Type 2 diabetes is a heterogeneous, progressive chronic condition for which management has traditionally focused on glycaemic control and cardiovascular risk factors, rather than focusing on altering long-term disease trajectory. Increasing evidence indicates that progression and complications might be modifiable, but the absence of a core outcome set for disease modification limits trial design and intervention comparison. To address this gap, we developed a core outcome set for disease modification in type 2 diabetes through a modified Delphi process conducted according to COMET guidance. Candidate outcomes were identified from the literature and refined by an international multidisciplinary steering group comprising clinicians, researchers, and people living with type 2 diabetes. Across two Delphi rounds involving health-care professionals, researchers, and patients (round one n=233; round two n=79), agreement was reached for 35 outcomes spanning 11 domains. This framework aims to support outcome selection, consistency across trials, comparison of interventions, and evaluation of disease-modifying strategies in type 2 diabetes.

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.

A 41-year-old woman with history of hypoglycemic symptoms underwent sleeve gastrectomy for weight loss. Her postoperative course was complicated by cardiac arrest due to polymorphic ventricular tachycardia arising from QT interval prolongation. Weeks after surgery, hypoglycemic symptoms worsened, with postprandial capillary glucose as low as 33 mg/dL (SI: 1.2 mmol/L) (reference, 70-140 mg/dL [SI: 3.9-7.8 mmol/L]). An inpatient fast indicated appropriate suppression of insulin. The combination of worsening hypoglycemia early postoperatively and prolonged QT interval prompted genetic testing, which revealed a likely pathogenic variant in KCNE1, encoding a subunit of the voltage-gated potassium channel Kv7.1, expressed in cardiomyocytes and pancreatic β cells. The patient was treated with nutrition therapy and diazoxide for hypoglycemia and β-blocker for long QT syndrome (LQTS). Patients with KCNE1 pathogenic variants are known to have LQTS and have been reported to have postprandial hypoglycemia. This case highlights the importance of considering genetic etiologies when encountering concomitant hypoglycemia and LQTS, and that preexisting LQTS may confer risk for hypoglycemia after upper gastrointestinal surgery.

The islet of Langerhans (or pancreatic islet) is a unique endocrine organ that secretes multiple hormones that in turn orchestrate energy metabolism in humans. As in other metabolic organs, growth factor(s) regulate functional islet mass to maintain whole-body glucose homeostasis. Over the past decades, a large body of evidence has pointed to insulin and insulin-like growth factors (IGFs) as playing central roles in modulating diverse aspects of islet cell biology and a dysregulated insulin/IGF pathway has come to be recognized as a pathophysiological hallmark of type 2 diabetes (T2D). Several recent reports, especially focused on β-cells, highlight emerging aspects of insulin/IGF signaling, including a role for RNA modifications, transcriptional regulation by nuclear insulin and IGF-1 receptors, and the discovery of an insulin inhibitory receptor, inceptor. In this review, we summarize the functional roles of insulin/IGF signaling in regulating islet cell biology, the short- and long-term effects of insulin therapy in humans, and discuss potential strategies to maximize the beneficial effects of insulin action in islets to counter diabetes.

The mechanisms driving progressive beta-cell dysfunction in type 2 diabetes (T2D) remain incompletely understood. This study aimed to identify pancreatic islet proteome changes that could predict diabetes onset. We isolated islets from non-diabetic subjects undergoing partial pancreatectomy, previously characterized for glucose tolerance, insulin sensitivity, and insulin secretion, using laser capture microdissection (LCM) and analyzed them via high-performance liquid chromatography-mass spectrometry (HPLC-MS). Proteomic analysis revealed that subjects with impaired glucose tolerance (IGT) had reductions in proteins regulating glycolysis (PGK1, G3P), lipid metabolism (ACBP, ARF1), glucose transport (14-3-3B), and insulin secretion (STARD10, CAPDS) compared to normal glucose tolerant (NGT) subjects. Additionally, IGT islets showed impaired expression of proteins involved in glucose- and incretin-stimulated insulin response (CREB1, IQGA1). Stratification by beta-cell glucose sensitivity (βGS) indicated that subjects with lower βGS exhibited reduced levels of insulin maturation (ERO1B) and anti-apoptotic proteins (CASP8, PAK2, SKP1), along with increased SEL1L, a factor promoting endocrine precursor differentiation. These findings suggest that early defects in glucose metabolism and insulin secretion characterize IGT, while reduced βGS may trigger compensatory mechanisms, through enhanced beta-cell survival or neogenesis, to delay T2D progression. Overall, proteomic alterations in prediabetic islets provide potential early predictive markers and targets for interventions aimed at preserving beta-cell function.