Pyrophosphatase 1 (PPA1) is upregulated in livers of high-fat diet-induced obese mice and metabolic dysfunction-associated steatotic liver disease patients. Hepatic PPA1 deletion protects mice against high-fat diet-induced obesity and related metabolic disorders by promoting whole-body energy expenditure. Deficiency of hepatic PPA1 expression facilitates fibroblast growth factor 21 production by activating the GCN2/eIF2α/ATF4 signaling pathway.

In global type 1 diabetes (T1D) population screening studies, there is an urgent need for a highly sensitive and specific insulin autoantibody (IAA) assay that can be implemented across multiple laboratories. This study aimed to develop and characterize a novel ELISA-based platform for IAA detection. We established a new bridging ELISA for IAA and validated it in cohorts of patients with stage 3 T1D, children positive for with multiple and single islet antibodies, and control children negative for islet autoantibodies. The bridging ELISA-IAA assay demonstrates excellent sensitivity and specificity, preferentially identifies high-risk individuals, and offers a practical, scalable solution for T1D population screening and clinical diagnosis across laboratories.

GLP-1 and its analogs enhance insulin secretion, but the specific intracellular mechanisms in β-cells remain unclear. Key intracellular mediators including calcium, glutamate, γ-aminobutyric acid, serotonin, and urocortin-3 are modulated by GLP-1 signaling with variable and sometimes contradictory effects. GLP-1 may affect mitochondrial dynamics and redox balance in β-cells, both critical for function and survival. Gaps in knowledge remain regarding cross talk between classical secretagogues and GLP-1 pathways. Further investigation is needed to clarify how GLP-1 integrates metabolic, signaling, and organelle-based processes in insulin secretion.

Our studies identify a role for the α-cell phosphoenolpyruvate cycle in sensing amino acids under hypoglycemic conditions. Leucine, in the presence of glutamine, opposes alanine/arginine-stimulated Ca2+ influx and glucagon secretion. Pyruvate kinase and phosphoenolpyruvate carboxykinase 2 are required for leucine to close α-cell KATP channels and limit Ca2+ influx. All of the amino acids tested regulate glucagon secretion, but none do so by modulating membrane depolarization or intracellular Ca2+ levels.

Red blood cells (RBCs) from older (representing longer duration of diabetes) but not young diabetic mice induce endothelial dysfunction. Protective miRNA-210-3p levels in RBCs are reduced in older diabetic mice compared with young ones. RBCs from individuals with long-lasting (>7 years) but not newly diagnosed type 2 diabetes (<1 year) induce endothelial dysfunction. RBCs from individuals with newly diagnosed type 2 diabetes induce endothelial dysfunction at a >7-year follow up, which is rescued by miRNA-210-3p mimic.

Glucagon/glucagon-like peptide 1 sensitizes glucose-induced microtubule remodeling in β-cells. Microtubule density in islets inversely correlates with the α-cell-to-β-cell ratio. Glucose-stimulated insulin secretion levels in single islets positively correlate with their α-cell-to-β-cell ratio. Glucagon and microtubule destabilization mobilize the same granule pool.

Leptin is known to enhance brown adipose tissue (BAT) activity through sympathetic stimulation. However, invitro studies suggest leptin could also act directly on adipocytes to promote lipolysis. Whether these peripheral effects of leptin are relevant to systemic metabolic control in obesity remains unclear. We addressed this question by selectively restoring leptin receptor (LEPR) expression in adipocytes of obese LEPR-conditional knockout mice. LEPR restoration selectively enhanced BAT activity in male mice, which led to improved glycemic control and cardiovascular function. These findings reveal a crucial role for BAT leptin signaling in regulating energy expenditure and glycemic and cardiovascular health, primarily in males.

Neurotransmission mechanisms at the final parasympathetic pathway in the pancreas have not been elucidated. We manipulated and recorded neuronal and target cell responses in living pancreatic slices to assess how intrapancreatic neurons affect pancreatic cell function. Activating muscarinic receptor signaling in intrapancreatic neurons was required to trigger exocrine cell activity and modulate endocrine cell secretion. Our findings revise conventional models of parasympathetic neuronal control of pancreatic function.

This study investigated the role of ferroptosis in angiotensin II (AngII)-induced kidney injury, addressing a critical gap in understanding AngII-mediated nephropathy mechanisms. We asked whether dipeptidase 1 (DPEP1)-mediated SLC3A2 degradation drives ferroptosis and renal damage under AngII activation. AngII upregulates DPEP1 via SP1, promoting SLC3A2 ubiquitination and glutathione depletion, ultimately triggering tubular ferroptosis. DPEP1 inhibition rescues renal function. Targeting the SP1-DPEP1-SLC3A2 axis offers a novel therapeutic strategy against ferroptosis-dependent kidney injury in hypertension and metabolic disorders.

To understand the heterogeneity of younger-onset type 2 diabetes, clinical data-driven clustering was performed, which identified three distinct subgroups that were replicated in an independent cohort. Compared with the mild obesity-related diabetes (MOD) subgroup, both severe insulin-deficient diabetes (SIDD) and severe insulin-resistant diabetes with insulin insufficiency (SIRD-II) subgroups had higher risk of developing diabetes-related complications. Differential molecular signatures confirmed the biological distinctiveness of younger-onset T2D subgroups and highlight potential mechanisms, such as glucolipotoxicity stress that may drive complications in the SIRD-II subgroup. Proteomic analyses validated previously reported biomarkers and identified novel candidates, providing a foundation for future mechanistic studies.