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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
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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
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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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Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus 6-29
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-
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Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus 6-30
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: Andrew.Hattersley@pms.ac.uk.
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.
Diabetologia. 50:6367.
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.
Diabetologia. 50:747751.
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-
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20. Tsuchiya, T., et al. 2006. Association of the
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10 delineate a novel apoptosis pathway in
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22. Saxena, R., et al. 2006. Common single
nucleotide
polymorphisms in TCF7L2 are reproducibly
associated
with type 2 diabetes and reduce the insulin
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23. Freathy, R.M., et al. 2007. Type 2 diabetes
TCF7L2
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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.
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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