Diabetes Mellitus
Terrence Swade, MD
Endocrinologist
The 800 pound gorilla
Classification of Diabetes Mellitus
by Etiology
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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, GAD65)
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 ”
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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


100
Insulin suppressed
70
Fed state:
Insulin production stimulates glucose
uptake by liver and muscle cells


Glucagon suppressed
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
Glycosuria
Impaired glucose
clearance
Less glucose enters
peripheral tissues
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).
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Metabolic Syndrome
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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:

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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
San Antonio/Finland Heart Study
Adjusted CV Mortality
7.3
Equal risk
1.5
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

Identifies 6 components:
1.
2.
3.
4.
5.
6.

Abdominal obesity
Atherogenic dyslipidemia
Hypertension
Insulin resistance
Proinflammatory state
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 in
Apple or pear?
 Subcutaneous vs. visceral
 Adipose tissue as
endocrine organ
 Genetics and ethnicity

The Fat Cell :
A Multi-Endocrine Organ
Type 2 DM
Lipoprotein
lipase
Hypertensio
n
Angiotensinogen
Interleukin-6
Tissue Necrosis Factor
Inflammatio
n
Dyslipidemia
Fat
stores
FFA
Leptin
Type 2 DM
Resistin
Adiponectin
ASCVD
Insulin
PAI-1
Thrombosi
s
Visceral Adipose Tissue
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Adiponectin : “cardioprotective”
Leptin : feeding behavior
Interleukin-6 : inflammation
Tissue Necrosis Factor : inflammation
PAI-1: blood clotting
“The American Dream”
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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:
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
glucose
220
170
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
1st phase insulin
Diabetes
1st phase insulin
diabetes
Basal insulin production
fasting
meal
postprandial
Postprandial Hyperglycemia

Defect in insulin secretion begins with loss of
1st phase response, causing postprandial
hyperglycemia.
elevated
Glucose excursion
diabetic
non-diabetic
Fasting
normal
meal
insulin
postprandial
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.
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“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
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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
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DCCT - 1993
Type 1, tight control reduced
complications 50 - 70%

UKPDS - 1998
Type 2, similar results
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Macrovascular:
 Heart Attack and
Stroke
 Serious Infections,
Amputations
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Kumamoto - 2000
Type 1
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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
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Desirable levels
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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:
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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
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glipizide: Glucotrol
5-20mg total per day,
take 30 min. AC

glimepiride: Amaryl
1- 4 mg at 1st meal
Meglitinides
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repaglinide: Prandin
0.5 - 4 mg. before each
meal
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nateglinide: Starlix
60 - 120 mg. before each
meal
“Don’t start a meal without it.”
Insulin Secretagogues, cont.
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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):
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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
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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
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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)
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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
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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
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Pancreatic alpha-cell
Inhibits glucagon secretion
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CNS
Promotes satiety, reduces food intake
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Liver
Reduces glucose output by
inhibiting glucagon release
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Stomach
Slows gastric emptying
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Periphery
Improves insulin sensitivity
Byetta and Victoza
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Injectable, for type 2, with OHA’s
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Controls postprandial hyperglycemia by
increasing insulin secretion
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Slows absorption of glucose from the gut
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Reduces appetite
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Reduces the action of glucagon
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Patients achieved A1C reduction and weight loss.
DPP- 4 Inhibitors
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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
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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
stroke by
33%
cardiovascular death
total mortality
Lancet 355:253-259
22%
24%
37%
“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
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Screening: annual
Goals: *LDL < 100
(< 70 with overt CVD)
TRG < 150
HDL > 40 (men), > 50 (women)
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Lifestyle: reduce sat fat, trans fat, cholesterol intake,
weight loss, exercise, smoking cessation
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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
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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
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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