Abstract
ABSTRACTAlongside the obesity epidemic, the prevalence of maternal diabetes is rising worldwide, and adverse effects on fetal development and metabolic disturbances in the offspring's later life have been described. To clarify whether metabolic programming effects are due to mild maternal hyperglycemia without confounding obesity, we investigated wild-type offspring of INSC93S transgenic pigs, which are a novel genetically modified large-animal model expressing mutant insulin (INS) C93S in pancreatic β-cells. This mutation results in impaired glucose tolerance, mild fasting hyperglycemia and insulin resistance during late pregnancy. Compared with offspring from wild-type sows, piglets from hyperglycemic mothers showed impaired glucose tolerance and insulin resistance (homeostatic model assessment of insulin resistance: +3-fold in males; +4.4-fold in females) prior to colostrum uptake. Targeted metabolomics in the fasting and insulin-stimulated state revealed distinct alterations in the plasma metabolic profile of piglets from hyperglycemic mothers. They showed increased levels of acylcarnitines, gluconeogenic precursors such as alanine, phospholipids (in particular lyso-phosphatidylcholines) and α-aminoadipic acid, a potential biomarker for type 2 diabetes. These observations indicate that mild gestational hyperglycemia can cause impaired glucose tolerance, insulin resistance and associated metabolic alterations in neonatal offspring of a large-animal model born at a developmental maturation status comparable to human babies.
Highlights
The prevalence of maternal diabetes, in particular of gestational diabetes mellitus (GDM), is rapidly increasing worldwide, primarily due to the increased prevalence of obesity
Founder boars 9776 and 9748 and their respective F1 offspring revealed the highest INSC93S to INS transcript ratios in the pancreas (Fig. 1B) along with reduced intravenous glucose tolerance (Fig. 1C) and highly reduced insulin secretion (Fig. 1D)
The C93S mutation was chosen on the basis of the analogous Munich Ins2C95S mutant mouse model (Herbach et al, 2007) and the human INSC95Y mutation (Colombo et al, 2008; Stoy et al, 2010), which lead to an early diabetic phenotype, i.e. permanent neonatal diabetes
Summary
The prevalence of maternal diabetes, in particular of gestational diabetes mellitus (GDM), is rapidly increasing worldwide, primarily due to the increased prevalence of obesity. In addition to clinical/epidemiological studies, diet-induced obese nonhuman primate (NHP) models have been used to dissect the underlying mechanisms (reviewed in Friedman, 2018). Since these NHP models represent the entire spectrum of the metabolic syndrome it is difficult to differentiate consequences of hyperglycemia from those of obesity (Thompson et al, 2017)
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