Abstract
ObjectivesElevated 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). MethodsFemale 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. ResultsIn 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. ConclusionsThese 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.
Highlights
Type 2 diabetes (T2D) is characterised by elevated circulating glucose
Insulin is a known paracrine inhibitor of glucagon [2,17,18], but the levels of circulating insulin were elevated in response to high-fat diet (HFD) feeding (Figure 1F), making it unlikely that the elevated plasma glucagon in HFD mice was secondary to reduced plasma insulin
As glucagon is a counterregulatory hormone, we explored whether glucagon was inappropriately secreted in HFD-fed mice during insulininduced hypoglycaemia in response to an insulin tolerance test (ITT; Figure 2C)
Summary
Type 2 diabetes (T2D) is characterised by elevated circulating glucose. Lack of insulin plays an important role in the development of hyperglycaemia and glucose intolerance in T2D. Glucose has been proposed to increase the intracellular ATP and that this, via closure of plasmalemmal ATP-regulated Kþ (KATP) channels, results in membrane depolarization and reduction in action potential height (due to voltage-dependent inactivation of the Naþ channels involved in action potential firing). This culminates in reduced activation of voltage-gated Ca2þ channels and, exocytosis of glucagon-containing granules [11]. Glucagon release is influenced by local paracrine signals These include somatostatin [15,16] and insulin [17,18] from islet delta- and beta-cells, respectively
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