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TYPE 2 DIABETES IN CHILDREN AND ADOLESCENTS

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Although type 1 diabetes continues to remain the most common form of childhood diabetes in most of the …

Although type 1 diabetes continues to remain the most common form of childhood diabetes in most of the
countries including India, the prevalence of type 2 diabetes is increasing worldwide. This increase is attributed to the modern sedentary lifestyle causing a phenotype of insulin resistance in genetically predisposed individuals. The differentiation between type 1 and type 2 diabetes can be done in most of the cases but may be difficult in obese adolescents with relatively acute presentation. The demonstration of various antibodies is helpful in such circumstances. The earlier age of onset puts patients at risk of earlier age of complications. The management is very challenging as lifestyle modification by the patient and the family is the mainstay of the management. Emphasis should be done on primary prevention with a focus on
healthier lifestyles among children.

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  • 1. Type 2 Diabetes in Children and Adolescents
  • 2. Review Article TYPE 2 DIABETES IN CHILDREN AND ADOLESCENTS Ganesh Jevalikar and Ambrish Mithal Apollo Centre for Obesity, Diabetes and Endoerinology (ACODE), Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Correspondence to: Dr Ambrish Mithal, Senior Consultant, Apollo Centre for Obesity, Diabetes and Endoerinology (ACODE), Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Although type 1 diabetes continues to remain the most common form of childhood diabetes in most of the countries including India, the prevalence of type 2 diabetes is increasing worldwide. This increase is attributed to the modern sedentary lifestyle causing a phenotype of insulin resistance in genetically predisposed individuals. The differentiation between type 1 and type 2 diabetes can be done in most of the cases but may be difficult in obese adolescents with relatively acute presentation. The demonstration of various antibodies is helpful in such circumstances. The earlier age of onset puts patients at risk of earlier age of complications. The management is very challenging as lifestyle modification by the patient and the family is the mainstay of the management. Emphasis should be done on primary prevention with a focus on healthier lifestyles among children. Key words: Type 2 diabetes, Children, Adolescents INTRODUCTION Type 2 diabetes mellitus is a heterogeneous disorder characterized by relative lack of insulin secretion in the face of insulin resistance. Progressive decline in the insulin secretory capacity and intercurrent illnesses may lead to a state of insulin dependency hence the previously used term ‘Non Insulin Dependent Diabetes Mellitus’ (NIDDM) is no more in use. While type 1 diabetes still remains the most common form of childhood diabetes in most of the countries including India, increasing prevalence of type 2 diabetes in children is being reported worldwide and is closely associated with increase in childhood obesity. Management of type 2 diabetes is a new challenge for the healthcare system because of parallel risk of metabolic syndrome and coronary artery disease. The extensive lifestyle modification which is the mainstay of management makes it more difficult to manage. EPIDEMIOLOGY There has been a sharp increase in cases of type 2 diabetes amongst children and adolescents in the past two decades. This was predominantly seen in the AfricanAmerican and Mexican Hispanic American population. These high risk ethnic groups constitute nearly 70-75% of the cases of pediatric type 2 diabetes in United States [1]. Among 15- to 19-year-old North American Indians, prevalence of type 2 diabetes per 1000 was 50.9 for Pima Indians, 4.5 for all US American Indians, and 2.3 for Canadian Cree and Ojibway Indians in Manitoba. From 357 1967-1976 to 1987-1996, prevalence increased 6-fold for Pima Indian adolescents. Among African Americans and whites aged 10 to 19 years in Ohio, type 2 diabetes accounted for 33% of all cases of diabetes [2]. In the search for diabetes in youth study from United States the proportion of T2DM ranged from 6% of new cases of diabetes (0.19 cases per 1000 youth for non-Hispanic white youth) to 76% (1.74 cases per 1000 youth for American Indian youth) [3]. The increasing prevalence of type 2 diabetes and obesity has also been reported from other countries. In Japan 80% of new cases of childhood diabetes were of type 2 diabetes [4]. Population based studies from India on the prevalence of type 2 diabetes in children are lacking. In a recently reported multicentric study from India, MEDI (Multicenter survey of early onset Diabetes in India) 6% of the 603 patients younger than 20 years were of type 2 diabetes [5]. Another report from north India showed 8 % cases amongst 160 predominantly middle socio-economic group patients with onset less than 18 years [6]. Mohan et al reported 26.7 % cases due to type 2 diabetes amongst 434 cases with age of onset less than 16 years [7]. In most of the studies BMI, waist circumference, family history of diabetes and sedentary lifestyle are significantly associated with risk of diabetes. The Asian Indian phenotype is well known to be associated with central adiposity and insulin resistance[8]. The high incidence of maternal malnutrition and low birth Apollo Medicine, Vol. 6, No. 4, December 2009
  • 3. Review Article weight coupled with sedentary lifestyle and easy availability of calorie dense food makes Indian children more susceptible to obesity, diabetes and other components of metabolic syndrome. ETIO-PATHOGENESIS The Thrifty genotype hypothesis [9] This is an adaptation to adverse nutritional conditions in an effort to conserve energy and survive periods of starvation. It is associated with insulin resistance as one of the mechanism. With the modern lifestyle and easy availability of high calorie food, the same genotype confers risk of visceral adiposity, insulin resistance and metabolic syndrome. Role of in-utero and childhood nutrition Maternal malnutrition causes adverse in utero nutrition to the fetus and low birth weight. This is associated with insulin resistance and limited capacity to secrete insulin. Birth weight has a U shaped relation with the risk of type 2 diabetes. Both low and high birth weights are associated with glucose intolerance later in life. In a recent study published by Brufani, et al, obese children who were born SGA failed to adequately compensate for their reduced insulin sensitivity manifesting deficit in early insulin response and reduced glucose disposal in comparison to children born AGA and LGA [10]. Overfeeding of SGA babies with high calorie feeds puts them at risk for diabetes. Exclusive breast feeding protects against obesity and diabetes. Role of gestational diabetes Gestational diabetes is associated with high amniotic fluid insulin levels. The children of mothers with gestational diabetes have been shown to be having significantly high BMI Z-scores and insulin resistance indices [11] which might put them at risk of diabetes. Role of obesity, diet and physical inactivity In a recent study from Mysore, India, 8.5% prevalence of overweight and 3.4% prevalence of obesity was reported [12]. Higher prevalence of overweight (15.3%) was reported amongst children from high socioeconomic status in Delhi [13]. The prevalence of obesity is likely to increase further due to the lifestyle changes. Obesity, especially the visceral fat deposition is associated with insulin resistance mediated by various adipokines and compensatory increase in insulin secretion. The risk increases with increasing BMI [14]. Apollo Medicine, Vol. 6, No. 4, December 2009 The South Asian diets have been reported to be having low intake of MUFA, omega-3 PUFA and fibre, and high intake of fats, saturated fats, carbohydrates and trans-fatty acids. These factors are associated with insulin resistance, hyperinsulinemia and dyslipidemia [15]. Physical inactivity resulting from decreased outdoor play, increased television viewing, internet surfing, video games etc is one of the major risk factor for obesity. Role of puberty In majority of the reports, the most common age of presentation of type 2 diabetes is peri-pubertal. Puberty is associated with increased activity of growth hormone- IGF axis leading to a state of insulin resistance. This is compensated by insulin hyper secretion in normal children. Failure to compensate for the physiological resistance results in impaired glucose tolerance and diabetes. Genetic predisposition [16] Type 2 diabetes is a polygenic trait. Its familial occurrence and high risk ethnic groups points to a genetic background of the condition. However genetic mechanisms alone can not explain the increase in prevalence which is more likely to be due to the lifestyle changes. Linkage analysis and genome wide association scans (GWAS) have identified certain candidate genes and polymorphisms that are significantly associated with risk of type 2 diabetes. The gene encoding the transcription factor 7-like 2 (TCF7L2) is the locus that confers the strongest effect on type 2 diabetes risk yet found. Polymorphisms in some genes like PPARG encoding peroxisome proliferator-activated receptor 2, KCNJ11 gene encoding Kir 6.2 subunit of the KATP channel, Hepatocyte Nuclear Factor 1 and others like HHEX, SCL30A8, CDKAL1, IGF2BP2 and CDKN2A/B have been significantly associated with the disease risk whereas in some of the genes like HNF 1A, HNF 4A etc suggestive evidence not quite reaching genome wide statistical significance has been identified. All these susceptibility genes have not been adequately studied in children. Current 2 diabetes risk variants may explain as little as 5-10% of the genetic basis of type 2 diabetes. CLINICAL FEATURES Type 2 diabetes may be incidentally detected on screening of the high risk population or it may present with osmotic symptoms of polyuria, polydipsia. Type 2 diabetes is almost exclusively seen in overweight or obese children and is very commonly associated with family history of type 2 diabetes in first or second degree relatives. In many of the reported series the most common age of presentation 358
  • 4. Review Article is around puberty, and there is a female preponderance. Physical examination may show signs of insulin resistance such as acanthosis nigricans. However with increasing prevalence of obesity, even patients with type 1 diabetes also may be obese. Acute clinical presentation and diabetic ketoacidosis at presentation are more common but not exclusive to type 1 diabetes and can be seen in type 2 diabetes due to beta cell dysfunction from glucotoxicity. The hyperglycemic hyperosmolar state is almost exclusive to type 2 diabetes. In patients with T2DM, both plasma insulin and C-peptide concentrations are usually high, reflecting underlying insulin resistance. Chronic hyperglycemia, however, can cause transient insulin deficiency (glucose toxicity) with a low initial plasma insulin concentration, despite insulin resistance. Insulin and C-peptide levels therefore may be low in the presence of acute metabolic deterioration at the time of presentation. Patients with type 1 diabetes can have detectable insulin and C-peptide secretion due to some retained cell function. Because of this overlap, measurement of insulin secretory capacity with insulin and C-peptide may contribute to the assessment (especially when elevated) but is not by itself diagnostic. Islet cell autoantibodies (ICAs), insulin autoantibodies (IAA), glutamic acid decarboxylase (GAD), and tyrosine phosphatase (ICA-512 or islet antigen-2) employed individually or in combination may be helpful in differentiation of type 1 and type 2 diabetes. Autoantibodies are more commonly found in patients with type 1 diabetes, although the titer decreases with the increasing duration of the disease. However, as many as 10-20% cases may lack evidence of autoimmunity at diagnosis. Conversely, 1520% of patients with clinical diagnosis of type 2 diabetes may show antibody positivity (termed as Latent Auto immune Diabetes of Adults by some). In these individuals insulin secretion goes down fast and they become insulin dependant at an earlier stage. SCREENING The American Diabetes Association consensus statement in 2000 recommends that overweight (defined as BMI >85th percentile for age and sex, weight for height >85th percentile, or weight >120% of ideal [50th percentile] for height) youths with any two of the risk factors listed below be screened. Testing should be done every 2 years starting at age 10 years or at the onset of puberty if it occurs at a younger age. Testing may be considered in other high-risk patients who display any of the following characteristics. • Have a family history of type 2 diabetes in first- and second-degree relatives; • Belong to a certain race/ethnic group (Native Americans, African-Americans, Hispanic Americans, Asians/South Pacific Islanders); • Have signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovary syndrome) [17]. As Indians are considered a high risk group, the Indian Academy of Pediatrics (IAP) recommends testing children who are overweight by national standards and have any one of either family history or signs of insulin resistance. Furthermore, it is recommended that clinical judgment be used to test for diabetes in high-risk patients who do not meet these criteria (for example in a morbidly obese patient without any other risk factor). Screening should be done irrespective of obesity in a predisposing condition like Turner, Klinefelter, Prader Willi or Cushing syndrome [18]. DIAGNOSIS [17] American Diabetes Association Criteria for the diagnosis of diabetes • Symptoms of diabetes plus casual plasma glucose concentration 200 mg/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 126 mg/dL (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h. OR • 2-h PG 200 mg/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 1.75 g/kg up to 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. Chronic complications and co-morbidities [19] Patients with type 2 diabetes have higher rate of complications and co-morbidities like hypertension, microalbuminuria, retinopathy, dyslipidemia etc at diagnosis. The rate of progression of these complications is faster compared to later onset of the disease. 359 Apollo Medicine, Vol. 6, No. 4, December 2009
  • 5. Review Article Poor adherence to treatment is very common amongst adolescents and is associated with higher A1Cs, higher body mass index, mean arterial pressure and abnormal lipid profile. Hypertension has been reported in 10-32% cases at diagnosis. Microalbuminuria has been reported in 14-22% cases at diagnosis. The progression to overt nephropathy is faster in comparison to type 1 diabetes and is associated with poor glycaemic control and hypertension. Retinopathy, neuropathy, non-alcoholic steatohepatitis and neuropsychiatric abnormalities have also been reported. Dyslipidemia are more common in type 2 diabetes in comparison to type 1 diabetes. Patients with type 2 diabetes in the search for diabetes in the youth had hypercholesterolemia (33%), hypertriglyceridemia (29%), high LDL (24%) and low HDL (44%). These abnormalities reflect reduction of insulin effect [20]. Treatment of type 2 diabetes is a therapeutic challenge because it requires extensive dietary and lifestyle modifications not just by the patient but by the entire family. This, as against the pharmacologic treatment is the mainstay of the management. Care of type 2 diabetes requires teamwork of patient, family, pediatric endocrinologist, diabetes nurse, dietician, counselor, clinical psychologist, foot care specialist and social worker. Close collaboration with adult endocrinologist is needed especially for transition into adulthood. Goals of the treatment are [22] Primary prevention of type 2 diabetes involves interventions to prevent the development of obesity in children who are not overweight. This include Optimizing the fetal environment in pregnancy by maintaining maternal nutrition and proper antenatal care. • Encouraging healthy eating habits amongst children. Avoiding westernization of diet and encouraging traditional Indian diet. To eliminate symptoms of hyperglycemia. To promote achievement of healthy body weight and normal growth. • To maintain near- normoglycemia (Fasting glucose <126 mg%), and HbA1C <7%. • To achieve a healthy diet and physical exercise schedule. • To treat co-morbidities to prevent long term metabolic and cardiovascular risk. Promotion of exclusive breast feeding. • • • PREVENTION • MANAGEMENT • Encouraging physical activity and avoiding sedentary activities like television viewing. The preventive measures should be implemented at family, school, community and national levels and should involve commitment and active participation on the part of media and politicians. The schools should provide healthy meals, incorporate healthy lifestyle training into curriculum, create opportunities for physical activity and do regular anthropometric assessment. The entire family should practice healthy eating habits, have rules regarding television viewing and encourage physical activity like walking or cycling. Parents should act as a role model for children. Secondary prevention includes early diagnosis by screening of the high risk children as discussed above and encouraging weight loss and lifestyle changes in these cases. Studies have proven that these interventions may delay the progression from impaired glucose tolerance to diabetes by several years [21]. Apollo Medicine, Vol. 6, No. 4, December 2009 DIET Patient should be referred to an experienced dietician/ nutritionist and diet plan should be individualized depending on culture and resources of the family. A simple starting intervention should be to eliminate frequent consumption of sugar containing drinks, juices, sweetened tea etc. The portion size should be controlled. Between meal snacking should be avoided. The diet should contain low total and saturated fats and high fiber. Prolonged fasting should be avoided. Meals should be taken on schedule, in one place, with no other activity (television, studying, reading, playing etc.). Eating disorders are very common in patients with type 2 diabetes and should be considered during evaluation. PHYSICAL ACTIVITY In general, children and adolescents should be encouraged to be physically active for at least 60 minutes per day. The activity should be age appropriate and should be enjoyable to the child. Even mild degrees of weight loss can cause significant benefit in glycaemic control. Time spent in sedentary activities (e.g., television viewing) should be minimized, and other barriers to physical activity should be identiûed and addressed. 360
  • 6. Review Article albuminuria, creatinine), retinopathy, neuropathy, nonalcoholic steatohepatitis (liver enzymes) should be done at diagnosis and annually thereafter. PHARMACOLOGIC MANAGEMENT Metformin Metformin is a biguanide and acts by reducing hepatic glucose output and improving insulin sensitivity. It causes mild weight loss in overweight children. It is the only drug universally approved for use in children and has minimal side effects. It was shown to be effective in doses upto 1000 mg twice daily in 82 subjects treated up to 16 weeks [23]. Side effects are mainly GI and include anorexia, abdominal discomfort, nausea and diarrhea. These can be minimized by taking the drug with the food or by using sustained release formulations. The starting dose should be low and slowly escalated over 1-3 weeks. Lactic acidosis is very rare. Metformin is contraindicated in renal or hepatic impairment, cardio respiratory insufficiency or use of radio-contrast material. It should not be given in diabetic ketoacidosis. Sulfonylureas In a randomized single blind comparative study, glimepride was as effective as metformin in terms of glycaemic control without an increase in incidence of hypoglycemia. However, it caused a significant weight gain compared to metformin [24]. Other drugs have not been studied well in children. Other hypoglycemic agents Other drugs used in adults include thiazolidinediones (rosiglitazone, pioglitazone), meglitinides, glucosidase inhibitors (acarbose, miglitol), amylin, DPP-IV inhibitors (sitagliptin) and incretin mimetics (exenatide) have not been approved for use below 18 years. Insulin Insulin may be the initial therapy for patients presenting with ketosis, ketoacidosis, dehydration, hyperosmolar state or during decompensation. It also can be given at diagnosis when differentiation between type 1 and type 2 diabetes is unclear. Addition of basal insulin at an earlier stage in combination with oral hypoglycemics has been shown to improve glycaemic control. With decreasing cell function eventually all patients may require insulin for day to day management, when oral medications fail. Treatment of comorbidities Complication screening for nephropathy (micro- Hypertension Blood pressure should be checked during each visit and should be maintained below the 90th centile for age, sex and height. High BP readings should be confirmed by taking additional readings. Mild hypertension can be initially managed with lifestyle and diet changes. If it does not respond to these interventions, the first line of pharmacological treatment is angiotensin-converting enzyme inhibitors Dyslipidemias Fasting lipid levels should be obtained after initial glycaemic control and annually thereafter. LDL should be maintained below 100 mg/dL. Dyslipidemia should be managed initially with diet and lifestyle changes and glycaemic control. If lipids remain elevated after 6 months of above, then statins can be started in children older than 10 years. TREATMENT RECOMMENDATIONS [22] Asymptomatic patients with type 2 diabetes may be initially managed with diet and exercise. Fasting and postprandial glucose should be monitored frequently in a week. Failure to maintain HbA1C < 7 % and glucose readings below 130 mg/dL fasting and below 180 mg/dL post meal after 3-6 month trial of diet and exercise is an indication to start metformin. Symptomatic patients without ketosis can be started on metformin and lifestyle modification. Blood glucose readings should be maintained as above and target HbA1C should be below 7%. Poor compliance is the most common reason for poor control and must be addressed before adding other treatment. Add on therapy with sulphonylureas or insulin can be considered if there is no control with adequate doses of metformin. Failure of single or multiple oral hypoglycemics is indication to start insulin. Patients with high blood glucose at diagnosis (>250 mg/ dL), HbA1C more than 9 % or ketosis at onset may be started on insulin. Metformin may be added later and insulin can be withdrawn gradually. SUMMARY Modern lifestyle and improved socioeconomic status has contributed to increased prevalence of type 2 diabetes in at younger age particularly in genetically prone individuals. It is a disease of the family, demanding 361 Apollo Medicine, Vol. 6, No. 4, December 2009
  • 7. Review Article extensive lifestyle changes not just by the patient but by the entire family. The differentiation between type 1 and type 2 diabetes is difficult in obese children with acute presentation. Therapeutic options are mainly metformin and insulin, with majority of the other drugs not being approved for use in children. The earlier onset also means longer duration of hyperglycemia and occurrence of complications at an earlier age. Primary prevention and screening of high risk individuals is far more cost effective and must be emphasized. REFERENCES 1. Jennifer Miller, Janet H Silverstein, Arlan L Rosenbloom. Type 2 diabetes in the child and adolescent. In Fima Lifshitz, ed. Pediatric Endocrinology. 5th ed, Vol 1: Informa Healthcare USA, 2007; 169-183. 2. Fagot-Campagna A, Pettitt DJ, Engelgau MM, et al. Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective. J Pediatr. 2000; 136(5): 664-672. Impaired -cell function during oral glucose tolerance test. J Clin Endocrinol Metab 2009; 94: 4448-4452. 11. Wroblewska-Seniuk K, Wender-Ozegowska E, et al. Long-term effects of diabetes during pregnancy on the offspring. Pediatr Diabetes. 2009;10(7):432-440. 12. Premanath M, Basavanagowdappa H, Shekar MA, et al. Mysore childhood obesity study. Indian Pediatrics 2009 Apr 15 [Epub ahead of print]. 13. Kaur S, Sachdev HP, Dwivedi SN, et al. Prevalence of overweight and obesity amongst school children in Delhi, India. Asia Pac J Clin Nutr. 2008; 17(4):592-596. 14. Caprio S, Tamborlane WV. Metabolic impact of obesity in childhood. Endocrinol Metab Clin North Am 1999; 28: 731747. 15. Misra A, Khurana L, Isharwal S, et al. South Asian diets and insulin resistance. Br J Nutr. 2009 Feb; 101(4):46573. 16. Jose C Florez. The Genetics of type 2 diabetes: A realistic appraisal in 2008. J Clin Endocrinol Metab 2008; 46334642. 3. Liese AD, D’Agostino RB Jr, Hamman RF, et al. The burden of diabetes mellitus among US youth: prevalence estimates from the search for Diabetes in Youth Study. Pediatrics. 2006; 118(4):1510-1518. 17. Type 2 diabetes in children and adolescents. American Diabetes Association. Diabetes Care. 2000;23(3):381389. 4. Pinhas-Hamiel O, Zeitler P. The global spread of type 2 diabetes mellitus in children and adolescents. J Pediatr. 2005; 146(5): 693-700. 18. Bhatia V. IAP National Task Force for Childhood Prevention of Adult Diseases: insulin resistance and type 2 diabetes mellitus in childhood. Indian Pediatr. 2004; 41(5):443-457. 5. Unnikrishnan AG, Bhatia Eesh, Bhatia Vijayalakshmi, et al. Type 1 diabetes versus Type 2 diabetes with onset in persons younger than 20 years of age-results from an Indian multicenter Study. Ann N Y Acad Sci. 2008; 1150: 239-244. 6. Bhatia V, Arya V, Dabadghao P, et al. Etiology and outcome of childhood and adolescent diabetes mellitus in North India. J Pediatr Endocrinol Metab. 2004; 17(7): 993999. 7. Mohan V, Jaydip R, Deepa R. Type 2 diabetes in Asian Indian youth. Pediatric Diabetes 2007; 8 (Suppl. 9): 28-34. 8. Ramachandran A, Snehalatha C, Viswanathan V, et al. Risk of noninsulin dependent diabetes mellitus conferred by obesity and central adiposity in different ethnic groups: a comparative analysis between Asian Indians, Mexican Americans and Whites. Diabetes Res Clin Pract 1997; 36: 121-125. 9. Sharma AM. The thrifty-genotype hypothesis and its implications for the study of complex genetic disorders in man. J Mol Med. 1998; 76(8):568-571. 10. Claudia Brufani, Armando Grossi, Danilo Fintini, et al. Obese children with low birth weight demonstrate Apollo Medicine, Vol. 6, No. 4, December 2009 19. Pinhas-Hamiel O, Zeitler P. Acute and chronic complications of type 2 diabetes mellitus in children and adolescents. Lancet. 2007; 369(9575):1823-1831. 20. Kershnar AK, Daniels SR, Imperatore G, et al. Lipid abnormalities are prevalent in youth with type 1 and type 2 diabetes: the search for Diabetes in Youth Study. J Pediatr. 2006; 149(3):314-319. 21. Weiss R. Impaired glucose tolerance and risk factors for progression to type 2 diabetes in youth. Pediatr Diabetes. 2007; 8 (Suppl 9):70-75. 22. Rosenbloom AL, Silverstein JH, Amemiya S, et al. ISPAD Clinical Practice Consensus Guidelines 2009 Compendium: Type 2 diabetes in children and adolescents. Pediatric Diabetes 2009: 10 (Suppl. 12): 17-32. 23. Jones KL, Arslanian S, Peterokova VA, et al. Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial. Diabetes Care. 2002; 25(1):89-94. 24. Gottschalk M, Danne T, Vlajnic A, et al. Glimepiride versus metformin as monotherapy in pediatric patients with type 2 diabetes: a randomized, single-blind comparative study. Diabetes Care. 2007; 30(4):790-794. 362
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