TYPE 2 DIABETES MELLITUS

Richard Sachson MD

Diabetes in the U.S.

Diabetes and Gestational Diabetes Trends Among

Adults in the U.S., BRFSS 1990, 1995 and 2000

1990

1995

2000
% incidence of diabetes among adults

< 4%

4-6%

> 6%

N/A

Source: Mokdad et al., Diabetes Care 2000;23:1278-83; J Am Med Assoc 2001;286(10).

DIABETES AND GESTATIONAL

DIABETES AMONG ADULTS IN THE
U.S. -2001

Global Projections for Diabetes 19952010

26.5
32.9
24%

14.2
17.5
23%

84.5
132.3
57%
9.4
14.1
50%
15.6
22.5
44%

Reprinted with permission from

Zimmet P et al. Nature.
2001;414:782787.

World
2000 = 151 million
2010 = 221 million
Increase: 46%

1.0
1.3
33%

Diabetes and Obesity:

The Continuing Epidemic
7.5

78

Diabetes
Mean Body Weight

77

6.5

76

6.0

kg

Prevalence (%)

7.0

75

5.5
74
5.0
73

4.5

72

4.0
1990

1992

1994

Year

1996

1998

2000

Prevalence of obesity
increased by 61%
since 1991
More than 50% of US
adults are overweight
Only 43% of obese
persons advised to lose
weight during checkups
BMI and weight gain
major
risk factors for diabetes

BMI = body mass index.

Mokdad AH et al. Diabetes Care. 2000;23:1278-1283; Mokdad AH et al. JAMA. 1999;282:
1519-1522; Mokdad AH et al. JAMA. 2001;286:1195-1200.

-Cell Function (%)

Pathophysiology
of
Type
2
Diabetes
o g e n e s is o f T y p e 2 D ia b e te s : In s u lin
e s is ta n c e a n d -C e ll D y s fu n c tio n
Defective
-Cell Secretion:

Pancreas

fu n c tio n

100
75
50
I n 25
s u l Ni n = R376e s i s
0
10 6 2

ta n c e
2

Years After Diagnosis

FFAs

Insulin
Resistance:

eas

Liver

Excess
Glucose
Production

L iv e r
Fasting Hyperglycemia

Muscle

Reduced
Glucose
Uptake

M uHyperglycemia
s c le
Postprandial

Fat

Fat

FFAs = free fatty acids.

Adapted from UK Prospective Diabetes Study Group. Diabetes. 1995;44:1249-1258.
DeFronzo RA. Diabetes. 1988;37:667-687.

Progression of Type 2 Diabetes

Post Meal Glucose

350
250

Glucose

Fasting Glucose

150
50
300

Insulin Resistance

Relative 200
Function
100
0

Insulin Level

At risk for
Diabetes
-10

-5

Beta cell failure

0

10

15

20

25

30

Years of Diabetes
Adapted from D Kendall, R Bergenstal, International Diabetes Center

Diabetes: 16 Million and Climbing

Estimated 10.3 million diagnosed + 5.4 million
undiagnosed cases
Type 2 diabetes accounts for 90-95% of cases
+60%

Diagnosed Cases (Millions)

12

+17%

1980

1990

From Centers for Disease Control and Prevention, 2000.

2000 (Estimated)

Insulin Resistance
FFA production

Glucose production

Hyperinsulinemia

Dyslipidemia

SNS activity
T2D

Abnormal Na+
handling

HTN
Atherosclerosis

ACANTHOSIS NIGRICANS

ACANTHOSIS NIGRICANS

Metabolic Syndrome

Also known as dysmetabolic syndrome, insulin resistance

syndrome, syndrome X, the deadly quartet
Prevalence in the United States: approximately 47 million
Defined by having 3 of the following:

Abdominal obesity: waist > 40" (men); > 35" (women)

TG 150 mg/dL
HDL < 40 mg/dL (men); < 50 mg/dL (women)
Blood pressure 130/85 mm Hg
FPG 110 mg/dL

New ICD-9-CM code for dysmetabolic syndrome X is 277.7

TG = triglycerides; FPG = fasting plasma glucose.
Ford ES et al. JAMA. 2002;287:356-359.
JAMA. 2001;285:2486-2497.
American Association of Clinical Endocrinologists. New ICD-9-CM code for dysmetabolic syndrome X.
Available at: http://www.aace.com/members/socio/syndromex.php. Accessed January 10, 2002.

Visceral Fat Distribution:

Normal vs Type 2 Diabetes

Normal

Type 2 Diabetes

2-11

Prevalence of Complications
at Time of Diagnosis: UKPDS
Complication
Prevalence (%)*
Any complication
50
Retinopathy
21
Abnormal ECG
18
Absent foot pulses ( 2)
and/or ischemic feet
14
Impaired reflexes and/or
decreased vibration sense
7
Myocardial infarction/angina/claudication 2-3
Stroke/transient ischemic attack
1
*Some patients had more than 1 complication at diagnosis.

Prevalence of each individual condition.

UKPDS = United Kingdom Prospective Diabetes Study.
UKPDS Group. Diabetologia. 1991;34:877-890.

16

National Cholesterol Education

Program

Adult Treatment Panel III

(ATP III) Guidelines

Diabetes
In ATP III, diabetes is regarded
as a CHD risk equivalent.

Type 2 diabetes and CHD: 7-year incidence

of fatal/nonfatal MI (East West Study)

7-year incidence
rate of MI

Nondiabetic
n = 1373

50
45
P < 0.001
40
35
30
25
20
15
10
4%
5
0 No prior MI*

Diabetic
n = 1059
P < 0.001

19%

MI

MI = myocardial infarction.
* These patients had no prior MI at baseline.
Haffner SM, et al. N Engl J Med. 1998;339:229234.

45%

20%

No prior MI* MI

Target Lipid Levels for

Adult Patients with Diabetes
LDL Cholesterol:
HDL Cholesterol:

Triglycerides:

< 100 mg/dL (high risk

< 70 mg/dl)

Men: > 45 mg/dL

Women: > 55 mg/dL
< 150 mg/dL

Note: The recent NCEP/ATP III guidelines suggest that in patients with triglycerides
200 mg/dL, the non-HDL cholesterol be calculated with a goal being < 130.
American Diabetes Association. Diabetes Care. 2002;25:S33.

Recommended Treatment Goals for

Hypertension for Adults With Diabetes
Target BP
Patients aged 18 years <130/80 mm Hg
Isolated systolic hypertension
180 mm Hg
<160 mm Hg
160179 mm Hg
of 20 mm Hg

American Diabetes Association. Diabetes Care. 2001;24(suppl 1):S33-S43.

Aspirin
Use aspirin therapy ( 75-325 mg/day ) in all
adult patients with diabetes and
macrovascular disease.
Consider aspirin therapy for primary
prevention in patients over age 40 with
diabetes and one or more other CV risk
factors ( including obesity ).
Also consider patients between age 30-40.

Type 2 Diabetes Prevention

Finnish Diabetes Prevention

Program

522 patients with IGT

Age: 40-65 years
Mean BMI: 31 kg/m2
Intervention: diet and exercise
Mean duration of follow up: 3.2
years

IGT = impaired glucose tolerance; BMI = body mass index.

Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.

100
80
60
40
20
0

58%
P < .001

Change from Baseline (mg/dL)

Incidence of Diabetes
(Cases/1000 Person-Years)

The Finnish Diabetes Prevention Study:

Lifestyle Modifications
10

FPG

2-Hour PPG

0
P < .001

-10

-20

Control
Intervention (Diet and Exercise)
FPG = fasting plasma glucose; PPG = postprandial glucose.
Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.

P < .003

Finnish DPP: Results

Quintile Weight Change (%) Risk Reduction (%)
1
2
3
4
5

11
5
2
No change
3

Each 3-kg weight loss doubles the benefit.

DPP = diabetes prevention program.
Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.

83
61
13
No change
218

United States Diabetes Prevention

Program
3234 patients with IGT
32.3% male; 67.7% female
Mean age: 50.6 years 10.7 years

55% Caucasian, 20% African American,

16% Hispanic, 9% Asian and American Indian
Interventions: diet (reduced calorie, 25% fat)
and exercise ( 150 minutes/week physical activity) or metformin
(850 mg b.i.d.)
Average follow-up: 2.8 years (range: 1.8-4.6 years)

IGT = impaired glucose tolerance.

Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

United States Diabetes Prevention

Program: Results
Placebo
(n = 1082)

Intensive Lifestyle
Intervention
(n = 1079)

Metformin
(n = 1073)

Wt loss: 0.1 kg*

Wt loss: 5.6 kg*

Wt loss: 2.1 kg*

Diabetes: 29%

Diabetes: 14%

Diabetes: 22%

*Average; Cumulative incidence at 3 years.

Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

United States Diabetes Prevention

Program: Results
Placebo
(n = 1082)

Intensive Lifestyle
Intervention
(n = 1079)

Metformin
(n = 1073)

Wt loss: 0.1 kg*

Wt loss: 5.6 kg*

Wt loss: 2.1 kg*

Diabetes: 29%

Diabetes: 14%
Risk reduction:
58%

Diabetes: 22%
Risk reduction:
31%

*Average; Cumulative incidence at 3 years.

Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

TREATMENT OF TYPE 2
DIABETES

Therapy for Type 2 Diabetes: Sites of Action

Liver

Muscle
Glucose
Insulin
Hyperglycemia
=
Uptake
Resistance

Hepatic Glucose
Production

Hyperglycemia

Rosiglitazone
Metformin

Pioglitazone

Carbohydrate
Metabolism
Acarbose
Miglitol

Gut

Hyperglycemia

Pancreas

Hyperglycemia
Impaired = Insulin
Deficiency
Insulin
Secretion
Sulfonylurea
Repaglinide
Nateglinide
Exogenous Insulin Rx

Sulfonylureas

Sulfonylurea Effects on the -cell

Ca++
VDCC
(+)
Depolarization

-Cell

K+ATP Channel
K+
SU
R

Sulfonylurea

[ATP]
[ADP]

Free
Ca++

Metabolism

Insulin
Release
Glucose
Hu S et al. J Pharmacol Exp Ther 2000;293:44452

Sulfonylureas
Mechanism of action: increases pancreatic
insulin secretion
Reported A1C reduction: 0.9%-2.5%
Advantages: well-established, decreases
microvascular risk, convenient daily dosing
Disadvantages: hypoglycemia, weight gain,
hyperinsulinemia (role uncertain)
FDA approval status: monotherapy;
combination with insulin, metformin,
thiazolidinedione, -glucosidase inhibitors
Inzucchi SE. JAMA. 2002;287:360-372.

Second-Generation Sulfonylureas
Drug
Glyburide

Glipizide
Glimepiride

Daily Dosage
Trade Names
(mg)

Duration of
Action

Micronase,
DiaBeta,
Glynase
Glucotrol

2.5-20

16-24 hours

5-40*

12-24 hours

Glucotrol XL

5-20

24 hours

Amaryl

1-8

16-24 hours

*The maximally effective dosage is 20 mg/d, although it is approved for dosages 40 mg/d.
DeFronzo RA. Ann Intern Med. 1999;131:281-303.

Nonsulfonylurea Secretagogues

Nonsulfonylurea Secretagogues
(Repaglinide or Nateglinide)
Mechanism of action: increases pancreatic
insulin secretion
Reported A1C reduction: 0.6%-1.9%
Advantages: targets postprandial glycemia, possibly
less hypoglycemia and weight gain than with
sulfonylureas
Disadvantages: 3-times daily dosing, hypoglycemia,
weight gain, no long-term data, hyperinsulinemia
(role uncertain)
FDA approval status: monotherapy; combination with
metformin
Inzucchi SE. JAMA. 2002;287:360-372.

Nonsulfonylurea Secretagogues
Drug

Daily Dosage
Trade Names
(mg)

Repaglinide

Prandin

1.5-16

Nateglinide

Starlix

180-360

DeFronzo RA. Ann Intern Med. 1999;131:281-303.

Starlix [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2000.

Biguanides

Biguanides (Metformin)

Mechanism of action: decreased hepatic glucose production

Reported A1C reduction: 0.8%-3.0%
Advantages: well established, weight loss, no hypoglycemia,
decreases microvascular risk, decreases macrovascular risk,
nonglycemic benefits (decreased lipid levels, increased
fibrinolysis, decreased hyperinsulinemia), convenient daily
dosing
Disadvantages: adverse gastrointestinal effects, many
contraindications, lactic acidosis (rare)
FDA approval status: monotherapy; combination with insulin,
sulfonylurea, nonsulfonylurea secretagogue, thiazolidinedione

Inzucchi SE. JAMA. 2002;287:360-372.

Metformin (Glucophage)

Usual starting dose is 500 mg b.i.d. or 850 mg q.d. given with meals

Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks up to
2000 mg q.d.
Maximum daily dose of 2550 mg per day

doses > 2000 mg may be better tolerated given t.i.d. with meals

Contraindications: renal disease or renal dysfunction*, congestive heart failure requiring

pharmacologic treatment, known hypersensitivity to the drug, acute or chronic metabolic
acidosis, including diabetic ketoacidosis with or without coma, temporarily discontinue in
patients undergoing radiologic studies involving intravascular administration of iodinated
contrast materials
Warning: if lactic acidosis is suspected, the drug should be discontinued immediately and
general supportive measures promptly instituted
Precautions: monitoring of renal function, hypoxic states, surgical procedures, alcohol intake,
impaired hepatic function, vitamin B 12 levels, change in clinical status, hypoglycemia, loss of
control of blood glucose
Pregnancy category B

*Serum creatine levels 1.5 mg/dL in males, 1.4 mg/dL in females.

Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2000.

Thiazolidinediones

Thiazolidinediones
Mechanism of action: increased peripheral glucose disposal
Reported A1C reduction: 1.5%-1.6%
Advantages: reverses one of the primary defects of type 2
diabetes, no hypoglycemia, nonglycemic benefits (decreased
lipid levels, increased fibrinolysis, decreased
hyperinsulinemia, improved endothelial function), possible
beta-cell preservation, convenient daily dosing
Disadvantages: liver function test monitoring, weight gain,
edema, slow onset of action, no long-term data
FDA approval status: monotherapy; combination with insulin ,
sulfonylurea, metformin

Inzucchi SE. JAMA. 2002;287:360-372.

Thiazolidinediones
Drug

Trade
Names

Daily Dosage
(mg)

Rosiglitazone

Avandia

2-8

Pioglitazone

Actos

15-45

DeFronzo RA. Ann Intern Med. 1999;131:281-303.

-Glucosidase Inhibitors

-Glucosidase Inhibitors
Mechanism of action: decreased gut carbohydrate absorption
Reported A1C reduction: 0.4%-1.3%
Advantages: targets postprandial glycemia, no
hypoglycemia, nonsystemic
Disadvantages: t.i.d. dosing, adverse gastrointestinal effects,
no long-term data
Miglitol FDA approval status: monotherapy; combination
with sulfonylurea
Acarbose FDA approval status: monotherapy; combination
with sulfonylurea, insulin, and metformin

Inzucchi SE. JAMA. 2002;287:360-372.

-Glucosidase Inhibitors
Daily
Dosage
(mg)

Drug

Trade Names

Acarbose

Precose

25 q.d. to
50-75 t.i.d.

Miglitol

Glyset

25 t.i.d. to
100 t.i.d.

DeFronzo RA. Ann Intern Med. 1999;131:281-303.

Combination Therapy

Synergistic Mechanisms of Action

of Glyburide and Metformin
Glyburide/
Metformin

Enhances
Insulin
Secretion

Decreases Insulin Resistance

Increases peripheral glucose uptake
Decreases hepatic glucose production
Decreases intestinal absorption of
glucose

Improves
Glycemic
Control

Complementary Mechanisms
of Action
Metaglip
(glipizide and metformin
HCl) tablets

Glipizide
Enhances insulin secretion

Metformin
Improves insulin sensitivity by
increasing peripheral glucose uptake
Decreases hepatic glucose production
Decreases intestinal absorption of
glucose

Improves
Glycemic
Control

Please see full prescribing information, including boxed WARNING regarding Lactic Acidosis.

Avandamet
Avandia + Metformin

Basic Steps in the Management of Type 2

Diabetes

die
ex t &
er
cis
e

mo O
no ral
th
er
a

co Or
mb al
ina
tio
n
py

Or
al
Ins plu
uli s
n

ins
uli
n

+ +
+

Insulin
Advantages
Can control all patients
Used to overcome
glucose toxicity
Flexibility in dosing
Multiple insulin
preparations available
Use during pregnancy

DeFronzo. Ann Intern Med. 1999;131:281

303.

Disadvantages
Hypoglycemia
Weight gain
Parenteral administration

Insulins for Type 2

Diabetes

72

Pre-Mixed Insulin Analogs

Humalog Mix75/25
Novolog mix 70/30

73

Why NPL Was Developed

R
L

L
R

NPH
L
L

+
NPL

74

Premix Insulin Profiles

Insulin aspart

30%

70%

30%

Insulin aspart
protamine suspension

Human regular

70%

NovoLog

Human

Mix 70/30

Premixed 70/30

Neutral
Protamine
Hagedorn
(NPH)

Glucose Infusion Rate

mg/min/kg

NPL Component Compared to Human NPH

8
7
6
5
4
3
2
1
0

Human NPH (0.4 U/kg)

NPL Component (0.4
U/kg)
n=8 Non-diabetic Subjects

6
8
10
12
Hours After Injection

14

16

76

Lispro Mix75/25: Pharmacodynamics

Glucose Infusion Rate

mg/kg/min

12
Lispro
Lispro Mix75/25

10
8

NPL

6
4
2
0
0

Heise T, et al. Diabetes Care. 1998;21:800-803.

12
Hours

16

20

24

Recommended Dosing

2/3 or
1/2 AM
Weight (kg*) x units/kg = total daily dose
Dosing Guidelines
0.20.5 for nonobese individuals
0.4 0.8 for obese individuals

1 kg = 2.2 lbs

Obese= BMI over 30Kgm

1/3 or
1/2 PM

GLP-1

GLP-1 Modes of Action in Humans

Upon ingestion of food

Stimulates glucose-dependent
insulin secretion
Suppresses glucagon secretion
Slows gastric emptying

GLP-1 is secreted
from the L-cells
in the intestine

Reduces food intake

Improves insulin sensitivity
Long term effects
demonstrated in animals

This in turn

Drucker DJ. Curr Pharm Des 2001; 7:1399-1412

Drucker DJ. Mol Endocrinol 2003; 17:161-171

Increases beta-cell mass and

maintains beta-cell efficiency

 Exendin-4 was originally

isolated from the
salivary secretions of
the Gila monster
Exendin-4 was
subsequently found to
circulate as a meal-related peptide
in this animal
Exendin-4 has possible
endocrine function in the
lizard Heloderma suspectum
(Gila monster)

Plasma Exendin-4 Concentration (pg/mL)

Exendin-4 in the Gila Monster

4 mice
1 rat

400000

300000

200000

100000

0
0

Data from: Young AA. Glucagon-like peptide-1, exendin and insulin sensitivity. In Hansen B, Shafrir E,
Editors. Insulin Resistance and Insulin Resistance Syndrome. 1st ed. Harwood Academic Press; 2002,

Time After Meal (h)

12

Questions:

ACANTHOSIS NIGRICANS

ACANTHOSIS NIGRICANS

ACANTHOSIS NIGRICANS