| Résumé: | <p><strong>Objectives:</strong> 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)—a widely used mouse model of prediabetes.</p>
<p><strong>Methods:</strong> We fed female mice expressing the Ca<sup>2+</sup> indicator GCaMP3 specifically in alpha-cells an HFD or control (CTL) diet. We then conducted <em>in vivo</em> phenotyping of these mice, as well as experiments on isolated (<em>ex vivo</em>) islets and in the <em>in situ</em> perfused pancreas.</p>
<p><strong>Results:</strong><em> In vivo,</em> HFD-fed mice exhibited increased fed plasma glucagon levels and a reduced response to elevations in plasma glucose. Glucagon secretion from isolated islets and in the perfused mouse pancreas was elevated under both hypo- and hyperglycaemic conditions. In mice fed a CTL diet, increasing glucose reduced intracellular Ca<sup>2+</sup> ([Ca<sup>2+</sup>]<sub>i</sub>) (oscillation frequency and amplitude). This effect was also observed in HFD mice; however, both the frequency and amplitude of the [Ca<sup>2+</sup>]<sub>i</sub> 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 mice was reduced but exogenous SST also failed to suppress glucagon secretion and [Ca<sup>2+</sup>]<sub>i</sub> activity from HFD alpha-cells, in contrast to observations in CTL mice.</p>
<p><strong>Conclusions:</strong> These findings suggest that reduced delta-cell function, combined with intrinsic changes in alpha-cell sensitivity to somatostatin, accounts for the hyperglucagonaemia in mice fed an HFD.</p>
|
|---|