Abstract
Emerging evidence indicates that the islet fibrosis is attributable to activation of islet stellate cells (ISCs). In the present study, we compared the differences in biological activity of ISCs isolated from diabetic db/db and non-diabetic db/m mice, and the effects of the regenerating islet-derived protein 1 (Reg1) on ISC function. We showed that ISCs isolated from db/db mice were activated more rapidly than those from db/m mice during culture. Both Reg1 and its putative receptor exostosin-like glycosyltransferase 3 (EXTL3) were highly expressed by diabetic ISCs. Treatment with Reg1 inhibited migration, viability, and synthesis and secretion of Type I Collagen(Col-I), Type III Collagen(Col-III) and Fibronectin(FN) by diabetic ISCs, and this was associated with deactivation of the PI3K/Akt, MAPK/Erk1/2 signaling pathway in an EXTL3-dependent manner. In conclusion, our observations (i) confirmed the presence of fibrogenic stellate cells within pancreatic islets, which are prone to be activated in Type 2 diabetes, and (ii) revealed a potential role for Reg1 in preventing ISC activation.
Highlights
Type 2 diabetes mellitus (T2DM) is a common group of metabolic disorders characterized by hyperglycemia, insulin resistance (IR) and β-cell dysfunction
These observations were confirmed by the immunofluorescence microscopy measurements shown in Figure 1C, in which both regenerating islet-derived protein 1 (Reg1) and exostosin-like glycosyltransferase 3 (EXTL3) immunoreactivities were higher in islet stellate cells (ISCs) isolated from db/db mice than in ISCs from db/m mice
Together these data demonstrate that Reg1 and EXTL3 are much more highly expressed in pancreatic tissues from diabetic mice than from control mice
Summary
Type 2 diabetes mellitus (T2DM) is a common group of metabolic disorders characterized by hyperglycemia, insulin resistance (IR) and β-cell dysfunction. Previous studies have shown that the deposition of islet amyloid, activation of the renin-angiotensin system (RAS) and low-grade chronic inflammation all accelerate the development of islet fibrosis [3,4,5]. The pathogenesis of islet fibrosis has not yet been fully clarified, it has been suggested that the activation of pancreatic stellate cells (PSCs) is a crucial mechanism initiating islet fibrosis in Type 2 diabetes [6]. Our recently research showed that PSCs may contribute to the efficient regulation of pancreatic development [7], which can be activated to proliferate and generate fibrotic extracellular matrix (ECM) by a range of environmental stimuli which are associated with T2DM [8]. Our recent in vitro study showed that a distinct population of islet stellate cells (ISCs) could be expanded from isolated islets. We observed the dynamic growth of ISCs by Live Cell www.impactjournals.com/oncotarget
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