Objectives

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).

Methods

Female mice expressing the Ca²⁺ 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.

Results

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 Ca²⁺ ([Ca²⁺]_i) oscillation frequency and amplitude. This effect was also observed in HFD mice; however, both the frequency and amplitude of the [Ca²⁺]_i 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 [Ca²⁺]_i activity from HFD alpha-cells, in contrast to observations in CTL mice.

Conclusions

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.

中文翻译：

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生长抑素信号的减少导致高脂饮食小鼠胰高血糖素分泌过多。

目标

血浆胰高血糖素升高是糖尿病的早期症状，发生在葡萄糖调节受损的受试者中。在这里，我们探索了喂食高脂肪饮食 (HFD) 的雌性小鼠的 α 细胞功能。

方法

给在 α 细胞中特异性表达 Ca ²⁺指示剂 GCaMP3 的雌性小鼠喂食高脂肪或对照 (CTL) 饮食。然后，我们对这些小鼠进行了体内表型分析，并对分离的（离体）胰岛和原位灌注胰腺进行了实验。

结果

在喂食 HFD 的小鼠中，喂食的血浆胰高血糖素水平升高，分离的胰岛和灌注小鼠胰腺中的胰高血糖素分泌也升高。在喂食 CTL 饮食的小鼠中，增加葡萄糖会降低细胞内 Ca ²⁺ ([Ca ²⁺ ] _i ) 振荡频率和振幅。在 HFD 小鼠中也观察到了这种效应。然而，[Ca ²⁺ ] _{i的频率和幅度}振荡高于 CTL α 细胞中的振荡。鉴于 α 细胞受到邻近分泌生长抑素的 δ 细胞的强旁分泌控制，我们假设这种 α 细胞输出的升高是由于缺乏生长抑素 (SST) 分泌。事实上，与在 CTL 小鼠中观察到的结果相反，来自 HFD 喂养小鼠的分离胰岛中的 SST 分泌减少，但外源性 SST 也未能抑制来自 HFD α 细胞的胰高血糖素分泌和 [Ca ²⁺ ] _i活性。

结论

这些发现表明，δ 细胞功能降低，加上 α 细胞的内在变化，包括对生长抑素的敏感性，是喂食 HFD 的小鼠出现高胰高血糖素血症的原因。