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Down-regulation of expression and function of nucleoside diphosphate kinase in insulin-secreting β-cells under in vitro conditions of glucolipotoxicity

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Abstract

Previously, we reported a significant reduction in expression and the activity of nucleoside diphosphate kinase (NDP kinase) in islets derived from the Goto-Kakizaki rat (GK rat), an animal model for type 2 diabetes. Herein, we examined the effects of chronic exposure of insulin-secreting β-(INS 832/13) cells to high glucose (a model for glucotoxicity), palmitate (a model for lipotoxicity), or glucose plus palmitate (a model for glucolipotoxicity) on the expression and activity of nm23-H1 (NDP kinase A) and nm23-H2 (NDP kinase B). Our findings indicate a marked reduction in the expression of both nm23-H1 and nm23-H2 and the associated NDP kinase activity under each of these conditions. A cell-permeable analog of ceramide (CER) also mimicked the effects of palmitate in significantly reducing the expression of nm23-H1 and nm23-H2 and NDP kinase activity in these cells. These findings suggest that de novo generation of intracellular CER from palmitate might represent at least one of the signaling steps involved in lipid-induced effects on NDP kinase expression and function in β-cells. Based on these data, we conclude that glucolipotoxic conditions significantly impair expression and function of NDP kinase in pancreatic β-cells. Potential significance of these findings, specifically at the level of abnormal G-protein activation and impaired insulin secretion under glucolipotoxic conditions is discussed.

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Abbreviations

ATPγS:

Adenosine 5′-[γ-thio] triphosphate

GDP:

Guanosine diphosphate

G-proteins:

Guanosine triphosphate-binding proteins

GSIS:

Glucose-stimulated insulin secretion

GTP:

Guanosine triphosphate

GTPγS:

Guanosine 5′-[γ-thio] triphosphate

NBT:

Nitroblue tetrazolium

NDPK:

Nucleoside diphosphate kinase

Mas:

Mastoparan

Mas-17:

Mastoparan-17

nm23-H1:

Tumor metastasis suppressor gene, which also represents the NDP kinase A isoform

nm23-H2:

Tumor metastasis suppressor gene, which also represents the NDP kinase B isoform

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Acknowledgments

This work was supported by grants to AK from the Department of VA Merit Review Award and the National Institutes of Health. AK is a recipient of Senior Research Career Scientist Award from the Department of VA. We thank Mr. Phillip McDonald for help in islet isolation.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Wayne State University and Beta Cell Biochemistry Research Laboratory, John D. Dingell VA Medical Center, Detroit, MI, 48201, USA

    Rajakrishnan Veluthakal, Madathilparambil V. Suresh & Anjaneyulu Kowluru

  2. Department of Pharmaceutical Sciences, Wayne State University, 3146 Eugene Applebaum College of Pharmacy, 259 Mack Avenue, Detroit, MI, 48201, USA

    Anjaneyulu Kowluru

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  1. Rajakrishnan Veluthakal
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  2. Madathilparambil V. Suresh
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  3. Anjaneyulu Kowluru
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Correspondence to Anjaneyulu Kowluru.

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Veluthakal, R., Suresh, M.V. & Kowluru, A. Down-regulation of expression and function of nucleoside diphosphate kinase in insulin-secreting β-cells under in vitro conditions of glucolipotoxicity. Mol Cell Biochem 329, 121–129 (2009). https://doi.org/10.1007/s11010-009-0113-6

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