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Type 2 Diabetes in the AdultA Collision Course

Kathleen M. Dungan, MDDivision of Endocrinology, Diabetes & Metabolism

The Ohio State University

Prevalence of Diabetes by Age2005

%

0

5

10

15

20

25

<20 >20 >60.9

%

www.cdc.org

Incidence of Diabetes in the U.S.*Age 18-79 Years

www.cdc.org*per 1000 Population

If current trends continue, 1 in 3 Americans and 1 in 2 minorities born in 2000 will develop diabetes during their lifetime!

Obesity Trends* Among U.S. AdultsBRFSS, 1990, 1998, 2006

(*BMI ≥30, or about 30 lbs. overweight for 5’4” person)

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

1998

2006

1990

www.cdc.gov

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The Toll of Diabetes• 6th leading cause of death in the U.S.

Only 35% of patients have DM listed on certificateCAD and stroke account for 65% of deaths

• Leading cause of new blindness in adults• Leading cause of renal failure• Leading cause of non-traumatic lower limb

amputationswww.diabetes.orgCheng et al Diabetes Care 2008;31:279-284

Economic Costs 2007Direct: $115 billion

Indirect: $58.2 billion$174 billion

• $11,744 per patient/yr• 1 in 5 healthcare dollars is spent on

patients with diabetes!

ADA; Diabetes Care 2008;31(3):1-20

Pre-Diabetes

• FBG 100-125 mg/dl

• 2 hour OGTT 140-199 mg/dl

www.diabetes.org

Prevalence of Glucose Abnormalities

(%)

4.9 2.1

18.2

74.8

Known Diagnosis Unknown Diagnosis

Prediabet es Normal Glucose Tolerance

Diabetes Prevention Program

• 3200 adults with IFG + IGT

• 3 GroupsStandard care

Intensive lifestyle

MTF

N Engl J Med. 2002 Feb 7;346(6):393-403.

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Diabetes Prevention Program

• Lifestyle interventionGoal 7% weight reductionLow-calorie, low fat dietExercise 150 min/weekIntensive education

• F/U 2.8 years

N Engl J Med. 2002 Feb 7;346(6):393-403.

Diabetes Prevention Program

• Metformin should be considered if

Very high risk: • IGT + IFG

Obese<60 years of age

% of Patients developing Diabetes

11

7.8

4.8

02468

1012

UsualCare

Metformin Lifestyle

N Engl J Med. 2002 Feb 7;346(6):393-403.

Weight Loss• 500-1000 calorie reduction• Diet alone is generally not effective long-

term• Exercise is important for weight

maintenance and improved insulin sensitivity

• Structured programs that include education, diet, exercise, and regular contact can produce sustained weight loss of 5-7%

ADA. Diabetes Care 31 (Suppl 1):S61-S78

MNT• Carbohydrates:

The total amount is more important than the type in determining glycemic effectLow glycemic index foods may reduce PPG

ADA. Diabetes Care 31 (Suppl 1):S61-S78

4

MNT• Protein

15-20% of total caloriesHigh-protein, low-carb diets • Short-term weight loss• Improved glycemia• Long-term safety and efficacy is

unknown• Increased LDL

ADA. Diabetes Care 31 (Suppl 1):S61-S78

MNT• Fats

Saturated fats <10% of total caloriesMonounsaturated fat and CHO should be 60-70% of total caloriesCholesterol • <200 mg/day if LDL >100 mg/dl

ADA. Diabetes Care 31 (Suppl 1):S61-S78

Efficacy of MNT

00.20.40.60.8

11.21.41.61.8

2

MNT MNT + DSMT

UKPDS

Franz

KulkarniGlasgo

Pastors et al. Diabetes Care 2002;25:608-613

A1C

Red

uctio

n %

• 4 states do not mandate that insurers cover diabetes treatment and supplies

Alabama IdahoOhio North Dakota

Insurance Coverage

Pastors et al. Diabetes Care 2002;25:608-613

5

• MNT was associated with a reduction in

Utilization of hospitalservices by 9.5% Utilization of physicianservices by 23.5%

• Savings exceed costs of MNT in patients > 55 years

Insurance Coverage

Pastors et al. Diabetes Care 2002;25:608-613

U.S. Adults with Diabetes who have ever attended Diabetes

Self-Management Class

www.cdc.org

NHANES Data

36.9

49.456.8

0102030405060708090

100

A1C <7%

1999-2000

2001-2002

2003-2004

Hoerger et al. Diabetes Care 31:81-86, 2008

Measuring SuccessADA1 ACE2

A1C <7%* <6.5%

Fasting/preprandial BG 90-130 <110

Postprandial BG <180 (peak)

<140 (2 hour)

*Goals should be individualizedRisks/Benefits of a “normal” A1c (< 6%) are unclear

1. ADA Clinical Practice Recommendations. Diabetes Care 30 (Supp. 1), 2007;2. AACE Medical Guidelines for Clinical Practice for the Management of Diabetes Mellitus; Endocr Pract;13(Supp 1), 2007.

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ADA/EASD Consensus Algorithm

Nathan et al. Diabetes Care 2006;29:1963-1972.

Matching Pharmacology to Pathophysiology

Plasmaglucose

↓Insulinsecretion

↑Hepaticglucoseoutput

↓Peripheralglucose uptake

α-GlucosidaseinhibitorsIncretins

Pramlintide

Metformin(glitazones)

Glitazones(metformin)

Insulin SFU

GlinidesIncretins

Glucose influx↑ Glucagon

secretionIncretins

Pramlintide

Proportion of Patients Achieving A1C <7.0%

Beta cell function declines over time regardless of therapy

Turner et al. UKPDS 49; JAMA. 1999;281(21):2005-12

05

101520253035404550

3 year 6 year 9 year

DietSFUMetforminInsulin

Greater glycemic durabililty with Metformin and Rosiglitazone

Monotherapy

p<0.001

p<0.001

Kahn et al. N Engl J Med. 2006;355:2427-43

0

5

10

15

20

25

30

35

Rosi Met Gly

Failure rate (%)

7

Conclusions• Diabetes places a substantial clinical and

economic burden on the U.S.

• Lifestyle changes, as part of a multi-disciplinary approach, can prevent or delay DM

• Initial therapy should be individualized and goal-directed

Type 2 Diabetes in Children

Dana S. Hardin, M.D.Associate Professor

The Ohio State University Nationwide Children’s Hospital

Incidence• Causes 2 - 3% of all cases of

diabetes in children• Mean age of diagnosis 12 - 14

years• Highest incidence in ethnic groups

with high prevalence of type 2 DM

Definition• Diabetes mellitus which does NOT

require insulin for survival• Occurs in someone less than 18 years

of age.• Does not meet the criterion for

maturity onset diabetes of youth (MODY)

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Characteristics Associated with Increased Incidence

of Type 2 DM• Obesity• Family history of adult-onset type 2 DM• Acanthosis nigricans• Children of mothers with gestational

diabetes• High-risk ethnicity

• Pima children ages:5-14 1:100015-24 9:1000

• Manitoba Native Indians ages:7-14 0.5:1000

• Japan:2.8-44.6:100,000

• Less well studied in other ethnic groups

Incidence by Ethnicity

Incidence in Hispanics and Blacks

• Southern California 21% of diabetic Hispanic patients (Glasser, J.Invest.Med. 1995)

• African-American children had odds ratio of 3.5:1 (boys) and 6.1:1 (girls) compared to whites (Pinhaus-Hamiel, J.Ped. 1996)

• Houston, TX 12.6% of all DM in children(Yafi and Hardin JPEM 2004)

Pathophysiology of Type 2 Diabetes is Similar to Adults

• Insulin resistance

• Impaired insulin secretion

• Excessive hepatic glucose production

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Insulin Secretion in Type 2 Diabetes

• Initially insulin secretion is augmented to meet the demands of impaired insulin action.

• Eventually β-cells become “exhausted” and glucose intolerance develops.

• First phase insulin response remains intact until type 2 DM has been on-going for some time.

• Cause of β-cell exhaustion is likely to be glucose toxicity in a genetically predisposed β-cell.

• Type 2 DM patients have significantly decreased insulin sensitivity

Demonstrated by fasting hyperinsulinemiaDemonstrated by high insulin to glucose ratio post-prandiallyConfirmed by hyperinsulimiceuglycemic clamp studies

Insulin Resistance in Type 2 DM

Insulin-Mediated Whole-Body Glucose Uptake

(DeFronzo, Jm.J.Phys., 1979)

0123456789

10

Controls NIDDMGlu

cose

Upt

ake

(mg/

kg/m

in)

Increased Hepatic Glucose Production in Type 2 DM

• Increased hepatic glucose production and hepatic insulin resistance (DeFronzo, Diabetes 1981)

• Increased hepatic glucose production in MZ twins discordant for type 2 DM (Vaag, J.Clin.Invest., 1995)

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Contribution of Gluconeogenesis and

Glycogenolysis

(Consoli, Diabetes, 1989)

Hep

atic

Glu

cose

Out

put

(µm

ol/k

g/m

in)

0

5

10

15

20

25

Control NIDDM

Dose-Response Curve Relating Insulin to the Suppression of HGP

Portal Insulin Concentration

Goals of Treatment• Correct hyperglycemia to prevent

complications.Traditional the focus has been on reducing pre-meal glucose levels.Reduction of post-prandial glucose levels is equally important.

• Minimize the risk of hypoglycemia.• Promote optimal psychological and social

adaptation to living with diabetes.

Glycemic and A1c Targets

< 7.0< 7.5< 8.0< 8.5%HbA1c

> 80> 90> 100> 1002-4 AM

80-15090-160100-180100-200Before bed

< 180< 180< 200< 2002-3 hour postmeal

70-15070-15070-150100-180Premeal

>13 years7-12 years3-6 years0-2 yearsBlood Glucosemg/dl

Kaufman et al Contemporary Pediatrics 16:112,1999

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Metabolic Consequences of Diabetes

• DehydrationFrequent drinking (polydipsia)Frequent urination (polyuria)

• Weight loss• Loss of muscle mass

Metabolic Consequences of Diabetes

• Type I diabetes – acidosis and death• Type 2 diabetes – hyperosmolar coma • Chronic Illness – worsening of

underlying disorder• Neonatal diabetes – failure to thrive

• Retinopathy• Nephropathy• Neuropathy• Co-Morbidities

Early cardiovascular diseaseHypertensionHyperlipidemia

Long-term Complications Resulting from Hyperglycemia

• Retinopathypre-pubertal diabetes duration related to retinopathy, 27% of pts (Donague et al, Diabetes Care 20:77,97)

• NephropathyMicroalbuminuria 9.0%, macro3.7% macroalbuinuria(Olsen et al, Diabetic Medicine 16:79,99)

• Neuropathy138 pts >9, duration >2 yrs, nerve conduction velocity, distal latency and action potential amplitude impaired in adolescent pts (Riihimaa et al, Diabetes Care 24:1087,2001)

• Macrovascular- autopsy data suggestive

Complications Begin Before Puberty

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• Early recognition and treatment Screening high risk groups (those with at least three risk factors: obese, FH, acanthosis, high risk ethnic group)Random Blood glucose levelFasting blood glucose levelOGTTInsulin levels

• Aggressive therapy • Prevention of diabetes development

Prevention of Diabetes Complications

Screening High Risk Groups –Type 2 Diabetes

• If at least three risk factors: obese, FH, acanthosis, high risk ethnic group

• Random Blood glucose level• Fasting blood glucose level• OGTT• Insulin levels

Acanthosis Nigricans; a Feature of Insulin

Resistance Syndrome

AXILLA NECK

Flow Sheet for Acanthosis Nigricans (AN)Referral AN (Use Hale scale to grade) – check posterior

neck and axilla

FBG > 126 orHbA1c > 9%

ketones moderate or high

Refer to Endo for immediate insulin treatment

YES

1. Body wt > 95%2. BMI > 27

YES Age

< 6 > 6Nutrition counseling Lab studies* Lab studies* Nutrition,

Random glucose level (RBG)

<126F/up in 6 months

w/ random glucose level

>126**check a 2hr OGTT check

urine for ketones

NO

FBG >126 and HbA1c < 9%ketones negativeGlucometer, Metformin(250 mg/day po)Refer to Endo for f/up consult

Refer to Specialist

Abnormal OGTT (fasting glucose >126 &/or 2hr >180)Prepubertal Pubertal (Tanner 2 - 5)

Negative ketones and Normal OGTTF/up 6 months

NO

No Treatment

** If random blood sugar >200 mg/dl, check HbA1c and fasting blood sugar –then follow as below

* Lab studiesIf patient also has short stature consider thyroid function tests &/or Cortisol levelsEvaluate for hypertension

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Prevention of Type 2 DM in Children

• Pediatricians need to teach healthy eating habits and encourage exercise.

• Address overweight patients directly about weight. They won’t “grow out of it!”

Adolescence Likely Increases Risk of Obesity

• Early puberty leads to reduced insulin sensitivity

• Insulin hyper-secretion: compensation for reducedinsulin sensitivityresponse to increased GH

Adolescence Likely Increases Risk of Obesity• Sex-dependent changes in insulin

sensitivity (Travers, et al. JCEM 80:172-178,1995)

• Systolic BP changes with pubertal stage independent of age(Weir, et al. J Adolesc Health Care 9: 465-469, 1988)

• Lipid variability by pubertal stage(Belcher, et al. Prev Med 22:143-153,1993)

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Females 6-11

Males 6-11

Percent Percent

Males 12-19

Females 12-19

Trends in Child & Adolescent Overweight

Note: Overweight is defined as BMI >= gender- and weight-specific 95th percentile from the2000 CDC Growth Charts for the United States. Source: National Health Examination Surveys II (ages 6-11) and III (ages 12-17), NationalHealth and Nutrition Examination Surveys I, II, III and 1999-2000, NCHS, CDC.

1963-67 1971-74 1976-80 1988-94 1999-20001966-700

5

10

15

20

0

5

10

15

20

20.6% obese17% overweight36.6%

BMI of OhioBMI of Ohio’’s 3s 3rdrd GradersGraders

Boys = girls

Poor, rural > urban

Ohio Dept Health, 2006

Environmental causes of Obesity in Children

• Food choicesFast food

• Increased portion sizes • Sedentary behavior

TelevisionVideo games

• Family environment• Socioeconomic issues

Summary• Type 2 diabetes in children is caused by the

same disordered metabolism as in adults. • Certain patients are at greater risk than

others.• High risk patients should be screened for type

2 diabetes.• Type 2 diabetes can be prevented, but when

present should be treated aggressively.