The Epidemic of Type 2 Diabetes During Childhood

Francine Ratner Kaufman, M.D.Professor of PediatricsThe Keck School of Medicine of USCHead, Center for Diabetes and EndocrinologyChildrens Hospital Los Angeles

Natural History of Type 2 Diabetes

GeneticsusceptibilityEnvironmentalfactors

NutritionObesityPhysical inactivity

Hyperinsulinemia HDL-C TriglyceridesAtherosclerosisHypertension

AtherosclerosisHyperglycemiaHypertension

RetinopathyNephropathyNeuropathy

BlindnessRenal failureCHDAmputation

Onset ofdiabetes Complications

Disability

DeathOngoing hyperglycemiaIGTInsulin resistance

New-onset NIDDM diagnosed among youth ages 8-21 years at Arkansas Children’s Hospital

21

3

1

67

13

17

0

2

4

6

8

10

12

14

16

18

1988 1989 1990 1991 1992 1993 1994 1995

Year of Diagnosis

Num

ber

of P

atie

nts

Scott et al. Pediatr. 1997

Characteristics - Case Series of 578 Patients at Diagnosis with Type 2

Fagot-Camgagna et al J Pediatr 2000

• Mean Age 12-14 years

• Girls > Boys 1.7:1

• Obese BMI >85th %

• Minority Groups 94%

• Strong Family History 74-100%

• Acanthosis Nigricans 56-92%

Characteristics Case Series of 578 Patients at Diagnosis

• Diagnosis made by Symptoms, not Screening• HbA1c 10-13%• Weight loss 19-62%• Glucose in urine 95%• Ketosis 16-79% • DKA 5-10%• Absence of Islet Autoimmunity >85-95%• Preservation of C-peptide >0.8-1nmol/l

Campagna et al J Pediatr 2000

Acanthosis Nigricans

TREATMENT OF

TYPE 2 DIABETES IN

CHILDREN AND TEENS

Treatment Protocols Multidisciplinary Team

• Set Glycemic Targets

• Diabetes Education – Patient and Family

• Role of Intensive Lifestyle

• Pharmacotherapy

• Regimens Advocated– What are the outcome measures to

assess efficacy, effectiveness

TREATMENT GOALS

• Glucose control, HbA1c <7%– Eliminate symptoms of hyperglycemia – Reduce microvascular complications

• Maintenance of reasonable body weight

• Improve cardiovascular risk factors

• Improvement in physical and emotional well-being

Glycemic Targets*

ParameterParameter NormalNormal GoalGoal Action SuggestedAction Suggested

Fasting (or Fasting (or Preprandial) Preprandial)

GlucoseGlucose<100<100 < 120< 120 <80 or >140<80 or >140

PostprandialPostprandialGlucoseGlucose

<140<140 <180<180 >180>180

Bedtime GlucoseBedtime Glucose <120<120 90 to 15090 to 150 <90 or >160<90 or >160

HbAHbA1c1c(DCCT Method)(DCCT Method) <6%<6% <7%<7% >8%>8%

Glucose values are plasma (mg/mL).Glucose values are plasma (mg/mL).

*Combined WHO recommendations and ADA guidelines.DCCT=Diabetes Control and Complications Trial.

ROLE OF FAMILY IN MANAGEMENT

• African-American Family Study• Group 1, direct family supervision• Group 2, no direct supervision• Group 1 ending HbA1c = 7.1+ 0.8%• Group 2 ending HbA1c = 12.3 + 0.6%• P=<0.0005

Bradshaw, J Pediatr Endocrinol Meta 15, 2002

Intensive Lifestyle Rationale

• Lifestyle and environment are risk factors • Consensus - modifying lifestyle primary goal• Might lead to remission

BUT• Mixed results in adult studies

– More or less effective in kids?

• Labor intensive and expensive – Do they work in the “real world” and school ?

HbA1c Statistics for CHLA 2002Type 2:

n Average ± SD

All patients 100 8.0 ± 2.3

Males 44 8.3 ± 2.2

Females 56 7.8 ± 2.3

Age < 5 years 0

Age 5-10 years 3 6.0 ± 0.9

Age 11-16 years 71 8.0 ± 2.2

Age >16 years 26 8.3 ± 2.5

Mechanisms To Lower Glucose Stimulate

insulin secretion

muscle glucose uptake

Correct insulin

deficiency

glucose production

Retard carbohydrate

absorption

Insulin or insulin analogues X

Sulfonylureas X

Thiazolidinediones X X

Biguanides X X

Repaglanide X

Alpha-glucosidase inhibitors X

TYPE 2 DIABETES . . . A PROGRESSIVE DISEASE

Progressive Decline of -Cell Function in the UKPDS

0

20

40

60

80

100

10 9 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6Years

-C

ell F

un

cti

on

(%

)

Adapted from UK Prospective Diabetes Study (UKPDS) Group. Diabetes. 1995; 44:1249-1258.

6-4

Treatment of Type 2 DM in Children

diet/exercisemonthly review x 3 mo

HbA1c <7%

FPG <120 mg/dl

continue

HbA1c>7%, FPG>120

metforminHbA1c>7% FPG>120

add sulfonylurea? TZD?

add insulin

DiagnosisDiagnosisAsymptomatic

Start with insulin and diet, exercise

Diet and exercise

Monthly review, A1c q 3 m

>7%>7%

Add metformin

Attempt toWean insulin

Add sulfonylureaSilverstein, RosenbloomJ Pediatr Endcrinol Metab, 13,2000

BG 250 mg/dlBG 250 mg/dl

Add Insulin

<7%<7%

>7%>7%

>7%>7%

SStudies to tudies to TTreat reat OOr r PPrevent revent PPediatric ediatric TType ype 22

DDiabetesiabetes((STOPP-T2DSTOPP-T2D))

The TODAY TrialThe TODAY Trial

STOPP-T2 TREATMENTPRIMARY AIM

To compare the efficacy of 3 treatment regimens– Metformin– Metformin + lifestyle– Metformin + TZD

On Time to Treatment Failure and on Glycemic Control

Outcome Measures• Glycemic Controls

• Insulin Sensitivity and Secretion

• Body Composition

• Fitness and Physical Activity

• Nutrition

• Microvascular complications

• CVD Risk

• Quality of Life

• Cost

How Do We Differentiate

Type 1 Diabetes from Type 2 Diabetes

Differentiation Between Type 1 and 2

• 48 with type 2 vs 39 with type 1

• Type 2

– Ethnicity, 1st degree relative, BMI>24, +C-peptide, acanthosis

Type 2 Type 1

DKA 33% 53%

C-peptide 2.2+2.2 ug/l 1.8+3.5 ug/l

Abs 8.1% ICA

30% GAD 35%IAA

Hathout et al Pediatrics 107e102,June,2001

Barriers to Accurate Classification

• 20-25% newly diagnosed TIDM obese

• > 15% of minority populations have FH T2DM baseline

• 3X increase FH of T2DM in patients with T1DM

• Overlap C-P measurements at onset & first year or so

• > 30% T2DM with ketosis at onset

CO-MORBIDITIES

ComorbiditiesPercent of Patients >8 years with

BP >97th PercentileType 1 Type 2

Systolic 3.4% 20.1%

Diastolic 1% 6%

Outcomes in First Nation Youth in Canada

Dean, et al, Diabetes, 2002

Young adults, 18-33 years of age, Diagnosed before age 17 years

Due to poor glycemic control 9% mortality rate 6.3% dialysis rate38% pregnancy loss

During 10-15 year observation period

100 PIMA CHILDREN & ADOLESCENTS

AT DIAGNOSIS

7% high cholesterol (>200 mg/dL)

18% hypertension (BP>140/90)

22% microalbuminuria (alb/Cr >30)

AFTER TEN YEARS [mean HbA1c 12%]

60% microalbuminuria

17% macroalbuminuria (alb/Cr >300)

Screening

Of Children and Youth for

Type 2 Diabetes

and Prediabetes

Who Should be Tested for Type 2- Case Finding

ADA/AAP RecommendationsDiabetes Care 23:2000

• Age > 10 years or onset of puberty• BMI > 85th%• First or Second Degree Relative• Race/Ethnic Group• Signs of Insulin Resistance –

– Acanthosis nigricans– Hypertension– PCOS– Dyslipidemia

Tests To Diagnose Diabetes

• FPG – Preferred • 2-h OGTT - Preferred• 2-h Postprandial or random post meal• HbA1c

• In context of health visit• Every 2 years

ADA/NIDDK Screening Recommendations For Prediabetes in

AdultsDiabetes Care, 25:2002

• Case Finding

• Test: – >45 years, BMI > 25 kg/m2 – <45 years with + FH, GDM, baby > 9 lbs,

dyslipidemia, hypertension, non-Caucasian – At 3 yr intervals, if negative

ADA/NIDDK Recommendations In Adults

Diabetes Care, 25:2002

• How to Test: – In context of health care visit

– FPG, 2-h OGTT

• Intervention: – Prediabetes counsel for weight loss and PA, Follow-

up counseling

– Monitor for DM q 1-2 years, CVD risk factors

– Avoid drug therapy

PreventionREDUCTION

In Obesity

Pharmacotherapyvs

Lifestyle

Agents that can be Used for Obesity

Agents that can be used for Obesity• Sibutramine

– Blocks central reuptake of norepinephrine, serotonin

– Suppresses appetite

– Increases energy expenditure

• Orlistat

– Inhibits pancreatic lipase

– Increases fecal fat loss

Prevention with Metformin

• Six month study in 29 obese, hyperinsulinemic adolescents, positive family history

• Randomized, double-blinded, placebo-controlled

• Freemark, Bursey, SPR, Boston, 2000. Freemark, Bursey Pediatrics 107:2001

Prevention with MetforminMetformin Placebo

P value

BMI 1.3% <0.05 2.3%

FPG 84.8 to

74.8

77.2 to

82.6

Fasting Insulin

31.3 to

19.3

<0.02 No change

No change

Insulin sensitivity

HbA1c

Lipids

Glucose Disposal

The Diabetes Prevention Program

A Randomized Clinical Trial to Prevent Type 2 Diabetes

in Persons at High Risk

The DPP Research Group

0 1 2 3 4

0

10

20

30

40Placebo (n=1082)Metformin (n=1073, p<0.001 vs. Plac)Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )

Percent developing diabetes

All participants

All participants

Years from randomization

Cu

mu

lativ

e in

cid

enc

e (

%)

Placebo Metformin

Lifestyle

Type 2 Diabetes PreventionType 2 Diabetes PreventionRisk reductionRisk reduction31% by metformin31% by metformin58% by lifestyle58% by lifestyle

The DPP Research Group, NEJM 346:393-403, 2002

Prevention of Type 2 with Lifestyle Intervention Tuomilehto, et al , Turku ADA 2000

• Intervention – 523 IGT, mean age 55, BMI 31

• Diet, exercise, frequent visits vs advice yearly

Weight

Loss

1st Year 2nd Year 4th Year

Intervention -4.2 -3.5 26 cases

10%

Control -0.8 -0.8 57 Cases

22%

Incidence of diabetes reduced – 58% (p=.0003)

PUBLIC HEALTH

RESPONSE

National Comprehensive Obesity-Diabesity Prevention Strategy

• Educational

• Behavioral

• Environmental

– Increase understanding and awareness– Change behavior– Ability to make the right choices

Key Targets

• Communities– Joint use schools, parks, libraries, organizations

• Workplace– Wellness programs, insurance,

• Government– Funding, policies

• Individual/Family– Behavior change

• Health Sector• Schools

– PE, nutrition services, health education

Breast Feeding

• Decrease in obesity• In Pima population, dose related decrease in

risk of type 2 with breast feeding• Most significant with exclusive breast feeding• Breast feeding regimen

– exclusive for 6 months– total for 12 months

Simmons D, Lancet 97, 157

Breast Feeding

• Native Canadian Population

• 4-Fold decrease in type 2 diabetes in adolescents

• Exclusive Breast Feeding

Young et al, Arch Pediatr Adolesc Med, 2002

Promotion of: RETURN TO ENERGY BALANCE

• Water intake

• Fruits and Vegetables

• Limiting Juice

• Avoiding Sugar Containing Sodas

• Decreasing Saturated Fat

• Near Eliminating High Density/Low Nutrient Foods

School Could Be A Setting For

• Public education

• Epidemiological studies

• Early intervention with at-risk groups

• Screening and early detection

SStudies to tudies to TTreat reat OOr r PPrevent revent PPediatric ediatric TType ype 22 DDiabetesiabetes((STOPP-T2DSTOPP-T2D))

• Population based trial

• Increase physical activity

• Nutrition promotion

• Social Marketing, Behavioral Component

• Biologic outcome measures – primary– Reduction in risk factors

CONCLUSIONS

• Why are Children Obese– Too much food, no activity

• Insulin Resistance and Relative Beta Cell Failure– Intrauterine environment, postnatal feeding

• Type 2 Diabetes– Symptomatic presentation, treatment algorithms,

screening

• Public Health/Advocacy – School policies, legislative agenda

– Concentrate on pre and perinatal periods