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

Type 2 Diabetes in Youth

Question

What Do We Know About Type 2 Diabetes in Youth?

Prevalence of Diabetes and IFG in US Adolescents – NHANES 1999-2002

• Type 2 Diabetes– 0.5% of adolescents have diabetes– 71% type 1 and 29% type 2

• Determined by insulin use vs no insulin use

– 39,005 US teens with T2D

• Impaired Fasting Glucose– 11% had IFG – 2,769,736 teens with IFG

• Diabetes Increased 41% from 4.9 to 6.9/1000 from 1997 to 2003 - adults

Duncan, Arch Pediatr Adolesc Med 2006;160:523; Geiss, Am J Prevent Med 2006;30:371

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

Controversies as to the Nature of this Epidemic

• Difficult to recruit for the TODAY trial• 13 centers across the country

• Presence of antibodies

• The SEARCH Trial • 19,000 new patients with T1D

• 4,100 new patients with T2D

Type 1a + Ab FCP < 0.8 ng/ml

Type 2 - Ab FCP > 2.9 ng/ml

Hybrid + Ab FCP > 2.9 ng/ml

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

Is Type 2 Diabetes An Epidemic?Is Type 2 Diabetes An Epidemic?Little Rock, Cincinnati, San AntonioLittle Rock, Cincinnati, San Antonio

0

5

10

15

20

25

30

35%

wit

h t

yp

e 2

87 88 89 90 91 92 93 94 95 96

J Pediatr 136:664-672, 2000

Ten-fold increase 0.7 vs 7.2/100000

8% to 43% of all new cases of diabetes in youth in US depending on ethnicity

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

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

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%

OGTT Feasibility StudyPre-diabetes and Diabetes by ADA Cut-offs

Fasting glucose

2-hour glucose

Normal

(< 140)

Pre-diabetes

(140-199)

Diabetes

( 200)

Normal

(< 100)57.6% 0.2% 0.0%

Pre-diabetes

(100-125)39.7% 2.0% 0.1%

Diabetes

( 126)0.4% 0.0% 0.1%

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

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

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

What distinguishes type 1 from type 2 diabetes in youth?

T1DM T2DM

Weight 20% may be overweight / obese Virtually all BMI > 85%th percentile

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 30% may have with T2DM

FH of T2 2-3Xs in person with T1

74%-100% - 1st –2nd degree with T2DM

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

Acanthosis nigricans

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

Antibody

Ethnicity

85%

Whites predominate

15% (reported as high as 30%)

NA, AA, HA, Asian, Pacific Islander

Type 1 Versus type 2 Diabetes in youth? Kaufman,Endocrinol Meta Clinics N Am, 34;659-676: 2005

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?

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?

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

Question

What are the Treatment Regimens for Youth?

GLP

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%

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

Diabetes

Type

Type 1

n=1534

Type 2

n=276

A1c % 8.07 + 1.48 7.85 + 2.21

Age years

13.57 + 4.70

Duration years

5.84 + 4.10

Visit Number

3.20 + 1.3 3.31 + 1.8

A1c at CHLA 2005

*Not statistically significant due to small number of events.†Showed statistical significance in subsequent epidemiologic analysis.DCCT Research Group. N Engl J Med. 1993;329:977-986; Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28:103-117; UKPDS 33: Lancet. 1998;352: 837-853; Stratton IM, et al. Brit Med J. 2000;321:405-412.

Intensive Therapy for Diabetes:Reduction in Incidence of Complications

T1DM DCCT

T2DMKumamoto

T2DMUKPDS

A1C 9% 7% 9% 7% 8% 7%

Retinopathy 63% 69% 17%–21%

Nephropathy 54% 70% 24%–33%

Neuropathy 60% 58% –

Cardiovascular disease

41%* 52* 16%*

T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.

Long term outcome

Arslanian S. Hormone Res 2002; 57 Suppl 1: 19-28 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

• 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

Uncontrolled diabetes can lead to…

Kidney failure

AmputationsLoss of Sensations

Heart disease and strokes

Blindness

Death

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

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

Primary Outcomes

• Treatment goal – HbA1c < 6% (glycemic control)

• Treatment failure– HbA1c 8.0% over 6 consecutive

monthsOR

– Inability to wean from temporary insulin therapy due to metabolic decompensation

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

National Diabetes Education Program’s Tip Sheets for Kids with Type 2

• What is Diabetes?What is Diabetes?• Be ActiveBe Active• Stay at a Healthy WeightStay at a Healthy Weight• Eat Healthy FoodsEat Healthy Foods

                        

Helping the Student with Diabetes Succeed

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

Fkaufman@chla.usc.edu