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
Nov 18, 2014
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
05
101520253035
% w
ith
type
2
87 88 89 90 91 92 93 94 95 96
J Pediatr 136:664-672, 2000
Ten-fold increase 0.7 vs 7.2/1000008% 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
Geneticsusceptibility Environmentalfactors
AtherosclerosisHyperglycemiaHypertension
RetinopathyNephropathyNeuropathy
BlindnessRenal failureCHDAmputation
Onset ofdiabetes
Complications
Disability
DeathOngoing hyperglycemiaPRE
Obesity Insulin resistanceRisk forDisease
MetabolicSyndrome
Pre-diabetes (IGT) and T2DOverweight Sample IGT T2D
Paulsen et al, 1968 66 multi-ethnic youth (4-16 years) 17% 6%
Weninger et al, 1980 15 subjects 33% 0%
Sinha et al, 2002 55 multi-ethnic youth (>95th %ile) 25% 0%
Sinha et al, 2002 112 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
AgeAgePubertyPuberty
Type 2 DiabetesType 2 Diabetes
PrediabetesPrediabetes
Beta Cell DefectBeta Cell Defect
ObesityObesityBP,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 GlucoseGlucose
toxicitytoxicity
Beta Cell DefectFat 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
CourseRapidFrom DPT-1 can be indolent
IndolentVirtually 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 T2DMFH of T2 2-3Xs in person with T1
74%-100% - 1st –2nd degree with T2DM
Comorbid Thyroid, adrenal, vitiligo, celiacIncrease in polycystic ovary syndromeAcanthosis 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 80-120PP 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
DiabetesType
Type 1
n=1534
Type 2
n=276A1c % 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