Francine Ratner Kaufman, MD Professor of Pediatrics The Keck School of Medicine of USC Head, Center...

Francine Ratner Kaufman, MDProfessor of PediatricsThe Keck School of Medicine of USCHead, Center for Diabetes and EndocrinologyChildrens Hospital Los Angeles

Type 2 Diabetes in Children and Youth

Paula Jameson, ARNP, MSN, CDE

Nemours Children’s ClinicDivision of Endocrinology

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Geneticsusceptibility Environmentalfactors

AtherosclerosisHyperglycemiaHypertension

RetinopathyNephropathyNeuropathy

BlindnessRenal failureCHDAmputation

Onset ofdiabetes

Complications

Disability

DeathOngoing hyperglycemiaPRE

Obesity Insulin resistance

Risk forDisease

MetabolicSyndrome

Question

What Do We Know About Type 2 Diabetes in Youth?

Is it an epidemic?

• The incidence is increasing and probably underestimated– Population based estimates indicate an ~10-fold

increase in incident cases over the past 10-15 years– 8% to 43% of all new cases of diabetes in the United

States depending on ethnicity – The SEARCH Trial– What about prevalence??

Bloomgarden ZT. Diabetes Care. 2004;27:998-1010 Centers for Disease Control. Diabetes Fact Sheet. 2005

Diabetes Trends Among Adults in the US BRFSS 1990, 1995 and 2001

Changing Face of Diabetes in Youth Changing Face of Diabetes in Youth in USin US

0

5

10

15

20

25

30

35%

wit

h t

yp

e 2

87 88 89 90 91 92 93 94 95 96

Cincinnati <19 years Little Rock 8-21 yearsSan Antonio <19 years

Source: Fagot-Campagna et al., J Pediatr 136:664-672, 2000

Question

Is the Pathophysiology the Same as in Adults?

Associated with significant ß-cell failure as well as insulin resistance

Occurs at the time of intense insulin resistance due to puberty






Onset ofdiabetes

Complications

Disability



Risk forDisease

MetabolicSyndrome

InsulinInsulinResistanceResistance

AgeAge

PubertyPuberty

Type 2 DiabetesType 2 Diabetes

PrediabetesPrediabetes

Beta Cell DefectBeta Cell Defect

ObesityObesity

BP,BP,

LipidsLipids

Gender – Girls Gender – Girls Polycystic ovary syndromePolycystic ovary syndrome

GeneticsGeneticsEthnicityEthnicity

Sedentary Sedentary LifestyleLifestyle

Beta Cell Defect

InsulinInsulinResistanceResistance

AutoimmunityAutoimmunity

Type 2 DiabetesType 2 Diabetes

PrediabetesPrediabetes

Beta Cell DefectBeta Cell Defect

Genetic DefectGenetic Defect

Intrauterine Intrauterine

IUGR, DMIUGR, DM GlucoseGlucosetoxicitytoxicity

Beta Cell Defect

Fat cellFat cell toxicitytoxicity

Question

Is the Presentation the Same as in Adults?

Does not appear to be preceded by long asymptomatic period

Do not find undiagnosed cases on screening






Onset ofdiabetes

Complications

Disability



Risk forDisease

MetabolicSyndrome

Pre-diabetes (IGT) and T2DOverweight Sample IGT T2D

Paulsen et al, 196866 multi-ethnic youth (4-

16 years)17% 6%

Weninger et al, 1980 15 subjects 33% 0%

Sinha et al, 200255 multi-ethnic youth

(>95th %ile)25% 0%

Sinha et al, 2002112 multi-ethnic teens

(>95th %ile)21% 4%

Goran et al, 2004150 Hispanic +FH

(8-13 years >85th %ile)28% 0%

Years from Clinical Diagnosis

B-c

ell F

unct

ion

(%)

UKPDS Data

Type 2 DiabetesProgressive Pancreatic B-cell Failure

Prevention and Early Treatment

? Curve for Youth

Question

What distinguishes type 1 from type 2 diabetes in youth?






Onset ofdiabetes

Complications

Disability



Risk forDisease

MetabolicSyndrome

Pediatric Diabetes 2002

Type 1 diabetes

Childhood obesity

Type 2

Monogenic Diabetes

Diabetes +

Syndromes

“Pediatric Diabetes is a DIFFICULT diagnostic speciality”

T1DM T2DM

Weight 20% may be obese All > 85% overweight

CourseRapid

From DPT-1 can be indolent

Indolent

Virtually none found on screening

DKA 35%-40%Ketonuria (33%)

Mild DKA (5%-25%)

Relative with DM

5% with T1DM

Up to 20% may have with T2DM74%-100% with T2DM

Comorbid thyroid, adrenal, vitiligo, celiacIncrease in polycystic ovary syndrome

Acanthosis nigricans (90%)

C-peptide C-peptide can be preserved at DX Normal or increased

Antibody

Ethnicity

85%

Whites predominate

15%

NA, AA, HA, Asian, Pacific Islander

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

85% have islet autoimmunity

Hathout et al Pediatrics 107e102,June,2001

Question

How Does Type 2 Present in Youth?

Is it asymptomatic or symptomatic in youth?






Onset ofdiabetes

Complications

Disability



Risk forDisease

MetabolicSyndrome

Diagnosis with Type 2Fagot-Campagna 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%

•Diagnosis made by Symptoms, not Screening

•HbA1c 10-13%

•Weight loss 19-62%

•Glucose in urine 95%

•Ketosis 16-79%

•DKA 5-10%

Question

What Are Treatment Targets in Youth with Type 2 Diabetes?

Are they the same as in adults?






Onset ofdiabetes

Complications

Disability



Risk forDisease

MetabolicSyndrome

TREATMENT GOALS

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

• Maintenance of reasonable body weight

• Improve cardiovascular risk factors

• Reduce microvascular complications

• Improvement in physical and emotional well-being

Goals Goals (Diabetes (Diabetes

Care, 2000)Care, 2000)

FG 80-120FG 80-120

PP 100-160PP 100-160

Bed 100-160Bed 100-160

A1c <7.0A1c <7.0

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

Question

What are the Treatment Regimens for Youth?






Onset ofdiabetes

Complications

Disability



Risk forDisease

MetabolicSyndrome

TZD = thiazolidinedioneSilverstein JH, Rosenbloom AL.J Pediatr Endcrinol Metab. 2000;13 Suppl 6:1406-1409.

DiagnosisDiagnosisAsymptomatic

Start with insulin and diet, exercise

Diet and exercise

Monthly review, A1C q3mo

>>7%7%

Add metformin

Add metforminAttempt to

wean insulin

Add insulin, TZD, sulfonylurea

BG 250 mg/dL or 12 mmol/LBG 250 mg/dL or 12 mmol/L

Add 3rd agent

<<7%7%

>>7%7%

>>7%7%

<<7%7%

Metformin improves glycaemia in type 2 diabetic adolescents

9.0

10.7

7.0

11.5

6

7

8

9

10

11

12

Metformin Placebo

FP

G (

mm

ol/L

) 8.2

8.9

7.2

8.9

5

6

7

8

9

Metformin Placebo

Hb

A1C

(%

)

–3.6 mmol/L

(p<0.001)

–1.2% (p<0.001)

Jones KL et al. Diabetes Care 2002; 25: 89–94

Baseline Last double-blind measurement

Metformin is well tolerated in pediatric subjects

• Obese nondiabetic adolescents

– Transient abdominal discomfort or diarrhea in21% on metformin vs. 6% on placebo

– Nausea in 6% on metformin vs. 0% on placebo

• Type 2 diabetic adolescents

– Abdominal pain in 25% on metformin vs. 12% on placebo

– Diarrhea 17% on metformin vs. 10% on placebo

• No treatment withdrawals for drug-related gastrointestinal side-effects in either trial

Use of Rosiglitazone in T2DM Children

Drug Naive Prior Therapy

• More homogeneous response throughout study

• Both groups well matched at screen and baseline

• Both groups behaved similarly

• Increase in HbA1c at all visits

• No improvement in HbA1c from screening

Visit (weeks)

-6 0 4 8 16 24

MeanHbA1c

(%)

6.8

7.0

7.2

7.4

7.6

7.8

8.0

8.2

8.4

8.6

8.8

Metformin (N=50)

Rosiglitazone (N=55)

Error Bar = SE

Screen Baseline

Visit (weeks)

-6 0 4 8 16 24

7.6

7.8

8.0

8.2

8.4

8.6

8.8

9.0

9.2

Screen Baseline

MeanHbA1c

(%)

Metformin (N=48)

Rosiglitazone (N=42)

Error Bar = SE

K. Jones et al, poster 1904-P, 65th ADA Scientific Sesssions

Adverse Events Of Interest

Metformin Rosiglitazone

Any GI adverse event 24 14

Diarrhea 13 1

Nausea 11 4

Vomiting 9 3

Anemia 1 0

Edema 0 1

Weight gain 0 2

Elevated liver function test 2 1

K. Jones et al, poster 1904-P, 65th ADA Scientific Sesssions

Glimepiride vs. Metformin as Monotherapy in Pediatric Subjects with T2DM: A Single

Blind Comparison Study.

– 26 week randomized, single-blind, parallel-group, forced-titration study to evaluate the efficacy and safety of GLIM and MET in subjects age 9-17 yrs inadequately controlled with diet/exercise and/or failed oral monotherapy

– Reduction in A1C and SMBG levels similar between groups

– GLIM and MET have comparable safety profiles

•Gottschalk M, Danne T, et al •Abstract 264-OR (ADA Oral Presentation,

LWPES Survey130 Clinical Practices

• 48% treated with insulin alone– 2 injections

• 44% with oral agents– 71% metformin– 46% sulfonylurea– 9% TZD– 4% meglitinide

• 8% lifestyle

An Answer

The Today Trial?

Studies to Treat Or Prevent Pediatric Type 2 Diabetes

STOPP-T2DFunded by

National Institute of Diabetes and Digestive and Kidney Diseases

National Institutes of Health

http://www.niddk.nih.gov/resources/nihlogo.htm

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

http://www.niddk.nih.gov/resources/nihlogo.htm

Outcome Measures• Glycemia

– HbA1c, fasting and postprandial glucose by home monitoring

• Insulin sensitivity and secretion – OGTT, HOMA, QUICKI, proinsulin, C-peptide

• Body composition – BMI, DEXA, waist circumference, abdominal height

• Fitness and physical activity – PDPAR, PWC 170, accelerometer

Outcome Measures (continued)

• Nutrition – food frequency questionnaire

• Cardiovascular disease risk– BP, lipids, inflammatory markers, coagulation factors

• Microvascular complications – microalbuminuria, neuropathy

• Quality of life• Cost

Inclusion Criteria• Age 10 to 17 years

• Duration of diabetes < 2 years

• BMI 85th percentile

• Adult involved in the daily activities of the child agrees to participate in the intervention

• Absence of pancreatic autoimmunity

• Fasting C-peptide > 0.6 mmol/L

• Fluency in English or Spanish

Question

What are the Complications & Co-Morbidities of Type 2 in Youth?

Are they the same as in adults?






Onset ofdiabetes

Complications

Disability



Risk forDisease

MetabolicSyndrome

Long term outcome

Arslanian S. Hormone Res 2002; 57 Suppl 1: 19-28 Yokoyama H. Kidney Int 2000; 58: 302-311 Dean., Diabetes 2002;51(Suppl 2):A24.

• Pima Indians - diagnosed < 20 years of age –22% had microalbuminuria at diagnosis–Increased to 60% at 20-29 years of age

•Japan -School Children•Retinopathy

•36% had incipient retinopathy at diagnosis•Increased to 39% at 2 years’ follow-up

•Young Diagnosed Patients•44% diagnosed at <30 years of age had nephropathy 25 years later

• Indigenous Canadians- mean age 23 yrs, 9 yrs duration of diabetes•HbA1c 10.9%

•67% poor glycemic control •45% hypertension requiring treatment•35% microalbuminuria (6% required dialysis) •38% pregnancy loss •9% mortality

Are there specific lipid and BP abnormalities documented in children

with T2DM?• Lipids

– Same as in adults– increased TG, slight elevation LDL, decreased

HDL– Added risk factor of obesity and metabolic

syndrome

• BP (CHLA)– 3.4% systolic > 97th%ile– 20.1% diastolic > 97th%ile

Management of Dyslipidemia in Children and Adolescents with

Diabetes• A consensus panel – In the absence of data,

get experts to give an opinion

• Consensus panel members – met July 2002

• Representing Pediatric Endocrinology, Cardiology and Nephrology– Kaufman FR, Arslanian S, Berenson G, Clark

NG, Gidding S, Jones KL, Lauer R, Schieken R, Sinaiko AR

Diabetes Care 26:2194;2003

Conclusion• Increased incidence• Difficult to distinguish from type 1• Occurs at the time of intense insulin resistance due

to puberty• Does not appear to be preceded by long

asymptomatic period• More insulin deficiency and requirement for

exogenous insulin early• Safety and efficacy of therapeutic agents• Rapid progression of co-morbidities and

complications

Thank you

[email protected]

Francine Ratner Kaufman, MD Professor of Pediatrics The Keck School of Medicine of USC Head, Center...

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