Mild maternal hyperglycemia in INSC93S transgenic pigs causes impaired glucose tolerance and metabolic alterations in neonatal offspring.

Abstract

Alongside 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.

• Authors: Simone Renner, Ana Sofia Martins, Elisabeth Streckel, Christina Braun-Reichhart, Mattias Backman, Cornelia Prehn, Nikolai Klymiuk, Andrea Bähr, Andreas Blutke, Christina Landbrecht-Schessl, Annegret Wünsch, Barbara Kessler, Mayuko Kurome, Arne Hinrichs, Sietse-Jan Koopmans, Stefan Krebs, Elisabeth Kemter, Birgit Rathkolb, Hiroshi Nagashima, Helmut Blum, Mathias Ritzmann, Rüdiger Wanke, Bernhard Aigner, Jerzy Adamski, Martin Hrabě de Angelis, Eckhard Wolf
• Journal: Disease models & mechanisms (Dis Model Mech) Vol. 12 Issue 8 (08 12 2019) ISSN: 1754-8411 [Electronic] England
• PMID: 31308048 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019. Published by The Company of Biologists Ltd.

Chemical References

• Insulin

Topics

• Animals
• Animals, Genetically Modified
• Animals, Newborn
• Female
• Glucose Intolerance (etiology)
• Hyperglycemia (etiology)
• Insulin (genetics)
• Insulin Secretion
• Insulin-Secreting Cells (metabolism)
• Pregnancy
• Prenatal Exposure Delayed Effects (pathology)
• Swine