Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet

Mol Metab. 2020 Oct;40:101021. doi: 10.1016/j.molmet.2020.101021. Epub 2020 May 21.

Abstract

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.

Keywords: Alpha cell; Calcium; Delta cell; Diabetes; High fat diet; Hyperglucagonemia; Insulin tolerance; Islet of Langerhans; Paracrine; Somatostatin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Diet, High-Fat / adverse effects
  • Female
  • Glucagon / genetics
  • Glucagon / metabolism*
  • Glucagon-Secreting Cells / metabolism*
  • Glucose / metabolism
  • Insulin / metabolism
  • Insulin Secretion / physiology
  • Insulin-Secreting Cells / metabolism
  • Islets of Langerhans / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Somatostatin / genetics
  • Somatostatin / metabolism*
  • Somatostatin-Secreting Cells / metabolism

Substances

  • Blood Glucose
  • Insulin
  • Somatostatin
  • Glucagon
  • Glucose