Therapeutic Strategy For Diabetes Mellitus Research Articles

Exploring exercise-driven inhibition of pyroptosis: novel insights into treating diabetes mellitus and its complications.

Diabetes mellitus (DM) and its complications are important, worldwide public health issues, exerting detrimental effects on human health and diminishing both quality of life and lifespan. Pyroptosis, as a new form of programmed cell death, plays a critical role in DM and its complications. Exercise has been shown to be an effective treatment for improving insulin sensitivity or preventing DM. However, the molecular mechanisms underlying the effects of exercise on pyroptosis-related diseases remain elusive. In this review, we provided a comprehensive elucidation of the molecular mechanisms underlying pyroptosis and the potential mechanism of exercise in the treatment of DM and its complications through the modulation of anti-pyroptosis-associated inflammasome pathways. Based on the existing evidence, further investigation into the mechanisms by which exercise inhibits pyroptosis through the regulation of inflammasome pathways holds promising potential for expanding preventive and therapeutic strategies for DM and facilitating the development of novel therapeutic interventions.

Synergistic Effects of Nigella sativa and Exercise on Diabetic Profiles: A Systematic Review.

Individually, Nigella sativa (NS) and physical training interventions have been shown to be effective preventive and therapeutic strategies for diabetes mellitus. However, the effect of these in combination on bioindicators of diabetes has not yet been evaluated; there is little information available in the literature. A systematic review was therefore performed to assess any mutually potentiating impacts of NS and physical training interventions in diabetic subjects. A search was performed on this topic in the PubMed, CINAHL, Google Scholar and Web of Science databases for randomised, quasi-randomised or non-randomised controlled trials, studies with factorial or single-cohort pre-post designs, case series as well as case reports. The search terms encompassed various combinations of the following: "exercise", "training", "physical activity", "NS", "treadmill", "swimming", "Thymoquinone", "Nigellone", "caraway oil" and "black seeds". Two reviewers screened the abstracts of 202 identified publications according to predetermined inclusion criteria-i.e. papers published from 2009 onwards in the English language, studies on human or animal subjects, and the assessment of diabetic bioindicators following the combined administration of NS and exercise regimens in comparison with just one of these interventions or against controls. Despite the rich data available regarding the effect of both interventions separately, two human studies and two animal studies were ultimately included in the review. However, the benefit of combined administration of NS and exercise regimens on glycemic and lipidemic control was much more obvious compared to exercise alone. In conclusion, these findings suggested thatcombined administration of NS and exercise regimens could be used as an effective adjuvant for oral antidiabetic drugs in diabetes control.

Phosphoproteome reveals molecular mechanisms of aberrant rhythm in neurotransmitter-mediated islet hormone secretion in diabetic mice.

BackgroundAcetylcholine (ACh) and norepinephrine (NE) are representative neurotransmitters of parasympathetic and sympathetic nerves, respectively, that antagonize each other to coregulate internal body functions. This also includes the control of different kinds of hormone secretion from pancreatic islets. However, the molecular mechanisms have not been fully elucidated, and whether innervation in islets is abnormal in diabetes mellitus also remains unclear.Methods and resultsImmunofluorescence colocalization and islet perfusion were performed and the results demonstrated that ACh/NE and their receptors were highly expressed in islet and rapidly regulated different hormones secretion. Phosphorylation is considered an important posttranslational modification in islet innervation and it was identified by quantitative proteomic and phosphoproteomic analyses in this study. The phosphorylated islet proteins were found involved in many biological and pathological processes, such as synaptic signalling transduction, calcium channel opening and insulin signalling pathway. Then, the kinases were predicted by motif analysis and further screened and verified by kinase‐specific siRNAs in different islet cell lines (αTC1‐6, Min6 and TGP52). After functional verification, Ksr2 and Pkacb were considered the key kinases of ACh and NE in insulin secretion, and Cadps, Mlxipl and Pdcd4 were the substrates of these kinases measured by immunofluorescence co‐staining. Then, the decreased expression of receptors, kinases and substrates of ACh and NE were found in diabetic mice and the aberrant rhythm in insulin secretion could be improved by combined interventions on key receptors (M3 (pilocarpine) or α2a (guanfacine)) and kinases (Ksr2 or Pkacb).ConclusionsAbnormal innervation was closely associated with the degree of islet dysfunction in diabetic mice and the aberrant rhythm in insulin secretion could be ameliorated significantly after intervention with key receptors and kinases in the early stage of diabetes mellitus, which may provide a promising therapeutic strategy for diabetes mellitus in the future.

Integrative biology of extracellular vesicles in diabetes mellitus and diabetic complications.

Diabetes mellitus (DM) is a chronic systemic disease with increasing prevalence globally. An important aspect of diabetic pathogenesis is cellular crosstalk and information exchange between multiple metabolic organs and tissues. In the past decade, increasing evidence suggested that extracellular vesicles (EVs), a class of cell-derived membrane vesicles that transmit information and perform inter-cellular and inter-organ communication, are involved in the pathological changes of insulin resistance (IR), inflammation, and endothelial injury, and implicated in the development of DM and its complications. The biogenesis and cargo sorting machinery dysregulation of EVs may mediate their pathogenic roles under diabetic conditions. Moreover, the biogenesis of EVs, their ubiquitous production by different cells, their function as mediators of inter-organ communication, and their biological features in body fluids have generated great promise as biomarkers and clinical treatments. In this review, we summarize the components of EV generation and sorting machinery and highlight their role in the pathogenesis of DM and associated complications. Furthermore, we discuss the emerging clinical implications of EVs as potential biomarkers and therapeutic strategies for DM and diabetic complications. A better understanding of EVs will deepen our knowledge of the pathophysiology of DM and its complications and offer attractive approaches to improve the prevention, diagnosis, treatment, and prognosis of these disorders.

Role of Postbiotics in Diabetes Mellitus: Current Knowledge and Future Perspectives.

In the last decade, the gastrointestinal microbiota has been recognised as being essential for health. Indeed, several publications have documented the suitability of probiotics, prebiotics, and symbiotics in the management of different diseases such as diabetes mellitus (DM). Advances in laboratory techniques have allowed the identification and characterisation of new biologically active molecules, referred to as “postbiotics”. Postbiotics are defined as functional bioactive compounds obtained from food-grade microorganisms that confer health benefits when administered in adequate amounts. They include cell structures, secreted molecules or metabolic by-products, and inanimate microorganisms. This heterogeneous group of molecules presents a broad range of mechanisms and may exhibit some advantages over traditional “biotics” such as probiotics and prebiotics. Owing to the growing incidence of DM worldwide and the implications of the microbiota in the disease progression, postbiotics appear to be good candidates as novel therapeutic targets. In the present review, we summarise the current knowledge about postbiotic compounds and their potential application in diabetes management. Additionally, we envision future perspectives on this topic. In summary, the results indicate that postbiotics hold promise as a potential novel therapeutic strategy for DM.

Effects of Jerusalem Artichoke Extract and Inulin on Blood Glucose Levels and Insulin Secretion in Streptozotocin Induced Diabetic Mice

Background To determine the effects of Jerusalem Artichoke extract (JAE) and inulin on blood glucose levels and insulin secretion in streptozotocin (STZ)-induced diabetic mice. Methods Thirty four mice were divided into a normal control group and three experimental groups: diabetic control, JAE, and inulin. STZ (50 mg/kg) was injected intraperitoneally to induce diabetes in the three experimental groups. The JAE and inulin groups were fed 10 g/kg JAE or fed 1 g/kg inulin, respectively, for 6 weeks. Fasting glucose was checked weekly. After 6 weeks, the oral glucose tolerance test (OGTT) was performed, and the insulin level was checked. Results Four mice from the JAE group (n = 9) died and autopsies revealed inflammation and ulceration of skin lesions on the chest areas. Fasting glucose levels were not decreased in the inulin or JAE group relative to diabetic control group. In the OGTT at 60 minutes and 120 minutes, the serum glucose levels were significantly higher in the inulin group (572.6 ± 52.0 mg/dL and 555.8 ± 72.9 mg/dL, respectively) than in diabetic control group (484.3 ± 81.6 mg/dL and 467.3 ± 111.1 mg/dL, respectively). Insulin levels were not increased in the inulin group relative to the diabetic control group. Conclusion These results indicate that JAE and inulin might not be useful therapeutic strategies for diabetes mellitus and indiscreet intake of Jerusalem Artichoke could exacerbate to diabetes. Keywords: Diabetes mellitus; Glucose; Helianthus; Insulin; Inulin

Targeting Glycoproteins as a therapeutic strategy for diabetes mellitus and its complications.

ObjectivesGlycoproteins are organic compounds formed from proteins and carbohydrates, which are found in many parts of the living systems including the cell membranes. Furthermore, impaired metabolism of glycoprotein components plays the main role in the pathogenesis of diabetes mellitus. The aim of this study is to investigate the influence of glycoprotein levels in the treatment of diabetes mellitus.MethodsAll relevant papers in the English language were compiled by searching electronic databases, including Scopus, PubMed and Cochrane library. The keywords of glycoprotein, diabetes mellitus, glycan, glycosylation, and inhibitor were searched until January 2019.ResultsGlycoproteins are pivotal elements in the regulation of cell proliferation, growth, maturation and signaling pathways. Moreover, they are involved in drug binding, drug transportation, efflux of chemicals and stability of therapeutic proteins. These functions, structure, composition, linkages, biosynthesis, significance and biological effects are discussed as related to their use as a therapeutic strategy for the treatment of diabetes mellitus and its complications.ConclusionsThe findings revealed several chemical and natural compounds have significant beneficial effects on glycoprotein metabolism. The comprehension of glycoprotein structure and functions are very essential and inevitable to enhance the knowledge of glycoengineering for glycoprotein-based therapeutics as may be required for the treatment of diabetes mellitus and its associated complications. Graphical abstract

Determination of Electroacupuncture Effects on circRNAs in Plasma Exosomes in Diabetic Mice: An RNA-Sequencing Approach.

circRNAs are involved in diabetes mellitus pathogenesis. Electroacupuncture (EA) is an effective therapeutic strategy for diabetes mellitus. However, whether the mechanism of action of EA on diabetes mellitus is related to altered circRNAs is unclear. The aim of this study was to reveal the effect of EA on circRNA expression in plasma exosomes and the underlying signaling pathway in mice with type 2 diabetes mellitus (T2DM). In total, 10 mice were randomly categorized into a normal group and 20 mice were used for the T2DM model preparation and randomly divided into the model and model + EA groups. Mice in the model + EA group were administered EA treatment. Changes in the fasting blood glucose (FBG) level and islet structure were evaluated. Plasma exosomes were subjected to RNA sequencing, and then bioinformatics analysis and real-time quantitative PCR (qPCR) verification were performed. EA treatment reduced the FBG level, preserved the islet structure, and reduced the islet β cell apoptotic rate in T2DM mice. After EA treatment, 165 differentially expressed circRNAs were found. GO and KEGG analyses revealed that thyroid hormone signaling was actively regulated by EA. circRNA/miRNA interaction analysis revealed mmu-mir-7092-3p to be closely associated with circINPP4B, suggesting that the phosphatidylinositol signaling pathway may be affected by EA. qPCR confirmed that 12 circRNAs had significant differences. These findings suggested that EA intervention can significantly protect islet function and improve the FBG level in T2DM, possibly via regulation of thyroid hormone and phosphatidylinositol signaling.

Sphingosine-1-phosphate induces islet β-cell proliferation and decreases cell apoptosis in high-fat diet/streptozotocin diabetic mice.

Sphingosine-1-phosphate (S1P) has been reported to enhance the function of islet β-cells, providing a potential therapeutic target for diabetes mellitus. In the present study, the effects of S1P on the proliferation and apoptosis of β-cells in type 2 diabetic mice were investigated. The mice were administered intraperitoneal S1P solution daily at a dose of 20 µg/kg for three weeks. The intraperitoneal glucose tolerance test (IPGTT) and homeostatic model assessment of insulin resistance (HOMA-IR) index determination were carried out. Immunohistochemical staining was used to detect the protein expression of insulin, antigen Ki-67 and S1P receptor isoforms (S1PR1/S1PR2/S1PR3) in pancreatic islets. Compared with the diabetic control (DC) group, the IPGTT results and HOMA-IR index in the S1P treatment group were decreased. The islets in the S1P group exhibited higher insulin immunostaining intensity than the DC group, as well as higher proliferation (P<0.05) and lower apoptosis rates (P<0.05). Positive staining for the S1P receptors S1PR1, S1PR2 and S1PR3 was observed in the cytoplasm and membrane of the islet cells. S1PR1 and S1PR2 proteins showed increased expression in the S1P and DC groups compared with the normal control group (P<0.01 and P<0.05, respectively), whereas no significant difference was observed in the expression of S1PR3 among these groups. In conclusion, extracellular S1P can induce islet β-cell proliferation and decrease cell apoptosis in diabetic mice. S1P function may be mediated via S1PR1 and S1PR2; therefore, targeting S1P/S1PR signalling pathways may be a novel therapeutic strategy for diabetes mellitus.

Wingless-type MMTV integration site family member5a is a key inhibitor of islet stellate cells activation.

Aims/IntroductionType 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.ResultsOur 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.ConclusionsOur 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.

Analysis of new therapeutic strategies for diabetes mellitus based on traditional Chinese medicine “xiaoke” formulae

Abstract Objective To develop new therapeutic strategies for diabetes mellitus (DM) by analyzing the mechanisms of action of traditional Chinese medicine (TCM) “xiaoke” formulae (TCM prescriptions for remedying xiaoke). Methods We characterized 291 xiaoke formulae, including the herbs contained, chemical composition, constituents' targets, and corresponding genes. Xiaoke-related genes were retrieved based on the relationships of constituents’ targets and xiaoke formulae, and a threshold of over 95.88% occurrence of each constituent target in the 291 TCM formulae served as a definition for xiaoke-related genes. Upon comparison with DM-related genes in the DisGeNET database, the genes differing in expression between cases administered TCM and synthetic drugs were explored using a TCM grammar system. Results The results showed that xiaoke formulae and 14 exclusively xiaoke-related genes were significantly associated with multiple biological processes closely related to DM and diabetic complications (P Conclusion The 14 xiaoke-related genes APEX1, EHMT2, TSHR, CBX1, FEN1, GMNN, JUN, KMT2A, MAPT, POLI, USP1, PIN1, POLB, and POLK can serve as candidate genes for anti-diabetic drug design. Compared with DM-related genes in DisGeNET, intervention in the expression of 14 xiaoke-related genes by TCM formulae has the potential to not only lower blood glucose, but also reduce the occurrence of some side effects and inhibit the development of diabetic complications. These findings will contribute to the discovery of new strategies for treating DM.

Synthesis and biological evaluation of a new substituted 4-carboxy benzamide derivative to provide new therapeutic strategy for diabetes mellitus

Synthesis and biological evaluation of a new substituted 4-carboxy benzamide derivative to provide new therapeutic strategy for diabetes mellitus

A Different Perspective for Management of Diabetes Mellitus: Controlling Viral Liver Diseases.

Knowing how to prevent and treat diabetes mellitus (DM) earlier is essential to improving outcomes. Through participating in synthesis and catabolism of glycogen, the liver helps to regulate glucose homeostasis. Viral related liver diseases are associated with glycometabolism disorders, which means effective management of viral liver diseases may be a therapeutic strategy for DM. The present article reviews the correlation between DM and liver diseases to give an update of the management of DM rooted by viral liver diseases.

Co-combination of islets with bone marrow mesenchymal stem cells promotes angiogenesis.

Islet transplantation is a commonly therapeutic strategy for diabetes mellitus. However, avascular phase and the poor formation of blood vessels in the late period lead to islet allograft loss which contributed to inefficiency and short-acting of islet transplantation. Recently, to speed up new angiogenesis and increase the density of blood vessels around transplanted islets became the hotspot in research of islet transplantation. In this study, we undergone co-combination transplantation of allogeneic islet and bone marrow mesenchymal stem cells (BM-MSCs) into non-obese diabetic (NOD) mice and investigated the influence of BM-MSCs in transplanted islet function and neovascularization. In mice of co-combination transplantation of islet with BM-MSCs, level of blood glucose was improved compared with only BM-MSCs transplanted mice; proliferation of islet cell was enhanced while apoptosis of islet cell was reduced; 2, 4, and 8 weeks post transplantation, peripheral vascular density of islet grafts were significantly more than the islet transplantation group alone; donor lymphocytic chimerism in graft was increased. In result of immunofluorescence analysis, we observed that BM-MSCs can migrate to transplanted islet, differentiate into vascular smooth muscle cells (VSMC) and vascular endothelial cells (VEC), and also secrete vascular endothelial growth factor (VEGF). BM-MSCs can migrate to transplanted islet and promote neovascularization. Also, it enhanced allograft immune tolerance of islet grafts via increasing donor lymphocytic chimerism.

Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR.

Throughout the globe, diabetes mellitus (DM) is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder. DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy. The mechanistic target of rapamycin (mTOR) is a promising agent for the development of novel regenerative strategies for the treatment of DM. mTOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis, insulin resistance, insulin secretion, stem cell proliferation and differentiation, pancreatic β-cell function, and programmed cell death with apoptosis and autophagy. mTOR is central element for the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), AMP activated protein kinase (AMPK), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), Wnt1 inducible signaling pathway protein 1 (WISP1), and growth factors. As a result, mTOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease. Future studies directed to elucidate the delicate balance mTOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.

Concise Review: Macrophages: Versatile Gatekeepers During Pancreatic β-Cell Development, Injury, and Regeneration.

Macrophages are classically considered detrimental for pancreatic β-cell survival and function, thereby contributing to β-cell failure in both type 1 (T1D) and 2 (T2D) diabetes mellitus. In addition, adipose tissue macrophages negatively influence peripheral insulin signaling and promote obesity-induced insulin resistance in T2D. In contrast, recent data unexpectedly uncovered that macrophages are not only able to protect β cells during pancreatitis but also to orchestrate β-cell proliferation and regeneration after β-cell injury. Moreover, by altering their activation state, macrophages are able to improve insulin resistance in murine models of T2D. This review will elaborate on current insights in macrophage heterogeneity and on the evolving role of pancreas macrophages during organogenesis, tissue injury, and repair. Additional identification of macrophage subtypes and of their secreted factors might ultimately translate into novel therapeutic strategies for both T1D and T2D. Diabetes mellitus is a pandemic disease, characterized by severe acute and chronic complications. Macrophages have long been considered prime suspects in the pathogenesis of both type 1 and 2 diabetes mellitus. In this concise review, current insights in macrophage heterogeneity and on the, as yet, underappreciated role of alternatively activated macrophages in insulin sensing and β-cell development/repair are reported. Further identification of macrophage subtypes and of their secreted factors might ultimately translate into novel therapeutic strategies for diabetes mellitus.

Anti-diabetic efficacy of KICG1338, a novel glycogen synthase kinase-3β inhibitor, and its molecular characterization in animal models of type 2 diabetes and insulin resistance

Selective inhibition of glycogen synthase kinase-3 (GSK3) has been targeted as a novel therapeutic strategy for diabetes mellitus. We investigated the anti-diabetic efficacy and molecular mechanisms of KICG1338 (2-(4-fluoro-phenyl)-3H-imidazo[4,5-b]pyridine-7-carboxylic acid(4-methyl-pyridin-3-yl)-amide), a GSK3β inhibitor, in three animal models: Otsuka Long-Evans Tokushima Fatty (OLETF) rats, leptin receptors-deficient db/db mice, and diet-induced obese (DIO) mice. Biochemical parameters including glucose tolerance tests and gene expressions associated with glucose metabolism were investigated. Glucose excursion decreased significantly by KICG1338-treated OLETF rats, accompanied by increase in insulin receptor substrate-1 and glucose transporter (GLUT)-4 expressions in muscle and decreased GLUT-2 expression in liver. Glucose-lowering effects were similarly observed in KICG1338-treated db/db and DIO mice. KICG1338 treatment increased adiponectin levels and decreased TNF-α levels. KICG1338 therapy also led to greater β-cell preservation and less hepatic fat infiltration with decreased expressions of genes involved in inflammation and endoplasmic reticulum stress. These data demonstrate anti-diabetic efficacy of KICG1338, a novel GSK3β inhibitor.

Electrofusion of mesenchymal stem cells and islet cells for diabetes therapy: a rat model.

Islet transplantation is a minimally invasive treatment for severe diabetes. However, it often requires multiple donors to accomplish insulin-independence and the long-term results are not yet satisfying. Therefore, novel ways to overcome these problems have been explored. Isolated islets are fragile and susceptible to pro-apoptotic factors and poorly proliferative. In contrast, mesenchymal stem cells (MSCs) are highly proliferative, anti-apoptotic and pluripotent to differentiate toward various cell types, promote angiogenesis and modulate inflammation, thereby studied as an enhancer of islet function and engraftment. Electrofusion is an efficient method of cell fusion and nuclear reprogramming occurs in hybrid cells between different cell types. Therefore, we hypothesized that electrofusion between MSC and islet cells may yield robust islet cells for diabetes therapy. We establish a method of electrofusion between dispersed islet cells and MSCs in rats. The fusion cells maintained glucose-responsive insulin release for 20 days in vitro. Renal subcapsular transplantation of fusion cells prepared from suboptimal islet mass (1,000 islets) that did not correct hyperglycemia even if co-transplanted with MSCs, caused slow but consistent lowering of blood glucose with significant weight gain within the observation period in streptozotocin-induced diabetic rats. In the fusion cells between rat islet cells and mouse MSCs, RT-PCR showed new expression of both rat MSC-related genes and mouse β-cell-related genes, indicating bidirectional reprogramming of both β-cell and MSCs nuclei. Moreover, decreased caspase3 expression and new expression of Ki-67 in the islet cell nuclei suggested alleviated apoptosis and gain of proliferative capability, respectively. These results show that electrofusion between MSCs and islet cells yield special cells with β-cell function and robustness of MSCs and seems feasible for novel therapeutic strategy for diabetes mellitus.

New possibility in the oral glucose lowering treatment of type 2 diabetes mellitus: sodium-glucose co-transporter-2 inhibitors

Sodium-glucose co-transporters (SGLTs) have a key role in the re-absorption of glucose in the kidneys. Therefore, inhibition of SGLTs may provide a novel therapeutic strategy for diabetes mellitus. SGLT2 inhibitors enhance renal glucose excretion by inhibiting renal glucose re-absorption and reduce plasma glucose level, as well as they decrease the body weight. Their action is insulin independent and they improve insulin resistance in diabetes mellitus. Numerous SGLT2 inhibitors have been developed and evaluated in clinical trials. Phase III trials are needed to assess the safety of SGLT2 inhibitors. Results suggest that the beneficial effects of SGLT2 inhibition might be achieved without the development of significant side effects.

Evaluation of Stem Cell Differentiation in Diabetic Rats Transplanted With Bone Marrow Mesenchymal Stem Cells

Objective Bone marrow mesenchymal stem cell (BM-MSC) transplantation has generated a great deal of excitement as a promising therapeutic strategy for diabetes mellitus. However, the exact mechanisms of reversing hyperglycemia remain elusive. Our objective was to investigate whether stem cell differentiation determined therapeutic efficacy. Materials and Methods Wistar rats were rendered diabetic by an intraperitoneal injection of streptozotocin. BM-MSCs isolated from diabetic Wistar rats were analyzed for phenotype characteristics. Subsequently, BM-MSCs were transplanted into diabetic rats, followed by intravenous injection of recombinant lentiviruses encoding 2 different small hairpin RNAs (shRNAs) for specific interference with neurogenin 3 (Ngn3). We measured blood glucose levels and insulin and performed histological analysis of the pancreas. Results BM-MSCs lowered blood glucose by increasing β-cell mass compared with sham-operated controls, but this effect was inhibited by interference with the Ngn3 gene. Conclusion Differentiation of stem cells, including BM-MSCs and endogenous pancreatic stem cells, plays a major role in the process of reversing hyperglycemia.