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Glucose Dependence of the Regulated Secretory Pathway in TC1-6 Cells

Lawson Health Research Institute (R.M., C.E.E., S.D.), London, Ontario, Canada N6A 4V2; Departments of Medical Biophysics and Medicine (S.D.), University of Western Ontario, London, Ontario, Canada N6A 5B8; London Regional Genomics Centre (D.E.C.), London, Ontario, Canada N6A 5K8; Vascular Biology Group (J.D.A.), Robarts Research Institute, London, Ontario, Canada N6A 5K8; Loma Linda University (Y.N.), Loma Linda, California 92350; and Charles R. Drew University (T.C.F.), Los Angeles, California 90059

Address all correspondence and requests for reprints to: Savita Dhanvantari, Ph.D., Lawson Health Research Institute, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2. E-mail: sdhanvan{at}uwo.ca.

We have investigated the effects of chronically elevated glucose concentrations on the pancreatic -cell line TC1-6. We show that basal glucagon secretion and proglucagon gene expression were increased in response to high glucose levels. The extent of acute stimulated secretion of glucagon was also increased in response to high glucose, as was the transcription of the prohormone processing enzymes PC1/3 and PC2. The secretion of GLP-1, a proglucagon-derived peptide produced by cleavage of proglucagon by PC1/3, was also increased in response to high glucose. Gene expression profiling experiments showed that a number of components of the regulated secretory pathway were up-regulated at high glucose concentrations, including processing enzymes and exocytotic proteins. Immunoblot analysis showed that the expression of the exocytotic SNARE proteins, as well as that of PC1/3, chromogranin A, and 7B2, were all increased after chronic exposure to high glucose levels. Immunocytochemistry showed no changes in the expression of the mature -cell markers glucagon and brn-4 and no induction of the immature -cell marker pdx-1. We conclude that chronically elevated glucose concentrations up-regulate the regulated secretory response of the -cell.

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