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Tamara Spaic A fellow forever…………. Objectives What is insulin resistance/sensitivity ? Insulin Secretion How is insulin sensitivity related to insulin secretion? How do we measure? What are the clinical manifestations? What test is the best? Pathophysiology of diabetes (2) 1. Beta cell function (insulin secretion) 2. Insulin resistance/sensitivity 3. Hepatic glucose output Secretion N ~ 30 U/day Basal and stimulated insulin secretion Basal – in the absence of exogenous stimuli (fasting state, 50%), pulsatile Stimulated insulin secretion (in response to glucose) Biphasic FIGURE 1. A: stimulus-secretion coupling of pancreatic {beta}-cells Rorsman, P. et al. News Physiol Sci 15: 72-77 2000 Copyright ©2000 American Physiological Society Measures of Insulin Secretion and Beta Cell Mass Fasting blood sugar Serum insulin concentration Oral and intravenous glucose tolerance tests Arginine stimulation Fasting glucose Fasting condition represents a basal steady state Glucose is homeostatically maintained in the same range Insulin levels are not significantly changing HGP is constant (matched whole body glucose disposal under fasting conditions) Rats : loss of 70% beta cell mass – N glucose Fasting Insulin Peripheral levels: 50-60% of pancreatic insulin is removed by liver on first pass effect Confounding effect of anti-insulin antibodies Cross-reactivity of insulin assay with proinsulin : 20% of circulating “insulin” may be proinsulin (and may be higher in IGT and Type 2DM) Not good measure of beta cell mass/function but can be used to determine insulin sensitivity What about C peptide? C peptide released equimolar with insulin Under steady-state conditions, reliable as marker of insulin secretion Due to long half life, C peptide levels in dynamic situations will not reflect insulin secretion Arginine stimulation Dependent on the prestimulus glucose concentration Acute serum insulin response to arginine (AIRarg) Slope of glucose potentiation of insulin secretion Maximum serum insulin response Insulin Resistance (IR) Presence of an impaired biologic response to either exogenously or endogenously secreted insulin Manifested by decreased insulin-stimulated glucose transport and metabolism in adipocytes and skeletal muscle and by impaired suppression of hepatic glucose output Williams textbook of Endocrinology, 2008 Insulin Sensitivity (IS) The capacity of cells to respond to insulinstimulated glucose uptake following ingestion of carbohydrates Influenced by – age, weight, ethnicity, body fat, physical activity, medications Disease vs not IR → impaired/decreased IS Insulin Sensitivity The ability of beta cells to compensate for IR determines whether one develops DM Compensation – insulin hypersecretion even when N glucose THIS OCCURS ONLY IF BETA CELL SENSITIVITY TO GLUCOSE IS INCREASD 2 factors – number of cells and increased expression of hexokinase (relative to glucokinase) This shifts the glucose-insulin secretion dose response curve to the LEFT, leading to increased insulin secretion across a wide range of glucose concentration Disposition Index Product of insulin secretion and sensitivity During the development of IR insulin secretion increases If DI remains N (N glucose) – able to compensate Once DI drops (inadequate secretion in relation to resistance) – diabetes develops Zucker Fatty Rat (ZFR) and Diabetic Rat (ZDR) ZFR – obese and resistant, but N glucose ZDR – obese, resistant, overt hyperglycemia At 6 weeks (before development of DM) increased beta cell mass (same in ZFR and ZDR and increased compared to lean control) Beta cell mass in ZFR increased fourfold vs 2-fold in ZDR as DM develops (failure of beta cell to compensate) Inhanced beta cell (apoptosis) Humans…….. Shift seen in pregnancy (three fold increase in F1 and F2 insulin secretion) IGT – flattened response, shift to the right, F1 decreased consistently decreased DM – F1 absent, further flattening and coordination of insulin secretory responses during oscillatory glucose infusion is almost lost Obesity Insulin resistance develops 2. Insulin secretion increased 3. If insulin sensitivity SAME – who will have higher insulin secretion a) IGT patient b) Normal glucose tolerance patient 1. Bariatric surgery 1. 2. 3. DI is Same Decreased Increased Direct measures of IS Hyperinsulinemic euglycemic clamp Overnight fast Insulin infusion D20% to keep glucose clamped in the normal range Needs K Steady state (increased disposition to muscle and adipocytes, HGP inhibited) No net change in glucose concentration then glucose infusion rate is equal to the glucose disposal rate (M) Insulin Suppression Test Octreotide or somatostatin infused to suppress endogenous secretion of insulin and glucagon Insulin and glucose infused Constant infusion will determine steady state plasma insulin (SSPI) and glucose (SSPG) SSPG inversly related to insulin sensitivity Indirect measures FSIVGTT OGTT FSIVGTT (Frequently sampled intravenous glucose tolerance test) To determine the disappearance rate of glucose per minute Reflects patient’s ability to dispose of glucose load (first phase) Screening siblings of DM1 or in pts with GI abnormalities Bypasses GI (?incretins) Insensitive Procedure IV 25% or 50% glucose solution over 2-3 minutes Sampling for glucose from indwelling catheter in the opposite side (0, 10, 15, 20, 30 minutes) Plasma glucose values plotted against time (rate of fall in % per minute) 75 g OGTT Measurement of IS Reflects the efficiency of the body to dispose of glucose after oral glucose load Mimics physiology Not primary screening test (if IFG or BG 5.6 - 6.0 but at risk) Just 0 and 120 min value Fasting for 8 hours prior 3 days prior should be on 150-200 g of CHO/day Surrogate Indexes 1/Fasting Insulin Glucose/Insulin ratio HOMA QUICKI HOMA Homeostasis model assessment Assumes feedback loop between liver and beta cells HOMA – IR = fasting insulin (uU/ml) x fasting glucose (mmol/L) /22.5 Normal IS HOMA-IR =1 Resonable correlation with clamp studies Not good if significantly impaired beta cell function QUICKI Quantitative insulin sensitivity check index Empirically derived mathematical transformation of fasting blood glucose and plasma insulin concentrsation Very good PPV 1/[log(fasting insulin, uU/mL)+ log(fasting glucose, mg/dL)] Performs best in insulin-resistant subjects But why do beta cells fail ? Glucotoxicity 1. Impaired glucose transport into the beta cell thru GLUT2 transporters 2. Reduced glucokinase activity in the beta cell 3. Downregulation of insulin transcription factors Lipotoxicity High fat diet steatosis: after prolonged high fat diet TG accumulate in skeletal muscle, islets, liver and elsewhere FA initially stimulate insulin production But as more fat enters islets, insulin secretion decreases as beta cells die Role of islet amyloid polypeptide High concentrations of amylin decrease glucose uptake and inhibit endogenous insulin secretion, suggesting that amylin may be directly involved in the pathogenesis of type 2 diabetes Impaired insulin processing Processing of proinsulin to insulin in the beta cells is impaired in type 2 diabetes, or that there is insufficient time for granules to mature properly so that they release more proinsulin. Insulin secretion in IGT/DM2 Delay in peak insulin response Dose response rate curve shiftes to the right First phase response decreased DM2 : absent first phase insulin and C-peptide response to IVG and reduced 2nd phase response Historic prospective Himsworth 1936 Vague 1947 Initially in patients on insulin that would develop Ab to insulin (today recombinant human insulin) IR not any longer a common complication but rather a component of several disorders Donohues syndrome (Leprechaunism) Rabson-Mendenhall syndrome Major causes of insulin resistance Inherited states of target cell resistance Leprechaunism (insulin-receptor mutations) Rabson-Mendenhall syndrome (insulin-receptor mutations) Type A syndrome of insulin resistance (insulin-receptor mutations in some, unknown signalling defect in most) Most cases of type 2 diabetes mellitus (unknown inherited defect in vast majority) Some lipodystrophies (unknown primary defect) Secondary insulin resistance Obesity (free fatty acids and tumor necrosis factor may contribute) Excess counterregulatory hormones (glucocorticoids, catecholamines, growth hormone, placental lactogen) Type 2 diabetes mellitus (secondary to obesity and other factors) Inactivity Stress, infection (counterregulatory hormones) Pregnancy (placental lactogen) Immune mediated (anti-insulin antibodies, anti-insulin receptor antibodies in type B syndrome) Miscellaneous (starvation, uremia, cirrhosis, ketoacidosis) Unknown etiology of insulin resistance Hypertension Polycystic ovary syndrome Metabolic Syndrome (Syndrome X) MONOGENIC FORMS OF DIABETES ASSOCIATED WITH INSULIN RESISTANCE Mutations in the insulin receptor gene • Type A insulin resistance • Leprechaunism • Rabson-Mendenhall syndrome Lipoatrophic diabetes Mutations in the PPARγ gene ASSOCIATED WITH DEFECTIVE INSULIN SECRETION Mutations in the insulin or proinsulin genes Mitochondrial gene mutations Maturity-onset Diabetes of the Young (MODY) HNF-4α (MODY 1) Glucokinase (MODY 2) HNF-1α (MODY 3) IPF-1 (MODY 4) HNF-1β (MODY 5) NeuroD1/Beta2 (MODY 6) Clinical manifestations of insulin resistance Glucose homeostasis Variable, including overt diabetes, impaired glucose tolerance, normal, and hypoglycemia Cutaneous Acanthosis nigricans Skin tags Alopecia Reproductive Amenorrhea Hirsutism Virilization Infertility (in women) Linear growth Variable, including normal, impaired, increased Adipose tissue Variable, including normal, lipoatrophy, lipohypertrophy, obesity Musculoskeletal Variable, including normal, cramps, muscle hypertrophy, pseudoacromegaly Lipid metabolism Normal or hypertriglyceridemia /low HDL Autoimmunity Type B syndrome with variety of immune phenotypes Abnormal glucose metabolism Hypoglycemia N (majority) IGT DM2 DM2 Polygenic Environment IR is associated with progression to IGT/DM2 although diabetes is rarely seen in in IR persons without some degree of beta cell dysfunction. Acanthosis nigricans Hyperkeratosis, epidermal papillomatosis, and increased numbers of melanocytes Reproductive abnormailities Not in male Ovarian hyperandrogenism The basis for the association between insulin resistance and ovarian hyperandrogenism is not known The ovary shows the histologic changes of hyperthecosis overt virilization or hirsutism, amenorrhea, and infertility Growth N in adults Pediatric Syndromes (leprechaunism and the Rabson- Mendenhall syndrome) Musculoskeletal changes Some patients with severe tissue resistance to insulin have muscle cramps unrelated to exercise The severity of cramping can sometimes be reduced by phenytoin Adipose tissue Obesity Lipodystrophy (primary vs acquired) Metabolic Syndrome The US National Cholesterol Education Program Adult Treatment Panel III (2001) requires at least three of the following: 1. Central obesity: waist circumference ≥ 102 cm (male), 2. ≥ 88 cm (female) 3. Dyslipidemia: TG ≥ 1.7 mmol/L 4. Dyslipidemia: HDL-C < 1.0 mmol/L (male), <1.3 mmol/L (female) 5. Blood pressure ≥ 130/85 mmHg 6. Fasting plasma glucose ≥ 6.1 mmol/L (2004 : >5.6 mmol/L or hypoglycemic agent) IS and BMI Association of IS and BMI (inverse) Why: abdominal fat is more lipolytically active More resistant to antilipolytic effect of insulin Altered LPL activity Greater flux of FFA 11 beta hydroxysteroid dehydrogenase (more cortisol) FFA Predict progression of IGT to DM Peripheral levels not helpful (efficiently extracted by the liver and muscle) Randel hypothesis (ability of FFA to inhibit muscle glucose utilization) Affect (decrease) glucose transport Impair insulin action