Wingless‐type MMTV integration site family member 5a is a key inhibitor of islet stellate cells activation

Abstract

Aims/Introduction Type 2 diabetes mellitus is a chronic metabolic disorder characterized by islet β‐cell dysfunction, which might result from the activation of islet stellate cells (ISCs). Our recent study showed that a specific population of ISCs is prone to be activated in type 2 diabetes mellitus accompanied by reduced secretion of insulin. The wingless‐type MMTV integration site family member 5a (Wnt5a)/frizzled‐5 signaling pathway might play an important role in this process. The present study aimed to explore the effects of Wnt5a on the activation of ISCs isolated from db/db mice. Materials and Methods ISCs were isolated from db/db mice and matched db/m mice. Immunohistochemistry and western blotting analysis were applied for the determination of Wnt5a expression. Exogenous Wnt5a and lentivirus containing the target gene Wnt5a short hairpin ribonucleic acid were used as a molecular intervention. The experiment of transwell and wound healing was used to evaluate the migration of the isolated ISCs. Results Our data showed that the expression of Wnt5a and frizzled‐5 was decreased in the ISCs isolated from db/db mice compared with db/m mice. Both the exogenous Wnt5a and the overexpression of Wnt5a could inhibit the outgrowth rate of ISCs from islets, and its viability, migration and α smooth muscle actin expression. These changes were associated with the inactivation of the Smad2/3 signaling pathway in a frizzled‐5‐dependent manner. Conclusions Our observations revealed a potential role of Wnt5a in preventing ISC activation. The maintenance of quiescent ISCs might be a desirable outcome of therapeutic strategies for diabetes mellitus.

Pancreatic Fat is not significantly correlated with β-cell Dysfunction in Patients with new-onset Type 2 Diabetes Mellitus using quantitative Computed Tomography

“…Our previous studies have confirmed the presence of stellate cells within the islets (ISCs), which are identical in the expression of retinoid-containing fat droplets [51,52,53,54,55]. A loss of oil red O-stained fat droplets was associated with the activation of diabetic ISCs, and we speculate whether the transfer of lipid droplets from the inside to the outside of the ISCs leads to local fat deposition and the inhibition of normal β-cell function.…”

Perilipin 2 Protects against Lipotoxicity-Induced Islet Fibrosis by Inducing Islet Stellate Cell Activation Phenotype Changes

“…These results indicate that dietary high-fat supplementation for 28 weeks induced a positive relationship between α -SMA expression and ISCs in obese rats. These observations are consistent with previous studies that showed in diabetic environment, the activation of ISCs leads to increase in ISC-derived secretory products and influences islet function [ 5 , 6 , 19 , 26 ]. Our group previously found that ISCs were similar but not identical to pancreatic stellate cells (PSCs) [ 27 ].…”

“…Our previous studies showed that stellate cells in islets, named islet stellate cells (ISCs), which are rich in LDs and positive for desmin and GFAP expression under physiological conditions, proliferate fast and generate the fibrotic extracellular matrix (ECM) when activated by various pathological stimuli. Furthermore, ISCs show specific expression of α -smooth muscle actin ( α -SMA), and secretion of collagen I (Col I), fibronectin (FN), and other ECM components that induce the formation of islet fibrosis with a parallel disappearance of LDs, consequently leading to T2DM [ 5 , 6 ]. However, the underlying pathogenesis and mechanism of ISCs activation have not yet been investigated.…”

Islet Stellate Cells Regulate Insulin Secretion via Wnt5a in Min6 Cells

“…To confirm Min6 cell proliferation, a 5-ethynyl-2′-deoxyuridine (EdU) assay was used for analysis as described previously [18]. Groups of 2 × 10 4 Min6 cells were incubated in the absence or presence of exogenous Wnt5a (0.05 μg/ml) for 48 h before labelling with 10 μM EdU for 4 h at 37°C, and cell proliferation was assessed by colorimetric quantification of EdU incorporation into cellular DNA [18].…”

“…A clinical study by our team showed that the serum Wnt5a level was significantly decreased in newly diagnosed T2DM patients compared with normal controls [17]. In addition, exogenous Wnt5a inhibited the activation of ISCs and increased insulin secretion from islets [7,18]. e FoxO1 and Pdx1-Glut2insulin pathway plays an important role in glucosestimulated insulin secretion (GSIS) [19].…”