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Diabetes Mellitus

Diabetes Mellitus. Terrence Swade, MD Endocrinologist. The 800 pound gorilla. Classification of Diabetes Mellitus by Etiology. Type 1: Beta cell destruction leading to complete lack of insulin Type 2: insulin resistance leading to beta cell dysfunction

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Diabetes Mellitus

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  1. Diabetes Mellitus Terrence Swade, MD Endocrinologist

  2. The 800 pound gorilla

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

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

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

  6. LADA - “Type 1 and a half ” • About half of patients with type 1 diabetes are diagnosed after age 18. • Autoimmune process may differ and is slower. • Often mistaken for type 2 diabetes—may make up 10%–30% of individuals diagnosed with type 2 diabetes. • Can be identified by ICA or GAD antibodies. • 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: • No caloric intake for 2-3 hours or more • Glucagon stimulates liver to release stored glucose into bloodstream • Insulin suppressed • Fed state: • Insulin production stimulates glucose uptake by liver and muscle cells • Glucagon suppressed 100 70

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

  9. Pathogenesis of Type 2 DiabetesThree Defects Impaired insulin secretion Hepatic insulin resistance Muscle/fat insulin resistance Hyperglycemia Excessive glucose production Impaired glucoseclearance More glucose entersthe blood stream Less glucose entersperipheral tissues Glycosuria

  10. Insulin Resistance • a condition in which the plasma insulin concentration is higher than the blood sugar level suggests it should be • Risk factors : overweight (especially abdominal adiposity), sedentary lifestyle, age • Due to metabolic changes, muscle, fat, and liver cells stop responding properly to insulin. • 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 • Association between diabetes,hypertension, dyslipidemia, heart disease long recognized. • Underlying metabolic profile characterized as “syndrome X” in 1988 (Gerald Reaven) • 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: • 2 - 4 X higher overall risk of coronary event • Poorer prognosis for survival of an event • 75% of diabetics die from CV disease and sequelae. • 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 7.3 Equal risk 2.4 Equal risk 1.7 1.5 1.0 2.6 2.5 0.3 No MI No MI Prior MI No MI Prior MI Prior MI No MI Prior MI No diabetesn=1525 Diabetesn=396 No diabetesn=1373 Diabetesn=1509 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 ProgramAdult Treatment Panel III • Identifies 6 components: • 1. Abdominal obesity • 2. Atherogenic dyslipidemia • 3. Hypertension • 4. Insulin resistance • 5. Proinflammatory state • 6. Prothrombotic state • CVD identified as primary clinical outcome of metabolic syndrome

  15. Atherogenic Dyslipidemia • Borderline LDL cholesterol 130 to 159 mg/dL • Small dense LDL particles • Elevated triglycerides 150 to 250 mg/dL • 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 • Waist Circumference : • Men >40 in • Women >35 in • Apple or pear? • Subcutaneous vs. visceral • Adipose tissue as • endocrine organ • Genetics and ethnicity

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

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

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

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

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

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

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

  24. Diagnosis • Fasting plasma glucose 126 mg/dl or higher (no caloric intake for at least 8 hr) OR • Casual plasma glucose 200 mg/dlwith symptoms of diabetes (polyuria, polydipsia, weight loss) OR • 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. • “Pre-diabetes” • IFG = FPG 100 mg/dl to 125 mg/dlOR • IGT = 2 hr plasma glucose 140 mg/dl to 199 mg/dl • Both categories, IFG and IGT, are risk factors for future diabetesand cardiovascular disease (CVD). • Pre-diabetes in reversible.

  26. Progressive Nature of Type 2 • At time of diagnosis, average beta cell function at 50% of normal. • Most patients are 7 -10 years into disease process. • 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. Microvascular: Blindness Nerve Damage Kidney Failure Macrovascular: Heart Attack and Stroke Serious Infections, Amputations DCCT - 1993 Type 1, tight control reduced complications 50 - 70% UKPDS - 1998 Type 2, similar results Kumamoto - 2000 Type 1 EDIC - 2005 Type 1, risk of heart disease reduced by 50% Long Term Complications

  29. For Heart Protection:Follow the ABC’s • A: Glucose - A1C less than 7% • B: Blood Pressure 130/80 or lower • C : LDL Cholesterol below 100mg/dl

  30. Desirable levels • Body weight: BMI 18.5 - 24.9 kg/m2 • LDL cholesterol <100 mg/dl • HDL cholesterol >40 in men, >50 in women • Triglycerides <150 mg/dl • Blood pressure <120/80 • 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 CareTreating Hyperglycemia • Goal: • A1C < 7%, or as close to 6% as possible • Match the drug to the defect: • Insulin deficiency Insulin secretagogue • or insulin • Insulin resistance Insulin sensitizer • Hepatic glucose overproduction • Restrain liver production of glucose

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

  33. Sulfonylureas glyburide: Micronase, Diabeta, Glynase1.25-20 mg total per day, take with meals glipizide:Glucotrol 5-20mg total per day, take 30 min. AC glimepiride:Amaryl 1- 4 mg at 1st meal Meglitinides repaglinide:Prandin 0.5 - 4 mg. before each meal nateglinide: Starlix 60 - 120 mg. before each meal “Don’t start a meal without it.” Insulin Secretagogues:stimulate beta cells to produce more insulin

  34. Insulin Secretagogues, cont. • Side effects: HYPOGLYCEMIA, weight gain • Contraindications: Type 1 diabetes, pregnancy • Least expensive of oral hypoglycemic drugs • Quick results • No longer considered first line drug. • 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): • pioglitazone - Actos (15 - 45 mg daily) • rosiglitazone - Avandia (2 -8 mg daily) • Note: Monitor liver enzymes. • May take 12 weeks to see maximum effect on BGs. • Side effects: edema, fatigue • Contraindications: active CHF, Type 1, pregnancy

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

  37. Insulin • Goal - Blood glucose as close to normal as possible with minimal hypoglycemia • Type 1 - Basal bolus method with multiple daily injections or insulin pump recommended • Type 2 - addition of insulin as OHA’s fail, to maintain A1C < 7% • Side effects: hypoglycemia, weight gain

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

  39. Incretin Mimetics • 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 • “Smart Drugs”

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

  41. Byetta and Victoza • Injectable, for type 2, with OHA’s • Controls postprandial hyperglycemia by increasing insulin secretion • Slows absorption of glucose from the gut • Reduces appetite • Reduces the action of glucagon • Patients achieved A1C reduction and weight loss.

  42. DPP- 4 Inhibitors • Gliptin class (Januvia, Onglyza, Tradjenta) • GLP-1 quickly degraded by DPP-4 • 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 AsssociationStandards of Medical Care • Treating Hypertension - Goal: <130/80 • Lifestyle and behavioral therapy • Na intake, fruits, vegetables, low-fat dairy products, ETOH intake, physical activity • Drug therapy - ACE or ARB for initial therapy, thiazide diuretic may be added

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

  47. Evidence • Heart Protection Study • Simvastatin (Pravachol) given to "high risk" diabetic patients, regardless of age, sex, or baseline cholesterol levels, lowers the risk of cardiovascular events by 25%. • 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 • Secondary Prevention with history CVD • Primary Prevention in both Type 1 and • Type 2 with additional risk factors and/or • > age 40

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

  50. The 800 pound gorilla

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