Fetal hyperglycemia and a high-fat diet contribute to aberrant glucose tolerance and hematopoiesis in adult rats

Abstract

BackgroundChildren exposed to gestational diabetes mellitus (GDM) during pregnancy are at increased risk of obesity, diabetes, and hypertension. Our goal was to identify metabolic and hematopoietic alterations after intrauterine exposure to maternal hyperglycemia that may contribute to the pathogenesis of chronic morbidities.MethodsStreptozotocin treatment induced maternal hyperglycemia during the last third of gestation in rat dams. Offspring of control mothers (OCM) and diabetic mothers (ODM) were evaluated for weight, glucose tolerance, insulin tolerance, and hematopoiesis defects. The effects of aging were examined in normal and high fat diet (HFD)-fed young (8-week-old) and aged (11-month-old) OCM and ODM rats.ResultsYoung adult ODM males on a normal diet, but not females, displayed improved glucose tolerance due to increased insulin levels. Aged ODM males and females gained more weight than OCM on a HFD and had worse glucose tolerance. Aged ODM males fed a HFD were also neutrophilic. Increases in bone marrow cellularity and myeloid progenitors preceded neutrophilia in ODM males fed a HFD.ConclusionWhen combined with other risk factors like HFD and aging, changes in glucose metabolism and hematopoiesis may contribute to the increased risk of obesity, type 2 diabetes, and hypertension observed in children of GDM mothers.

Fetal hyperglycemia acutely induces persistent insulin resistance in skeletal muscle

“…Human offspring exposed to maternal diabetes during fetal life have increased risk of insulin resistance in adulthood, beyond genetic risks (Dabelea et al 2000, Clausen et al 2008. Likewise, animal models of diabetes during pregnancy produce offspring that exhibit insulin resistance (Segar et al 2009, Blue et al 2015. Due to the complex pathology induced by diabetes, the role of hyperglycemia alone in this process has been difficult to define.…”

“…Thus, the diabetes-altered fetal environment induces a long-lasting change in offspring susceptibility to adverse metabolic outcomes. Likewise in animals, adult offspring that were exposed to maternal diabetes exhibit insulin resistance, as demonstrated in multiple models (Simmons et al 2001a, Segar et al 2009, Khalyfa et al 2013, Kahraman et al 2014, Latouche et al 2014, Yokomizo et al 2014, Blue et al 2015. However, the underlying mechanisms that produce insulin resistance are not clearly understood.…”

“…Nearly all animal studies to date examining fetally programmed insulin resistance have focused on the physiologic and molecular perturbations later rather than early in life (Simmons et al 2001a, Segar et al 2009, Khalyfa et al 2013, Latouche et al 2014, Yokomizo et al 2014, Blue et al 2015. Although these later life findings are crucial to understanding the biology underlying offspring complications, they may not identify the primary molecular mechanisms, in that secondary and tertiary pathology from other postnatal factors may be at play.…”

Epigenetic and developmental influences on the risk of obesity, diabetes, and metabolic syndrome

“… 30 In another study of rats exposed to maternal hyperglycemia, male offspring who were fed a high-fat diet demonstrated significantly increased leptin levels compared to male offspring not exposed to maternal hyperglycemia. 31 Female offspring exposed to maternal hyperglycemia and fed a high-fat diet demonstrated only moderate increase in leptin levels compared to female offspring not exposed to maternal hyperglycemia. 31 This evidence supports the programming of leptin sensitivity in response to maternal diet, with potentially sex-specific effects.…”

“… 31 Female offspring exposed to maternal hyperglycemia and fed a high-fat diet demonstrated only moderate increase in leptin levels compared to female offspring not exposed to maternal hyperglycemia. 31 This evidence supports the programming of leptin sensitivity in response to maternal diet, with potentially sex-specific effects. Furthermore, this research suggests leptin as a mediator of the association between intrauterine exposures and metabolic disturbances in the offspring.…”