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The next generation cohort: a description of a cohort at high risk for childhood onset type 2 diabetes

  • F. Jabar (a1), S. Colatruglio (a1), E. Sellers (a1) (a2), K. Kroeker (a3) and B. Wicklow (a1) (a2)...


Children of mothers with youth-onset (<18 years) type 2 diabetes (T2D) are at increased risk of youth-onset T2D. In Canada, the highest reported prevalence of youth-onset T2D is in First Nation youth, some of whom harbor a unique genetic predisposition HNF1α polymorphism which has been associated with age of onset and clinical presentation. To describe the characteristics of the Next Generation birth cohort (n=260) at 7–9 years (n=88) and 14–16 years of age (n=27). This is a cross-sectional study of offspring exposed in utero to T2D (Next Generation Birth Cohort). Annual assessments from age 7 include height and weight, and biochemical testing (glucose, insulin, lipids, HbA1c). Descriptive statistics were employed. χ2 tests and repeated-measures ANOVA were used to compare categorical and continuous characteristics, respectively. In total, 11.9% of the total cohort have developed T2D. Of those 14–16.9 years of age, 16.0% have developed T2D. 92% of the offspring ages 7–9 and 70.3% of offspring ages 14–16 are overweight or obese. Children had a significantly higher body mass index z-score than adolescents (2.9 v. 1.5, P=0.001). Comparing the different HNF1α genotypes (G/G wildtype, G/S heterozygote, S/S homozygote); HbA1c (GG: 5.5% v. G/S: 5.7% v. S/S: 8.8%; P=0.0052), insulin (GG: 103 v. G/S: 202; P=0.05) and T2D status (G/G: 5.7% v. G/S: 28.1% v. S/S: 72.7%; P<0.0001) were significantly different between groups. T2D is very common among adolescents of mothers with youth-onset T2D. Early childhood obesity and the HNF1α G319S allele are associated with the incidence of T2D in the Next Gen offspring.


Corresponding author

*Address for correspondence: B. A. Wicklow, The Children’s Hospital Research Institute of Manitoba, FE307-685 William Avenue, Winnipeg Manitoba Canada, R3E 0Z2. E-mail:


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1. Pinhas-Hamiel, O, Zeitler, P. The global spread of type 2 diabetes mellitus in children and adolescents. J Pediatr. 2005; 146, 693700.
2. Amed, S, Dean, H, Panagiotopoulos, S, et al. Type 2 diabetes, medication-induced diabetes, and monogenic diabetes in Canadian children: a prospective national surveillance study. Diabetes Care. 2010; 33, 786791.
3. Sellers, EAC, Wicklow, BA, Dean, HJ. Clinical and demographic characteristics of type 2 diabetes in youth at diagnosis in Manitoba and Northwestern Ontario (2006–2011). Can J Diab. 2012; 36, 114118.
4. Dart, AB, Martens, PJ, Rigatto, C, et al. Earlier onset of complications in youth with type 2 diabetes. Diabetes Care. 2014; 37, 436443.
5. Dabelea, D, Hanson, RL, Lindsay, RS, et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes. 2000; 49, 22082211.
6. Young, TK, Martens, PJ, Taback, SP, et al. Type 2 diabetes mellitus in children: prenatal and early infancy risk factors among native Canadians. Arch Pediatr Adolesc Med. 2002; 156, 651655.
7. Dabelea, D, Mayer-Davis, EJ, Lamichhane, AP, et al. Association of intrauterine exposure to maternal diabetes and obesity with type 2 diabetes in youth: the SEARCH Case-Control Study. Diabetes Care. 2008; 31, 14221426.
8. Dean, H. Type 2 diabetes in youth: a new epidemic. Adv Exp Med Biol. 2001; 498, 15.
9. Dean, HJ, Mundy, RL, Moffatt, M. Non-insulin-dependent diabetes mellitus in Indian children in Manitoba. CMAJ. 1992; 147, 5257.
10. Hegele, RA, Cao, H, Harris, SB, Hanley, AJ, Zinman, B. The hepatic nuclear factor-1alpha G319S variant is associated with early-onset type 2 diabetes in Canadian Oji-Cree. J Clin Endocrinol Metab. 1999; 84, 10771082.
11. Pontoglio, M, Sreenan, S, Roe, M, et al. Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice. J Clin Invest. 1998; 101, 22152222.
12. Okita, K, Yang, Q, Yamagata, K, et al. Human insulin gene is a target gene of hepatocyte nuclear factor-1alpha (HNF-1alpha) and HNF-1beta. Biochem Biophys Res Commun. 1999; 263, 566569.
13. Yang, Q, Yamagata, K, Yamamoto, K, et al. Structure/function studies of hepatocyte nuclear factor-1alpha, a diabetes-associated transcription factor. Biochem Biophys Res Commun. 1999; 266, 196202.
14. Harries, LW, Sloman, MJ, Sellers, EA, Hattersley, AT, Ellard, S. Diabetes susceptibility in the Canadian Oji-Cree population is moderated by abnormal mRNA processing of HNF1A G319S transcripts. Diabetes. 2008; 57, 19781982.
15. Triggs-Raine, BL, Kirkpatrick, RD, Kelly, SL, et al. HNF-1alpha G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community. Proc Natl Acad Sci U S A. 2002; 99, 46144619.
16. Sellers, EA, Triggs-Raine, BL, Rockman-Greenberg, C, Dean, HJ. The prevalence of the HNF-1alpha G319S mutation in Canadian aboriginal youth with type 2 diabetes. Diabetes Care. 2002; 25, 22022206.
17. Jonasson, ME, Wicklow, BA, Sellers, EA, Dolinsky, VW, Doucette, CA. Exploring the role of the HNF-1alpha G319S polymorphism in beta cell failure and youth-onset type 2 diabetes: lessons from MODY and Hnf-1alpha-deficient animal models. Biochem Cell Biol. 2015; 93, 487494.
18. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2008 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes, 2008: 37: S1–S201.
19. Kuczmarski, RJ, Ogden, CL, Grummar-Strawn, LM, et al. CDC growth charts: United States. Adv Data. 2000; 314, 127.
20. Amed, S, Islam, N, Sutherland, J, Reimer, K. Incidence and prevalence trends of youth-onset type 2 diabetes in a cohort of Canadian youth: 2002-2013. Pediatr Diabetes. 2018; 19: 630–636.
21. Matyka, KA. Type 2 diabetes in childhood: epidemiological and clinical aspects. Br Med Bull. 2008; 86, 5975.
22. Linares Segovia, B, Gutierrez Tinoco, M, Izquierdo Arrizon, A, Guizar Mendoza, JM, Amador Licona, N. Long-term consequences for offspring of paternal diabetes and metabolic syndrome. Exp Diabetes Res. 2012; 2012, 684562.
23. Ruchat, SM, Hivert, MF, Bouchard, L. Epigenetic programming of obesity and diabetes by in utero exposure to gestational diabetes mellitus. Nutr Rev. 2013; 71(Suppl. 1), S88S94.
24. Houde, AA, Ruchat, SM, Allard, C, et al. LRP1B, BRD2 and CACNA1D: new candidate genes in fetal metabolic programming of newborns exposed to maternal hyperglycemia. Epigenomics. 2015; 7, 11111122.
25. del Rosario, MC, Ossowski, V, Knowler, WC, et al. Potential epigenetic dysregulation of genes associated with MODY and type 2 diabetes in humans exposed to a diabetic intrauterine environment: an analysis of genome-wide DNA methylation. Metabolism. 2014; 63, 654660.
26. Quilter, CR, Cooper, WN, Cliffe, KM, et al. Impact on offspring methylation patterns of maternal gestational diabetes mellitus and intrauterine growth restraint suggest common genes and pathways linked to subsequent type 2 diabetes risk. FASEB J. 2014; 28, 48684879.
27. O’Connor, EA, Evans, CV, Burda, BU, et al. Screening for obesity and intervention for weight management in children and adolescents: evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2017; 317, 24272444.
28. Dabelea, D, Harrod, CS. Role of developmental overnutrition in pediatric obesity and type 2 diabetes. Nutr Rev. 2013; 71(Suppl 1), S62S67.
29. Bjerregaard, LG, Jensen, BW, Angquist, L, et al. Change in overweight from childhood to early adulthood and risk of type 2 diabetes. N Engl J Med. 2018; 378, 13021312.
30. Charison, J, Wicklow, BA, Dean, HJ, Sellers, EA. The metabolic phenotype of youth onset type 2 diabetes: the role of pregestational diabetes exposure and the hepatic nuclear factor 1Alpha G319S Polymorphism. Can J Diabetes. 2016; 40, 210215.
31. Wicklow, BA, Wittmeier, KD, MacIntosh, AC, et al. Metabolic consequences of hepatic steatosis in overweight and obese adolescents. Diabetes Care. 2012; 35, 905910.
32. Saad, V, Wicklow, B, Wittmeier, K, et al. A clinically relevant method to screen for hepatic steatosis in overweight adolescents: a cross sectional study. BMC Pediatr. 2015; 15, 151.
33. Volkmar, M, Dedeurwaerder, S, Cunha, DA, et al. DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. EMBO J. 2012; 31, 14051426.
34. Strawbridge, RJ, Dupuis, J, Prokopenko, I, et al. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes. Diabetes. 2011; 60, 26242634.
35. Chen, P, Piaggi, P, Trautig, M, et al. Differential methylation of genes in individuals exposed to maternal diabetes in utero. Diabetologia. 2017; 60, 645655.



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