Homeobox C4 (HOXC4) links metabolic pathways and correlates inversely with mouse body weight and positively with Ucp1 expression in mouse adipose tissue. Gain- and loss-of-function experiments in mice demonstrated HOXC4's essential role in promoting adipose thermogenesis and providing metabolic benefits. HOXC4 interacts with the nuclear receptor coactivator 1 cofactor via its hexapeptide motif to activate Ucp1 transcription, revealing a novel mechanism of thermogenic gene regulation.

Genetic screens were performed across PPARG to study how disruptive mutations across the full coding sequence affect function. An alternative translational start site in PPARG generates a truncated isoform, peroxisome proliferator-activated receptor γ (PPARγ) M135, which lacks the N-terminal activation function 1 (AF-1) domain and shows increased agonist-induced transactivation of target genes. In human carriers of rare PPARG variants, AF-1 domain-disrupting genetic variants increase agonist-induced PPARγ activity and decrease metabolic syndrome severity. Targeting the AF-1 domain is a potential therapeutic strategy for insulin sensitization.

Endurance exercise is widely recognized for its role in mitigating insulin resistance, yet the precise mechanisms remain unclear. In this Classics in Diabetes article, we revisit the article by Amati et al., "Skeletal Muscle Triglycerides, Diacylglycerols, and Ceramides in Insulin Resistance: Another Paradox in Endurance-Trained Athletes?" Published in the October 2011 issue of Diabetes, this article was among the first to highlight the nuanced roles of exercise-induced changes in bioactive lipids such as ceramide and diacylglycerol (DAG) in insulin signaling. The authors' groundbreaking work challenged some existing paradigms, revealing a more complex relationship between DAGs and insulin resistance than previously thought. Their findings helped lay the foundation for further exploration to unravel the intricate biochemical pathways through which exercise influences insulin sensitivity and metabolic health.

Diabetes leads to a more rapid development of diabetic cardiomyopathy (dbCM) and progression to heart failure in women than in men. Combination of high-fat diet (HFD) and freshly injected streptozotocin (STZ) has been widely used for diabetes induction; however, emerging data show that anomer-equilibrated STZ produces an early-onset and robust diabetes model. We designed a novel protocol using a combination of multiple doses of anomer-equilibrated STZ injections and HFD to develop a stable murine diabetes model featuring dbCM analogous to that in humans. Furthermore, we examined the effect of biological sex on the evolution of cardiometabolic dysfunction in diabetes. Our study included six experimental protocols (8 weeks) in male and female C57BL/6J mice (N = 109): fresh STZ + HFD, anomer-equilibrated STZ + HFD, HFD, fresh STZ, anomer-equilibrated STZ, and control diet + vehicle. Animals were characterized by extensive phenotyping in vivo and ex vivo. Anomer-equilibrated STZ + HFD led to induction of stable experimental murine diabetes characterized by impaired glucose homeostasis, cardiometabolic dysfunction, and altered metabolome of liver, skeletal muscle, kidney, and plasma. dbCM was more severe in female mice, including systolic dysfunction and reduced cardiac energy reserve. This study establishes a novel robust model of inducible murine diabetes and emphasizes the impact of biological sex on diabetes progression and severity.

CD4+ T cells from patients with type 1 diabetes (T1D) have a significant response to post-translationally modified (PTM) deamidated IA-2 peptides; autoantibodies to these PTM neoepitopes remain to be identified in T1D. We aimed to identify autoantibodies specifically targeting reported T-cell reactive, deamidated epitopes of IA-2 and explore their relationship with T1D development. Autoantibodies to deamidated IA-2 were specific to deamidated epitopes and were predominantly present during the late stages of T1D development, challenging the hypothesis that the loss of immune tolerance occurs via post-translational modification of islet antigens. Newly identified autoantibodies to deamidated IA-2 are new biomarkers of islet autoimmunity and have the potential to aid in T1D diagnosis.

Type 1 diabetes (T1D) is an autoimmune disease mediated by autoreactive T cells. Our studies indicate that CD4 T cells reactive to hybrid insulin peptides (HIPs) play a critical role in T-cell-mediated β-cell destruction. We have shown that HIPs form in human islets between fragments of the C-peptide and cleavage products of secretory granule proteins. To identify T-cell specificities contributing to T1D pathogenesis, we tested T-cell reactivity from T1D patients or healthy control individuals using an IFN-γ enzyme-linked immunosorbent spot assay against a library of 240 C-peptide HIPs. We observed elevated T-cell responses to peptide pools containing HIPs that form at the amino acid residues G15, A18, and L26 of C-peptide. In a second cohort of healthy control individuals, at-risk individuals, and T1D patients, T-cell reactivity to HIPs forming at these three residues was monitored. Results indicate that, prior to clinical onset of T1D, there were significantly elevated responses to multiple pools of HIPs, and the magnitude of T-cell reactivity to HIPs forming at residue A18 of the C-peptide was increased. Overall, our study identifies new T-cell specificities in at-risk individuals and indicates that T-cell reactivity to HIPs can be observed before T1D onset.

Cancer survivors who receive cisplatin chemotherapy have an increased risk of type 2 diabetes, but the underlying mechanisms remain unclear. The aim of this study was to investigate whether cisplatin impacts β-cell health and function, thereby contributing to increased type 2 diabetes risk in cancer survivors. In vivo and in vitro cisplatin exposure dysregulated insulin secretion in male and female mice. In vitro cisplatin exposure reduced oxygen consumption, impaired β-cell exocytotic capacity, and altered expression of genes within the insulin secretion pathway in mouse islets. Understanding how chemotherapeutic drugs cause β-cell injury is critical for designing targeted interventions to reduce the risk of cancer survivors developing type 2 diabetes after treatment.

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related disorder that is associated with macrovascular diseases, such as coronary artery disease and stroke. However, the effects of CHIP on microvascular complication have not been explored in individuals with type 2 diabetes. We wanted to determine whether CHIP is associated with diabetic microvascular complications (DMCs). CHIP was associated with a high risk of DMCs, specifically, diabetic retinopathy and diabetic kidney disease, but not diabetic neuropathy. Gene-specific analyses suggested that some driver genes were associated with risk of developing DMCs. These findings indicated that CHIP may represent a novel risk factor for DMCs among individuals with type 2 diabetes, distinct from traditional risk factors, which may have implications for prevention and management of DMCs.

Diabetes is a major risk factor for cardiovascular diseases. The mechanisms of hyperglycemia-induced endothelial dysfunction have been elusive. We found that inositol hexakisphosphate kinase 1 (IP6K1) mediates hyperglycemia-induced endothelial senescence by switching liver kinase B1 (LKB1) activation of the AMPK pathway to activation of the p53 pathway. Hyperglycemia upregulates IP6K1, which stabilizes LKB1 by disrupting Hsp/Hsc70 and carboxyl terminus of Hsc70-interacting protein-mediated LKB1 degradation but suppresses LKB1-dependent AMPK activation. Elevated LKB1 binds more to p53, resulting in p53-dependent endothelial senescence. Endothelial cell-specific deletion of IP6K1 attenuates, whereas endothelial cell-specific overexpression of IP6K1 exaggerates, hyperglycemia-induced endothelial senescence.

Impaired cardiac microvascular function is a significant contributor to diabetic cardiomyopathy. Rnd3 expression is notably downregulated in cardiac microvascular endothelial cells under diabetic conditions. Rnd3 overexpression mitigates diabetic myocardial microvascular injury and improves cardiac function through the Rock1/myosin light chain signaling pathway. Rnd3 facilitates the recruitment and interaction with Trim40 to promote Rock1 ubiquitination, thereby preserving endothelial barrier integrity in the diabetic heart.

Intragastric overfeeding reveals insights into the homeostatic recovery from experimental weight gain. Protection against short-term, overfeeding-induced weight gain primarily involves a profound reduction in food intake and possibly an adaptive increase in energy expenditure. UCP1-mediated thermogenesis is not essential for homeostatic protection against short-term, overfeeding-induced weight gain.

New research builds on previous findings that JMJD8 mediates insulin resistance by promoting adipocyte hypertrophy. We identified PLIN2 as a binding partner of JMJD8 using proteomics approaches. This study reveals a physical interaction between JMJD8 and PLIN2, which plays a crucial role in driving adipocyte hypertrophy and insulin resistance. JMJD8 suppresses fasting-induced lipophagy and reduces energy production by inhibiting PLIN2 phosphorylation. These findings highlight the importance of JMJD8 and PLIN2 in regulating lipid droplet homeostasis and suggest a potential mechanism for controlling fat mobilization during energy deprivation.

Pancreatic cystic changes in adults are increasingly identified through advanced cross-sectional imaging. However, the impact of initial/intralobular epithelial remodeling on the local β-cell population remains unclear. In this study, we examined 10 human cadaveric donor pancreases (tail and body regions) via integration of stereomicroscopy, clinical hematoxylin and eosin histology, and three-dimensional (3D) immunohistochemistry, identifying 36 microcysts (size: 1.22 ± 0.56 mm) alongside 54 low-grade pancreatic intraepithelial neoplasias (positive control of epithelial remodeling; size: 2.42 ± 1.05 mm). Both conditions exhibited significant increases in cytokeratin 7 (CK7) and insulin immunoreactive signals compared with normal lobules. Importantly, despite luminal contents of microcysts causing false positives (autofluorescence) in fluorescence imaging, the defined cystic epithelium showed distinct duct-β-cell associations-including β-cells in the epithelium and duct-β-cell clusters-visualized via antifade 3D/Airyscan superresolution imaging in the high-refractive-index polymer. The periluminal β-cells displayed insulin-positive vesicles residing near the basal domain, while the CK7+ cytokeratins in duct cells accumulated in the apical domain, underlining polarized tissue and cellular organizations. Overall, in microcyst formation, we demonstrate local and associated pancreatic exocrine and endocrine tissue remodeling. Because artifacts are a concern in β-cell investigations in a novel environment, our work using 3D-labeled human pancreas with cytokeratin and vesicle resolving powers provides a robust approach for characterizing the duct-β-cell association in a clinically relevant setting.

Approximately one out of two patients with diabetes develops diabetic neuropathy; of these, 20% experience neuropathic pain. Risk factors for neuropathic pain are largely unknown; however, DNA methylation was recently associated with neuropathies and degeneration of nerve fibers. The aim of this work was to describe the DNA methylation signature and identify genes associated with neuropathic pain in type 2 diabetes mellitus (T2DM). We discovered distinct DNA methylation signatures that differentiate painful and painless neuropathy phenotypes associated with T2DM and identified genes with potential as therapeutic targets for neuropathic pain, such as GCH1, MYT1L, and MED16. This work can serve as reference hallmark for future studies on painful diabetic neuropathy and other chronic pain conditions.

Postprandial hypotension (PPH) occurs frequently in type 2 diabetes. Metformin has cardiovascular effects independent of its glucose-lowering capacity, which may modulate the risk of PPH. We investigated the effects of metformin on postprandial blood pressure, including PPH events, heart rate, glucose, insulin, glucagon-like peptide 1 (GLP-1), and gastric emptying, in individuals with type 2 diabetes. Metformin attenuated postprandial decrease in blood pressure and reduced PPH events, in association with augmentation of plasma GLP-1, slowed gastric emptying, and increased heart rate, in type 2 diabetes. These findings establish novel cardiovascular effects of metformin that may mitigate the risk of PPH in type 2 diabetes.

Identification of circulating proteins that may play a role in the pathogenesis of type 1 diabetes can provide promising targets for biomarker and drug target identification. Supported by multiple lines of evidence, circulating abundances of CTSH, IL27RA, SIRPG, and PGM1 were associated with the risk of type 1 diabetes. Tissues and cell types with enrichment of target protein-coding gene expression were identified. CTSH, IL27RA, SIRPG, and PGM1 may be explored as biomarkers or drug targets for type 1 diabetes.

Renin-angiotensin system (RAS) activation plays an important role in the progression of diabetic kidney disease (DKD). However, systemic RAS blockade alone is insufficient to reverse DKD progression. We hypothesized that intrarenal renin-angiotensin system (iRAS) activation plays a crucial role in the progression of DKD. We sought to elucidate the role of the iRAS in DKD progression. Selective deletion of angiotensinogen in renal tubules ameliorated the pathological features of DKD. Our study indicates that iRAS inactivation may be a potential approach for preventing DKD disease severity and its progression.

The COVID-19 pandemic has profoundly affected human health; however, the mechanisms underlying its impact on metabolic and vascular systems remain incompletely understood. Clinical evidence suggests that SARS-CoV-2 directly disrupts vascular homeostasis, with perfusion abnormalities observed in various tissues. The pancreatic islet, a key endocrine miniorgan reliant on its microvasculature for optimal function, may be particularly vulnerable. Studies have proposed a link between SARS-CoV-2 infection and islet dysfunction, but the mechanisms remain unclear. Here, we investigated how SARS-CoV-2 spike S1 protein affects human islet microvascular function. Using confocal microscopy and living pancreas slices from organ donors without diabetes, we show that a SARS-CoV-2 spike S1 recombinant protein activates pericytes, key regulators of islet capillary diameter and β-cell function, and induces capillary constriction. These effects are driven by a loss of ACE2 from pericytes' plasma membrane, impairing ACE2 activity and increasing local angiotensin II levels. Our findings highlight islet pericyte dysfunction as a potential contributor to the diabetogenic effects of SARS-CoV-2 and offer new insights into the mechanisms linking COVID-19, vascular dysfunction, and diabetes.