Ribozyme-mediated attenuation of pancreatic β-cell glucokinase expression in transgenic mice results in impaired glucose-induced insulin secretion

Shimon Efrat, Margarita Leiser, Y. Jian Wu, David Fusco-Demane, Obaidullah A. Emran, Manju Surana, Thomas L. Jetton, Mark A. Magnuson, Gordon Weir, Norman Fleischer

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

Phosphorylation of glucose to glucose 6-phosphate by glucokinase (GK; EC 2.7.1.2) serves as a glucose-sensing mechanism for regulating insulin secretion in β cells. Recent findings of heterozygous GK gene mutations in patients with maturity-onset diabetes of the young (MODY), a form of type II (non-insulin-dependent) diabetes characterized by autosomal dominant inheritance, have raised the possibility that a decrease in β-cell GK activity may impair the insulin secretory response of these cells to glucose. To generate an animal model for MODY we have expressed in transgenic mice a GK antisense RNA with a ribozyme element under control of the insulin promoter. Mice in two independent lineages had about 30% of the normal islet GK activity. Insulin release in response to glucose from in situ-perfused pancreas was impaired; however, the plasma glucose and insulin levels of the mice remained normal. These mice are likely to be predisposed to type II diabetes and may manifest increased susceptibility to genetic and environmental diabetogenic factors. They provide an animal model for studying the interaction of such factors with the reduced islet GK activity.

Original languageEnglish (US)
Pages (from-to)2051-2055
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number6
StatePublished - Mar 15 1994

Fingerprint

Glucokinase
Catalytic RNA
Transgenic Mice
Insulin
Glucose
Animal Models
Antisense RNA
Glucose-6-Phosphate
Genetic Predisposition to Disease
Pancreas
Phosphorylation
Mutation
Genes

Keywords

  • β-cell lines
  • antisense RNA
  • diabetes
  • glucose phosphorylation
  • glucose sensing

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Ribozyme-mediated attenuation of pancreatic β-cell glucokinase expression in transgenic mice results in impaired glucose-induced insulin secretion. / Efrat, Shimon; Leiser, Margarita; Wu, Y. Jian; Fusco-Demane, David; Emran, Obaidullah A.; Surana, Manju; Jetton, Thomas L.; Magnuson, Mark A.; Weir, Gordon; Fleischer, Norman.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 91, No. 6, 15.03.1994, p. 2051-2055.

Research output: Contribution to journalArticle

Efrat, S, Leiser, M, Wu, YJ, Fusco-Demane, D, Emran, OA, Surana, M, Jetton, TL, Magnuson, MA, Weir, G & Fleischer, N 1994, 'Ribozyme-mediated attenuation of pancreatic β-cell glucokinase expression in transgenic mice results in impaired glucose-induced insulin secretion', Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 6, pp. 2051-2055.
Efrat, Shimon ; Leiser, Margarita ; Wu, Y. Jian ; Fusco-Demane, David ; Emran, Obaidullah A. ; Surana, Manju ; Jetton, Thomas L. ; Magnuson, Mark A. ; Weir, Gordon ; Fleischer, Norman. / Ribozyme-mediated attenuation of pancreatic β-cell glucokinase expression in transgenic mice results in impaired glucose-induced insulin secretion. In: Proceedings of the National Academy of Sciences of the United States of America. 1994 ; Vol. 91, No. 6. pp. 2051-2055.
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