Hyperinsulinism induced by targeted suppression of beta cell KATP channels

J. C. Koster, M. S. Remedi, T. P. Flagg, J. D. Johnson, K. P. Markova, B. A. Marshall, C. G. Nichols

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

ATP-sensitive K+ (KATP) channels couple cell metabolism to electrical activity. To probe the role of KATP in glucose-induced insulin secretion, we have generated transgenic mice expressing a dominant-negative, GFP-tagged KATP channel subunit in which residues 132-134 (Gly-Tyr-Gly) in the selectivity filter were replaced by Ala-Ala-Ala, under control of the insulin promoter. Transgene expression was confirmed by both beta cell-specific green fluorescence and complete suppression of channel activity in those cells (≈70%) that did fluoresce. Transgenic mice developed normally with no increased mortality and displayed normal body weight, blood glucose levels, and islet architecture. However, hyperinsulinism was evident in adult mice as (i) a disproportionately high level of circulating serum insulin for a given glucose concentration (≈2-fold increase in blood insulin), (ii) enhanced glucose-induced insulin release from isolated islets, and (iii) mild yet significant enhancement in glucose tolerance. Enhanced glucose-induced insulin secretion results from both increased glucose sensitivity and increased release at saturating glucose concentration. The results suggest that incomplete suppression of KATP channel activity can give rise to a maintained hyperinsulinism.

Original languageEnglish
Pages (from-to)16992-16997
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number26
DOIs
StatePublished - Dec 24 2002

Keywords

  • K current
  • Kir6.2
  • Pancreas
  • Transgenic

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