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

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 & 6 others Mathias Ritzmann, Rüdiger Wanke, Bernhard Aigner, Jerzy Adamski, Martin Hrabě de Angelis, Eckhard Wolf

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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 languageEnglish
JournalDisease Models & Mechanisms
Volume12
Issue number8
DOIs
Publication statusPublished - 12 Aug 2019

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Glucose Intolerance
Hyperglycemia
Insulin Resistance
Swine
Mothers
Insulin
Glucose
Fasting
Animal Models
Obesity
Medical problems
Colostrum
Genetically Modified Animals
Metabolomics
Metabolome
Animals
Fetal Development
Phosphatidylcholines
Alanine
Type 2 Diabetes Mellitus

Keywords

  • Developmental programming
  • Maternal diabetes
  • Metabolomics
  • Pig
  • Transgenic

Cite this

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. / Mild maternal hyperglycemia in INSC93S transgenic pigs causes impaired glucose tolerance and metabolic alterations in neonatal offspring. In: Disease Models & Mechanisms. 2019 ; Vol. 12, No. 8.
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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.",
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author = "Simone Renner and Martins, {Ana Sofia} and Elisabeth Streckel and Christina Braun-Reichhart and Mattias Backman and Cornelia Prehn and Nikolai Klymiuk and Andrea B{\"a}hr and Andreas Blutke and Christina Landbrecht-Schessl and Annegret W{\"u}nsch and Barbara Kessler and Mayuko Kurome and Arne Hinrichs and Koopmans, {Sietse Jan} and Stefan Krebs and Elisabeth Kemter and Birgit Rathkolb and Hiroshi Nagashima and Helmut Blum and Mathias Ritzmann and R{\"u}diger Wanke and Bernhard Aigner and Jerzy Adamski and {Hrabě de Angelis}, Martin and Eckhard Wolf",
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Renner, S, Martins, AS, Streckel, E, Braun-Reichhart, C, Backman, M, Prehn, C, Klymiuk, N, Bähr, A, Blutke, A, Landbrecht-Schessl, C, Wünsch, A, Kessler, B, Kurome, M, Hinrichs, A, Koopmans, SJ, Krebs, S, Kemter, E, Rathkolb, B, Nagashima, H, Blum, H, Ritzmann, M, Wanke, R, Aigner, B, Adamski, J, Hrabě de Angelis, M & Wolf, E 2019, 'Mild maternal hyperglycemia in INSC93S transgenic pigs causes impaired glucose tolerance and metabolic alterations in neonatal offspring', Disease Models & Mechanisms, vol. 12, no. 8. https://doi.org/10.1242/dmm.039156

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 journalArticleAcademicpeer-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 -