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Background: Vitamin A (VA) plays an essential role in pancreatic homeostasis. Islet stellate cells (ISCs) are VA-storing cells in pancreatic islets. Herein, we have investigated the effect of VA on glucose homeostasis trough regulation of ISCs function in dietary VA deficiency model mice. Methods: Male C57BL/6 mice were randomly fed a VA-sufficient, a VA-deficient (VAD) or a VAD-rescued diet. Glucose metabolism was assessed by glucose tolerance tests and immunohistochemistry. ISCs activation degree was evaluated by immunofluorescence, quantitative PCR and western blotting in both, retinol-treated cultured ISCs and model mice. Changes in ISCs phenotype and their effect on islets were assessed by lentiviral transduction and enzyme-linked immunosorbent assays in a co-culture system. Results: VAD mice showed irregular shaped islet, glucose intolerance, islet size distribution excursions, and upregulated expression of α-smooth muscle actin (α-SMA, marker of ISCs activation). Reintroduction of dietary VA restored pancreatic VA levels, endocrine hormone profiles, and inhibited ISCs activation. Incubation with retinol increased the expression of VA signaling factors in ISCs, including cellular retinol binding protein 1 (CRBP1). The knockdown of CRBP1 maintained the quiescent ISCs phenotype and reduced the damage of activated ISCs on islet function. Conclusions: VA deficiency reduced islet function by activating ISCs in VAD mice. Restoring ISCs quiescence via CRBP1 inhibition could reverse the impairment of islet function caused by activated ISCs exposure.

The progressive decline and eventual loss of islet β-cell function underlies the pathophysiological mechanism of the development of both type 1 and type 2 diabetes mellitus. The recovery of functional β-cells is an important strategy for the prevention and treatment of diabetes. Based on similarities in developmental biology and anatomy, in vivo induction of differentiation of other types of pancreatic cells into β-cells is a promising avenue for future diabetes treatment. Pancreatic stellate cells (PSCs), which have attracted intense research interest due to their effects on tissue fibrosis over the last decade, express multiple stem cell markers and can differentiate into various cell types. In particular, PSCs can successfully differentiate into insulin- secreting cells in vitro and can contribute to tissue regeneration. In this article, we will brings together the main concepts of the translational physiology potential of PSCs that have emerged from work in the field and discuss possible ways to develop the future renewable source for clinical treatment of pancreatic diseases.

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Vitamin A (VA), which is stored in several forms in most tissues, is required to maintain metabolite homeostasis and other processes, including the visual cycle, energy balance, epithelial cell integrity, and infection resistance. In recent years, VA molecules, also known as retinoids, have been extensively explored and used in the treatment of skin disorders and immune-related tumors. To date, several observational and interventional studies have explored the relationship between VA status and the pathogenesis of diabetes. In particular, VA micronutrients have been shown to regulate pancreatic development, β-cell function, pancreatic innate immune responses, and pancreatic stellate cells phenotypes through multiple mechanisms. However, there are still many problems to be proven or resolved. In this review, we summarize and discuss recent and available evidence on VA biological metabolism in the pancreas. Analysis of the effects of VA on metabolism in the pancreas will contribute to our understanding of the supportive physiological roles of VA in pancreas protection.

Aims. The underlying mechanisms involved in Vitamin A- (VA-) related changes in glucose metabolic disorders remain unclear. Recent evidence suggests that intestinal microbiota is closely linked to the metabolic syndrome. Here, we explored whether and how intestinal microbiota affects glucose homeostasis in VA-deficient diet-fed mice. Methods. Six-week-old male C57BL/6 mice were randomly placed on either a VA-sufficient (VAS) or VA-deficient (VAD) diet for 10 weeks. Subsequently, a subclass of the VAD diet-fed mice was switched to a VA-deficient rescued (VADR) diet for an additional 8 weeks. The glucose metabolic phenotypes of the mice were assessed using glucose tolerance tests and immunohistochemistry staining. Changes in intestinal microbiota were assessed using 16S gene sequencing. The intestinal morphology, intestinal permeability, and inflammatory response activation signaling pathway were assessed using histological staining, western blots, quantitative-PCR, and enzyme-linked immunosorbent assays. Results. VAD diet-fed mice displayed reduction of tissue VA levels, increased area under the curve (AUC) of glucose challenge, reduced glucose-stimulated insulin secretion, and loss of β cell mass. Redundancy analysis showed intestinal microbiota diversity was significantly associated with AUC of glucose challenge and β cell mass. VAD diet-driven changes in intestinal microbiota followed the inflammatory response with increased intestinal permeability and higher mRNA expression of intestinal inflammatory cytokines through nuclear factor-κB signaling pathway activation. Reintroduction of dietary VA to VAD diet-fed mice restored tissue VA levels, endocrine hormone profiles, and inflammatory response, which are similar to those observed following VAS-controlled changes in intestinal microbiota. Conclusions. We found intestinal microbiota effect islet function via controlling intestinal inflammatory phenotype in VAD diet-fed mice. Intestinal microbiota influences could be considered as an additional mechanism for the effect of endocrine function in a VAD diet-driven mouse model.

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AimsWe evaluated the efficacy and significant changes in the levels of retinol-binding protein 4 (RBP-4) and insulin resistance in patients with type 2 diabetes mellitus (T2DM) treated with chiglitazar versus sitagliptin.MethodsEighty-one T2DM patients with haemoglobin A1c (HbA1c) level of 7.5%–10.0% were selected. Based on the study criteria, patients were randomly assigned to receive chiglitazar (32 mg), chiglitazar (48 mg), or sitagliptin (100 mg) orally for 24 weeks. Sociodemographic and anthropometric characteristics, lipid profiles, glucose profiles, and serum RBP-4 levels were determined at baseline and at the end of the therapy.ResultsAfter treatment for 24 weeks, significant changes in fasting blood glucose (FBG), fasting insulin (Fins), 2 h-blood glucose (2h-BG), the score values of insulin resistance/insulin secretion/β cell function (HOMA-IR, HOMA-IS, and HOMA-β), triglyceride (TG), free fatty acid (FFA), high-density lipoprotein cholesterol (HDL-C), and RBP-4 levels were detected in patients with chiglitazar administration and sitagliptin administration. Changes in RBP-4 levels were positively correlated with changes in HOMA-IR and 2 h-BG in linear regression.ConclusionsChiglitazar showed a greater improvement in parameters of diabetes than sitagliptin, and changes in serum RBP-4 levels were associated with changes in insulin-sensitizing parameters.Clinical Trial RegistrationClinicalTrials.gov, CT.gov identifier: NCT02173457.