Clinical Presentation of Type 2 Diabetes 1 Age ≥45 years Family history of T2D or cardiovascular - PowerPoint Presentation

Clinical Presentation ofType 2 Diabetes 1

Age ≥45 yearsFamily history of T2D or cardiovascular disease Overweight or obeseSedentary lifestyle Non-Caucasian ancestry Previously identified IGT, IFG, and/or metabolic syndromePCOS, acanthosis nigricans, or NAFLDHypertension (BP >140/90 mmHg)Dyslipidemia (HDL-C <35 mg/dL and/or triglycerides >250 mg/dL) History of gestational diabetesDelivery of baby weighing>4 kg (>9 lb)Antipsychotic therapy for schizophrenia or severe bipolar diseaseChronic glucocorticoid exposureSleep disordersObstructive sleep apneaChronic sleep deprivationNight shift work Risk Factors for Prediabetes and Type 2 Diabetes 2 BP, blood pressure; HCL-C, high density lipoprotein cholesterol; IFG, impaired fasting glucose ; IGT, impaired glucose tolerance; NAFLD, nonalcoholic fatty liver disease; PCOS, polycystic ovary syndrome; T2D, type 2 diabetes. Handelsman YH, et al. Endocr Pract . 2015;21(suppl 1):1-87.

Development of Type 2 Diabetes Depends on Interplay Between Insulin Resistance and β -Cell Dysfunction 3 Insulin resistance Insulin resistance Abnormal β -Cell Function Relative insulin deficiency Gerich JE. Mayo Clin Proc . 2003;78:447-456. Type 2 diabetes Normal β -Cell Function Compensatory hyperinsulinemia No diabetes Genes & environment Genes & environment

Etiology of β-cell Dysfunction 4 Poitout V, Robertson RP. Endocrine Rev. 2008;29:351-366. Genetic predisposition Lean phenotype Obese phenotype IGT, IFG Elevated FFA Oxidative stress and glucotoxicity Cellular lipid synthesis and glucolipotoxicity Progressive -cell failure and type 2 diabetes Initial glucolipoadaptation (increased FFA usage) Hyperglycemia Glucolipotoxicity and glucotoxicity

EMBS, estimated metabolic body size; IGT, impaired glucose tolerance; NGT, normal glucose tolerance. Weyer C et al. J Clin Invest . 1999;104:787-794. Progression to Type 2 Diabetes: “Falling Off the Curve”5 0 100 200 300 400 500 0 1 2 3 4 5 Glucose disposal (insulin sensitivity) (mg/kg EMBS/min)Acute insulin response (U/mL) DIA IGT NGT Progressors NGT NGT NGT Nonprogressors

Pathophysiology ofType 2 Diabetes 6 Organ System Defect Major Role Pancreatic beta cells Decreased insulin secretion Muscle Inefficient glucose uptake Liver Increased endogenous glucose secretion Contributing Role Adipose tissue Increased FFA productionDigestive tract Decreased incretin effectPancreatic alpha cellsIncreased glucagon secretionKidneyIncreased glucose reabsorption Nervous systemNeurotransmitter dysfunctionDeFronzo RA. Diabetes. 2009;58:773-795

Tissues Involved in T2D Pathophysiology 7 Organ System Normal Metabolic Function Defect in T2D Major Role Pancreatic beta cells Secrete insulin Decreased insulin secretion Muscle Metabolizes glucose for energy Inefficient glucose uptakeLiverSecretes glucose during fasting periods to maintain brain function; main site of gluconeogenesis (glucose production in the body)Increased endogenous glucose secretion Contributing RoleAdipose tissue (fat)Stores small amounts of glucose for its own use. When fat is broken down, glycerol is released, which is used by the liver to produce glucose Increased FFA productionDigestive tractDigests and absorbs carbohydrates and secretes incretin hormonesDecreased incretin effectPancreatic alpha cellsSecrete glucagon, which stimulates hepatic glucose production between meals and also helps suppress insulin secretion during fasting periodsIncreased glucagon secretionKidneyReabsorbs glucose from renal filtrate to maintain glucose at steady-state levels; also an important site for gluconeogenesis (glucose production)Increased glucose reabsorption BrainUtilizes glucose for brain and nerve functionRegulates appetiteNeurotransmitter dysfunctionT2D, type 2 diabetes. DeFronzo RA. Diabetes. 2009;58:773-795

Natural History of Type 2 Diabetes 8 Figure courtesy of CADRE. Adapted from Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25;Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789; Nathan DM. N Engl J Med . 2002;347:1342-1349; UKPDS Group. Diabetes. 1995;44:1249-1258 Fasting glucose Type 2 diabetes Years from diagnosis 0 5 –10 –5 10 15 PrediabetesOnsetDiagnosis Postprandial glucose Macrovascular complications Microvascular complications Insulin resistance Insulin secretion -Cell function

Dashed line = extrapolation based on Homeostasis Model Assessment (HOMA) data. Data points from obese UKPDS population, determined by HOMA model. Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25.-cell Loss Over Time9 UKPDS Type 2 Diabetes  -Cell Function (%) Years from Diagnosis 25 – 100 – 75 – 0 – 50 – l -12 l -10 l -6 l -2 l 0l 2l6 l 10 l 14 Postprandial Hyperglycemia Impaired Glucose Tolerance

M ü ller WA, et al. N Engl J Med. 1970;283:109-115. Normal Glucose Homeostasis and Pre- and Postmeal Insulin and Glucagon Dynamics10 Premeal Postmeal  Insulin  Insulin  Glucagon  HGP  Glucagon  HGP Just enough glucose to meet metabolic needs between meals Modest postprandial increase with prompt return to fasting levels Glucose (mg %) Glucagon (pg/mL) Time (min) -60 0 60 120 180 240 Meal 120 90 60 30 0 140 130 120 110 100 90 Insulin ( µ U/mL) 360 330 300 270 240 110 80 Normal (n=11)

Hyperglycemia in Type 2 Diabetes Results from Abnormal Insulin and Glucagon Dynamics 11 Premeal Postmeal  Insulin  Insulin  Glucagon  HGP  Glucagon  HGP  FPG  PPG Glucose (mg %) Insulin ( µ U/mL) Glucagon (pg/mL) Time (min) -60 0 60 120 180 240 Meal 120 90 60 30 0 140 130 120 110 100 90 360 330 300 270 T2D (n=12) Normal (n=11) 240 110 80 T2D, type 2 diabetes. M ü ller WA, et al. N Engl J Med . 1970;283:109-115.

Acute Insulin Response Is Reduced in Type 2 Diabetes 12 IRI, immunoreactive insulin. Pfeifer MA, et al. Am J Med. 1981;70:579-588. Plasma IRI (µU/ml) Time (minutes) 20 g glucose infusion 2nd phase 1st -30 0 20 40 60 80 100 0 30 60 90 120 120 Normal (n=85) Type 2 diabetes (n=160)

Defective Insulin Actionin Type 2 Diabetes 13 Leg Glucose Uptake (mg/kg leg wt per min) Time (minutes) 0 P <0.01 12 180 140 100 60 2 0 8 4 0 Total Body Glucose Uptake (mg/kg • min) T2D Normal 0 7 6 5 4 3 2 1 T2D, type 2 diabetes. DeFronzo RA. Diabetes . 2009;58:773-795; DeFronzo RA, et al. J Clin Invest . 1985;76:149-155.

FPG, fasting plasma glucose; HGP, hepatic glucose production; T2D, type 2 diabetes. DeFronzo RA, et al. Metabolism . 1989;38:387-395. Elevated Fasting Glucose in Type 2 Diabetes Results From Increased HGP 14 Basal HGP (mg/kg • min) FPG (mg/dL) 2.0 2.5 3.0 3.5 4.0 100 200 300 r=0.85 P <0.001 Control T2D 0

* P ≤.05. Nauck M, et al. Diabetologia . 1986;29:46-52. The Incretin Effect Is Diminished in Type 2 Diabetes 15 Normal Glucose Tolerance (n=8) Type 2 Diabetes (n=14) IV Glucose Oral Glucose 0 60 120 180 240 Plasma Glucose (mg/dL) 180 90 0 0 60 120 180 Plasma Glucose (mg/dL) 240 180 90 0 * * * * * * * * 0 60 120 180 C-Peptide (nmol/L) Time (min) 30 20 10 0 0 60 120 180 C-peptide (nmol/L) Time (min) 30 20 10 0

Actions of GLP-1 and GIP GLP-1 Released from L cells in ileum and colon Stimulates insulin release from -cell in a glucose-dependent mannerPotent inhibition of gastric emptying Potent inhibition of glucagon secretionReduction of food intake and body weightSignificant effects on -cell growth and survivalGIPReleased from K cells in duodenumStimulates insulin release from -cell in a glucose dependent manner Minimal effects on gastric emptyingNo significant inhibition of glucagon secretionNo significant effects on satiety or body weight Potential effects on -cell growth and survival 16Drucker DJ. Diabetes Care 2003;26:2929-2940.

Renal Glucose Reabsorption in Type 2 Diabetes Sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2) reabsorb glucose in the proximal tubule of kidney Ensures glucose availability during fasting periods Renal glucose reabsorption is increased in type 2 diabetesContributes to fasting and postprandial hyperglycemiaHyperglycemia leads to increased SGLT2 levels, which raises the blood glucose threshold for urinary glucose excretion 17 Wright EM, et al. J Intern Med . 2007;261:32-43.

90% of glucose SGLT1 (180 L/day) (90 mg/dL) = 162 g glucose per day 10% of glucose Glucose No Glucose S1 S3 Normal Renal Handling of Glucose 18 SGLT2 Abdul-Ghani MA, et al. Endocr Pract . 2008;14:782-790.

Increased SGLT2 Protein Levels Change Glucose Reabsorption and Excretion Thresholds 19 Tm G , glucose transport maximum.Abdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008;14:782-790. 270 90 Renal Glucose Reabsorption Tm G 180 Tm G Blood Glucose Concentration (mg/dL) Reabsorption Reabsorption increases 27090180 Blood Glucose Concentration (mg/dL) Excretion threshold increases Excretion Renal Glucose Excretion Reabsorption Excretion

Hypothalamic Dopaminergic Tone and Autonomic Imbalance 20 In diabetes: Low dopaminergic tone in hypothalamus in early morning Sympathetic tone HPA axis tone  Hepatic gluconeogenesis  FFA and TG  Insulin resistance  Inflammation/hypercoagulation Impaired glucose metabolism Hyperglycemia Insulin resistance Adverse cardiovascular pathology 20 Fonseca V. Dopamine Agonists in Type 2 Diabetes . New York, NY: Oxford University Press; 2010. Cincotta AH. In: Hansen B, Shafrir E, eds. Insulin Resistance and Insulin Resistance Syndrome. New York, NY: Taylor & Francis; 2002:271-312.