Imeglimin is a novel antidiabetic agent that improves glycemic control by enhancing glucose-stimulated insulin secretion (GSIS). Although previous studies have suggested that imeglimin acts through increased NAD+ production and CD38-dependent calcium signaling, the mechanism responsible for its insulinotropic effect at clinically relevant concentrations remains incompletely understood. In particular, how clinically relevant concentrations of imeglimin affect mitochondrial bioenergetics in pancreatic beta cells remains unclear. To address this question, we examined the effects of imeglimin in normal glucose-tolerant C57BL/6 mice and isolated mouse islets using concentrations corresponding to clinically achieved plasma levels. Chronic administration of imeglimin at a pharmacological dose corresponding to clinically relevant exposure enhanced GSIS without affecting insulin sensitivity in vivo. In isolated islets, continuous exposure to imeglimin at a clinically relevant concentration (10 μmol/l) significantly enhanced GSIS, whereas supraphysiological imeglimin (1000 μmol/l) reduced GSIS. Mechanistically, 10 μmol/l imeglimin increased mitochondrial respiration, mitochondrial membrane potential, and ATP production while suppressing glucose-induced reactive oxygen species generation. Notably, blue native polyacrylamide gel electrophoresis revealed that clinically relevant concentrations of imeglimin promoted mitochondrial respiratory supercomplex formation, whereas supraphysiological concentrations did not. These findings suggest that mitochondrial respiratory supercomplex formation may contribute to the insulinotropic action of imeglimin. Our results provide new insight into mitochondrial regulation of pancreatic beta cell function and suggest that enhancement of mitochondrial supercomplex assembly represents a potential mechanism by which clinically relevant imeglimin improves beta cell function, in addition to previously proposed NAD+-dependent pathways.

Individual variation in sexually differentiated brain structures may contribute to variation in sex-related behavior, but the developmental origins of such individual differences remain unclear. We first examined several sexually dimorphic nuclei in the preoptic area and bed nucleus of the stria terminalis to identify brain structures associated with individual variation in partner preference in adult mice. In males, female-directed partner preference was consistently associated with the characteristics of the sexually dimorphic nucleus of the preoptic area (SDN-POA), including its volume, number of calbindin-D28K (Calb)-positive neurons, and neuronal activity. Therefore, we examined whether natural variation in fetal testosterone was associated with development of this nucleus. At embryonic day 18.5, higher fetal testosterone was associated with increased expression of genes related to GABAergic neuronal differentiation and phenotype in hypothalamic tissue and with altered spatial organization of developing GABAergic neurons around the presumptive SDN-POA. A longitudinal follow-up showed that males exposed to higher fetal testosterone concentrations during the late fetal period subsequently developed a larger SDN-POA and stronger female-directed partner preference. They also showed more frequent tail rattling toward unfamiliar males and initiated sexual behavior more readily toward receptive females. The difference in partner preference disappeared after orchiectomy and re-emerged following testosterone replacement despite comparable circulating testosterone concentrations between the fetal testosterone groups. These findings suggest that natural variation in fetal testosterone during brain sexual differentiation contributes to individual differences in SDN-POA development and the expression of adult male social behaviors.

Metabolic dysfunction-associated liver disease (MASLD) is characterized by the accumulation of triglycerides in hepatocytes and can progress to metabolic dysfunction-associated steatohepatitis (MASH) with inflammation, hepatocyte ballooning, and fibrosis. MASLD is associated with increased plasma homocysteine levels. Homocysteine is an amino acid generated by the S-adenosylmethionine-dependent transmethylation pathway of the methionine cycle, and it is remethylated to methionine by the betaine-homocysteine S-methyltransferase (BHMT) in hepatocytes. Mice fed a high-fat, cholesterol, and fructose (HFCF) diet develop MASLD and MASH associated with increased peroxisome proliferator-activated receptor γ (PPARγ, Pparg) expression and homocysteine levels, and decreased hepatic Bhmt expression. Here, we sought to determine whether the hepatocyte-specific knockout of Pparg (PpargΛHep) or restoration of Bhmt expression in hepatocytes (BhmtHep) in mice with HFCF-induced MASH reduce MASLD progression. To this end, adult male Pparg-floxed mice were fed an HFCF diet for 20 weeks to induce MASH. Then, we generated PpargΛHep and/or BhmtHep mice using an adeno-associated virus encoding Cre recombinase or Bhmt in hepatocytes, respectively. HFCF diet-induced MASH increased hepatic Pparg expression and reduced Bhmt expression. 8 weeks after the induction of PpargΛHep, hepatic Bhmt expression was increased, and both MASH severity and homocysteine levels decreased. The restoration of hepatocyte BHMT in BhmtHep (Pparg-intact) mice reduced hepatic triglyceride and homocysteine levels, which were associated with reduced expression of the steatogenic genes Cidea and Cidec. Overall, our results indicate a protective role for BHMT in hepatocytes of mice with MASH, even in mice expressing Pparg in hepatocytes.

Critical illness profoundly affects the hypothalamus-pituitary-adrenocortical (HPA) axis. In the acute phase of sepsis and other critical conditions, systemic cortisol levels rise markedly, yet circulating ACTH is low. Peripheral adaptations - reduced cortisol metabolism, decreased cortisol-binding proteins, and tissue-specific modulation of glucocorticoid receptor signaling - rather than sustained central HPA axis activation generate compartmentalized increased cortisol actions. As illness persists beyond one week, patients transition into prolonged critical illness characterized by a central HPA suppression, impaired adrenocortical structure and function, together increasing the risk for ICU-acquired adrenal insufficiency beyond 4 weeks. Although glucocorticoids, in stress doses, remain widely used for shock reversal, they exacerbate this HPA suppression and aggravate acute and long-term complications of critical illness. A better mechanistic understanding is essential to guide targeted and adequately dosed therapies.

This Review discusses the current evidence on the relationship between food insecurity, obesity, metabolic syndrome and type 2 diabetes mellitus (T2DM), and identifies potential interventions to mitigate the effect of food insecurity on these conditions. Studies in adults (mainly cross-sectional) have consistently found associations between food insecurity and several cardiometabolic diseases, including obesity (mainly among women), hyperlipidaemia, metabolic syndrome, hypertension, cardiovascular disease and T2DM. These associations represent plausible causal relationships given that food insecurity can be a powerful psycho-emotional stressor that can cause distress, anxiety and depressive symptoms across the life course; poor dietary quality can increase the risk of metabolic syndrome and T2DM through increased visceral adiposity and insulin resistance, inflammation and an unhealthy microbiome; and food insecurity can cause healthcare behavioural trade-offs such as prioritizing purchasing food over medications for T2DM prevention or management. Community-based, healthy lifestyle promotion, early-life nutrition and Food as Medicine programmes could mitigate the negative effect of food insecurity on T2DM risk and metabolic health. There is a need to rigorously evaluate the results of promising large-scale interventions on food insecurity and cardiometabolic health outcomes.

Pancreatic β-cells integrate metabolic and electrical signals to couple nutrient sensing with insulin secretion, yet the physiological contribution of the neuronal K+Cl- cotransporter-2, Kcc2 (Slc12a5) to β-cell function and whole-body metabolic regulation remains incompletely understood. To define its role in vivo, we generated mice lacking Kcc2 selectively in insulin-secreting β-cells (Kcc2βKO) and evaluated growth, body composition, feeding behavior, glucose homeostasis and islet function from weaning through early adulthood. Kcc2βKO mice developed sex- and age-dependent metabolic phenotypes. Females exhibited lower body weight at weaning and increased lean mass during adulthood, whereas males displayed reduced body-weight gain despite increased food intake. Feeding microstructure analyses identified age-dependent alterations in meal patterning in male Kcc2βKO mice. Morphometric analysis demonstrated increased mean islet area without changes in endocrine cell composition, and isolated islets exhibited enhanced glucose-stimulated insulin secretion at younger ages. Male, but not female, Kcc2βKO mice showed improved glucose tolerance and age-dependent differences in glycemic responses to exogenous insulin, whereas both sexes exhibited attenuated glycemic responses to alanine challenge. Fasting blood glucose remained largely preserved across genotypes, although fasting plasma insulin concentrations varied according to sex, age and fasting duration. These findings identify β-cell Kcc2 as a physiological contributor to nutrient-stimulated insulin secretion and demonstrate that disruption of β-cell chloride homeostasis is accompanied by integrated, age- and sex-dependent adaptations in body-weight regulation, feeding behavior and glucose homeostasis.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by long-term and dynamic interactions between the immune system and pancreatic β-cells, ultimately leading to severe insulin deficiency. A paradigm shift in T1DM research has occurred in the past few years, with research now focusing on the human disease because of access to human pancreatic tissue and pancreas-draining lymph nodes. Advances in high-resolution imaging, single-cell and spatial multi-omics, and histopathology based on artificial intelligence have profoundly reshaped our understanding of disease initiation and progression. These studies revealed that β-cell loss and/or dysfunction might begin earlier than previously appreciated, preferentially affecting small β-cell-rich islets and insulin-positive cell clusters, with larger islets showing transient resistance. Substantial β-cell mass often persists at diagnosis, accompanied by functional impairment rather than immediate cell death. Across disease stages, β-cells exhibit conserved molecular signatures dominated by interferon signalling, enhanced antigen presentation and adaptive immune-evasion programmes, with evidence of heterogeneity linked to age, disease duration and immune context. Parallel analyses of pancreatic lymph nodes show early immune dysregulation, including altered regulatory T cell signatures and expansion of stem-like cytotoxic T cell populations, even before overt hyperglycaemia. Together, these findings support an integrated model of T1DM progression that enables alignment of clinical staging with evolving β-cell and immune phenotypes.