Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways

I B Leibiger; B Leibiger; T Moede; P O Berggren

doi:10.1016/s1097-2765(00)80093-3

Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways

Mol Cell. 1998 May;1(6):933-8. doi: 10.1016/s1097-2765(00)80093-3.

Authors

I B Leibiger¹, B Leibiger, T Moede, P O Berggren

Affiliation

¹ Department of Molecular Medicine, Rolf Luft Center for Diabetes Research, Karolinska Institute, Stockholm, Sweden.

PMID: 9660977
DOI: 10.1016/s1097-2765(00)80093-3

Abstract

The control of glucose homeostasis by insulin requires, in addition to the glucose-induced insulin release, a highly dynamic control of insulin biosynthesis. Although elevated glucose concentrations have been shown to trigger insulin biosynthesis at the levels of transcription and translation, the molecular mechanisms underlying the immediate transcriptional control are poorly understood. By investigating signal transduction pathways involved in the "glucose-dependent" transcriptional control, thereby analyzing endogenous (prepro)insulin mRNA levels and monitoring on-line insulin promoter-driven GFP expression, we provide, for the first time, evidence that physiologically stimulated insulin secretion from the pancreatic beta cell promotes insulin biosynthesis by enhancing insulin gene transcription in an autocrine manner. We show that secreted insulin acts via beta-cell insulin receptors and up-regulates insulin gene transcription by signaling through the IRS-2/PI-3 kinase/p70 s6k and CaM kinase pathways.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
Cells, Cultured
Exocytosis / genetics
Gene Expression Regulation, Enzymologic / drug effects
Gene Expression Regulation, Enzymologic / physiology
Glucose / pharmacology
Insulin / genetics*
Insulin / metabolism
Insulin / pharmacology
Islets of Langerhans / chemistry
Islets of Langerhans / cytology
Islets of Langerhans / metabolism
Phosphatidylinositol 3-Kinases / genetics*
Phosphatidylinositol 3-Kinases / metabolism
Rats
Receptor, Insulin / genetics*
Receptor, Insulin / metabolism
Ribosomal Protein S6 Kinases / genetics*
Ribosomal Protein S6 Kinases / metabolism
Signal Transduction / genetics
Transcription, Genetic / physiology
Transfection

Substances

Insulin
Phosphatidylinositol 3-Kinases
Receptor, Insulin
Ribosomal Protein S6 Kinases
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases
Glucose