Francine Ratner Kaufman, MD

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Type 2 Diabetes in Children and Youth
Francine Ratner Kaufman, MD Professor of
Pediatrics The Keck School of Medicine of
USC Head, Center for Diabetes and
Endocrinology Childrens Hospital Los Angeles
Paula Jameson, ARNP, MSN, CDE Nemours Childrens
Clinic Division of Endocrinology
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Natural History of Type 2 Diabetes
Complications
Geneticsusceptibility Environmentalfactors
Onset ofdiabetes
Disability
PRE
Ongoing hyperglycemia
Obesity Insulin resistance
Death
Risk for Disease
Metabolic Syndrome
BlindnessRenal failureCHDAmputation
RetinopathyNephropathyNeuropathy
AtherosclerosisHyperglycemiaHypertension
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Question
What Do We Know About Type 2 Diabetes in Youth?
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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. 200427998-1010
  Centers for Disease Control. Diabetes Fact Sheet.
  2005

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Diabetes Trends Among Adults in the US BRFSS
1990, 1995 and 2001
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Changing Face of Diabetes in Youth in US
35
30
25
20
with type 2
15
10
5
0
87
88
89
90
91
92
93
94
95
96
Cincinnati
Little Rock 8-21 years
San Antonio
Source Fagot-Campagna et al., J Pediatr
136664-672, 2000
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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
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Natural History of Type 2 Diabetes
Complications
Geneticsusceptibility Environmentalfactors
Onset ofdiabetes
Disability
PRE
Ongoing hyperglycemia
Obesity Insulin resistance
Death
Risk for Disease
Metabolic Syndrome
BlindnessRenal failureCHDAmputation
RetinopathyNephropathyNeuropathy
AtherosclerosisHyperglycemiaHypertension
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Type 2 Diabetes Prediabetes Beta Cell Defect
Beta Cell Defect
Age Puberty
Obesity BP, Lipids
InsulinResistance
Genetics Ethnicity
Sedentary Lifestyle
Gender Girls Polycystic ovary syndrome
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Type 2 Diabetes Prediabetes Beta Cell Defect
Autoimmunity
Genetic Defect
Beta Cell Defect
Fat cell toxicity
Intrauterine IUGR, DM
Glucose toxicity
InsulinResistance
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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

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Natural History of Type 2 Diabetes
Complications
Geneticsusceptibility Environmentalfactors
Onset ofdiabetes
Disability
PRE
Ongoing hyperglycemia
Obesity Insulin resistance
Death
Risk for Disease
Metabolic Syndrome
BlindnessRenal failureCHDAmputation
RetinopathyNephropathyNeuropathy
AtherosclerosisHyperglycemiaHypertension
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Pre-diabetes (IGT) and T2D
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Type 2 Diabetes
Progressive Pancreatic B-cell Failure
UKPDS Data
B-cell Function ()
? Curve for Youth
Years from Clinical Diagnosis
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Question
What distinguishes type 1 from type 2 diabetes in
youth?
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Natural History of Type 2 Diabetes
Complications
Geneticsusceptibility Environmentalfactors
Onset ofdiabetes
Disability
PRE
Ongoing hyperglycemia
Obesity Insulin resistance
Death
Risk for Disease
Metabolic Syndrome
BlindnessRenal failureCHDAmputation
RetinopathyNephropathyNeuropathy
AtherosclerosisHyperglycemiaHypertension
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Pediatric Diabetes 2002
Pediatric Diabetes is a DIFFICULT diagnostic
speciality
Childhood obesity
Type 2
Diabetes Syndromes
Monogenic Diabetes
Type 1 diabetes
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Differentiation Between Type 1 and 2

• 48 with type 2 vs 39 with type 1
• Type 2
• Ethnicity, 1st degree relative, BMI24,
  C-peptide, acanthosis

Hathout et al Pediatrics 107e102,June,2001
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Question
How Does Type 2 Present in Youth?
Is it asymptomatic or symptomatic in youth?
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Natural History of Type 2 Diabetes
Complications
Geneticsusceptibility Environmentalfactors
Onset ofdiabetes
Disability
PRE
Ongoing hyperglycemia
Obesity Insulin resistance
Death
Risk for Disease
Metabolic Syndrome
BlindnessRenal failureCHDAmputation
RetinopathyNephropathyNeuropathy
AtherosclerosisHyperglycemiaHypertension
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Diagnosis with Type 2Fagot-Campagna et al J
Pediatr 2000

• Mean Age 12-14 years
• Girls Boys 1.71
• 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

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Question
What Are Treatment Targets in Youth with Type 2
Diabetes?
Are they the same as in adults?
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Natural History of Type 2 Diabetes
Complications
Geneticsusceptibility Environmentalfactors
Onset ofdiabetes
Disability
PRE
Ongoing hyperglycemia
Obesity Insulin resistance
Death
Risk for Disease
Metabolic Syndrome
BlindnessRenal failureCHDAmputation
RetinopathyNephropathyNeuropathy
AtherosclerosisHyperglycemiaHypertension
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TREATMENT GOALS

• Glucose control, HbA1c
• Eliminate symptoms of hyperglycemia
• Maintenance of reasonable body weight
• Improve cardiovascular risk factors
• Reduce microvascular complications
• Improvement in physical and emotional well-being

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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 outcomes1
• Lifestyle Coaching
• Preconception counseling
• Immunizations
• Dental care
• Smoking and alcohol counseling

1. Bradshaw, J Pediatr Endocrinol Meta 15,
2002 2. Pediatrics 1122003 Prevention and
treatment of type 2 diabetes in children with
special emphasis on Native American Youth
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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
• Bradshaw, J Pediatr Endocrinol Meta 15, 2002

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Question
What are the Treatment Regimens for Youth?
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Natural History of Type 2 Diabetes
Complications
Geneticsusceptibility Environmentalfactors
Onset ofdiabetes
Disability
PRE
Ongoing hyperglycemia
Obesity Insulin resistance
Death
Risk for Disease
Metabolic Syndrome
BlindnessRenal failureCHDAmputation
RetinopathyNephropathyNeuropathy
AtherosclerosisHyperglycemiaHypertension
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Diagnosis
Asymptomatic
BG 250 mg/dL or 12 mmol/L
Start with insulin and diet, exercise
Diet and exercise
Monthly review, A1C q3mo
Add metformin Attempt to wean insulin
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Add metformin
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Add insulin, TZD, sulfonylurea
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Add 3rd agent
TZD thiazolidinedione Silverstein JH,
Rosenbloom AL. J Pediatr Endcrinol Metab. 200013
Suppl 61406-1409.
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Metformin improves glycaemia in type 2 diabetic
adolescents
D 3.6 mmol/L (pD 1.2 (pFPG (mmol/L)
HbA1C ()
Jones KL et al. Diabetes Care 2002 25 8994
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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

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Use of Rosiglitazone in T2DM Children
Drug Naive
Prior Therapy
9.2
8.8
9.0
8.6
8.8
8.4
8.2
8.6
MeanHbA1c()
8.0
MeanHbA1c()
8.4
7.8
7.6
8.2
7.4
8.0
7.2
Screen Baseline
7.8
7.0
6.8
7.6
-6
0
4
8
16
24
-6
0
4
8
16
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Visit (weeks)
Visit (weeks)
Screen Baseline

• 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

K. Jones et al, poster 1904-P, 65th ADA
Scientific Sesssions
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Adverse Events Of Interest
K. Jones et al, poster 1904-P, 65th ADA
Scientific Sesssions
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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,

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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

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An Answer
The Today Trial?
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Studies to Treat Or Prevent Pediatric Type 2
DiabetesSTOPP-T2D

• Funded by
• National Institute of Diabetes and Digestive
• and Kidney Diseases
• National Institutes of Health

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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

TODAY
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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

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Outcome Measures (continued)

• Nutrition
• food frequency questionnaire
• Cardiovascular disease risk
• BP, lipids, inflammatory markers, coagulation
  factors
• Microvascular complications
• microalbuminuria, neuropathy
• Quality of life
• Cost

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Inclusion Criteria

• Age 10 to 17 years
• Duration of diabetes
• 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

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Question
What are the Complications Co-Morbidities of
Type 2 in Youth?
Are they the same as in adults?
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Natural History of Type 2 Diabetes
Complications
Geneticsusceptibility Environmentalfactors
Onset ofdiabetes
Disability
PRE
Ongoing hyperglycemia
Obesity Insulin resistance
Death
Risk for Disease
Metabolic Syndrome
BlindnessRenal failureCHDAmputation
RetinopathyNephropathyNeuropathy
AtherosclerosisHyperglycemiaHypertension
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Long term outcome

• Pima Indians - diagnosed
• 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 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

Arslanian S. Hormone Res 2002 57 Suppl 1
19-28 Yokoyama H. Kidney Int 2000 58 302-311
Dean., Diabetes 200251(Suppl 2)A24.
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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 97thile
• 20.1 diastolic 97thile

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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 2621942003

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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

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Thank you

• Fkaufman_at_chla.usc.edu