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.
| Original language | English |
|---|---|
| Journal | Disease Models & Mechanisms |
| Volume | 12 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 12 Aug 2019 |
Fingerprint
Keywords
- Developmental programming
- Maternal diabetes
- Metabolomics
- Pig
- Transgenic
Cite this
}
Mild maternal hyperglycemia in INSC93S transgenic pigs causes impaired glucose tolerance and metabolic alterations in neonatal offspring. / Renner, Simone; Martins, Ana Sofia; Streckel, Elisabeth; Braun-Reichhart, Christina; Backman, Mattias; Prehn, Cornelia; Klymiuk, Nikolai; Bähr, Andrea; Blutke, Andreas; Landbrecht-Schessl, Christina; Wünsch, Annegret; Kessler, Barbara; Kurome, Mayuko; Hinrichs, Arne; Koopmans, Sietse Jan; Krebs, Stefan; Kemter, Elisabeth; Rathkolb, Birgit; Nagashima, Hiroshi; Blum, Helmut; Ritzmann, Mathias; Wanke, Rüdiger; Aigner, Bernhard; Adamski, Jerzy; Hrabě de Angelis, Martin; Wolf, Eckhard.
In: Disease Models & Mechanisms, Vol. 12, No. 8, 12.08.2019.Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Mild maternal hyperglycemia in INSC93S transgenic pigs causes impaired glucose tolerance and metabolic alterations in neonatal offspring
AU - Renner, Simone
AU - Martins, Ana Sofia
AU - Streckel, Elisabeth
AU - Braun-Reichhart, Christina
AU - Backman, Mattias
AU - Prehn, Cornelia
AU - Klymiuk, Nikolai
AU - Bähr, Andrea
AU - Blutke, Andreas
AU - Landbrecht-Schessl, Christina
AU - Wünsch, Annegret
AU - Kessler, Barbara
AU - Kurome, Mayuko
AU - Hinrichs, Arne
AU - Koopmans, Sietse Jan
AU - Krebs, Stefan
AU - Kemter, Elisabeth
AU - Rathkolb, Birgit
AU - Nagashima, Hiroshi
AU - Blum, Helmut
AU - Ritzmann, Mathias
AU - Wanke, Rüdiger
AU - Aigner, Bernhard
AU - Adamski, Jerzy
AU - Hrabě de Angelis, Martin
AU - Wolf, Eckhard
PY - 2019/8/12
Y1 - 2019/8/12
N2 - 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.
AB - 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.
KW - Developmental programming
KW - Maternal diabetes
KW - Metabolomics
KW - Pig
KW - Transgenic
U2 - 10.1242/dmm.039156
DO - 10.1242/dmm.039156
M3 - Article
VL - 12
JO - Disease Models & Mechanisms
JF - Disease Models & Mechanisms
SN - 1754-8411
IS - 8
ER -