PMID- 37010236 OWN - NLM STAT- MEDLINE DCOM- 20230516 LR - 20230828 IS - 1469-7793 (Electronic) IS - 0022-3751 (Linking) VI - 601 IP - 10 DP - 2023 May TI - Hyperglycaemia, pregnancy outcomes and maternal metabolic disease risk during pregnancy and lactation in a lean gestational diabetes mouse model. PG - 1761-1780 LID - 10.1113/JP284061 [doi] AB - Hyperglycaemia in pregnancy (HIP) is a pregnancy complication characterized by mild to moderate hyperglycaemia that negatively impacts short- and long-term health of mother and child. However, relationships between severity and timing of pregnancy hyperglycaemia and postpartum outcomes have not been systemically investigated. We investigated the impact of hyperglycaemia developing during pregnancy (gestational diabetes mellitus, GDM) or already present pre-mating (pre-gestational diabetes mellitus, PDM) on maternal health and pregnancy outcomes. GDM and PDM were induced in C57BL/6NTac mice by combined 60% high fat diet (HF) and low dose streptozotocin (STZ). Animals were screened for PDM prior to mating, and all underwent an oral glucose tolerance test on gestational day (GD)15. Tissues were collected at GD18 or at postnatal day (PN)15. Among HFSTZ-treated dams, 34% developed PDM and 66% developed GDM, characterized by impaired glucose-induced insulin release and inadequate suppression of endogenous glucose production. No increased adiposity or overt insulin resistance was observed. Furthermore, markers of non-alcoholic fatty liver disease (NAFLD) were significantly increased in PDM at GD18 and were positively correlated with basal glucose levels at GD18 in GDM dams. By PN15, NAFLD markers were also increased in GDM dams. Only PDM affected pregnancy outcomes such as litter size. Our findings indicate that GDM and PDM, resulting in disturbances of maternal glucose homeostasis, increase the risk of postpartum NAFLD development, related to the onset and severity of pregnancy hyperglycaemia. These findings signal a need for earlier monitoring of maternal glycaemia and more rigorous follow-up of maternal health after GDM and PDM pregnancy in humans. KEY POINTS: We studied the impact of high-fat diet/streptozotocin induced hyperglycaemia in pregnancy in mice and found that this impaired glucose tolerance and insulin release. Litter size and embryo survival were compromised by pre-gestational, but not by gestational, diabetes. Despite postpartum recovery from hyperglycaemia in a majority of dams, liver disease markers were further elevated by postnatal day 15. Maternal liver disease markers were associated with the severity of hyperglycaemia at gestational day 18. The association between hyperglycaemic exposure and non-alcoholic fatty liver disease signals a need for more rigorous monitoring and follow-up of maternal glycaemia and health in diabetic pregnancy in humans. CI - (c) 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society. FAU - Tol, Angela J C AU - Tol AJC AD - Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. FAU - Hribar, Kaja AU - Hribar K AD - Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. FAU - Kruit, Janine AU - Kruit J AUID- ORCID: 0000-0002-5414-0485 AD - Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. FAU - Bongiovanni, Laura AU - Bongiovanni L AD - Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands. AD - Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy. FAU - Vieira-Lara, Marcel A AU - Vieira-Lara MA AD - Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. FAU - Koster, Mirjam H AU - Koster MH AUID- ORCID: 0000-0001-6219-0901 AD - Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. FAU - Kloosterhuis, Niels J AU - Kloosterhuis NJ AD - Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. FAU - Havinga, Rick AU - Havinga R AD - Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. FAU - Koehorst, Martijn AU - Koehorst M AD - Department of Laboratory Medicine, University Medical Center Groningen, Groningen, the Netherlands. FAU - de Bruin, Alain AU - de Bruin A AD - Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. AD - Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands. FAU - Bakker, Barbara M AU - Bakker BM AUID- ORCID: 0000-0001-6274-3633 AD - Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. FAU - Oosterveer, Maaike H AU - Oosterveer MH AD - Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. AD - Department of Laboratory Medicine, University Medical Center Groningen, Groningen, the Netherlands. FAU - van der Beek, Eline M AU - van der Beek EM AUID- ORCID: 0000-0002-7923-3653 AD - Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230418 PL - England TA - J Physiol JT - The Journal of physiology JID - 0266262 RN - 5W494URQ81 (Streptozocin) RN - 0 (Insulin) RN - IY9XDZ35W2 (Glucose) SB - IM CIN - J Physiol. 2023 Aug;601(16):3449-3451. PMID: 37405678 MH - Humans MH - Pregnancy MH - Female MH - Child MH - Mice MH - Animals MH - *Diabetes, Gestational MH - *Hyperglycemia/complications MH - Pregnancy Outcome MH - *Non-alcoholic Fatty Liver Disease MH - Streptozocin/adverse effects MH - Mice, Inbred C57BL MH - Insulin MH - Glucose/metabolism MH - Lactation OTO - NOTNLM OT - endogenous glucose production OT - gestational diabetes mellitus OT - insulin secretion OT - non-alcoholic fatty liver disease OT - pre-gestational diabetes OT - pregnancy outcomes EDAT- 2023/04/04 06:00 MHDA- 2023/05/16 06:42 CRDT- 2023/04/03 08:42 PHST- 2022/11/03 00:00 [received] PHST- 2023/03/10 00:00 [accepted] PHST- 2023/05/16 06:42 [medline] PHST- 2023/04/04 06:00 [pubmed] PHST- 2023/04/03 08:42 [entrez] AID - 10.1113/JP284061 [doi] PST - ppublish SO - J Physiol. 2023 May;601(10):1761-1780. doi: 10.1113/JP284061. Epub 2023 Apr 18.