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Francine Ratner Kaufman, M.D. Distinguished Professor of Pediatrics The Keck School of Medicine of USC Head, Center for Diabetes and Endocrinology Childrens 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
FCP > 2.9 ng/ml + Ab Hybrid FCP > 2.9 ng/ml - Ab Type 2 FCP < 0.8 ng/ml + Ab Type 1a

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

Is Type 2 Diabetes An Epidemic? Little Rock, Cincinnati, San Antonio 0 5 10 15 20 25 30 35 % with type 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 Diabetes Genetic susceptibility Environmental factors Atherosclerosis Hyperglycemia Hypertension Retinopathy Nephropathy Neuropathy Blindness Renal failure CHD Amputation Onset of diabetes Complications Disability Death Ongoing hyperglycemia PRE Obesity Insulin resistance Risk for Disease Metabolic Syndrome

Pre-diabetes (IGT) and T2D 0% 33% 15 subjects Weninger et al, 1980 4% 21% 112 multi-ethnic teens (>95 th %ile) Sinha et al, 2002 0% 28% 150 Hispanic +FH (8-13 years >85 th %ile) Goran et al, 2004 0% 25% 55 multi-ethnic youth (>95 th %ile) Sinha et al, 2002 6% 17% 66 multi-ethnic youth (4-16 years) Paulsen et al, 1968 T2D IGT Overweight Sample

OGTT Feasibility Study Pre-diabetes and Diabetes by ADA Cut-offs 0.1% 0.0% 0.4% Diabetes (  126) 0.1% 2.0% 39.7% Pre-diabetes (100-125) 0.0% 0.2% 57.6% Normal (< 100) Diabetes (  200) Pre-diabetes (140-199) Normal (< 140) Fasting glucose 2-hour glucose

Years from Clinical Diagnosis B-cell Function (%) UKPDS Data Type 2 Diabetes Progressive Pancreatic B-cell Failure ? Curve for Youth Prevention and Early Treatment

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

Insulin Resistance Age Puberty Type 2 Diabetes Prediabetes Beta Cell Defect Obesity BP, Lipids Gender – Girls Polycystic ovary syndrome Genetics Ethnicity Sedentary Lifestyle Beta Cell Defect

Insulin Resistance Autoimmunity Type 2 Diabetes Prediabetes Beta Cell Defect Genetic Defect Intrauterine IUGR, DM Glucose toxicity Beta Cell Defect Fat cell toxicity

Question What distinguishes type 1 from type 2 diabetes in youth?

Type 1 Versus type 2 Diabetes in youth? Kaufman, Endocrinol Meta Clinics N Am, 34;659-676: 2005 Antibody Ethnicity C-peptide Comorbid Relative with DM DKA Course Weight 15% (reported as high as 30%) NA, AA, HA, Asian, Pacific Islander 85% Whites predominate Normal or increased C-peptide can be preserved at DX Increase in polycystic ovary syndrome Acanthosis nigricans Thyroid, adrenal, vitiligo, celiac 74%-100% - 1 st –2 nd degree with T2DM 5% with T1DM Up to 30% may have with T2DM FH of T2 2-3Xs in person with T1 Ketonuria (33%) Mild DKA (5%-25%) 35%-40% Indolent Virtually none found on screening Rapid From DPT-1 can be indolent Virtually all BMI > 85%th percentile 20% may be overweight / obese T2DM T1DM

Differentiation Between Type 1 and 2
48 with type 2 vs 39 with type 1
Type 2
Ethnicity, 1 st degree relative, BMI>24, +C-peptide, acanthosis
Hathout et al Pediatrics 107e102,June,2001
85% have islet autoimmunity 8.1% ICA 30% GAD 35%IAA Abs 1.8 + 3.5 ug/l 2.2 + 2.2 ug/l C-peptide 53% 33% DKA Type 1 Type 2

Question How Does Type 2 Present in Youth? Is it asymptomatic or symptomatic in youth?

Diagnosis with Type 2 Fagot-Campagna et al J Pediatr 2000
Mean Age 12-14 years
Girls > Boys 1.7:1
Obese BMI >85 th %
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
A1c <7.0 Bed 100-160 FG 80-120 PP 100-160 Goals (Diabetes Care, 2000)

Treatment Issues
Self-monitoring of blood glucose
Fasting and postprandial
Frequency depends on regimen
Medical Nutrition Therapy
Diabetes Education
Involves family
Direct family supervision produces better glycemic control outcomes 1
Lifestyle Coaching
Preconception counseling
Immunizations
Dental care
Smoking and alcohol counseling
1. Bradshaw, J Pediatr Endocrinol Meta 15, 2002
2. Pediatrics 112:2003 Prevention and treatment of type 2 diabetes in children with special emphasis on Native American Youth

Question What are the Treatment Regimens for Youth?

TZD = thiazolidinedione Silverstein JH, Rosenbloom AL. J Pediatr Endcrinol Metab . 2000;13 Suppl 6:1406-1409. Diagnosis Asymptomatic Start with insulin and diet, exercise Diet and exercise Monthly review, A1C q3mo > 7% Add metformin Add metformin Attempt to wean insulin Add insulin, TZD, sulfonylurea BG 250 mg/dL or 12 mmol/L Add 3rd agent < 7% > 7% > 7% < 7%

LWPES Survey 130 Clinical Practices
48% treated with insulin alone
2 injections
44% with oral agents
71% metformin
46% sulfonylurea
9% TZD
4% meglitinide
8% lifestyle

A1c at CHLA 2005 3.31 + 1.8 3.20 + 1.3 Visit Number 5.84 + 4.10 Duration years 13.57 + 4.70 Age years 7.85 + 2.21 8.07 + 1.48 A1c % Type 2 n=276 Type 1 n=1534 Diabetes Type

Intensive Therapy for Diabetes: Reduction in Incidence of Complications *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. T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus . 16%*  52* 41%* Cardiovascular disease – 58% 60% Neuropathy 24% – 33% 70% 54% Nephropathy 17% – 21% 69% 63% Retinopathy 8%  7% 9%  7% 9%  7% A1C T2DM UKPDS T2DM Kumamoto T1DM DCCT

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 Amputations Loss of Sensations Heart disease and strokes Blindness Death

An Answer The Today Trial?

Studies to Treat Or Prevent Pediatric Type 2 Diabetes STOPP-T2D Funded by National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health

STOPP-T2 TREATMENT PRIMARY AIM
To compare the efficacy of 3 treatment regimens
Metformin
Metformin + lifestyle
Metformin + TZD
On Time to Treatment Failure and on Glycemic Control
TODAY

Primary Outcomes
Treatment goal
HbA1c < 6% (glycemic control)
Treatment failure
HbA1c  8.0% over 6 consecutive months
OR
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  85 th 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?
Be Active
Stay at a Healthy Weight
Eat 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 [email_address]

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