Physiology of Endocrine Pancreas and

PATHOPHYSIOLOGY COURSE - ENDOCRINE MODULE Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus (DM) Abbas E. Kitabchi, Ph.D.
, M.D. Friday, December 4, 2009, 8:00-9:50am

Objectives 1. 2. 3. List hormones in the islets of Langerhans, their location and their relation to each other. Describe general function of these hormones and their inhibitors and stimulators. Define general principle of insulin synthesis, its precursor, proinsulin and its byproduct, C-peptide, and their biological potencies. Describe the action of insulin and its role, as well as the role of counterregulatory hormones in regulation of fuel metabolism in fed and fasted states. Define diabetes, its epidemiology, complications and their impact on the U.S. population. Classify the latest method of diabetes diagnosis and recent criteria for diagnosis of DM, impaired glucose tolerance (IGT), impaired fasting, and gestational diabetes (GDM). Characterize the differences between type 1 and type 2 DM. Describe the general principles relating to the pathogenesis of type 1 versus type 2 DM. Classify various causes of insulin resistance and the factors leading to insulin resistance in type 2 DM. Distinguish it from metabolic syndrome.
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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 the diabetic syndrome.
12. Know how to calculate: a) Ideal body weight (IBW), b) Body mass index, c) Caloric requirement 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 of glycemic 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 action of its adipokines.
Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus 6-1
HORMONES OF THE ENDOCRINE PANCREAS The adult pancreas contains about one million islets, with the largest concentration in the tail. These constitute less than 3% of pancreatic mass. The islets are highly vascularized through 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 by the autonomic nervous system-parasympathetic (vagus nerve) and sympathetic (middle splanchnic 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, responsible for the production of pancreatic polypeptide. (Figure 1 depicts the architecture of major cells 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. 56:778838, 1976.
Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus
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Insulin Insulin biosynthesis occurs in rough endoplasmic reticulum from a single-chain precursor, preproinsulin, with a molecular weight of 11,500 and containing 109 amino acids. This molecule consists of proinsulin plus a hydrophobic extension of 23 amino acids (preregion) on the N terminus of proinsulin. This hydrophobic region is rapidly removed in vivo before the peptide chain is completed. Human proinsulin is a single polypeptide of 86 amino acids with a molecular weight of 9000. It has A and B chains, as does insulin, but the A chain is linked to the B chain by a connecting peptide of 35 amino acids that connects the C terminus of the B chain to the N terminus of the A chain (Figure 2). Proinsulin is stored in golgi secretory granules, where it is converted to insulin by proteolysis and is secreted into the circulation upon stimulation. On a molar basis, proinsulin has 5-10% of the biologic activity of insulin.
FIGURE 2 Structure of Human Proinsulin
The C-peptide, which is shown at the top, enclosed by the curved line, is the result of loss of four basic amino acids (2 from each side) from connecting peptide during conversion of proinsulin to insulin (indicated with asterisks). C-Peptide is equimolar to insulin. The numbering of the proinsulin molecule for each component of the molecule is designated by A for the A chain, B for the B chain, and C for the C-peptide. Adapted from Kitabchi et al., Metabolic Effects of Neuropeptides, in Givens JR (ed): Hormone-Secreting Pituitary Tumors. Chicago, YearBook, 1982, pp 45-62. C-PEPTIDE PROPERTIES: C-peptide, consisting of 31 amino acids, is the connecting peptide minus one dibasic amino acid from each end. The connecting peptide (and consequently C-peptide) are produced in equimolar ratio to insulin during insulin secretion. Although C-peptide was previously thought to have no biologic activity, it is now clearly established that C-peptide
has multiple biological activities through G protein. In addition, recent studies suggest that C-peptide may have therapeutic properties in improving nephropathies and neuropathies in type 1 diabetics who are deficient in C-peptide. Because of its common antigenic determinant with proinsulin, C-peptide cross-reacts with proinsulin but not with insulin in their specific radioimmunoassays (RIAs). Hence assay of C-peptide in blood, under conditions when endogenous insulin cannot be measured, may be a clinically useful method for assessing pancreatic insulin reserve. For example, patients who receive exogenous insulin treatment may develop antibodies direct ed against that foreign insulin protein. While these antibodies usually do not significantly influence the biologic effect of the 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, arranged as two polypeptide chains. The A chain has 21 amino acids and is linked to the B chain by two disulfide bridges. There is a single intrachain disulfide bridge on the A chain. The fasting insulin concentration in blood is about 10 -11M. It is stored in the -cells and is secreted 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 10-5M, lasts only a few minutes. It is stimulated by compounds such as glucose and amino acids, and Ca2+ plays an important role. Thus, Ca2+, like sulfonylurea (a class of oral hypoglycemic
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 cyclic adenosine monophosphate (cAMP). Release of insulin involves two processes: 1) a microtubular system (margination) for transport of granules from the cytoplasm toward the plasma 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 for insulin secretion, as noted in Table 1. TABLE 1 Stimulators and Inhibitors of Insulin Release Stimulators Carbohydrates Glucose Fructose Polypeptide Glucagon ACTH (not in human) Growth hormone Amino Acids Inhibitors Carbohydrates 2-Deoxyglucose D-Mannoheptulose Hormones Epinephrine Norepinephrine Somatostatin Miscellaneous Starvation Diazoxide Hypoxia Hypothermia Vagotomy Hypoglycemia
Fatty acids Enteric hormones Secretin Pancreozymin Gastrin Gut glucagon Miscellaneous Cyclic 3, 5-AMP Glucocorticoids Ketones, Calcium Potassium, Sulfonylurea Vagal stimulation Methylxanthines
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Thus, the -cell response to insulin secretagogues is biphasic fashion. An initial, rapid burst occurs within the first few minutes that releases preformed insulin from a rapidly mobilizable pool. This phase usually responds to glucose, amino acids sulfonylurea, glucagon and gastrointestinal (GI) hormones. The second phase, which occurs after about 10 minutes and continues for as long as an hour, is stimulated by glucose and amino acids, 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 insulin response occurs following oral glucose (OGTT), as compared to an intravenous glucose challenge (IVGTT). An adult human secretes approximately 40-50 units of insulin per day. Depending on the purity of the preparation, 1mg of insulin is equal to approximately 26 to 30 units, of which approximately 50% is unstimulated or basal (preprandial) and the remaining is secreted as 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-sensitive tissues (e.g., fat, muscle, liver), where its action is exerted at physiologic concentrations of the hormone (10-11 to 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 anabolic hormone that stimulates protein, glycogen, and lipid synthesis, and inhibits lipolysis and gluconeogenesis.
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TABLE 2 Effects of Insulin on Target Tissues Immediate Membrane transport of glucose Membrane transport of amino acids Membrane transport of certain ions (?) Intermediate Carbohydrate metabolism Glycogen synthesis Glycogenolysis Gluconeogenesis Lipid metabolism Lipogenesis Esterification Lipolysis Cholesterol synthesis Ketogenesis Utilization of dietary lipid Fatty acid oxidation Protein metabolism Protein synthesis Proteolysis Long-term Promotion of cell growth Promotion of cell division Although the molecular basis of insulin action has been the subject of intensive investigation, and numerous low and higher molecular weight compounds have been proposed as putative mediators of insulin action on certain enzymes, to date the identity of these 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 is initiated 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 the LDL receptor gene.) This receptor is highly specific for insulin with high affinity. The receptor has two subunits, a) an alpha subunit with molecular weight of 130,000, which is located extracellularly and binds to insulin molecule; and b) a small beta subunit with molecular weight of 90,000, which spans cell membrane and extends in the cytoplasm. It contains tyrosine kinase, which becomes activated when insulin binds to the receptor. This
Tissue Muscle, adipose, liver Muscle, adipose, liver Red blood cell (?)
Muscle, liver Muscle, Liver Liver Liver, adipose Liver, adipose Adipose Liver Liver Liver, adipose Liver, adipose Liver, muscle, adipose Liver, muscle
results in autophosphorylation of the beta subunit and cascade of phosphorylation which eventually leads to movement of glucose transporter (GLUT 4) from the cytoplasm to the membrane to facilitate glucose transport across the cell membrane, plus many other events 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 kinase that undergoes autophorylation, and catalyses the phosphorylation, these proteins interact with signaling molecules through their SH2 domains, resulting in a diverse series of signaling pathways, including activation of Pl(3)K and downstream Ptdlns(3,4,5) P3dependent protein kinases, Ras and the MAP kinase cascade, and Cbl/CAP and the activation of TC10. These pathways act in a concerted fashion to coordinate the regulation of vesicle trafficking, protein synthesis, enzyme activation and inactivation, and gene expression, 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 Transporter GLUT 1 GLUT 1 GLUT 4 GLUT 4 GLUT 2 GLUT 2 GLUT 3-symporter GLUT 3-symporter
Organ Brain Erythrocyte Adipocyte Muscle Liver GK -cell Gut Kidney
HK Coupler HK-I HK-I HK-II HK-II HK-IVL HK-IVB (glucokinase) -
Classification Glucose dependent Glucose dependent Insulin dependent Insulin dependent Glucose sensor Glucose sensor Sodium dependent 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 and adipose cells: (1) insulin binding to its receptor in the plasma membrane initiates a cascade of signals resulting in (2) the translocation of glucose transporters from an intracellular pool associated 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
glucose transport in muscle in diabetes, obesity, and other insulin-resistant states. Defects may involve (1) deficient signaling, (2) impaired translocation, (3) persistent docking without fusion, (4) partial fusion rendering transporters cryptic with inadequate exposure to the extracellular milieu, or (5) reduced activation of transporters. Glucagon The second hormone produced by the islets of Langerhans is glucagon, (whose gene is on human chromosome 2) a single-chain, 3485 mol. wt., polypeptide hormone made up of 29 amino acids. It is synthesized and released from the pancreatic -cells from a larger 160 amino acid precursor (proglucagon). In this larger precursor exists many other glucagon-like peptides (GLP) I and II which are released after meals from the proximal small intestine. A truncated GLP-1 (GLP-1 minus 1st six amino acids) is also more potent stimulator than pancreatic glucagon (incretin). An intestinal hormone Glicentin is part of proglucagon molecule. Whereas insulin and C-peptide have species specificity, human glucagon structure is 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 a gradual, modest increase in the rate of secretion. However, in type 1 diabetes, glucagon levels rise abruptly to a peak after 30 minutes. Conventional insulin therapy significantly reduces the glucagon response in diabetics, but usually levels are still above those found in normal subjects. The major action of glucagon is in the liver through specific membrane receptor. Glucagon stimulates glycogen breakdown (glycogenolysis), glucose production from non-carbohydrate precursor (gluconeogenesis) and ketone production (ketogenesis). Table 4 lists the inhibitors and stimulators of glucagon secretion and Table 5 summarizes the physiologic actions of glucagon. TABLE 4 Stimulator and Inhibitor of Glucagon Release Stimulators Amino Acids (i.e., Arginine) Acetylcholine Epinephrine Norepinephrine VIP CCK Hypoglycemia Inhibitors Glucose Insulin Somatostatin Ketones FFA Hyperglycemia
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TABLE 5 Effects of Glucagon on Intermediary Metabolism Effects Carbohydrate Metabolism Stimulation of glycogenolysis Inhibition of glycogen synthesis Stimulation of gluconeogenesis Inhibition of glycolysis Lipid Metabolism Stimulation of lipolysis Stimulation of ketogenesis Inhibition of triglyceride synthesis Protein metabolism Stimulation of proteolysis? Tissue
Liver Liver Liver, Kidney, Cortex Liver
Adipose Liver Liver
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 Endocrine Pituitary Pancreatic islets Gastrointestinal tract Inhibition of Secretion or Reduction Growth hormone, ACTH, Thyrotropin Insulin; Glucagons, Pancreatic Polypeptide Gastrin, Pancreozymin, Secretin, Vasoactive Intestinal Peptide, Gastric Inhibitory Polypeptide, Motilin, Gut Glucagon-Like (GLP) Peptide Gastric acid secretion, pancreatic bicarbonate & enzyme release, gastric motility, gallbladder contraction Splanchnic blood flow
Nonendocrine Gastrointestinal tract
Liver
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TABLE 8 Actions of Pancreatic Polypeptide Endocrine Pancreas Inhibits insulin secretion Inhibits somatostatin secretion Gastrointestinal Tract Inhibits pancreatic zymogen secretion Decreases gall bladder contractility Reduces gastrointestinal motility Inhibits 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 rim of the -cell and the -cell core are scattered somatostatin-containing -cells, which comprise approximately 10% of the total cells. All these three cell types are in contact with each other through gap junctions. Glucagon is a potent stimulant of insulin and somatostatin secretion. On the other hand, somatostatin inhibits both insulin and glucagon secretion. Somatostatin, in conjunction with insulin, inhibits glucagon secretion and diminishes postprandial hyperglycemia by approximately 50%. These relationships are summarized in Table 6. In addition to inhibiting insulin and glucagon secretion and being stimulated by almost all insulin secretogogues, somatostatin acts in several other ways (Table 7). These include prolongation of gastric emptying time, decreasing gastrin acid and gastrin secretions, diminishing pancreas exocrine secretion, decreasing splanchnic blood flow and restraining movement of nutrients from intestinal tract into the circulation. Calcium is important for optimum secretion of somatostatin. Pancreatic Polypeptide (PP) PP is a 36 amino acid peptide with molecular weight of 4200. It is synthesized and secreted by F cells (or PP cells). The level of PP is increased with ingestion of a mixed meal, but not IV infusion of glucose or triglyceride. Although the physiologic role of this peptide is not known, it is increased in pancreatic endocrine tumors such as glucagonoma, vipoma and in all patients with 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 fasting situations and relate this to the pathophysiology of diabetes mellitus, we will describe the physiologic 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, amino acid and glucose (as well as effects of various hormones produced by the gut) and their effect on 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 about generation of certain substrates and chemicals which stimulate insulin secretion while other components such as amino acids, GIP and VIP specifically stimulate glucagon production. Thus interaction and synchronization of these two hormones facilitate assimilation of substrates into energy (without hypoglycemic effect of insulin), while through action of glucagon (and somatostatin), euglycemia prevails and both hypoglycemia and hyperglycemia are prevented in normal subjects. Figure 7 illustrates the sources and fates of glucose, and shows how glucose homeostasis is maintained through a variety of processes. Note that muscle glycogen cannot directly contribute to blood glucose because of a lack of glucose-6-phosphatase in muscle. Muscle glycogen must, therefore, be converted to various intermediates before it can be used as a source of energy outside the muscle itself.
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FIGURE 7 Sources and Fate of Glucose

Gluconeogenesis Fat
Ingested Carbohydrate
Blood Glucose
Oxidation
Hepatic Glycogen
Lactic Acid
Muscle Glycogen
Oxidation
From Kitabchi AE: Metabolic effects of neuropeptides, in Givens JR (ed): HormoneSecreting 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 is proportional to the rise in serum glucose for a short time and promotes the assimilation of glucose, 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-dependent tissues 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. During this 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 fasting state (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 against deficiency of its specific fuel, glucose. In order to accomplish this, certain hormonal adjustment 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 the brain two processes must be accomplished: 1) decreased glucose utilization by insulin sensitive tissues, and 2) increased glucose production by the liver from non-carbohydrate precursors (gluconeogenesis). These are accomplished by reduced secretion of insulin by the pancreas and increased secretion of counterregulatory hormones in the fasting state. The
detailed mechanism of these changes will be further discussed under the heading of acute complications of DM (i.e., DKA). When ingestion of food is delayed, the prevailing condition is that of the non-absorptive or fasted state. The blood insulin concentration falls to a level that prevents significant transport 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 blood cells (RBC). Thus, of the total amount of glucose produced by the liver as a result of glycogenolysis and gluconeogenesis, approximately 60% of the glucose is used by the brain, 20% by WBC, and 20% by RBC, with negligible amounts going to adipose tissue or muscle. Glucagon favors hepatic utilization of amino acids, especially alanine, to produce glucose (gluconeogenesis), and stimulation of glycogenolysis to augment hepatic glucose output. In the presence of decreased insulin levels in the fasting state, the anti-lipolytic effect of insulin is reduced. This, along with some increase in catecholamines, stimulates breakdown of tissue triglyceride to glycerol and FFA (lipolysis). Fatty acids are used not only by muscle for energy, but they also serve as substrates for ketogenesis. Thus, the major hormones 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 glucose utilization, and 3) cortisol, which, along with increased glucagon (in the absence of insulin), brings about decreased synthesis of protein and increased proteolysis, resulting in increased amino acids (namely alanine) which provides substrate for gluconeogenesis. Glycerol serves as a carbon skeleton for gluconeogenesis, whereas oxidation of fatty acids provides reducing equivalents for the gluconeogenic pathway. Excess FFA (as a result of increased lipolysis) is also used as substrate for VLDL production and ketogenesis in the liver, as well as fuel for cardiac and skeletal muscles through conversion to acetyl COA and entrance into the Krebs Cycle (TCA cycle). Therefore, in the fasting state, in addition to reduction of insulin secretion, three major hormones which have the opposite effect to that of insulin (and hence are called counterregulatory hormones) are increased. As stated, these hormones are: glucagon, catecholamines, and cortisol. Growth hormone may also contribute to this mechanism as a fourth counterregulatory hormone. Fasting, similar to hypoglycemic state results in reduced insulin and increased counterregulatory hormones. Figure 8 depicts the response of counterregulatory hormones and C-peptide to insulininduced hypoglycemia in a normal subject. Notice transient severe changes in many hormones with hypoglycemia (or other metabolic insults) and a return to basal levels after recovery from hypoglycemia.
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FIGURE 8
DIABETES MELLITUS Diabetes mellitus (DM) is a chronic disorder characterized by fasting hyperglycemia or plasma 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 detailed in Table 9 and the newly established diagnostic criteria for various forms of hyperglycemia are 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 of carbohydrate, 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 for type 2 diabetes in order to make an appropriate intervention.
TABLE 9 Classification of Various Hyperglycemias Diabetes Mellitus (DM) Type 1 diabetes a. Immune Mediated (type 1A) b. Idiopathic (type 1B) Type 2 diabetes Individuals with insulin resistance who usually have relative rather than absolute insulin deficiency. (Obese or non-obese) Other types of diabetes Pancreatic disease and pancreatic surgery Endocrinopathies (Cushings, Acromegaly, Pheochromo cytoma, 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 Control Normal IFG (Impaired fasting glucose) or IGT Diabetes* > 126 Fasting Plasma Glucose < 100 OGTT (2-hr Postload Glucose) < 140 100 - 125 140 - 199 > 200
* Third criterion: >200 mg/dL casual plasma glucose (regardless of the time since last meal) 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 over one million as type 1 DM (prevalence of 0.4%) and 22 million as type 2 DM (prevalence of 8%), of whom about 440,000 (prevalence of 3%) are not diagnosed. There are approximately 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., which represents more than 4300 new cases every day. Diabetes has reached epidemic proportions. Thus, it is estimated that by the year 2030 India 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 in 2000) persons with diabetes. The risk factors that are controllable in T2DM are sedentary lifestyle, central obesity and BMI. The risk factors that are not controllable in T2DM are ethnicity, age, and heredity. Type 1 DM constitutes 5- 10% of all DM in the U.S. It is believed to be an autoimmune related 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 American Indians about 5 times more than in Whites. The incidence of type 2 DM is also increased with age, adiposity and number of family members with diabetes (Tables 11 and 12.) Thus a 60 year old Pima Indian has a 60 % chance of developing type 2 DM. TABLE 11 Estimated Lifetime Risks of Type 1 DM Classification GENERAL POPULATION Background risk DR 3/4 Susceptible DR/DQ alleles FAMILY MEMBERS Parents Offspring Sibling Identical twins HLA identical haploidentical non-identical 3 5 6-8 30 - 50 10 - 16 2-9 0-1 0.4 2.4 6 - 8.5 Risk (%)
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Diabetes is one of the four major risk factors for cardiovascular diseases. Coronary artery disease (CAD) is seen twice as often in men and four times as frequently in women with diabetes as in the nondiabetic population. The incidence of peripheral vascular disease at the 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 for over 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 of glaucoma and cataract. Kidney disease occurs in 35% of type 1 and 20% of type 2 patients, 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 with diabetes in 2007 is estimated at 174 billion dollars. About 70% of the total cost of DM was for outpatient and in-patient care of DM patients. In addition there is an un-estimated amount of psychological problems. In general, detection of type 1 DM is based on the acuteness of the disease in the majority of the cases and therefore, screening is not recommended in routine medical care, but is important 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, in type 2 DM the appearance of the disease is insidious; therefore, people who are at risk for development of diabetes (Table 12) need to be screened to detect DM [i.e. fasting blood glucose (FBG) or OGTT)]. Table 12 lists the populations who are at risk and, therefore, need to be tested for diabetes by 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, be screened every three years. *Adapted from ADA Guidelines, Diabetes Care 1997
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 Age at onset Proportion of all diabetes Seasonal trend Appearance of symptoms Metabolic Ketoacidosis Obesity at onset -Cells Insulin Inflammatory cells in islets Family history of diabetes Concordance in identical twins HLA Association Antibody to islet cells (ICA) Insulin autoantibodies (IAA) 64K GAD* antibodies Treatment
Type 1 DM Usually <40 About 10% Fall and Winter Acute or sub acute Frequent Uncommon Decreased Decreased or absent Present initially Uncommon 30-50% Yes Yes Yes (in younger age) Yes Insulin and diet & pancreas transplant
Type 2 DM Usually >40 About 90% None Slow or sub acute Rare*** Common Variable Variable Absent Common 90-95% No Uncommon No No Diet, weight reduction, exercise, OHA**, Insulin
*Glutamic acid decarboxylase (GAD); ** Oral hypoglycemic agents; *** Except in AfricanAmericans
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PATHOGENESIS OF DIABETES MELLITUS Type 1 Diabetes T1DM Multifactorial inheritance and poorly understood environmental factors are involved in the pathogenesis 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 -cell which characterizes type 1 diabetes, the hallmark of which is insulin deficiency. In type 1 diabetes an increased incidence of antibodies to various organs such as thyroid, adrenal glands and gastric cells has been observed. Furthermore, antibodies to pancreatic islets have been detected by immunofluorescent techniques prior to diagnosis of overt disease, and some investigators have reported the presence of insulin autoantibodies in newly diagnosed 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 chromosome six (6), and consists of class I, class II and class III. Class II consists of DR, DQ, and DP loci. Certain HLA types (HLA-DR3 and HLA-DR4) are highly correlated with T1DM in Caucasians, although only 70% of type 1 diabetics have these HLA markers. These HLA types 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 a certain haplotype of DR4, namely DQ3.1, is the susceptibility antigen most associated with diabetes, 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 are not known, certain factors appear to play important roles. These consist of the following components: 1) Introduction of environmental or pancreotropic virus into the pancreas which leads to 2) production of an antigen. 3) This antigen is then processed by macrophages which are antigen-presenting cells in whose membranes are located the major histocompatibility complex [MHC II (DR3, DR4, etc.)] 4) The appropriate antigen consisting of a peptide which fits into the groove of the class MHC II molecule of the macrophage must further fit into a receptor of the T-lymphocyte for CD4 T-helper cell activation. 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 of diabetes is usually preceded by production of multiple antibodies, including islet cell antibody (ICA), specific antibodies against 64K antigen (now identified as glutamic acid decarboxylase (GAD) (From the islet?), and insulin autoantibody (IAA). These relationships are depicted in Figure 9.
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FIGURE 9
GENETIC SUSCEPTIBILITY INEFFECTIVE DEFENSE BARRIERS INEFFECTIVE IMMUNE RESPONSE
Insulting Agent e.g., Pancreotropic Virus
Autoimmune Process Begins
T-Lymphocytes
Macrophages (Ag presenting cell)
CD 4
TNF
Ag Peptide
INF
-Cell Destruction
Interleukin 1
LEGEND: Ag Antigen INF Interferon TNF Tumor Necrosis Factor
>90% Destruction
Precipitating Factors or Stressors TYPE I Diabetes Mellitus
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FIGURE 10
LIFESTYLE
GENETIC PREDISPOSITION
ENVIRONMENT
OBESITY INSULIN RESISTANCE POSTPRANDIAL HYPERGLYCEMIA HYPERINSULINEMIA
GLUCO-LIPO TOXICITY
GENETIC FACTORS
DECREASED -CELL SECRETION HYPERGLYCEMIA POSSIBLE MECHANISM TYPE 2 DIABETES FOR PATHOGENESIS OF OBESE TYPE 2 DIABETES Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus FASTING
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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 and accounts for greater overall morbidity. Genetic and environmental factors, aging and adiposity 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 diabetes indicates approximately 90% concordance in the other twin. (Concordance in type 1 is about 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 be a 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 depending on 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 develop T2DM, both insulin resistance and -cell dysfunction must coexist. As obesity occurs in 85-90% of T2DM patients, the natural history of T2DM may start with insulin resistance and obesity where near normal FBG is maintained (IFG) with compensatory increase in insulin in the prediabetic (IGT) state but with gradual increase in postprandial glucose. Both postprandial hyperglycemia and increased FFA, which are prevalent in IGT, may lead to decreased secretion of insulin from -cell as a result of both glucotoxicity and lipotoxicity, leading to exhaustion of -cells and development of insulinopenia and frank diabetes. These events are depicted in Figures 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. These patients present with a fasting blood glucose value > 125 mg/dl. The high insulin level is due to a compensatory increase in phase 2 insulin secretion as phase 1 insulin secretion in type 2 diabetes is decreased. (See Figure 3 for description of phase 1 and 2 insulin secretion). With the progression of the disease, even phase 2 insulin secretion is reduced and the fasting plasma glucose gradually increases, so that when the latter value ranges between 160-200 mg/dl there is generally a significant reduction of insulin secretion (and low C-peptide). As can be seen from Figure 12, hepatic glucose production in both diabetic and nondiabetic subjects is proportional to fasting plasma glucose. The hallmark of type 2 DM is insulin resistance, as can be seen from Figure 13 where glucose uptake and metabolism is reduced by about 50% in the muscle. The major sites of insulin resistance in type 2 DM are in muscle tissue and liver. Figure 14 depicts the whole body glucose uptake in control vs. normal and obese T2DM, compared to normal and obese non-diabetic subjects in regards to glucose oxidation and glucose storage.
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Figure 11: Natural History of Patients With Type 2 Diabetes Genetic Susceptibility Environmental Factors:
Nutrition Obesity Physical inactivity
Onset of diabetes Complications Disability Death
Prediabetes
Ongoing hyperglycemia
Atherosclerosis Hyperglycemia Hypertension Retinopathy Nephropathy Neuropathy
Insulin resistance Hyperinsulinemia HDL TG
Blindness Death Renal failure CHD Amputation
The natural history of DM2 is depicted in Figure 11 indicating that as time progresses, hyperinsulinemia and near normal fasting blood glucose (IGT) eventually leads to hyperglycemia, insulinopenia and frank diabetes.
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FIGURES 12, 13, & 14
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.
Figure 14 (above). Insulinmedicated rates (euglycemic insulin-clamp technique) of whole-body glucose intake (total height of bar), glucose oxidation, and nonoxidative glucose disposal in control, normal-weight diabetic, obese nondiabetic, obese glucoseintolerant, and obese diabetic subjects.
From: DeFronzo (1991) Genetics of Type 2 Diabetes: Type 2 diabetes, which now affects more than 20 million Americans, is a chronic disease of multifactorial origin of polygenic nature, which means it cannot be ascribed to one gene or single environmental factor. Although various animal studies recently have discovered some 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 of the candidate genes for type 2 diabetes, with their function, effect, and their linkage to a particular form of diabetes in animals and man.
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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-1Transcription Insulin MODY Factor secretion Oji-Cree diabetes ________________________________________________________________ Glucokinase Glucose Insulin MODY Metabolism secretion ________________________________________________________________ Calpain-10 Protease Unknown Diabetes 2 in Mexican and African Americans ________________________________________________________________ PPARTranscription Insulin Diabetes 2 Factor sensitivity ________________________________________________________________ Insulin receptor Transmits Insulin Human diabetes insulin signals sensitivity (rare); mouse into cell and secretion models ________________________________________________________________ IRS 1 and 2 Insulin Insulin Mouse models signaling sensitivity ________________________________________________________________ Akt2 Insulin Insulin Mouse models signaling sensitivity ________________________________________________________________ 11- -HSD Glucocorticoid Blood Mouse Models synthesis lipids, insulin sensitivity ________________________________________________________________ UCP2 ATP Insulin Mouse models synthesis secretion ________________________________________________________________ Resistin Fat cell Insulin Mouse studies hormone sensitivity ________________________________________________________________ Adiponectin Fat cell Insulin Mouse, human hormone sensitivity studies Reference: Science, Vol 216, pages 685-689, 2002
Prime suspect: the TCF7L2 gene and type 2 diabetes risk

Andrew T. Hattersley
Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, United Kingdom.
Transcription factor-7like 2 (TCF7L2) is the most important type 2 dia-betes susceptibility gene identified to date, with common intronic variants strongly associated with diabetes in all major racial groups. This ubiquitous transcription factor in the Wnt signaling pathway was not previously known to be involved in glucose homeostasis, so defining the underlying 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 risk allele increases TCF7L2 expression in the pancreatic cell, reducing insulin secretion and hence predisposing the individual to diabetes (see the related article beginning on page 2155). 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 the fundamental 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 of JCI, is turning this genetic information into novel biological insights (1). Early genetic studies in type 2 diabetes Early attempts to identify the genes responsible for type 2 diabetes were slow and 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. 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 detect modest 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 polymorphisms 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
established, understanding the associated pathophysiology was relatively straightforward. 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 gene At 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 attention during 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 tracking of genes have both been greatly helped by new technologies. Because of techno-
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Figure 1
From genetic association to pathophysiology in TCF7L2 genotypes predisposing to type 2 diabetes. Diagram of proposed pathophysiological pathway explaining how TCF7L2 risk genotypes predispose to type 2 diabetes. The risk genotype results in overexpression of TCF7L2 in pancreatic cells, which in turn results in reduced insulin secretion. Reduced insulin secretion results in a predisposition to type 2 diabetes directly and also indirectly by increasing hepatic glucose output. Dotted arrows represent previous genetic associations. Solid arrows show observations reported by Lyssenko and colleagues in the current issue of the JCI (1).
logical advances, the majority of common genetic variations can be assessed on a single chip at a very reasonable cost. This directly led to a whole new series of largescale 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 TCF7L2 alleles predispose to diabetes Defining 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 of type 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). TCF7L2 polymorphisms are clearly guilty of predisposing to type 2 diabetes on the
basis of strong, reproducible association in multiple populations and would appear to be the 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 biological pathway 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 there are 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 have funding 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-
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 was contrary 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 levels were 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 TCF7L2 expression, 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 of TCF7L2 did not result in the increased glucagon secretion seen in the type 2 diabetic islets.
Conclusion So 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 of TCF7L2 in the pancreatic cell, which reduces insulin
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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 expression reduce 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 Trust Research 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 association signals in UK samples reveals risk loci PPARgamma for type 2 diabetes. Science. 316:13361341. Pro12Ala polymorphism is associated with 14. Sladek, R., et al. 2007. A genome-wide decreased association study identifies novel risk loci for type risk of type 2 diabetes. Nat. Genet. 26:7680. 2 diabetes. Nature. 445:881885. 3. Gloyn, A.L., et al. 2003. Large-scale association 15. Scott, L.J., et al. 2007. A genome-wide studies of variants in genes encoding the pancreatic association beta-cell K-ATP channel subunits Kir6.2 study of type 2 diabetes in Finns detects multiple (KCNJ11) and SUR1 ABCC8) confirm that the susceptibility variants. Science. 316:13411345. KCNJ11 E23K variant is associated with Type 2 16. Saxena, R., et al. 2007. Genome-wide diabetes. Diabetes. 52:568572. association 4. Barroso, I., et al. 1999. Dominant negative analysis identifies loci for type 2 diabetes and mutations triglyceride levels. Science. 316:13311336. in human PPARgamma associated with severe 17. Steinthorsdottir, V., et al. 2007. A variant in insulin resistance, diabetes mellitus and CDKAL1 influences insulin response and risk of hypertension. Nature. 402:880883. type 2 diabetes. Nat. Genet. 39:770775. 5. Gloyn, A.L., et al. 2004. Activating mutations in 18. Horikawa, Y., et al. 2000. Genetic variation in the the gene encoding the ATP-sensitive potassiumgene encoding calpain-10 is associated with type 2 channel subunit Kir6.2 and permanent neonatal diabetes mellitus. Nat. Genet. 26:163175. diabetes. N. Engl. J. Med. 350:18381849. 19. Weedon, M.N., et al. 2003. Meta-analysis and 6. Grant, S.F., et al. 2006. Variant of transcription a large association study confirm a role for calpainfactor 7-like 2 (TCF7L2) gene confers risk of type 10 variation in type 2 diabetes susceptibility. Am. 2 diabetes. Nat. Genet. 38:320323. J. 7. Zeggini, E., and McCarthy, M.I. 2007. TCF7L2: Hum. Genet. 73:12081212. the biggest story in diabetes genetics since HLA? 20. Tsuchiya, T., et al. 2006. Association of the Diabetologia. 50:14. calpain8. Chandak, G.R., et al. 2007. Common variants in 10 gene with type 2 diabetes in Europeans: results the of pooled and meta-analyses. Mol. Genet. Metab. TCF7L2 gene are strongly associated with type 2 89:174184. diabetes mellitus in the Indian population. 21. Johnson, J.D., et al. 2004. RyR2 and calpainDiabetologia. 50:6367. 10 delineate a novel apoptosis pathway in 9. Hayashi, T., Iwamoto, Y., Kaku, K., Hirose, H., pancreatic islets. J. Biol. Chem. 279:2479424802. and 22. Saxena, R., et al. 2006. Common single Maeda, S. 2007. Replication study for the nucleotide association of TCF7L2 with susceptibility to type 2 polymorphisms in TCF7L2 are reproducibly diabetes in a Japanese population. Diabetologia. associated 50:980984. with type 2 diabetes and reduce the insulin 10. Horikoshi, M., et al. 2007. A genetic variation response to glucose in nondiabetic individuals. of the Diabetes.55:28902895. transcription factor 7-like 2 gene is associated with 23. Freathy, R.M., et al. 2007. Type 2 diabetes risk of type 2 diabetes in the Japanese population. TCF7L2 Diabetologia. 50:747751. risk genotypes alter birth weight: a study of 24,053 11. Lehman, D.M., et al. 2007. Haplotypes of individuals. Am. J. Hum. Genet. 80:11501161. transcription factor 7-like 2 (TCF7L2) gene and its 24. Florez, J.C., et al. 2006. TCF7L2 upstream region are associated with type 2 diabetes polymorphisms and progression to diabetes in the and age of onset in Mexican Americans. Diabetes. Diabetes Prevention 56:389393. Program. N. Engl. J. Med. 355:241250. 12. Helgason, A., et al. 2007. Refining the impact 25. Loos, R.J., et al. 2007. TCF7L2 of TCF7L2 gene variants on type 2 diabetes and polymorphisms modulate proinsulin levels and adaptive evolution. Nat. Genet. 39:218225. beta-cell function in a 13. Zeggini, E., et al. 2007. Replication of genome-wide British Europid population. Diabetes. 56:19431947.
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Obese Type 2 DM About 85% of Type 2 diabetics are obese. These patients have an insensitivity to endogenous insulin, which is positively correlated to upper body fat distribution (so called apple shaped or android habitus as opposed to pear shaped or gynoid habitus), producing a high waist to hip ratio (W/H). Hypertrophy of panc reatic -cells in the early phase of DM (IGT) accounts for the exaggerated insulin responses to glucose and other stimuli. As IGT progresses to T2DM, secondary to failure of pancreatic -cells as a result of hyperglycemia (glucose toxicity) and high FFA (lipotoxicity), frank T2DM emerges. This -cell toxicity is selective for glucose, but the -cell may recover with correction of hyperglycemia (see below). Insulin Resistance in Type 2 DM (Figures 14 & 15) Insulin resistance may be defined as a condition where insulin responsive tissues exhibit insensitivity to physiological levels of insulin. Therefore, in order for the body to maintain fasting euglycemia (or near euglycemia) insulin secretion is stepped up to compensate for this insulin insensitivity. This leads to hyperinsulinemia. Although not all insulin resistant states lead to T2DM this increased secretion may occur in the 2nd phase of T2DM, as the 1st 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 may be the initial event in cascade of DM (Figure 13), which may lead to hyperinsulinemia as the 1st clinical demonstration of insulin resistance in type 2 DM. This brings about down regulation of insulin receptors with subsequent diminution of glucose transporters leading to post prandial hyperglycemia and glucose toxicity. The latter may reduce -cell secretion (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 any modality that reduces hyperglycemia (i.e., diet and exercise, or treatment with insulin sensitizers), which leads to reduction of insulin, improves insulin sensitivity and reverses insulin resistance.
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Other Conditions Associated With Insulin Resistance: In addition to type 2 DM, many physiological and clinical conditions are also associated with insulin resistance, which are depicted in Figure 15. Figure 15
Interrelationship Between Insulin Resistance & Atherosclerosis

Hypertension Endothelial dysfunction Hyperinsulinemia Hyperglycemia
Insulin Resistance Atherosclerosis
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 may also be a compensatory mechanism to prevent severe obesity in man. In addition to the above, there are three mechanisms (although much more rare) besides T2DM or metabolic syndrome, which are associated with clinical insulin resistance. These are summarized in Table 15. Fig. 6 depicts coordination between three major conditions, T2DM, insulin resistance and metabolic syndrome. Common among all three are proinflammatory states and endothelial dysfunction. Each and all three conditions are highly associated with cardiovascular events.
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TABLE 15 Mechanism of Apparent Insulin Resistance Type of Defect Prereceptor Mechanism (s) Circulating antinsulin factors: antibodies against insulin; Abnormal insulin synthesis Accelerated insulin degradation
Receptor number of affinity, Primary defects or both Circulating antireceptor antibodies (membrane receptors) Physiological regulatory mechanisms (i.e., down-or up-regulation) Absent target site Postreceptor events Defective receptor second-messenger activity Accelerated 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 glucose tolerance (IGT), c) obesity (especially abdominal or visceral), d) dyslipidemia of high triglyceride and/or low HDL type and hypertension plus other conditions depicted in Figure 16 & its multiple components & criteria for diagnosis. The minimum criteria for this syndrome are summarized on Table 16. Role of Fat Tissue and Obesity in Metabolic Homeostasis: As obesity plays a pivotal role 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 include secretory products from the gut, muscle and fat. Pancreas and gut could interact with major neurotransmitter in the brain, the control feeding and satiety center. This figure is an attempt to interdigitate these agents presence, some of which are demonstrated but others are in progress of identification. Important among these chemicals are the secretory products 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 called adipokines. The above compounds are resistance components of adipokine. But an important anti-insulin resistance compound produced by fat tissue is the recently discovered adiponectin 30,000KD plasma protein which is found in high concentration (210 mg/dL) in normal man but reduced in obesity. Table 17 summarizes properties of adiponectin 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 Group NCEP ATPIII WHO Glucose (mg/dl) 3 or more of the following: FPG > 110mg/dl > 130/85 > 150 IFG, IGT or DM and/or insulin resistance plus 2 or more of the following: > 140/90 > 150 >1.7 >1.7 or HDL-cholesterol <1.0 (women) <0.9 (men) <50 (women) <40 (men) <1.3 (women) <1.0 (men) Waist >35 (women) >40 (men) * WHR >0.85 (women) >0.9 (men) or BMI>30Kg/m2 <39 (women) <35 (men)
Blood pressure (mmHg) Triglycerides (mg/dl) Serum Triglycerides (mmol/l)
HDL cholesterol (mg/dl)
HDL cholesterol (mmol/l)
Abdominal obesity Serum Glucose (mg/dl)
>109.8 (>100.8 may be acceptable) None Alb/Cr > 20 mg/g
Microalbuminuria Urinary Albumin Excretion Rate Urinary Albumin: Creatinine Ratio
>20g/min
> 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
Environmental & Genetic Factors

Insulin Resistance (Dyslipidemia)
PMN activation TNF- IL-6
Fibrinogen PAI-1 CRP
Inflammation (stress) Diabetes Mellitus

Hyperglycemia -cell dysfunction insulin sensitivity Dyslipidemia coagulation AGE proteins
Endothelial Dysfunction
ROS NO VCAM ICAM
Vasoconstriction
Metabolic Syndrome
Cardiovascular Diseases
Microvascular Macrovascular Cerebrovascular
HPTN Dyslipidemia Central obesity IGT
Kitabchi, IAMA Bulletin, 2006
It is important to recognize that both diabetes and atherosclerosis are inflammatory diseases in which endothelial dysfunction leads to production of reactive oxygen species and free radical production with reduction of NO (a vasodilating agent) and reduction of vasodilation. Numerous adipokines affect metabolic homeostasis.
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Figure 17
Intake
Diabetes and Obesity Biomarkers Food Energy Body Weight

BRAIN (Hypothalamus )
NPY MCH AgRP Orexin
Expenditure
PANCREAS
Proinsulin C-peptide Amylin Glucagon PP Somatostatin
MUSCLE
? ?
Insulin
Musclin Myostatin Leptin

IL-6 TNF MCP-1 PAI-1 ASP Cortisol Adipsin
PYY3-36 GLP-1
GIP GLP-2 GRP PYY Gastrin Oxyntomodulin VIP CCK
+ ?
Gut
Ghrelin
Adiponectin
Resistin
Fat
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Figure 18
Deficient Insulin: Hypersecreted Glucagon TYPE 2 DIABETES

Without Diabetes (n=14) Type 2 Diabetes (n=12)
120
Defects in diabetes: Deficient insulin release Glucagon not suppressed (postprandially) Hyperglycemia
Insulin (U/mL)
60 0 140
Glucagon 120 (pg/mL)

100 360
Glucose (mg/dL)
300
240 110 80 -60 0 60 120 180 240
Meal
Time (min)
Data from Muller WA, et al. N Engl J Med 1970; 283:109-115. Figure 19
Multihormonal Regulation of Glucose Appearance and Disappearance

0.6 Mixed Meal (with ~85 g Dextrose) Regulated by hormones: amylin, CCK, GLP-1, etc.
Grams of Glucose flux/min
0.4 0.2 0
Meal-Derived Glucose Hepatic Glucose Production Total Glucose Uptake
Balance of insulin suppression and glucagon stimulation
-0.2 -0.4 -0.6 -30 0 Insulin-mediated glucose uptake
120
240
360
480
Time (min) From Start of Mixed Meal
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
GLP-1: Secreted upon the ingestion of food
Promotes satiety and reduces appetite
Alpha cells:
Postprandial glucagon secretion
Liver: Beta cells:

Enhances glucose-dependent insulin secretion Glucagon reduces hepatic glucose output
Stomach:
Helps regulate gastric emptying
Data from: Flint A, et al. J Clin Invest. 1998;101:515-520 Larsson H, et al. Acta Physiol Scand. 1997;160:413-422 Nauck MA, et al. Diabetologia 1996; 39:1546-1553 Drucker DJ. Diabetes. 1998;47:159-169
Figure 21
The Incretin Effect in Healthy Subjects

Oral Glucose Intravenous (IV) Glucose
* *
Plasma Glucose (mg/dL) C-peptide (nmol/L)
200
2.0
1.5
* * Incretin Effect * *
100
1.0 * 0.5 0.0
0 0 60 Time (min) 120 180
60 120 Time (min)
180
N = 6; Mean (SE); *P0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498.
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 syndrome c. Obese women with PCOS d. Patients with type 2 diabetes e. Patients with CAD f. Those at risk for type 2 diabetes and first-degree relatives g. Some adiponectin gene mutations associated with increased type 2 diabetes h. 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 Reprod 18:1790-1796, 2003 Diez JJ, et al. Eur J Endocrinol 148:293-300, 2003 Spranger, et al. Lancet 361:226-228, 2003 Daimon M, et al. Diabetes Care 26:2015-2020, 2003 Matsubara M, et al. Eur J Endocrinol 148:343-350, 2003 Mohlig M, et al. Horm Metab Res 34:655-658, 2002; Nemet D, et al. Pediatr Res 53:148152, 2003 Yatagai T, et al. Endocr J 50:233-238, 2003 Monzillo LU, et al. Obes Res 11:1048-1054, 2003 Engeli S, et al. Diabetes 52:942-947, 2003 English PJ, et al. Obes Res 11:839-844, 2003; Ryan AS, et al. Diabetes Care 26:23832388, 2003
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Table 18 correlates various chemical abnormalities with metabolic defects and clinical abnormalities in severely uncontrolled diabetes. TABLE 18 Correlation of Clinical Conditions and Diabetic Syndromes with Various Metabolic Defects Metabolic Defects Chemical Abnormalities Clinical Abnormalities Polyuria, polydipsia, polyphagia fatigue, muscle weakness, pruritus
Carbohydrate Metabolism 1. Diminished uptake of glucose by tissues such as muscle, adipose tissue and liver 2. Overproduction of glucose (via glycogenolysis and glyconeogenesis by the liver)
Hyperglycemia
Blurred vision Diminished mental alertness
Protein Metabolism 1. Diminished uptake of amino Negative nitrogen Loss of muscle mass and diminished synthesis balance Weakness of protein Elevated levels of branchchain amino acids Elevated blood urea nitrogen level 2. Increased proteolysis Fat Metabolism 1. Increased lipolysis Elevated potassium level
Elevated plasma fatty acids level Elevated plasma glycerol level
Loss of adipose tissue
2. Decreased lipogenesis 3. Increased production of triglycerides Hypertriglyceridemia
Loss of adipose tissue Exudative xanthoma (skin lesions) Lipemia retinalis Pancreatitis (abdominal pain) Hyperventilation, metabolic acidosis, abdominal pain
4. Decreased removal of ketones and increased ketone production
Elevated plasma and urine ketones
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Table 19 provides important guidelines for calculation of body weight and caloric requirement 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 Men
100 lb for first 5 feet + 5 lb for each additional inch 106 lb for first 5 feet + 6 lb for each additional inch Wt.(kg)/height (M)2 normal value 20-25, obese >27
Body Mass Index (BMI)
Calorie Requirement
Basal requirement Average activity Strenuous activity Weight loss Pregnancy Lactation Dietary Composition Carbohydrate Protein Fat Fiber
Ideal body weight x 10 Add 30% to basal requirement Add 100% - 200% to basal requirement Subtract 500 calories/day to lose 1 lb/week Add 300 calories/day Add 500 calories/day
50% - 55% of total calories 15% - 20% of total calories 30% of total calories (<10% saturated fat) 30 gm soluble fiber
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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 Pregnant
70 - 99 mg/dl 69 - 90 mg/dl
70 - 120 mg/dl 69 - 90 mg/dl
Postprandial Blood Glucose (2 hr) Pregnant (1 hr)
< 140 mg/dl < 140 mg/dl
< 180 mg/dl 120 mg/dl
Glycosylated Hemoglobin A1c Cholesterol
4 - 6% < 200 mg/dl
< 7% < 200 mg/dl
HDL Cholesterol Men Women
> 35 mg/dl > 45 mg/dl
> 35 mg/dl > 45 mg/dl
LDL Cholesterol
< 130 mg/dl
< 75 mg/dl
Triglycerides
< 150 mg/dl
< 150 mg/dl
Body Mass Index* (BMI) (kg [weight] m2 [height]) *BMI >27 is defined as overweight.
19 - 25
19 - 25
Some ethnic groups such as Asians have lower BMI
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Glycosylated (Glycated) Hemoglobin HbA1c Under normal conditions, a certain amount of glucose attaches to the valine molecule of the chain 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 form of 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 hemiketal structure. The percentage of hemoglobin which is glycated in normal subjects is 4 to 6%, but in diabetics with hyperglycemia ranges up to 14%. Since this reaction is slow and irreversible and 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 correlation between HbA1c and blood glucose is stronger with the postprandial blood glucose than fasting blood glucose levels. It has been shown in certain studies that the progression of chronic complications of DM may be correlated with prevailing levels of HbA1c and that reduction of HbA1c decreases the risk of these complications (secondary to reduction of level of hyperglycemia). (See below.) Any condition that alters erythrocyte turnover lowers HbA1c levels (i.e., bleeding, pregnancy or splenectomy). On the other hand, uremia, fetal Hb, aspirin or high levels of ethanol may falsely elevate levels of HbA1c. These interfering substances do not affect HbA 1c levels measured by more specific methods such as affinity chromatography. Assessment of average glycemic control from a shorter (~2-3 weeks) duration of time can be accomplished by measurement of other glycated proteins with shorter half-lives such as serum fructosamine or albumin. Correlation of Blood Glucose Control and Diabetic Complications For many years controversies have existed as to whether hyperglycemia could lead to microvascular (retinopathy, nephropathy or neuropathy) or macrovascular (cardiovascular disease, stroke, etc.) diseases. This important issue was finally settled by four important prospective randomized long-term studies. The first study was the Diabetes Control and Complication Trial (DCCT) for type 1 DM, which was sponsored by NIH and conducted by 29 clinical centers in the United States and Canada from 1983-1992. The second study was a European Study, also in type 1 DM. The third study was the Kumamoto study for type 2 DM, which was conducted in Japan. The fourth study 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 that control of blood sugar (reduction in HbA1c) resulted in significant risk reduction in diabetic complications. The results are summarized in Table 21.
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Table 21 Relationship of Glycemic Control to Reduction in Diabetic Complications Outcome Parameters Studies (1) (2) SDIS DCCT Kumamoto (3) UKPDS (4) Type of DM Number of Patients Mean age (y) Duration of follow-up (y) Change in HbA1c Reduction in risk (%) Retinopathy Nephropathy Neuropathy Myocardial infarctions Any diabetes related endpoint 52 89 NS ----63 54 60 ----69 70 ------21 33 --16 25 Type 1 102 30 7.5 - 2.4 Type 1 1441 27 6.5 - 1.9 Type 2 102 49 6 - 2.3 Type 2 4200 53 10 - 0.9
(1) Reichard P, Nilsson BY, Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Eng J Med 329:304, 1993. (2) The DCCT Research Group, The effect of intensive treatment of diabetes on the development and progression of long-term complications of insulin-dependent diabetes mellitus. N Eng J Med 329:977, 1993. (3) Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 28:103, 1995. (4) UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Lancet 352_837-53, 1998. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352_854-65, 1998
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 globally, primarily due to sedentary lifestyle and obesity. Among precursors of diabetes is impaired glucose tolerance (IGT), which affects 21 million Americans and 200 million subjects worldwide. In the last few years, three major landmark studies reported success in the prevention of T2DM in high-risk individuals with IGT. Lifestyle modification to affect weight loss of 7% with moderate exercise was most effective in reducing risk of conversion from IGT to T2DM. The usual rate of conversion in such high risk individuals (regardless of ethnicity) appears to be between 10-11% per year in the Diabetes Prevention Program, conducted in the United States. Table 22 summarizes the results of these studies in China, Finland and U.S., demonstrating effectiveness of lifestyle modification as well as metformin in reducing the risk for developing type 2 diabetes. Table 22: Summary of Landmark Diabetes Prevention Studies Study Da Qing1 577 Finnish2 522 DPP**
3
Age (yr) 45 55 50.6
BMI 26 31 34
Ethnicity Chinese
Length 6 yr 3.2 yr 2.8 yr
Intervention
% reduction* 33-47% 58% 58% 31%
Diet + Exercise Diet + Exercise Lifestyle Metformin
European Multi-ethnic
3234
* Percentage reduction in incidence of diabetes compared with control ** DPP, Diabetes Prevention Program 1. Pan XR, et al. The Da Qing IGT and Diabetes Study, Diabetes Care 20:537-544, 1997. 2. Tuomilehto J, et al. Finnish Diabetes Prevention Study Group, N Eng J Med 344:134350, 2001. 3. Diabetes Prevention Program Research Group, N Eng J Med 345:393-403, 2002.
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MORNING HYPERGLYCEMIA IN INSULIN-TREATED DIABETES Morning Hyperglycemia (Figure 22) There are generally three reasons for morning hyperglycemia in an insulin-treated diabetic (type 1 or 2): 1) the dawn phenomenon, 2) mere waning of insulin and 3) post-hypoglycemic hyperglycemia (Somogyi phenomenon). It is critical to the management of such patients to distinguish between these causes. This can be done by analyzing the overnight pattern of changes in blood glucose levels. Figure 22 illustrates typical overnight blood glucose patterns found with insulin waning, the dawn phenomenon and the Somogyi phenomenon. With simple waning of insulin, blood glucose values generally increase progressively throughout the night. A similar pattern is observed with the dawn phenomenon, except that blood glucose values usually do not increase until after 3 a.m. (the time when blood glucose is at its lowest level). It is not necessary to distinguish between these two causes of morning hyperglycemia because their management is the same, i.e., provision of additional insulin. If patients are being treated with an insulin pump (a device which delivers insulin under the skin continuously as basal insulin with a bolus of insulin before each meal), the basal infusion rate needs to be increased after 3 a.m. The mechanism for the dawn phenomenon has been shown to be due to counterregulatory effect of growth hormone (GH) after REM sleep. Since the hyperglycemic effect of GH is slow, but gradual, this hyperglycemic event occurs 2-4 hours after peak GH secretion. The dawn phenomenon also occurs in non-diabetic individuals, but in them morning blood glucose never exceeds 110 in spite of the fact that there is nadir of blood glucose at 3 a.m. Somatistatin infusion studies have been demonstrated to reduce hyperglycemia of dawn phenomenon in DM patients. With the Somogyi phenomenon, blood glucose levels usually decrease to the hypoglycemic or near- hypoglycemic range. Of course, the lowest blood glucose level may not be detected, and thus it is important to remember that blood glucose levels as high as 70 mg/dl may be sufficient to activate counterregulatory hormone (i.e., glucagon, catecholamines, cortisol) secretion. When the overnight blood glucose pattern is equivocal, it is prudent to assume that a Somogyi phenomenon is operative and assess the consequences of either reducing the dose of insulin that is active overnight or increasing the pre-bedtime snack. If morning hyperglycemia is not reduced by this method, it is likely that waning insulin or a dawn phenomenon is responsible, and overnight insulin coverage should be increased.
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FIGURE 22 Characteristic Overnight Patterns of Blood Glucose Observed in the Dawn Phenomenon, Somogyi Phenomenon and Mere Waning of Insulin __ 250 __ 200
BLOOD GLUCOSE mg/dl
INSULIN WANING
__ 150 __ 100 __ 50 __ 0
SOMOGYI PHEMOMENON DAWN PHENOMENON
ACTIVATION OF COUNTERREGULATION
9 PM
MN
3 AM
6 AM
9 AM
TIME OF DAY
From Gerich JE, Diabetes Clinic NOTES: __________________________________________________________________________ __________________________________________________________________________ __________________________________________________________________________ __________________________________________________________________________ __________________________________________________________________________ __________________________________________________________________________ __________________________________________________________________________ __________________________________________________________________________ __________________________________________________________________________ _____________________________________________________________
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POTENTIAL QUESTIONS TO ASK THUS FAR: 1. ___________________________________________________________________ _______________________________________________________________ 2. ___________________________________________________________________ ___________________________________________________________________ 3. ___________________________________________________________________ ___________________________________________________________________ 4. ___________________________________________________________________ ___________________________________________________________________ 5. ___________________________________________________________________ ___________________________________________________________________
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PATHOPHYSIOLOGY COURSE - ENDOCRINE MODULE Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus (DM) Abbas E. Kitabchi, Ph.D.

, M.D. Friday, December 4, 2009, 8:00-9:50am

FIGURE 1 Arrangement of Cells in a Typical Islet

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

FIGURE 2 Structure of Human Proinsulin

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Organ Brain Erythrocyte Adipocyte Muscle Liver GK -cell Gut Kidney

HK Coupler HK-I HK-I HK-II HK-II HK-IVL HK-IVB (glucokinase) -

FIGURE 5 Hypothetical Model of Insulins Action on Glucose Transport

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Liver Liver Liver, Kidney, Cortex Liver

Adipose Liver Liver

Insulin Glucagon Somatostatin

Nonendocrine Gastrointestinal tract

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

FIGURE 7 Sources and Fate of Glucose

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

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

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Insulting Agent e.g., Pancreotropic Virus

Autoimmune Process Begins

Macrophages (Ag presenting cell)

LEGEND: Ag Antigen INF Interferon TNF Tumor Necrosis Factor

Precipitating Factors or Stressors TYPE I Diabetes Mellitus

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

OBESITY INSULIN RESISTANCE POSTPRANDIAL HYPERGLYCEMIA HYPERINSULINEMIA

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Onset of diabetes Complications Disability Death

Insulin resistance Hyperinsulinemia HDL TG

Blindness Death Renal failure CHD Amputation

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

FIGURES 12, 13, & 14

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Prime suspect: the TCF7L2 gene and type 2 diabetes risk

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Interrelationship Between Insulin Resistance & Atherosclerosis

Hypertriglyceridemia Small, dense LDL

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Blood pressure (mmHg) Triglycerides (mg/dl) Serum Triglycerides (mmol/l)

HDL cholesterol (mg/dl)

HDL cholesterol (mmol/l)

Abdominal obesity Serum Glucose (mg/dl)

>109.8 (>100.8 may be acceptable) None Alb/Cr > 20 mg/g

Microalbuminuria Urinary Albumin Excretion Rate Urinary Albumin: Creatinine Ratio

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus

Figure 16 Role of T-cells and E-cells in T2DM & CVD

Environmental & Genetic Factors

Inflammation (stress) Diabetes Mellitus

HPTN Dyslipidemia Central obesity IGT

Kitabchi, IAMA Bulletin, 2006

Physiology of Endocrine Pancreas and Pathophysiology of Diabetes Mellitus