Keratin 8 modulates β-cell stress responses and normoglycaemia

Parvez Alam, Jonas Silvander, Ebot N. Daniel, Guo-Zhong Tao, Sofie M. Kvarnström, Catharina Alam, M. Bishr Omary, Arno Hänninen, Diana Toivola

Research output: Contribution to journalArticleScientificpeer-review

27 Citations (Scopus)

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.

Original languageUndefined/Unknown
Pages (from-to)5635–5644
JournalJournal of Cell Science
Volume126
Issue number24
DOIs
Publication statusPublished - 2013
MoE publication typeA1 Journal article-refereed

Keywords

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

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