The Metabolic Phenotype of Youth Onset Type 2 Diabetes: The Role of Pregestational Diabetes Exposure and the Hepatic Nuclear Factor 1Alpha G319S Polymorphism

Introduction: The influence of exposure to diabetes in utero and the HNF-1α G319S polymorphism on the metabolic phenotype of youth with T2DM at diagnosis is unknown. The objective of this study is to describe the metabolic phenotype at diagnosis of youth with T2DM: a) by exposure to gestational or pregestational diabetes and b) by HNF-1α G319S genotype.

Methods: A cross-sectional retrospective chart review of youth with T2DM diagnosed between 2006 and 2011 seen at a single centre was performed. The primary variables of interest and selected clinical and biochemical characteristics at birth and at diagnosis of diabetes were extracted. Descriptive statistics and regression analyses were undertaken.

Results: One hundred eighty-four youth were included. Youth exposed to pregestational diabetes were younger at diagnosis (-1.26 years, p<0.001), had a shorter gestation (-1.73 weeks, p<0.001) and a lower waist z-score (-2.77, p<0.001) compared to those not exposed to diabetes in utero. Youth homozygous for the HNF-1α G319S polymorphism were younger (-1.77 years p<0.001), had a lower BMI z-score (-0.32, p=0.04), waist z-score (-1.91, p=0.04), HbA1c (-1.73%; 18.9 mmol/mol, p<0.01), triglycerides (-90.3 mg/dl; -1.02 mmol/L, p=0.04) and higher HDL-c (8.88 mg/dl; 0.23 mmol/L, p=0.001) compared to wild-type youth at diagnosis. Homozygote youth were less likely to have hypertension or acanthosis nigricans at diagnosis (OR 0.27, p=0.03; OR 0.32, p=0.04 respectively).

Conclusion: Differences in the metabolic phenotype of subgroups of youth with T2DM suggest differences in the pathophysiology of diabetes. An understanding of specific phenotypes is necessary to plan and inform both prevention and intervention strategies.