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Diabetes Mellitus Terrence Swade, MD Endocrinologist
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Diabetes Mellitus Terrence Swade, MD Endocrinologist.

Dec 25, 2015

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Page 1: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

Diabetes Mellitus

Terrence Swade, MD

Endocrinologist

Page 2: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

The 800 pound gorilla

Page 3: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 4: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

Hyperglycemia

Pathogenesis of Type 1 Diabetes:One Defect

Unrestrainedglucose production

Impaired glucoseclearance

No hepaticinsulin effect

No muscle/fatinsulin effect

Absentinsulin

secretion

Glycosuria

More glucose entersthe blood

Less glucose entersperipheral tissues

Page 5: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

Putativetrigger

Circulating autoantibodies (ICA, GAD65)

Cellular autoimmunityCellular autoimmunity

Loss of first-phase insulin response

Glucose intolerance

Clinicalonset—

only 10% of-cells remain

Time

-Cell mass 100%

“Pre”-diabetes

Geneticpredisposition

Insulitis-Cell injury

Eisenbarth GS. N Engl J Med. 1986;314:1360-1368

Diabetes

Natural History Of Type 1 Diabetes

Page 6: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 7: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 8: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

Normal Regulation, cont.

Hepaticinsulin response

Muscle/fatinsulin response

Controlledglucose production

Controlledglucose clearance

Insulinsecretion

Normalplasma glucose Glucose enters

peripheral tissuesGlucose enters

the blood

70 - 100 mg/dl

Page 9: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

Pathogenesis of Type 2 DiabetesThree Defects

Excessiveglucose production

Impaired glucoseclearance

Hepaticinsulin

resistance

Muscle/fatinsulin

resistance

Impairedinsulin

secretion

Hyperglycemia

More glucose entersthe blood stream

Less glucose entersperipheral tissues

Glycosuria

Page 10: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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).

Page 11: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 12: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 13: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

Diabetes a CV Risk Equivalent

Myocardial Infarction Onset StudyAdjusted Total Mortality After MI

San Antonio/Finland Heart StudyAdjusted CV Mortality

1.0

1.5

No diabetesn=1525

Diabetesn=396

1.7

2.4Equal risk

0.3

No diabetesn=1373

Diabetesn=1509

Equal risk

2.6 2.5

7.3

No MI No MINo MI No MIPrior MIPrior MI Prior 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

Page 14: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 15: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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.

Page 16: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

Intra-Abdominal Adiposity

Waist Circumference : Men >40 in

Women >35 inApple or pear? Subcutaneous vs. visceral Adipose tissue as endocrine organ Genetics and ethnicity

Page 17: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 18: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

Visceral Adipose Tissue

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

Page 19: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

“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.

Page 20: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

The Defining Feature of Diabetes:

Hyperglycemia

Liver excessive

glucose production

Impaired glucose clearance from blood

Tissue injury

Page 21: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789

Natural History of Type 2 Diabetes

Macrovascular complications

Microvascular complications

Insulin resistanceInsulin resistance

ImpairedImpairedglucose toleranceglucose tolerance

UndiagnosedUndiagnoseddiabetesdiabetes

Known Known diabetesdiabetes

Insulin secretionInsulin secretion Postprandial glucose

Fasting glucoseFasting glucose

70

120

170

220

Page 22: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

Ist phase insulin release:blunted in diabetes

meal

Normal

1st phase insulin

Basal insulin production

Diabetes

1st phase insulin

fasting postprandial

diabetes

Page 23: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

Postprandial Hyperglycemia

Defect in insulin secretion begins with loss of 1st phase response, causing postprandial hyperglycemia.

non-diabeticdiabetic

meal postprandialFasting

Glucose excursion

insulin

normal

elevated

Page 24: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

Diagnosis

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

Page 25: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

Diagnosis, cont.

“Pre-diabetes” IFG = FPG 100 mg/dl to 125 mg/dl OR

IGT = 2 hr plasma glucose 140 mg/dl to 199 mg/dl

Both categories, IFG and IGT, are risk factors for future diabetes and cardiovascular disease (CVD).

Pre-diabetes in reversible.

Page 26: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 27: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

Prevalence of Diabetes:1994 to 2004

Page 28: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

Long Term Complications

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%

Page 29: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 30: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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.

Page 31: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

ADA Standards of Medical Care Treating 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

Page 32: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 33: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

Insulin Secretagogues:stimulate beta cells to produce more insulin

Sulfonylureas glyburide: Micronase, Diabeta, Glynase

1.25-20 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.”

Page 34: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 35: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 36: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 37: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 38: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 39: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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”

Page 40: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

Physiologic Actions of GLP-1

Site Action

Pancreatic beta-cell Stimulates 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

Page 41: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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.

Page 42: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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.

Page 43: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 44: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 45: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

“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)

Page 46: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 47: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 48: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 49: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

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

Page 50: Diabetes Mellitus Terrence Swade, MD Endocrinologist.

The 800 pound gorilla