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Sandra K Szlapinski London, Ontario, Canada

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David J Hill Diabetes, Endocrinology and Metabolism, Lawson Health Research Institute, London, Ontario, Canada
Physiology and Pharmacology, Western University, London, Ontario, Canada

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Insulin resistance contributes to the development of various diseases, including type 2 diabetes and gestational diabetes. Even though gestational diabetes is specific to pregnancy, it can result in long-term glucose intolerance and type 2 diabetes after delivery. Given the substantial health and economic burdens associated with diabetes, it is imperative to better understand the mechanisms leading to insulin resistance and type 2 diabetes so that treatments targeted at reversing symptoms can be developed. Considering that the endocrine cells of the pancreas (islets of Langerhans) largely contribute to the pathogenesis of diabetes (beta-cell insufficiency and dysfunction), the elucidation of the various mechanisms of endocrine cell plasticity is important to understand. By better defining these mechanisms, targeted therapeutics can be developed to reverse symptoms of beta-cell deficiency and insulin resistance in diabetes. Animal models play an important role in better understanding these mechanisms, as techniques for in vivo imaging of endocrine cells in the pancreas are limited. Therefore, this review article will discuss the available rodent models of gestational and type 2 diabetes that are characterized by endocrine cell impairments in the pancreas, discuss the models with a comparison to human diabetes, and explore the potential mechanisms of endocrine cell plasticity that contribute to these phenotypes, as these mechanisms could ultimately be used to reverse blood glucose dysregulation in diabetes.

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Sandra K Szlapinski Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
Lawson Health Research Institute, St Joseph’s Health Care, London, Ontario, Canada

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Anthony A Botros Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
Lawson Health Research Institute, St Joseph’s Health Care, London, Ontario, Canada

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Sarah Donegan Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
Lawson Health Research Institute, St Joseph’s Health Care, London, Ontario, Canada

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Renee T King Lawson Health Research Institute, St Joseph’s Health Care, London, Ontario, Canada

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Gabrielle Retta Lawson Health Research Institute, St Joseph’s Health Care, London, Ontario, Canada

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Brenda J Strutt Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
Lawson Health Research Institute, St Joseph’s Health Care, London, Ontario, Canada

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David J Hill Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
Lawson Health Research Institute, St Joseph’s Health Care, London, Ontario, Canada

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Gestational diabetes mellitus increases the risk of dysglycemia postpartum, in part, due to pancreatic β-cell dysfunction. However, no histological evidence exists comparing endocrine pancreas after healthy and glucose-intolerant pregnancies. This study sought to address this knowledge gap, in addition to exploring the contribution of an inflammatory environment to changes in endocrine pancreas after parturition. We used a previously established mouse model of gestational glucose intolerance induced by dietary low protein insult from conception until weaning. Pancreas and adipose samples were collected at 7, 30 and 90 days postpartum for histomorphometric and cytokine analyses, respectively. Glucose tolerance tests were performed prior to euthanasia and blood was collected via cardiac puncture. Pregnant female mice born to dams fed a low protein diet previously shown to develop glucose intolerance at late gestation relative to controls continued to be glucose intolerant until 1 month postpartum. However, glucose tolerance normalized by 3 months postpartum. Glucose intolerance at 7 days postpartum was associated with lower beta- and alpha-cell fractional areas and higher adipose levels of pro-inflammatory cytokine, interleukin-6. By 3 months postpartum, a compensatory increase in the number of small islets and a higher insulin to glucagon ratio likely enabled euglycemia to be attained in the previously glucose-intolerant mice. The results show that impairments in endocrine pancreas compensation in hyperglycemic pregnancy persist after parturition and contribute to prolonged glucose intolerance. These impairments may increase the susceptibility to development of future type 2 diabetes.

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