GDF15 knockout does not substantially impact perinatal body weight or neonatal outcomes in mice.

Growth differentiation factor-15 (GDF15) increases in circulation during pregnancy and has been implicated in food intake, weight loss, complications of pregnancy, and metabolic illness. We used a Gdf15 knockout mouse model (Gdf15-/- ) to assess the role of GDF15 in body weight regulation and food intake during pregnancy. We found that Gdf15-/- dams consumed a similar amount of food and gained comparable weight during the course of pregnancy compared to Gdf15+/+ dams. Insulin sensitivity on gestational day 16.5 was also similar between genotypes. In the postnatal period, litter size, and survival rates were similar between genotypes. There was a modest reduction in birth weight of Gdf15-/- pups, but this difference was no longer evident postnatal day 3.5 to 14.5. We observed no detectable differences in milk volume production or milk fat percentage. These data suggest that GDF15 is dispensable for changes in food intake, and body weight as well as insulin sensitivity during pregnancy in a mouse model.

Gestational Early-Time Restricted Feeding Results in Sex-Specific Glucose Intolerance in Adult Male Mice.

The timing of food intake is a novel dietary component that impacts health. Time-restricted feeding (TRF), a form of intermittent fasting, manipulates food timing. The timing of eating may be an important factor to consider during critical periods, such as pregnancy. Nutrition during pregnancy, too, can have a lasting impact on offspring health. The timing of food intake has not been thoroughly investigated in models of pregnancy, despite evidence that interest in the practice exists. Therefore, using a mouse model, we tested body composition and glycemic health of gestational early TRF (eTRF) in male and female offspring from weaning to adulthood on a chow diet and after a high-fat, high-sucrose (HFHS) diet challenge. Body composition was similar between groups in both sexes from weaning to adulthood, with minor increases in food intake in eTRF females and slightly improved glucose tolerance in males while on a chow diet. However, after 10 weeks of HFHS, male eTRF offspring developed glucose intolerance. Further studies should assess the susceptibility of males, and apparent resilience of females, to gestational eTRF and assess mechanisms underlying these changes in adult males.

Developing Priorities to Alleviate the Long-Term Impact of the COVID-19 Pandemic on Women Engaged in Diabetes Research, Education, and Care: A Concept Mapping Study.

Objective: The aim of this study was to develop priorities through stakeholder engagement to alleviate the impact of the coronavirus disease 2019 (COVID-19) pandemic on the professional careers of women engaged in diabetes research, education, and care. Research Design and Methods: This study used concept mapping, a mixed-methods, multistep process, to generate a conceptual map of recommendations through the following steps: 1) identify stakeholders and develop the focus prompt, 2) generate ideas through brainstorming, 3) structure ideas through sorting and rating on priority and likelihood, 4) analyze the data and create a cluster map, and 5) interpret and use results. Results: Fifty-two participants completed the brainstorming phase, and 24 participated in sorting and rating. The final concept map included seven clusters. Those rated as highest priority were to ensure supportive workplace culture (µ = 4.43); promote practices to achieve gender parity in hiring, workload, and promotion (µ = 4.37); and increase funding opportunities and allow extensions (µ = 4.36). Conclusion: This study identified recommendations for institutions to better support women engaged in diabetes-related work to alleviate the long-term impact of the COVID-19 pandemic on their careers. Some areas were rated as high in priority and high in likelihood, such as ensuring a supportive workplace culture. In contrast, family-friendly benefits and policies were rated as high in priority but low in likelihood of being implemented; these may take more effort to address, including coordinated efforts within institutions (e.g., women's academic networks) and professional societies to promote standards and programs that advance gender equity in medicine.

Longitudinal Metabolic Impacts of Perinatal Exposure to Phthalates and Phthalate Mixtures in Mice.

Developmental exposures to phthalates are suspected to contribute to risk of metabolic syndrome. However, findings from human studies are inconsistent, and long-term metabolic impacts of early-life phthalate and phthalate mixture exposures are not fully understood. Furthermore, most animal studies investigating metabolic impacts of developmental phthalate exposures have focused on diethylhexyl phthalate (DEHP), whereas newer phthalates, such as diisononyl phthalate (DINP), are understudied. We used a longitudinal mouse model to evaluate long-term metabolic impacts of perinatal exposures to three individual phthalates, DEHP, DINP, and dibutyl phthalate (DBP), as well as two mixtures (DEHP+DINP and DEHP+DINP+DBP). Phthalates were administered to pregnant and lactating females through phytoestrogen-free chow at the following exposure levels: 25 mg of DEHP/kg of chow, 25 mg of DBP/kg of chow, and 75 mg of DINP/kg of chow. One male and female per litter (n = 9 to 13 per sex per group) were weaned onto control chow and followed until 10 months of age. They underwent metabolic phenotyping at 2 and 8 months, and adipokines were measured in plasma collected at 10 months. Longitudinally, females perinatally exposed to DEHP only had increased body fat percentage and decreased lean mass percentage, whereas females perinatally exposed to DINP only had impaired glucose tolerance. Perinatal phthalate exposures also modified the relationship between body fat percentage and plasma adipokine levels at 10 months in females. Phthalate-exposed males did not exhibit statistically significant differences in the measured longitudinal metabolic outcomes. Surprisingly, perinatal phthalate mixture exposures were statistically significantly associated with few metabolic effects and were not associated with larger effects than single exposures, revealing complexities in metabolic effects of developmental phthalate mixture exposures.

Gestational exposure to metformin programs improved glucose tolerance and insulin secretion in adult male mouse offspring.

Pancreatic ß-cells are exquisitely sensitive to developmental nutrient stressors, and alterations in nutrient sensing pathways may underlie changes observed in these models. Here we developed a mouse model of in utero exposure to the anti-diabetic agent metformin. We have previously shown that this exposure increases offspring pancreatic ß-cell mass at birth. We hypothesized that adult offspring would have improved metabolic parameters as a long-term outcome of metformin exposure. Virgin dams were given 5 mg/mL metformin in their water from E0.5 to delivery at E18.5. Body weight, glucose tolerance, insulin tolerance and glucose stimulated insulin secretion were analyzed in the offspring. When male offspring of dams given metformin during gestation were tested as adults they had improved glucose tolerance and enhanced insulin secretion in vivo as did their islets in vitro. Enhanced insulin secretion was accompanied by changes in intracellular free calcium responses to glucose and potassium chloride, possibly mediated by increased L channel expression. Female offspring exhibited improved glucose tolerance at advanced ages. In conclusion, in this model in utero metformin exposure leads to improved offspring metabolism in a gender-specific manner. These findings suggest that metformin applied during gestation may be an option for reprogramming metabolism in at risk groups.

Formation of a human ß-cell population within pancreatic islets is set early in life.

CONTEXT: Insulin resistance can be compensated by increased functional pancreatic ß-cell mass; otherwise, diabetes ensues. Such compensation depends not only on environmental and genetic factors but also on the baseline ß-cell mass from which the expansion originates. OBJECTIVE: Little is known about assembly of a baseline ß-cell mass in humans. Here, we examined formation of ß-cell populations relative to other pancreatic islet cell types and associated neurons throughout the normal human lifespan. DESIGN AND METHODS: Human pancreatic sections derived from normal cadavers aged 24 wk premature to 72 yr were examined by immunofluorescence. Insulin, glucagon, and somatostatin were used as markers for ß-, α-, and δ-cells, respectively. Cytokeratin-19 marked ductal cells, Ki67 cell proliferation, and Tuj1 (neuronal class III ß-tubulin) marked neurons. RESULTS: Most ß-cell neogenesis was observed preterm with a burst of ß-cell proliferation peaking within the first 2 yr of life. Thereafter, little indication of ß-cell growth was observed. Postnatal proliferation of α- and δ-cells was rarely seen, but a wave of ductal cell proliferation was found mostly associated with exocrine cell expansion. The ß-cell to α-cell ratio doubled neonatally, reflecting increased growth of ß-cells, but during childhood, there was a 7-fold change in the ß-cell to δ-cell ratio, reflecting an additional loss of δ-cells. A close association of neurons to pancreatic islets was noted developmentally and retained throughout adulthood. Negligible neuronal association to exocrine pancreas was observed. CONCLUSION: Human baseline ß-cell population and appropriate association with other islet cell types is established before 5 yr of age.