Type 2 diabetes (T2D) was an adult disease until recently, but the rising rates of obesity around the world have resulted in a younger age at presentation. Children who have T2D have several comorbidities and complications reminiscent of adult diabetes, but these are appearing in teens instead of midlife. In this review, we discuss the clinical presentation and management options for youth with T2D. We discuss the elements of lifestyle intervention programs and allude to pharmacotherapeutic options used in the treatment of T2D youth. We also discuss comorbidities and complications seen in T2D in children and adolescents. 1. Introduction Type 2 diabetes (T2D) is increasing in youth, driven by the obesity epidemic that is affecting millions of children around the world [1]. T2D is a serious disorder with multiple complications that appear early in the course of the disease. Since T2D in young people has been only recognized over the past few years, knowledge of its natural history is lacking, and there are only few studies examining treatments beyond metformin and insulin. Even in case of the latter two medications, randomized controlled trials are very few, and knowledge is still accumulating in this field. One study whose results were published about the role of different treatment modalities in T2D is the treatment options for type 2 diabetes in youth (TODAY) study [2]. This was a large, longitudinal, randomized, multicenter study that recruited 699 children and adolescents with an age range of 10–17 years and female to male ratio of 2？:？1. These patients were randomized to three treatment groups that included metformin alone or in combination with lifestyle intervention (LSI) or rosiglitazone. The mean time since diagnosis of T2D was 7.8 months and HbA1c less than 8% on enrollment. The primary outcomes, defined as failure to maintain HbA1c less than 8% over 6 months or metabolic decompensation requiring insulin therapy at diagnosis or restarting after stopping insulin within 3 months, occurred in 51.7%, 46.6%, and 38.6% in the above groups, respectively [2]. Metformin alone was no different from metformin plus LSI in improving metabolic outcomes, and higher failure rates in black participants were noted. Combination therapy of metformin plus rosiglitazone offered better success rates especially in girls but was associated with more weight gain. Despite intensive LSI, the rates of clinically important weight loss (7% or more) were achieved in only 24.3% in the metformin group, 31.2% in the metformin plus LSI groups, and in only 16.7% in the metformin
P. Zeitler, K. Hirst, L. Pyle et al., “A clinical trial to maintain glycemic control in youth with type 2 diabetes,” The New England Journal of Medicine, vol. 366, no. 24, pp. 2247–2256, 2012.
[3]
M. J. Weigensberg and M. I. Goran, “Type 2 diabetes in children and adolescents,” The Lancet, vol. 373, no. 9677, pp. 1743–1744, 2009.
[4]
M. E. Tucker, “FDA panel advises easing restrictions on rosiglitazone,” BMJ, vol. 346, Article ID f3769, 2013.
[5]
S. Arslanian, “Type 2 diabetes in children: clinical aspects and risk factors,” Hormone Research, vol. 57, supplement 1, pp. 19–28, 2002.
[6]
T. S. Hannon, G. Rao, and S. A. Arslanian, “Childhood obesity and type 2 diabetes mellitus,” Pediatrics, vol. 116, no. 2, pp. 473–480, 2005.
[7]
C. D. A. C. P. G. E. Committee, “Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada,” Canadian Journal of Diabetes, vol. 37, supplement 1, pp. S1–S212, 2013.
[8]
A. L. Rosenbloom, J. H. Silverstein, S. Amemiya, P. Zeitler, and G. J. Klingensmith, “Type 2 diabetes mellitus in the child and adolescent,” Pediatric Diabetes, vol. 9, no. 5, pp. 512–526, 2008.
[9]
D. Dabelea, D. J. Pettitt, K. L. Jones, and S. A. Arslanian, “Type 2 diabetes mellitus in minority children and adolescents,” Endocrinology and Metabolism Clinics of North America, vol. 28, no. 4, pp. 709–729.
[10]
J. N. Wei, F. C. Sung, C. Y. Li, et al., “Low birth weight and high birth weight infants are both at an increased risk to have type 2 diabetes among schoolchildren in Taiwan,” Diabetes Care, vol. 26, no. 2, pp. 343–348, 2003.
[11]
S. Shalitin, M. Abrahami, P. Lilos, and M. Phillip, “Insulin resistance and impaired glucose tolerance in obese children and adolescents referred to a tertiary-care center in Israel,” International Journal of Obesity, vol. 29, no. 6, pp. 571–578, 2005.
[12]
M. I. Goran, R. N. Bergman, Q. Avilla, et al., “Impaired glucose tolerance and reduced beta-cell function in overweight Latino children with a positive family history of type 2 diabetes,” Journal of Clinical Endocrinology and Metabolism, vol. 89, pp. 207–212, 2004.
[13]
M. Juonala, M. J. J？rvisalo, N. M？ki-Torkko, M. K？h？nen, J. S. A. Viikari, and O. T. Raitakari, “Risk factors identified in childhood and decreased carotid artery elasticity in adulthood: the cardiovascular risk in young finns study,” Circulation, vol. 112, no. 10, pp. 1486–1493, 2005.
[14]
G. S. Berenson and S. R. Srnivasan, “Cardiovascular risk factors in youth with implications for aging: the Bogalusa Heart study,” Neurobiology of Aging, vol. 26, no. 3, pp. 303–307, 2005.
[15]
N. Gungor, T. Hannon, I. Libman, F. Bacha, and S. Arslanian, “Type 2 diabetes mellitus in youth: the complete picture to date,” Pediatric Clinics of North America, vol. 52, no. 6, pp. 1579–1609, 2005.
[16]
A. Flint and S. Arslanian, “Treatment of type 2 diabetes in youth,” Diabetes Care, vol. 34, aupplement 2, pp. S177–S183, 2011.
[17]
American Diabetes Association, “Diagnosis and classification of diabetes mellitus,” Diabetes Care, vol. 36, supplement 1, pp. S67–S74, 2013.
[18]
A. L. Rosenbloom, “Distinguishing type 1 and type 2 diabetes at diagnosis: what is the problem?” Pediatric Diabetes, vol. 8, no. 2, pp. 51–52, 2007.
[19]
G. J. Klingensmith, L. Pyle, S. Arslanian, et al., “The presence of GAD and IA-2 antibodies in youth with a type 2 diabetes phenotype,” Diabetes Care, vol. 33, no. 9, pp. 1970–1975, 2010.
[20]
V. Umpaichitra, M. A. Banerji, and S. Castells, “Autoantibodies in children with type 2 diabetes mellitus,” Journal of Pediatric Endocrinology and Metabolism, vol. 15, no. 1, pp. 525–530, 2002.
[21]
T. Reinehr, E. Schober, S. Wiegand, A. Thon, and R. Holl, “β-cell autoantibodies in children with type 2 diabetes mellitus: subgroup or misclassification?” Archives of Disease in Childhood, vol. 91, no. 6, pp. 473–477, 2006.
[22]
H. Tfayli, F. Bacha, N. Gungor, and S. Arslanian, “Phenotypic type 2 diabetes in obese youth insulin sensitivity and secretion in islet cell antibody-negative versus -positive patients,” Diabetes, vol. 58, no. 3, pp. 738–744, 2009.
[23]
S. Amed, H. J. Dean, C. Panagiotopoulos, et al., “Type 2 diabetes, medication-induced diabetes, and monogenic diabetes in canadian children,” Diabetes Care, vol. 33, no. 4, pp. 786–791, 2010.
[24]
T. H. Inge, M. Zeller, V. F. Garcia, and S. R. Daniels, “Surgical approach to adolescent obesity,” Adolescent Medicine Clinics, vol. 15, no. 3, pp. 429–453, 2004.
[25]
T. H. Inge, G. Miyano, J. Bean, et al., “Reversal of type 2 diabetes mellitus and improvements in cardiovascular risk factors after surgical weight loss in adolescents,” Pediatrics, vol. 123, no. 1, pp. 214–222, 2009.
[26]
S. Caprio, S. R. Daniels, A. Drewnowski et al., “Influence of race, ethnicity, and culture on childhood obesity: implications for prevention and treatment: a consensus statement of Shaping America's Health and the Obesity Society,” Diabetes Care, vol. 31, no. 11, pp. 2211–2221, 2008.
[27]
T. Reinehr, E. Schober, C. L. Roth, S. Wiegand, and R. Holl, “Type 2 diabetes in children and adolescents in a 2-year follow-up: insufficient adherence to diabetes centers,” Hormone Research, vol. 69, no. 2, pp. 107–113, 2008.
[28]
American Diabetes Association, “Type 2 diabetes in children and adolescents: consensus conference report,” Diabetes Care, vol. 23, pp. 381–389, 2000.
[29]
A. Ceriello and S. Colagiuri, “International Diabetes Federation guideline for management of postmeal glucose: a review of recommendations,” Diabetic Medicine, vol. 25, no. 10, pp. 1151–1156, 2008.
K. C. Copeland, J. Silverstein, K. R. Moore, et al., “Management of newly diagnosed type 2 diabetes mellitus (T2DM) in children and adolescents,” Pediatrics, vol. 131, no. 2, pp. 364–382, 2013.
[32]
E. S. Loghmani, “Nutrition therapy for overweight children and adolescents with type 2 diabetes,” Current Diabetes Reports, vol. 5, no. 5, pp. 385–390, 2005.
[33]
A. L. Rosenbloom, J. H. Silverstein, S. Amemiya, P. Zeitler, and G. J. Klingensmith, “Type 2 diabetes in children and adolescents,” Pediatric Diabetes, vol. 10, no. 12, pp. 17–32, 2009.
[34]
V. S. Malik, M. B. Schulze, and F. B. Hu, “Intake of sugar-sweetened beverages and weight gain: a systematic review,” The American Journal of Clinical Nutrition, vol. 84, no. 2, pp. 274–288, 2006.
[35]
L. J. Gillis and O. Bar-Or, “Food away from home, sugar-sweetened drink consumption and juvenile obesity,” Journal of the American College of Nutrition, vol. 22, no. 6, pp. 539–545, 2003.
[36]
J. McGavock, E. Sellers, and H. Dean, “Physical activity for the prevention and management of youth-onset type 2 diabetes mellitus: focus on cardiovascular complications,” Diabetes and Vascular Disease Research, vol. 4, no. 4, pp. 305–310, 2007.
[37]
O. Pinhas-Hamiel and P. A. Zeitler, “Weighty problem: diagnosis and treatment of type 2 diabetes in adolescents,” Diabetes Spectrum, vol. 10, no. 4, pp. 292–298, 1997.
[38]
N. F. Krebs and M. S. Jacobson, “Prevention of pediatric overweight and obesity,” Pediatrics, vol. 112, no. 2, pp. 424–430, 2003.
[39]
M. Foretz, S. Hébrard, J. Leclerc et al., “Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state,” Journal of Clinical Investigation, vol. 120, no. 7, pp. 2355–2369, 2010.
[40]
P. W. Caton, N. K. Nayuni, J. Kieswich, N. Q. Khan, M. M. Yaqoob, and R. Corder, “Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5,” Journal of Endocrinology, vol. 205, no. 1, pp. 97–106, 2010.
[41]
C. R. Sirtori and C. Pasik, “Re-evaluation of a biguanide, metformin: mechanism of action and tolerability,” Pharmacological Research, vol. 30, no. 3, pp. 187–228, 1994.
[42]
J. Grisouard, K. Timper, T. M. Radimerski et al., “Mechanisms of metformin action on glucose transport and metabolism in human adipocytes,” Biochemical Pharmacology, vol. 80, no. 11, pp. 1736–1745, 2010.
[43]
B. T. Bikman, D. Zheng, D. A. Kane, et al., “Metformin improves insulin signaling in obese rats via reduced IKK-beta action in a fiber-type specific manner,” Journal of Obesity, vol. 2010, Article ID 970865, 8 pages, 2010.
[44]
J. M. Cacicedo, N. Yagihashi, J. F. Keaney Jr., N. B. Ruderman, and Y. Ido, “AMPK inhibits fatty acid-induced increases in NF-kappaB transactivation in cultured human umbilical vein endothelial cells,” Biochemical and Biophysical Research Communications, vol. 324, no. 4, pp. 1204–1209, 2004.
[45]
N. Musi, M. F. Hirshman, J. Nygren et al., “Metformin increases AMP-activated protein-kinase activity in skeletal muscle of subjects with type 2 diabetes,” Diabetes, vol. 51, no. 7, pp. 2074–2081, 2002.
[46]
G. Zhou, R. Myers, Y. Li et al., “Role of AMP-activated protein kinase in mechanism of metformin action,” Journal of Clinical Investigation, vol. 108, no. 8, pp. 1167–1174, 2001.
[47]
A. J. Mulherin, A. H. Oh, H. Kim, A. Grieco, L. M. Lauffer, and P. L. Brubaker, “Mechanisms underlying metformin-induced secretion of glucagon-like peptide-1 from the intestinal L cell,” Endocrinology, vol. 152, no. 12, pp. 4610–4619, 2011.
[48]
K. L. Jones, S. Arslanian, V. A. Peterokova, J.-S. Park, and M. J. Tomlinson, “Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial,” Diabetes Care, vol. 25, no. 1, pp. 89–94, 2002.
[49]
J. H. Silverstein and A. L. Rosenbloom, “Treatment of type 2 diabetes mellitus in children and adolescents,” Journal of Pediatric Endocrinology and Metabolism, vol. 13, no. 6, pp. 1403–1409, 2000.
[50]
E. A. C. Sellers and H. J. Dean, “Short-term insulin therapy in adolescents with type 2 diabetes mellitus,” Journal of Pediatric Endocrinology and Metabolism, vol. 17, no. 11, pp. 1561–1564, 2004.
[51]
M. I. Zuhri-Yafi, P. G. Brosnan, and D. S. Hardin, “Treatment of type 2 diabetes mellitus in children and adolescents,” Journal of Pediatric Endocrinology and Metabolism, vol. 15, no. 1, pp. 541–546, 2002.
[52]
R. G. Bretzel, U. Nuber, W. Landgraf, D. R. Owens, C. Bradley, and T. Linn, “Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial,” The Lancet, vol. 371, no. 9618, pp. 1073–1084, 2008.
[53]
J. A. Cramer, “A systematic review of adherence with medications for diabetes,” Diabetes Care, vol. 27, no. 5, pp. 1218–1224, 2004.
[54]
V. S. Raman and R. A. Heptulla, “New potential adjuncts to treatment of children with type 1 diabetes mellitus,” Pediatric Research, vol. 65, no. 4, pp. 370–374, 2009.
[55]
M. Gottschalk, T. Danne, A. Vlajnic, and J. F. Cara, “Glimepiride versus metformin as monotherapy in pediatric patients with type 2 diabetes: a randomized, single-blind comparative study,” Diabetes Care, vol. 30, no. 4, pp. 790–794, 2007.
[56]
H. E. Lebovitz, J. F. Dole, R. Patwardhan, E. B. Rappaport, and M. I. Freed, “Rosiglitazone monotherapy is effective in patients with type 2 diabetes,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 4, pp. 280–288, 2001.
[57]
P. L. Brubaker, “Minireview: update on incretin biology: focus on glucagon-like peptide-1,” Endocrinology, vol. 151, no. 5, pp. 1984–1989, 2010.
[58]
D. J. Drucker and M. A. Nauck, “The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes,” The Lancet, vol. 368, no. 9548, pp. 1696–1705, 2006.
[59]
J. H. Martin, C. F. Deacon, M. D. Gorrell, and J. B. Prins, “Incretin-based therapies: review of the physiology, pharmacology and emerging clinical experience,” Internal Medicine Journal, vol. 41, no. 4, pp. 299–307, 2011.
[60]
G. Rizzo and D. Arduini, “Intrauterine growth restriction: diagnosis and management. A review,” Minerva Ginecologica, vol. 61, no. 5, pp. 411–420, 2009.
[61]
A. Peters, “Incretin-based therapies: review of current clinical trial data,” The American Journal of Medicine, vol. 123, no. 3, pp. S28–S37, 2010.
[62]
A. D. Kshirsagar, A. S. Aggarwal, U. N. Harle, and A. D. Deshpande, “DPP IV inhibitors: successes, failures and future prospects,” Diabetes and Metabolic Syndrome, vol. 5, no. 2, pp. 105–112, 2011.
[63]
L. Sj？str？m, K. Narbro, C. D. Sj？str？m, et al., “Effects of bariatric surgery on mortality in Swedish obese subjects,” The New England Journal of Medicine, vol. 357, no. 8, pp. 741–752, 2007.
[64]
R. Nandagopal, R. J. Brown, and K. I. Rother, “Resolution of type 2 diabetes following bariatric surgery: implications for adults and adolescents,” Diabetes Technology & Therapeutics, vol. 12, no. 8, pp. 671–677, 2010.
[65]
E. Spanakis and C. Gragnoli, “Bariatric surgery, safety and type 2 diabetes,” Obesity Surgery, vol. 19, no. 3, pp. 363–368, 2009.
[66]
D. M. Maahs, B. M. Snively, R. A. Bell et al., “Higher prevalence of elevated albumin excretion in youth with type 2 than type 1 diabetes: the SEARCH for diabetes in youth study,” Diabetes Care, vol. 30, no. 10, pp. 2593–2598, 2007.
[67]
O. Pinhas-Hamiel and P. Zeitler, “Acute and chronic complications of type 2 diabetes mellitus in children and adolescents,” The Lancet, vol. 369, no. 9575, pp. 1823–1831, 2007.
[68]
J. P. H. Shield, L. P. Hunt, J. D. Baum, and C. A. Pennock, “Screening for diabetic microalbuminuria in routine clinical care: which method?” Archives of Disease in Childhood, vol. 72, no. 6, pp. 524–525, 1995.
[69]
C. A. Houlihan, C. Tsalamandris, A. Akdeniz, and G. Jerums, “Albumin to creatinine ratio: a screening test with limitations,” The American Journal of Kidney Diseases, vol. 39, no. 6, pp. 1183–1189, 2002.
[70]
R. J. Hogg, S. Furth, K. V. Lemley, et al., “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, vol. 111, pp. 1416–1421, 2003.
[71]
K. C. Donaghue, F. Chiarelli, D. Trotta, J. Allgrove, and K. Dahl-Jorgensen, “Microvascular and macrovascular complications associated with diabetes in children and adolescents,” Pediatric Diabetes, vol. 10, no. 12, pp. 195–203, 2009.
[72]
I. M. Libman and S. A. Arslanian, “Prevention and treatment of type 2 diabetes in youth,” Hormone Research, vol. 67, no. 1, pp. 22–34, 2007.
[73]
American Diabetes Association, “Management of dyslipidemia in children and adolescents with diabetes,” Diabetes Care, vol. 26, pp. 2194–2197, 2003.
[74]
K. J. Nadeau, G. Klingensmith, and P. Zeitler, “Type 2 diabetes in children is frequently associated with elevated alanine aminotransferase,” Journal of Pediatric Gastroenterology and Nutrition, vol. 41, pp. 94–98, 2005.
[75]
B. A. Wicklow, K. D. Wittmeier, A. C. MacIntosh, E. A. Sellers, et al., “Metabolic consequences of hepatic steatosis in overweight and obese adolescents,” Diabetes Care, vol. 35, pp. 905–910, 2012.
[76]
A. Kotronen and H. Yki-J？rvinen, “Fatty liver: a novel component of the metabolic syndrome,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 1, pp. 27–38, 2008.
[77]
A. Alisi, A. E. Feldstein, A. Villani, M. Raponi, and V. Nobili, “Pediatric nonalcoholic fatty liver disease: a multidisciplinary approach,” Nature Reviews Gastroenterology and Hepatology, vol. 13, pp. 152–161, 2012.
[78]
R. S. Legro, A. R. Kunselman, W. C. Dodson, and A. Dunaif, “Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women,” Journal of Clinical Endocrinology and Metabolism, vol. 84, no. 1, pp. 165–169, 1999.
[79]
B. Rossi, S. Sukalich, J. Droz et al., “Prevalence of metabolic syndrome and related characteristics in obese adolescents with and without polycystic ovary syndrome,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 12, pp. 4780–4786, 2008.
[80]
B. C. J. M. Fauser, “Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome,” Fertility and Sterility, vol. 81, no. 1, pp. 19–25, 2004.
[81]
B. C. Fauser, B. C. Tarlatzis, R. W. Rebar et al., “Consensus on women's health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group,” Fertility and Sterility, vol. 97, no. 1, pp. 28.e25–38.e25, 2012.
[82]
E. Carmina, S. E. Oberfield, and R. A. Lobo, “The diagnosis of polycystic ovary syndrome in adolescents,” The American Journal of Obstetrics and Gynecology, vol. 203, no. 3, pp. 201.e5–205.e5, 2010.
[83]
K. F. Nicandri and K. Hoeger, “Diagnosis and treatment of polycystic ovarian syndrome in adolescents,” Current Opinion in Endocrinology Diabetes and Obesity, vol. 19, pp. 497–504, 2012.
[84]
D. A. Ehrmann, “Polycystic ovary syndrome,” The New England Journal of Medicine, vol. 352, no. 12, pp. 1223–1277, 2005.
[85]
B. W. Rackow, “Polycystic ovary syndrome in adolescents,” Current Opinion in Obstetrics and Gynecology, vol. 24, no. 5, pp. 281–287, 2012.
[86]
G. Jean-Louis, F. Zizi, L. T. Clark, C. D. Brown, and S. I. McFarlane, “Obstructive sleep apnea and cardiovascular disease: role of the metabolic syndrome and its components,” Journal of Clinical Sleep Medicine, vol. 4, no. 3, pp. 261–272, 2008.
[87]
S. Sookoian and C. J. Pirola, “Obstructive sleep apnea is associated with fatty liver and abnormal liver enzymes: a meta-analysis,” Obesity Surgery. In press.
[88]
J. Krakoff, R. S. Lindsay, H. C. Looker, R. G. Nelson, R. L. Hanson, and W. C. Knowler, “Incidence of retinopathy and nephropathy in youth-onset compared with adult-onset type 2 diabetes,” Diabetes Care, vol. 26, no. 1, pp. 76–81, 2003.
[89]
M. C. Eppens, M. E. Craig, J. Cusumano et al., “Prevalence of diabetes complications in adolescents with type 2 compared with type 1 diabetes,” Diabetes Care, vol. 29, no. 6, pp. 1300–1306, 2006.
[90]
H. Yokoyama, M. Okudaira, T. Otani et al., “Existence of early-onset NIDDM Japanese demonstrating severe diabetic complications,” Diabetes Care, vol. 20, no. 5, pp. 844–847, 1997.
