Delta-cells and beta-cells are electrically coupled and regulate alpha-cell activity via somatostatin

• Glucagon, the body's principal hyperglycaemic hormone, is released from alpha-cells of the pancreatic islet. Secretion of this hormone is dysregulated in type 2 diabetes mellitus but the mechanisms controlling secretion are not well understood. Regulation of glucagon secretion by factors secreted by neighbouring beta- and delta-cells (paracrine regulation) have been proposed to be important. In this study, we explored the importance of paracrine regulation by using an optogenetic strategy. Specific light-induced activation of beta-cells in mouse islets expressing the light-gated channelrhodopsin-2 resulted in stimulation of electrical activity in delta-cells but suppression of alpha-cell activity. Activation of the delta-cells was rapid and sensitive to the gap junction inhibitor carbenoxolone, whereas the effect on electrical activity in alpha-cells was blocked by CYN 154806, an antagonist of the somatostatin-2 receptor. These observations indicate that optogenetic activation of the beta-cells propagates to the delta-cells via gap junctions, and the consequential stimulation of somatostatin secretion inhibits alpha-cell electrical activity by a paracrine mechanism. To explore whether this pathway is important for regulating alpha-cell activity and glucagon secretion in human islets, we constructed computational models of human islets. These models had detailed architectures based on human islets and consisted of a collection of >500 alpha-, beta- and delta-cells. Simulations of these models revealed that this gap junctional/paracrine mechanism accounts for up to 23% of the suppression of glucagon secretion by high glucose.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Physiology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)

Nyckelord

alpha cell

delta cell

beta cell

Islet cell

computer modelling

electrophysiology

somatostatin

inhibit glucagon-secretion

gap-junction channels

k-atp channels

pancreatic-islets

functional-characterization

insulin-release

glucose

control

mouse

paracrine

receptor

Neurosciences & Neurology

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