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Functional inactivation by interleukin-1β of glyceraldehyde-3-phosphate dehydrogenase in insulin-secreting cells

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Abstract

Aims/hypothesis: It is well established that long-term exposure of isolated β cells to cytokines [e.g., IL-1β] results in increased expression of inducible nitric oxide synthase and subsequent release of nitric oxide, which in turn, has been shown to mediate a wide array of effects, including alterations in cellular high-energy metabolism. In this context, several extant studies have demonstrated significant reduction in adenine and guanine nucleotide triphosphate levels in β cells exposed to IL-1β. Herein, we examined the functional status of glyceraldehyde-3-phosphate dehydrogenase [GAPDH] in insulin-secreting cells exposed to IL-1β, since it represents the first enzyme in the glycolytic pathway that is involved in the generation of ATP.

Methods: GAPDH was assayed spectrophotometrically in the cytosolic fraction derived from control and IL-1β -treated [300 pM for 24 hrs] insulin-secreting cell lines [HIT-T15 and RINm5F].

Results: IL-treatment resulted in marked attenuation of GAPDH activity in HIT and RIN cells; such a reduction in this activity was not due to inhibition of its expression by IL-1. Instead, we observed that incubation of HIT and RIN lysates with peroxynitrite, a reactive intermediate of nitric oxide with superoxide anion, resulted in significant reduction in the GAPDH activity.

Conclusion/interpretation: These results identify a GAPDH as one of the biochemical loci for the effects of IL-derived peroxynitrite in the islet β cell. The previously reported reduction in high-energy phosphate levels in an IL-treated β cell may, in part, be due to inhibition of GAPDH activity, and subsequent reduction in the glycolytic efficiency of the β cell.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Wayne State University, USA

    R. Veluthakal, I. Khan, M. Tannous & A. Kowluru

  2. β Cell Biochemistry Research Laboratory, John D. Dingell VA Medical Center, Detroit, MI, 48201, USA

    R. Veluthakal, I. Khan, M. Tannous & A. Kowluru

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  1. R. Veluthakal
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  2. I. Khan
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  3. M. Tannous
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  4. A. Kowluru
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Veluthakal, R., Khan, I., Tannous, M. et al. Functional inactivation by interleukin-1β of glyceraldehyde-3-phosphate dehydrogenase in insulin-secreting cells. Apoptosis 7, 241–246 (2002). https://doi.org/10.1023/A:1015347702855

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