Physiology of Endocrine Pancreas And

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Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus 6-1

PATHOPHYSIOLOGY COURSE - ENDOCRINE MODULEPhysiology of Endocrine Pancreas and

Pathophysiology of Diabetes Mellitus (DM)Abbas E. Kitabchi, Ph.D., M.D.

Friday, December 4, 2009, 8:00-9:50amObjectives

1. List hormones in the islets of Langerhans, their location and their relation to each other.

2. Describe general function of these hormones and their inhibitors and stimulators.

3. Define general principle of insulin synthesis, its precursor, proinsulin and its by-product, C-peptide, and their biological potencies.

4. Describe the action of insulin and its role, as well as the role of counterregulatoryhormones in regulation of fuel metabolism in fed and fasted states.

5. Define diabetes, its epidemiology, complications and their impact on the U.S. population.

6. Classify the latest method of diabetes diagnosis and recent criteria for diagnosis ofDM, impaired glucose tolerance (IGT), impaired fasting, and gestational diabetes(GDM).

7. Characterize the differences between type 1 and type 2 DM.

8. Describe the general principles relating to the pathogenesis of type 1 versus type 2 DM.

9. Classify various causes of insulin resistance and the factors leading to insulin

resistance in type 2 DM. Distinguish it from metabolic syndrome.

10. Identify subjects at risk for development of type 1 and type 2 DM.

11 Correlate clinical conditions to metabolic defects and clinical manifestations of thediabetic syndrome.

12. Know how to calculate: a) Ideal body weight (IBW), b) Body mass index, c) Caloricrequirement based on ideal body weight.

13. Know significance of glycated hemoglobin (HbA1c) in DM.

14. Know the study objectives and outcome of four landmark studies regarding relation ofglycemic control to microvascular and macrovascular complications in diabetes.

15. Know the landmark studies and outcomes in the prevention of type 2 DM.

16. Know the emerging concept on physiology of fat tissues and its mechanism of actionof its adipokines.


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HORMONES OF THE ENDOCRINE PANCREAS

The adult pancreas contains about one million islets, with the largest concentration in thetail. These constitute less than 3% of pancreatic mass. The islets are highly vascularizedthrough the pancreatic artery, which is drained into the portal vein, which delivers the

entire secretion of pancreatic hormones into the liver. The islets are also innervated bythe autonomic nervous system-parasympathetic (vagus nerve) and sympathetic (middlesplanchnic nerve) fibers on or near secretory cells. There are four major cell types in the

islets of Langerhans: -cell, responsible for the production of glucagon, -cell for

production of insulin, -cell for production of somatostatin, and F (or PP) cell, responsiblefor the production of pancreatic polypeptide. (Figure 1 depicts the architecture of majorcells in the islet of Langerhans).

FIGURE 1

Arrangement of Cells in a Typical Islet

From Unger and Orci, Physiology and Pathophysiology of Glucagon, Physiol. Rev. 56:778-838, 1976.


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has multiple biological activities through G protein. In addition, recent studies suggest thatC-peptide may have therapeutic properties in improving nephropathies and neuropathiesin type 1 diabetics who are deficient in C-peptide. Because of its common antigenicdeterminant with proinsulin, C-peptide cross-reacts with proinsulin but not with insulin intheir specific radioimmunoassays (RIAs). Hence assay of C-peptide in blood, under

conditions when endogenous insulin cannot be measured, may be a clinically usefulmethod for assessing pancreatic insulin reserve. For example, patients who receiveexogenous insulin treatment may develop antibodies directed against that foreign insulinprotein. While these antibodies usually do not significantly influence the biologic effect ofthe injected insulin, they do interfere with the RIA for insulin. In that situation,measurement of C-peptide will provide an estimate of the patients own remaining insulin-secretory capacity and may help in distinction between type 1 and type 2 diabetes.

Human insulin is a 6000-molecular weight protein made up of 51 amino acids, arrangedas two polypeptide chains. The A chain has 21 amino acids and is linked to the B chainby two disulfide bridges. There is a single intrachain disulfide bridge on the A chain.

The fasting insulin concentration in blood is about 10-11

M. It is stored in the -cells and issecreted in two phases as shown in Figure 3.

FIGURE 3

The first phase, which is coupled to increases in cytosolic Ca2+

from 10-7

to 10-5

M, lastsonly a few minutes. It is stimulated by compounds such as glucose and amino acids, andCa

2+plays an important role. Thus, Ca

2+, like sulfonylurea (a class of oral hypoglycemic


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agents used in the treatment of type 2 DM), stimulates insulin secretion but not synthesis.The second phase of insulin secretion, which lasts longer, may be mediated through cyclicadenosine monophosphate (cAMP). Release of insulin involves two processes: 1) amicrotubular system (margination) for transport of granules from the cytoplasm toward theplasma membrane, and 2) a microfilamentous system for final delivery of the granule to

membrane (exocytosis). In addition to glucose, there are other stimuli and inhibitors forinsulin secretion, as noted in Table 1.

TABLE 1

Stimulators and Inhibitors of Insulin Release

Stimulators Inhibitors

Carbohydrates CarbohydratesGlucose 2-DeoxyglucoseFructose D-Mannoheptulose

Polypeptide HormonesGlucagon Epinephrine

ACTH (not in human) NorepinephrineGrowth hormone Somatostatin

Amino Acids MiscellaneousStarvationDiazoxideHypoxia

Fatty acids Hypothermia

VagotomyEnteric hormones HypoglycemiaSecretinPancreozyminGastrinGut glucagon

MiscellaneousCyclic 3, 5-AMPGlucocorticoidsKetones, Calcium

Potassium, SulfonylureaVagal stimulationMethylxanthines


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Thus, the -cell response to insulin secretagogues is biphasic fashion. An initial, rapidburst occurs within the first few minutes that releases preformed insulin from a rapidlymobilizable pool. This phase usually responds to glucose, amino acids sulfonylurea,glucagon and gastrointestinal (GI) hormones. The second phase, which occurs after about10 minutes and continues for as long as an hour, is stimulated by glucose and aminoacids, and involves the release of preformed insulin, newly synthesized insulin, and

proinsulin. GI hormones (e.g., glucose-dependent insulinotropic polypeptide, gastrin,secretin and gut glucagon) are also stimulatory to insulin secretion. Thus, a greater insulinresponse occurs following oral glucose (OGTT), as compared to an intravenous glucosechallenge (IVGTT).

An adult human secretes approximately 40-50 units of insulin per day. Depending on thepurity of the preparation, 1mg of insulin is equal to approximately 26 to 30 units, of whichapproximately 50% is unstimulated or basal (preprandial) and the remaining is secretedas pulses in response to food ingestion (postprandial).

Insulin action: Insulin is essential for survival; its lack leads to rapid wasting and death.

Insulin has major effects on lipid, protein and carbohydrate metabolism in insulin-sensitivetissues (e.g., fat, muscle, liver), where its action is exerted at physiologic concentrations ofthe hormone (10

-11to 10

-10M). The actions of insulin may be classified as immediate,

intermediate or long-term as indicated in Table 2. Insulin, in general, is an anabolichormone that stimulates protein, glycogen, and lipid synthesis, and inhibits lipolysis andgluconeogenesis.


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TABLE 2

Effects of Insulin on Target Tissues

Immediate TissueMembrane transport of glucose Muscle, adipose, liver

Membrane transport of amino acids Muscle, adipose, liverMembrane transport of certain ions (?) Red blood cell (?)

IntermediateCarbohydrate metabolism

Glycogen synthesis Muscle, liver

Glycogenolysis Muscle, Liver

Gluconeogenesis Liver

Lipid metabolism

Lipogenesis Liver, adipose

Esterification Liver, adipose

Lipolysis Adipose

Cholesterol synthesis Liver

Ketogenesis Liver

Utilization of dietary lipid Liver, adipose

Fatty acid oxidation Liver, adipose

Protein metabolism

Protein synthesis Liver, muscle, adipose

Proteolysis Liver, muscle

Long-termPromotion of cell growthPromotion of cell division

Although the molecular basis of insulin action has been the subject of intensiveinvestigation, and numerous low and higher molecular weight compounds have beenproposed as putative mediators of insulin action on certain enzymes, to date the identity ofthese second messengers has remained elusive. However, following is the summary of

the mechanism of action of insulin, as we understand it at this time. Insulin action isinitiated by its binding to specific cell receptor on insulin sensitive tissues (i.e. muscle, fat,liver). (The insulin receptor gene is located on the short arm of chromosome 1 near theLDL receptor gene.) This receptor is highly specific for insulin with high affinity. Thereceptor has two subunits, a) an alpha subunit with molecular weight of 130,000, which islocated extracellularly and binds to insulin molecule; and b) a small beta subunit withmolecular weight of 90,000, which spans cell membrane and extends in the cytoplasm. Itcontains tyrosine kinase, which becomes activated when insulin binds to the receptor. This


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results in autophosphorylation of the beta subunit and cascade of phosphorylation whicheventually leads to movement of glucose transporter (GLUT 4) from the cytoplasm to themembrane to facilitate glucose transport across the cell membrane, plus many otherevents shown in Figures 4 and 5.

Table 3 demonstrates numerous glucose transporters. However, only two of these GLUTs

are insulin sensitive.

FIGURE 4

Figure 4: Signal transduction in insulin action. The insulin receptor is a tyrosine kinasethat undergoes autophorylation, and catalyses the phosphorylation, these proteins interactwith signaling molecules through their SH2 domains, resulting in a diverse series ofsignaling pathways, including activation of Pl(3)K and downstream Ptdlns(3,4,5) P3-dependent protein kinases, Ras and the MAP kinase cascade, and Cbl/CAP and theactivation of TC10. These pathways act in a concerted fashion to coordinate the regulationof vesicle trafficking, protein synthesis, enzyme activation and inactivation, and geneexpression, which results in the regulation of glucose, lipid and protein metabolism.


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TABLE 3

Classification of Glucose Transport and Hexokinase (HK) Activity According to

Their Tissue Distribution and Functional Regulation

Glucose

Organ Transporter HK Coupler Classification

Brain GLUT 1 HK-I Glucose dependentErythrocyte GLUT 1 HK-I Glucose dependent

Adipocyte GLUT 4 HK-II Insulin dependentMuscle GLUT 4 HK-II Insulin dependentLiver GLUT 2 HK-IVL Glucose sensor

GK -cell GLUT 2 HK-IVB (glucokinase) Glucose sensorGut GLUT 3-symporter - Sodium dependentKidney GLUT 3-symporter - Sodium dependent

FIGURE 5

Hypothetical Model of Insulins Action on Glucose Transport

(A) Sequence of events involved in insulin stimulation of glucose transport in muscle andadipose cells: (1) insulin binding to its receptor in the plasma membrane initiates a cascade ofsignals resulting in (2) the translocation of glucose transporters from an intracellular poolassociated with membrane vesicles to the plasma membrane where they (3) dock, (4) fuse,and (5) are further activated. (B) Potential functional defects contributing to insulin-resistant


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glucose transport in muscle in diabetes, obesity, and other insulin-resistant states. Defectsmay involve (1) deficient signaling, (2) impaired translocation, (3) persistent docking withoutfusion, (4) partial fusion rendering transporters cryptic with inadequate exposure to theextracellular milieu, or (5) reduced activation of transporters.

Glucagon

The second hormone produced by the islets of Langerhans is glucagon, (whose gene is onhuman chromosome 2) a single-chain, 3485 mol. wt., polypeptide hormone made up of 29amino acids. It is synthesized and released from the pancreatic -cells from a larger 160amino acid precursor (proglucagon). In this larger precursor exists many other glucagon-likepeptides (GLP) I and II which are released after meals from the proximal small intestine. Atruncated GLP-1 (GLP-1 minus 1st six amino acids) is also more potent stimulator thanpancreatic glucagon (incretin). An intestinal hormone Glicentin is part of proglucagonmolecule. Whereas insulin and C-peptide have species specificity, human glucagon structureis similar to all other species. The concentration of glucagon in blood is normally 10

-10M, and

it occurs as a monomer. Unlike insulin secretion, which is biphasic in normal individuals, the

glucagon response to a standard meal containing carbohydrate, fat, and protein involves agradual, modest increase in the rate of secretion. However, in type 1 diabetes, glucagonlevels rise abruptly to a peak after 30 minutes. Conventional insulin therapy significantlyreduces the glucagon response in diabetics, but usually levels are still above those found innormal subjects. The major action of glucagon is in the liver through specific membranereceptor. Glucagon stimulates glycogen breakdown (glycogenolysis), glucose productionfrom non-carbohydrate precursor (gluconeogenesis) and ketone production (ketogenesis).Table 4 lists the inhibitors and stimulators of glucagon secretion and Table 5 summarizes thephysiologic actions of glucagon.

TABLE 4

Stimulator and Inhibitor of Glucagon Release

Stimulators Inhibitors

Amino Acids (i.e., Arginine) GlucoseAcetylcholine InsulinEpinephrine SomatostatinNorepinephrine KetonesVIP FFACCK HyperglycemiaHypoglycemia


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TABLE 5

Effects of Glucagon on Intermediary Metabolism

Effects Tissue

Carbohydrate Metabolism

Stimulation of glycogenolysis LiverInhibition of glycogen synthesis LiverStimulation of gluconeogenesis Liver, Kidney, CortexInhibition of glycolysis Liver

Lipid MetabolismStimulation of lipolysis AdiposeStimulation of ketogenesis LiverInhibition of triglyceride synthesis Liver

Protein metabolism

Stimulation of proteolysis? Liver, Muscle

TABLE 6

Paracrine, Autocrine and Juxtacrine Control of Pancreatic Hormones

Insulin Glucagon Somatostatin

Insulin - - -

Glucagon + - +

Somatostatin - - -

- Negative sign denotes inhibition.

+ Positive sign denotes stimulation.

TABLE 7

Biological Activities of Somatostatin

Body System Inhibition of Secretion or ReductionEndocrine

Pituitary Growth hormone, ACTH, ThyrotropinPancreatic islets Insulin; Glucagons, Pancreatic PolypeptideGastrointestinal tract Gastrin, Pancreozymin, Secretin, Vasoactive

Intestinal Peptide, Gastric Inhibitory Polypeptide,

Motilin, Gut Glucagon-Like (GLP) Peptide

Nonendocrine Gastric acid secretion, pancreatic bicarbonate &Gastrointestinal tract enzyme release, gastric motility, gallbladder

contraction

Liver Splanchnic blood flow


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TABLE 8

Actions of Pancreatic Polypeptide

Endocrine PancreasInhibits insulin secretionInhibits somatostatin secretion

Gastrointestinal TractInhibits pancreatic zymogen secretionDecreases gall bladder contractilityReduces gastrointestinal motilityInhibits gastric acid secretion

Somatostatin

A third hormone of the endocrine pancreas is somatostatin, a cyclic tetradecapeptide, with a

molecular weight of 1640, which is secreted by -cells of the islets of Langerhans.

Somatostatin is derived from a larger precursor called prosomatostatin. Between the outer rimof the -cell and the -cell core are scattered somatostatin-containing -cells, which compriseapproximately 10% of the total cells. All these three cell types are in contact with each otherthrough gap junctions. Glucagon is a potent stimulant of insulin and somatostatin secretion.On the other hand, somatostatin inhibits both insulin and glucagon secretion. Somatostatin, inconjunction with insulin, inhibits glucagon secretion and diminishes postprandialhyperglycemia by approximately 50%. These relationships are summarized in Table 6.

In addition to inhibiting insulin and glucagon secretion and being stimulated by almost allinsulin secretogogues, somatostatin acts in several other ways (Table 7). These includeprolongation of gastric emptying time, decreasing gastrin acid and gastrin secretions,

diminishing pancreas exocrine secretion, decreasing splanchnic blood flow and restrainingmovement of nutrients from intestinal tract into the circulation. Calcium is important foroptimum secretion of somatostatin.

Pancreatic Polypeptide (PP)

PP is a 36 amino acid peptide with molecular weight of 4200. It is synthesized and secretedby F cells (or PP cells). The level of PP is increased with ingestion of a mixed meal, but not IVinfusion of glucose or triglyceride. Although the physiologic role of this peptide is not known, itis increased in pancreatic endocrine tumors such as glucagonoma, vipoma and in all patientswith tumors of pancreatic F cells. PP is also increased in old age, alcohol abuse, diarrhea and

chronic renal disease. PP is increased about ten-fold in pancreatic tumors.


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HORMONAL CONTROL OF INTERMEDIARY METABOLISM

In order to understand the interrelationships of fuel metabolism under feeding and fastingsituations and relate this to the pathophysiology of diabetes mellitus, we will describe thephysiologic conditions in the fed and fasting states and their role in intermediary metabolism.Figure 6 illustrates the effect of an ordinary meal with its three components (fat, protein and

carbohydrate) as they interact with gut mucosa with their respective breakdown to FFA, aminoacid and glucose (as well as effects of various hormones produced by the gut) and their effecton insulin and glucagon secretion.

FIGURE 6

Effects of an Ordinary Meal Containing Fat, Carbohydrate and Protein

From Kitabchi AE: Hormonal control of glucose metabolism. Otolaryngol Clin North

Am 8:335, 1975

This figure demonstrates how the interaction of foodstuff with intestinal mucosa brings aboutgeneration of certain substrates and chemicals which stimulate insulin secretion while othercomponents such as amino acids, GIP and VIP specifically stimulate glucagon production.Thus interaction and synchronization of these two hormones facilitate assimilation ofsubstrates into energy (without hypoglycemic effect of insulin), while through action ofglucagon (and somatostatin), euglycemia prevails and both hypoglycemia and hyperglycemiaare prevented in normal subjects.

Figure 7 illustrates the sources and fates of glucose, and shows how glucose homeostasis ismaintained through a variety of processes. Note that muscle glycogen cannot directlycontribute to blood glucose because of a lack of glucose-6-phosphatase in muscle. Muscleglycogen must, therefore, be converted to various intermediates before it can be used as asource of energy outside the muscle itself.


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FIGURE 7

Sources and Fate of Glucose

From Kitabchi AE: Metabolic effects of neuropeptides, in Givens JR (ed): Hormone-Secreting Pituitary Tumor, Chicago, Year Book, 1982a, pp 45-62.

Fed State: Insulin is the major hormone of the fed state.

The ingestion of a meal increases insulin secretion immediately. The rise in serum insulin isproportional to the rise in serum glucose for a short time and promotes the assimilation ofglucose, amino acids and fatty acids to energy. For each 100g of glucose ingested,approximately 60g is taken by the liver for glycogen synthesis, 25g by noninsulin-dependenttissues and 15g by insulin-dependent tissues, especially muscle and fat, to increase protein

and fat synthesis in these tissues respectively while inhibiting lipolysis and proteolysis. Duringthis period of food intake there is a reduced requirement for fatty acids for fuel; in fact,lipolysis of triglycerides to glycerol and free fatty acid (FFA) is inhibited by insulin.Carbohydrate ingestion is a signal for reduced secretion of the catabolic hormone glucagon.Thus, eating a meal usually reduces the need for glucagon-mediated fuel mobilization.

Fasting State: Glucagon, catecholamines and cortisol are the major hormones of fastingstate (stress or severe metabolic decompensation in DM).

Fasting is defined as the condition where the body is deprived of food for at least four hours.The body responds to fasting similar to stress or hyperglycemia. This fasting situation,

therefore, brings about certain metabolic alterations in order to protect the brain againstdeficiency of its specific fuel, glucose. In order to accomplish this, certain hormonaladjustment will prevail in the body which is very similar to other stressful situations in general,but only to a different degree of severity. To accomplish the goal of ensuring glucose for thebrain two processes must be accomplished: 1) decreased glucose utilization by insulinsensitive tissues, and 2) increased glucose production by the liver from non-carbohydrateprecursors (gluconeogenesis). These are accomplished by reduced secretion of insulin by thepancreas and increased secretion of counterregulatory hormones in the fasting state. The

Ingested

Carboh drate

Hepatic

Glycogen

Oxidation

Lactic Acid

Blood

Glucose

Muscle

Glycogen

Oxidation

FatGluconeogenesis


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detailed mechanism of these changes will be further discussed under the heading of acutecomplications of DM (i.e., DKA).

When ingestion of food is delayed, the prevailing condition is that of the non-absorptive orfasted state. The blood insulin concentration falls to a level that prevents significanttransport of glucose to muscle and adipose tissue, while still permitting glucose uptake by

noninsulin-dependent tissues such as the brain, white blood cells (WBC), and red bloodcells (RBC). Thus, of the total amount of glucose produced by the liver as a result ofglycogenolysis and gluconeogenesis, approximately 60% of the glucose is used by thebrain, 20% by WBC, and 20% by RBC, with negligible amounts going to adipose tissue ormuscle. Glucagon favors hepatic utilization of amino acids, especially alanine, to produceglucose (gluconeogenesis), and stimulation of glycogenolysis to augment hepatic glucoseoutput. In the presence of decreased insulin levels in the fasting state, the anti-lipolyticeffect of insulin is reduced. This, along with some increase in catecholamines, stimulatesbreakdown of tissue triglyceride to glycerol and FFA (lipolysis). Fatty acids are used not onlyby muscle for energy, but they also serve as substrates for ketogenesis. Thus, the majorhormones of starvation are 1) glucagon, which stimulates gluconeogenesis and

ketogenesis, 2) catecholamines, which in humans serve as the major lipolytic hormones,facilitating breakdown of triglycerides to FFA and glycerol, and also inhibit glucoseutilization, and 3) cortisol, which, along with increased glucagon (in the absence of insulin),brings about decreased synthesis of protein and increased proteolysis, resulting inincreased amino acids (namely alanine) which provides substrate for gluconeogenesis.Glycerol serves as a carbon skeleton for gluconeogenesis, whereas oxidation of fatty acidsprovides reducing equivalents for the gluconeogenic pathway. Excess FFA (as a result ofincreased lipolysis) is also used as substrate for VLDL production and ketogenesis in theliver, as well as fuel for cardiac and skeletal muscles through conversion to acetyl COA andentrance into the Krebs Cycle (TCA cycle).

Therefore, in the fasting state, in addition to reduction of insulin secretion, three majorhormones which have the opposite effect to that of insulin (and hence are calledcounterregulatory hormones) are increased. As stated, these hormones are: glucagon,catecholamines, and cortisol. Growth hormone may also contribute to this mechanism as afourth counterregulatory hormone.

Fasting, similar to hypoglycemic state results in reduced insulin and increasedcounterregulatory hormones.

Figure 8 depicts the response of counterregulatory hormones and C-peptide to insulin-induced hypoglycemia in a normal subject. Notice transient severe changes in manyhormones with hypoglycemia (or other metabolic insults) and a return to basal levels afterrecovery from hypoglycemia.


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FIGURE 8

DIABETES MELLITUS

Diabetes mellitus (DM) is a chronic disorder characterized by fasting hyperglycemia orplasma glucose levels that are above defined limits during oral glucose tolerance testing(OGTT), or on random blood glucose measurements, as defined by established criteria.The newly (2003) established classification for various forms of hyperglycemias is detailedin Table 9 and the newly established diagnostic criteria for various forms of hyperglycemiaare summarized in Table 10. There are only 3 methods by which diabetes is diagnosed

(Table 10).

DM is a heterogeneous group of clinical disorders with abnormalities in the metabolism ofcarbohydrate, protein and fat that results primarily from the deficiency in the synthesis,secretion or function of insulin. The disease is associated with microvascular,macrovascular, and metabolic complications.

If we are to reduce morbidity and/or mortality of DM, we must identify people at risk fortype 2 diabetes in order to make an appropriate intervention.


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TABLE 9

Classification of Various Hyperglycemias

Diabetes Mellitus (DM)

Type 1 diabetesa. Immune Mediated (type 1A)

b. Idiopathic (type 1B)Type 2 diabetes

Individuals with insulin resistance who usually have relative rather thanabsolute insulin deficiency. (Obese or non-obese)

Other types of diabetesPancreatic disease and pancreatic surgeryEndocrinopathies (Cushings, Acromegaly, Pheochromocytoma,Hyperaldosteronism)Drug-induced

Gestational diabetes (GDM)

Impaired Glucose Tolerance (IGT)

TABLE 10

Criteria for the Diagnosis of Hyperglycemias: 2003 ADA Guidelines

Plasma Glucose (mg/dl)

Stage of Glycemic Fasting Plasma OGTT

Control Glucose (2-hr Post load Glucose)

Normal < 100 < 140

IFG (Impaired fasting glucose) 100 - 125orIGT 140 - 199

Diabetes* > 126 > 200

* Third criterion: >200 mg/dL casual plasma glucose (regardless of the time since lastmeal) plus symptoms of diabetes (polyuria, polydipsia, unexplained weight loss) ADA,Diabetes Care 26:2003.


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Epidemiology and Risk Factors in DM

There are approximately 23.6 million persons with diabetes in the United States with overone million as type 1 DM (prevalence of 0.4%) and 22 million as type 2 DM (prevalence of8%), of whom about 440,000 (prevalence of 3%) are not diagnosed. There areapproximately 57 million persons with IFG (prediabetes), or 25.9% of the U.S. population.

In 2007, there were 1.6 million new cases of diabetes diagnosed in the U.S., whichrepresents more than 4300 new cases every day.

Diabetes has reached epidemic proportions. Thus, it is estimated that by the year 2030India will have about 80 million (from 32 million in year 2000), China will have 45 million(from 21 million in 2000). And the U.S. will have 30 million (projected from 16 million in2000) persons with diabetes. The risk factors that are controllable in T2DM are sedentarylifestyle, central obesity and BMI. The risk factors that are not controllable in T2DM areethnicity, age, and heredity.

Type 1 DM constitutes 5- 10% of all DM in the U.S. It is believed to be an autoimmunerelated disorder which results in insulinopenia. The disease is not familial, nevertheless,the risk is increased in family members. Table 11 provides lifetime risks for type 1 DM.

The incidence of type 2 DM is related to multiple factors as well as based on ethnic group.Thus the incidence of type 2 DM in Blacks is twice, in Hispanics 3 times, and in AmericanIndians about 5 times more than in Whites. The incidence of type 2 DM is also increasedwith age, adiposity and number of family members with diabetes (Tables 11 and 12.) Thusa 60 year old Pima Indian has a 60 % chance of developing type 2 DM.

TABLE 11

Estimated Lifetime Risks of Type 1 DMClassification Risk (%)

GENERAL POPULATION

Background risk 0.4DR 3/4 2.4Susceptible DR/DQ alleles 6 - 8.5

FAMILY MEMBERS

Parents 3Offspring 5Sibling 6 - 8Identical twins 30 - 50HLA

identical 10 - 16haploidentical 2 - 9non-identical 0 - 1


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Diabetes is one of the four major risk factors for cardiovascular diseases. Coronary arterydisease (CAD) is seen twice as often in men and four times as frequently in women withdiabetes as in the nondiabetic population. The incidence of peripheral vascular disease atthe time of diagnosis of type 2 DM is about 8%, with an increase to 45% after 20 years.The risk of stroke in diabetes is increased two to four times, and diabetes is responsible forover 60% of nontraumatic lower limb amputations. In addition to these problems, diabetes

is the leading cause of blindness in adults and is associated with an increased risk ofglaucoma and cataract. Kidney disease occurs in 35% of type 1 and 20% of type 2patients, and diabetes accounts for 43% of the new cases of end stage renal disease(ESRD) each year. The annual cost of care, wages lost, etc., for all U.S. patients withdiabetes in 2007 is estimated at 174 billion dollars. About 70% of the total cost of DM wasfor outpatient and in-patient care of DM patients. In addition there is an un-estimatedamount of psychological problems.

In general, detection of type 1 DM is based on the acuteness of the disease in the majorityof the cases and therefore, screening is not recommended in routine medical care, but isimportant if clinical investigation is indicated for prevention of type 1 DM for those with high

risk. Table 11 provides information on estimated lifetime risk for type 1 DM. However, intype 2 DM the appearance of the disease is insidious; therefore, people who are at risk fordevelopment of diabetes (Table 12) need to be screened to detect DM [i.e. fasting bloodglucose (FBG) or OGTT)].

Table 12 lists the populations who are at risk and, therefore, need to be tested for diabetesby OGTT or FBG.

TABLE 12*

Population at Risk for Type 2 Diabetes Mellitus (younger than 45 years old)

1. Persons with classic signs and symptoms of diabetes (i.e., polyuria, polydipsia,

polyphagia, and loss of weight).

2. Obesity (particularly upper body adiposity) with BMI 27 Kg/m2

or 120% of ideal body

weight.

3. Strong family history of Type 2 DM.

4. Ethnic groups (i.e., Blacks, Hispanics, Native Americans, and Asians)

5. History of delivering infant weighing greater than nine pounds.

6. Having a HDL 35 mg/dl or TG 250 mg/dl.

7. History of impaired glucose tolerance or impaired fasting glucose.

8. History of gestational diabetes.

9. History of coronary artery disease and/or hypertension ( 140/90)

10. Persons ingesting high doses of corticosteroids.

All persons 45 years or older should be screened for DM every year and if normal, bescreened every three years. *Adapted from ADA Guidelines, Diabetes Care 1997


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Table 13 (below) provides the characteristics of Type 1 and Type 2 diabetes mellitus.

TABLE 13*Major Characteristics of Types 1 and 2 Diabetes Mellitus

Features Type 1 DM Type 2 DM

Age at onset Usually 40

Proportion of all diabetes About 10% About 90%

Seasonal trend Fall and Winter None

Appearance of symptoms Acute or sub acute Slow or sub acute

Metabolic Ketoacidosis Frequent Rare***

Obesity at onset Uncommon Common

-Cells Decreased Variable

Insulin Decreased or absent Variable

Inflammatory cells in islets Present initially Absent

Family history of diabetes Uncommon Common

Concordance in identical twins 30-50% 90-95%

HLA Association Yes No

Antibody to islet cells (ICA) Yes Uncommon

Insulin autoantibodies (IAA) Yes (in younger age) No

64K GAD* antibodies Yes No

Treatment Insulin and diet & Diet, weight reduction,pancreas transplant exercise, OHA**, Insulin

*Glutamic acid decarboxylase (GAD); ** Oral hypoglycemic agents; *** Except in African-Americans


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PATHOGENESIS OF DIABETES MELLITUS

Type 1 Diabetes T1DM

Multifactorial inheritance and poorly understood environmental factors are involved in thepathogenesis of type 1 diabetes. The association of certain kinds of human leukocyte

antigens (HLA), abnormal immunologic response, infection with pancreatrophic viruses(mumps, rubella, Coxsackie B4, infectious mononucleosis, infectious hepatitis), toxins and

excessive stress may all be contributing factors to bring about destruction of the -cellwhich characterizes type 1 diabetes, the hallmark of which is insulin deficiency. In type 1diabetes an increased incidence of antibodies to various organs such as thyroid, adrenalglands and gastric cells has been observed. Furthermore, antibodies to pancreatic isletshave been detected by immunofluorescent techniques prior to diagnosis of overt disease,and some investigators have reported the presence of insulin autoantibodies in newlydiagnosed type 1 diabetics prior to therapy with insulin.

The term HLA is used to describe the major histocompatibility complex (MHC) in man,

which consists of three classes of closely linked genes on the short arm of chromosomesix (6), and consists of class I, class II and class III. Class II consists of DR, DQ, and DPloci. Certain HLA types (HLA-DR3 and HLA-DR4) are highly correlated with T1DM inCaucasians, although only 70% of type 1 diabetics have these HLA markers. These HLAtypes may vary with race as Blacks and Japanese may have different haplotypes.

Recent studies with refinement of DNA technology on HLA typing have shown that acertain haplotype of DR4, namely DQ3.1, is the susceptibility antigen most associated withdiabetes, whereas, DR2 is protective.

Additionally, some HLA types (such as DR4) may be associated with diabetic

complications such as proliferative retinopathy of DKA, but not DR3 in patients with T1DM.

Although the detailed mechanisms for destruction of -cells leading to type 1 diabetes arenot known, certain factors appear to play important roles. These consist of the followingcomponents: 1) Introduction of environmental or pancreotropic virus into the pancreaswhich leads to 2) production of an antigen. 3) This antigen is then processed bymacrophages which are antigen-presenting cells in whose membranes are located themajor histocompatibility complex [MHC II (DR3, DR4, etc.)] 4) The appropriate antigenconsisting of a peptide which fits into the groove of the class MHC II molecule of themacrophage must further fit into a receptor of the T-lymphocyte for CD4 T-helper cellactivation. 5) This brings about production of numerous cytokines and destruction of -

cells. These hypothetical relationships are depicted in Figure 10. When more than 90% of-cells are destroyed, the clinical condition of type 1 diabetes emerges. Presence ofdiabetes is usually preceded by production of multiple antibodies, including islet cellantibody (ICA), specific antibodies against 64K antigen (now identified as glutamic aciddecarboxylase (GAD) (From the islet?), and insulin autoantibody (IAA). Theserelationships are depicted in Figure 9.


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FIGURE 9

INEFFECTIVE

DEFENSE

BARRIERS

GENETIC

SUSCEPTIBILITY

INEFFECTIVE

IMMUNE

RESPONSE

Insulting Agent

e.g., Pancreotropic Virus

Autoimmune Process Begins

T-Lymphocytes Macrophages

(Ag presenting cell)

CD 4 TNF

Ag

Peptide

-Cell Destruction

>90% Destruction

Interleukin 1INF

Precipitating Factors orStressors

TYPE I Diabetes Mellitus

LEGEND:

AgAntigen

INFInterferon TNF Tumor

Necrosis Factor


23/48


FIGURE 10

GENETICPREDISPOSITIONLIFESTYLE ENVIRONMENT

OBESITY

INSULINRESISTANCE

HYPERINSULINEMIA

POSTPRANDIALHYPERGLYCEMIA

DECREASED -CELLSECRETION

FASTINGHYPERGLYCEMIA

TYPE 2 DIABETES

GLUCO-LIPO TOXICITY GENETICFACTORS

POSSIBLE

MECHANISM

FOR

PATHOGENESIS

OF OBESE TYPE

2 DIABETES


24/48


Type 2 Diabetes T2DM (Figure 10)

Type 2 diabetes is a heterogenous form of diabetes which usually occurs in individuals of

older age (i.e., 40 years). It is eight to ten times more common than type 1 andaccounts for greater overall morbidity. Genetic and environmental factors, aging andadiposity play important roles, but viral disease, HLA type, and other immune factors are

apparently not correlated with the disease. Analysis of identical twins with type 2 diabetesindicates approximately 90% concordance in the other twin. (Concordance in type 1 isabout 25-50%). One subclassification of type 2 is maturity-onset diabetes of the young(MODY), which seems to be transmitted as an autosomal dominant. MODY appears to bea rare condition which results in a less severe form of diabetes (see Table 14 for details).

The rates of insulin secretion and insulin levels in type 2 diabetes are variable dependingon age, the duration of diabetes, dietary regimen, prior glycemic control and adiposity.

NATURAL HISTORY OF TYPE 2 DIABETES

As can be seen from Figure 9 and Figure 10, insulin resistance is the precursor of T2DM,but not all subjects with insulin resistance develop T2DM. Therefore in order to developT2DM, both insulin resistance and -cell dysfunction must coexist. As obesity occurs in85-90% of T2DM patients, the natural history of T2DM may start with insulin resistanceand obesity where near normal FBG is maintained (IFG) with compensatory increase ininsulin in the prediabetic (IGT) state but with gradual increase in postprandial glucose.Both postprandial hyperglycemia and increased FFA, which are prevalent in IGT, may leadto decreased secretion of insulin from -cell as a result of both glucotoxicity andlipotoxicity, leading to exhaustion of -cells and development of insulinopenia and frankdiabetes. These events are depicted inFigures 9 and 10.

Thus, a newly discovered, obese, type 2 diabetic has a high basal insulin level(hyperinsulinemia) and fewer insulin receptors on insulin-sensitive target tissues. Thesepatients present with a fasting blood glucose value > 125 mg/dl. The high insulin level isdue to a compensatory increase in phase 2 insulin secretion as phase 1 insulin secretionin type 2 diabetes is decreased. (See Figure 3 for description of phase 1 and 2 insulinsecretion). With the progression of the disease, even phase 2 insulin secretion is reducedand the fasting plasma glucose gradually increases, so that when the latter value rangesbetween 160-200 mg/dl there is generally a significant reduction of insulin secretion (andlow C-peptide).

As can be seen from Figure 12, hepatic glucose production in both diabetic and non-

diabetic subjects is proportional to fasting plasma glucose. The hallmark of type 2 DM isinsulin resistance, as can be seen from Figure 13 where glucose uptake and metabolismis reduced by about 50% in the muscle. The major sites of insulin resistance in type 2 DMare in muscle tissue and liver. Figure 14 depicts the whole body glucose uptake in controlvs. normal and obese T2DM, compared to normal and obese non-diabetic subjects inregards to glucose oxidation and glucose storage.


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Figure 11: Natural History of Patients With Type 2 Diabetes

GeneticSusceptibility

EnvironmentalFactors:Nutrition

ObesityPhysical inactivity

PrediabetesOngoing

hyperglycemia

DeathInsulin resistanceHyperinsulinemia

HDL

TG

AtherosclerosisHyperglycemiaHypertension

RetinopathyNephropathyNeuropathy

BlindnessRenal failureCHDAmputation

Onset ofdiabetes

Complications

Disability

Death

The natural history of DM2 is depicted in Figure 11 indicating that as time progresses, hyperinsulinemia and near normalfasting blood glucose (IGT) eventually leads to hyperglycemia, insulinopenia and frank diabetes.


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FIGURES 12, 13, & 14

Genetics of Type 2 Diabetes:

Type 2 diabetes, which now affects more than 20 million Americans, is a chronic diseaseof multifactorial origin of polygenic nature, which means it cannot be ascribed to one geneor single environmental factor. Although various animal studies recently have discoveredsome candidate genes for diabetes, their connection to human diabetes is not certain.However, one form of type 2 diabetes, called Maturity Onset Diabetes of the Young(MODY), has now been associated with multiple forms of glucokinase genes including the

recently discovered glucokinase mutation gene HNF-4- . The table below lists some ofthe candidate genes for type 2 diabetes, with their function, effect, and their linkage to aparticular form of diabetes in animals and man.

Figure 12 (above). Relation of

Hepatic glucose production to

fasting plasma glucose in normal

weight diabetic subjects (o) vs.

age, weight matched control

subjects ().

Figure 13 (right). Glucose

metabolism during euglycemic

hyperinsulinemic clamp studies.

38 normal weight T2DM (NIDD)

and 33 age weight matched

controls.

From: DeFronzo (1991)

Figure 14 (above). Insulin-

medicated rates (euglycemic

insulin-clamp technique) ofwhole-body glucose intake

(total height of bar), glucose

oxidation, and nonoxidative

glucose disposal in control,

normal-weight diabetic, obese

nondiabetic, obese glucose-

intolerant, and obese diabetic

subjects.


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TABLE 14

SOME CANDIDATE GENES FOR TYPE 2 DIABETES

Mutated Gene Function Effect Linked to

HNF-4- , HNF-1- Transcription Insulin MODY (human)

IPF-1, NeuroD1 factors secretion________________________________________________________________

HNF-1- Transcription Insulin MODYFactor secretion Oji-Cree diabetes

________________________________________________________________

Glucokinase Glucose Insulin MODYMetabolism secretion

________________________________________________________________Calpain-10 Protease Unknown Diabetes 2 in

Mexican andAfrican Americans

________________________________________________________________

PPAR- Transcription Insulin Diabetes 2Factor sensitivity

________________________________________________________________

Insulin receptor Transmits Insulin Human diabetesinsulin signals sensitivity (rare); mouseinto cell and secretion models

________________________________________________________________

IRS 1 and2 Insulin Insulin Mouse modelssignaling sensitivity

________________________________________________________________

Akt2 Insulin Insulin Mouse modelssignaling sensitivity

________________________________________________________________

11- -HSD Glucocorticoid Blood Mouse Modelssynthesis lipids,

insulinsensitivity

________________________________________________________________

UCP2 ATP Insulin Mouse modelssynthesis secretion

________________________________________________________________Resistin Fat cell Insulin Mouse studieshormone sensitivity

________________________________________________________________

Adiponectin Fat cell Insulin Mouse, humanhormone sensitivity studies

Reference: Science, Vol 216, pages 685-689, 2002


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Prime suspect: the TCF7L2geneand type 2 diabetes risk

Andrew T. HattersleyInstitute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, United Kingdom.

Transcription factor-7

like 2 (TCF7L2) is the most important type 2 dia-betes susceptibilitygene identified to date, with common intronic variants strongly associated with diabetes inall major racial groups. This ubiquitous transcription factor in the Wnt signaling pathwaywas not previously known to be involved in glucose homeostasis, so defining theunderlying mechanism(s) will provide new insights into diabetes. In this issue of the JCI,Lyssenko and colleagues report on their human and isolated islet studies and suggest

that the r isk allele increases TCF7L2expression in the pancreatic cell, reducing insulinsecretion and hence predisposing the individual to diabetes (see the related articlebeginning on page 2155).

established, understanding the associatedpathophysiology was relatively straightfor-

ward. However, the very reasoning that led

to the genes being chosen also meant there

was not a lot of new scientific insights to be

learned from identifying these two genes.

TCF7L2: the most important type 2

diabetes geneAt the start of 2006, transcription factor-7

like 2 (TCF7L2) was revealed as an

unexpected suspect for a type 2 diabetes

gene by the DECODE group in Iceland (6).

This gene had initially drawn attentionduring follow-up research on a small

linkage sig-nal on chromosome 10, but it

turned out that, despite not explaining this

linkage, multiple polymorphisms within the

gene showed strong association with

diabetes in multiple cohorts. The initial

study was rapidly followed by widespread

replication not only in white Europeans (7)

but also in Indian and Japanese people (8

10), Mexican Americans (11), and West

Africans (12) - representing the major racial

groups with a high prevalence of type 2

diabetes. In all populations, TCF7L2

showed strong association, with the odds of

developing type 2 diabetes being increased

by 30%50% for each allele inherited -

approximately double the odds ratio seen

with most other diabetes susceptibility

polymorphisms.

The tracking of criminals and the track-

ing of genes have both been greatly helped

by new technologies. Because of techno-

Over 170 million people in the world can

blame their type 2 diabetes, at least in part,

on their genes. It has been hoped for over 2

decades that identifying the guilty genes

would help us to understand thefundamental pathophysiology of this

common and important disorder. Now, at

last, not only are common gene variants

being reproducibly associated with type 2

diabetes, but work such as that of Lyssenko

and colleagues, reported in this issue ofJCI,

is turning this genetic information into

novel biological insights (1).

Early genetic studies

in type 2 diabetesEarly attempts to identify the genes respon-

sible for type 2 diabetes were slow and

unsuccessful: faced with 30,000

suspects, geneticists were only able to

examine less than 5% and, in most

cases, the coverage of the gene and

sample size were too small to detectmodest effects. The choice of genes

studied was primarily based on

evidence that these genes played

biologically important roles in glucose

homeostasis. By the end of 2005,

despite considerable research

throughout the world, only 2 polymor-

phisms were considered guilty beyond a

reasonable doubt of predisposing to

type 2 diabetes: P12A in PPARG (2)

and E23K in KCNJ11 (3). One

advantage of using biological candidacy

to choose genes for further study was

that we already knew the critical science

of the proteins encoded by these genes -

the nuclear transcription factor PPAR

and the potassium inward-rectifying 6.2

subunit (Kir6.2) of the potassium ATP

channel. Both genes were diabetes drug

targets, and mutations in both could

cause monogenic diabetes (4, 5).

This meant that once the

association with disease was

Nonstandard abbreviations used:TCF7L2, transcription factor-7like 2 gene.

Conflict of interest: The author has

declared that no conflict of interest exists.

Citation for this article: J. Clin. Invest.

117:20772079 (2007).

doi:10.1172/JCI33077.


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Figure 1From genetic association to pathophysiology in TCF7L2genotypes predisposing to type 2 dia-betes. Diagram of proposed pathophysiological pathway explaining how TCF7L2 riskgenotypes predispose to type 2 diabetes. The risk genotype results in overexpression of

TCF7L2 in pancreatic cells, which in turn results in reduced insulin secretion. Reducedinsulin secretion results in a predisposition to type 2 diabetes directly and also indirectly byincreasing hepatic glucose output. Dotted arrows represent previous genetic associations.Solid arrows show observations reported by Lyssenko and colleagues in the current issue ofthe JCI(1).

tion factor involved in the Wnt signaling

pathway and is ubiquitously expressed. The

studies from Lyssenko and colleagues (1)

confirm earlier studies (2225) showing that

the predisposition to type 2 diabetes is the

result of reduced insulin secretion rather than

reduced insulin action, making the pancreatic

cell the most likely primary cell target of

altered TCF7L2 activity. However, this wascontrary to an initial, much repeated

hypothesis, suggesting that the risk genotype

was altering insulin secretion indirectly by

reducing intestinal TCF7L2 activity, which

in turn reduced the secretion of incretins,

glucagon intestinal peptide (GIP), and

glucagon-like peptide 1 (GLP-1) (6).

Lyssenko et al. (1), in their detailed studies,

show that insulin secretion in subjects with

the at-risk genotype was reduced in response

to a variety of stimuli including i.v. glucose

and arginine and not just oral glucose. In

addition, GIP levels were not reduced,

suggesting that even though GLP-1 levelswere not measured, there was a reduced

cell response to incretin secretion rather than

reduced incretin secretion. The final question

is how exactly the crime is performed

within the cell and here there is a final

twist in the story. Lyssenko et al. (1) show

that TCF7L2 expression was increased 5-fold

in type 2 diabetes islets, rather than being

reduced. This vital and surprising

observation came from studies of pancreatic

islets carefully purified from type 2 diabetic

and nondiabetic human cadavers. In addition,

there was some suggestion that in the

nondiabetic islets that the risk genotype was

associated with increased TCF7L2expression, but the numbers are small and

caution must be exercised in interpreting

these data until a greater number of islets are

examined. Finally, in a reconstruction of the

crime, over expressing TCF7L2 in human

islets using an adenovirus system reduced

insulin secretion. As with much of science

that has been reported in the study of type 2

diabetes, there are bits of the story that do

not fit: insulin gene mRNA was positively

correlated with TCF7L2 mRNA, out of

keeping with the reduced insulin secretion

observed, and the overexpression ofTCF7L2

did not result in the increased glucagonsecretion seen in the type 2 diabetic islets.

ConclusionSo the interim verdict is that TCF7L2 risk

alleles predispose to type 2 diabetes by

crimes against the cell (Figure 1). The risk

allele results in overexpression ofTCF7L2 in

the pancreatic cell, which reduces insulin

logical advances, the majority of common

genetic variations can be assessed on asingle chip at a very reasonable cost. This

directly led to a whole new series of large-

scale genome-wide genetic studies. As with

many other polygenic conditions, this

approach has been dramatically successful in

studying type 2 diabetes, and within a few

months, the number of established

associated polymorphisms increased from 3

to 9 (1317). A key result was that TCF7L2

polymorphisms have been most strongly

associated with type 2 diabetes in the initial

scan in 4 of the 5 recently published

genome-wide scans (1317).

Defining the mechanism

by which TCF7L2alleles

predispose to diabetesDefining the biological functions of

polygenes found through genetic approaches

can be very hard. Calpain 10 was the first

type 2 diabetes susceptibility gene to be

defined through linkage rather than a

candidate gene route (18). Calpain 10 had

not been previously thought to be involved

in the pathogenesis of diabetes; it showed

initial association with intronic SNPs, and

replication required large studies (19, 20).

We now recognize that these three

characteristics are typical of the majority oftype 2 diabetes susceptibility genes, and this

may mean that the biological function of

such genes will be difficult to define. In the

case of Calpain 10, it was 5 years before the

gene was shown to play a role in apoptosis

in pancreatic islets (21).

TCF7L2polymorphisms are clearly guilty of

predisposing to type 2 diabetes on the

basis of strong, reproducible association in

multiple populations and would appear to bethe leader among a gang of susceptibility

genes. The next challenge, as with all

genome-wide scans, is to define how the

polymorphism predisposes to disease. The

associated TCF7L2 haplotype was in the

noncoding region of the gene without

obvious function in gene regulation, so it

was uncertain how or even whether such

variants alter TCF7L2 expression. What is

the critical variant of the large number of

polymorphisms that are coinherited as a

haplotype? Is the risk variant altering the

gene it is situated in, or does it have a distant

regulatory function? What biologicalpathway are the altered gene or genes acting

in and how does this predispose to diabetes?

These are the fundamental questions that

need to be answered if we are to move

forward from the genetic association to gain

new insights into diabetes.

It is the hypothesis-free results from

genome-wide association studies that have

the potential to create major breakthroughs

in our understanding of disease, but thereare intrinsic difficulties in working on these

leads. Most polymorphisms are in genes on

which there has been little previous work,

and the leading scientists working in cell

biology and rodent models already havefunding for worthy work in other areas, so

why should they risk time and money

working on a gene whose role is not 100%

certain?

The difficulty had been trying to place

TCF7L2 at the scene of the crime, especially

as there was some doubt regarding which

organ and cell type(s) were involved in the

pathophysiology. TCF7L2 is a transcript-


30/48


secretion in response to a variety of stimuli

(1). The reduced insulin secretion in turn

explains the increased hepatic glucose

production observed. There are still many

unanswered questions: Is the concentration

of TCF7L2 protein increased in the cell in

addition to TCF7L2 RNA? How is

expression increased by intronic variants?

How does increased TCF7L2 expressionreduce insulin secretion? This is the first in

a series of steps toward understanding the

associated pathophysiology. In the end,

what is desired from scientific

breakthroughs is improved prevention of

type 2 diabetes and improved treatment of

those who develop the disease. We are still a

long way from this, but there is now a new

cell pathway to be further investigated to see

if it can be manipulated by drugs or lifestyle

changes.

Acknowledgments

Andrew T. Hattersley is a Wellcome TrustResearch Leave Fellow.

Address correspondence to: Andrew T.

Hatter-sley, Peninsula Medical School,

Barrack Road,

Exeter, EX2 5DW, United Kingdom.

Phone:

44-1392-406806; Fax: 44-1392-406767;

E-mail: [email protected].

1. Lyssenko, V., et al. 2007. Mechanisms by which

common variants in the TCF7L2 gene increase risk of

type 2 diabetes. J. Clin. Invest. 117:21552163.

doi:10.1172/JCI30706.

2. Altshuler, D., et al. 2000. The common

PPARgamma

Pro12Ala polymorphism is associated with

decreased

risk of type 2 diabetes.Nat. Genet. 26:7680.

3. Gloyn, A.L., et al. 2003. Large-scale association

studies of variants in genes encoding the pancreatic

beta-cell K-ATP channel subunits Kir6.2

(KCNJ11) and SUR1 ABCC8) confirm that the

KCNJ11 E23K variant is associated with Type 2

diabetes.Diabetes. 52:568572.4. Barroso, I., et al. 1999. Dominant negative

mutations

in human PPARgamma associated with severe

insulin resistance, diabetes mellitus and

hypertension.Nature. 402:880883.

5. Gloyn, A.L., et al. 2004. Activating mutations in

the

gene encoding the ATP-sensitive potassium-

channel subunit Kir6.2 and permanent neonatal

diabetes.N. Engl. J. Med. 350:18381849.

6. Grant, S.F., et al. 2006. Variant of transcription

factor 7-like 2 (TCF7L2) gene confers risk of type

2 diabetes.Nat. Genet. 38:320323.

7. Zeggini, E., and McCarthy, M.I. 2007. TCF7L2:

the biggest story in diabetes genetics since HLA?

Diabetologia. 50:14.

8. Chandak, G.R., et al. 2007. Common variants in

the

TCF7L2 gene are strongly associated with type 2

diabetes mellitus in the Indian population.


9. Hayashi, T., Iwamoto, Y., Kaku, K., Hirose, H.,

and

Maeda, S. 2007. Replication study for the

association of TCF7L2 with susceptibility to type 2

diabetes in a Japanese population. Diabetologia.

50:980984.

10. Horikoshi, M., et al. 2007. A genetic variation

of the

transcription factor 7-like 2 gene is associated with

risk of type 2 diabetes in the Japanese population.


11. Lehman, D.M., et al. 2007. Haplotypes of

transcription factor 7-like 2 (TCF7L2) gene and its

upstream region are associated with type 2 diabetes

and age of onset in Mexican Americans. Diabetes.

56:389393.12. Helgason, A., et al. 2007. Refining the impact

of TCF7L2 gene variants on type 2 diabetes and

adaptive evolution.Nat. Genet. 39:218225.

13. Zeggini, E., et al. 2007. Replication of genome-w

association signals in UK samples reveals risk loci

for type 2 diabetes. Science. 316:13361341.

14. Sladek, R., et al. 2007. A genome-wide

association study identifies novel risk loci for type

2 diabetes. Nature. 445:881885.

15. Scott, L.J., et al. 2007. A genome-wide

association

study of type 2 diabetes in Finns detects multiple

susceptibility variants. Science. 316:13411345.

16. Saxena, R., et al. 2007. Genome-wide

associationanalysis identifies loci for type 2 diabetes and

triglyceride levels. Science. 316:13311336.

17. Steinthorsdottir, V., et al. 2007. A variant in

CDKAL1 influences insulin response and risk of

type 2 diabetes.Nat. Genet. 39:770775.

18. Horikawa, Y., et al. 2000. Genetic variation in

the

gene encoding calpain-10 is associated with type 2

diabetes mellitus.Nat. Genet. 26:163175.

19. Weedon, M.N., et al. 2003. Meta-analysis and

a large association study confirm a role for calpain-

10 variation in type 2 diabetes susceptibility. Am.

J.

Hum. Genet. 73:12081212.

20. Tsuchiya, T., et al. 2006. Association of the

calpain-

10 gene with type 2 diabetes in Europeans: results

of pooled and meta-analyses. Mol. Genet. Metab.

89:174184.

21. Johnson, J.D., et al. 2004. RyR2 and calpain-

10 delineate a novel apoptosis pathway in

pancreatic islets.J. Biol. Chem. 279:2479424802.

22. Saxena, R., et al. 2006. Common single

nucleotide

polymorphisms in TCF7L2 are reproducibly

associated

with type 2 diabetes and reduce the insulin

response to glucose in nondiabetic individuals.

Diabetes.55:28902895.

23. Freathy, R.M., et al. 2007. Type 2 diabetes

TCF7L2

risk genotypes alter birth weight: a study of 24,053

individuals. Am. J. Hum. Genet. 80:11501161.

24. Florez, J.C., et al. 2006. TCF7L2

polymorphisms and progression to diabetes in the

Diabetes Prevention

Program.N. Engl. J. Med. 355:241250.25. Loos, R.J., et al. 2007. TCF7L2

polymorphisms modulate proinsulin levels and

beta-cell function in a

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Obese Type 2 DM

About 85% of Type 2 diabetics are obese. These patients have an insensitivity toendogenous insulin, which is positively correlated to upper body fat distribution (so calledapple shaped or android habitus as opposed to pear shaped or gynoid habitus),producing a high waist to hip ratio (W/H). Hypertrophy of pancreatic -cells in the early

phase of DM (IGT) accounts for the exaggerated insulin responses to glucose and otherstimuli. As IGT progresses to T2DM, secondary to failure of pancreatic -cells as a resultof hyperglycemia (glucose toxicity) and high FFA (lipotoxicity), frank T2DM emerges. This

-cell toxicity is selective for glucose, but the -cell may recover with correction ofhyperglycemia (see below).

Insulin Resistance in Type 2 DM (Figures 14 & 15)

Insulin resistance may be defined as a condition where insulin responsive tissues exhibitinsensitivity to physiological levels of insulin. Therefore, in order for the body to maintainfasting euglycemia (or near euglycemia) insulin secretion is stepped up to compensate for

this insulin insensitivity. This leads to hyperinsulinemia. Although not all insulin resistantstates lead to T2DM this increased secretion may occur in the 2nd phase of T2DM, as the1st phase of insulin secretion in Type 2 DM is markedly impaired.

As stated above, insulin resistance in the muscle and fat is the hallmark of T2DM and maybe the initial event in cascade of DM (Figure 13), which may lead to hyperinsulinemia asthe 1st clinical demonstration of insulin resistance in type 2 DM. This brings about downregulation of insulin receptors with subsequent diminution of glucose transporters leading

to post prandial hyperglycemia and glucose toxicity. The latter may reduce -cellsecretion (2nd phase) and final alteration of post receptor events. Therefore, in type 2 DM,hyperinsulinemia of early DM (or IGT) leads to decreased receptor numbers and alteration

of post receptor events. This insulin resistance at early stages may be reversible with anymodality that reduces hyperglycemia (i.e., diet and exercise, or treatment with insulinsensitizers), which leads to reduction of insulin, improves insulin sensitivity and reversesinsulin resistance.


32/48


Other Conditions Associated With Insulin Resistance: In addition to type 2 DM, manyphysiological and clinical conditions are also associated with insulin resistance, whichare dep icted in Figure 15.

Figure 15

Interrelationship Between Insulin Resistance & Atherosclerosis

Atherosclerosis

Insulin

Resistance

Hypertension

Endothelial dysfunction

Hyperinsulinemia

Hyperglycemia

Hypertriglyceridemia

Small, dense LDL

Low HDL-C

Impaired fibrinolysis

Hypercoagulability

PCOS

Insulin resistance is defined as impaired response to the physiological effects of insulin,including those on glucose, lipids, protein metabolism and vascular endothelial function.

About 92% of patients with type 2 diabetes have insulin resistance. Insulin resistance mayalso be a compensatory mechanism to prevent severe obesity in man.

In addition to the above, there are three mechanisms (although much more rare) besidesT2DM or metabolic syndrome, which are associated with clinical insulin resistance. Theseare summarized in Table 15.

Fig. 6 depicts coordination between three major conditions, T2DM, insulin resistance andmetabolic syndrome. Common among all three are proinflammatory states and endothelialdysfunction. Each and all three conditions are highly associated with cardiovascularevents.


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TABLE 15

Mechanism of Apparent Insulin Resistance

Type of Defect Mechanism (s)

Prereceptor Circulating antinsulin factors: antibodies against insulin;Abnormal insulin synthesisAccelerated insulin degradation

Receptor number of affinity, Primary defectsor both Circulating antireceptor antibodies (membrane receptors)

Physiological regulatory mechanisms (i.e., down-or up-regulation)Absent target site

Postreceptor events Defective receptor second-messenger activityAccelerated destruction of insulin intracellularly

Distal steps in insulin action

Metabolic syndrome: This is another form of insulin resistance that consists of a)compensatory hyperinsulinemia (to maintain fasting euglycemia), b) impaired glucosetolerance (IGT), c) obesity (especially abdominal or visceral), d) dyslipidemia of hightriglyceride and/or low HDL type and hypertension plus other conditions depicted in Figure16 & its multiple components & criteria for diagnosis. The minimum criteria for thissyndrome are summarized on Table 16.

Role of Fat Tissue and Obesity in Metabolic Homeostasis: As obesity plays a pivotalrole in metabolic syndrome, insulin resistance and T2DM, it has provided impetus to many

studies including a greater understanding on the physiology of fat tissue.

Figure 17 depicts a cartoon regarding diabetes and biomarkers of obesity which includesecretory products from the gut, muscle and fat. Pancreas and gut could interact withmajor neurotransmitter in the brain, the control feeding and satiety center. This figure is anattempt to interdigitate these agents presence, some of which are demonstrated butothers are in progress of identification. Important among these chemicals are the secretoryproducts of fat tissue depicted earlier in Figure 2, Chapter 1, which are TNF, IL-6,Resistin and leptin. The chemicals elaborated by fat tissues are collectively calledadipokines. The above compounds are resistance components of adipokine. But animportant anti-insulin resistance compound produced by fat tissue is the recently

discovered adiponectin 30,000KD plasma protein which is found in high concentration (2-10 mg/dL) in normal man but reduced in obesity. Table 17 summarizes properties ofadiponectin and its link to CV risk factors.


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Table 16

Criteria for Metabolic (or Insulin Resistance) Syndrome by WHO1

or NCEP ATPIII2 GroupNCEP ATPIII WHO

Glucose (mg/dl) 3 or more of IFG, IGT or DM and/orthe following: insulin resistance plus 2FPG > 110mg/dl or more of the following:

Blood pressure (mmHg) > 130/85 > 140/90

Triglycerides (mg/dl) > 150 > 150

Serum Triglycerides (mmol/l) >1.7 >1.7 or HDL-cholesterol 20 mg/g

Urinary Albumin

Excretion Rate >20g/min

Urinary Albumin:

Creatinine Ratio > 30mg/g

1. Alberti KG et al, Diabetic Med 15:539-53, 1998

2. National Cholesterol Education Program Adult Treatment Panel III, JAMA 285:2486-97,2001

* inches


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Figure 16

Role of T-cells and E-cells in T2DM & CVD

Diabetes

Mellitus

Environmental & Genetic Factors

PMN TNF-

activation IL-6

InsulinResistance

(Dyslipidemia)

Hyperglycemia

-cell dysfunction

insulin sensitivity

Dyslipidemia

coagulation

AGE proteins

ROS

NO

VCAM

ICAM

Vasoconstriction

Inflammation (stress)

Endothelial Dysfunction

Fibrinogen

PAI-1

CRP

Metabolic

Syndrome

HPTN

Dyslipidemia

Central obesity

IGTCardiovascular

Diseases

MicrovascularMacrovascular

Cerebrovascular

Kitabchi, IAMA Bulletin, 2006

It is important to recognize that both diabetes and atherosclerosis are inflammatorydiseases in which endothelial dysfunction leads to production of reactive oxygen speciesand free radical production with reduction of NO (a vasodilating agent) and reduction ofvasodilation. Numerous adipokines affect metabolic homeostasis.


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Figure 17

Diabetes and Obesity

Body WeightFoodIntake

Energy

Expenditure

PANCREAS MUSCLEBRAIN(Hypothalamus

Insulin

PYY3-36

GLP-1

Ghrelin

Adiponectin

Resistin

Leptin

Myostatin

Musclin

Proinsulin

C-peptide

Amylin

Glucagon

PP

Somatostatin

GIPGLP-2

GRP

PYY

Gastrin

Oxyntomodulin

VIP

CCK

IL-6TNF

MCP-1

PAI-1

ASP

Cortisol

Adipsin

Gut Fat

-

-

-

-

?-

+

?

?

NPY AgRPMCH Orexin


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Figure 18

Deficient Insulin: Hypersecreted Glucagon

Defects in diabetes:

Deficient insulin

release

Glucagon not

suppressed

(postprandially)

Hyperglycemia

Meal

120

60

0

Insulin

(U/mL)

100

120

140

-60 0 60 120 180 240

Time (min)

Glucagon

(pg/mL)

360

300

240110

80

Glucose

(mg/dL)

Without Diabetes (n=14)

Type 2 Diabetes (n=12)

TYPE 2 DIABETES

Data from Muller WA, et al. N Engl J Med1970; 283:109-115.

Figure 19

Multihormonal Regulation of Glucose Appearance and Disappearance

Time (min) From Start of Mixed Meal

Mixed Meal (with ~85 g Dextrose)

0 120 240 360 480

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

GramsofGlucoseflux/min

-30

Insulin-mediated

glucose uptake

Balance of insulin

suppression and

glucagon stimulation

Regulated by hormones:

amylin, CCK, GLP-1, etc.

Meal-Derived Glucose

Hepatic Glucose Production

Total Glucose Uptake

Adapted and calculated from Pehling G., et al. J. Clin. Invest. 1984; 74: 985-991.


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Figure 20

GLP-1 Modulates Numerous Functions in Humans

Stomach:Helps regulate gastric

emptying

Promotes satiety and

reduces appetite

Liver:

Glucagon reduces hepatic

glucose outputBeta cells:Enhances glucose-dependent

insulin secretion

Alpha cells:Postprandial

glucagon secretion

GLP-1: Secreted upon the

ingestion of food

Data from:Flint A, et al. J Clin Invest. 1998;101:515-520Larsson H, et al.Acta Physiol Scand. 1997;160:413-422Nauck MA, et al. Diabetologia 1996; 39:1546-1553Drucker DJ. Diabetes. 1998;47:159-169

Figure 21

The Incretin Effect in Healthy Subjects

C-peptide(nmol/L)

Time (min)

0.0

0.5

1.0

1.5

2.0

Incretin Effect*

*

*

*

**

*

Oral Glucose

Intravenous (IV) Glucose

PlasmaGlucose(mg/dL)

200

100

0

Time (min)

60 120 180060 120 1800

N = 6; Mean (SE); *P0.05Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498.


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Table 17:

Adiponectin Properties

35K Dalton Plasma Protein Produced by Adipose Tissue

1. Lower in:a. Men than in women

b. Obese individuals with metabolic syndromec. Obese women with PCOSd. Patients with type 2 diabetese. Patients with CADf. Those at risk for type 2 diabetes and first-degree relativesg. Some adiponectin gene mutations associated with increased type 2 diabetesh. Diabetes-susceptibility locus mapped to chromosome 3q27, site of adiponectin

gene

2. Higher levels are protective for type 2 diabetes

3. Positively correlates with insulin sensitivity (independent of age, BP, adiposity, lipids)and HDL-C in patients with and without type 2 diabetes.

4. Inversely relates to degree of adiposity (BMI, fat mass), glucose, insulin, TG levels,systolic BP, intramuscular fat content, CRP, TNF, IL-6, and endothelin.

5. Increased with weight loss (most studies) and glitazone therapy.

6. Not increased with exercise.

References:

Panidis D, et al. Hum Reprod18:1790-1796, 2003Diez JJ, et al. Eur J Endocrinol148:293-300, 2003Spranger, et al. Lancet361:226-228, 2003Daimon M, et al. Diabetes Care 26:2015-2020, 2003Matsubara M, et al. Eur J Endocrinol148:343-350, 2003Mohlig M, et al. Horm Metab Res 34:655-658, 2002; Nemet D, et al. Pediatr Res 53:148-152, 2003Yatagai T, et al. Endocr J50:233-238, 2003Monzillo LU, et al. Obes Res 11:1048-1054, 2003Engeli S, et al. Diabetes 52:942-947, 2003English PJ, et al. Obes Res 11:839-844, 2003; Ryan AS, et al. Diabetes Care 26:2383-

2388, 2003


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Table 18 correlates various chemical abnormalities with metabolic defects and clinicalabnormalities in severely uncontrolled diabetes.

TABLE 18

Correlation of Clinical Conditions and Diabetic Syndromes with Various Metabolic

Defects

Metabolic Defects Chemical Abnormalities Clinical Abnormalities

Carbohydrate Metabolism Polyuria, polydipsia, polyphagia1. Diminished uptake of Hyperglycemia fatigue, muscle weakness,

glucose by tissues such pruritusas muscle, adipose tissueand liver

2. Overproduction of glucose Blurred vision(via glycogenolysis and Diminished mental alertness

glyconeogenesis by the liver)

Protein Metabolism1. Diminished uptake of amino Negative nitrogen Loss of muscle mass

and diminished synthesis balance Weaknessof protein Elevated levels of branch-

chain amino acidsElevated blood ureanitrogen level

2. Increased proteolysis Elevated potassium level

Fat Metabolism1. Increased lipolysis Elevated plasma fatty Loss of adipose tissue

acids levelElevated plasmaglycerol level

2. Decreased lipogenesis Loss of adipose tissue

3. Increased production Hypertriglyceridemia Exudative xanthomaof triglycerides (skin lesions)

Lipemia retinalisPancreatitis(abdominal pain)

4. Decreased removal Elevated plasma and Hyperventilation,of ketones and increased urine ketones metabolic acidosis,ketone production abdominal pain


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Table 19 provides important guidelines for calculation of body weight and caloricrequirement and recommended dietary composition in healthy individuals.

TABLE 19

Calculation for Ideal Body Weight (IBW), Body Mass Index (BMI) and

Recommendation for Proper Dietary Composition

Ideal Body Weight (IBW)

Women 100 lb for first 5 feet + 5 lb for each additional inchMen 106 lb for first 5 feet + 6 lb for each additional inch

Body Mass Index (BMI) Wt.(kg)/height (M)2

normal value 20-25, obese >27

Calorie Requirement

Basal requirement Ideal body weight x 10

Average activity Add 30% to basal requirement

Strenuous activity Add 100% - 200% to basal requirement

Weight loss Subtract 500 calories/day to lose 1 lb/week

Pregnancy Add 300 calories/day

Lactation Add 500 calories/day

Dietary Composition

Carbohydrate 50% - 55% of total calories

Protein 15% - 20% of total calories

Fat 30% of total calories (


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Table 20 provides a rough guideline for various metabolic goals in patients with diabetes.

TABLE 20

Metabolic Goals in Diabetes

Normal Value Goal Value

Fasting Blood Glucose 70 - 99 mg/dl 70 - 120 mg/dlPregnant 69 - 90 mg/dl 69 - 90 mg/dl

Postprandial Blood Glucose (2 hr) < 140 mg/dl < 180 mg/dl

Pregnant (1 hr) < 140 mg/dl 120 mg/dl

Glycosylated Hemoglobin A1c 4 - 6% < 7%Cholesterol < 200 mg/dl < 200 mg/dl

HDL CholesterolMen > 35 mg/dl > 35 mg/dlWomen > 45 mg/dl > 45 mg/dl

LDL Cholesterol < 130 mg/dl < 75 mg/dl

Triglycerides < 150 mg/dl < 150 mg/dl

Body Mass Index* (BMI) 19 - 2519 - 25

(kg [weight] m2

[height])

*BMI >27 is defined as overweight.Some ethnic groups such as Asianshave lower BMI


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Glycosylated (Glycated) Hemoglobin HbA1c

Under normal conditions, a certain amount of glucose attaches to the valine molecule of thechain of hemoglobin in the red blood cell (RBC) which leads to stable glycated hemoglobin(HbA1c). This reaction proceeds through formation of Schiff base between the aldehyde formof sugar and free amino acid. This is followed by an Amodori rearrangement of the Schiff

base to a ketoamine derivative that is stabilized by cyclization and formation of hemiketalstructure. The percentage of hemoglobin which is glycated in normal subjects is 4 to 6%, butin diabetics with hyperglycemia ranges up to 14%. Since this reaction is slow and irreversibleand the rate is proportional to the blood glucose concentration over the 120 day life of RBC,its value reflects chronic glycemic control over the previous 3-4 months. The correlationbetween HbA1c and blood glucose is stronger with the postprandial blood glucose than fastingblood glucose levels.

It has been shown in certain studies that the progression of chronic complications of DM maybe correlated with prevailing levels of HbA1c and that reduction of HbA1c decreases the risk ofthese complications (secondary to reduction of level of hyperglycemia). (See below.)

Any condition that alters erythrocyte turnover lowers HbA1c levels (i.e., bleeding, pregnancy orsplenectomy). On the other hand, uremia, fetal Hb, aspirin or high levels of ethanol mayfalsely elevate levels of HbA1c. These interfering substances do not affect HbA1c levelsmeasured by more specific methods such as affinity chromatography.

Assessment of average glycemic control from a shorter (~2-3 weeks) duration of time can beaccomplished by measurement of other glycated proteins with shorter half-lives such asserum fructosamine or albumin.

Correlation of Blood Glucose Control and Diabetic Complications

For many years controversies have existed as to whether hyperglycemia could lead tomicrovascular (retinopathy, nephropathy or neuropathy) or macrovascular (cardiovasculardisease, stroke, etc.) diseases. This important issue was finally settled by four importantprospective randomized long-term studies.

The first study was the Diabetes Control and Complication Trial (DCCT) for type 1 DM, whichwas sponsored by NIH and conducted by 29 clinical centers in the United States and Canadafrom 1983-1992. The second study was a European Study, also in type 1 DM. The thirdstudy was the Kumamoto study for type 2 DM, which was conducted in Japan. The fourthstudy was in England under United Kingdom Prospective Study of Diabetes (UKPDS) which

was also done in type 2 DM (newly diagnosed). These studies clearly demonstrated thatcontrol of blood sugar (reduction in HbA1c) resulted in significant risk reduction in diabeticcomplications. The results are summarized in Table 21.


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Table 21Relationship of Glycemic Control to Reduction in Diabetic Complications

Outcome Parameters Studies

SDIS(1)

DCCT(2)

Kumamoto(3)

UKPDS(4)

Type of DM Type 1 Type 1 Type 2 Type 2

Number of Patients 102 1441 102 4200

Mean age (y) 30 27 49 53

Duration of follow-up (y) 7.5 6.5 6 10

Change in HbA1c - 2.4 - 1.9 - 2.3 - 0.9

Reduction in risk (%)

Retinopathy 52 63 69 21

Nephropathy 89 54 70 33

Neuropathy NS 60 --- ---

Myocardial infarctions --- --- --- 16

Any diabetes related endpoint --- --- --- 25

(1) Reichard P, Nilsson BY, Rosenqvist U. The effect of long-term intensified insulin treatment on the development ofmicrovascular complications of diabetes mellitus. N Eng J Med329:304, 1993.

(2) The DCCT Research Group, The effect of intensive treatment of diabetes on the development and progression oflong-term complications of insulin-dependent diabetes mellitus. N Eng J Med329:977, 1993.

(3) Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascularcomplications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-yearstudy. Diabetes Res Clin Pract28:103, 1995.

(4) UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulincompared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Lancet352_837-53, 1998. Effect of intensive blood-glucose control with metformin on complications in overweight patientswith type 2 diabetes (UKPDS 34). Lancet352_854-65, 1998


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Studies and Method in the Prevention of Type 2 Diabetes

Type 2 Diabetes (T2DM) has now reached an epidemic proportion both in the U.S. and globaprimarily due to sedentary lifestyle and obesity. Among precursors of diabetes is impairglucose tolerance (IGT), which affects 21 million Americans and 200 million subjects worldwidIn the last few years, three major landmark

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