Type 2 Diabetes in Youth
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
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
% with type 2
Is Type 2 Diabetes An Epidemic?
Little Rock, Cincinnati, San Antonio
35
30
25
20
15
10
5
0
87
88
89
90
91 92 93 94 95
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
J Pediatr 136:664-672, 2000
96
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
Complications
Onset of
diabetes
Disability
P
Obesity Insulin resistance R Ongoing hyperglycemia
Death
E
Risk for Metabolic
Retinopathy Blindness
Disease
Atherosclerosis
Syndrome
Hyperglycemia Nephropathy Renal failure
Neuropathy
CHD
Hypertension
Amputation
Pre-diabetes (IGT) and T2D
Overweight Sample
Paulsen et al, 1968
Weninger et al, 1980
Sinha et al, 2002
Sinha et al, 2002
Goran et al, 2004
IGT
T2D
66 multi-ethnic youth (417%
16 years)
6%
15 subjects
55 multi-ethnic youth
(>95th %ile)
112 multi-ethnic teens
(>95th %ile)
150 Hispanic +FH
(8-13 years >85th %ile)
33%
0%
25%
0%
21%
4%
28%
0%
OGTT Feasibility Study
Pre-diabetes and Diabetes by ADA Cut-offs
Fasting
glucose
Normal
(< 100)
Pre-diabetes
(100-125)
Diabetes
( 126)
2-hour glucose
Normal
(< 140)
Pre-diabetes
(140-199)
Diabetes
( 200)
57.6%
0.2%
0.0%
39.7%
2.0%
0.1%
0.4%
0.0%
0.1%
Type 2 Diabetes
B-cell Function (%)
Progressive Pancreatic B-cell Failure
Prevention and Early Treatment
UKPDS Data
? Curve for Youth
Years from Clinical Diagnosis
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
Type 2 Diabetes
Prediabetes
Beta Cell Defect
Beta Cell Defect
Obesity
BP,
Lipids
Insulin
Resistance
Sedentary
Lifestyle
Age
Puberty
Genetics
Ethnicity
Gender – Girls
Polycystic ovary syndrome
Type 2 Diabetes
Genetic Defect
Prediabetes
Beta Cell Defect
Beta Cell Defect
Intrauterine
IUGR, DM
Insulin
Resistance
Autoimmunity
Fat cell
toxicity
Glucose
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
T1DM
T2DM
Weight
20% may be overweight / obese
Virtually all BMI > 85%th percentile
Course
Rapid
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, celiac
Increase in polycystic ovary syndrome
Acanthosis nigricans
C-peptide
C-peptide can be preserved at DX
Normal or increased
Antibody
85%
15% (reported as high as 30%)
Ethnicity
Whites predominate
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?
Diagnosis with Type 2
Fagot-Campagna et al J Pediatr 2000
•
•
•
•
•
•
Mean Age
Girls > Boys
Obese BMI
Minority Groups
Strong Family History
Acanthosis Nigricans
12-14 years
1.7:1
>85th %
94%
74-100%
56-92%
•Diagnosis made by Symptoms, not Screening
•HbA1c
10-13%
•Weight loss
19-62%
•Glucose in urine
•Ketosis
•DKA
95%
16-79%
5-10%
Question
What Are Treatment Targets in Youth with
Type 2 Diabetes?
Are they the same as in adults?
TREATMENT GOALS
Goals
(Diabetes
Care, 2000)
FG
PP
80-120
100-160
Bed 100-160
• 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
Question
What are the Treatment Regimens for
Youth?
GLP
Diagnosis
BG 250 mg/dL or 12 mmol/L
Start with insulin
and diet, exercise
Asymptomatic
Diet and exercise
<7%
Monthly review, A1C q3mo
Add metformin
Attempt to
wean insulin
>7%
Add metformin
>7%
Add insulin, TZD, sulfonylurea
>7%
Add 3rd agent
TZD = thiazolidinedione
Silverstein JH, Rosenbloom AL.
J Pediatr Endcrinol Metab. 2000;13 Suppl 6:1406-1409.
<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
Diabetes
Type
Type 1
Type 2
A1c %
n=1534
8.07 + 1.48
n=276
7.85 + 2.21
Age
13.57 + 4.70
years
Duration
5.84 + 4.10
years
Visit
Number
3.20 + 1.3
3.31 + 1.8
Intensive Therapy for Diabetes:
Reduction in Incidence of Complications
A1C
Retinopathy
Nephropathy
Neuropathy
Cardiovascular
disease
T1DM
DCCT
T2DM
Kumamoto
T2DM
UKPDS
9%  7%
63%
54%
9%  7%
69%
70%
8%  7%
17%–21%
24%–33%
60%
41%*
58%
52*
–
16%*
T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.
*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.
Long term outcome
• 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
Arslanian S. Hormone Res 2002; 57 Suppl 1: 19-28
Dean., Diabetes 2002;51(Suppl 2):A24.
Amputations
Loss of Sensations
Heart disease
and strokes
Blindness
Death
Kidney failure
Uncontrolled diabetes
can lead to…
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
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  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?
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
Fkaufman@chla.usc.edu