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Dis Model Mech. 2019 Aug 12;12(8). pii: dmm039156. doi: 10.1242/dmm.039156.

Mild maternal hyperglycemia in INS C93S transgenic pigs causes impaired glucose tolerance and metabolic alterations in neonatal offspring.

Author information

1
Chair for Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, 81377 Munich, Germany simone.renner@lmu.de.
2
German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
3
MWM Biomodels, 84184 Tiefenbach, Germany.
4
Chair for Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, 81377 Munich, Germany.
5
Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany.
6
Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
7
Research Unit Analytical Pathology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
8
Wageningen UR Livestock Research, de Elst 1 and CARUS Animal Facilities, Wageningen University, 6708 WD Wageningen, The Netherlands.
9
German Mouse Clinic (GMC), Helmholtz Zentrum München, 85764 Neuherberg, Germany.
10
Meiji University International Institute for Bio-Resource Research, Kawasaki 214-8571, Japan.
11
Clinic for Swine, Center for Clinical Veterinary Medicine, LMU Munich, 85764 Oberschleißheim, Germany.
12
Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, LMU Munich, 80539 Munich, Germany.
13
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117596 Singapore.
14
Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, 85764 Neuherberg, Germany.
15
Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.

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 INS C93S 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.

KEYWORDS:

Developmental programming; Maternal diabetes; Metabolomics; Pig; Transgenic

Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

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