Diabetes Mellitus Terrence Swade, MD Endocrinologist
Diabetes Mellitus
Terrence Swade, MD
Endocrinologist
The 800 pound gorilla
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
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
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
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
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
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
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
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).
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
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
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
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
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.
Intra-Abdominal Adiposity
Waist Circumference : Men >40 in
Women >35 inApple or pear? Subcutaneous vs. visceral Adipose tissue as endocrine organ Genetics and ethnicity
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
Visceral Adipose Tissue
Adiponectin : “cardioprotective” Leptin : feeding behavior Interleukin-6 : inflammation Tissue Necrosis Factor : inflammation PAI-1: blood clotting
“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.
The Defining Feature of Diabetes:
Hyperglycemia
Liver excessive
glucose production
Impaired glucose clearance from blood
Tissue injury
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
Ist phase insulin release:blunted in diabetes
meal
Normal
1st phase insulin
Basal insulin production
Diabetes
1st phase insulin
fasting postprandial
diabetes
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
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
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.
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
Prevalence of Diabetes:1994 to 2004
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%
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
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.
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
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
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.”
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
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
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
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
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
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”
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
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.
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.
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
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
“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)
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
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
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
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
The 800 pound gorilla