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MANAGEMENT OF TYPE 2 DIABETES IN CHILDREN AND ADOLESCENTS Dr. Huen Kwai Fun Chief of Service & Consultant Paediatrician Dept. of Paediatrics Tseung Kwan O Hospital Outline (I) Q1: What is the classification of diabetes in children and adolescents? Q2: What is the epidemiology of type 2 diabetes in children and adolescents? Q3: What is the pathophysiology of type 2 diabetes in children and adolescents? Q4: Who should be tested for diabetes? Testing recommendations Population selection Test methods Outline (II) Q5: How should children and adolescents with type 2 diabetes be treated? Lifestyle changes Pharmaceutical therapy Monitoring for complications Hypertension treatment Hyperlipidemia treatment Q6: Can type 2 diabetes in children and adolescents be prevented? Criteria for the diagnosis of diabetes Symptoms of diabetes plus casual plasma glucose concentration ≧ 200mg/dl (11.1 mmol/l). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss. OR, FPG ≧126mg/dl (7.0 mmol/l). intake for at least 8 hours. Fasting is defined as no caloric OR, 2-h PG ≧ 200mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in water. In the absence of unequivocal hyperglycemia with acute metabolic decompensation, these criteria should be confirmed by repeat testing on a different day. The third measure (OGTT) is not recommended for routine clinical use. Adapted from the Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Etiologic classification of diabetes Type 1 diabetes* (β-cell destruction, usually leading to absolute insulin deficiency) Immune-mediated Idiopathic Type 2 diabetes* (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance) Other specific types Genetic defects of β-cell function (e.g. MODY) Genetic defects in insulin action (e.g. lipoatrophic diabetes) Diseases of the exocrine pancreas (e.g. cystic fibrosis) Endocrinopathies (e.g. Cushing’s syndrome) Drug- or chemical- induced (e.g. glucocorticoids) Infections (e.g. congenital rubella) Uncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated with diabetes (e.g. PraderWilli syndrome) Gestational diabetes mellitus (GDM) * Patients with any form of diabetes may require insulin treatment at some stage at their disease. Use of insulin does not, of itself, classify the patient. Adapted from the Report of the Expert Committee on Research schema for classification of diabetes in children and youths Obese Yes No Autoantibodies Fasting C-peptide/insulin No Yes Fasting C-peptide/insulin High Low Autoantibodies Yes Type 2 1M Type 1 No Low Idiopathic Type 1 or MODY High Type 2 1M Type 1 Estimates of the magnitude of type 2 diabetes in North American Children (I) Years Race / Ethnicity Age (Years) Estimates Study types Population-based studies Arizona Manitoba 1992-96 Prevalence per 1,000 Pima Indians 10-14 22.3 15-19 50.9 1996-97 First Nations 10-19 36.0 in girls 1988-94 Whites, Africans 12-19 4.1* NHANES IlI all US Americans, Mexican Americans Clinic-based studies Indian Health 1996 American Indians 0-14 1.3* Services (all U.S.) Manitoba 1998 First Nations 15-19 4.5* 5-14 1.0 15-19 2.3 Estimates of the magnitude of type 2 diabetes in North American Children (II) Clinic-based studies Cincinnati, OH Case series Years Race / Ethnicity 1994 Whites, AfricanAmericans Cincinnati, OH 1994 Charleston, SC San Diego, CA 1997 1993-94 San Antonio, TX Ventura, CA 1990-97 1990-94 Whites, AfricanAmericans Blacks Whites, AfricanAmericans, Hispanics, AsianAmericans Hispanics, Whites Hispanics Age (Years) Estimates Incidence per 100,000/year 10-19 7.2 Percentage of type 2 diabetes among new cases of diabetes 0-19 10-19 0-19 0-16 16 33 46+ 8 0-17 18 45 * Estimates include type 1 and 2 diabetes + Percentage of type 2 among nonincident cases of diabetes Annual incidence of type 2 diabetes in Tokyo 1976-80 7.3 per 100,000 1981-85 12.1 per 100,000 1991-95 13.9 per 100,000 Junior high school children Urine glucose screening Confirmed by OGTT Characteristics & Risk Factors Obesity Decreased exercise Increased calorie and fat intake Family History Low birth weight Females Pubertal age period Research needs Magnitude of type 2 diabetes Confirm any significant rising trend Characteristics of those affected Risk factors Natural history Pathophysiology Type 2 diabetes is a complex metabolic disorder of heterogeneous etiology with social, behavioral, and environmental risk factors unmasking the effects of genetic susceptibility Primary Defect The constellation of clinical characteristics in type 2 diabetes suggests that the initial abnormality is impaired insulin action (insulin resistance), compounded later with β-cell failure (insulin insufficiency) Evolution Prediabetic Normoglycaemic Impaired G tolerance Insulin Resistance Worsening of insulin resistance Compensatory Hyperinsulinaemia uncompensated hyperinsulinaemia (relative insulin insufficiency) Clinical diabetes Impaired insulin action Insulin secretory failure Glucose toxicity Hyper G beget more hyper G by worsening both insulin resistance and insulin secretory abnormalities Ameliorated by correction of hyper G Puberty-related insulin resistance Insulin-mediated glucose disposal is on average 30% lower in adolescents between Tanner stages II and IV compared with prepubertal children and compared with young adults Increased GH secretion is most likely responsible Sex steroids – unlikely cause Peak ages at presentation coincides with usual age of mid-puberty Obesity Obese children are hyperinsulinaemic and have ~40% lower insulin-stimulated glucose metabolism compared with non obese BMI increase, insulin resistance increase, fasting insulin levels increase Relationship stronger with abdominal visceral fat than for subcutaneous fat Hyperandrogenism PCOS – increased risk of type 2 DM 31% IGT, 7.5-16% type 2 diabetes Profound insulin resistance (indep of obesity) Abnormal β-cell function Genetic predisposition Racial differences Family History African-Americans adolescents – 30% lower insulin sensitivity of White American Indians, Hispanic, Asian/ Pacific Inlanders increase risk Testing for type 2 diabetes on children Criteria* Overweight (BMI > 85th percentile for age and sex, weight for height > 85th percentile, or weight >120%of ideal for height) PLUS Any two of the following risk factors: Family history of type 2 diabetes in first- or second-degree relatives Race/ethnicity (American Indian, African-American, Hispanic, Asian / Pacific Islander) Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricians, hypertension, dyslipidemia, PCOS) Age of initiation: age 10 years or at onset of puberty if puberty occurs at a younger age Frequency: every 2 years Test: FPG preferred * Clinical judgment should be used to test for diabetes in high-risk patients who do not meet these criteria Recommendations based on limited data. School or community-based studies needed. Other possible influencing factors Blood pressure Fat distribution Socioeconomic status Low birth weight Other tests: 2-h PG Random glucose HbAlc Treatment goals Normalization of blood glucose and HbAlc [ADA: Standards of Medical Care for Patients with Diabetes Mellitus (Position Statement). Diabetes Care 22 (Suppl 1): S32-S41, 1999] Successful control of hypertension and hyperlipidaemia Decrease risk of acute and chronic complications Treatment Diabetic ketoacidosis (DKA) Hyperglycaemic hyperosmolar nonketotic (HHNK) states Associated with high morbidity and mortality in children Risk of cerebral oedema Early consultation and referral Management Medical nutrition therapy Exercise drugs Lifestyle changes Comprehensive self-management education [ADA: Clinical Practice Recommendations 1999. Diabetes Care 22 (Suppl. 1): S1-S114, 1999] Self-monitoring of blood glucose (SMBG) (Fasting, postprandial, acute illness, Sxs of hyper G or hypo G) Nutritional Mx: Culturally appropriate Sensitive to family resources Given to all caregivers Healthy eating habits by entire family Decrease high-caloric high fat food choices Behavior modification [Willet WC et al – Guidelines for healthy weight. N Engl J Med 341:427-434, 1999] Increase daily physical activity Decrease sedentary activity Pharmaceutical therapy [DeFronzo RA: Ann Intern Med 131:281-303, 1999] 5 types of of oral hypoglycaemic agents: Biguanides: decrease hepatic glucose output and enhance primarily hepatic and also muscle insulin sensitivity without a direct effect on β-cell function: metformin Sulfonylureas: promote insulin secretion: acetohexamide, chlorpropamide, gliclazide, glimepiride, glipizide, glyburide, tolazamide, and tolbutamide Meglitinide: short-term promotion of glucose-stimulated insulin secretion: repaglinide Glucosidase inhibitors: slow hydrolysis of complex carbohydrates and slow carbohydrate absorption: acarbose and miglitol Thiazolidenediones: improve peripheral insulin sensitivity: troglitazone, rosiglitazone, and pioglitazone No oral agent should be used during pregnancy Important to counsel adolescents with type 2 diabetes about sexuality and pregnancy Metformin – 1st oral agent used No risk of hypo G Weight decreased or remains stable LDL – cholesterol and TG decrease May normalize ovulatory abnormalities in girls with PCOS and increase risk unplanned pregnancy – preconception and pregnancy counseling CI in impaired renal function (lactic acidosis), hepatic disease, hypoxemic conditions, severe infections, alcohol abuse Discontinued with administration of radiocontrast material, acute illness associated with dehydration/hypoxemia SE: GI disturbances Proper dosing in children not been evaluated Add sulfonylurea if not successful over 3-6 months Monitoring for complications Microalbuminuria Dilated eye examinations Foot examinations BP Lipid abnormalities Hypertension treatment ACE inhibitors – 1st line α- blockers, calcium antagonists (long-acting), low dose diuretics β- blockers – hypo G, mask hypo G Sxs Hyperlipidaemia treatment Weight loss Increase activity Improve glycaemic control Change food choices and preparation Medications [Pediatrics 89 (Suppl.):525-584, 1992] HMG CoA reductase inhibitors (“statins”) absolutely CI in pregnancy – should not be used in females of childbearing potential unless highly effective contraception in use and patient extensively counseled Prevention (I) Primary prevention directed to high-risk or to overall population of children Primary care providers have an obligation to encourage lifestyle modifications that might delay or prevent onset of type 2 diabetes in children at high risk To whatever degree hyperinsulinaemia and insulin resistance contribute to long term cardiovascular morbidity and mortality, early lifestyle intervention have long-term beneficial effects Intervention using oral hypo G agents for prevention of diabetes in children not recommended Prevention (II) Nutritional interventions guided by health care provider with knowledge and expertise in growth and development in children Drug therapy to reduce weight not recommended until more safety and efficacy data available Use of very-low-calorie or high-protein diets or other fad diets not recommended Quick-fix weight loss programs unsafe for children and rarely result in long-term weight control. They do not promote long-term healthy eating behavior Prevention (III) 6-year Da Qing IGT and Diabetes Study (Diabetes Care 20:537-544, 1997) 126 Chinese men with IGT Randomized to a program with both dietary and exercise intervention Developed type 2 diabetes 32% less frequently than 133 men in control group Prevention (IV) Ideally public health approach targets general population School- and community-based programs to promote improved dietary and physical activity behaviors for all children and their families Schools, religious organizations, youth and family organizations, and government agencies should assume some responsibility for promoting a healthy life style