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Albert Salehi

S Albert Salehi

Research team manager

Albert Salehi

A K-ATP channel-dependent pathway within alpha cells regulates glucagon release from both rodent and human islets of langerhans

Author

  • Patrick E. MacDonald
  • Yang Zhang De Marinis
  • Reshma Ramracheya
  • S Albert Salehi
  • Xiaosong Ma
  • Paul R. V. Johnson
  • Roger Cox
  • Lena Eliasson
  • Patrik Rorsman

Summary, in English

Glucagon, secreted from pancreatic islet a cells, stimulates gluconeogenesis and liver glycogen breakdown. The mechanism regulating glucagon release is debated, and variously attributed to neuronal control, paracrine control by neighbouring beta cells, or to an intrinsic glucose sensing by the a cells themselves. We examined hormone secretion and Ca2+ responses of a and b cells within intact rodent and human islets. Glucose-dependent suppression of glucagon release persisted when paracrine GABA or Zn (2+) signalling was blocked, but was reversed by low concentrations (1-20 mu M) of the ATP-sensitive K+ (K-ATP) channel opener diazoxide, which had no effect on insulin release or b cell responses. This effect was prevented by the K-ATP channel blocker tolbutamide (100 mu M). Higher diazoxide concentrations (>= 30 mu M) decreased glucagon and insulin secretion, and alpha-and beta-cell Ca2+ responses, in parallel. In the absence of glucose, tolbutamide at low concentrations (< 1 mu M) stimulated glucagon secretion, whereas high concentrations (> 10 mu M) were inhibitory. In the presence of a maximally inhibitory concentration of tolbutamide (0.5 mM), glucose had no additional suppressive effect. Downstream of the K-ATP channel, inhibition of voltage-gated Na+ (TTX) and N-type Ca2+ channels (omega-conotoxin), but not L-type Ca2+ channels (nifedipine), prevented glucagon secretion. Both the N-type Ca2+ channels and alpha-cell exocytosis were inactivated at depolarised membrane potentials. Rodent and human glucagon secretion is regulated by an a-cell K-ATP channel-dependent mechanism. We propose that elevated glucose reduces electrical activity and exocytosis via depolarisation-induced inactivation of ion channels involved in action potential firing and secretion.

Department/s

  • Department of Experimental Medical Science
  • Diabetes - Islet Cell Exocytosis

Publishing year

2007

Language

English

Pages

1236-1247

Publication/Series

PLoS Biology

Volume

5

Issue

6

Document type

Journal article

Publisher

Public Library of Science

Topic

  • Biological Sciences

Status

Published

Research group

  • Diabetes - Islet Cell Exocytosis

ISBN/ISSN/Other

  • ISSN: 1545-7885