Different mechanisms control glucagon secretion in hypo- and hyperglycaemia

What is it about?

ATP derived from glucose metabolism in beta cells is essential for initiation of insulin secretion and implicated in different models for how alpha cells sense glucose and release glucagon. In support for such a role we demonstrate that ATP’s dependence on the glucose concentration is left-shifted in alpha as compared to beta cells, mirroring control of glucagon release in hypoglycaemia and insulin secretion in hyperglycaemia, respectively. We also found that the beta cell Ca2+ oscillations that generate pulsatile insulin release in response to hyperglycaemia are synchronized in the same phase as the alpha cell Ca2+ oscillations. Such a relationship is surprising since pulsatile insulin and glucagon release are known to be synchronized in opposite phase. Our data indicate that glucagon secretion is regulated by alpha cell-intrinsic mechanisms in hypoglycaemia and that paracrine inhibition generates pulsatile glucagon release in hyperglycaemia.

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Why is it important?

Hypersecretion of glucagon is a major factor underlying hyperglycaemia that leads to severe long-term complications in diabetic patients. Also the glucagon response to hypoglycaemia is compromised in diabetes, explaining deteriorated defence against dangerously low blood glucose that may accidentally occur in diabetes therapy. Clarification of the mechanisms that underlie glucose control of glucagon secretion may therefore identify novel targets for more efficient diabetes therapy.

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