A mouse model of gestation-specific transient hyperglycemia for translational studies

Abstract

The prevalence of gestational diabetes mellitus (GDM) is estimated at 14% globally, and in some countries, such as Singapore, exceeds 20%. Both women and children exposed to GDM have an increased risk of later metabolic diseases, cardiovascular disease and other health issues. Beyond lifestyle changes and pharmaceutical intervention using existing type 2 diabetes medications for expecting women, there are limited treatment options for women with GDM; targeting better outcomes of potentially affected infants is unexplored. Numerous animal models have been generated for understanding of pathological processes of GDM development and for development of treatment strategies. These models, however, suffer from limited windows of opportunity to examine risk factors and potential intervention options. By combining short-term high-fat diet (HFD) feeding and low-dose streptozotocin (STZ) treatments before pregnancy, we have established a mouse model with marked transient gestation-specific hyperglycemia, which allows testing of nutritional and pharmacological interventions before, during and beyond pregnancy.

Hyperglycaemia, pregnancy outcomes and maternal metabolic disease risk during pregnancy and lactation in a lean gestational diabetes mouse model

“…In contrast to previous animal models based on STZ and/or HF (Li et al, 2020;Pasek & Gannon, 2013), the current preclinical approach induces a unique (mostly) transient hyperglycaemia that more closely mimics the human situation. The high reproducibility of the model, which is often challenging in preclinical research (Kafkafi et al, 2018), is another strength.…”

“…The HFSTZ group is depicted as GDM and PDM, depending on their hyperglycaemic phenotype as described in Fig. at 20 min (peak glucose in LF control dams) during the OGTT (Li et al, 2020). This resulted in a group size of 9.…”

“…Most models develop (severe) hyperglycaemia prior to pregnancy (Pasek & Gannon, 2013), limiting the ability to link the severity of hyperglycaemia to adverse health consequences and possible translation to the human situation. Recently, a mouse model for lean GDM was developed combining short term high fat (HF) feeding and multiple low‐dose streptozotocin (STZ) injections (Li et al., 2020). This two‐hit approach (HFSTZ), which was designed to concomitantly impair insulin sensitivity and secretion, resulted in transient gestational hyperglycaemia and glucose intolerance without increased body weight or adiposity.…”

“…This two‐hit approach (HFSTZ), which was designed to concomitantly impair insulin sensitivity and secretion, resulted in transient gestational hyperglycaemia and glucose intolerance without increased body weight or adiposity. Most dams who developed GDM recovered from hyperglycaemia after delivery (Li et al., 2020). The initial characterization of this mouse model allows for further investigation of the link between severity of hyperglycaemia and adverse outcomes in mothers and their offspring.…”

Hepatic IGF2/H19 Epigenetic Alteration Induced Glucose Intolerance in Gestational Diabetes Mellitus Offspring via FoxO1 Mediation

“…On day 6 and day 12 of pregnancy, GDM dams were fasted 8 h and received a streptozotocin (STZ) injection (100 mg/kg i.p.) (Sigma-Aldrich, St. Louis, MO, USA) (22,23) (Figure 1A). Control dams received an equal volume of citrate buffer.…”