title: Keratin 8 modulates β-cell stress responses and normoglycaemia.
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, reduced 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-induced stress caused increased exocrine damage in K8(-/-) mice. β-cell keratin upregulation occurred 2 weeks after treatments with low-dose STZ in 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.
authors.affiliation: Department of Biosciences, Cell Biology, Åbo Akademi University, Tykistökatu 6A, FIN-20520 Turku, Finland.
authors.forename: Catharina M
authors.initials: CM
authors.lastname: Alam
authors.forename: Jonas S G
authors.initials: JS
authors.lastname: Silvander
authors.forename: Ebot N
authors.initials: EN
authors.lastname: Daniel
authors.forename: Guo-Zhong
authors.initials: GZ
authors.lastname: Tao
authors.forename: Sofie M
authors.initials: SM
authors.lastname: Kvarnström
authors.forename: Parvez
authors.initials: P
authors.lastname: Alam
authors.forename: M Bishr
authors.initials: MB
authors.lastname: Omary
authors.forename: Arno
authors.initials: A
authors.lastname: Hänninen
authors.forename: Diana M
authors.initials: DM
authors.lastname: Toivola
mesh_terms: D000818:Animals; D001786:Blood Glucose; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D053538:Keratin-18 / Q000378:metabolism; D053552:Keratin-7 / Q000378:metabolism; D053533:Keratin-8 / Q000502:physiology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D013312:Stress, Physiological
chemical_list: D001786:Blood Glucose; D051273:Glucose Transporter Type 2; D007328:Insulin; D053538:Keratin-18; D053552:Keratin-7; D053533:Keratin-8; C507496:Krt7 protein, mouse; C486595:Krt8 protein, mouse; C495682:Slc2a2 protein, mouse
keywords: Blood glucose; Diabetes model; Endocrine pancreas; K8; Keratin