Search Results (1,042)

Background/Objective: Type 2 diabetes mellitus (T2DM) is a known risk factor for cardiovascular disease (CVD); however, not all individuals with T2DM have the same CVD risk. Traditional glycemic cluster analyses of individuals with diabetes using the homeostatic model assessment estimate of insulin resistance (HOMA-R) as an indicator of insulin resistance have identified severe insulin-resistant diabetes as a high-risk factor for incident CVD. To extend this observation, we further classified non-diabetic individuals to identify risk clusters for incident CVD. Methods: We performed hierarchical cluster analysis of 577 non-diabetic Japanese individuals using the glycated hemoglobin level, body mass index, homeostasis model assessment estimate of β-cell function, and the triglyceride-glucose (TyG) index instead of the HOMA-R to assess incident CVD risk over up to 188 months. Results: Analysis using a multiple risk factor-adjusted Cox proportional-hazard regression model showed that in addition to impaired glucose tolerance (IGT), among the four clusters observed, a cluster labeled “low insulin secretion (Low-IS (TyG))” was a risk factor for incident CVD (hazard ratio, [95% confidence interval]: 2.77 [1.11–6.91]). Furthermore, when the participants were stratified on the basis of the presence of IGT, the Low-IS (TyG) cluster was associated with an increased risk of CVD only in the non-IGT group (3.29 [1.32–8.18]), but not in the IGT group (1.66 [0.34–8.15]). Conclusions: Glycemic clustering incorporating the TyG index identified a novel at-risk group for incident CVD among non-diabetic individuals, offering a useful tool for early CVD risk stratification beyond traditional measures of glucose tolerance. Full article

Background: Metabolic instability, encompassing fluctuations in body weight, glucose, insulin, and sex hormones, may create a pro-inflammatory and proliferative endometrial microenvironment even in women with normal BMI. Methods: A systematic literature review was performed in PubMed, Embase, and Google Scholar, including studies assessing the relationship between metabolic, endocrine, and inflammatory factors and the risk of endometrial cancer in non-obese women. Results: Variability in body weight and hormonal parameters was associated with chronic subclinical inflammation, altered leptin/adiponectin secretion, decreased sex hormone-binding globulin, and increased estrogen bioavailability. These changes disrupt the homeostatic rhythm of endometrial cell regeneration and increase the likelihood of neoplastic transformation. Conclusions: Metabolic instability represents a novel integrated risk factor for endometrial cancer among women without obesity and should be incorporated into future risk stratification and prevention models. Full article

Post-translational modifications (PTMs) provide an integrated regulatory layer that couples nutrient and hormonal signals to whole-body energy homeostasis across metabolic organs. PTMs modulate protein activity, localization, stability, and metabolic networks in a tissue- and state-specific manner. Through network remodeling, PTMs integrate receptor signaling with chromatin and organelle function and align transcriptional control with mitochondrial function, proteostasis, and membrane trafficking. PTM crosstalk connects kinase cascades, nutrient-sensing pathways, and ubiquitin-family modifiers to orchestrate gluconeogenesis, lipolysis, glucose uptake, thermogenesis, and insulin secretion in response to nutrient cues. The metabolic state regulates PTM enzymes through changes in cofactors, redox tone, and compartmentalization, and PTM-dependent changes in transcription and signaling feedback to metabolic tone. In obesity and diabetes, dysregulated post translational modification networks disrupt insulin receptor signaling, disturb organelle quality control, and impair beta cell function, which promotes insulin resistance and beta cell failure. Consequently, PTMs organize metabolic information flow and modulate tissue responses to overnutrition and metabolic stress. A systems-level understanding of PTMs clarifies mechanisms of whole-body energy homeostasis and supports the discovery of new therapeutic targets in metabolic disease. Full article

Background/Objectives: Proinsulin, the precursor to insulin, has limited activity on the insulin receptor. Proinsulin levels increase with increasing insulin resistance in type 2 diabetes due to incomplete processing by the β-cell. To assess whether the development of peptides that could convert circulating proinsulin to insulin in the blood would provide therapeutic value, we used a quantitative systems pharmacology (QSP) model of glucose homeostasis. In silico hypothesis testing such as this is an example of how modeling can inform decisions in drug discovery. Methods: In silico hypothesis testing involved (1) the addition and qualification of proinsulin biology into a preexisting QSP model, (2) the creation and validation of virtual patients (VPs) for subpopulations of type 2 diabetics based on phenotypic traits, and (3) the simulation of clinical trials evaluating the therapeutic value of the conversion of circulating proinsulin to insulin in the VPs created. Results: Proinsulin conversion led to a ~0.2% reduction in HbA1c in VPs at varying stages of diabetes, a decrease that does not hold meaningful therapeutic value. The lack of significant impact on HbA1c was likely a result of the surprisingly small effect on plasma insulin levels from proinsulin, which has a significantly slower secretion and clearance rate. Although patients with higher proinsulin/insulin ratios showed the largest reductions, clinically significant ≥ 0.5% reduction in HbA1c required ratios of proinsulin/insulin above the reported physiological range. Conclusions: This effort demonstrates how in silico hypothesis testing using QSP modeling can provide insights on the probability of success of novel interventions with minimal time and resources. These efficiencies are a means of overcoming the pressures on the pharmaceutical industry to do more with less in providing therapies that improve the lives of patients. Full article

The prevalence of maternal obesity is rapidly increasing, which represents a major public health concern worldwide. Currently more than 50% of all adult women are overweight or obese, and this trend is reflected in women of child-bearing age. Maternal obesity is characterized by metabolic dysfunction and chronic inflammation, and is associated with health problems in both the mother and the offspring. Intrauterine programming occurs during embryonic and fetal development, a critical period not only for the formation of tissues and organs but also for the etiology of diseases later in life. The principal mechanisms underlying fetal programming in the offspring of obese mothers appear to involve DNA methylation and chromatin remodeling within progenitor cells. Aberrant DNA methylation patterns have been identified in genes involved in insulin signaling, lipid metabolism, and appetite regulation in the placenta and fetal tissues. Histone modifications, such as acetylation and methylation of histone tails, may also play a crucial role in modulating chromatin structure and accessibility of transcriptional machinery to DNA. The persistence of such modifications throughout life, and potentially across generations, can lead to permanent alterations in gene expression, thereby contributing to the intergenerational transmission of metabolic disorders. The aim of this paper is to present an overview of the current knowledge regarding the effects of maternal obesity on fetal development and the occurrence of fetal complications, as well as long-term complications observed in adulthood related to intrauterine exposure to maternal obesity, including hypertension and cardiovascular diseases, impaired insulin secretion and resistance, diabetes mellitus, and metabolic syndrome. The mechanisms underlying fetal programming are also discussed. Full article

Mitochondria are essential for β-cell function, coupling glucose metabolism to ATP production and insulin secretion. In diabetes, β-cell mitochondrial dysfunction arises from oxidative stress, impaired quality control and disrupted dynamics, leading to reduced oxidative phosphorylation, defective insulin release and progressive cell loss. Key transcriptional regulators link genetic susceptibility to mitochondrial dysfunction in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). These disruptions impair mitophagy, mitochondrial translation and redox homeostasis. Therapeutic strategies that restore mitochondrial function, including mitophagy enhancers, mitochondrial antioxidants, and transcriptional regulators, have shown potential in preserving β-cell integrity. As mitochondrial failure precedes β-cell loss, targeting mitochondrial pathways may represent a critical approach to modifying diabetes progression. Full article

Background: Hypoxia-induced oxidative stress compromises the survival and function of transplanted islets, contributing to high rates of islet transplantation failure. Methods: This study investigated the small-molecule mitochondrial fusion agonist S89, which specifically activates mitofusin 1 (MFN1). We assessed its protective effects against hypoxia-induced oxidative stress and apoptosis in pancreatic β-cells. Results: In mouse insulinoma cells (Min6), S89 enhanced cell viability by promoting mitochondrial fusion to inhibit mitochondrial reactive oxygen species (mtROS) overaccumulation (S89 reduced mtROS by approximately 30%) and attenuated mitochondrial lipid peroxidation; furthermore, it suppressed hypoxia-induced apoptosis via downregulation of the BAX/BCL-2 ratio, thus protecting the cells from hypoxia-induced oxidative damage. Notably, S89 significantly potentiated glucose-stimulated insulin secretion (GSIS) in both the Min6 β-cell line and primary mouse islets. Critically, S89 pretreatment enhanced hypoxia resistance in islets and significantly increased graft survival upon transplantation into streptozotocin (STZ)-induced type 1 diabetic (T1D) mice, maintaining prolonged blood glucose homeostasis. Conclusions: These findings demonstrate that S89 protects β-cells from hypoxic injury, indicating its efficacy as a therapeutic approach for improving islet transplantation outcomes. Full article

This study presents a protocol for co-culturing pancreatic islet cell clusters derived from pancreatic tissue with human umbilical vein endothelial cells (HUVECs) on Matrigel using a specialized culture medium to form vascularized pancreatic islet organoids. We established a novel culture system for vascularized pancreatic islet organoids and compared the survival and insulin secretion capabilities of pancreatic islet cells in the presence and absence of glucose stimulation. Our results indicate that matrix adhesive materials can effectively facilitate the self-assembly of the vascularized endothelial cell–pancreatic islet organoids complex. Vascularized HUVEC prolongs the survival of pancreatic islet organoids in vitro. Moreover, the interaction between vascularized HUVEC and pancreatic islets significantly enhances the insulin secretion ability in response to glucose stimulation. This study reports a protocol for the long-term in vitro culture of pancreatic islet organoids, offering methods for the vascularization of pancreatic islet organoids on Matrigel. These data contribute to the understanding of how vascularization impacts the fate and function of pancreatic islet organoids, although the specific mechanism still requires further clarification. Full article

Insulin is a key anabolic hormone traditionally considered to be exclusively produced by pancreatic β-cells. Insulin exerts several systemic effects involved in glucose uptake and metabolism. In the retina, insulin signaling acts as a regulator of photoreceptor- retinal pigment epithelium (RPE) metabolic coupling as well as of neuronal survival via the PI3K/Akt and MAPK/ERK pathways. Impaired insulin signaling contributes to diabetic retinopathy, retinitis pigmentosa, and age-related degeneration by disrupting energy homeostasis and trophic support. However, growing evidence suggests that the retina, particularly RPE, locally synthesizes and secretes insulin. Although the role of local insulin production in the retina remains to be clarified, this discovery introduces a paradigm shift in retinal physiology, suggesting a self-sustaining insulin signaling system that supports glucose uptake, lipid metabolism, and neurovascular integrity. Emerging data indicate that RPE-derived insulin is stimulated by photoreceptor outer segment (POS) phagocytosis and may act through autocrine and paracrine mechanisms to maintain retinal function, even under conditions of systemic insulin deficiency. Understanding this extra-pancreatic insulin source opens new therapeutic perspectives aimed at enhancing local insulin signaling to preserve vision and prevent retinal degeneration. Thus, the objective of this review is to summarize current evidence on RPE-derived insulin and to discuss its potential implications for retinal homeostasis and disease. Full article

Type 2 diabetes (T2D) is a complex metabolic disease characterized by insulin resistance, progressive β-cell dysfunction, and persistent hyperglycemia. While GLP-1 receptor agonists have revolutionized the management of T2D by improving glycemic control and reducing body weight, their insulinotropic effects increase the workload on pancreatic β-cells, which may hasten β-cell decline in certain individuals. Peptide YY (PYY), a gut-derived hormone secreted alongside glucagon-like peptide-1 (GLP-1) from L-cells, presents a unique and complementary therapeutic approach. In contrast to GLP-1, PYY does not directly induce insulin release but confers metabolic advantages by suppressing appetite through Y2 receptor pathways, enhancing insulin sensitivity via peripheral Y1/Y4 receptors, and slowing gastric emptying to minimize postprandial glucose surges. Notably, recent research suggests PYY supports the preservation and restoration of pancreatic islets by improving their structure and function without increasing the secretory demand. PYY levels are substantially increased after bariatric surgery, where it plays a pivotal role in weight-loss-independent improvements in glycemic regulation and islet hormone dynamics. These attributes position PYY as a strong candidate for use in combination with GLP-1 analogs, especially in individuals with advanced β-cell impairment or those who respond inadequately to GLP-1 monotherapy. This review discusses PYY’s physiological functions, mechanistic actions, and therapeutic opportunities in T2D, highlighting its potential as a valuable adjunct or alternative in gut-hormone-oriented treatment strategies. Full article

Type 2 diabetes and gout are both common metabolic disorders that frequently occur together. Research indicates that disturbances in intracellular calcium balance may be a key molecular factor linking the development of these two diseases. Calcium signaling disturbances promote the synergistic progression of both diseases through multiple pathways: In pancreatic β-cells, endoplasmic reticulum (ER) calcium imbalance triggers ER stress, mitochondrial dysfunction, and apoptosis, autophagy, and pyroptosis, leading to impaired insulin secretion. Concurrently, calcium overload exacerbates insulin resistance by disrupting insulin signal transduction in peripheral tissues, while hyperinsulinemia further inhibits uric acid excretion through activation of the renal URAT1 transporter, creating a vicious cycle. Additionally, calcium homeostasis dysregulation activates the NLRP3 inflammasome and promotes the release of pro-inflammatory cytokines, aggravating chronic low-grade inflammation, which further deteriorates β-cell function and peripheral metabolic disorders, collectively driving the pathological link between type 2 diabetes and gout. Although calcium channel modulators show potential in improving β-cell function and reducing inflammation, their clinical application faces challenges such as tissue-specific effects and a lack of high-quality clinical trials. We propose that intracellular calcium dysregulation serves as a central pathological amplifier in the diabetes–gout nexus. Future research on targeted calcium signaling interventions, guided by this integrative concept, may help overcome the therapeutic challenges in managing type 2 diabetes complicated by gout. Full article

In this review we propose the hypothesis that an energy-dissipating process precedes the continuous stimulation of insulin secretion by glucose. This process is mediated by connexin 36 hemichannels (Cx36H), or Cx36 connexons. Cx36H oligomers are expressed at the plasma membrane, and their gating activity (opening) is activated by plasma membrane depolarization after the closure of K⁺ATP channels by glucose (>5 mM) metabolism. This initial depolarization (1st step) might be responsible for the first phase of insulin secretion, with the subsequent opening of Cx36H increasing β-cell plasma membrane permeability, allowing for the efflux of metabolites (less than 1KD) (GABA, adenine nucleotides) and K⁺ (2nd step). This provokes a breakdown of oxidative glucose metabolism and the repolarization of the plasma membrane. As the extracellular glucose concentration increases further (>>5 mM), it exerts a progressive inhibition effect on Cx36H opening, allowing for the continuous stimulation of insulin secretion (3d step, second phase,). The glucose feature of regulating Cx36H closing with sigmoidal kinetics (8 mM IC₅₀ and around 20 mM at maximum) has been confirmed in mouse Cx36 connexin expression in Xenopus oocytes and in mouse islets stimulated by a range of glucose concentrations in the presence of 70 mM KCl. This gating activity was also inhibited by some non-metabolized glucose analogs. Glucose inhibition of Cx3H opening might not only contribute to making the insulin secretory response more specific for glucose but might also play a role in the pulsatility of sustained insulin secretion. Cx36H opening also offers the opportunity to potentiate the secretory effect in vivo by, permeant or not, metabolic stimuli. Confirmation of this novel physiological role for Cx36H in β-cells would place them as new susceptibility locus for type 1 and type 2 diabetes, whose physiological implication in the mechanism of insulin secretion regulation should be evaluated by in vivo studies in diabetic patients. Full article

Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with new-onset diabetes (NOD) in adults aged ≥ 50 years. Accordingly, NOD may serve as an early clinical marker for PDAC, although the causal links remain incompletely defined. This review synthesises clinical and experimental evidence into an islet-centric view in which tumour-derived signals and microenvironmental changes impair β-cell insulin secretion and disrupt α- and δ-cell regulation. We distinguish findings established in PDAC from mechanisms inferred from islet physiology and systemic metabolism. Key uncertainties include the timing of systemic versus local drivers, the clinical relevance of tumour-derived signals in driving dysglycaemia, the status of endocrine cell signalling and endocrine–exocrine crosstalk, and the effects of microvascular and matrix changes on endocrine–vascular exchange. This synthesis highlights mechanisms that remain incompletely defined and prioritises areas for further research. Full article

TAAR1 agonists have emerged as promising therapeutic agents capable of modulating glucose homeostasis, enhancing insulin secretion and suppressing appetite, making them attractive candidates for the treatment of obesity and related metabolic disorders. Despite their potential, the number of TAAR1-targeting compounds with well-defined pharmacological profiles remains limited. In this study, we identified and characterized JP-14, a novel aminoguanidine-based TAAR1 agonist, in a comprehensive panel of pharmacological assays. JP-14 promoted glucose uptake in HepG2 cells and reduced lipid deposition during 3T3-L1 adipocyte differentiation, with both actions dependent on TAAR1 signaling. In differentiated 3T3-L1 adipocytes, JP-14 reduced intracellular levels of both neutral lipids and phospholipids, indicating dual anti-steatotic and anti-phospholipidotic activity. In zebrafish larvae, toxicity profiling confirmed 10 µg/mL as a safe concentration for further in vivo studies. These assays showed that JP-14 promoted lipid mobilization and partially prevented fructose-induced lipid accumulation, demonstrating systemic metabolic benefits in vivo. Moreover, JP-14 markedly delayed gastric emptying in mice, an effect similar to loperamide and reversed by TAAR1 antagonism, supporting its role in regulating satiety and energy balance. Collectively, our findings establish JP-14 as a safe and metabolically active TAAR1 agonist with multifaceted effects on glucose and lipid metabolism. JP-14 represents a valuable pharmacological tool for probing TAAR1-mediated mechanisms in metabolic regulation. Full article

Background/Objectives: Dyslipidemia is one of the major problems of long-term management in people living with human immunodeficiency virus (HIV) (PLH) as a risk factor for cardiovascular diseases. Lipoprotein lipase (LPL) is anchored on the surface of the capillary endothelial cells and plays a pivotal role in triglyceride metabolism by catabolizing dietary chylomicrons and very low-density lipoprotein synthesized in the liver. However, the details of the mechanisms in the era of integrase strand transfer inhibitor-based antiretroviral therapy have not yet been clarified. Methods: This study was a cross-sectional, single-center, non-interventional study evaluating the underlying factors associated with dyslipidemia, insulin resistance or secretion, and changes in the body composition of PLH. Results: Among PLH (n = 48), lower LPL (<60.8 ng/mL) and older age independently predicted antilipemic drug (ALD) necessity. A comparison of ALD-naïve PLH (n = 33) and age- and sex-matched non-HIV controls (n = 33) showed that PLH were significantly associated with lower high-density lipoprotein cholesterol (HDL-C) and higher HOMA-β. LPL was also the independent predictor of HDL-C < 40 mg/dL in PLH (adjusted odds ratio = 0.901, p = 0.044). Furthermore, LPL < 65.3 ng/mL predicted HDL-C < 40 mg/dL with 100% sensitivity and 60.9% specificity. Low levels of HIV-RNA were detected in the high HOMA-β group. Conclusions: In Japanese individuals, compared to non-HIV controls, PLH has low HDL-C and LPL. The measurement of LPL may confer the risk assessment and decision-making with relevance to ALD in PLH. Additionally, the effectiveness of HIV antiviral therapy and glucose tolerance may interact with each other. Full article