Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, Churchill Hospital, Oxford OX3 7LE, UK.
Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Denmark.
Mol Metab. 2020 Oct;40:101021. doi: 10.1016/j.molmet.2020.101021. Epub 2020 May 21.
Elevated plasma glucagon is an early symptom of diabetes, occurring in subjects with impaired glucose regulation. Here, we explored alpha-cell function in female mice fed a high-fat diet (HFD).
Female mice expressing the Ca indicator GCaMP3 specifically in alpha-cells were fed a high-fat or control (CTL) diet. We then conducted in vivo phenotyping of these mice, as well as experiments on isolated (ex vivo) islets and in the in situ perfused pancreas.
In HFD-fed mice, fed plasma glucagon levels were increased and glucagon secretion from isolated islets and in the perfused mouse pancreas was also elevated. In mice fed a CTL diet, increasing glucose reduced intracellular Ca ([Ca]) oscillation frequency and amplitude. This effect was also observed in HFD mice; however, both the frequency and amplitude of the [Ca] oscillations were higher than those in CTL alpha-cells. Given that alpha-cells are under strong paracrine control from neighbouring somatostatin-secreting delta-cells, we hypothesised that this elevation of alpha-cell output was due to a lack of somatostatin (SST) secretion. Indeed, SST secretion in isolated islets from HFD-fed mice was reduced but exogenous SST also failed to suppress glucagon secretion and [Ca] activity from HFD alpha-cells, in contrast to observations in CTL mice.
These findings suggest that reduced delta-cell function, combined with intrinsic changes in alpha-cells including sensitivity to somatostatin, accounts for the hyperglucagonaemia in mice fed a HFD.
升高的血浆胰高血糖素是糖尿病的早期症状，发生于葡萄糖调节受损的患者中。在这里，我们探索了高脂饮食（HFD）喂养的雌性小鼠的胰岛α细胞功能。
表达 Ca 指示剂 GCaMP3 的雌性小鼠特异性在胰岛α细胞中，用高脂肪或对照（CTL）饮食喂养。然后我们对这些小鼠进行了体内表型分析，以及对分离的（离体）胰岛和原位灌注胰腺的实验。
在 HFD 喂养的小鼠中，血浆胰高血糖素水平升高，并且分离的胰岛和灌注的小鼠胰腺中的胰高血糖素分泌也增加。在 CTL 饮食喂养的小鼠中，增加葡萄糖可降低细胞内 Ca（[Ca]）振荡频率和幅度。这种作用也在 HFD 小鼠中观察到；然而，[Ca]振荡的频率和幅度均高于 CTL α细胞。由于胰岛α细胞受到来自相邻生长抑素分泌的δ细胞的强烈旁分泌控制，我们假设这种胰岛α细胞输出的增加是由于生长抑素（SST）分泌减少所致。事实上，HFD 喂养的小鼠的分离胰岛中的 SST 分泌减少，但外源性 SST 也未能抑制 HFD 胰岛α细胞的胰高血糖素分泌和[Ca]活性，与 CTL 小鼠的观察结果相反。
这些发现表明，δ细胞功能降低，加上胰岛α细胞的内在变化，包括对生长抑素的敏感性，导致 HFD 喂养的小鼠发生高胰高血糖症。
