Xiang Y1*, Hribar K1*, Munteanu R1, Koster MH1, Mulder NL1, Smit M1, van der Beek EM1,2, Kruit JK1
1Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
2 Nestlé Institute of Health Sciences, Nestlé Research, Lausanne, Switzerland
*Both authors contributed equally
Background: Gestational diabetes mellitus (GDM) is associated with an increased risk of type 2 diabetes mellitus (T2DM) in offspring. As impaired pancreatic islet function plays a pivotal role in the development of T2DM, we investigated the impact of exposure to hyperglycemia in pregnancy on the development and function of the endocrine pancreas in the offspring.
Method: Maternal hyperglycaemia was induced in C57BL/6N mice by short-term high-fat (HF) diet and low-dose streptozotocin. Prior to mating, animals were screened for glycemia to classify for normoglycemia and pre-gestational diabetes (PDM), while GDM was confirmed on gestational day 15. Control dams either received HF or low-fat (LF) diets. Following weaning, offspring were fed a chow or high-fat high-sucrose (HFHS) diet and glucose tolerance, β-cell function, and β-cell area were assessed in the female offspring.
Results: On the HFHS diet, offspring of PDM dams exhibited impaired glucose tolerance compared to those of LF dams (glucose AUC; LF 439 ± 21 vs PDM 585 ± 14, p<0.05). Beta-cell function was decreased in PDM and GDM offspring compared to LF offspring (delta insulin/delta glucose; LF 0.100 ± 0.014 vs HF 0.069 ± 0.023 vs GDM 0.050 ± 0.019 vs PDM 0.012 ± 0.011, p<0.05, p<0.01). In the GDM and PDM offspring, beta-cell area was decreased (beta-cell area %; LF 0.75 ± 0.07, HF 0.64 ± 0.05, GDM 0.47 ± 0.06, PDM 0.44 ± 0.08, p<0.05, p<0.05). RNA-seq analysis of isolated islets revealed 243 genes differently expressed in GDM offspring compared to LF offspring fed the HFHS diet. Pathway analysis showed impaired upregulation of the protein processing in endoplasmic reticulum pathway in GDM offspring fed a HFHS diet.
Conclusion: These results demonstrate that GDM significantly affects offspring glucose tolerance, beta-cell area and beta-cell function following HFHS diet exposure. Thus, in utero exposure to hyperglycaemia influences islet development, which could predispose offspring to develop T2DM.