Keratin 8 modulates β-cell stress responses and normoglycaemia

A1 Journal article (refereed)


Internal Authors/Editors


Publication Details

List of Authors: Catharina M. Alam, Jonas S. G. Silvander, Ebot N. Daniel, Guo-Zhong Tao, Sofie M. Kvarnström, Parvez Alam, M. Bishr Omary, Arno Hänninen, Diana M. Toivola
Publisher: Company of Biologists Ltd
Place: Cambridge
Publication year: 2013
Journal: Journal of Cell Science
Journal acronym: J. Cell Sci.
Volume number: 126
Issue number: 24
Start page: 5635
End page: 5644
eISSN: 1477-9137


Abstract

Keratin intermediate filament (IF) proteins are epithelial cell cytoskeletal components that provide structural stability and protection from cell stress, among other cellular and tissue-specific functions. Numerous human diseases are associated with IF gene mutations, but the function of keratins in the endocrine pancreas and their potential significance for glycaemic control are unknown. The impact of keratins on β-cell organisation and systemic glucose control was assessed using keratin 8 (K8) wild-type (K8+/+) and K8 knockout (K8−/−) mice. Islet β-cell keratins were characterised under basal conditions, in streptozotocin (STZ)-induced diabetes and in non-obese diabetic (NOD) mice. STZ-induced diabetes incidence and islet damage was assessed in K8+/+ and K8−/− mice. K8 and K18 were the predominant keratins in islet β-cells and K8−/− mice expressed only remnant K18 and K7. K8 deletion resulted in lower fasting glucose levels, increased glucose tolerance and insulin sensitivity, blunted glucose stimulated insulin secretion and decreased pancreatic insulin content. GLUT2 localisation and insulin vesicle morphology were disrupted in K8−/− β-cells. The increased levels of cytoplasmic GLUT2 correlated with resistance to high-dose STZ-induced injury in K8−/− mice. However, K8 deletion conferred no long-term protection from STZ-induced diabetes and prolonged STZ-stress caused increased exocrine damage in K8−/− mice. β-cell keratin upregulation occurred 2 weeks after low-dose STZ-treated K8+/+ mice and in diabetic NOD mice, suggesting a role for keratins particularly in non-acute islet stress responses. These results demonstrate previously unrecognised functions for keratins in β-cell intracellular organisation as well as for systemic blood glucose control under basal conditions and in diabetes-induced stress.


Keywords

Blood Glucose, Diabetes model, Endocrine pancreas, K8, keratin

Last updated on 2019-22-07 at 05:43

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