Keratin 8 modulates β-cell stress responses and normoglycaemia

A1 Originalartikel i en vetenskaplig tidskrift (referentgranskad)


Interna författare/redaktörer


Publikationens författare: 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
Förläggare: Company of Biologists Ltd
Förlagsort: Cambridge
Publiceringsår: 2013
Tidskrift: Journal of Cell Science
Tidskriftsakronym: J. Cell Sci.
Volym: 126
Nummer: 24
Artikelns första sida, sidnummer: 5635
Artikelns sista sida, sidnummer: 5644
eISSN: 1477-9137


Abstrakt

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.


Nyckelord

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

Senast uppdaterad 2019-16-07 vid 06:33