glucagon (LY 900018 / glucagon, Eli Lilly / Baqsimi)

m6A mRNA methylation regulates pancreatic α-cell plasticity.

De Jesus Dario F DF, Brown Natalie K NK, Fogarty Garrett G, Gabriel Guilherme G et al.

Pancreatic α-cells are central regulators of glucose and amino acid homeostasis, yet the mechanisms that preserve α-cell identity and function remain incompletely understood. N6-methyladenosine (m6A) is a widespread mRNA modification that is essential for β-cell biology and pancreatic endocrine differentiation. Here we show that m6A is a key regulator of α-cell function and plasticity. In α-cells, metabolic cues that stimulate glucagon secretion such as L-arginine increase METTL3, METTL14 and m6A levels. Loss of m6A impairs amino acid-stimulated glucagon secretion, disrupts α-cell identity programmes and induces metabolic rewiring. In mice, α-cell-specific Mettl14 deletion reduces α-cell mass, increases β-cell mass and promotes α-to-β-cell conversion, accompanied by the emergence of late β-like states with features of incomplete maturation. Mechanistically, m6A-eCLIP identifies Yy1 as a direct m6A-sensitive target, and elevated YY1 links m6A loss to signalling rewiring and erosion of α-cell identity. These findings identify m6A as a central regulator of α-cell state and reveal an epitranscriptomic mechanism controlling endocrine cell plasticity.

Enhancement of Harvested Islet Functionality Through Photostimulation.

Fowlds Kelli K, Darden Carly M CM, Lawrence Michael C MC, Cho Michael M

Allogeneic islet transplantation is a promising treatment for Type I diabetes, but its success is limited by islet loss during isolation, purification, and engraftment, resulting in variable long-term insulin independence. Our previous studies demonstrated that photobiomodulation (PBM) significantly enhances insulin and glucagon secretion in pancreatic cells, likely through modulation of ATP production and calcium signaling pathways involved in hormone release. Building on these mechanistic findings, we investigated whether PBM could similarly improve the functionality of whole islets before transplantation. Mouse islets were isolated by pancreatectomy, cultured ex vivo, and treated daily with PBM for 7 days. Fluorescence imaging and functional assays were used to assess insulin expression and secretion. PBM significantly enhanced insulin secretion, with an approximately twofold increase observed after 3 days of treatment. These findings support PBM as a promising, noninvasive approach for improving islet function before transplantation.

Orforglipron: An Oral GLP-1 Receptor Agonist for Obesity Treatment.

Wietholter Jon P JP, Terpening Chris M CM

To describe the properties of a newly approved oral glucagon-like peptide-1 receptor agonist for the treatment of obesity. A literature search of MEDLINE and SCOPUS was performed without date range exclusions using the search terms orforglipron and obesity. Additional articles were identified from review of clinical trial bibliographies and product monograph. Two phase 1 studies in healthy individuals and in patients with type 2 diabetes mellitus and 4 phase 2/3 clinical trials specifically evaluating orforglipron use for obesity were identified for analysis, using no date exclusion criteria. Orforglipron was evaluated in 4 phase 2/3 trials regarding its efficacy for weight loss. These trials showed a mean 7.1% to 10.6% placebo-adjusted weight reduction with orforglipron. Adverse events seen with its use were primarily gastrointestinal.Relevance to Patient Care and Clinical Practice in Comparison With Existing Drugs:Orforglipron provides an oral weight management option that is potentially more effective than liraglutide, similarly effective compared with semaglutide, and less effective than tirzepatide. As a non-injectable option that does not require strict oral administration parameters, orforglipron has advantages in certain patient populations. Orforglipron is a potentially useful addition for the treatment of obesity, but it still requires additional data on efficacy in treatment of obesity-related comorbidities for full comparison.

Trends in Glucagon-Like Peptide-1 Receptor Agonist Prescriptions in Heart Failure With Reduced Ejection Fraction.

Zingano Carolina P CP, Spiazzi Bernardo F BF, Blankson George G, Acheampong Irene Animah IA et al.