1. Diabetes Mellitus Terrence Swade, MD Endocrinologist

2. The 800 pound gorilla

3. Classification of Diabetes Mellitus by Etiology l Type 1:  Beta cell destruction leading to complete lack of insulin l Type 2: insulin resistance leading to beta cell dysfunction l LADA: Latent Autoimmune Diabetes of Adults l Gestational: insulin resistance and beta cell dysfunction during pregnancy

4. Hyperglycemia Pathogenesis of Type 1 Diabetes: One Defect Unrestrained glucose production Impaired glucose clearance No hepatic insulin effect No muscle/fat insulin effect Absent insulin secretion Glycosuria More glucose enters the blood Less glucose enters peripheral tissues

5. Putative trigger Circulating autoantibodies (ICA, GAD65) Cellular autoimmunity Loss of first-phase insulin response Glucose intolerance Clinical onset— only 10% of  -cells remain Time  -Cell mass 100% “Pre”- diabetes Genetic predisposition Insulitis  -Cell injury Eisenbarth GS. N Engl J Med. 1986;314:1360-1368 Diabetes Natural History Of Type 1 Diabetes

6. LADA - “Type 1 and a half ” l About half of patients with type 1 diabetes are diagnosed after age 18. l Autoimmune process may differ and is slower. l Often mistaken for type 2 diabetes—may make up 10%–30% of individuals diagnosed with type 2 diabetes. l Can be identified by ICA or GAD antibodies. l Oral agents are usually ineffective—insulin therapy is eventually required. Naik RG, Palmer JP. Curr Opin Endocrinol Diabetes. 1997;4:308-315

7. Normal Regulation of Plasma Glucose Fasting state: l No caloric intake for 2-3 hours or more l Glucagon stimulates liver to release stored glucose into bloodstream l Insulin suppressed Fed state: l Insulin production stimulates glucose uptake by liver and muscle cells l Glucagon suppressed 100 70

8. Normal Regulation, cont. Hepatic insulin response Muscle/fat insulin response Controlled glucose production Controlled glucose clearance Insulin secretion Normal plasma glucose Glucose enters peripheral tissues Glucose enters the blood 70 - 100 mg/dl

9. Pathogenesis of Type 2 Diabetes Three Defects Excessive glucose production Impaired glucose clearance Hepatic insulin resistance Muscle/fat insulin resistance Impaired insulin secretion Hyperglycemia More glucose enters the blood stream Less glucose enters peripheral tissues Glycosuria

10. Insulin Resistance l a condition in which the plasma insulin concentration is higher than the blood sugar level suggests it should be l Risk factors : overweight (especially abdominal adiposity), sedentary lifestyle, age l Due to metabolic changes, muscle, fat, and liver cells stop responding properly to insulin. l Pancreas compensates by increasing insulin production to maintain normal blood glucose (hyperinsulinemia).

11. Metabolic Syndrome A cluster of factors that are linked to increased risk of cardiovascular disease and type 2 diabetes l Association between diabetes,hypertension, dyslipidemia, heart disease long recognized. l Underlying metabolic profile characterized as “syndrome X” in 1988 (Gerald Reaven) l Criteria for clinical diagnosis recommended by several organizations: ATP III, WHO, AACE. Reaven, GM. Pathophysiology of insulin resistance in human disease. Physical Rev 1995; 75: 473-486

12. Diabetes & CV Risk Individuals with diabetes vs. nondiabetic: l 2 - 4 X higher overall risk of coronary event l Poorer prognosis for survival of an event l 75% of diabetics die from CV disease and sequelae. l Presence of additional CV risk factors (smoking, elevated cholesterol, etc.) cause greater incremental rise in risk. Multiple Risk Factor Intervention Trial (MRFIT) Diabetes Care 1993

13. Diabetes a CV Risk Equivalent Myocardial Infarction Onset Study Adjusted Total Mortality After MI San Antonio/Finland Heart Study Adjusted CV Mortality 1.0 1.5 No diabetes n=1525 Diabetes n=396 1.7 2.4Equal risk 0.3 No diabetes n=1373 Diabetes n=1509 Equal risk 2.6 2.5 7.3 No MI Prior MI Haffner SM et al. N Engl J Med. 1998;339:229-234; Mukamal KJ et al. Diabetes Care. 2001;24:1422-1427

14. National Cholesterol Education Program Adult Treatment Panel III l Identifies 6 components: 1. Abdominal obesity 2. Atherogenic dyslipidemia 3. Hypertension 4. Insulin resistance 5. Proinflammatory state 6. Prothrombotic state l CVD identified as primary clinical outcome of metabolic syndrome

15. Atherogenic Dyslipidemia l Borderline LDL cholesterol 130 to 159 mg/dL l Small dense LDL particles l Elevated triglycerides 150 to 250 mg/dL l Low HDL cholesterol <40 mg/dL in men and <50 mg/dL for women Grundy,S. Circulation. 1997;95:1-4.

16. Intra-Abdominal Adiposity l Waist Circumference : Men >40 in Women >35 in l Apple or pear? l Subcutaneous vs. visceral l Adipose tissue as endocrine organ l Genetics and ethnicity

17. The Fat Cell : A Multi-Endocrine Organ Fat stores Type 2 DM Hypertension Dyslipidemia Type 2 DM Thrombosis Inflammation ASCVD Angiotensinogen FFA Insulin Resistin Lipoprotein lipase PAI-1 Adiponectin Interleukin-6 Leptin Tissue Necrosis Factor

18. Visceral Adipose Tissue l Adiponectin : “cardioprotective” l Leptin : feeding behavior l Interleukin-6 : inflammation l Tissue Necrosis Factor : inflammation l PAI-1: blood clotting

19. “The American Dream” l We are a culture of overweight and obese people (60% of population). l Most Americans are sedentary. (62% of diabetes patients report no physical activity of any kind.) l Fast food is cheap, accessible, and “cool.” l Children are bombarded with fast food commercials, Ronald McDonald play areas, and toys in their happy meals. l Parents, working moms “deserve a break today.” l High fat convenience foods are quick and easy in a busy world.

20. The Defining Feature of Diabetes: Hyperglycemia Liver excessive glucose production Impaired glucose clearance from blood Tissue injury

21. Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789 Natural History of Type 2 Diabetes Macrovascular complications Microvascular complications Insulin resistance Impaired glucose tolerance Undiagnoseddiabetes Knowndiabetes Insulin secretion Postprandial glucose Fasting glucose 70 120 170 220

22. Ist phase insulin release: blunted in diabetes meal Normal 1st phase insulin Basal insulin production Diabetes 1st phase insulin fastingpostprandial diabetes

23. Postprandial Hyperglycemia l Defect in insulin secretion begins with loss of 1st phase response, causing postprandial hyperglycemia. non-diabetic diabetic meal postprandialFasting Glucose excursion insulin normal elevated

24. Diagnosis l Fasting plasma glucose 126 mg/dl or higher (no caloric intake for at least 8 hr) OR l Casual plasma glucose 200 mg/dl with symptoms of diabetes (polyuria, polydipsia, weight loss) OR l 2-hr plasma glucose 200 mg/dl during a glucose tolerance test, using a 75-g glucose load. ADA Standards of Medical Care in Diabetes - 2007

25. Diagnosis, cont. l “Pre-diabetes” IFG = FPG 100 mg/dl to 125 mg/dl OR IGT = 2 hr plasma glucose 140 mg/dl to 199 mg/dl l Both categories, IFG and IGT, are risk factors for future diabetes and cardiovascular disease (CVD). l Pre-diabetes in reversible.

26. Progressive Nature of Type 2 l At time of diagnosis, average beta cell function at 50% of normal. l Most patients are 7 -10 years into disease process. l Average patient will progress to beta cell failure and require insulin 6 years after diagnosis. UKPDS, Diabetes, 1995;44:1249-1258

27. Prevalence of Diabetes: 1994 to 2004

28. Long Term Complications l Microvascular: l Blindness l Nerve Damage l Kidney Failure l Macrovascular: l Heart Attack and Stroke l Serious Infections, Amputations DCCT - 1993 Type 1, tight control reduced complications 50 - 70% UKPDS - 1998 Type 2, similar results l Kumamoto - 2000 Type 1 l EDIC - 2005 Type 1, risk of heart disease reduced by 50%

29. For Heart Protection: Follow the ABC’s A : Glucose - A 1 C less than 7% B : Blood Pressure 130/80 or lower C : LDL Cholesterol below 100mg/dl

30. Desirable levels l Body weight: BMI 18.5 - 24.9 kg/m 2 l LDL cholesterol <100 mg/dl l HDL cholesterol >40 in men, >50 in women l Triglycerides <150 mg/dl l Blood pressure <120/80 l Fasting glucose 70 - 99 mg/dl Carey,RM, Gibson,RS. Hormones and your heart. J Clin Endo & Metab. 2006;91:10.

31. ADA Standards of Medical Care Treating Hyperglycemia l Goal: A 1 C < 7%, or as close to 6% as possible Match the drug to the defect: l Insulin deficiency Insulin secretagogue or insulin l Insulin resistance Insulin sensitizer l Hepatic glucose overproduction Restrain liver production of glucose

32. Biguanides: Decreases hepatic glucose overproduction metformin - Glucophage l Max. therapeutic dose: 2000 mg. Daily l May take 3-4 weeks to see maximum effect. l Side effects: GI upset, diarrhea l Take at end of meal. Start with low dose. FPatients often lose weight. l Contraindications: serum creatinine > 1.5, CHF, lactic acidosis

33. Insulin Secretagogues: stimulate beta cells to produce more insulin Sulfonylureas l glyburide: Micronase, Diabeta, Glynase 1.25-20 mg total per day, take with meals l glipizide: Glucotrol 5-20mg total per day, take 30 min. AC l glimepiride: Amaryl 1- 4 mg at 1st meal Meglitinides l repaglinide: Prandin 0.5 - 4 mg. before each meal l nateglinide: Starlix 60 - 120 mg. before each meal “Don’t start a meal without it.”

34. Insulin Secretagogues, cont. l Side effects: HYPOGLYCEMIA, weight gain l Contraindications: Type 1 diabetes, pregnancy l Least expensive of oral hypoglycemic drugs l Quick results l No longer considered first line drug. l Glyburide may increase risk of cardiovascular death. Canadian Medical Association Journal, Jan. 2006

35. Insulin Sensitizers: reduces insulin resistance in muscle & liver Thiazolidinediones (TZD’s): l pioglitazone - Actos ( 15 - 45 mg daily) rosiglitazone - Avandia ( 2 -8 mg daily) l Note: Monitor liver enzymes. l May take 12 weeks to see maximum effect on BGs. l Side effects: edema, fatigue Contraindications: active CHF, Type 1, pregnancy

36. Other Oral Agents Alpha-glucosidase inhibitors l acarbose - Precose: 50-100 mg at first bite of each meal. l miglitol - Glyset: 25 -100 mg at 1st bite l Delays digestion of ingested carbohydrates, resulting in a smaller rise in blood glucose concentration following meals. l Note: Unlikely to cause hypoglycemia l Contraindications: Type 1, acute or chronic bowel diseases

37. Insulin Goal - Blood glucose as close to normal as possible with minimal hypoglycemia l Type 1 - Basal bolus method with multiple daily injections or insulin pump recommended l Type 2 - addition of insulin as OHA’s fail, to maintain A 1 C < 7% l Side effects: hypoglycemia, weight gain

38. pramlintide (Symlin) l Injectable, for type 1 and insulin-requiring type 2 l Controls postprandial hyperglycemia by increasing insulin secretion l Reduces amount of insulin needed l Slows absorption of glucose from the gut l Side effect: nausea l Can cause severe hypoglycemia

39. Incretin Mimetics l Incretins = hormones produced in the gut when stimulated by food: GLP-1 Enhances insulin secretion by pancreas, depending on glucose level Incretin mimetics = drugs that “mimic” the action of incretin hormones l “Smart Drugs”

40. Physiologic Actions of GLP-1 Site Action l Pancreatic beta-cellStimulates insulin secretion in response to meals l Pancreatic alpha-cell I nhibits glucagon secretion l CNS Promotes satiety, reduces food intake l Liver Reduces glucose output by inhibiting glucagon release l Stomach Slows gastric emptying l Periphery Improves insulin sensitivity

41. Byetta and Victoza l Injectable, for type 2, with OHA’s l Controls postprandial hyperglycemia by increasing insulin secretion l Slows absorption of glucose from the gut l Reduces appetite l Reduces the action of glucagon l Patients achieved A 1 C reduction and weight loss.

42. DPP- 4 Inhibitors l Gliptin class (Januvia, Onglyza, Tradjenta) GLP-1 quickly degraded by DPP-4 l Preventing the rapid degradation of GLP-1 through inhibition of DPP-4 prolongs the action of insulin and reduces glucagon and its effects, representing a new oral therapeutic approach for type 2 diabetes.

43. American Diabetes Asssociation Standards of Medical Care  Treating Hypertension - Goal: <130/80 l Lifestyle and behavioral therapy Na intake, fruits, vegetables, low-fat dairy products, ETOH intake, physical activity l Drug therapy - ACE or ARB for initial therapy, thiazide diuretic may be added

44. Evidence l HOPE (Heart Outcomes Evaluation Study)  Ramipril (Altace) substantially reduces risk of CV events in diabetics with or without HTN, LV dysfuncton, proteinuria, independent of the decrease in BP. myocardial infarction 22% stroke by 33% cardiovascular death 37% total mortality 24% Lancet 355:253-259

45. “ACE’s” and “ARB’s” l Angiotensin-Converting Enzyme (ACE) inhibitors prevent an enzyme from converting angiotensin I to angiotensin II, a potent vasoconstrictor. Lisinopril (Prinivil, Zestril) Enalapril (Vasotec) Benazepril (Lotensin) l Angiotensin II Receptor Blockers block the action of angiotensin II, allowing blood vessels to dilate. Candesartan (Atacand)Irbesartan (Avapro) Losartan (Cozaar)Valsartan (Diovan)

46. ADA standards, cont. Treating Dyslipidemia l Screening: annual l Goals: *LDL < 100 (< 70 with overt CVD) TRG < 150 HDL > 40 (men), > 50 (women) l Lifestyle: reduce sat fat, trans fat, cholesterol intake, weight loss, exercise, smoking cessation l Drug therapy: Statins drug of choice for LDL, possibly fibrates for high Trg low HDL

47. Evidence Heart Protection Study l Simvastatin (Pravachol) given to "high risk" diabetic patients, regardless of age, sex, or baseline cholesterol levels, lowers the risk of cardiovascular events by 25%. l Recommendation: Statin therapy should be considered routinely for all diabetic patients at high risk of major CV events, regardless of their cholesterol level. Lancet 2003; 361: 2005 - 16

48. ADA Standards, cont. Antiplatelet therapy - ASA 75 - 162 mg/day l Secondary Prevention with history CVD l Primary Prevention in both Type 1 and Type 2 with additional risk factors and/or > age 40

49. Summary of Guidelines l Earlier identification l Intensive program of nutrition counseling, exercise and weight loss: bariatric surgery? l Diabetes Education l ACE or ARB l Statin l ASA l Smoking Cessation l Metformin? Insulin sensitizer? GLP-1 action? Insulin? l Eye Exam, Foot Check, Urine Microalbumin, Stress test

50. The 800 pound gorilla