Glucagon like peptide-1 (GLP-1) is an incretin secretory molecule. GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes (T2DM) due to their attributes such as body weight loss, protection of islet β cells, promotion of islet β cell proliferation and minimal side effects. Studies have found that GLP-1R is widely distributed on pancreatic and other tissues and has multiple biological effects, such as reducing neuroinflammation, promoting nerve growth, improving heart function, suppressing appetite, delaying gastric emptying, regulating blood lipid metabolism and reducing fat deposition. Moreover, GLP-1RAs have neuroprotective, anti-infectious, cardiovascular protective, and metabolic regulatory effects, exhibiting good application prospects. Growing attention has been paid to the relationship between GLP-1RAs and tumorigenesis, development and prognosis in patient with T2DM. Here, we reviewed the therapeutic effects and possible mechanisms of action of GLP-1RAs in the nervous, cardiovascular, and endocrine systems and their correlation with metabolism, tumours and other diseases.

Metabolic reprogramming for adaptation to the tumor microenvironment is recognized as a hallmark of cancer. Although many altered metabolic genes have been reported to be associated with tumor pathological processes, systematic analysis of metabolic genes implicated in hepatocellular carcinoma prognosis remains rare. The aim of this study was to identify key metabolic genes related to hepatocellular carcinoma, and to explore their clinical significance. We downloaded mRNA expression profiles and clinical hepatocellular carcinoma data from The Cancer Genome Atlas database to explore the prognostic roles of metabolic genes. Five prognosis-associated metabolic genes, including POLA1, UCK2, ACYP1, ENTPD2, and TXNRD1, were screened via univariate Cox regression analysis and a LASSO Cox regression model, which divided patients into high- and low-risk groups. Furthermore, gene set enrichment analysis revealed that significantly-enriched gene ontology terms and pathways involving high-risk patients were focused on regulation of nucleic and fatty acid metabolism. Taken together, our study identified five metabolic genes related to survival, which can be used to predict the prognosis of patients with hepatocellular carcinoma. These genes may play essential roles in metabolic microenvironment regulation, and represent potentially important candidate targets in metabolic therapy.

Purpose: The glucagon-like peptide-1 receptor (GLP-1R) is an effective therapeutic target for type 2 diabetes mellitus (T2DM) and non-alcoholic steatohepatitis (NASH). Research has focused on small-molecule GLP-1R agonists because of their ease of use in oral formulations and improved patient compliance. However, no small-molecule GLP-1R agonists are currently available in the market. We aimed to screen for a potential oral small-molecule GLP-1R agonist and evaluated its effect on blood glucose and NASH. Methods: The Connectivity map database was used to screen for candidate small-molecule compounds. Molecular docking was performed using SYBYL software. Rat pancreatic islets were incubated in different concentrations glucose solutions, with cinchonine or Exendin (9– 39) added to determine insulin secretion levels. C57BL/6 mice, GLP-1R^−/− mice and hGLP-1R mice were used to conduct oral glucose tolerance test. In addition, we fed ob/ob mice with the GAN diet to induce the NASH model. Cinchonine (50 mg/kg or 100 mg/kg) was administered orally twice daily to the mice. Serum liver enzymes were measured using biochemical analysis. Liver tissues were examined using Hematoxylin-eosin staining, Oil Red O staining and Sirius Red staining. Results: Based on the small intestinal transcriptome of geniposide, a recognized small-molecule GLP-1R agonist, we identified that cinchonine exerted GLP-1R agonist-like effects. Cinchonine had a good binding affinity for GLP-1R. Cinchonine promoted glucose-dependent insulin secretion, which could be attenuated significantly by Exendin (9– 39), a specific GLP-1R antagonist. Moreover, cinchonine could reduce blood glucose in C57BL/6 and hGLP-1R mice, an effect that could be inhibited with GLP-1R knockout. In addition, cinchonine reduced body weight gain and food intake in ob/ob-GAN NASH mice dose-dependently. 100 mg/kg cinchonine significantly improved liver function by reducing the ALT, ALP and LDH levels. Importantly, 100 mg/kg cinchonine ameliorated hepatic steatosis and fibrosis in NASH mice. Conclusion: Cinchonine, a potential oral small-molecule GLP-1R agonist, could reduce blood glucose and ameliorate NASH, providing a strategy for developing small-molecule GLP-1R agonists. Graphical Abstract:

The pathogenesis of type 2 diabetes mellitus (T2DM) is very complicated. The currently well-accepted etiology is the Ominous Octet theory proposed by Professor Defronzo. Since presently used drugs for T2DM have limitations and harmful side effects, studies regarding alternative treatments are being conducted. Analyzing the pharmacological mechanism of biomolecules in view of pathogenesis is an effective way to assess new drugs. Sphingosine 1 phosphate (S1P), an endogenous lipid substance in the human body, has attracted increasing attention in the T2DM research field. This article reviews recent study updates of S1P, summarizing its effects on T2DM with respect to pathogenesis, promoting β cell proliferation and inhibiting apoptosis, reducing insulin resistance, protecting the liver and pancreas from lipotoxic damage, improving intestinal incretin effects, lowering basal glucagon levels, etc. With increasing research, S1P may help treat and prevent T2DM in the future.

Dopamine (DA) has a vital role in the central nervous system and also modulates lipid and glucose metabolism. The present study aimed to investigate the effect of dopamine on insulin secretion and the underlying mechanisms in rat pancreatic β-cells. Data from the radioimmunoassay indicated that dopamine inhibited insulin secretion in a glucose- and dose-dependent manner. This inhibitory effect of dopamine was mediated mainly by D2-like receptors, but not D1-like receptors. Whole-cell patch-clamp recordings showed that dopamine decreased voltage-dependent Ca²⁺ channel currents, which could be reversed by inhibition of the D2-like receptor. Dopamine increased voltage-dependent potassium (K_V) channel currents and shortened action potential duration, which was antagonized by inhibition of D2-like receptors. Further experiments showed that D2-like receptor activation by quinpirole increased K_V channel currents. In addition, using calcium imaging techniques, we found that dopamine reduced intracellular Ca²⁺ concentration, which was also reversed by D2-like receptor antagonists. Similarly, quinpirole was found to decrease intracellular Ca²⁺ levels. Taken together, these findings demonstrate that dopamine inhibits insulin secretion mainly by acting on D2-like receptors, inhibiting Ca²⁺ channels, and activating Kv channels. This process results in shortened action potential duration and decreased intracellular Ca²⁺ levels in β-cells. This work offers new insights into a glucose-dependent mechanism whereby dopamine regulates insulin secretion.