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From Clinical Pediatrics, presented by the American Academy of Pediatrics, California Chapter 2

Dennis M. Styne, MD, Professor and Rumsey Chair of Pediatric Endocrinology, Department of Pediatrics, University of California Davis Medical Center, Sacramento

Educational Objectives

The goal of this program is to improve the management of childhood obesity and diabetes. After hearing and assimi­lating this program, the clinician will be better able to:

1.   Discuss the causes of childhood obesity.

2.   Determine which pediatric patients require treatment for hyperlipidemia and hypertension.

3.   Differentiate between type 1 diabetes and type 2 diabetes in children.

4.   Recognize when to screen for diabetes in children.

5.   Determine the appropriate treatment for the child with diabetes.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and plan­ning committee reported nothing to disclose.

Acknowledgements

Dr. Styne was recorded at Clinical Pediatrics, held February 12-15, 2009, in Palm Springs, CA, and sponsored by the American Academy of Pediatrics, California Chapter 2. The Audio-Digest Foundation thanks Dr. Styne and the Amer­ican Academy of Pediatrics, California, Chapter 2, for their cooperation in the production of this program.

Childhood Obesity

Introduction: change of terminology  —  previously, “overweight” >95th percentile of body mass index (BMI) for age and sex (now called obesity); those in 85th to 95th percentiles previously called “risk for overweight” (now “over­weight”); BMI of 25 in adult roughly equivalent to 85th to 95th percentiles for any age in child (BMI of 30 roughly equivalent to >95th percentile); severe childhood obesity at >99th percentile; measuring waist circumference future recommendation; >17% to 18% of childhood population at >95th percentile (should be only 5%, but weight/height charts based on 20-yr-old data); all ethnic groups, except whites, have greater tendency towards obesity; American Indians have highest incidence; complications of obesity follow same trend

Causes of obesity: central nervous system (CNS) setpoint  —“tells” us amount to eat; as weight gained, we tend to keep it on and more difficult to lose weight; genetics  —  found that monozygotic twins separated at birth and fol­lowed into adulthood had BMIs related to biologic rather than adoptive parents; some people gain weight more rap­idly than others with same amount of calories and activity; hypothyroidism does not lead to obesity (just mild weight gain); diet  —  high-fructose corn syrup intake unequivocally related to metabolic syndrome and insulin resis­tance; diet and activity part of answer; television  —  modifiable factor in obesity epidemic; cutting down television leads to decrease in weight gain; environment  —  eg, buildings where stairs not conveniently located; medications  —  atypical antipsychotics cause weight gain; everything done to improve life has added to epidemic; activity  —  teenage girls perform minimal activity (worse for blacks than for whites); obese black child has greater chance of becoming obese black adult (tracking of obesity ethnicity-dependent)

Insulin resistance: causal relationship controversial, but definitely contributes; leads to impaired glucose tolerance (IGT) and type 2 diabetes (T2D); also dyslipidemia, hypertension, protein in urine with renal impairment, and clot­ting abnormalities; amount of visceral adipose tissue also factor; can treat components, but not syndrome; highest BMI leads to most clustering of symptoms of metabolic syndrome

Hyperlipidemia: cholesterol  —  in adults, <200 mg/dL ideal (<170 mg/dL in children); low-density lipoprotein (LDL) —<110 mg/dL; high-density lipoprotein (HDL)  —  >45 mg/dL; abnormal HDL/cholesterol ratio leads to in­creased risk for heart disease; triglycerides  —  <75 mg/dL (younger age) and >90 mg/dL (older age); should start treatment when LDL persistently >190 mg/dL and no other risk for coronary artery disease (CAD); if risk factors present (eg, hypertension, cigarette smoking, family history of heart disease), start treatment at 160 mg/dL; if pa­tient has diabetes mellitus, start treatment at 130 mg/dL; treatment  —  diet and exercise best; if medical therapy nec­essary, use statins; however, due to  teratogenicity, girls on statins must use contraception

Hypertension in childhood obesity: often, diagnosis made because of  mismeasurement (wrong-sized cuff); must have correct size of cuff; need to remeasure frequently with manual cuff; blood pressure (BP) normally low in childhood; speaker alerted by staff if systolic BP >120 mm Hg; treatment  —lifestyle modification; therapy with “adult” drugs; angiotensin-converting enzyme (ACE) inhibitors used particularly in children with diabetes, but ter­atogenic (recommend contraception); use b-blocker in athletes (slows heart rate); ACE inhibitors for those with re­nal disease

Liver disease: nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH); type 1 liver disease in adults; type 2 in childhood; histologically different and have different outcomes; fatty liver disease in childhood causes fibrosis, leading to cirrhosis and, eventually, need for liver transplantation; to determine if child has liver dis­ease, biopsy 100% diagnostic but not practical; ultrasonography 60% to 80% diagnostic; enzyme levels 30% to 50% diagnostic; elevated enzyme levels in obese children may lead to missed diagnosis of Wilson’s disease; im­proved by lifestyle

Birth weight: relates to metabolic syndrome, insulin resistance, and obesity; large for gestational age infants more likely to develop obesity and insulin resistance (also true for small for gestational age infants); increasing evidence for 2-generation effect; environment of egg while patient’s mother was in utero also may have effect (epigenetic); even if obesity cured in present, 2-generation effect may persist; in utero, programming of child’s metabolism “set for life” to some degree

Exercise: not possible to offset poor diet with exercise; improves insulin sensitivity; least physically fit benefit most; 20 min of activity 3 times/wk improves insulin resistance

Diabetes Prevention Study: participants large group of men likely to develop diabetes; first group given no interven­tion; second group given metformin; third group given intense support to maintain proper diet and exercise; best re­sults in third group

Sleep: studies suggest that disordered sleep leads to obesity (controversial); sleep disorders worse in lower socioeco­nomic groups (more affected by obesity; also controversial); some sleep experts believe that healthy sleep reduces likelihood of obesity

Evaluation of child for obesity: every 6 mo or 1 yr, obtain height, weight, BMI, and BP; look for comorbidities; in future, waist circumference; acanthosis nigricans (AN) not reliable as indicator of insulin resistance; Cushing’s dis­ease (rare) characterized by short stature and obesity; look for early puberty or polycystic ovary syndrome; melano­cortin-4 receptor (MC4R) mutation  —  syndrome related to obesity; monogenetic type of obesity characteristic in population; seen in 3% to 5% of severely obese individuals; those with mutation tend to be tall with rapid growth (rapid bone age advancement); obtain history for cardiovascular disease, hypertension, and early death from heart disease; determine ethnic background; obtain weight and birth history; determine lipid levels if BMI between 85th and 95th percentiles; obtain comprehensive metabolic panel and alanine aminotransferase (ALT) level for diagnosis of liver disease; diabetes screening with fasting blood glucose (FBG); urine microalbumin not presently recom­mended; action  —  lifestyle modification; drugs for obesity not effective in childhood; surgery increasing in preva­lence; no effective programs available

Diabetes: Evaluation And Treatment

Type 1 diabetes (T1D): b-cell destruction; autoimmune disease; leads to absolute insulin deficiency; initially, b-cell mass and insulin normal, then precipitating event (nature unknown; possibly Coxsackie virus, rhinovirus, or toxin in environment) occurs; second event occurs, or patient may have genetic predisposition; antibodies form and b-cells destroyed; b-cell mass decreases until »80% of cell mass destroyed and BG increases; process takes months to years; certain HLA haplotypes predispose to development of or resistance to diabetes; 3% increase in new cases an­nually worldwide (affected by migration of ethnic groups); unequivocally suggests causation related to environ­mental toxin or infection; probabilities within families  —  parent of offspring with diabetes has 3% chance of having diabetes; offspring of parent with diabetes has 6% chance (greater with diabetic father); sibling has 5% chance; HLA-identical twins have 33% chance (£70% with long-term follow-up)

Type 2 diabetes: insulin resistance and deficiency present; 2 defects in T2D; suspect either type of diabetes with clas­sic polyuria and polydipsia, unexplained and unplanned weight loss, and blurred vision; signs include abnormal BG, glycosuria, ketosis (seen in both types), and associated dyslipidemia; suspected in  —  obesity (BMI >95th per­centile) in teen years; overweight with risk factors (eg, family history)

Diagnosis: in classic polyuria, polydipsia, or diabetic ketoacidosis (DKA), glucose tolerance test (GTT) not neces­sary; random elevated or FBG enough if symptoms also present; nonclassic presentation may require GTT; 2-hr postprandial sample adequate; normal values  —  FBG <100 mg/dL and 2-hr postprandial BG <140 mg/dL; diabetes mellitus defined as FBG >126 mg/dL or 2-hr postprandial BG >200 mg/dL; gap between normal and diabetic, where FBG 101 to 125 mg/dL and 2-hr postprandial BG 140 to 199 mg/dL, called impaired glucose tolerance (IGT) or prediabetes; if T1D suspected, should not wait overnight for BG test results (DKA develops quickly); dif­ferentiating T1D from T2D in difficult cases  —  in early phase of T1D, insulin still present; antibody levels might help, but not infallible; 2-hr postprandial BG may help to determine whether diabetes present, but cannot distin­guish type; C-peptide determination (indicates endogenous insulin production) not recommended at time of presen­tation; history and examination  —  family history; mitochondrial diseases associated with deafness, optic atrophy, or other syndromes; drug history (glucocorticoids raise BG); BMI; birth weight (both high and low birth weights predispose to insulin resistance); laboratory measurements  —  BG; blood ketones and electrolytes; autoantibodies; urinalysis

Type 1 diabetes  —  ketosis and antibodies to islet cells, insulin, and glutamic acid decarboxylase (found in cell mem­brane) seen; once insulin given, difficult to measure; treat with insulin; polygenic; diabetics prone to other autoim­mune diseases

Type 2 diabetes: possible to have ketosis and antibodies; treat with diet and exercise, if possible, then oral hypogly­cemics; insulin last option; polygenic; BMI almost always high, except in Asia, where BMIs may be normal; “flat­bush” diabetes  —  inherited in autosomal dominant pattern in black males; maturity-onset diabetes of young (MODY)  —  now called monogenic diabetes; 6 types; autosomal dominant inheritance; generally mild

Antibody positivity: part of American Diabetes Association definition of T1D; 10% to 15% of white adults with T2D autoantibody-positive and do not initially require insulin (latent autoimmune diabetes in adults); 10% to 74% of children with T2D (depending on study) autoantibody-positive for ³1 antibody and do not initially require insu­lin; if 3 positive, almost certain T1D; if only 1 positive, equivocal and need to base on clinical judgment; if T2D an­tibody-positive, likelihood of younger age of onset, less overweight, higher hemoglobin A1c (Hb_A1c) when diagnosed, and more rapid progression; 15% to 20% of children with T1D obese or overweight; severe DKA oc­curs in both types; low pH seen in T2D when patients present in emergency room; T2D so common in minority populations that family history becomes less significant; in early phase, insulin level high

Search for Diabetes in Youth (SEARCH) study: showed that in prepuberty, T1D predominates over T2D, except in American Indians; in teenage years, more T2D in every ethnic group, except whites; in American Indians T2D makes up majority of teenage cases; incidence of T2D »20 cases/100  000 annually; obesity epidemic, but diabetes not yet so; metabolic syndrome almost 100% in youth with T2D; of obese preadolescents, 24% had IGT; in adoles­cents, 25% had problem, 20% had IGT, and 4% had silent T2D; when subjects followed over 20 mo, one-third had IGT and two-thirds had normal GT; of those with IGT, one-third remained with IGT, one-third reverted to normal, and one-third progressed to T2D; of those who started out normal, 90% remained normal and 10% progressed to IGT; conclusion  —  progression from IGT to diabetes can occur within 20 mo (much faster than in adults); well-controlled TID does not lead to long-term health issues in many patients; T2D leads to catastrophic issues if not well controlled

Screening: not cost-effective to screen everyone; whom to screen  —  those in 85th to 95th percentiles with risk fac­tors; those >95th percentile should be screened with FBG; 2-hr postprandial BG better test, but not yet recom­mended; Asian children with high or low birth weight or family history of diabetes; children with BMI ³95th percentile, regardless of family history

Management: once diagnosed, recommend diet and exercise (not always effective); obtain Hb_A1c every 3 mo, FBG monthly; if FBG <130 mg/dL and Hb_A1c <7%, maintain; if not, prescribe metformin (only oral medication ap­proved for children ³10 yr of age with T2D; safe; can cause upset stomach, but does not cause acidosis); if symp­toms mild , use metformin first; if symptomatic with high BG and high Hb_A1c, start insulin; attempt to wean off insulin because disease can be treated orally in most cases; if BG and Hb_A1cnot controlled, check for noncompli­ance; consider adding sulfonylurea (although not approved for children and can cause hypoglycemia); metformin does not cause hypoglycemia (stops liver from producing glucose); complications  —  blindness, cardiovascular and kidney failure, limb amputation, and nerve damage; Hb_A1c  —  used to monitor; reflects average BG over last 3 mo; weighted towards most recent BG; normal range <6.5% to 7%; cutoff of good control in late adolescence 7% (means BG of »150-160 mg/dL); the higher the Hb_A1c, the greater risk for complications; consequence of tight control  —  severe hypoglycemia; the lower the Hb_A1c, higher risk for severe hypoglycemia; Diabetes Control and Complications Trial  —keeping Hb_A1c low (<7) leads to fewer complications (in adults); in children, Hb_A1c should be 7.5%; 6 to 12 yr of age, probably higher; younger children, 7.5% to 8.5%

Mimicking normal insulin secretion: prescribe insulin glargine or long-acting insulin; no DKA, but does not pro­vide adequate control; better simulation of normal insulin secretion with multiple-dose injections at mealtimes (recommended for children); insulin pump  —  variable basal rates; requires training and intelligence; tubes re­placed every 2 days (clog and need careful monitoring); continuous glucose monitoring device cannot be used to decide insulin dose yet

Best practices in childhood diabetes: requires team of doctor, nurse, social worker, and dietitian; poor control of di­abetes associated with noncompliance, quality of life issues, and normal human resistance to change and control (social rather than medical issues); screening  —  recommendations of International Society for Pediatric and Ado­lescent Diabetes; regular monitoring of thyroid and thyroid-stimulating hormone not yet recommended; celiac dis­ease common in children with diabetes; recommendation changing to include screening for celiac disease

Suggested Reading

Agus MS et al: Diabetic ketoacidosis in children. Pediatr Cli.North Am. 52:1147, 2005; Burgert TS et al: Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and vis­ceral fat. J Clin Endocrinol Metab 91:4287, 2006; Falkner B, et al: The relationship of body mass index and blood pressure in primary care pediatric patients. J Pediatr 148:195, 2006; Jones KL: Role of obesity in complicating and confusing the diagnosis and treatment of diabetes in children. Pediatrics 121:361, 2008; Kwiterovich PO Jr: Recog­nition and management of dyslipidemia in children and adolescents. J Clin Endocrinol Metab 93:4200, 2008; Lan­dau Z et al: Sulfonylurea-responsive diabetes in childhood. J Pediatr 150:553, 2007;  Landhuis CE et al: Childhood sleep time and long-term risk for obesity: a 32-year prospective birth cohort study. Pediatrics 122:955, 2008; Lee S et al: Waist circumference is an independent predictor of insulin resistance in black and white youths. J Pediatr 148:188, 2006; Lipton RB et al: Obesity at the onset of diabetes in an ethnically diverse population of children: what does it mean for epidemiologists and clinicians?. Pediatrics 115:e553, 2005; Maahs DM et al: Dyslipidemia in youth with diabetes: to treat or not to treat?. J Pediatr 153:458, 2008; Manlhiot C et al: Spectrum and management of hy­pertriglyceridemia among children in clinical practice. Pediatrics 123:458, 2009; Molven A et al: Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. Diabetes 57:1131, 2008; National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents: The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediat­rics 114(2 Suppl 4th Report):555, 2004; Ten S et al: Insulin resistance syndrome in children. J Clin Endocrinol Metab 89:2526, 2004.