Diabetes 2013: Achieving GoalsThrough Comprehensive Treatment

Joshua L. Cohen, M.D., F.A.C.P.

Professor of Medicine

Interim Director, Division of Endocrinology &Metabolism

The George Washington University School ofMedicine

Session 1 Agenda

• Diabetes epidemiology andpathophysiology

• Diagnosis and classification

• Goals of therapy and long-termoutcomes

• Overview of stepped approach topharmacotherapy

• Insulin therapy

The Increasing Global Burdenof Noncommunicable Diseases

1990 2010

Percent attributabledeaths

Communicable, maternal, neonatal and nutritionaldisorders

34.1 24.9

Noncommunicable diseases 57.1 65.3

Injuries 8.8 9.6

Cause of death rank

Diabetes 15 9

93% increase in deaths attributed to diabetes

The Global Burden of Diabetes

• Approximately 371 million people haddiabetes in 2012

» 50% of cases are undiagnosed

• By 2030 there will be about 552 millionpeople living with diabetes (49% increase)

Change in Disability-AdjustedLife Years (DALY) 1990 – 2010

Cause Percent Change

All cause -23.4

Communicable, maternal, neonataland nutritional disorders

-43.5

HIV/AIDS & Tb 26.9

Nutritional Deficiencies -41.3

Noncommunicable diseases -3.8

Cancers -2.1

Cardiovascular -5.7

Diabetes 30.0

Injury -12.7

Murray CJL, et al. Lancet. 2012; 380:2197–2223

Global Disease Risk Factors:Per cent Disability Adjusted Life Years

2010

1990

58% increase inDALY’sattributed tohigh fastingplasma glucose

Lim SS et al.Lancet. 2012;380:2224 - 2260

9

7

Chen, L. et al. Nat. Rev. Endocrinol. 2011; doi:10.1038/nrendo.2011.183

Global Projections for theDiabetes Epidemic: 2010–2030

BMI and Diabetes Risk

0

10

20

30

40

50

60

70

80

90

100

<22* 23-23.9 25-26.9 29-30.9 33-34.9

Body Mass Index (kg/m2)

Relative risk of diabetes

* RR=1.0 for BMI <22 Colditz GA Ann Int Med 1995; 122:481

Obesity and Diabetes in the U.S.Obesity (BMI ≥30 kg/m2)

Diabetes

1994 2000

No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0%

No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0%

CDC’s Division of Diabetes Translation. National Diabetes SurveillanceSystem available at http://www.cdc.gov/diabetes/statistics

2009

Diabetes Mellitus in the US:Health Impact of the Disease

DiabetesBlindness*

Renalfailure*

Amputation*

Life expectancy5 to 10 yr

Cardiovasculardisease 2X to 4X

*Diabetes is the no. 1 cause of renal failure, new cases of blindness, andnontraumatic amputations

Nerve damage in60% to 70% of patients

7th leading cause ofdeath

Diabetes Healthcare Costs

0500

100015002000250030003500

General Health Costs

Additional costs from diabetesUS $/year

PATHOGENESIS ANDNATURAL HISTORY OF

TYPE 2 DIABETES

Hyperglycemia

Metabolic Defects in Diabetes

Pancreas

LiverMuscleFat

Hepatic GlucoseProduction

GlucoseUptake

Progressiveinsulin secretorydefect

Insulinresistance

Main Pathophysiological Defects in T2DM

++

--

--

peripheralglucoseuptake

hepaticglucoseproduction

pancreaticinsulinsecretion

pancreaticglucagonsecretion

gutcarbohydratedelivery &absorption

incretineffect

HYPERGLYCEMIAHYPERGLYCEMIA

?

Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Insulin Resistance

• Definition: Impaired cellular responses tothe physiological effects of insulin. Forexample, decreased glucose uptake bymuscle in response to insulin.

• A core defect in type 2 diabetes – 92% ofpatients with type 2 diabetes have insulinresistance

• If pancreatic beta cell function is normal,insulin resistance may be associated withhyperinsulinism

From Weyer et al. J Clin Invest. 1999;104:787-794.

EMBS = estimated metabolic body size (or fat-free mass + 17.7 kg)

INSULIN SENSITIVITY ANDINSULIN SECRETION500

400

300

200

100

00 1 2 3 4 5

Insu

lin

Secre

tio

n(

U/m

L)

Insulin Sensitivity (mg/kg EMBS per minute)

Insulin Resistance

-c

ell

Fa

ilure

ProgressorsDIA

IGT

IGT

95% CI

Nonprogressors

NGTNGTNGT

Natural History of Type 2 Diabetes

Obesity IFG* Diabetes Uncontrolled Hyperglycemia

50

100

150

200

250

300

350

50

100

150

200

250

Glu

co

se

(mg

/dL

)R

ela

tive

Fu

ncti

on

(%)

-10-10 -5-5 00 55 1010 1515 2020 2525 3030

Years of DiabetesYears of Diabetes

Post-meal Glucose

Fasting Glucose

Insulin Resistance

Insulin Level-cell Failure

*IFG = impaired fasting glucose

Fat Topography In Type 2Diabetic Subjects

Intramuscular

Intrahepatic

Subcutaneous

Intra-abdominal

Relationship Between VisceralAdipose Tissue and Insulin Action

Banerji M et al. Am J Physiol 1997;273(2 pt 1):E425–E432.

18

16

14

12

10

8

6

4

2

01000 2000 3000 4000 5000

Visceral adipose tissue volumeper unit surface area (mL/m2)

Glu

co

se

dis

po

sa

l(m

g/k

gL

BM

/min

)WomenMen

Signals from Adipose Tissue:Hormones and Cytokines

Leptin

Adiponectin

TNF

IL-6

PAI-1

Fasshauer M, Paschke R. Diabetologia. Nov. 6, 2003 [online].Arner P. Trends in Endo and Met. 2003;14:137-145.

Free FattyAcids

Fat Cells?Resistin

Angiotensinogen

11 hydroxysteroiddehydrogenase

Beta Cell Failure

• Beta cell dysfunction begins early in thedevelopment of type 2 diabetes, eventhough patients may have elevatedinsulin levels

• At the time of diagnosis with diabetes, apatient may already have lost 50% ofinsulin secretory capability (UKPDS)

• Progressive beta cell failure continuesafter diagnosis

Potential Causes of -CellFailure in Type 2 Diabetes

• Genetic factors

• Reduced -cell mass

» Apoptosis

» Reduced proliferation

» Amyloid deposition

• -cell exhaustion

• Glucotoxicity

• Lipotoxicity

• Diminished incretin effect

Beta Cell Volume in Obesityand Diabetes

Costes S et al. Diabetes 2013;62:327-335

Insulin and Amyloid Deposition inNormal and Diabetic Islets

Diabetes Susceptibility Genes

Effect of TCF7L2 T allele oninsulin secretion: Loss ofinsulin secretion over time

Lyssenko V, et al. J Clin Invest. 2007;117:2155

Worldwide Distribution of Type 2Diabetes-Associated TCF7L2 SNP

Guinan KJ. Biochem Genet. 2012; 50:159-179

Odds ratio of rs7903146 SNP associationwith type 2 diabetes = 1.46

Adapted from Saltiel & Olefsky. Diabetes 1996;45:1661–9

Insulin Resistance

Insulin Resistance andHyperinsulinemia

Insulin Resistance andDeclining Insulin Levels:Impaired GlucoseTolerance “Prediabetes”

Further decline in insulin:Type 2 Diabetes

Impaired b-Cell Function

Genes Environment

Neal, 1962.

The Thrifty Gene Hypothesis

• Fuel efficiency

» Evolutionary pressure selected hunter gatherers forefficient fuel storage during times of famine. Whenfood became plentiful and exercise less, this becamea liability

» Examples: Native Americans, Australian Aborigines,Pacific Islanders

PIMA INDIANS LIVING IN MEXICO

24.9BMI

>40 hr/weekWork

>50 gmFiber

23%Fat

63%Carb

Diet

160 cmHeight

PIMA INDIANS LIVING INARIZONA

33.4BMI

3 hr/weekWork

<30 gmFiber

40%Fat

40%Carb

Diet

164 cmHeight

DIABETES PREVALENCE INTHE PIMA INDIANS

10.5%37%Women

6.3%54%Men

MexicoArizona

The Impact of Social and CulturalFactors on Diabetes Prevalence in

Different Ethnic Groups

King H, et al. Diabetes Care. 1993; 16:157

Worldwide Trend in DiabetesCases 2010-2030

0

100

200

300

400

500

600

Total High Low/Middle

Mil

lio

ns

Income

2011 2030

Diabetes: A disease associated withrapid socioeconomic change invulnerable populations

The result of adoption of a high-calorie, low-exercise lifestyle as aresult of emigration oreconomic/cultural changes

Socioeconomic FactorsAssociated with Increased

Obesity• Urbanization

» Women may be more vulnerable than men

• Diet

» Sweetened beverages

» Energy-dense oils

» Increased meat consumption

• Decreased energy expenditure at work

Diabetes Prevalence in the MiddleEast and North Africa 2012

DiabetesPrevalence

IDF Diabetes Atlas.5th edition

Diabetes Prevalence in the MiddleEast and North Africa

0 10 20 30

AlgeriaBahrainEgyptIranIraqJordanKuwaitLebanonLibyaMoroccoOmanPalestinian Terr.PakistanQatarSaudi ArabiaSudanSyriaTunesiaUAEYemen

PercentIDF Diabetes Atlas. 5th edition

Countries with the HighestDiabetes Prevalence

IDF Diabetes Atlas. 5th edition

Physician Attitudes About Diabetes• It’s considered impolite to turn down a second

helping of food when visiting (Egypt)

• Women were able to be more active whenthey lived in villages than they are in the cities(Saudi Arabia)

• Men don’t go to doctors because they don’twant to be told not to eat sweets (Jordan)

• People are very traditional and won’t takemedications if they feel well (Dubai)

Attitudes About Diabetes(Continued)

• There is nothing to do in the evening exceptto go to restaurants or people’s houses fordinner (Saudi Arabia)

• Women wont lose weight because theirhusbands want them to be heavy. (SaudiArabia)

Prevalence of Overweight andObesity in Gulf StatesChildren and Adolescents Adults (15+ years)

Year Age Sex Overweight(%)

Obesity(%)

Year Sex Overweight(%)

Obesity(%)

Bahrain 2006 15-18M 15.8 13.7

2007M 34.8 32.3

F 17.4 19.4 F 35.1 40.3

Kuwait 2006 10-14M 29.3 14.9

2007M 38.9 39.2

F 32.1 14.2 F 28.9 53.0

Oman 2000M 30.6 15.5

F 27.2 22.3

Qatar20032004

6-9M 16.3 3.5

F 15.5 2.8

KSA 2005 5-12M 19.9 7.8

2005M 43.0 31.5

F 19.2 11.0 F 28.8 50.4

UAE 2005 10-19M 21.2 13.2

F 21.3 11.0

Musaiger AO, et al. Int J Environ Res Public Health. 2011; 8:3637-71

Diabetes Prevalence in theMid East 2012 and 2030

0

5

10

15

20

25 2012 2030

IDF Diabetes Atlas. 5th edition

Age Distribution of Diabetes in theEastern Mediterranean and Middle East

0

10

20

30

40

50

60

70

20-39 40-59 60-79

Age Range

Bahrain

Iran

Iraq

Jordan

Kuwait

Lebanon

Libya

Morocco

Pakistan

Qatar

Saudi Arabia

Syria

Tunesia

Percent of total cases

Diagnosed and UndiagnosedDiabetes in the United States

3.7%

13.7%

26.9%

0%

5%

10%

15%

20%

25%

30%

20-44 45-64 ≥65

Perc

en

t

Age Group, Years

Estimated percentage of people ages ≥20 years with diagnosed and undiagnosed diabetes, by age group, United States, 2005-

2008

Type 2 Diabetes: Diagnosisand Clinical Presentations

Diagnostic Criteria for Diabetesin Nonpregnant Adults

• Fasting plasma glucose 126 mg/dlor

• HbA1C 6.5%or

• Random plasma glucose 200 mg/dltogether with symptoms ofhyperglycemia (polyuria, polydipsia,weight loss, blurred vision, etc.)or

• 2 hour plasma glucose 200 during 75 gOGTT

Undiagnosed Diabetes by WorldRegion

IDF Diabetes Atlas. 5th edition

Diabetes and Prediabetes

0

50

100

150

200

250

300

Fasting 2 hr pp

Glu

co

se

(mg

/dl)

Nl

IGT

DM

100

126 140

200

IFG

IFG: Impaired fasting glucoseIGT: Impaired glucose tolerance “Prediabetes”}

Major Indicators of Risk forType 2 Diabetes

• Family history of diabetes (1st degree relatives)

• Obesity

• Sedentary lifestyle

• Ethnic background

• Previously identified IGT or IFG (“Pre-diabetes”)

• History of gestational diabetes

• Polycystic ovary syndrome (PCOS)

• Dyslipidemia ( Triglyceride, HDL, small LDLparticle size)

• Hypertension

Etiologic Classification ofDiabetes Mellitus

I. Type 1 diabetes

II. Type 2 diabetes

III. Gestational diabetes

IV. Secondary forms

Gestational Diabetes Mellitus• Develops in 2-13% of screened populations

• Develops in 3rd trimester

• Asymptomatic, diagnosed by OGTT with specificcriteria

• Neonatal complications of poorly treated GDM:

» Macrosomia, hypoglycemia, hyperbilirubinemia,hypocalcemia

• Often can be treated by diet alone

• Some women may require insulin. Oral agentsgenerally are not used during pregnancy

• Marker of increased risk for the development oftype 2 diabetes

Autoimmunity in Type 1 Diabetes

• Glutamic acid decarboxylase (GAD-65)

• Protein tyrosine phosphatase 2 (IA-2)

• Insulin

• Zinc transporter 8 (ZnT8, Slc30A8)

Major Antigens

Is it type 1 or type 2?

• Adolescents

» Increasing incidence of type 2 diabetes

• Late onset type 1

» LADA: Latent autoimmune diabetes of adults

» May present initially as apparent type 2 diabetes butmay progress rapidly to insulin requiring

• Monogenic diabetes

» Previously called “MODY”: Maturity onset diabetes ofthe young

» Autosomal dominant inheritance

» Rare

You can’t always tell by age.