Guanqiao Wang

BACKGROUND: A physiological hallmark of patients with type 2 diabetes mellitus (T2DM) is β cell dysfunction. Despite adequate treatment, it is an irreversible process that follows disease progression. Therefore, the development of novel therapies that restore β cell function is of utmost importance. METHODS: This study aims to unveil the mechanistic action of mesenchymal stem cells (MSCs) by investigating its impact on isolated human T2DM islets ex vivo and in vivo. FINDINGS: We propose that MSCs can attenuate β cell dysfunction by reversing β cell dedifferentiation in an IL-1Ra-mediated manner. In response to the elevated expression of proinflammatory cytokines in human T2DM islet cells, we observed that MSCs was activated to secret IL-1R antagonist (IL-1Ra) which acted on the inflammed islets and reversed β cell dedifferentiation, suggesting a crosstalk between MSCs and human T2DM islets. The co-transplantation of MSCs with human T2DM islets in diabetic SCID mice and intravenous infusion of MSCs in db/db mice revealed the reversal of β cell dedifferentiation and improved glycaemic control in the latter. INTERPRETATION: This evidence highlights the potential of MSCs in future cell-based therapies regarding the amelioration of β cell dysfunction.

BACKGROUND AND OBJECTIVES: Adipose tissue-derived mesenchymal stem cells (ASCs) are recognized as an advantaged source for the prevention and treatment of diverse diseases including type 2 diabetes mellitus (T2DM). However, alterations in characteristics of ASCs from the aforementioned T2DM patients are still obscure, which also hinder the rigorous and systematic illumination of progression and pathogenesis. METHODS AND RESULTS: In this study, we originally isolated peripancreatic adipose tissue-derived mesenchymal stem cells from both human type 2 diabetic and non-diabetic donors (T2DM-ASCs, ND-ASCs) with the parental consent, respectively. We noticed that T2DM-ASCs exhibited indistinguishable immunophenotype, cell vitality, chondrogenic differentiation and stemness as ND-ASCs. Simultaneously, there's merely alterations in migration and immunoregulatory capacities in T2DM-ASCs. However, differing from ND-ASCs, T2DM-ASCs exhibited deficiency in adipogenic and osteogenic differentiation, and in particular, the delayed cell cycle and different cytokine expression spectrum. CONCLUSIONS: The conservative alterations of T2DM-ASCs in multifaceted characteristics indicated the possibility of autologous application of ASCs for cell-based T2DM treatment in the future.

The cyclooxygenase2 (COX-2) enzyme catalyzes the first step of prostanoid biosynthesis, and is known for its crucial role in the pathogenesis of several inflammatory diseases including type 2 diabetes mellitus (T2DM). Although a variety of studies revealed that COX-2 played a role in the IL-1β induced β cell dysfunction, the molecular mechanism remains unclear. Here, using a cDNA microarray and in silico analysis, we demonstrated that inflammatory responses were upregulated in human T2DM islets compared with non-diabetic (ND) islets. COX-2 expression was significantly enhanced in human T2DM islets, correlated with the high inflammation level. PGE2, the catalytic product of COX-2, downregulated the functional gene expression of PDX1, NKX6.1, and MAFA and blunted the glucose induced insulin secretion of human islets. Conversely, inhibition of COX-2 activity by a pharmaceutical inhibitor prevented the β-cell dysfunction induced by IL-1β. COX-2 inhibitor also abrogated the IL-1β autostimulation in β cells, which further resulted in reduced COX-2 expression in β cells. Together, our results revealed that COX-2/PGE2 signaling was involved in the regulation of IL-1β autostimulation, thus forming an IL-1β/COX-2/PGE2 pathway loop, which may result in the high inflammation level in human T2DM islets and the inflammatory impairment of β cells. Breaking this IL-1β/COX-2/PGE2 pathway loop provides a potential therapeutic strategy to improve β cell function in the treatment of T2DM patients.

Glucagon like peptide-1 (GLP-1) plays a vital role in glucose homeostasis and sustaining β-cell function. Currently there are two major methods to enhance endogenous GLP-1 activity; inhibiting dipeptidyl peptidase-4 (DPP4) or activating G protein-coupled receptor 119 (GPR119). Here we describe and validate a novel dual-target compound, HBK001, which can both inhibit DPP4 and activate GPR119 ex and in vivo. We show that HBK001 can promote glucose-stimulated insulin secretion in mouse and human primary islets. A single administration of HBK001 in ICR mice can increase plasma incretins levels much more efficiently than linagliptin, a classic DPP4 inhibitor. Long-term treatment of HBK001 in KKAy mice can ameliorate hyperglycemia as well as improve glucose tolerance, while linagliptin fails to achieve such glucose-lowing effects despite inhibiting 95% of serum DPP4 activity. Moreover, HBK001 can increase first-phase insulin secretion in KKAy mice, suggesting a direct effect on islet β-cells via GPR119 activation. Furthermore, HBK001 can improve islet morphology, increase β-cell proliferation and up-regulate genes involved in improved β-cell function. Thus, we have identified, designed and synthesized a novel dual-target compound, HBK001, which represents a promising therapeutic candidate for type 2 diabetes, especially for patients who are insensitive to current DPP4 inhibitors.