Intrauterine Exposure to Diabetic Milieu Does Not Induce Diabetes and Obesity in Male Adulthood in a Novel Rat Model

Abstract

Several studies show an association of maternal diabetes during pregnancy with adverse offspring metabolic health. Other studies, however, suggest that this effect might be biased by obesity, which is independently associated with offspring metabolic disease and often coexistent to maternal diabetes. We performed a prospective study in a rat model to test the hypothesis that the burden of a diabetic pregnancy without obesity deteriorates metabolic health in male offspring. We generated maternal type 2 diabetes before conception that persisted during pregnancy by knockdown of the insulin receptor in small hairpin RNA–expressing transgenic rats. Male WT (wild type) offspring were followed up until adulthood and metabolically challenged by high-fat diet. Blood glucose was measured continuously via a telemetry device. Glucose and insulin tolerance tests were performed, and body composition was analyzed. Weight gain and glucose levels during adolescence and adulthood were similar in male offspring of diabetic and control pregnancies. Body weight and fat mass after high-fat diet, as well as glucose and insulin tolerance tests, were unaltered between male adult offspring of both groups. Glycemic control consisting of up to 49 000 individual glucose measures was comparable between both groups. Intrauterine exposure to maternal hyperglycemia and hyperinsulinemia without obesity had no impact on male offspring metabolic health in our model. We conclude that the intrauterine exposure itself does not represent a mechanism for fetal programming of diabetes and obesity in our model. Other maternal metabolic parameters during pregnancy, such as obesity, might impact long-term offspring metabolic health.

Diabetic pregnancy as a novel risk factor for cardiac dysfunction in the offspring—the heart as a target for fetal programming in rats

“…6e). In addition, blood glucose, insulin and C-peptide levels and glycaemic control during GTT and ITT were unaltered as shown recently [23]. Systolic BP, diastolic BP and MAP were significantly reduced in NC-fed dbtc offspring in comparison with ctrl and prior to dietary challenge in dbtc offspring compared with ctrl (ESM Table 4).…”

“…1b). Maternal blood glucose is based on data from Schütte et al and was appropriately adapted [23]. Litter sizes were not altered between diabetic and control pregnancies, but mean birthweight of all pups was decreased in diabetic pregnancies compared with control pregnancies (data not shown).…”

“…Litter sizes were not altered between diabetic and control pregnancies, but mean birthweight of all pups was decreased in diabetic pregnancies compared with control pregnancies (data not shown). However, only the heavier diabetic pregnancy offspring which did not differ in body weight from normoglycaemic pregnancy offspring survived the raising by foster mothers and could be taken into investigation and analysis of our study [23].…”

“…At week 36 of age, offspring were decapitated, weighed, blood was collected and organs were withdrawn, weighed and cryogenically preserved. The metabolic characterisation of the animals within this study including GTT, ITT and telemetric continuous glucose measurement has already been reported [23]. We focus here on the cardiac analysis of the animals.…”

“…Therefore, we aimed to characterise the cardiac phenotype of HFD-fed adult male offspring descended from a diabetic dam in a transgenic rat model [21][22][23] based on insulin receptor knockdown mediated by small hairpin RNA (shRNA). We performed an extensive, thorough study on offspring health in this model and have already shown that there is no difference in glucose intolerance and body weight in adult male offspring both on normal chow (NC) and HFD after a diabetic pregnancy compared with a control pregnancy [23]. This gives us the opportunity to investigate potential cardiac maladaptation independent of metabolic risk factors.…”