TYPE 2 DIABETES MELLITUSTYPE 2 DIABETES MELLITUS

Richard Sachson MD

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

Diabetes and Gestational Diabetes Trends Among Adults in the U.S., BRFSS 1990, 1995 and 2000

1990 1995

2000

Diabetes in the U.S. Diabetes in the U.S.

< 4% 4-6% > 6% % incidence of diabetes among adults N/A

DIABETES AND GESTATIONAL DIABETES AMONG ADULTS IN THE

U.S. -2001

Global Projections for Diabetes 1995–2010

14.217.523%

15.622.544%

26.532.924%

1.01.3 33%

9.414.150%

WorldWorld2000 = 151 million2000 = 151 million2010 = 221 million2010 = 221 million

Increase: 46%Increase: 46%

84.5132.3 57%

Reprinted with permission from Zimmet P et al. Nature. 2001;414:782–787.

Diabetes and Obesity: The Continuing Epidemic

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.

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

1990 1992 1994 1996 1998 2000

• Prevalence of obesityincreased by 61%since 1991

• More than 50% of US adults are overweight

• Only 43% of obesepersons advised to loseweight during checkups

• BMI and weight gain majorrisk factors for diabetes

Pre

vale

nce

(%

)

kgYear

72

73

74

75

76

77

78

Diabetes

Mean Body Weight

ExcessGlucoseProduction

ReducedGlucoseUptake

Pancreas

MuscleLiver

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

0

25

50

75

100

–10 –6 –2 2 6-C

ell

Fu

nctio

n (

%)

Years After Diagnosis

N = 376

Insulin Resistance:

Defective -Cell Secretion:

Pathophysiology of Type 2 Diabetes

R EASN 14-6/2000

Pathogenesis of Type 2 Diabetes: InsulinResistance and -Cell Dysfunction

-Cell Dysfunction

Pancreas Liver Muscle Fat

Insulin Resistance

Fat

FFAs

Fasting Hyperglycemia Postprandial Hyperglycemia

Progression of Type 2 Diabetes

Glucose

Relative Function

0

100

200

300

-10 -5 0 5 10 15 20 25 30

50

150

250

350

Years of Diabetes

Insulin Resistance

Insulin Level

Fasting Glucose

Beta cell failure

Post Meal Glucose

At risk for Diabetes

Adapted from D Kendall, R Bergenstal, © International Diabetes Center

0

4

8

12

1980 1990 2000 (Estimated)From Centers for Disease Control and Prevention, 2000.

Dia

gnos

ed C

ases

(M

illi

ons)

+17%

+60%

Diabetes: 16 Million and Climbing• Estimated 10.3 million diagnosed + 5.4 million

undiagnosed cases• Type 2 diabetes accounts for 90-95% of cases

Insulin Resistance

FFA production Glucose production

Hyperinsulinemia

Dyslipidemia

T2D

SNS activityAbnormal Na+

handling

HTN

Atherosclerosis

ACANTHOSIS NIGRICANS

ACANTHOSIS NIGRICANS

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.

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

Visceral Fat Distribution:Normal vs Type 2 Diabetes

Normal Type 2 Diabetes

2-11

16

Complication Prevalence (%)*Any complication 50Retinopathy 21Abnormal ECG 18Absent foot pulses ( 2) and/or ischemic feet 14 Impaired reflexes and/or decreased vibration sense 7Myocardial 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.

Prevalence of Complicationsat Time of Diagnosis: UKPDS

Adult Treatment Panel III (ATP III) Guidelines

National Cholesterol Education Program

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)

MI = myocardial infarction.* These patients had no prior MI at baseline.Haffner SM, et al. N Engl J Med. 1998;339:229–234.

05

101520253035404550

7-y

ea

r in

cid

enc

e ra

te o

f M

I

No prior MI* MI No prior MI* MI

Nondiabetic Diabeticn = 1373 n = 1059

P < 0.001 P < 0.001

4%

19% 20%

45%

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.

Target Lipid Levels forAdult Patients with Diabetes

< 150 mg/dLTriglycerides:

Men: > 45 mg/dL

Women: > 55 mg/dLHDL Cholesterol:

< 100 mg/dL (high risk < 70 mg/dl)

LDL Cholesterol:

Target BP Patients aged 18 years <130/80 mm Hg

Isolated systolic hypertension180 mm Hg <160 mm Hg160–179 mm Hg of 20 mm Hg

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

Recommended Treatment Goals for Hypertension for Adults With Diabetes

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

IGT = impaired glucose tolerance; BMI = body mass index.Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.

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

The Finnish Diabetes Prevention Study: Lifestyle Modifications

FPG = fasting plasma glucose; PPG = postprandial glucose.Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.

0

20

40

60

80

100

Inci

denc

e of

Dia

bete

s(C

ases

/100

0 P

erso

n-Y

ears

)

58%P < .001

-20

-10

0

102-Hour PPGFPG

P < .001

P < .003

Cha

nge

from

Bas

elin

e (m

g/dL

)ControlIntervention (Diet and Exercise)

Quintile Weight Change (%) Risk Reduction (%)

1 11 832 5 613 2 134 No change No change5 3 218

Finnish DPP: Results

Each 3-kg weight loss doubles the benefit.DPP = diabetes prevention program.Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.

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.

Intensive Lifestyle Placebo Intervention Metformin

(n = 1082) (n = 1079) (n = 1073)

Wt loss: 0.1 kg* Wt loss: 5.6 kg* Wt loss: 2.1 kg*

Diabetes: 29%† Diabetes: 14%† Diabetes: 22%†

United States Diabetes Prevention Program: Results

*Average; †Cumulative incidence at 3 years.Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

Intensive Lifestyle Placebo Intervention Metformin

(n = 1082) (n = 1079) (n = 1073)

Wt loss: 0.1 kg* Wt loss: 5.6 kg* Wt loss: 2.1 kg*

Diabetes: 29%† Diabetes: 14%† Diabetes: 22%†

Risk reduction: Risk reduction: 58% 31%

United States Diabetes Prevention Program: Results

*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

Rosiglitazone

Pioglitazone

Glucose Uptake

Insulin Resistance

=

MuscleHyperglycemia

GutCarbohydrate Metabolism

Miglitol

Acarbose

Hyperglycemia

Metformin

Hepatic GlucoseProduction Hyperglycemia

Liver

Exogenous Insulin Rx

Sulfonylurea

Repaglinide

Nateglinide

Impaired Insulin Secretion

Insulin Deficiency

=

PancreasHyperglycemia

Sulfonylureas

Sulfonylurea Effects on the -cell

SulfonylureaMetabolism

FreeCa++

Glucose

K+

K+ATP Channel

[ATP]

[ADP]

Ca++

VDCC(+)

-Cell

Insulin Release

SUR

Depolarization

Hu S et al. J Pharmacol Exp Ther 2000;293:444–52

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

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

Second-Generation Sulfonylureas

24 hours5-20Glucotrol XL®

16-24 hours

12-24 hours

16-24 hours

Duration of Action

1-8Amaryl®Glimepiride

5-40*Glucotrol®Glipizide

2.5-20Micronase®, DiaBeta®, Glynase®

Glyburide

Daily Dosage (mg)Trade NamesDrug

*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 pancreaticinsulin 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

180-360Starlix®Nateglinide

1.5-16Prandin®Repaglinide

Daily Dosage (mg)Trade NamesDrug

DeFronzo RA. Ann Intern Med. 1999;131:281-303.Starlix® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2000.

Biguanides

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

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

*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.

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 B12 levels, change in clinical status, hypoglycemia, loss of control of blood glucose

• Pregnancy category B

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

15-45Actos®Pioglitazone

2-8Avandia®Rosiglitazone

Daily Dosage (mg)

Trade NamesDrug

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

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

Glyset®Miglitol

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

Precose®Acarbose

Daily Dosage

(mg)Trade NamesDrug

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

Combination Therapy

Synergistic Mechanisms of Action of Glyburide and Metformin

ImprovesGlycemicControl

MetforminGlyburide/

Decreases Insulin Resistance• Increases peripheral glucose uptake• Decreases hepatic glucose production• Decreases intestinal absorption of

glucose

Enhances Insulin

Secretion

Complementary Mechanisms of Action

ImprovesImprovesGlycemicGlycemicControlControl

ImprovesImprovesGlycemicGlycemicControlControl

Metaglip™

(glipizide and metformin HCl) tablets

Metformin• Improves insulin sensitivity by

increasing peripheral glucose uptake • Decreases hepatic glucose production• Decreases intestinal absorption of

glucose

Glipizide•Enhances insulin secretionEnhances insulin secretion

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

Avandamet

Avandia + Metformin

Basic Steps in the Management of Type 2 Diabetes

+ +

diet &exercise

Oral monotherapy

insulin

+

Oralcombination

Oral plusInsulin

DeFronzo. Ann Intern Med. 1999;131:281–303.

InsulinAdvantages• Can control all patients• Used to overcome

glucose toxicity• Flexibility in dosing• Multiple insulin

preparations available• Use during pregnancy

Disadvantages

• Hypoglycemia

• Weight gain

• Parenteral administration

Insulins for Type 2 Diabetes

7272

Pre-Mixed Insulin Analogs

Humalog Mix75/25

Novolog mix 70/30

7373

R

LRL

R

NPH

+

+

Why NPL Was DevelopedWhy NPL Was Developed

L

NPL

L

L

7474

Premix Insulin Profiles

Insulin aspart protamine suspension

Insulin aspart30%

70% NeutralProtamine Hagedorn

(NPH)

Human regular30%

70%

NovoLog®

Mix 70/30

Human

Premixed 70/30

NPL Component Compared to Human NPH

Hours After Injection

00

11

22

33

44

55

66

77

88

00 22 44 66 88 1010 1212 1414 1616

Human NPH (0.4 U/kg)

NPL Component (0.4 U/kg)

n=8 n=8 Non-diabetic Subjects

Glu

cose

Infu

sio

n R

ate

mg

/min

/kg

7676

00 44 88 1212 1616 2020 2424

00

22

44

66

88

1010

1212

Glu

cose

Infu

sio

n R

ate

Glu

cose

Infu

sio

n R

ate

mg

/kg

/min

mg

/kg

/min

HoursHours

LisproLispro

Lispro Mix75/25Lispro Mix75/25

NPLNPL

Lispro Mix75/25: PharmacodynamicsLispro Mix75/25: Pharmacodynamics

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

Recommended Dosing

Weight (kg*) x units/kg = total daily dose

2/3 or 1/2 AM2/3 or 1/2 AM

1/3 or 1/2 PM1/3 or 1/2 PM

1 kg = 2.2 lbs

Dosing Guidelines

0.2—0.5 for nonobese individuals

0.4 – 0.8 for obese individuals

Obese= BMI over 30Kgm

GLP-1

GLP-1 Modes of Action in Humans

GLP-1 is secretedfrom the L-cellsin the intestine

This in turn…

• Stimulates glucose-dependent insulin secretion

• Suppresses glucagon secretion

• Slows gastric emptying

Long term effectsdemonstrated in animals…

• Increases beta-cell mass and maintains beta-cell efficiency

• Improves insulin sensitivity

• Reduces food intake

Upon ingestion of food…

Drucker DJ. Curr Pharm Des 2001; 7:1399-1412Drucker DJ. Mol Endocrinol 2003; 17:161-171

0 3 6 9 12

0

100000

200000

300000

400000

Time After Meal (h)

Pla

sma

Exe

nd

in-4

Co

nce

ntr

atio

n (

pg

/mL

)

Exendin-4 in the Gila Monster

• Exendin-4 was originallyisolated from thesalivary secretions ofthe Gila monster

• Exendin-4 wassubsequently found tocirculate as a meal-related peptide in this animal

• Exendin-4 has possibleendocrine function in thelizard Heloderma suspectum(Gila monster)

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, 235-262

4 mice1 rat

Questions:

ACANTHOSIS NIGRICANS

ACANTHOSIS NIGRICANS

ACANTHOSIS NIGRICANS