FGF19 Promotes the Proliferation and Insulin Secretion from Human Pancreatic ß Cells Via the IRS1/GLUT4 Pathway.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a commonly observed complication associated with obesity. The effect of fibroblast growth factor 19 (FGF19), a promising therapeutic agent for metabolic disorders, on pancreatic ß cells in obesity-associated T2DM remains poorly understood. METHODS: Human pancreatic ß cells were cultured with high glucose (HG) and palmitic acid (PA), followed by treatment with FGF19. The cell proliferation, apoptosis, and insulin secretion were evaluated by CCK-8, qRT-PCR, ELISA, flow cytometry, and western blotting. The expression of the insulin receptor substrate (IRS)/glucose transporter (GLUT) pathway was evaluated. The interaction between FGF19 and IRS1 was predicted using the STRING database and verified by co-immunoprecipitation and immunofluorescence. The regulatory effects of the IRS1/GLUT4 pathway on human pancreatic ß cells were assessed by overexpressing IRS1 and silencing IRS1 and GLUT4. RESULTS: HG+PA treatment reduced the human pancreatic ß cell proliferation and insulin secretion and promoted cell apoptosis. However, FGF19 treatment restored these alterations and significantly increased the expressions of IRS1, GLUT1, and GLUT4 in the IRS/GLUT pathway. Furthermore, FGF19 and IRS1 were found to interact. IRS1 overexpression partially promoted the proliferation of pancreatic ß cells and insulin secretion through GLUT4. Additionally, the silencing of IRS1 or GLUT4 attenuated the therapeutic effects of FGF19. CONCLUSION: In conclusion, FGF19 partly promoted the proliferation and insulin secretion of human pancreatic ß cells and inhibited apoptosis by upregulating the IRS1/GLUT4 pathway. These findings establish a theoretical framework for the clinical utilization of FGF19 in the treatment of obesity-associated T2DM.

Colorectal Cancer Stem Cells and Targeted Agents.

Since their discovery, cancer stem cells have become a hot topic in cancer therapy research. These cells possess stem cell-like self-renewal and differentiation capacities and are important factors that dominate cancer metastasis, therapy-resistance and recurrence. Worse, their inherent characteristics make them difficult to eliminate. Colorectal cancer is the third-most common cancer and the second leading cause of cancer death worldwide. Targeting colorectal cancer stem cells (CR-CSCs) can inhibit colorectal cancer metastasis, enhance therapeutic efficacy and reduce recurrence. Here, we introduced the origin, biomarker proteins, identification, cultivation and research techniques of CR-CSCs, and we summarized the signaling pathways that regulate the stemness of CR-CSCs, such as Wnt, JAK/STAT3, Notch and Hh signaling pathway. In addition to these, we also reviewed recent anti-CR-CSC drugs targeting signaling pathways, biomarkers and other regulators. These will help researchers gain insight into the current agents targeting to CR-CSCs, explore new cancer drugs and propose potential therapies.

Effect of Ketogenic Diets on Body Composition and Metabolic Parameters of Cancer Patients: A Systematic Review and Meta-Analysis.

A ketogenic diet characterized by high fat and low carbohydrate can drive the body to produce a large number of ketone bodies, altering human metabolism. Unlike normal cells, tumor cells have difficulty in consuming ketone bodies. Therefore, the application of ketogenic diets in cancer therapy is gaining attention. However, the effect of ketogenic diets on body parameters of cancer patients is not well established. This meta-analysis aimed to summarize the effects of ketogenic diets on cancer patients in earlier controlled trials. PubMed, Embase, and Cochrane Library were searched for clinical trials that enrolled cancer patients who received ketogenic diets intervention. Ten controlled trials were included in this meta-analysis. Data were extracted and checked by three authors independently. Pooled effect sizes revealed a significant effect of ketogenic diets on body weight (SMD −1.83, 95% CI −2.30 to −1.35; p < 0.00001) and fat mass (SMD −1.52, 95% CI −1.92 to −1.07; p < 0.00001). No significant effect on blood glucose, insulin, or lipid profile except triglycerides was found in the analysis. It had no effect on liver and kidney function except that GGT were decreased a little. There were no significant changes in IGF-1 and TNF-α related to tumor growth. Mental health improvement of cancer patients was supported by several trials. Taken together, findings in this study confirmed that the ketogenic diet was a safe approach for cancer patients reducing body weight and fat mass. In addition, cancer treatment-related indicators changed insignificantly. Ketogenic diets may be beneficial to the quality of life of cancer patients. However, intervention duration in most studies is shorter than 6 months, and the effect of a long-term ketogenic diet is still required further validation. More trials with a larger sample size are necessary to give a more conclusive result; PROSPERO registration number: CRD42021277559.

Effect of Gut Microbiota-Derived Metabolites on Immune Checkpoint Inhibitor Therapy: Enemy or Friend?

The human gut is inhabited by hundreds of billions of commensal microbiota that collectively produce thousands of small molecules and metabolites with local and systemic effects on the physiology of the host. Much evidence from preclinical to clinical studies has gradually confirmed that the gut microbiota can regulate anti-tumor immunity and affect the efficacy of cancer immune checkpoint inhibitors (ICIs) therapy. In particular, one of the main modes of gut microbiota regulating anti-tumor immunity is through metabolites, which are small molecules that can be transported in the body and act on local and systemic anti-tumor immune responses to promote ICIs immunotherapy efficacy. We discuss the functions of microbial metabolites in humans, focusing on the effects and mechanisms of microbial metabolites on immunotherapy, and analyze their potential applications as immune adjuvants and therapeutic targets to regulate immunity and enhance ICIs. In summary, this review provides the basis for the rational design of microbiota and microbial metabolite-based strategies of enhancing ICIs.

Epidermal Growth Factor Protects Against High Glucose-Induced Podocyte Injury Possibly via Modulation of Autophagy and PI3K/AKT/mTOR Signaling Pathway Through DNA Methylation.

AIM: Diabetic nephropathy (DN) is a serious health problem worldwide. Epidermal growth factor (EGF) has suggested as a potential biomarker for the progression of chronic kidney disease. In this study, we examined the effects of EGF on the high glucose (HG)-induced podocyte injury and explored the underlying molecular mechanisms. METHODS: The cell proliferation, toxicity, and cell apoptosis of podocytes were determined by CCK-8 assay, lactate dehydrogenase release assay, and flow cytometry, respectively, and protein levels in the podocytes were determined by Western blot assay. Mechanistically, DNA methylation analysis, bioinformatic analysis, methylation­specific PCR and quantitative real-time PCR were used to analyze functional pathways in differentially methylated genes and the expression of the key methylated genes in the podocytes after different interventions. RESULTS: EGF treatment significantly increased the protein expression level of LC3 and decreased the protein level of P62 in HG-stimulated podocytes, which was attenuated by autophagy inhibitor, 3-methyladenine. EGF increased the cell proliferation and the protein expression levels of nephrin and synaptopodin, but reduced cell toxicity and cell apoptosis and protein expression level of cleaved caspase-3, which was partially antagonized by 3-methyladenine. DNA methylation expression profiles revealed the differential hypermethylation sites and hypomethylation sites among podocytes treated with normal glucose, HG and HG+EGF. GO enrichment analysis showed that DNA methylation was significantly enriched in negative regulation of phosphorylation, cell-cell junction and GTPase binding. KEGG pathway analysis showed that these genes were mainly enriched in PI3K-Akt, Hippo and autophagy pathways. Further validation studies revealed that six hub genes (ITGB1, GRB2, FN1, ITGB3, FZD10 and FGFR1) may be associated with the protective effects of EGF on the HG-induced podocyte injury. CONCLUSION: In summary, our results demonstrated that EGF exerted protective effects on HG-induced podocytes injury via enhancing cell proliferation and inhibiting cell apoptosis. Further mechanistic studies implied that EGF-mediated protective effects in HG-stimulated podocytes may be associated with modulation of autophagy and PI3K/AKT/mTOR signaling pathway.

The association between insulin therapy and depression in patients with type 2 diabetes mellitus: a meta-analysis.

OBJECTIVES: Several patients with type 2 diabetes mellitus (T2DM) have depressive disorders. Whether insulin treatment was associated with increased risk of depression remains controversial. We performed a meta-analysis to evaluate the association of insulin therapy and depression. DESIGN: A meta-analysis. METHODS: We conducted a systematic search of PubMed, PsycINFO, Embase and the Cochrane Library from their inception to April 2016. Epidemiological studies comparing the prevalence of depression between insulin users and non-insulin users were included. A random-effects model was used for meta-analysis. The adjusted and crude data were analysed. RESULTS: Twenty-eight studies were included. Of these, 12 studies presented with adjusted ORs. Insulin therapy was significantly associated with increased risk of depression (OR=1.41, 95% CI 1.13 to 1.76, p=0.003). Twenty-four studies provided crude data. Insulin therapy was also associated with an odds for developing depression (OR=1.59, 95% CI 1.41 to 1.80, p<0.001). When comparing insulin therapy with oral antidiabetic drugs, significant association was observed for adjusted (OR=1.42, 95% CI 1.08 to 1.86, p=0.008) and crude (OR=1.61, 95% CI 1.35 to 1.93, p<0.001) data. CONCLUSIONS: Our meta-analysis confirmed that patients on insulin therapy were significantly associated with the risk of depressive symptoms.

A patient with agranulocytosis following the discontinuation of methimazole treatment for 4 months: A case report.

Agranulocytosis is a rare and serious adverse effect of antithyroid drugs (ATD), in particular methimazole (MMI), and usually develops within 3 months following the start of uninterrupted ATD treatment. Agranulocytosis may also develop for the first time following interruption and subsequent resumption of the same ATD treatment. In this case report, a 27-year-old female, who was treated for thyrotoxicosis with MMI, developed agranulocytosis following the discontinuation of MMI treatment for four months. To the best of our knowledge, this is the first study to report this. The aim of this report is to increase the awareness of physicians of the onset of agranulocytosis when MMI is discontinued, and to demonstrate that MMI should be used with caution.

Clinical characteristics of fulminant type 1 diabetes associated with pregnancy in China.

To report 12 cases of pregnancy-associated fulminant type 1 diabetes mellitus (PF) found in China from 2003 to 2010. The clinical and biochemical characteristics of these cases with PF were compared with a group of cases of child-bearing age with fulminant type 1 diabetes that was not associated with pregnancy (NPF). The clinical and biochemical characteristics of 12 PF cases were analyzed retrospectively and then compared with those characteristics of 20 NPF cases in China. The difference between Chinese and Japanese PF cases was investigated. The mean values of the characteristics from PF and NPF cases in China, including postprandial serum C-peptide concentration, plasma glucose concentration, and serum chloride were different. Compared to the 22 PF cases in Japan, the mean age of these 12 PF cases was much younger. The mean fasting and postprandial serum C-peptide concentration level were lower, and the mean HbA1c levels was higher in 12 PF cases in China. Eight of 12 PF cases in China developed the disease during pregnancy. Other four PF case developed the disease within 2 weeks after delivery. 12 PF cases in China showed more severe beta-cell destruction, the prognosis of their fetuses was extremely poor.