Diabetes Mellitus Terrence Swade MD Endocrinologist The 800

Diabetes Mellitus Terrence Swade, MD Endocrinologist

The 800 pound gorilla

Classification of Diabetes Mellitus by Etiology l l 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

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

Natural History Of Type 1 Diabetes -Cell mass 100% Putative trigger Cellular autoimmunity Circulating autoantibodies (ICA, GAD 65) Loss of first-phase insulin response Glucose intolerance Genetic predisposition Insulitis -Cell injury Time Eisenbarth GS. N Engl J Med. 1986; 314: 1360 -1368 “Pre”diabetes Clinical onset— only 10% of -cells remain Diabetes

LADA - “Type 1 and a half ” l l l 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

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

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

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

Insulin Resistance l l 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).

Metabolic Syndrome l l 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

Diabetes & CV Risk Individuals with diabetes vs. nondiabetic: l l 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

Diabetes a CV Risk Equivalent Myocardial Infarction Onset Study Adjusted Total Mortality After MI Equal risk 1. 5 San Antonio/Finland Heart Study Adjusted CV Mortality 7. 3 2. 4 Equal risk 1. 7 1. 0 2. 6 2. 5 Prior MI No MI 0. 3 No MI Prior MI No diabetes n=1525 No MI Prior MI Diabetes n=396 No MI No diabetes n=1373 Prior MI Diabetes n=1509 Haffner SM et al. N Engl J Med. 1998; 339: 229 -234; Mukamal KJ et al. Diabetes Care. 2001; 24: 1422 -1427

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

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

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

The Fat Cell : A Multi-Endocrine Organ Lipoprotein lipase Type 2 DM Hypertensio n Angiotensinogen Interleukin-6 Tissue Necrosis Factor Inflammatio n Dyslipidemi Fat stores FFA a Leptin ASCV D Insulin Type 2 DM Resistin Adiponectin PAI 1 Thrombos is

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

“The American Dream” l l l 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 Mc. Donald 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.

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

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

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

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

Diagnosis l l l Fasting plasma glucose 126 mg/dl or higher (no caloric intake for at least 8 hr) OR Casual plasma glucose 200 mg/dl with 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

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 l Both categories, IFG and IGT, are risk factors for future diabetes and cardiovascular disease (CVD). Pre-diabetes in reversible.

Progressive Nature of Type 2 l l l 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

Prevalence of Diabetes: 1994 to 2004

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

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

Desirable levels l l l Body weight: BMI 18. 5 - 24. 9 kg/m 2 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.

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 l l Insulin deficiency Insulin secretagogue or insulin Insulin resistance Insulin sensitizer Hepatic glucose overproduction Restrain liver production of glucose

Biguanides: Decreases hepatic glucose overproduction metformin - Glucophage 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. F Patients often lose weight. l Contraindications: serum creatinine > 1. 5, CHF, lactic acidosis l

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 -20 mg total per day, take 30 min. AC l glimepiride: Amaryl 1 - 4 mg at 1 st 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. ”

Insulin Secretagogues, cont. l l l 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

Insulin Sensitizers: reduces insulin resistance in muscle & liver Thiazolidinediones (TZD’s): l l l 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

Other Oral Agents Alpha-glucosidase inhibitors l l l acarbose - Precose: 50 -100 mg at first bite of each meal. miglitol - Glyset: 25 -100 mg at 1 st 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

Insulin l l 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 A 1 C < 7% Side effects: hypoglycemia, weight gain

pramlintide (Symlin) l l l 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

Incretin Mimetics l 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 “Smart Drugs”

Physiologic Actions of GLP-1 Site Action l Pancreatic beta-cell Stimulates insulin secretion in response to meals l Pancreatic alpha-cell Inhibits 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

Byetta and Victoza l l Injectable, for type 2, with OHA’s 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.

DPP- 4 Inhibitors l l l 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.

American Diabetes Asssociation Standards of Medical Care Treating Hypertension - Goal: <130/80 l l 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

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 stroke by 33% cardiovascular death total mortality Lancet 355: 253 -259 22% 24% 37%

“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)

ADA standards, cont. Treating Dyslipidemia l l Screening: annual 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

Evidence Heart Protection Study l 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%. 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

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

Summary of Guidelines l l l l l 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

The 800 pound gorilla