Overweight-Obesity And Glucose Intolerance In Offspring Of Indian Diabetic Mothers

Abstract Aims Maternal diabetes in pregnancy increases offspring obesity and diabetes risk. We investigated body size and composition, and glucose tolerance in offspring born to Indian diabetic mothers (ODM) and to non-diabetic mothers (ONDM), and studied maternal and paternal determinants. Methods We compared the physical characteristics, body composition (Dual energy X-ray Absorptiometry) and glycemia of ODMs and matched ONDMs. Overweight-obesity was defined using International Obesity Task Force (IOTF) for 2-18 years (cutoff of BMI > 25 kg/m 2 ) and World Health Oraganization (WHO) criteria for >18 years (BMI > 25 kg/m 2 ). Glycemic measures included capillary blood glucose measurement in children <10 years of age and a 1.75g/kg glucose OGTT in those >=10 years. We calculated separate SD scores for capillary fasting, capillary random and venous fasting plasma glucose. Those above median SD score were classified as glucose intolerant. We evaluated insulin sensitivity (Homeostatic Model Assessment HOMA-S and Matsuda index), beta cell function (HOMA-β and insulinogenic index) and β-cell compensatory response (Disposition Index: [Log (Insulinogenic index) + Log (Matsuda index)]). We studied the association of maternal and paternal body size and glycemia with outcomes in the child. Results We studied 200 ODMs of 176 diabetic mothers (133 GDM, 21 type 2 diabetes, 22 type 1 diabetes), and 177 ONDMs at an average of 9.7 years after delivery. ODMs were heavier, more adipose and more glucose intolerant than ONDMs. Differences for body size parameters were more prominent in males and they also had a wider spectrum of metabolic abnormalities. Three (4%) ODM were receiving treatment for diabetes (diagnosed between 10-25 years of age). On OGTT, the older ODMs (>= 10 years) had higher prevalence of glucose intolerance (1 DM, 14 IFG, 12 IGT and 4 both IFG and IGT) compared to ONDM, (0 DM, 7 IFG, 9 IGT and 1 both IFG and IGT). None of the diabetic and pre-diabetic ODMs, including children of type 1 diabetic mothers, were positive for circulating GAD or ZnT8 antibodies. Younger ODMs (<10 years) also had higher capillary blood glucose concentrations compared to ONDM. Overall, ODMs had higher prevalence of glucose intolerance compared to ONDMs, both in younger and older, and in boys and girls. HOMA-S and Disposition index were lower in ODM compared to ONDM. Other indices of insulin secretion and action (HOMA-β, Insulinogenic index and Matsuda index) were similar in the two groups. Type 2 diabetic and GDM mothers were heavier compared to type 1 diabetic mothers, and their children were more likely to be overweight-obese. Children of type 1 diabetic mothers were glucose intolerant despite lack of overweight-obesity. In addition, fathers had an independent influence on the child’s phenotype, especially for overweight-obesity. Maternal hyperglycemia during pregnancy had an overriding influence on offspring glucose intolerance. Conclusions ODMs were more overweight-obese and glucose intolerant compared to ONDMs. We propose that these two outcomes in the ODMs are independently programmed by respective parental phenotypes. Preventive strategies will need to be informed by these findings. Studies of genetic and epigenetic mechanisms involved in fetal programming of body size and glycemia will further help our understanding. Research in Context What is already known about this subject? India has experienced a rapid escalation of diabetes in young individuals including diabetes in pregnancy. Short-term effects of maternal hyperglycemia on the offspring are well known. What is the key question? There is little data on long-term effects of maternal hyperglycemia on offspring body size and cardiometabolic risk factors. We compared these in the offspring of diabetic mothers compared to those of non-diabetic mothers. We also sought differences within types of diabetes (type 1, type 2, GDM) and studied paternal determinants of these outcomes. What are the new findings? Type 1 diabetic mothers were thinnest and most hyperglycemic; type 2 diabetic mothers were most overweight-obese, GDM mothers were intermediate. Gestational maternal hyperglycemia was the overriding determinant of offspring hyperglycemia. Maternal hyperglycemia predicted offspring glucose intolerance but not overweight obesity; maternal overweight-obesity predicted offspring overweight-obesity but not hyperglycemia, suggesting an uncoupling of these phenotypes often considered congruent. Fathers had an additive influence on offspring size. How might this impact on clinical practice in the foreseeable future? Knowing the relative independence of influences on body size and metabolic outcomes will inform strategies of their primordial and primary prevention. Establishing genetic and epigenetic mechanisms will help.