Abstract
Background Emerging evidence suggests that T2DM is attributable to the dysfunction of β-cells and the activation of islet stellate cells (ISCs). The wingless-type MMTV integration site family member 5a (Wnt5a)/frizzled 5 (Fzd5) signalling pathway might take part in this process. Our study is aimed at defining the status of ISCs during β-cell insulin secretion homeostasis by determining the role of the Wnt5a protein in the regulation of insulin production. We examined the effects of the status of ISCs on β-cell insulin secretion in normoglycemic db/m and hyperglycaemic db/db mice. Methods iTRAQ protein screening and RNA interference were used to determine novel ISC-derived secretory products that may use other mechanisms to influence the function of islets. Results We showed a significant reduction in insulin secretion by β-cells in vitro when they were cocultured with db/db ISCs compared to when they were cocultured with ISCs isolated from normoglycemic db/m mice; in addition, both Wnt5a and its receptor Fzd5 were more highly expressed by quiescent ISCs than by activated db/db ISCs. Treatment with exogenous Wnt5a increased the secretion of insulin in association with the deactivation of ISCs. Conclusion Our observations revealed that the Wnt5a protein is a key effector of ISC-mediated improvement in islet function.
Highlights
Type 2 diabetes mellitus islet stellate cells (ISCs) (T2DM) is one of the most common metabolic disorders characterised by resistance to the action of insulin (IR), increased rates of endogenous glucose production, reduced insulin secretion, and β-cell dysfunction [1]
Emerging evidence suggests that islet dysfunction and the activation of pancreatic stellate cells (PSCs) play an important role in the pathogenesis of diabetes [4,5,6,7,8,9]; when activated by a range of high-glucose, inflammation environmental stimuli that are associated with Type 2 diabetes mellitus ISCs (T2DM), PSC activation produces an excessive extracellular matrix (ECM) involved in islet fibrosis leading to diabetes [10, 11]
To assess the levels of wingless-type MMTV integration site family member 5a (Wnt5a) expression, as shown in Figure 1(b), western blotting analysis revealed that the expression of Wnt5 and frizzled 5 (Fzd5) in the ISCs isolated from db/db mice was significantly reduced compared with those of normoglycemic db/m mice
Summary
T2DM is one of the most common metabolic disorders characterised by resistance to the action of insulin (IR), increased rates of endogenous glucose production, reduced insulin secretion, and β-cell dysfunction [1]. Our study is aimed at defining the status of ISCs during β-cell insulin secretion homeostasis by determining the role of the Wnt5a protein in the regulation of insulin production. ITRAQ protein screening and RNA interference were used to determine novel ISC-derived secretory products that may use other mechanisms to influence the function of islets. We showed a significant reduction in insulin secretion by β-cells in vitro when they were cocultured with db/db ISCs compared to when they were cocultured with ISCs isolated from normoglycemic db/m mice; in addition, both Wnt5a and its receptor Fzd were more highly expressed by quiescent ISCs than by activated db/db ISCs. Treatment with exogenous Wnt5a increased the secretion of insulin in association with the deactivation of ISCs. Conclusion. Our observations revealed that the Wnt5a protein is a key effector of ISC-mediated improvement in islet function
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