Insulin

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss and profound systemic metabolic dysfunction, including hypermetabolism, weight loss, insulin resistance, and altered glucose and lipid homeostasis. Increasing recognition of these metabolic abnormalities has driven interest in repurposing antidiabetic therapies, particularly glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists (GLP-1RAs), for ALS. Beyond their established metabolic actions, GLP-1RAs exert pleiotropic effects relevant to neurodegeneration, including modulation of neuroinflammation, mitochondrial function, oxidative stress, excitotoxicity, and cell-survival signaling, with selected agents demonstrating central nervous system penetration. This narrative review summarizes current knowledge on metabolic impairment in ALS and critically evaluates the mechanistic rationale, preclinical evidence, and emerging clinical data supporting or opposing the use of GLP-1-based therapies in this disease. Preclinical studies suggest that GLP-1 signaling can provide neuroprotective and neurotrophic effects in ALS models, although findings are heterogeneous and highly dependent on compound selection, delivery strategy, and experimental design. In contrast, available clinical evidence is limited and does not demonstrate therapeutic benefit in ALS, while raising important safety concerns, particularly related to weight loss, lean mass reduction, and altered glucose regulation, factors associated with a worse prognosis in ALS. Collectively, current data indicate that although GLP-1-based therapies may have compelling biological plausibility and beneficial effects in other neurodegenerative disorders (NDGs), their role in ALS remains uncertain and potentially harmful. Well-designed, ALS-specific clinical studies are required to clarify safety, efficacy, and patient selection before GLP-1RAs can be considered for therapeutic use in this vulnerable population.

Abstract

Obesity results from an imbalance between energy intake and energy expenditure (EE). Glucagon-like peptide-1 receptor (GLP-1R) agonists, reduce weight through appetite suppression but exert minimal influence on EE, potentially limiting long-term efficacy due to adaptive declines in metabolic rate. In contrast, glucagon, traditionally regarded as a glucose counter-regulatory hormone, has emerged as a potent catabolic signal with actions on lipid oxidation, substrate mobilization, and EE. These properties position glucagon receptor (GCGR) agonists as complements to GLP-1R agonism, with the potential to close the EE gap in obesity pharmacotherapy.

Abstract

Over the past 2 decades, treatment for type 2 diabetes (T2D) has evolved with the introduction of medications that offer greater simplicity. The Simplicity of Diabetes Treatment Questionnaire (Sim-Q™) was developed to assess the simplicity or complexity of treatment for T2D. This study assessed the psychometric properties of the Sim-Q.

Abstract

Hypothalamic obesity (HO) is a rare, complex disorder characterized by disruption of brain pathways regulating energy intake, expenditure, autonomic function, and hormonal signaling. It occurs in rare monogenic obesity syndromes affecting central leptin-melanocortin pathways or can be acquired (aHO) as a consequence of hypothalamic injury due to a tumor (e.g., craniopharyngioma), its treatment, or trauma. In this narrative review, we focus on aHO. Damage to specific hypothalamic nuclei leads to hyperphagia, central insulin and leptin resistance, decreased sympathetic activity, reduced energy expenditure, and rapid weight gain. Traditional obesity treatments, including lifestyle interventions, often fail to achieve sustained weight loss in patients with aHO. Recent advances in pharmacotherapy show promise by targeting the distinct pathophysiology of aHO. Effective treatment requires personalized approaches due to the heterogeneity of hypothalamic dysfunction and associated comorbidities. Early intervention may improve outcomes, as rapid postoperative weight gain frequently occurs. Emerging therapies target mechanisms of disturbed energy homeostasis pathways. These agents include stimulants, incretin-based therapies (e.g., glucagon-like peptide-1 receptor agonists), insulin modulators, and melanocortin receptor agonists such as setmelanotide. While monotherapies often fail in long-term treatment, combination therapies hold potential to restore energy balance and reduce or eliminate the need for bariatric surgery. Future research should focus on identifying clinical and biomarker profiles of aHO subtypes and evaluating combination therapies. Although challenging, aHO is no longer untreatable. Patients should be referred and managed at specialized centers, with pharmacological treatment preferably conducted within research settings to optimize and personalize care, and to develop evidence-based protocols for this debilitating condition.

Abstract

Obesity is frequently associated with metabolic alterations like hypercholesterolemia and hyperinsulinemia and represents a major risk factor for several diseases, including breast cancer (BC). Insulin signaling, as well as the frequent overexpression of the insulin receptor (IR), play a key role in BC progression. Emerging evidence suggests that the widely prescribed lipid-lowering drugs, named statins, may reduce the risk of recurrence and blunt BC cell proliferation, mainly inhibiting the HMGCR-dependent activation of the mevalonate pathway. In this study, we investigated the effects of simvastatin, atorvastatin and rosuvastatin in BC cells stimulated by insulin. To this end, we used as a BC model system MCF7 cells and naturally immortalized BCAHC-1 cells, which are characterized by high IR-expression levels. Our investigation demonstrates that statins reduce the proliferation and clonogenic capacity of BC cells prompted by insulin treatment. Mechanistically, statins impair the IR-mediated signaling and downregulate the stress-inducible transcription factor NUPR1, a known regulator of cancer progression. Importantly, NUPR1 inhibition blunted the stimulatory action of insulin on BC cells. Consistent with these findings, survival analyses of large cohorts of patients revealed that high levels of NUPR1 are associated with poor BC prognosis. Overall, our results provide novel mechanistic evidence supporting the repositioning of statins in BC, particularly in tumors characterized by elevated IR expression and activity.

Abstract

Epidemiological evidence suggests that atherosclerosis (AS) may precede or coexist with type 2 diabetes mellitus (T2DM); however, whether anti-atherosclerotic interventions can reduce T2DM risk remains unclear. Chensinin-1b (C-1b), an antimicrobial peptide derived from the skin secretions of Rana chensinensis, has previously demonstrated anti-atherosclerotic activity, suggesting a potential therapeutic effect against T2DM in the context of AS.

Abstract

Glucagon-like peptide-1 (GLP-1), an incretin secreted by intestinal L-cells in response to nutrients, regulates glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and reducing appetite via hypothalamic signaling. Beyond these canonical actions, emerging evidence reveals GLP-1's pleiotropic functions across multiple systems, with relevance to metabolic disorders, chronic inflammation, and aging-related pathologies. This review summarizes molecular mechanisms underlying GLP-1's protective roles, highlighting its contributions to metabolic balance, inhibition of NF-κB-mediated inflammation, and attenuation of cellular aging through mitochondrial enhancement and autophagy promotion. GLP-1 also influences immune cell function and alleviates hallmarks of senescence, thereby offering therapeutic potential beyond diabetes. We further critically assess the translational potential of GLP-1 receptor agonists (GLP-1RAs), pharmacological agents with superior pharmacokinetics versus native GLP-1, in treating conditions linked to dysregulated metabolism, persistent inflammation, and accelerated aging. Despite demonstrated efficacy in preclinical models and clinical studies, important challenges persist, including inter-individual variability, off-target risks, and uncertainties regarding long-term safety. We conclude by emphasizing the necessity of integrated strategies to target the metabolic-inflammatory-aging axis and by advocating optimization of GLP-1RA formulations, identification of predictive biomarkers, and expansion of their utility for age-associated diseases.

Abstract

The study aimed to assess sympathetic (SNS) and parasympathetic (PSNS) activity in individuals with obesity and different states of prediabetes and to assess their associations with markers of inflammation.A total of 104 participants (mean age 46.7±10.3 years; mean body mass index (BMI) 31.5±6.3 kg/m2) were categorized into three age- and BMI-matched groups based on glucose tolerance: 1) with normal glucose tolerance (n=20); 2) with high 1-h plasma glucose > 8.6 mmol/l (n=25) 3) with impaired glucose tolerance (n=59). All participants underwent an oral glucose tolerance test, and the area under the curves for glucose, insulin, and C-peptide were calculated. Creatinine (CKD-EPI calculation), lipids, glycated haemoglobin, and inflammatory markers (C-reactive protein (CRP), serum amyloid A, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, interleukin-6 (IL-6), IL-8, and tumor necrosis factor-α) levels were measured. Body composition was assessed by bioimpedance analysis. Tissue advanced glycation end-products (AGEs) were evaluated by AGE-Reader. Autonomic function was measured with the АNX-3.0 autonomic monitoring system.A progressive decline in resting and stimulated PSNS and SNS activity was observed with worsening glucose tolerance. Some of the inflammatory markers were numerically elevated in prediabetic stages. After adjustment for age, there was a reciprocal relationship between PSNS and SNS tone and CRP (r=-0.23 to-0.40, all p<0.025). An independent inverse relationship was found between PSNS tone and systolic blood pressure and CRP. However, after adjustment for BMI and/or body composition parameters, waist circumference was the only independent predictor of PSNS activity (p<0.0001), explaining 26% of its variation.This study demonstrates an inverse relationship between PSNS activity and both systolic blood pressure and CRP levels, though this association is largely mediated by visceral obesity.

Abstract

Background and objective Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), especially semaglutide, are commonly used to treat obesity and diabetes. They may influence sebaceous gland activity, hidradenitis suppurativa (HS), and acne via metabolic and anti-inflammatory pathways. This study aimed to assess the effects of semaglutide on acne severity, HS activity, and sebaceous gland function, and to evaluate associations with metabolic improvements. Materials and methods This prospective, observational, single-arm study was conducted at the Department of Dermatology, Hayatabad Medical Complex, Peshawar, from January 2023 to December 2024. Adults with acne, HS, or increased sebaceous gland activity who initiated semaglutide therapy between the ages of 18 and 65 years were included. Sebumetry, HS severity using the Hidradenitis Suppurativa Area and Severity Index - Revised (HASI-R), and acne grading using the Investigator's Global Assessment (IGA) were evaluated at baseline and at three, six, 12, 18, and 24 months. Concurrent measurements of metabolic markers, including BMI, HbA1c, fasting glucose, and insulin, were also obtained. Statistical analyses included Pearson and Spearman correlations, multivariate regression to adjust for confounders, and paired t-tests for pre- and post-treatment comparisons. P-values below 0.05 were considered statistically significant. Results Of the 120 enrolled participants, 110 completed the follow-up (91.7%). Over 24 months, acne severity decreased from 1.92 ± 0.78 to 1.21 ± 0.63, HS activity declined from 11.34 ± 4.56 to 7.45 ± 3.21, and sebaceous gland activity was reduced from 186.45 ± 52.34 to 138.56 ± 42.78 µg/cm². Improvements in BMI, HbA1c, fasting glucose, and insulin were significantly associated with dermatologic improvement (p < 0.05). Adverse events were mild and transient and occurred in 17 participants (15.45%). Conclusions Semaglutide therapy was significantly associated with improvement in acne, HS activity, and sebaceous gland function, independently correlated with metabolic enhancements. These findings indicate a potential dermatologic benefit of GLP-1 agonists, supporting the need for further controlled studies.

Abstract

Diabetes-associated cognitive dysfunction (DACD) is one of the common chronic complications of diabetes mellitus in the central nervous system. Given that current therapeutic agents are limited, exploring novel therapeutic agents is particularly important. The novel IDO-1 inhibitor 3-047 and icaritin (ICT) demonstrate efficacy in ameliorating neuroinflammation and cognitive dysfunction, and their combination exhibits certain hypoglycemic effects. However, the impact of this combination therapy on DACD remains unclear.

Abstract

Organophosphates have been used for decades as pesticides, insecticides and herbicides, both in agricultural and industrial settings. However, their toxic effects on multiple body systems limit their safety. The clinical presentation of organophosphate toxicity varies depending on the route and duration of exposure. Although most research is focused on their cholinergic toxicity, emerging evidence points to their crucial contribution to metabolic dysfunction, including Type 2 diabetes and neuroinflammation. Beyond acetylcholinesterase inhibition, recent research highlights the potential role of organophosphates in disrupting endocannabinoid signalling, particularly by affecting endogenous ligands that modulate G protein-coupled receptors. This dysregulation may contribute to organophosphate-induced metabolic disturbances and inflammation. This review aims to explore how chronic subtoxic exposure to organophosphates contributes to metabolic syndrome and neuroinflammation through disruption of insulin and endocannabinoid signalling. It highlights the role of the endocannabinoid system in mediating these effects and evaluates its potential as a therapeutic target in organophosphate-induced toxicity.

Abstract

The phenomenon where excessive activation of branched-chain amino acid (BCAA) degrading enzymes caused by high concentrations of leucine (Leu) leads to a decrease in the overall concentration of BCAA [including isoleucine (Ile) and valine (Val)] is called BCAA antagonism. Although this phenomenon has long been widely studied, the specific mechanism of its occurrence is still poorly understood. In this study, we investigated the specific mechanism by which Val and Ile alleviate the antagonistic effect caused by high concentrations of Leu through influencing insulin function. First, the ratios of Ile and Val in the low-protein diet were adjusted up and down by 15% to observe the metabolic status of broilers at the end of the experiment (the experiment period was from 0 to 42 d). Subsequently, the physiological and biochemical changes related to antagonism were determined using transcriptome and lipid metabolome analyses.

Abstract

Insulin is an important endocrine peptide hormone with pleiotropic effects on metabolic regulation and cellular growth. Insulin resistance (IR), characterized by insensitivity of metabolic tissues to insulin stimulation, has emerged as a major impediment to overall metabolic health. Triggered by multiple environmental factors and genetic predisposition, IR paves the way for several related diseases, including metabolic associated diseases, cardiovascular diseases and cancer. Of note, the liver plays a central role in whole-body metabolism and is the portal encountering high concentrations of insulin. Excess glucose, lipids and the compensatory hyperinsulinemia resulting from IR may collectively impose a huge burden on the liver, driving the progression of chronic liver diseases and fostering a pro-carcinogenic environment by increasing mutagenic susceptibility and angiogenic dysregulation. Better understanding of this mechanistic link is important to highlight the underestimated role of IR in progressive diseases and may contribute to stratified diagnosis and treatment. This review summarizes the risk factors and molecular mechanisms of IR, with a specific focus on its role in carcinogenesis, taking hepatocellular carcinoma (HCC) as an example. Finally, we discuss the effective lifestyle and pharmacological interventions for IR and emphasize the necessity of incorporating IR management into the prevention, stratified diagnosis and treatment of HCC.

Abstract

Youth with obesity are at risk for accumulating liver fat, even below the threshold for metabolic dysfunction-associated steatotic liver disease (MASLD), defined as ≥ 5% by MRI. While prior studies suggest that sub-threshold liver fat may carry metabolic risk, the role of fibroblast growth factor-21 (FGF21)-a liver-derived hormone responsive to metabolic stress-has not been well characterised in this context.

Abstract

Biomaterial-based skeletal muscle tissue engineering approaches have largely focused on mimicking the 3D aligned architecture of native muscle, which is critical for guiding myotube formation and force transmission. In contrast, fewer studies incorporate glycosaminoglycan (GAG)-mediated biochemical cues despite their known role in regulating myogenesis and growth factor sequestration. In this study, we develop aligned collagen-GAG (CG) scaffolds using directional freeze-drying and systematically vary GAG type by incorporating GAGs of increasing sulfation levels (hyaluronic acid, chondroitin sulfate, and heparin). While all scaffold variants support myoblast adhesion, metabolic activity, and myotube alignment, heparin-modified CG scaffolds significantly enhance myoblast metabolic activity and myogenic differentiation as measured by myosin heavy chain (MHC) expression and myotube size. We additionally show that heparin-modified scaffolds sequester and retain significantly higher levels of insulin-like growth factor-1 (IGF-1), a potent promoter of myogenesis, compared to other scaffold groups. Together, these results highlight the importance of tailoring GAG type in CG scaffolds for targeted applications and underscore the promise of heparin-modified CG scaffolds as a material platform for skeletal muscle tissue engineering.

Abstract

Development of a measurement scale to assess the safe disposal of insulin pen needles in patients with diabetes.

Abstract

Biologic therapies for diabetes have advanced significantly through molecular engineering strategies that optimize therapeutic stability, pharmacokinetics, and delivery. This review presents an integrated overview of design principles used to develop insulin, glucagon, amylin analogs, and GLP-1 receptor agonists, highlighting their unique physicochemical challenges and therapeutic requirements. Structural modifications-including amino acid substitutions, peptide stapling, glycosylation, and PEGylation-are discussed for their roles in enhancing stability, reducing aggregation, and extending half-life. Strategies for tuning pharmacokinetics are examined, ranging from sequence-driven solubility modulation to formulation-based depot formation and vascular binding mechanisms. Various administration routes, including oral, inhaled, and intranasal delivery, are evaluated for their potential to improve adherence and more closely mimic endogenous hormone profiles. The review also addresses the development of combination therapies and multi-receptor agonists designed to synergize complementary hormonal pathways. Finally, recent progress in glucose-responsive systems is reviewed, emphasizing molecular and materials-based approaches that enable real-time, glucose-triggered therapeutic activation. Taken together, the evolution of diabetes therapeutics exemplifies the application of core molecular design concepts in biologic drug development. The strategies outlined herein not only address the complex demands of glycemic control but also provide a broadly applicable framework for engineering next-generation protein-based therapies for applications beyond diabetes.

Abstract

Metabolic dysfunctions such as obesity and diabetes predispose the brain to heightened excitotoxic vulnerability, aggravating neuronal injury and cognitive decline. This study investigated the mechanistic role of lipocalin-2 (LCN2) in metabolic stress-amplified hippocampal damage following kainic acid (KA) exposure. Using high-fat diet (HFD)-fed diabetic wild type (WT) and LCN2 knockout (LCN2KO) mice, we found that LCN2 deficiency improved systemic insulin sensitivity and alleviated hepatic steatosis. In the diabetic hippocampus, LCN2 deletion markedly reduced KA-induced neuronal apoptosis, blood-brain barrier leakage, and iron-mediated oxidative stress. LCN2 ablation suppressed activation of microglia and astrocytes, downregulated galectin-3 and pro-inflammatory cytokines, and inhibited signal transducer and activator of transcription 3 (STAT3)-NF-κBp65-dependent signaling in KA-treated diabetic hippocampus. Reduced autophagy-related protein expression and protein aggregation in KA-treated diabetic LCN2KO mice indicated that LCN2 amplifies excitotoxic stress through autophagic and inflammatory mechanisms. These results identify LCN2 as a pivotal mediator linking metabolic dysfunction to neuroinflammation, ferroptosis, microglial activation, and autophagy in the diabetic hippocampus with excitotoxicity, suggesting that targeting the microglial LCN2-STAT3-NF-κBp65 axis may offer therapeutic potential for metabolic disease-associated acute brain injury.

Abstract

To demonstrate the relationship between adiponectin and insulin resistance among adolescents and young adults.

Abstract

Hyperglycemia is a hallmark of type-2 diabetes and a key pathogenic driver of diabetic complications. Cullin RING E3 ligases (CRLs) are multi-subunit E3 ubiquitin ligases that mediate cellular protein turnover. The activity of CRLs requires cullin neddylation, a post-translational modification that can be pharmacologically targeted with therapeutic potentials. By using hyperinsulinemic-euglycemic clamp analysis, we discover that pan neddylation inhibitor exerts both insulin sensitization effect in liver and muscle and insulinotropic effect in pancreatic β cells. This dual action is mediated by Cullin 3 (Cul3), a member of the 7 canonical cullin family proteins. DI-1859, a selective Cul3 neddylation inhibitor, effectively protects against hyperglycemia in obese mice. DI-1859 enhances insulin signaling by preventing Cul3-mediated insulin receptor substrate degradation in liver and muscle cells. DI-1859 increases insulin secretion in a glucagon-like peptide-1-independent manner in mice and directly potentiates glucose-stimulated insulin secretion in INS-1 832/13 β cells and human islets. Mechanistic studies reveal that DI-1859 does not promote glycolytic flux or bioenergetics function but potentiates glucose-stimulated insulin secretion via mechanisms involving RhoA activation and cytoskeleton remodeling in β cells. This study shows that a single agent targeting Cul3 neddylation simultaneously promotes insulin sensitization and insulin secretion to attenuate hyperglycemia in mice.

Abstract

The perception of taste is a complex physiological process that extends far beyond the simple detection of flavor molecules, serving as a critical interface between nutrient sensing, metabolic regulation, and feeding behavior. Emerging evidence reveals that this process is profoundly modulated by endocrine and neuromodulatory systems, creating a sophisticated gut-brain-taste axis that integrates peripheral gustatory signals with central homeostatic and hedonic mechanisms. Hormones such as glucagon-like peptide-1, leptin, ghrelin, and CCK not only regulate appetite and energy balance but also directly influence taste receptor expression and function in the tongue and gastrointestinal tract. Concurrently, neuromodulators like dopamine, serotonin, and norepinephrine fine-tune taste sensitivity at both peripheral (taste buds) and central (reward circuitry) levels, linking chemosensation to motivational states. These interactions are further complicated by metabolic conditions such as obesity and diabetes, where hormonal resistance (e.g., leptin, insulin) and neurotransmitter dysregulation contribute to altered taste preferences and compulsive eating behaviors.

Abstract

Metabolic dysfunction significantly influences cardiovascular outcomes following ST-elevation myocardial infarction (STEMI). The triglyceride-glucose (TyG) index and triglyceride-glucose-body mass index (TyG-BMI) serve as surrogate markers of insulin resistance, whereas B-type natriuretic peptide (BNP) levels reflect cardiac dysfunction. However, the combined prognostic value of these biomarkers for predicting major adverse cardiovascular events (MACEs) in patients with STEMI remains underexplored.

Abstract

Mechanisms responsible for skeletal muscle kidney crosstalk have not been defined. We have determined that a circulating mediator, signal regulatory protein α (SIRPα), impairs intracellular insulin-mediated functions. To elucidate the effect of myokine SIRPα on diabetic kidney disease (DKD), flox mice and muscle-specific (m-specific) SIRPα-KO mice were subjected to an obesity-induced model of diabetes, high-fat diet (HFD; 60%) or insulin-deficient hyperglycemia model, streptozotocin (STZ), and were subsequently exposed to anti-SIRPα monoclonal antibodies. In the obesity-induced diabetic mice, serum SIRPα increased. Genetic deletion of muscle SIRPα protected against obesity and improved intracellular insulin signaling in muscle and adipose tissue, with reduced intramuscular fat deposition when compared with flox mice on HFD. Moreover, mSIRPα-KO mice displayed enhanced kidney tubular fatty acid oxidation (FAO) expression with suppressed intraorgan triglycerides deposition, and importantly, protection against DKD. Conversely, exogenous SIRPα impaired kidney proximal tubular cell FAO, ATP production, and exacerbated fibrosis. Finally, suppressing SIRPα in skeletal muscles or treatment with anti-SIRPα monoclonal antibodies in STZ-treated mice mitigated cachexia, hyperlipidemia, kidney triglyceride deposition, and renal dysfunction in spite of significant hyperglycemia. Importantly, serum SIRPα was upregulated in patients with DKD. In conclusion, SIRPα serves as a potential biomarker and therapeutic target in DKD.

Abstract

Extracellular vesicles (EV) are emerging regulators of metabolic homeostasis through their bioactive cargo. This study first investigated the lipidomic profile and functional effects of plasma EV derived from adiponectin-knockout (KO) mice to identify EV-associated lipid signatures linked to metabolic dysfunction. Lipidomic profiling revealed that KO EV were enriched in sphingolipids and polyunsaturated phospholipids compared to wild-type (WT) EV. To evaluate functional consequences, recipient cell assays were conducted using macrophages, skeletal muscle cells, and pancreatic beta cells. KO EV showed an increased uptake in RAW 264.7 macrophages and induced elevated reactive oxygen species (ROS) and activation of NF-κB and IRF inflammatory pathways. In L6 skeletal muscle cells, WT EV increased ATP production, while KO EV failed to elicit this effect. Furthermore, KO EV impaired glucose-stimulated insulin secretion in INS-1 pancreatic beta cells. These findings suggested that altered lipid composition in EV from KO mice contributes to oxidative stress, inflammation, and impaired metabolic regulation in recipient cells. Next, translational relevance was established by documenting that plasma EV from patients with metabolic syndrome exhibited lipidomic remodeling features in parallel to the murine KO phenotype, in particular enriched PUFA-containing lipids. Together, these findings identify a conserved adiponectin-EV lipid composition axis regulating oxidative stress, inflammation, and impaired metabolic regulation. The new knowledge presented in this study has implications for biomarker discovery and therapeutic targeting in metabolic disease.

Abstract

Ovulation enables mature oocytes to exit the ovary for potential fertilization. In Drosophila, ovulation is induced by mating but also occurs spontaneously in virgins, with rates varying widely in natural populations: short oocyte retention is ancestral, while longer retention is favored in colder climates. The molecular regulation of spontaneous ovulation remains unclear. Here, we show that disrupting the relaxin/insulin-like peptide Dilp8 or its receptor Lgr3-an orthologue of vertebrate RXFP1/2-in follicle cells or specific neurons, respectively, delays ovulation, slows average egg transit time in the reproductive tract, and facilitates oogenesis progression beyond ∼2 mature oocytes per ovariole, leading to mature follicle accumulation in the ovary. Mating largely rescues these defects, suggesting the pathway is dispensable post-mating. Dilp8-Lgr3 signaling ensures high oocyte quality by promoting elimination of lower-quality aging oocytes and by antagonizing oogenesis progression via an undefined mechanism downstream of Lgr3+ neurons. Our findings provide a molecular basis for oocyte retention time regulation in Drosophila involving ovarian-nervous system cross-talk, and bring further support for an ancient, conserved role for relaxin-like signaling in regulating ovulation and overall female reproductive physiology.

Abstract

Diabetes management has continued to evolve with new treatments and technology. This article discusses the approach to evaluation and management of two distinctive subsets of patients: (1) patients who manage their diabetes with an insulin pump (artificial pancreas) and (2) patients who have received a pancreas transplant. The most current literature is reviewed and pearls and pitfalls distinctive to these two patient populations are discussed. Relevant diagnostics are reviewed with emphasis on recognition of complications faced in the emergency department management of these unique patient populations.

Abstract

This article reviews the most current literature on diabetic ketoacidosis, including how to make the diagnosis and management. It discusses euglycemic diabetic ketoacidosis and the risk factors for this rare but dangerous disease process. Pertinent pearls and pitfalls encountered by the emergency physician when managing these patients are included. Because these patients often stay in the emergency department for prolonged periods, recommendations on transitioning to subcutaneous insulin are included, along with dosing recommendations. Finally, the article reviews how to disposition patients with diabetic ketoacidosis and examines important factors that lead to a successful discharge home.

Abstract

To delineate organ-specific and systemic drivers of metabolic dysfunction-associated steatotic liver disease (MASLD), we applied integrative causal inference across clinical, imaging, and proteomic domains in individuals with and without type 2 diabetes (T2D).

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown both protective and adverse effects on ocular outcomes. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA, achieves greater glycemic and cardiometabolic improvements than non-GIP agonistic GLP-1RAs, yet its ocular safety profile remains poorly characterized.

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease defined by persistent hyperglycemia, primarily caused by insulin (INS) resistance and β-cell dysfunction. However, current pharmacological therapies are limited by adverse effects, highlighting the need for safe adjunctive strategies. Plant polysaccharides and their fermentation-derived degradation products exhibit multiple bioactivities and may be promising nutraceutical candidates. This study used degradation products of a water-soluble polysaccharide of finger citron from Guangdong Province (FCP-2-1) by gut micro biota fermentation (DFPG) as the research subject to investigate its hypoglycemic effects and underlying mechanisms in mice with T2DM. The findings indicated that degradation products of FCP-2-1 by gut micro biota fermentation after 8 h (DFPG-8) attenuated body weight loss, polydipsia, polyphagia, high fasting blood glucose, impaired oral glucose tolerance (OGT), and the elevated serum INS and glycated serum protein (GSP) in T2DM mice. In addition, DFPG-8 ameliorated lipid metabolism and attenuated pancreatic islet injury. Mechanistically, DFPG-8 activated colonic cyclic adenosine monophosphate (cAMP) /Protein Kinase A (PKA) and cAMP/Epac by cAMP signaling, up regulated cAMP response element-binding protein (CREB) and caudal type homeobox 2 (Cdx-2), enhanced glucagon gene (GCG) transcription, and promoted glucagon-like peptide-1 (GLP-1) synthesis. It also restored hypothalamic GLP-1 receptor (GLP-1R) expression, thereby modulating appetite and energy balance, reducing food intake, and increasing GLP-1 responsiveness, contributing to improved glycemic homeostasis. Collectively, these findings demonstrate that DFPG-8 may exert hypoglycemic effects by regulating the cAMP/PKA/Epac/GCG/GLP-1/GLP-1R signaling pathway, thereby improving glucose and lipid metabolism as well as appetite regulation, and support its potential development as a functional dietary supplement for the adjunctive management of T2DM.