Type 2 Diabetes in Children and Adolescents. By: Jennifer Harris November 17, 2005. Outline . Pediatric Obesity – How big is the problem, and why should we care? How does DM2 develop? Clinical Heterogeneity in DM2 – What are the implications? What can we do to stop the epidemic?
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By: Jennifer Harris
November 17, 2005
1999-2002 NHANES (National Health and Nutrition Examination Survey):
This is not just an American trend. Other countries, like Japan, New Zealand, and Thailand, are also seeing increases in childhood development of DM2.
Annual obesity-related hospital costs in 6-17 year olds = $127 million/year, a 3-fold increase in the past 20 years
Wang and Dietz, Pediatrics. 109;E81
Must have at least 3 to diagnose (in children, all adjusted for age and sex):
Weiss, et al. NEJM. 2004;350:2362-74.
McGarry, J.D. “Dysregulation of Fatty Acid Metabolism in the Etiology of Type 2 Diabetes.” Diabetes.
1. Obesity/sedentary lifestyle
3. Family history
a. The Bogalusa Heart Study (Srinivasan, et al. Metabolism. 2003; 52:443-450.) looked at >6500 kids age 4-17, with and without parental DM, from childhood to adulthood.
b. In kids with parental DM:
1. Increased BMI and SBP starting in childhood.
2. Increased fasting insulin, glucose, and insulin resistance index starting in puberty.
3. Increased TGs and LDL, decreased HDL starting in adulthood.
4. Puberty: increased GH/IGF-1 levels cause insulin resistance
a. Insulin-mediated glucose disposal decreased 30% in Tanner Stages 2-4 compared to Stage 1 in some hyperinsulinemic euglycemic clamp studies.
b. Caprio et al. (Journal of Pediatrics. June 1989: 963-967) showed, via a hyperglycemic clamp study, that both early and late responses to hyperglycemia were enhanced during puberty (leading to hyperinsulinemia). This differs from the hyperinsulinemia seen in early DM2, where the early phase release of insulin is impaired, and late phases exhibit a compensatory increased insulin release.
6. Intrauterine factors (GDM, low birth weight, small head circumference)
a. A study in Pima Indians showed that intrauterine factors were separate from family history. Kids born after mom developed DM2 were more likely to get DM than siblings born before mom developed DM2. (Pettitt, et al. Diabetes Care. 1993;16:310-14)
b. LBW: thrifty gene hypothesis. Associated with increased fasting insulin and decreased beta cell function.
Insulin resistance pancreatic insulin secretion increases beta cell failure decompensation clinical DM.
This way of thinking may underemphasize the role of beta cell dysfunction.
There is some evidence that there is beta cell dysfunction present before the onset of impaired glucose tolerance.
It is important to note that just because insulin secretion increases in the early stages of DM2, this doesn’t necessarily mean the beta cells are functioning properly. Late hyperinsulinemia may in fact be a result of inadequate beta cell response to hyperglycemia that is itself a result of early impaired insulin release.
Gerich, J.E. Endocrine Reviews. 1998;19(4): 491-503.
1. Diabetogenic genes: Genes that, if inherited, will cause most people to develop DM. Essential and specific to the development of DM, but may not be enough by themselves to cause DM. Example: mutation in insulin receptor gene that leads to insulin resistance.
2. Diabetes-related genes: Not specific. By themselves, not enough to cause DM. Genetically-determined risk factors. Example: genes that regulate appetite and energy expenditure.
(Not always as easy as it may seem!)
1. Increased incidence of other autoimmune disorders
2. Ususally low insulin/c-peptide levels (may be normal during “honeymoon phase”)
3. Usually non-obese
1. Increased c-peptide levels (may be normal at time of diagnosis)
2. Usually no auto-antibodies (can sometimes see these, however, and this is usually prognostic for a more severe clinical picture/rapid progression)
3. Strong family history of diabetes
4. Usually obese
5. Signs of insulin resistance (HTN, acanthosis, PCOS)
Currently thought to be an effect of IGF-1. At one point was thought to be a result of skin folds rubbing together.
One study cited in The Journal of Pediatrics (2001;138:453-4) showed acanthosis was directly associated with:
1. Increased fasting insulin levels
2. Increased insulin/glucose ratio
3. Increased insulin responses and decreased glucose disposal rates during hyperglycemic clamps
4. These effects seen in patients with acanthosis more than in overweight patients without acanthosis. (However, after adjusting for differences in total body fat, there was no significant difference between overweight patients with and without acanthosis.)
1. AA: decreased hepatic extraction of insulin
2. Hispanic: increased 2nd phase secretion of insulin
HHNK (hyperglycemic hyperosmolar non-ketosis) is a common presentation of DM2 in kids. Fourtner, et al. (Pediatric Diabetes. 2005;6:129-135) conducted a chart review at CHOP, and found that 7/190 patients diagnosed with DM2 presented with HHNK, one of whom subsequently died. HHNK doesn’t seem to be associated with concurrent infections/stresses like commonly seen in adult HHNK.
African American children appear to be more likely to present in DKA than other races/ethnicities, for reasons not fully understood.
MODY (maturity-onset diabetes of the young)
1. nonketotic DM
2. onset usually <25 years old
3. primary defect of beta cell function
4. at least 6 different genes have been implicated
5. can be affected/precipitated by factors affecting insulin sensitivity (puberty, pregnancy, infection)
HPI: polyuria, polydipsia, weight loss
FH: + family history of DM, no family history of autoimmune diseases
VS: 103/53, 79, 37C
Weight=60kg, height=61in; BMI=25 (85th percentile)
PE: + acanthosis, Tanner stage 5
UA: glucose >1000 mg/dl, ketones=40 mg/dl
Serum glucose=726, bicarbonate=21, venous pH=7.37
A1C=8.6%, c-peptide=1.0 ng/ml (nl=0.6-3.2)
Type 1 or Type 2??
1. Glucose 126-200 and A1C <8.5 lifestyle modifications +/- metformin
2. Glucose >200 and A1C >8.5, +/- ketosis insulin
3. Do NOT give metformin if patient is ketotic, because this increases the risk of lactic acidosis.
1. Start with diet and exercise.
2. If goals not met, start monotherapy (usually metformin).
3. If goals still not met, add a second oral agent (sulfonylurea, meglitinide, or a TZD).
4. If goals still not met, start insulin. You should start insulin immediately if the patient presents with DKA.
There are trials currently looking at rosiglitazone, meglitinide, and glucovance in kids. One example is the STOPP-T2D trial (Studies to Treat of Prevent Pediatric Type 2 Diabetes), sponsored by National Institutes of Diabetes, Digestive, and Kidney Diseases
Kids with diagnosis for <2 years are randomized to one of 3 arms:
2. Metformin + Rosiglitazone
3. Metformin + intensive lifestyle program
Failure = A1C >8% for 6 months start glargine insulin
Secondary outcomes to be studied: beta cell function, insulin resistance, body composition, nutrition, physical activity/fitness, CV risk factors, microvascular complications, quality of life, and psychological outcomes.
Guidelines from American Pediatric Surgery Association Clinical Task Force on Bariatric Surgery:
Bottom line: Long term effects on adolescents not known.
Dr. Frank Franklin, UAB
Dr. Amy Potter, Vanderbilt