Daily Endocrinology Research Analysis

Mechanisms responsible for skeletal muscle kidney crosstalk have not been defined. We have determined that a circulating mediator, signal regulatory protein α (SIRPα), impairs intracellular insulin-mediated functions. To elucidate the effect of myokine SIRPα on diabetic kidney disease (DKD), flox mice and muscle-specific (m-specific) SIRPα-KO mice were subjected to an obesity-induced model of diabetes, high-fat diet (HFD; 60%) or insulin-deficient hyperglycemia model, streptozotocin (STZ), and were subsequently exposed to anti-SIRPα monoclonal antibodies. In the obesity-induced diabetic mice, serum SIRPα increased. Genetic deletion of muscle SIRPα protected against obesity and improved intracellular insulin signaling in muscle and adipose tissue, with reduced intramuscular fat deposition when compared with flox mice on HFD. Moreover, mSIRPα-KO mice displayed enhanced kidney tubular fatty acid oxidation (FAO) expression with suppressed intraorgan triglycerides deposition, and importantly, protection against DKD. Conversely, exogenous SIRPα impaired kidney proximal tubular cell FAO, ATP production, and exacerbated fibrosis. Finally, suppressing SIRPα in skeletal muscles or treatment with anti-SIRPα monoclonal antibodies in STZ-treated mice mitigated cachexia, hyperlipidemia, kidney triglyceride deposition, and renal dysfunction in spite of significant hyperglycemia. Importantly, serum SIRPα was upregulated in patients with DKD. In conclusion, SIRPα serves as a potential biomarker and therapeutic target in DKD.

UNLABELLED: Enteroviruses (EVs) have long been implicated in the development of islet autoimmunity (IA) and type 1 diabetes. However, given the ubiquity of EV infections in children, disease susceptibility is likely driven by host-specific immune responses rather than viral exposure alone. To investigate the host antibody response to EVs, we used virome-wide serological profiling (VirScan) to compare the EV antigen landscapes in IA-positive case children versus IA-negative control children across two independent pediatric cohorts separated by 12 years, using samples collected at the time point of seroconversion. We identified a reproducible and distinct EV-specific antibody signature in IA-positive case samples, with an enriched immunogenic hotspot localized within a highly conserved region in the 3D RNA-dependent RNA polymerase. Additionally, IA-positive male children exhibited significantly heightened antibody responses against a motif in the VP1 capsid protein compared to IA-negative male children (RR 1.24; 95% CI 1.02, 1.52; P = 0.03). Our findings provide paradigm-shifting evidence that differential antiviral humoral responses, rather than the specific types of EV infection, play a central role in IA development, highlighting the need for an updated framework to study host-virus interactions in autoimmune pathogenesis. ARTICLE HIGHLIGHTS: Children positive for islet autoimmunity (IA) in two different Australian cohorts showed a distinct enterovirus (EV) antibody signature against specific regions of the EV genome polyprotein. A specific motif in the 3D region of the EV polyprotein was consistently enriched across cohorts and sexes, making it a potential marker for IA onset. Anti-VP1 motif antibody levels varied by sex, with significantly elevated levels in male children linked to early IA onset highlighting possible sex-specific antiviral immunity. Findings support that host immune responses against EVs drive IA development, calling for a new framework to study host-virus interactions in IA.

BACKGROUND: Peripheral artery disease (PAD) is a prevalent and debilitating complication of diabetes and obesity, yet it remains underrecognized and undertreated. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, have shown cardiovascular benefits, but their impact on peripheral vascular outcomes remains unclear. OBJECTIVE: We conducted a systematic review and meta-analysis to evaluate the effect of semaglutide on limb events (LEs) in individuals with type 2 diabetes and/or overweight or obesity. METHODS: Following PRISMA guidelines, 19 randomized controlled trials encompassing 51,557 participants were included. Major limb events, prespecified and reported as safety outcomes in the original trials, were defined a priori as the primary outcome of this meta-analysis, comprising revascularizations, amputations, and PAD progression. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: Semaglutide significantly reduced the risk of LEs compared to control interventions (OR 0.70; 95% CI 0.60-0.82; p < 0.0001), with no heterogeneity across studies (I² = 0%). Benefits were consistent across patient subgroups, in patients with diabetes (OR 0.70; 95% CI: 0.57-0.87; p = 0.001) or obesity (OR 0.71; 95% CI: 0.56-0.89; p = 0.003); oral formulation (0.71; 95% CI: 0.53-0.94; p = 0.02) or subcutaneous (0.68; 95% CI: 0.49-0.95; p = 0.02 and 0.71; 95% CI: 0.57-0.89; p = 0.003, for 1.0 mg and 2.4 mg, respectively); and regardless of background SGLT2 inhibitor use. Meta-regression showed no significant effect modification by age, BMI, HbA1c, follow-up duration, or SGLT2i use. CONCLUSIONS: This meta-analysis suggest that semaglutide is associated with a significant reduction in major limb events across diverse populations and treatment settings, supporting a potential protective effect on limb-related vascular safety. This meta-analysis evaluates whether semaglutide can reduce the risk of peripheral artery disease (PAD) complications in people with diabetes or obesity. By analyzing data from 19 randomized controlled trials involving over 51,000 participants, the findings highlight semaglutide’s potential role in lowering the risk of amputations, revascularizations, and disease progression, beyond its established benefits on weight loss and glicemic control. Key findings:Semaglutide reduced the risk of PAD-related events by about 30% compared with other treatments.The protective effect was consistent across patient subgroups, formulations (oral or injectable), and irrespective of concomitant SGLT2 inhibitor use.