Regulation of α‐cell glucagon secretion: The role of second messengers

Simple Summary As a native breed to the Inner Mongolian Plateau (Inner Mongolia, China), Mongolian sheep are tolerant to cold. However, their cold-adaptive processes, such as the physiological feedback adjustments that occur during the cold season in the plateau environment, remain unexplored. Therefore, this study aimed to evaluate the adaptations of grazing Mongolian sheep in the plateau environment by investigating the changes in physiological mechanisms and serum biochemistry of sheep reared in the warm and cold seasons. We observed that many of the biochemical functions were stimulated to meet the requirements of organismal metabolic regulation in order to enable grazing Mongolian sheep to physiologically adapt to cold climatic conditions. However, the function of resisting oxidation of the grazing Mongolian sheep was impaired during the cold season. The findings from this study provide helpful information for understanding the physiological requirements for grazing Mongolian sheep to adapt to extremely cold environments. The manuscript also provides information for optimizing the management of these animals during the cold season, increasing farm profits and designing genetic selection strategies. Abstract Mongolian sheep are characteristically cold-tolerant. However, their cold adaptive processes, such as the physiological feedback adjustments that occur during the cold season, remain unexplored. Therefore, the present study aimed to evaluate the physiological adaptations of Mongolian sheep in cold plateau environments. A comparative analysis of the serum biochemical parameters, immune response, antioxidant capacity, and glucose and lipid metabolism of grazing Mongolian sheep in the cold and warm seasons was conducted. The results showed that in the cold season, the glucose and lipid metabolism and thermogenesis of the grazing Mongolian sheep were notably enhanced. Moreover, the immune responses were stimulated by increased levels of cytokines, such as IL-2, IL-1β, and IL-6, during the cold season. However, the antioxidant defense system was damaged; this damage was mainly characterized by decreased activity of antioxidant enzymes and an increased level of MDA during the cold season. Overall, glucose metabolism, lipid metabolism, thermogenesis, and immune responses were stimulated to meet the requirements of organismal metabolic regulation to enable grazing Mongolian sheep to physiologically adapt to cold climatic conditions.

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Physiological, Immune Response, Antioxidant Capacity and Lipid Metabolism Changes in Grazing Sheep during the Cold Season

Metabolic Messengers: glucagon

Metabolism-disrupting chemicals (MDCs) are endocrine disruptors with obesogenic and/or diabetogenic action. There is mounting evidence linking exposure to MDCs to increased susceptibility to diabetes. Despite the important role of glucagon in glucose homeostasis, there is little information on the effects of MDCs on α-cells. Furthermore, there are no methods to identify and test MDCs with the potential to alter α-cell viability and function. Here we used the mouse α-cell line αTC1-9 to evaluate the effects of MDCs on cell viability and glucagon secretion. We tested six chemicals at concentrations within human exposure (from 0.1 pM to 1 μM): bisphenol-A (BPA), tributyltin (TBT), perfluorooctanoic acid (PFOA), triphenylphosphate (TPP), triclosan (TCS), and dichlorodiphenyldichloroethylene (DDE). Using two different approaches, MTT assay and DNA-binding dyes, we observed that BPA and TBT decreased α-cell viability via a mechanism that depends on the activation of estrogen receptors and PPARγ, respectively. These two chemicals induced ROS production, but barely altered the expression of endoplasmic reticulum (ER) stress markers. Although PFOA, TPP, TCS, and DDE did not alter cell viability nor induced ROS generation or ER stress, all four compounds negatively affected glucagon secretion. Our findings suggest that αTC1-9 cells seem an appropriate model to test chemicals with metabolism-disrupting activity and that the improvement of the test methods proposed herein could be incorporated into protocols for the screening of diabetogenic MDCs.

/pdf/screening-of-metabolism-disrupting-chemicals-on-pancreatic-a-2qjeqjkn.pdf

Screening of Metabolism-Disrupting Chemicals on Pancreatic α-Cells Using In Vitro Methods

Abstract Metabolism-disrupting chemicals (MDCs) are endocrine disruptors with obesogenic and/or diabetogenic action. There is mounting evidence linking exposure to MDCs to increased susceptibility to diabetes. Despite the important role of glucagon in glucose homeostasis, there is little information on the effects of MDCs on α-cells. Furthermore, there are no methods to identify and test MDCs with the potential to alter α-cell viability and function. Here we used the mouse α-cell line αTC1-9 to evaluate the effects of MDCs on cell viability and glucagon secretion. We tested six chemicals at concentrations within human exposure (from 0.1 pM to 1 μM): bisphenol-A (BPA), tributyltin (TBT), perfluorooctanoic acid (PFOA), triphenylphosphate (TPP), triclosan (TCS), and dichlorodiphenyldichloroethylene (DDE). Using two different approaches, MTT assay and DNA-binding dyes, we observed that BPA and TBT decreased α-cell viability via a mechanism that depends on the activation of estrogen receptors and PPARγ, respectively. These two chemicals induced ROS production, but barely altered the expression of endoplasmic reticulum (ER) stress markers. Although PFOA, TPP, TCS, and DDE did not alter cell viability nor induced ROS generation or ER stress, all four compounds negatively affected glucagon secretion. Our findings suggest that αTC1-9 cells seem an appropriate model to test chemicals with metabolism-disrupting activity and that the improvement of the test methods proposed herein could be incorporated into protocols for the screening of diabetogenic MDCs. 

https://www.biorxiv.org/content/biorxiv/early/2022/11/14/2022.11.07.515443.full.pdf

Quan Zhang

Papers

Regulation of α-cell glucagon secretion: The role of second messengers