians Coseph #on )ering and 5skar )inkowski surgically remo#ed the pancreas from dogs. The dogs immediately de#eloped diabetes. Aow that a link was established between the pancreas gland and diabetes, research focused on isolating the pancreatic e'tract that could treat diabetes. ;hen Dr. 2rederick 8anting took up the challenge of isolating a pancreatic e'tract, he was met with much skepticism. )any great physiologists had tried and failed to isolate an internal secretion from the pancreas. 8ut 8anting, a surgeon, persisted and in )ay 1421, he began work in the laboratory of 1rofessor Cohn )acloed in Toronto, (anada. (harles 8est, a medical student at the time, worked as his assistant. To concentrate what we now know as insulin, 8anting tied the pancreatic ducts of dogs. The pancreatic cells that released digesti#e enBymes !and could also destroy insulin" degenerated, but the cells that secreted insulin were spared. 5#er se#eral weeks the pancreas degenerated into a residue from which insulin could be e'tracted. %n Culy 1421, a dog that had had its pancreas surgically remo#ed was inDected with an e'tract collected from a duct.tied dog. %n the two hours that followed the inDection, the blood sugar le#el of the dog fell, and its condition impro#ed. $nother de.pancreatiBed !diabetic.like" dog was kept ali#e for eight days by regular inDections until supplies of the e'tract, at that time called isletin , were e'hausted. 2urther e'periments on dogs showed that e'tracts from the pancreas caused a drop in blood sugar, caused glucose in the urine to disappear, and produced a marked impro#ement in clinical condition. ,o long as the e'tract was being gi#en, the dogs were kept ali#e. The supply of the e'tract was impro#ed: the pancreas of different animals were used until that of the cow was settled upon. This e'tract kept a de.pancreatiBed dog ali#e for :/ days. Dr. C. (ollip, a biochemist, was drafted to continue impro#ing the purity of the pancreas e'tract, and later, 8est carried on this work. $ young boy, =eonard Thompson, was the first patient to recei#e insulin treatment. 5n Canuary 11, 1422, aged 17 and weighing only +7 pounds, he was e'tremely ill. The first inDections of insulin only produced a slight lowering of blood sugar le#el. The e'tract still was not pure enough, and abscesses de#eloped at the inDection site. (ollip continued to refine the e'tract. ,e#eral weeks later, =eonard was treated again and showed a remarkable reco#ery. 6is blood sugar le#els fell, he gained weight and li#ed for another 10 years. 6e died from pneumonia at the age of 2:. During the spring of 1422, 8est increased the production of insulin to enable the treatment of diabetic patients coming to the Toronto clinic. 5#er the ne't +/ years,

insulin was further refined and purified, and long.acting and intermediate types were de#eloped to pro#ide more fle'ibility. $ re#olution came with the production of recombinant human DA$ insulin in 14:?. %nstead of collecting insulin from animals, new human insulin could be synthesiBed. %n 1420, 8anting and )acloed were awarded the Aobel 1riBe for the disco#ery of insulin. 8anting split his priBe with 8est, and )acloed split his priBe with (ollip. %n his Aobel =ecture, 8anting concluded the following about their disco#ery: %nsulin is not a cure for diabetes; it is a treatment. %t enables the diabetic to burn sufficient carbohydrates, so that proteins and fats may be added to the diet in sufficient 3uantities to pro#ide energy for the economic burdens of life.

Physiology and Biochemistry of Sugar Regulation

Overview of lucose !etabolism

9lucose is an essential fuel for the body !2igure 1".The amount of glucose in the bloodstream is regulated by many hormones, the most important being insulin. %nsulin is the hormone of plenty stimulates the following:

it is released when glucose is abundant and

muscle and fat cells to remo#e glucose from the blood cells to breakdown glucose, releasing its energy in the form of $T1 !#ia glycolysis and the citric acid cycle" the li#er and muscle to store glucose as glycogen !short.term energy reser#e" adipose tissue to store glucose as fat !long.term energy reser#e" cells to use glucose in protein synthesis

9lucagon is the main hormone opposing the action of insulin and is released when food is scarce. ;hereas insulin triggers the formation of glycogen !an energy.re3uiring process, or an anabolic effect", glucagon triggers glycogen breakdown, which releases energy !a catabolic effect". 9lucagon also helps the body to switch to using resources other than glucose, such as fat and protein !2igure 2". Regulation of Blood lucose

8lood glucose le#els are not constant they rise and fall depending on the body's needs, regulated by hormones. This results in glucose le#els normally ranging from :/ to 11/ mgEdl. The blood glucose le#el can rise for three reasons: diet, breakdown of glycogen, or through hepatic synthesis of glucose.

&ating produces a rise in blood glucose, the e'tent of which depends on a number of factors such as the amount and the type of carbohydrate eaten !i.e., the glycemic inde'", the rate of digestion, and the rate of absorption. 8ecause glucose is a polar molecule, its absorption across the hydrophobic gut wall re3uires specialiBed glucose transporters !9=>T," of which there are fi#e types. %n the gut, 9=>T2 and 9=>T- are the most common. The li#er is a maDor producer of glucose it releases glucose from the breakdown of glycogen and also makes glucose from intermediates of carbohydrate, protein, and fat metabolism. The li#er is also a maDor consumer of glucose and can buffer glucose le#els !see 8o' 1". %t recei#es glucose.rich blood directly from the digesti#e tract #ia the portal #ein !2igure 0". The li#er 3uickly remo#es large amounts of glucose from the circulation so that e#en after a meal, the blood glucose le#els rarely rise abo#e 11/ mgEdl in a non. diabetic. "fter a !eal the Role of #nsulin

The rise in blood glucose following a meal is detected by the pancreatic beta cells, which respond by releasing insulin. %nsulin increases the uptake and use of glucose by tissues such as skeletal muscle and fat cells. This rise in glucose also inhibits the release of glucagon, inhibiting the production of glucose from other sources, e.g., glycogen break down !2igure 7". 1. Use Glucose 5nce inside the cell, some of the glucose is used immediately #ia glycolysis. This is a central pathway of carbohydrate metabolism because it occurs in all cells in the body, and because all sugars can be con#erted into glucose and enter this pathway. During the well. fed state, the high le#els of insulin and low le#els of glucagon stimulate glycolysis, which releases energy and produces carbohydrate intermediates that can be used in other metabolic pathways.

9lycolysis in ,tryer's Biochemistry 2. Make Glycogen $ny glucose that is not used immediately is taken up by the li#er and muscle where it can be con#erted into glycogen !glycogenesis". %nsulin stimulates glycogenesis in the li#er by:

stimulating hepatic glycogen synthetase !the enByme that catalyBes glycogen synthesis in the li#er" inhibiting hepatic glycogen phosphorylase !the enByme that catalyBes glycogen breakdown in the li#er" inhibiting glucose synthesis from other sources !inhibits gluconeogenesis"

%nsulin also encourages glycogen formation in muscle, but by a different method. 6ere it increases the number of glucose transporters !9=>T7" on the cell surface. This leads to a rapid uptake of glucose that is con#erted into muscle glycogen. 9lycogen metabolism in ,tryer's Biochemistry 3. Make Fat ;hen glycogen stores are fully replenished, e'cess glucose is con#erted into fat in a process called lipogenesis. 9lucose is con#erted into fatty acids that are stored as triglycerides !three fatty acid molecules attached to one glycerol molecule" for storage. %nsulin promotes lipogenesis by:

increasing the number of glucose transporters !9=>T7" e'pressed on the surface of the fat cell, causing a rapid uptake of glucose increasing lipoprotein lipase acti#ity, which frees up more fatty acids for triglyceride synthesis

%n addition to promoting fat synthesis, insulin also inhibits fat breakdown by inhibiting hormone.sensiti#e lipase !an enByme that breaks down fat stores". $s a result, there are lower le#els of fatty acids in the blood stream. 2atty acid metabolism in ,tryer's Biochemistry %nsulin also has an anabolic effect on protein metabolism. %t stimulates the entry of amino acids into cells and stimulates protein production from amino acids. $asting the Role of lucagon

2asting is defined as more than eight hours without food. The resulting fall in blood sugar le#els inhibits insulin secretion and stimulates glucagon release. 9lucagon opposes many actions of insulin. )ost importantly, glucagon raises blood sugar le#els by stimulating the mobiliBation of glycogen stores in the li#er, pro#iding a rapid burst of glucose. %n 1/ 1? hours, the glycogen stores are depleted, and if fasting continues, glucagon continues to stimulate glucose production by fa#oring the hepatic uptake of amino acids, the carbon skeletons of which are used to make glucose. %n addition to low blood glucose le#els, many other stimuli stimulate glucagon release including eating a protein.rich meal !the presence of amino acids in the stomach stimulates the release of both insulin and glucagon, glucagon pre#ents hypoglycemia that could result from unopposed insulin" and stress !the body anticipates an increased glucose demand in times of stress". Starvation

The metabolic state of star#ation in the >,$ is more commonly found in people trying to lose weight rapidly or in those who are too unwell to eat. $fter a couple of days without food, the li#er will ha#e e'hausted its stores of glycogen but continues to make glucose from protein !amino acids" and fat !glycerol". The metabolism of fatty acids !from adipose tissue" is a maDor source of energy for organs such as the li#er. 2atty acids are broken down to acetyl.(o$, which is channeled into the citric acid cycle and generates $T1. $s star#ation continues, the le#els of acetyl. (o$ increase until the o'idati#e capacity of the citric acid cycle is e'ceeded. The li#er processes these e'cess fatty acids into ketone bodies !0.hydro'ybutyrate" to be used by many tissues as an energy source. The most important organ that relies on ketone production is the brain because it is unable to metaboliBe fatty acids. During the first few days of star#ation, the brain uses glucose as a fuel. %f star#ation continues for more than two weeks, the le#el of circulating ketone bodies is high enough to be used by the brain. This slows down the need for glucose production from amino acid skeletons, thus slowing down the loss of essential proteins. %Starvation in the !idst of Plenty% Diabetes is often referred to as star#ation in the midst of plenty because the intracellular le#els of glucose are low, although the e'tracellular le#els may be e'tremely high. $s in star#ation, type 1 diabetics use non.glucose sources of energy, such as fatty acids and ketone bodies, in their peripheral tissues. 8ut in contrast to the star#ation state, the production of ketone bodies can spiral out of control. 8ecause the ketones are weak acids, they acidify the blood. The result is the metabolic state of diabetic ketoacidosis !D<$". 6yperglycemia and ketoacidosis are the hallmark of type 1 diabetes !2igure -". 6ypertriglyceridemia is also seen in D<$. The li#er combines triglycerol with protein to form #ery low density lipoprotein !@=D=". %t then releases @=D= into the blood. %n diabetics, the enByme that normally degrades lipoproteins !lipoprotein lipase" is inhibited by the low le#el of insulin and the high le#el of glucagon. $s a result, the le#els of @=D= and chylomicrons !made from lipid from the diet" are high in D<$. &ow'Carbohydrate Diet =ow.carbohydrate diets, such as the $tkins and ,outh 8each diets, are currently popular ways to lose weight. ,uch diet plans in#ol#e restricting the type and amount of carbohydrate eaten. 5ne of the earliest descriptions of a low.carbohydrate diet was by ;illiam 8anting in the 1?+/s in &ngland. $t the age of ++, 8anting found success in following a carbohydrate. restricted diet: in the course of one year, he lost 7+ pounds of his initial weight of 2/2

pounds. 6is impression was that any starchy or saccharine matter tends to the disease of corpulence in ad#anced life . 6e claimed he was ne#er hungry and that the great charms and comfort of the system are that its effects are palpable within a week of trial and creates a natural stimulus to perse#ere for a few weeks more . %n a recent small trial, +0 obese men and women were assigned to either a low. carbohydrate diet or a low.fat diet ! 1". 1eople on both diets lost weight. The carbohydrate.restricted group initially lost weight at a faster rate, but when re#iewed at the end of the year there was no significant difference in weight loss between the two groups ! 1". %t was found that low.carbohydrate dieters !who were allowed unrestricted amounts of protein and fat" actually had a lower energy intake than the low.fat diets !who were limited in their calorie intake". %t may be that when carbohydrates are restricted, weight loss is due to a lower calorie intake due to the monotony of the diet. %t is also possible that the lower calorie intake may be because of a change in peripheral or central saiety signals, lea#ing people feeling more full after a meal. $ second study compared the effects of a carbohydrate.restricted diet on the risk of de#eloping atherosclerosis ! 2". 102 se#erely obese men and women were assigned to either a low.carbohydrate or low.fat diet. $gain, after a +.month period both groups lost weight. They became more sensiti#e to insulin, and their triglyceride !T9" le#els, a type of fat that is a risk factor for atherosclerosis, impro#ed. 6owe#er, the carbohydrate. restricted group lost more weight and showed a greater impro#ement in insulin sensiti#ity and T9 le#els. $fter one year, the weight loss between the two groups was similar, but the cardiogenic risk factors were impro#ed in the low.carbohydrate dieters, T9 le#els were lower, and le#els of 6D= cholesterol, a type of fat that protects against atherosclerosis, were higher ! 0". $lso, long.term sugar control, which can be measured by checking for the amount of glycosylated hemoglobin !6b$1c", was better in people on the low.carbohydrate diet. 6owe#er, it remains unclear whether these beneficial effects would continue after 1 year. $t present, the risks of obesity are well known, and the benefits of weight loss by traditional low.calorie, low.fat, and high.comple' carbohydrate diets are also well documented. 2uture research will clarify the long.term outcomes of a low.carbohydrate diet for achie#ing and maintaing a healthy weight together with the effects on the heart and other systems of the body. References 1. 2oster 9D, ;yatt 6*, 6ill C5, )c9uckin 89, 8rill (, )ohammed 8,, ,Bapary 15, *ader DC, &dman C,, <lein ,. $ randomiBed trial of a low.carbohydrate diet for obesity. A &ngl C )ed 2//0; 07?:2/?2.2/4/. !1ub)ed" (. ,amaha 22, %3bal A, ,eshadri 1, (hicano <=, Daily D$, )c9rory C, ;illiams T, ;illiams ), 9racely &C, ,tern =. $ low.carbohydrate as compared with a low.fat diet in se#ere obesity. A &ngl C )ed 2//0; 07?:2/:7.2/?1. !1ub)ed" ). ,tern =, %3bal A, 1rakash ,eshadri, (hicano <=, Daily D$, )c9rory C, ;illiams T,

;illiams ), 9racely &C, ,amaha 22. The effects of low.carbohydrate #ersus con#entional weight loss diets in se#erely obese adults: one.year follow.up of a randomiBed trial. $nn %ntern )ed 2//7; 17/:::?.:?-. !1ub)ed"

*he Story of #nsulin

#nsulin Synthesis The insulin.making cells of the body are called beta cells, and they are found in the pancreas gland. These cells clump together to form the islets of =angerhans , named for the 9erman medical student who described them. The synthesis of insulin begins at the translation of the insulin gene, which resides on chromosome 11. During translation, two introns are spliced out of the m*A$ product, which encodes a protein of 11/ amino acids in length. This primary translation product is called preproinsulin and is inacti#e. %t contains a signal peptide of 27 amino acids in length, which is re3uired for the protein to cross the cell membrane. 5nce the preproinsulin reaches the endoplasmic reticulum, a protease clea#es off the signal peptide to create proinsulin. 1roinsulin consists of three domains: an amino. terminal 8 chain, a carbo'yl.terminal $ chain, and a connecting peptide in the middle known as the (.peptide. ;ithin the endoplasmic reticulum, proinsulin is e'posed to se#eral specific peptidases that remo#e the (.peptide and generate the mature and acti#e form of insulin. %n the 9olgi apparatus, insulin and free (.peptide are packaged into secretory granules, which accumulate in the cytoplasm of the beta cells. &'ocytosis of the granules is triggered by the entry of glucose into the beta cells. The secretion of insulin has a broad impact on metabolism. #nsulin Structure %n 14-?, 2rederick ,anger was awarded his first Aobel 1riBe for determining the se3uence of the amino acids that make up insulin. This marked the first time that a protein had had the order of its amino acids !the primary se3uence" determined. %nsulin is composed of two chains of amino acids named chain $ !21 amino acids" and chain 8 !0/ amino acids" that are linked together by two disulfide bridges. There is a 0rd disulfide bridge within the $ chain that links the +th and 11th residues of the $ chain together. %n most species, the length and amino acid compositions of chains $ and 8 are similar, and the positions of the three disulfide bonds are highly conser#ed. 2or this reason, pig insulin can be used to replace deficient human insulin le#els in diabetes patients. Today, porcine insulin has largely been replaced by the mass production of human proinsulin by bacteria !recombinant insulin".

%nsulin molecules ha#e a tendency to form dimers in solution, and in the presence of Binc ions, insulin dimers associate into he'amers. ;hereas monomers of insulin readily diffuse through the blood and ha#e a rapid effect, he'amers diffuse slowly and ha#e a delayed onset of action. %n the design of recombinant insulin, the structure of insulin can be modified in a way that reduces the tendency of the insulin molecule to form dimers and he'amers but that does not interrupt binding to the insulin receptor. %n this way, a range of preparations of insulin is made, #arying from short acting to long acting. #nsulin secretion *ising le#els of glucose inside the pancreatic beta cells trigger the release of insulin:

1. 9lucose is transported into the beta cell by type 2 glucose transporters !9=>T2". 5nce inside, the first step in glucose metabolism is the phosphorylation of glucose to produce glucose.+.phosphate. This step is catalyBed by glucokinase it is the rate.limiting step in glycolysis, and it effecti#ely traps glucose inside the cell. (. $s glucose metabolism proceeds, $T1 is produced in the mitochondria. ). The increase in the $T1:$D1 ratio closes $T1.gated potassium channels in the beta cell membrane. 1ositi#ely charged potassium ions !<F" are now pre#ented from lea#ing the beta cell. +. The rise in positi#e charge inside the beta cell causes depolariBation.

,. @oltage.gated calcium channels open, allowing calcium ions !(a2F" to flood into the cell. -. The increase in intracellular calcium concentration triggers the secretion of insulin #ia e'ocytosis.

There are two phases of insulin release in response to a rise in glucose. The first is an immediate release of insulin. This is attributable to the release of preformed insulin, which is stored in secretory granules. $fter a short delay, there is a second, more prolonged release of newly synthesiBed insulin. 5nce released, insulin is acti#e for a only a brief time before it is degraded by enBymes. %nsulinase found in the li#er and kidneys breaks down insulin circulating in the plasma, and as a result, insulin has a half.life of only about + minutes. This short duration of action allows rapid changes in the circulating le#els of insulin. #nsulin Rece.tor The net effect of insulin binding is to trigger a cascade of phosphorylation and dephosphorylation reactions. These actions are terminated by dephosphorylation of the insulin receptor. ,imilar to the receptors for other polypeptide hormones, the receptor for insulin is embedded in the plasma membrane and is composed of a pair of alpha subunits and a pair of beta subunits !2igure 1". The alpha subunits are e'tracellular and contain the insulin. binding site. The beta subunits span the membrane and contain the enByme tyrosine kinase. <inases are a group of enBymes that phosphorylate proteins !the re#erse reaction is catalyBed by a group of enBymes called phosphatases". %nsulin binding to the alpha subunits induces a conformational change that is transmitted to the beta subunits and causes them to phosphorylate themsel#es !autophosphorylation". $ specific tyrosine of each beta subunit is phosphorylated along with other target proteins, such as insulin receptor substrate !%*,". $s these and other proteins inside the cell are phosphorylated, this in turn alters their acti#ity, bringing about the wide biological effects of insulin. #nsulin "ction The binding of insulin results in a wide range of actions that take place o#er different periods of time. $lmost immediately, insulin promotes the uptake of glucose into many tissues that e'press 9=>T7 glucose transporters, such as skeletal muscle and fat. %nsulin increases the the acti#ity of these transporters and increases their numbers by stimulating their recruitment from an intracellular pool to the cell surface. Aot all tissues re3uire insulin for glucose uptake. Tissues such as li#er cells, red blood cells, the gut mucosa, the

kidneys, and cells of the ner#ous system use a glucose transporter that is not insulin dependent. 5#er minutes to hours, insulin alters the acti#ity of #arious enBymes as a result of changes in their phosphorylation status. 5#er a period of days, insulin increases the amounts of many metabolic enBymes. These reflect an increase in gene transcription, m*A$, and enByme synthesis.

*able 1. Com.arison of *y.e 1 and *y.e ( Diabetes Type 1 diabetes Type 2 diabetes

1henotype 5nset primarily in 5nset predominantly after 7/ years of ageG childhood and adolescence 5ften thin or normal weight 5ften obese 1rone to ketoacidosis Ao ketoacidosis %nsulin administration %nsulin administration not re3uired for sur#i#al re3uired for sur#i#al 1ancreas is damaged by an 1ancreas is not damaged by an autoimmune attack autoimmune attack $bsolute insulin deficiency *elati#e insulin deficiency andEor insulin resistance Treatment: insulin Treatment: !1" healthy diet and increased inDections e'ercise; !2" hypoglycemic tablets; !0" insulin inDections 9enotype %ncreased pre#alence in %ncreased pre#alence in relati#es relati#es %dentical twin studies: %dentical twin studies: usually abo#e :/I H-/I concordance concordance 6=$ association: Jes 6=$ association: Ao G Type 2 diabetes is increasingly diagnosed in younger patients.