Type 2 Diabetes in Children and Adolescents

Canadian Diabetes Association Clinical Practice Guidelines Expert Committee

Constadina Panagiotopoulos MD, FRCPC Michael C. Riddell PhD Elizabeth A.C. Sellers MD, FRCPC

  • Key Messages
  • Recommendations
  • Figures
  • Full Text
  • References

Key Messages

Note: Unless otherwise specified, the term “child” is used for individuals 0 to 18 years of age, and the term “adolescent” for those 13 to 18 years of age.

  • Anticipatory guidance regarding healthy eating and active lifestyle is recommended to prevent obesity.
  • Regular targeted screening for type 2 diabetes is recommended in children at risk.
  • Children with type 2 diabetes should receive care in consultation with an interdisciplinary pediatric diabetes healthcare team.
  • Early screening, intervention and optimization of glycemic control are essential, as the onset of type 2 diabetes during childhood is associated with severe and early onset of microvascular complications.

Introduction

Type 2 diabetes in children has increased in frequency around the world over the past 2 decades (1) . Children from ethnic groups at high risk for type 2 diabetes in their adult populations, namely, those of Aboriginal, African, Arabic, Hispanic or Asian descent, are disproportionally affected. A recent Canadian national surveillance study demonstrated a minimum incidence of type 2 diabetes in children and adolescents <18 years of age of 1.54 per 100 000 children per year (2) . Significant regional variation was observed with the highest minimum incidence seen in Manitoba of 12.45 per 100 000 children per year. In this study, 44% of children with new onset type 2 diabetes were of Aboriginal heritage, 25% Caucasian, 10.1% Asian, 10.1% African/Caribbean and the remaining of other or mixed ethnic origin (2) . Recent data from the United States (US) demonstrated an incidence of 8.1 per 100 000 person years in the 10- to 14-year age group and 11.8 per 100 000 person years in the 15- to 19-year group. In this study, the highest rates were found in American Indian, African American, Asian/Pacific Islander and Hispanic youth (in descending order), and the lowest incidence occurred in non-Hispanic white youth (3) .

Prevention

Breastfeeding has been shown to reduce the risk of youth-onset type 2 diabetes in some populations (4) .

Obesity is a major modifiable risk factor for the development of type 2 diabetes (2) . In 2004, 18% of Canadian children and adolescents were overweight and 8% were obese (5) . Studies on the prevention of obesity in children are limited and have generally not been demonstrated to be successful (6) . In obese children, standard lifestyle interventions in the form of dietary recommendations and regular clinic visits have been shown to have little benefit for weight reduction (6) . While data are limited, family-based lifestyle interventions with a behavioural component aimed at changes in diet and physical activity patterns have been shown to result in significant weight reduction in both children and adolescents (6) . Health Canada–endorsed recommendations for physical activity and nutrition in children can be accessed on the Canadian Society for Exercise Physiology ( Link ) and Health Canada ( Link ) websites (7,8) .

The role of pharmacotherapy in the treatment of childhood obesity is controversial, as there are few controlled trials and no long-term safety or efficacy data (9) . Several studies suggest that lifestyle changes plus pharmacotherapy may act synergistically when lifestyle intervention is aggressively pursued (10) . Orlistat may be considered to aid in weight reduction and weight maintenance when added to a regimen of lifestyle intervention in adolescents (11–13) . Metformin has been observed to promote modest weight loss in small, short-term trials in children and adolescents (9) . However, while both metformin and orlistat have potential for short-term positive effects on weight, glycemic control, insulin sensitivity and/or lipids, no pediatric studies have been performed to assess the prevention of diabetes or long-term complications. In obese adolescents with evidence of severe insulin resistance, pharmacological therapy with metformin or orlistat should only be considered after a comprehensive evaluation of the child's metabolic status, family history and review of lifestyle interventions. Due to a lack of data in prepubertal children, the use of antiobesity drugs should only be considered in this population within the context of a supervised clinical trial. Bariatric surgery in adolescents should be limited to exceptional cases and be performed only by experienced teams (14) .

Screening and Diagnosis

The microvascular complications of type 2 diabetes have been identified at diagnosis, implying long-term, unrecognized hyperglycemia (15) . Children may also present with acute decompensation in diabetic ketoacidosis (DKA) and/or hyperosmolar coma. This argues for a systematic screening program aimed to identify children with type 2 diabetes in order to prevent acute, life-threatening presentation and to decrease the development of chronic complications. Although not proven in children, it is generally assumed that earlier diagnosis of diabetes will lead to interventions that will improve glycemic control and reduce the related short- and long-term complications (15) .

Risk factors for the development of type 2 diabetes in children include a history of type 2 diabetes in a first- or second-degree relative (16), being a member of a high-risk population (e.g. people of Aboriginal, Hispanic, South Asian, Asian or African descent) (1), obesity (2), impaired glucose tolerance (17), polycystic ovary syndrome (PCOS) (18), exposure to diabetes in utero (19–21), acanthosis nigricans (22), hypertension and dyslipidemia (23), and nonalcoholic fatty liver disease (NAFLD) (24) . Atypical antipsychotic medications are associated with significant weight gain, insulin resistance and impaired fasting glucose/type 2 diabetes in children (25) . Neuropsychiatric disorders and the use of neuropsychiatric medications are more common in obese children at diagnosis of type 2 diabetes compared to the general pediatric population (26) . In the recent national Canadian incidence study, the mean age of diagnosis of type 2 diabetes in youth was 13.7 years (2) . However, 8% of all newly diagnosed children with type 2 diabetes were <10 years of age. In children of Aboriginal, Caucasian and Asian origin, 11%, 8.8% and 8.7%, respectively, presented at <10 years of age. Thus, consideration should be given for screening at a younger age in high-risk individuals (2) . A fasting plasma glucose (FPG) is the recommended routine screening test for children, although ensuring a fasting state may be a challenge. The reproducibility of the FPG is high (27) . The oral glucose tolerance test may have a higher detection rate (28,29) in children who are very obese (body mass index [BMI] ≥99th percentile for age and gender) and who have multiple risk factors for type 2 diabetes, but it has poor reproducibility (27) . Glycated hemoglobin (A1C) is not recommended as a method to diagnose type 2 diabetes in children. Otherwise, the diagnostic criteria for diabetes in children are the same as for adults.

Classification

In most children, the presence of clinical risk factors, mode of presentation and early course of the disease indicate whether the child has type 1 or type 2 diabetes. However, differentiation may be difficult in some. Children with type 2 diabetes can present with DKA (30,31) . Testing for the absence of islet autoantibodies may be useful (32–34) . Fasting insulin levels are not helpful at diagnosis, as levels may be low due to glucose toxicity (35) . DNA diagnostic testing for genetic defects in beta cell function should be considered in children who have a strong family history suggestive of autosomal dominant inheritance and who are lacking features of insulin resistance. This may be helpful when diabetes classification is unclear and may lead to more appropriate management (36,37) .

Management

Children with type 2 diabetes should receive care in conjunction or consultation with an interdisciplinary pediatric diabetes healthcare team. The target glycated hemoglobin (A1C) for most children with type 2 diabetes should be ≤7.0%. To be effective, treatment programs for adolescents with type 2 diabetes need to address the lifestyle and health habits of the entire family, emphasizing healthy eating and physical activity (38) . While a recent systematic review found no good-quality studies directly assessing the effects of physical activity in youth with type 2 diabetes, it is reasonable to recommend (in the absence of direct evidence for this population) that children with type 2 diabetes strive to achieve the same activity level recommended for children in general: 60 minutes daily of moderate-to-vigorous physical activity and limiting sedentary screen time to no more than 2 hours per day (39) . Canadian physical activity guidelines for children and youth are available from the Canadian Society for Exercise Physiology ( www.csep.ca ). In a retrospective review of a predominantly First Nations population of youth with type 2 diabetes, target A1C (≤7%) was achieved and maintained on lifestyle monotherapy for 12 months after diagnosis in 54% of individuals who had presented with an A1C <9% at diagnosis (40) . In addition, psychological issues, such as depression, binge eating (41) and smoking cessation, need to be addressed and interventions offered as required. In 1 retrospective cohort of pediatric patients, the prevalence of neuropsychiatric disorders at presentation of type 2 diabetes was 19.4% (26) .

Insulin is required in those with severe metabolic decompensation at diagnosis (e.g. DKA, glycated hemoglobin [A1C] ≥9.0%, symptoms of severe hyperglycemia) but may be successfully weaned once glycemic targets are achieved, particularly if lifestyle changes are effectively adopted (42) . There are limited data about the safety or efficacy of oral antihyperglycemic agents in the pediatric population, and none of the oral antidiabetic agents have been approved by Health Canada for use in children. Metformin has been shown to be safe in adolescents for up to 16 weeks, reducing A1C by 1.0% to 2.0% and lowering FPG with similar side effects as seen in adults (43) . Glimepiride has also been shown to be safe and effective in adolescents for up to 24 weeks, reducing A1C (−0.54%) to a similar extent as metformin (−0.71%) but resulting in a significant weight increase of 1.3 kg (44) . The Treatment Options for Type 2 Diabetes in Youth (TODAY) study was a multicentre trial that randomized youth with type 2 diabetes to metformin alone, metformin plus a lifestyle intervention, or metformin plus rosiglitazone (45) . The study population included youth 10 to 17 years of age with a mean diabetes duration of 7.8 months and A1C <8%. In the entire study population, treatment failure (defined as A1C ≥8% over 6 months or sustained metabolic decompensation requiring insulin therapy) occurred in 51.7% of the metformin group, 46.6% of the metformin plus lifestyle group, and 38.6% of the metformin plus rosiglitazone group (metformin-rosiglitazone vs. metformin alone; p=0.006). However, there were important differences in response between genders and ethnic groups. This study demonstrated that a significant proportion of youth with type 2 diabetes requires aggressive intervention early in the course of the disease, and treatment failure is common. Serious adverse events thought to be related to study medication were uncommon over mean follow-up of 3.9 years. Given the concerns raised around the long-term safety of rosiglitazone since the start of this trial, it is premature to recommend its routine use in children on the basis of this study. A pharmacokinetic and safety study of a single injection of exenatide in 13 adolescents being treated with metformin demonstrated good tolerability and improved postprandial glucose levels (46) .

The experience of bariatric surgery in adolescents with type 2 diabetes is very limited with specific eligibility criteria (BMI >35 kg/m 2 , Tanner stage IV or V, and skeletal maturity). A single retrospective case series of 11 postpubertal adolescents with type 2 diabetes who underwent roux-en-Y gastric bypass demonstrated significant improvements in BMI, glycemic control, serum lipid levels and blood pressure (BP) compared to 67 adolescents who were medically managed over 1 year (47) . Notably, 10 of the 11 surgically treated youth experienced remission of their diabetes without the need for medication.

Table 1
Screening for diabetes complications and comorbidities in children with type 2 diabetes
ACR, albumin to creatinine ratio; ALT, alanine aminotransferase; BP, blood pressure; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NAFLD, nonalcoholic fatty liver disease; PCOS, polycystic ovary syndrome; TC, total cholesterol; TG, triglycerides.
Complication/comorbid condition Indications and intervals for screening Screening test
Dyslipidemia Screening should commence at diagnosis of diabetes and every 1–3 years thereafter as clinically indicated Fasting TC, HDL-C, TG, calculated LDL-C
Hypertension At diagnosis of diabetes and every diabetes-related clinical encounter thereafter (at least twice annually). BP measurement using appropriately sized cuff
NAFLD Yearly screening commencing at diagnosis of diabetes ALT
Nephropathy Yearly screening commencing at diagnosis of diabetes
  • First morning (preferred) or random ACR
  • Abnormal ACR requires confirmation at least 1 month later with either a first morning ACR or timed overnight urine collection for ACR
  • Repeated sampling should be done every 3 to 4 months over a 6- to 12-month period to demonstrate persistence
Neuropathy Yearly screening commencing at diagnosis of diabetes Questioned and examined for:
  • Symptoms of numbness, pain, cramps and paresthesia
  • Vibration sense
  • Light touch and ankle reflexes
PCOS Yearly clinical screening commencing at diagnosis of diabetes in pubertal females Clinical assessment on history and physical exam for oligo/amenorrhea, acne and/or hirsutism
Retinopathy Yearly screening commencing at diagnosis of diabetes
  • Seven-standard field, stereoscopic colour fundus photography with interpretation by a trained reader (gold standard); or
  • Direct ophthalmoscopy or indirect slit-lamp funduscopy through dilated pupil; or
  • Digital fundus photography

Immunization

The recommendations for influenza and pneumococcal immunization in Canada do not address the issue of type 2 diabetes in children, and there are no studies evaluating the usefulness of the influenza or pneumococcal vaccine in this population. There is no reason not to manage these children in a similar fashion to those with type 1 diabetes in whom influenza immunization is recommended to be offered as a way to avoid an intercurrent illness that could complicate diabetes management. Some children with type 2 diabetes may also have other factors (e.g. Aboriginal heritage) that may place them at higher risk of increased influenza- and pneumococcal-related morbidity (48–50) .

Complications

Short-term complications of type 2 diabetes in children include DKA and hyperglycemic hyperosmolar state (HHS); 10% of Canadian youth present with DKA at the time of diagnosis (2) . High mortality rates (up to 37% in 1 series) have been reported in youth presenting with combined DKA and HHS at onset of type 2 diabetes (51–53) . Evidence suggests that early-onset type 2 diabetes in adolescence is associated with severe and early-onset microvascular complications, including retinopathy, neuropathy and nephropathy (54–56) . Although neither retinopathy nor neuropathy has been described in adolescents with type 2 diabetes at diagnosis, 1 study found that 1 in 5 youth with type 2 diabetes had peripheral nerve abnormalities, and more than half had autonomic neuropathy after a median duration of diabetes of 1.3 years (56) . Micro- or macroalbuminuria has been noted in 14.2% of Canadian youth at diagnosis (2) and in up to 22.2% of US youth with a mean diabetes duration of 1.9 years (57) . Therefore, it is prudent to consider screening for these complications at diagnosis and yearly thereafter until the natural history is better understood ( Table 1 ). Furthermore, Aboriginal youth in Canada are at increased risk of renal diseases that are not associated with diabetes (58) . Given that the documentation of persistent albuminuria may indicate one of several possible diagnoses, including underlying primary renal disease, diabetic nephropathy or focal sclerosing glomerulosclerosis (a comorbid condition associated with obesity), referral to a pediatric nephrologist for assessment of etiology and treatment is recommended (58) .

Comorbid Conditions

Children with type 2 diabetes have an increased prevalence of dyslipidemia (56,57,59,60), with 44.8% of Canadian children reported to have dyslipidemia at the time of diagnosis (2) . Thus, screening for dyslipidemia at diagnosis and every 1 to 3 years as clinically indicated thereafter is recommended. In children with familial dyslipidemia and a positive family history of early cardiovascular events, a statin should be started if the low-density lipoprotein cholesterol level remains >4.1 mmol/L after a 3- to 6-month trial of dietary intervention (61) . A similar approach seems reasonable in the absence of evidence to recommend a specific intervention in children with type 2 diabetes.

Similarly, screening for high BP should begin at diagnosis of diabetes and continue at every diabetes-related clinical encounter thereafter (62), since up to 36% of adolescents with type 2 diabetes have hypertension (56) (see Type 1 Diabetes in Children and Adolescents chapter, p. S153, for additional discussion on the treatment of dyslipidemia and hypertension).

Since 95% of adolescents with type 2 diabetes present with obesity and 73% have clinical evidence of insulin resistance as manifested by acanthosis nigricans (2), surveillance should occur for comorbid conditions associated with insulin resistance, including PCOS (63) and NAFLD (64) (Table 1 ). PCOS was reported in 12.1% and NAFLD (defined as alanine aminotransferase [ALT] >3× the upper limit of normal or fatty liver on ultrasound) in 22.2% of children and youth at diagnosis of type 2 diabetes (2) .

Recommendations

  1. 1.Anticipatory guidance promoting healthy eating, maintenance of a healthy weight and regular physical activity is recommended as part of routine pediatric care [Grade D, Consensus].
  2. 2.Intensive lifestyle intervention, including dietary and exercise interventions, family counselling and family-oriented behaviour therapy, should be undertaken for obese children in order to achieve and maintain a healthy body weight [Grade D, Consensus].
  3. 3.Screening for type 2 diabetes should be performed every 2 years using an FPG test in children with any of the following:
    1. I.≥3 risk factors in nonpubertal or ≥2 risk factors in pubertal children [Grade D, Consensus]
      1. a.Obesity (BMI ≥95th percentile for age and gender) [Grade D, Level 4 (2)]
      2. b.Member of a high-risk ethnic group (e.g. Aboriginal, African, Asian, Hispanic or South Asian descent) [Grade D, Level 4 (2)]
      3. c.Family history of type 2 diabetes and/or exposure to hyperglycemia in utero [Grade D, Level 4 (2)]
      4. d.Signs or symptoms of insulin resistance (including acanthosis nigricans, hypertension, dyslipidemia, NAFLD [ALT >3X upper limit of normal or fatty liver on ultrasound], PCOS) [Grade D, Level 4 (2)]
    2. II.Impaired fasting glucose or impaired glucose tolerance [Grade D, Consensus]
    3. III.Use of atypical antipsychotic medications [Grade D, Consensus]
  4. 4.An oral glucose tolerance test (1.75 g/kg; maximum 75 g) may be used as a screening test in very obese children (BMI ≥99th percentile for age and gender) or those with multiple risk factors who meet the criteria in recommendation 3 [Grade D, Consensus].
  5. 5.Commencing at the time of diagnosis of type 2 diabetes, all children should receive ongoing intensive counselling, including lifestyle modification, from an interdisciplinary pediatric healthcare team [Grade D, Level 4 (40)].
  6. 6.The target A1C for most children with type 2 diabetes should be ≤7.0% [Grade D, Consensus].
  7. 7.In children with type 2 diabetes and A1C ≥9.0% and in those with severe metabolic decompensation (e.g. DKA), insulin therapy should be initiated but may be successfully weaned once glycemic targets are achieved, particularly if lifestyle changes are effectively adopted [Grade D, Level 4 (42)].
  8. 8.In children with type 2 diabetes, if glycemic targets are not achieved within 3–6 months using lifestyle modifications alone, one of the following should be initiated:
    • Metformin [Grade B, Level 2 (43)] OR
    • Glimepiride [Grade B, Level 2 (44)] OR
    • Insulin [Grade D, Consensus]

If the decision is made to use an oral antihyperglycemic agent, metformin should be used over glimepiride [Grade D, Consensus]. Metformin may be used at diagnosis in those children presenting with A1C >7.0% [Grade B, Level 2 (43)].

  1. 9.Children with type 2 diabetes should be screened annually for microvascular complications (nephropathy, neuropathy, retinopathy) beginning at diagnosis of diabetes [Grade D, Level 4 (56)].
  2. 10.Children with type 2 diabetes should be screened for microalbuminuria with a first morning urine ACR (preferred) [Grade B, Level 2 (65)] or a random ACR [Grade D, Consensus]. Abnormal results should be confirmed [Grade B, Level 2 (66)] at least 1 month later with a first morning ACR and, if abnormal, followed by timed, overnight urine collection for albumin excretion rate [Grade D, Consensus]. Microalbuminuria [ACR > 2.5 mg/mmol (67)] should not be diagnosed in adolescents unless it is persistent as demonstrated by 2 consecutive first morning ACR or timed collections obtained at 3- to 4-month intervals over a 6- to 12-month period [Grade D, Consensus]. Those with persistent albuminuria should be referred to a pediatric nephrologist for assessment of etiology and treatment [Grade D, Level 4 (58)].
  3. 11.Children with type 2 diabetes should have a fasting lipid profile measured at diagnosis of diabetes and every 1–3 years thereafter, as clinically indicated [Grade D, Consensus].
  4. 12.Children with type 2 diabetes should be screened for hypertension beginning at diagnosis of diabetes and at every diabetes-related clinical encounter thereafter (at least biannually) [Grade D, Consensus].
  5. 13.Children with type 2 diabetes should be screened at diagnosis for comorbid conditions associated with insulin resistance, including NAFLD [Grade D, Level 4 (2,64)] and PCOS in pubertal females [Grade D, Level 4 (2)], and yearly thereafter as clinically indicated [Grade D, Consensus].

Abbreviations:
A1C, glycated hemoglobin; ACR, albumin to creatinine ratio; ALT, alanine aminotransferase; BMI, body mass index; DKA, diabetic ketoacidosis; FPG, fasting plasma glucose; NAFLD, nonalcoholic fatty liver disease; PCOS, polycystic ovary syndrome.

References

  1. 1 K. Nadeau D. Dabelea Epidemiology of type 2 diabetes in children and adolescents Endocr Res 33 2008 35 58
  2. 2 S. Amed H.J. Dean C. Panagiotopoulos Type 2 diabetes, medication-induced diabetes, and monogenic diabetes in Canadian children: a prospective national surveillance study Diabetes Care 33 2010 786 791
  3. 3 Writing Group for the SEARCH for Diabetes in Youth Study Group D. Dabelea R.A. Bell R.B. D'Agostino Jr. Incidence of diabetes in youth in the United States JAMA 297 2007 2716 2724
  4. 4 J.S. Taylor J.E. Kacmar M. Nothnagle R.A. Lawrence A systematic review of the literature associating breastfeeding with type 2 diabetes and gestational diabetes J Am Coll Nutr 24 2005 320 326
  5. 5 M. Shields Measured Obesity: Overweight Canadian children and adolescents. Nutrition: Findings from the Canadian Community Health Survey 2005 Statistics Canada Ottawa, ON 1–34. Catalogue no. 82-620-MWE2005001
  6. 6 H. Oude Luttikhuis L. Baur H. Jansen Interventions for treating obesity in children Cochrane Database Syst Rev 1 2009 CD001872
  7. 7 Canadian Society for Exercise Physiology. Canadian Physical Activity Guidelines and Canadian Sedentary Behaviour Guidelines. Available here . Accessed February 25, 2013.
  8. 8 Health Canada. Children—Canada's food guide. Available here . Accessed February 25, 2013.
  9. 9 A.L. Rogovik J.P. Chanoine R.D. Goldman Pharmacotherapy and weight-loss supplements for treatment of paediatric obesity Drugs 70 2010 335 346
  10. 10 M. Freemark Pharmacotherapy of childhood obesity: an evidence-based, conceptual approach Diabetes Care 30 2007 395 402
  11. 11 J.R. McDuffie K.A. Calis G.I. Uwaifo Efficacy of orlistat as an adjunct to behavioral treatment in overweight African American and Caucasian adolescents with obesity-related co-morbid conditions J Pediatr Endocrinol Metab 17 2004 307 319
  12. 12 B. Ozkan A. Bereket S. Turan S. Keskin Addition of orlistat to conventional treatment in adolescents with severe obesity Eur J Pediatr 163 2004 738 741
  13. 13 J.P. Chanoine S. Hampl C. Jensen Effect of orlistat on weight and body composition in obese adolescents: a randomized controlled trial JAMA 293 2005 2873 2883
  14. 14 E.A. Sellers Pharmacotherapy and bariatric surgery for the treatment of obesity in children and adolescents, 2006 Canadian clinical practice guidelines on the management and prevention of obesity in adults and children CMAJ 176 2007 S89 S91
  15. 15 O. Pinhas-Hamiel P. Zeitler Acute and chronic complications of type 2 diabetes mellitus in children and adolescents Lancet 369 2007 1823 1831
  16. 16 O. Pinhas-Hamiel L.M. Dolan S.R. Daniels Increased incidence of non-insulin-dependent diabetes mellitus among adolescents J Pediatr 128 5 pt 1 1996 608 615
  17. 17 R. Weiss S.E. Taksali W.V. Tamborlane Predictors of changes in glucose tolerance status in obese youth Diabetes Care 28 2005 902 909
  18. 18 M.R. Palmert C.M. Gordon A.I. Kartashov Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome J Clin Endocrinol Metab 87 2002 1017 1023
  19. 19 D. Dabelea R.L. Hanson R.S. Lindsay Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships Diabetes 49 2000 2208 2211
  20. 20 T.K. Young P.J. Martens S.P. Taback Type 2 diabetes mellitus in children: prenatal and early infancy risk factors among native Canadians Arch Pediatr Adolesc Med 156 2002 651 655
  21. 21 M. Mendelson J. Cloutier L. Spence Obesity and type 2 diabetes mellitus in a birth cohort of first nation children born to mothers with pediatric-onset type 2 diabetes Pediatr Diabetes 12 3 pt 2 2011 219 228
  22. 22 M.L. Stoddart K.S. Blevins E.T. Lee Cherokee Diabetes Study. Association of acanthosis nigricans with hyperinsulinemia compared with other selected risk factors for type 2 diabetes in Cherokee Indians: the Cherokee Diabetes Study Diabetes Care 25 2002 1009 1014
  23. 23 R. Weiss J. Dziura T.S. Burgert Obesity and the metabolic syndrome in children and adolescents N Engl J Med 350 2004 2362 2374
  24. 24 G. Perseghin R. Bonfanti S. Magni Insulin resistance and whole body energy homeostasis in obese adolescents with fatty liver disease Am J Physiol Endocrinol Metab 291 2006 E697 E703
  25. 25 C. Panagiotopoulos R. Ronsley J. Davidson Increased prevalence of obesity and glucose intolerance in youth treated with second-generation antipsychotic medications Can J Psychiatry 54 2009 743 749
  26. 26 L.E. Levitt Katz S. Swami M. Abraham Neuropsychiatric disorders at the presentation of type 2 diabetes mellitus in children Pediatr Diabetes 6 2005 84 89
  27. 27 I.M. Libman E. Barinas-Mitchell A. Bartucci Reproducibility of the oral glucose tolerance test in overweight children J Clin Endocrinol Metab 93 2008 4231 4237
  28. 28 R. Sinha G. Fisch B. Teague Prevalence of impaired glucose tolerance among children and adolescents with marked obesity N Engl J Med 346 2002 802 810
  29. 29 T. Reinehr W. Andler T. Kapellen Clinical characteristics of type 2 diabetes mellitus in overweight European Caucasian adolescents Exp Clin Endocrinol Diabetes 113 2005 167 170
  30. 30 O. Pinhas-Hamiel L.M. Dolan P.S. Zeitler Diabetic ketoacidosis among obese African-American adolescents with NIDDM Diabetes Care 20 1997 484 486
  31. 31 E.A. Sellers H.J. Dean Diabetic ketoacidosis: a complication of type 2 diabetes in Canadian aboriginal youth Diabetes Care 23 2000 1202 1204
  32. 32 D. Dabelea J.P. Palmer P.H. Bennett Absence of glutamic acid decarboxylase antibodies in Pima Indian children with diabetes mellitus Diabetologia 42 1999 1265 1266
  33. 33 E. Sellers G. Eisenbarth T.K. Young H.J. Dean Diabetes-associated autoantibodies in aboriginal children Lancet 355 2000 1156
  34. 34 E.H. Hathout W. Thomas M. El-Shahawy Diabetic autoimmune markers in children and adolescents with type 2 diabetes Pediatrics 107 2001 E102
  35. 35 E. Ferrannini Insulin resistance versus insulin deficiency in non-insulin-dependent diabetes mellitus: problems and prospects Endocr Rev 19 1998 477 490
  36. 36 E.A. Sellers B. Triggs-Raine C. Rockman-Greenberg H.J. Dean The prevalence of the HNF-1alpha G319S mutation in Canadian aboriginal youth with type 2 diabetes Diabetes Care 25 2002 2202 2206
  37. 37 A.T. Hattersley Molecular genetics goes to the diabetes clinic Clin Med 5 2005 476 481
  38. 38 O. Pinhas-Hamiel D. Standiford D. Hamiel The type 2 family: a setting for development and treatment of adolescent type 2 diabetes mellitus Arch Pediatr Adolesc Med 153 1999 1063 1067
  39. 39 S.T. Johnson A.S. Newton M. Chopra In search of quality evidence for lifestyle management and glycemic control in children and adolescents with type 2 diabetes: a systematic review BMC Pediatr 10 2010 97
  40. 40 K.D.M. Wittmeier B.A. Wicklow E.A.C. Sellers Success with lifestyle monotherapy in youth with new-onset type 2 diabetes Paediatr Child Health 17 2012 129 132
  41. 41 TODAY Study Group D. Wilfley R. Berkowitz A. Goebbel-Fabbri Binge eating, mood, and quality of life in youth with type 2 diabetes: baseline data from the TODAY study Diabetes Care 34 2011 858 860
  42. 42 E.A. Sellers H.J. Dean Short-term insulin therapy in adolescents with type 2 diabetes mellitus J Pediatr Endocrinol Metab 17 2004 1561 1564
  43. 43 K.L. Jones S. Arslanian V.A. Peterokova Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial Diabetes Care 25 2002 89 94
  44. 44 M. Gottschalk T. Danne A. Vlajnic J.F. Cara Glimepiride versus metformin as monotherapy in pediatric patients with type 2 diabetes: a randomized, single-blind comparative study Diabetes Care 30 2007 790 794
  45. 45 TODAY Study Group P. Zeitler K. Hirst A clinical trial to maintain glycemic control in youth with type 2 diabetes N Engl J Med 366 2012 2247 2256
  46. 46 J. Malloy E. Capparelli M. Gottschalk Pharmacology and tolerability of a single dose of exenatide in adolescent patients with type 2 diabetes mellitus being treated with metformin: a randomized, placebo-controlled, single-blind, dose-escalation, crossover study Clin Ther 31 2009 806 815
  47. 47 T.H. Inge G. Miyano J. Bean Reversal of type 2 diabetes mellitus and improvements in cardiovascular risk factors after surgical weight loss in adolescents Pediatrics 123 2009 214 222
  48. 48 Advisory Committee on Immunization Practices Preventing pneumococcal disease among infants and young children. Recommendations of the advisory committee on immunization practices (ACIP) MMWR Recomm Rep 49 RR-9 2000 1 35
  49. 49 E.J. Crighton S.J. Elliott R. Moineddin P. Kanaroglou R. Upshur A spatial analysis of the determinants of pneumonia and influenza hospitalizations in Ontario (1992-2001) Soc Sci Med 64 2007 1636 1650
  50. 50 S.T. Fanella M.A. Pinto N.A. Bridger Pandemic (H1N1) 2009 influenza in hospitalized children in Manitoba: nosocomial transmission and lessons learned from the first wave Infect Control Hosp Epidemiol 32 2011 435 443
  51. 51 A.L. Rosenbloom Hyperglycemic hyperosmolar state: an emerging pediatric problem J Pediatr 156 2010 180 184
  52. 52 S.H. Fourtner S.A. Weinzimer L.E. Levitt Katz Hyperglycemic hyperosmolar non-ketotic syndrome in children with type 2 diabetes Pediatr Diabetes 6 2005 129 135
  53. 53 R.M. Carchman M. Dechert-Zeger A.S. Calikoglu B.D. Harris A new challenge in pediatric obesity: pediatric hyperglycemic hyperosmolar syndrome Pediatr Crit Care Med 6 2005 20 24
  54. 54 J. Krakoff R.S. Lindsay H.C. Looker Incidence of retinopathy and nephropathy in youth-onset compared with adult-onset type 2 diabetes Diabetes Care 26 2003 76 81
  55. 55 H. Yokoyama M. Okudaira T. Otani Existence of early-onset NIDDM Japanese demonstrating severe diabetic complications Diabetes Care 20 1997 844 847
  56. 56 M.C. Eppens M.E. Craig J. Cusumano Prevalence of diabetes complications in adolescents with type 2 compared with type 1 diabetes Diabetes Care 29 2006 1300 1306
  57. 57 D.M. Maahs B.M. Snively R.A. Bell Higher prevalence of elevated albumin excretion in youth with type 2 than type 1 diabetes: the SEARCH for diabetes in youth study Diabetes Care 30 2007 2593 2598
  58. 58 E.A. Sellers T.D. Blydt-Hansen H.J. Dean Macroalbuminuria and renal pathology in first nation youth with type 2 diabetes Diabetes Care 32 2009 786 790
  59. 59 E.A.C. Sellers G. Yung H.J. Dean Dyslipidemia and other cardiovascular risk factors in a Canadian First Nation pediatric population with type 2 diabetes mellitus Pediatr Diabetes 8 2007 384 390
  60. 60 A.K. Kershnar S.R. Daniels G. Imperatore Lipid abnormalities are prevalent in youth with type 1 and type 2 diabetes: the SEARCH for diabetes in youth study J Pediatr 149 2006 314 319
  61. 61 National Cholesterol Education Program (NCEP): highlights of the report of the expert panel on blood cholesterol levels in children and adolescents Pediatrics 89 1992 495 501
  62. 62 L.M. Ettinger K. Freeman J.R. DiMartino-Nardi J.T. Flynn Microalbuminuria and abnormal ambulatory blood pressure in adolescents with type 2 diabetes mellitus J Pediatr 147 2005 67 73
  63. 63 A.W. Norris B.M. Svoren Complications and comorbidities of type 2 diabetes Pediatr Ann 34 2005 710 718
  64. 64 K.J. Nadeau G. Klingensmith P. Zeitler Type 2 diabetes in children is frequently associated with elevated alanine aminotransferase J Pediatr Gastroenterol Nutr 41 2005 94 98
  65. 65 J.P. Shield L.P. Hunt J.D. Baum Screening for diabetic microalbuminuria in routine clinical care: which method? Arch Dis Child 72 1995 524 525
  66. 66 C.A. Houlihan C. Tsalamandris A. Akdeniz Albumin to creatinine ratio: a screening test with limitations Am J Kidney Dis 39 2002 1183 1189
  67. 67 R.I. Hogg S. Furth K.V. Lemley National Kidney Foundation's Kidney Disease Outcomes Quality Initiative. Clinical practice guidelines for chronic kidney disease in children and adolescents: evaluation, classification, and stratification Pediatrics 111 2003 1416 1421
 
Reproduced with permission from Canadian Journal of Diabetes © 2013 Canadian Diabetes Association. To cite this article, please refer to For citation.