Gestational diabetes mellitus (GDM) is a common obstetric complication. Half of women who have GDM will go on to develop type 2 diabetes. Understanding the mechanisms by which this occurs requires an animal model of GDM without ongoing diabetes at conception. C57Bl/6J mice react acutely to a high-fat, high-sucrose (HFHS) challenge. Here, we hypothesized that a periconceptional HFHS challenge will induce glucose intolerance during gestation. C57Bl/6J female mice were placed on an HFHS either 1 or 3 weeks prior to mating and throughout pregnancy. Intraperitoneal glucose tolerance tests, insulin measurements, and histological analysis of pancreatic islets were used to assess the impact of acute HFHS. C57Bl/6J females fed HFHS beginning 1 week prior to pregnancy became severely glucose intolerant, with reduced insulin response to glucose, and decreased pancreatic islet expansion during pregnancy compared to control mice. These GDM characteristics did not occur when the HFHS diet was started 3 weeks prior to mating, suggesting the importance of acute metabolic stress. Additionally, HFHS feeding resulted in only mild insulin resistance in nonpregnant females. When the diet was discontinued at parturition, symptoms resolved within 3 weeks. However, mice that experienced glucose intolerance in pregnancy became glucose intolerant more readily in response to a HFHS challenge later in life than congenic females that experienced a normal pregnancy, or that were fed the same diet outside of pregnancy. Thus, acute HFHS challenge in C57Bl/6 mice results in a novel, nonobese, animal model that recapitulates the long-term risk of developing type 2 diabetes following GDM.

Obesity affects male fertility and maternal diabetes affects the offspring sperm epigenome. However, the effects of in utero exposure to maternal glucose intolerance in combination with postnatal high fat, high sucrose (HFHS) diet consumption on offspring spermatogenesis is not clear. The present study was designed to test these effects. One week before and during pregnancy, dams were fed either control or HFHS diet to induce gestational glucose intolerance, and returned to standard diet during lactation. Male offspring from each maternal group were split into control and HFHS-fed groups for eight weeks prior to sacrifice at 11, 19 or 31 weeks of age, and reproductive tissues were harvested for analysis of testicular germ cell apoptosis and sperm output. Postnatal HFHS diet suppressed spermatogonia apoptosis in all age groups and maternal HFHS diet reduced testosterone levels at 11 weeks. At 31 weeks of age, the postnatal HFHS diet increased body weight, and reduced epididymis weight and sperm count. The combination of in utero and postnatal exposure impacted sperm counts most significantly. In summary, HFHS diet during pregnancy puts male offspring at greater risk of infertility, particularly when combined with postnatal high fat diet feeding.

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