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Apoptosis

, Volume 19, Issue 12, pp 1691–1701 | Cite as

Glucotoxic and diabetic conditions induce caspase 6-mediated degradation of nuclear lamin A in human islets, rodent islets and INS-1 832/13 cells

  • Syeda Khadija
  • Rajakrishnan Veluthakal
  • Vaibhav Sidarala
  • Anjaneyulu Kowluru
Original Paper

Abstract

Nuclear lamins form the lamina on the interior surface of the nuclear envelope, and regulate nuclear metabolic events, including DNA replication and organization of chromatin. The current study is aimed at understanding the role of executioner caspase 6 on lamin A integrity in islet β-cells under duress of glucotoxic (20 mM glucose; 24 h) and diabetic conditions. Under glucotoxic conditions, glucose-stimulated insulin secretion and metabolic cell viability were significantly attenuated in INS-1 832/13 cells. Further, exposure of normal human islets, rat islets and INS-1 832/13 cells to glucotoxic conditions leads to caspase 6 activation and lamin A degradation, which is also observed in islets from the Zucker diabetic fatty rat, a model for type 2 diabetes (T2D), and in islets from a human donor with T2D. Z-Val-Glu-Ile-Asp-fluoromethylketone, a specific inhibitor of caspase 6, markedly attenuated high glucose-induced caspase 6 activation and lamin A degradation, confirming that caspase 6 mediates lamin A degradation under high glucose exposure conditions. Moreover, Z-Asp-Glu-Val-Asp-fluoromethylketone, a known caspase 3 inhibitor, significantly inhibited high glucose-induced caspase 6 activation and lamin A degradation, suggesting that activation of caspase 3 might be upstream to caspase 6 activation in the islet β-cell under glucotoxic conditions. Lastly, we report expression of ZMPSTE24, a zinc metallopeptidase involved in the processing of prelamin A to mature lamin A, in INS-1 832/13 cells and human islets; was unaffected by high glucose. We conclude that caspases 3 and 6 could contribute to alterations in the integrity of nuclear lamins leading to metabolic dysregulation and failure of the islet β-cell.

Keywords

Pancreatic islet Glucotoxicity Caspase 3 Caspase 6 Lamin A Diabetes 

Abbreviations

ELISA

Enzyme-linked immunosorbent assay

ER

Endoplasmic reticulum

FTI

Farnesyl transferase inhibitor

GSIS

Glucose stimulated insulin secretion

IFNγ

Interferon gamma

IL-1β

Interleukin-1beta

iNOS

Inducible nitric oxide synthase

LMNA

Lamin A gene

NO

Nitric oxide

T2D

Type 2 Diabetes

TNF α

Tumor necrosis factor alpha

Z-DEVD-FMK

Caspase 3 inhibitor (Z-Asp-Glu-Val-Asp-fluoromethylketone)

ZDF

Zucker diabetic fatty

ZLC

Zucker lean control

ZMPSTE24

Zinc metallopeptidase (STE24 homolog)

Z-VEID-FMK

Caspase 6 inhibitor (Z-Val-Glu-Ile-Asp-fluoromethylketone)

Notes

Acknowledgments

This research was supported in part by a Merit Review award (to AK; 1BX000469) from the Department of Veterans Affairs, the National Institutes of Health (DK94201 and EY022230), the Juvenile Diabetes Research Foundation (5-2012-257), and Research Stimulation Funds from the Office of Vice President for Research-Wayne State University. AK is also the recipient of a Senior Research Career Scientist Award from the Department of VA (13S-RCS-006). KS is the recipient of Rumble Fellowship from Wayne State University. We thank Prof. Chris Newgard for providing INS-1 832/13 cells.

Conflict of interest

The authors declare no conflict of interests.

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Copyright information

© Springer Science+Business Media New York (outside the USA) 2014

Authors and Affiliations

  • Syeda Khadija
    • 1
    • 2
  • Rajakrishnan Veluthakal
    • 1
    • 2
  • Vaibhav Sidarala
    • 1
    • 2
  • Anjaneyulu Kowluru
    • 1
    • 2
  1. 1.B-4237 Research Service, β-Cell Biochemistry LaboratoryJohn D. Dingell VA Medical CenterDetroitUSA
  2. 2.Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health SciencesWayne State UniversityDetroitUSA

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