Chronic exposure of pancreatic beta-cells to saturated fatty acids leads to loss of viability, an effect that has been implicated in the process of beta-cell 'lipotoxicity' associated with the progression of type 2 diabetes. The mechanisms involved are unknown but recent evidence has implicated the delta isoform of protein kinase C (PKCdelta) in mediating fatty acid toxicity. We have investigated this proposition in the clonal insulin-secreting cell line, BRIN-BD11. BRIN-BD11 cells were found to undergo apoptosis when exposed to palmitate and this response was attenuated by the purportedly selective inhibitor of PKCdelta, rottlerin. However, activation of PKCdelta with the phorbol ester, phorbol-12-myristate-13-acetate (PMA), failed to promote cell death and down-regulation of PKCdelta did not prevent the cytotoxic effects of palmitate. Moreover, rottlerin remained effective as a blocker of the palmitate response in cells depleted of PKCdelta. Since rottlerin can inhibit various other kinases in addition to PKCdelta, a range of additional kinase inhibitors was also tested. Of these, only the putative Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) inhibitor, KN-62, was found to inhibit palmitate-induced cell death. However, this effect was not reproduced by a more selective pseudo-substrate inhibitor of CaM kinase II. Therefore, the present results reveal that palmitate induces cell death in BRIN-BD11 cells and suggest that this may involve the activation of a rottlerin (and KN-62)-sensitive kinase. However, it is clear that PKCdelta is not required for this response.

This article has been cited by other articles:

				C. Schmitz-Peiffer and T. J. Biden PKC{delta} Blues for the {beta}-Cell Diabetes, January 1, 2010; 59(1): 1 - 3. [Full Text] [PDF]

				A. M. Hennige, F. Ranta, I. Heinzelmann, M. Dufer, D. Michael, H. Braumuller, S. Z. Lutz, R. Lammers, G. Drews, F. Bosch, et al. Overexpression of Kinase-Negative Protein Kinase C{delta} in Pancreatic {beta}-Cells Protects Mice From Diet-Induced Glucose Intolerance and {beta}-Cell Dysfunction Diabetes, January 1, 2010; 59(1): 119 - 127. [Abstract] [Full Text] [PDF]

				S. Park, S. Hong, J. Lee, S. Sung, and S. Kim Chlorpromazine attenuates pancreatic {beta}-cell function and mass through IRS2 degradation, while exercise partially reverses the attenuation J Psychopharmacol, July 1, 2008; 22(5): 522 - 531. [Abstract] [PDF]

				A. K. Busch, E. Gurisik, D. V. Cordery, M. Sudlow, G. S. Denyer, D. R. Laybutt, W. E. Hughes, and T. J. Biden Increased Fatty Acid Desaturation and Enhanced Expression of Stearoyl Coenzyme A Desaturase Protects Pancreatic {beta}-Cells from Lipoapoptosis Diabetes, October 1, 2005; 54(10): 2917 - 2924. [Abstract] [Full Text] [PDF]