A mouse model of gestational glucose intolerance through exposure to a low protein diet during fetal and neonatal development

Abstract

Key points Pancreatic β‐cell dysfunction is hypothesized to be the significant determinant of gestational diabetes pathogenesis, however pancreatic samples from patients are scarce. This study reports a novel mouse model of gestational glucose intolerance in pregnancy, originating from previous nutrition restriction in utero, in which glucose intolerance was restricted to late gestation as is seen in human gestational diabetes. Glucose intolerance was attributed to reduced β‐cell proliferation, leading to impaired gestational β‐cell mass expansion in maternal endocrine pancreas, in addition to reduced glucose‐stimulated insulin secretion. This model reproduces some of the features of gestational diabetes and is suitable for testing safe therapeutic interventions that increase β‐cell mass during pregnancy and prevent or reverse gestational glucose intolerance. Abstract Gestational diabetes mellitus (GDM) is an increasingly prevalent form of diabetes that appears during pregnancy. Pathological studies link a failure to adaptively increase maternal pancreatic β‐cell mass (BCM) in pregnancy to GDM. Due to the scarcity of pancreatic samples from GDM patients, we sought to develop a novel mouse model for impaired gestational glucose tolerance. Mature female C57Bl/6 mouse offspring (F1) born to dams fed either a control (C) or low‐protein (LP) diet during gestation and lactation were randomly allocated into two subsequent study groups: pregnant (CP, LPP) or non‐pregnant (CNP, LPNP). Glucose tolerance tests were performed at gestational day (GD) 9, 12 and 18. Subsequently, pancreata were removed for fluorescence immunohistochemistry to assess α‐cell mass (ACM), BCM and β‐cell proliferation. An additional group of animals was used to measure insulin secretion from isolated islets at GD18. LPP females displayed glucose intolerance compared to CP females at GD18 (P < 0.001). BCM increased threefold at GD18 in CP females. However, LPP females had reduced BCM expansion (P < 0.01) concurrent with reduced β‐cell proliferation at GD12 (P < 0.05). LPP females also had reduced ACM expansion at GD18 (P < 0.01). LPP islets had impaired glucose‐stimulated insulin secretion in vitro compared to CP islets (P < 0.01). Therefore, impaired glucose tolerance during pregnancy is associated with a failure to adequately adapt BCM, as a result of reduced β‐cell proliferation, in addition to lower glucose‐stimulated insulin secretion. This model could be used to evaluate novel interventions during pregnancy to increase BCM or function as a strategy to prevent/reverse GDM.

Increased alpha and beta cell mass during mouse pregnancy is not dependent on transdifferentiation

“…These data could implicate a contribution for α-cell neogenesis from small endocrine clusters to the adaptive expansion of ACM at GD18.5, which has also been shown to be a mechanism of BCM expansion. 7,8,25 However, our data suggest that adaptive α-cell mechanisms were impaired in GDM.…”

“…7,8 GD18.5 was chosen as this is the timepoint where BCM is maximal in a control pregnancy 7,8 but has been shown to be reduced in GDM pregnancy resulting in glucose intolerance. 8 Females (F1) were euthanized by CO 2 asphyxia for comparison to non-pregnant age-matched F1 females. The pancreas was removed at each assigned day of gestation ( n = 4–6 C and LP animals for each timepoint during gestation and for the non-pregnant groups), fixed in 4% paraformaldehyde for histology and embedded in optical cutting temperature compound.…”

Gestational Diabetes Mellitus: A Harbinger of the Vicious Cycle of Diabetes

“…In another mouse model, researchers used the F1 offspring born to dams fed a low-protein (LP) diet during gestation and lactation. The F1 females develop glucose intolerance and reduced β-cell proliferation during pregnancy [ 196 ]. These models demonstrated that exposure to GDM or glucose intolerance during gestation increases the susceptibility of the offspring (F1) to developing GDM.…”

Gestational diabetes mellitus: a (nearly) perfect mouse model

“…In a recent issue of The Journal of Physiology , Szlapinski and colleagues demonstrated that pregnant mice classified as having GDM displayed pancreata with significantly decreased α‐ and β‐cell mass, corresponding to an overall decrease in insulin production and secretion, and therefore a globally reduced glucose sensitivity (Szlapinski et al . ). This pathology represents approximately 80% of GDM cases, which are classified based on β‐cell dysfunction with previous history or worsening peripheral insulin resistance (Plows et al .…”

“…Maternal placental hormones then trigger a response in pancreatic β-cells to attempt to restore euglycaemia -β-cells and often α-cells of the pancreas undergo hypertrophy and hyperplasia. In a recent issue of The Journal of Physiology, Szlapinski and colleagues demonstrated that pregnant mice classified as having GDM displayed pancreata with significantly decreased αand β-cell mass, corresponding to an overall decrease in insulin production and secretion, and therefore a globally reduced glucose sensitivity (Szlapinski et al 2019). This pathology represents approximately 80% of GDM cases, which are classified based on β-cell dysfunction with previous history or worsening peripheral insulin resistance (Plows et al 2018), indicating a diabetic disorder that includes aspects of all three major categories of the disease (Type I, Type II and other).…”