Decreased levels of keratin 8 sensitize mice to streptozotocin‐induced diabetes

Abstract

AimDiabetes is a result of an interplay between genetic, environmental and lifestyle factors. Keratin intermediate filaments are stress proteins in epithelial cells, and keratin mutations predispose to several human diseases. However, the involvement of keratins in diabetes is not well known. K8 and its partner K18 are the main β‐cell keratins, and knockout of K8 (K8−/−) in mice causes mislocalization of glucose transporter 2, mitochondrial defects, reduced insulin content and altered systemic glucose/insulin control. We hypothesize that K8/K18 offer protection during β‐cell stress and that decreased K8 levels contribute to diabetes susceptibility.MethodsK8‐heterozygous knockout (K8+/−) and wild‐type (K8+/+) mice were used to evaluate the influence of keratin levels on endocrine pancreatic function and diabetes development under basal conditions and after T1D streptozotocin (STZ)‐induced β‐cell stress and T2D high‐fat diet (HFD).ResultsMurine K8+/− endocrine islets express ~50% less K8/K18 compared with K8+/+. The decreased keratin levels have little impact on basal systemic glucose/insulin regulation, β‐cell health or insulin levels. Diabetes incidence and blood glucose levels are significantly higher in K8+/− mice after low‐dose/chronic STZ treatment, and STZ causes more β‐cell damage and polyuria in K8+/− compared with K8+/+. K8 appears upregulated 5 weeks after STZ treatment in K8+/+ islets but not in K8+/−. K8+/− mice showed no major susceptibility risk to HFD compared to K8+/+.ConclusionPartial K8 deficiency reduces β‐cell stress tolerance and aggravates diabetes development in response to STZ, while there is no major susceptibility to HFD.

Cytokeratin 8 Inhibits Hepatic Glycogen Synthesis in Type 2 Diabetes Mellitus by Modulating Insulin-dependent IRS1/PI3K/Akt-GSK3β Pathway

“…Recent studies have found that CK8 plays an important role in regulating glycogen synthesis and glucose metabolism. Alam et al has demonstrated that CK8 was upregulated in islets of mice in high glucose condition and knockdown of CK8 decreased fasting blood glucose and increased glucose tolerance and insulin sensitivity [42]. Mathew et al also has reported that knockdown of CK8 enhanced insulinstimulated glycogen formation in normal and cancerous hepatic cells [19].…”

Enhanced longitudinal differential expression detection in proteomics with robust reproducibility optimization regression

“…Two keratins, KRT31 and KRT86, were detected as highly differentially expressed by RolDE (Figure 4A, Supplementary Table 1). Decreased levels of keratins [32] as well as increased keratin metabolism [33] have been previously associated with diabetes and hyperglycemia with keratinocyte proliferation, differentiation and function [34]. Downregulation of another RolDE detected protein (Figure 4B), cell growth regulator with EF-hand domain 1 (CGREF1), has been associated with hyperglycemia in humans [35].…”

Benchmarking tools for detecting longitudinal differential expression in proteomics data allows establishing a robust reproducibility optimization regression approach

“…5a, Supplementary Table 2). Decreased levels of keratins 36 as well as increased keratin metabolism 37 have been previously associated with diabetes and hyperglycemia with keratinocyte proliferation, differentiation, and function 38 . Downregulation of another detected protein (Fig.…”