Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets.

Simultaneous activation of the incretin G-protein-coupled receptors (GPCRs) via unimolecular dual-receptor agonists (UDRA) has emerged as a new therapeutic approach for type 2 diabetes. Recent studies also advocate triple agonism with molecules also capable of binding the glucagon receptor. In this scoping review, we discuss the cellular mechanisms of action (MOA) underlying the actions of these novel and therapeutically important classes of peptide receptor agonists. Clinical efficacy studies of several UDRAs have demonstrated favorable results both as monotherapies and when combined with approved hypoglycemics. Although the additive insulinotropic effects of dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic peptide receptor (GIPR) agonism were anticipated based on the known actions of either glucagon-like peptide-1 (GLP-1) or glucose-dependent insulinotropic peptide (GIP) alone, the additional benefits from GCGR were largely unexpected. Whether additional synergistic or antagonistic interactions among these G-protein receptor signaling pathways arise from simultaneous stimulation is not known. The signaling pathways affected by dual- and tri-agonism require more trenchant investigation before a comprehensive understanding of the cellular MOA. This knowledge will be essential for understanding the chronic efficacy and safety of these treatments.

Alanine transferase levels (ALT) and triglyceride-glucose index are risk factors for type 2 diabetes mellitus in obese patients.

AIMS: The role of liver steatosis and increased liver enzymes (ALT) in increasing incident type 2 diabetes mellitus (T2DM) is debated, because of their differential effects on different ethnicities and populations. The aim of this study was to evaluate the role of elevated ALT in the development of T2DM in non-diabetic obese subjects receiving routine medical treatment. METHODS: A total of 1005 subjects [296 men and 709 women, aged 45.7 ± 13.12 years, body mass index (BMI) 39.5 ± 4.86 kg/m2] were followed for a mean period of 14.3 ± 4.44 years. Subjects were evaluated for several metabolic variables, including the triglyceride-glucose index and the presence of metabolic syndrome (IDF 2005 definition), and were subdivided into ALT quartiles. RESULTS: T2DM developed in 136 subjects, and the difference was significant between the first and the fourth ALT quartile (p = 0.048). Both at univariate analysis and at stepwise regression, ALT quartiles were associated with incident T2DM. Traditional risk factors for T2DM coexisted, with a somehow greater predictive value, such as triglyceride-glucose index, age, arterial hypertension, LDL-cholesterol, and metabolic syndrome. CONCLUSIONS: These data suggest an association between elevated ALT levels and the risk of incident T2DM in obesity.

Glucagon-like peptide 1 receptor is a T cell-negative costimulatory molecule.

Glucagon-like peptide-1 receptor (GLP-1R) is a key regulator of glucose metabolism known to be expressed by pancreatic ß cells. We herein investigated the role of GLP-1R on T lymphocytes during immune response. Our data showed that a subset of T lymphocytes expresses GLP-1R, which is upregulated during alloimmune response, similarly to PD-1. When mice received islet or cardiac allotransplantation, an expansion of GLP-1Rpos T cells occurred in the spleen and was found to infiltrate the graft. Additional single-cell RNA sequencing (scRNA-seq) analysis conducted on GLP-1Rpos and GLP-1Rneg CD3+ T cells unveiled the existence of molecular and functional dissimilarities between both subpopulations, as the GLP-1Rpos are mainly composed of exhausted CD8 T cells. GLP-1R acts as a T cell-negative costimulatory molecule, and GLP-1R signaling prolongs allograft survival, mitigates alloimmune response, and reduces T lymphocyte graft infiltration. Notably, GLP-1R antagonism triggered anti-tumor immunity when tested in a preclinical mouse model of colorectal cancer.

Effect of Prolonged and Substantial Weight Loss on Incident Atrial Fibrillation: A Systematic Review and Meta-Analysis.

Background. Overweight and obesity are associated with atrial fibrillation (AF), and bariatric surgery (BS), able to induce sustained and prolonged weight loss, might represent the ideal treatment in the prevention of AF. Previous studies could not definitely establish a role for weight loss and BS in preventing incident AF so far. During the last few years, several studies on the effect of bariatric surgery on cardiovascular diseases have been published, and we performed a systematic review and meta-analysis to evaluate the role of weight loss through BS in the prevention of incident AF in obesity. Methods. This meta-analysis followed the PRISMA guideline. Eligible studies were controlled trials evaluating the appearance of atrial fibrillation in patients undergoing weight loss through BS as compared with patients receiving medical treatment. Quality of studies was assessed according to the Newcastle-Ottawa Quality Assessment Scale, and risk-of-bias was evaluated employing the Egger's test. All analyses were run by a random-effects model according to Hartung and Knapp and sensitivity analyses were performed. Heterogeneity was assessed through Q and I2 statistics for each comparison, and potential publication bias was formally investigated. Results. Ten studies were included in the meta-analysis, and the overall result was statistically significant [OR = 0.665 (0.475-0.929), p = 0.017], with significant heterogeneity (Q = 48.98, p < 0.001; I2 = 81.6%), but with no publication bias. In sensitivity analyses, the amount of weight loss, percentage of patients with diabetes and value of the Newcastle-Ottawa Quality Assessment Scale, were all associated with significance of effect. Since age was different in one study, a sensitivity analysis was performed by excluding this study; OR was similar [OR = 0.608 (0.454-0.814), p < 0.001]; heterogeneity was reduced but still significant (Q = 35.74, p < 0.001, I2 = 77.6%) and again no publication bias was detected. Conclusions. Bariatric surgery as compared to medical treatment is associated with reduced appearance of incident AF.