Insulin, a vital hormone for glucose homeostasis is produced by pancreatic beta-cells and when secreted, stimulates the uptake and storage of glucose from the blood. In the pancreas, insulin is stored in vesicles termed insulin secretory granules (ISGs). In Type 2 diabetes (T2D), defects in insulin action results in peripheral insulin resistance and beta-cell compensation, ultimately leading to dysfunctional ISG production and secretion. ISGs are functionally dynamic and many proteins present either on the membrane or in the lumen of the ISG may modulate and affect different stages of ISG trafficking and secretion. Previously, studies have identified few ISG proteins and more recently, proteomics analyses of purified ISGs have uncovered potential novel ISG proteins. This review summarizes the proteins identified in the current ISG proteomes from rat insulinoma INS-1 and INS-1E cell lines. Here, we also discuss techniques of ISG isolation and purification, its challenges and potential future directions.

O-Fucosylation plays crucial roles in various essential biological events. Alongside the well-established O-fucosylation of epidermal growth factor-like repeats by protein O-fucosyltransferase 1 (POFUT1) and thrombospondin type 1 repeats by POFUT2, we recently identified a type of O-fucosylation on the elastin microfibril interface (EMI) domain of Multimerin-1 (MMRN1). Here, using AlphaFold2 screens, co-immunoprecipitation, enzymatic assays combined with mass spectrometric analysis and CRISPR–Cas9 knockouts, we demonstrate that FUT10 and FUT11, originally annotated in UniProt as α1,3-fucosyltransferases, are actually POFUTs responsible for modifying EMI domains; thus, we renamed them as POFUT3 and POFUT4, respectively. Like POFUT1/2, POFUT3/4 function in the endoplasmic reticulum, require folded domain structures for modification and participate in a non-canonical endoplasmic reticulum quality control pathway for EMI domain-containing protein secretion. This finding expands the O-fucosylation repertoire and provides an entry point for further exploration in this emerging field of O-fucosylation.

Human commensal species are thought to depend so closely on resources provided by humans that they are effectively ‘natives' of urban environments. However, while their adaptations to urban existence are well understood, their ecology and habitat choices have not been closely examined. This study investigated the habitat preferences of the archetypal commensal species, the invasive black rat Rattus rattus , at the urban–bushland interface in Sydney, Australia, and modelled the results using isodar analysis. Unexpectedly, we found evidence that rats perceived bushland as a more resource‐rich habitat compared to urban areas, resulting in higher rat abundance in bushland areas. Resultant spillover of commensal species into native vegetation may pose acute ecological risks in the future, yet management of commensal pests remains focused on urban areas. Ultimately, these findings highlight the complex nature of commensal ecology, suggesting that adaptation to human coexistence does not necessarily lead to a preference for human‐modified landscapes. We suggest that inter‐specific interactions with competitors, or the lack thereof, likely modulate the habitat preferences of commensals.

BACKGROUND: Checkpoint inhibitor–associated autoimmune diabetes mellitus (CIADM) is a rare but life-altering complication of immune checkpoint inhibitor (ICI) therapy. Biomarkers that predict type 1 diabetes (T1D) are unreliable for CIADM. AIM: In the present study, we sought to identify biomarkers for the prediction of CIADM. METHODS: From our prospective biobank, we identified 14 patients with CIADM who had metastatic melanoma treated with anti–programed antibody death 1 (anti–PD-1) with or without anti–cytotoxic T lymphocyte–associated antibody protein 4 (anti-CTLA4). Controls were selected from the same biobank, matched 2:1. Pretreatment, on-ICI, and post-CIADM serum and PBMCs were analyzed. Serum was analyzed for T1D autoantibodies, C-peptide, glucose, and cytokines. PBMCs were profiled using flow cytometry. Pancreatic volume was measured using CT volumetry. RESULTS: Before treatment, patients with CIADM had smaller pancreatic volume (27% reduction, P = 0.044) and higher anti–glutamic acid decarboxylase autoantibody (anti-GAD) titers (median 2.9 vs. 0, P = 0.01). They had significantly higher baseline proportions of Th17 cells ( P = 0.03), higher CD4 ⁺ central memory cells ( P = 0.04), and lower naive CD4 ⁺ T cells ( P = 0.01). With ICI treatment, greater declines in pancreatic volume were seen in patients with CIADM ( P < 0.0001). Activated CD4 ⁺ T cell subsets increased significantly in CIADM and controls with immune-related adverse effects (IRAEs) but not in controls without IRAEs. Using only pretreatment results, we found that pancreatic volume, anti-GAD antibody titers, and the baseline immune flow profile were highly predictive of CIADM development, with an AUC of greater than 0.96. CONCLUSIONS: People who develop CIADM are immunologically predisposed and have antecedent pancreatic and immunological changes that accurately predict disease with excellent sensitivity. These biomarkers could be used to guide ICI use, particularly when planning treatment for low-risk tumors. FUNDING: National Health and Medical Research Council (NHMRC) Investigator grants 2033228, 2009476, and 2007839.

Type 2 diabetes (T2D) is a pressing global health challenge, primarily driven by modern dietary and lifestyle patterns. Central to T2D progression is the dysfunction of insulin-secreting pancreatic β-cells, which critically disrupts glucose homeostasis. The progression to T2D relies on the β-cells’ inability to compensate for increasing insulin resistance. Initially, β-cells enhance the insulin output, but chronic nutrient overload, ER stress and inflammation ultimately compromise their function and survival. This review examines the molecular and cellular drivers of β-cell failure, focusing on endoplasmic reticulum stress, mitochondrial dysfunction and inflammatory pathways amid chronic metabolic stress. We also explore the loss of β-cell identity and altered interactions within the islet microenvironment. Understanding these mechanisms is essential for developing strategies to prevent β-cell dysfunction and slow T2D progression, ultimately supporting better metabolic health outcomes.

A ketogenic diet (KD) is a low-carbohydrate, high-fat dietary approach. Beyond treating neurologic disorders, KDs have attracted significant media attention for their potential to improve obesity and diabetes. The diet induces a metabolic shift from glucose toward fatty acid oxidation and ketone body production. This shift leads to ketosis, which may reduce hunger, partly through the anorexigenic effects of ketone bodies, thereby contributing to weight loss and improved metabolic parameters, including glycaemic control and insulin sensitivity. In particular, the positive effects of KDs lower insulin demand and may thereby improve β-cell function. However, the long-term efficacy, safety, and sustainability of KDs, especially for diabetes, remain debated. This review offers current insights into the effects of ketogenesis and ketosis, as well as the potential mechanisms underlying them. We explore the metabolic effects of KDs in obesity and diabetes, drawing on preclinical and clinical studies, and suggest that combining KDs with antidiabetic agents may provide synergistic benefits. However, combining KDs with these pharmacotherapies, particularly SGLT-2 inhibitors, requires careful clinical supervision because of potential risks, including euglycaemic diabetic ketoacidosis. We explore how a KD alters the composition of the gut microbiota, thereby affecting host health. We conclude by highlighting challenges and future directions for optimising KD-based therapies and by outlining the limitations of the current review.