RARE DISEASE
Myopathy and diabetes mellitus
Myopathy and diabetes mellitus
Myopathy and diabetes mellitus
Drug discovery
0
drugs
With orphan designations
Overview
Diabetic myopathy is a metabolic complication of diabetes mellitus (DM) characterized by skeletal muscle atrophy, weakness, mitochondrial dysfunction, and impaired glucose uptake. It arises from chronic hyperglycemia-induced oxidative stress, insulin resistance, and reduced mitochondrial biogenesis, leading to fiber-type shifts (glycolytic dominance), exercise intolerance, and functional decline. It affects both type 1 (T1DM) and type 2 (T2DM) diabetes, exacerbating comorbidities like neuropathy and nephropathy [1][4][15].
Therapies
Exercise: Combined aerobic (moderate intensity) and resistance training improves mitochondrial function, insulin sensitivity, and glycemic control [1][3].
Medical nutrition therapy: Low-carbohydrate or Mediterranean diets optimize metabolic health [5][14].
Mitochondrial-targeted interventions: Antioxidants (e.g., MitoQ) and SGLT2 inhibitors (cautiously) address oxidative stress [17][13].
Categories: rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
332 drug discovery papers about Myopathy and diabetes mellitus. Recent publications:
332 drug discovery papers about Myopathy and diabetes mellitus. Recent publications:
categories:
Small molecules
small molecules
2026-07-08 | The Central Role of the AMPK/SIRT1/PGC-1α Signaling Axis in Skeletal Muscle Physiology and Pathology and Its Targeted Therapeutic Strategies
Considered by some to be the largest metabolic organ of the body, the functional integrity of skeletal muscle is highly dependent on its exceptional plasticity, which is primarily governed by mitochondrial quality control. The signaling axis composed of AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) serves as a critical hub that senses cellular energy status, coordinates mitochondrial biogenesis, regulates muscle fiber type switching, and maintains protein homeostasis. This review systematically delineates the structural functions and synergistic regulatory network of the AMPK/SIRT1/PGC-1α signaling axis. It further elucidates the regulatory roles of this pathway under physiological conditions—such as exercise adaptation and muscle fiber-type transformation—and its dysregulated mechanisms in the pathogenesis of various skeletal muscle disorders, including sarcopenia, disuse atrophy, cachexia, neurogenic atrophy, muscular dystrophy, and type 2 diabetes mellitus-related myopathy. Building on this foundation, this review critically analyzes current multifaceted therapeutic strategies targeting this pathway, encompassing exercise and physical therapy, nutritional and natural products, and small molecule drugs, as well as gene and cell-based therapies. Finally, this review delves into the challenges facing clinical translation in this field, such as the complexity of the signaling network, individual variability, and bioavailability issues. It also proposes future research directions focused on developing precision intervention tools, establishing effective biomarker systems, and exploring combination intervention strategies. Collectively, the AMPK/SIRT1/PGC-1α signaling axis is central to maintaining skeletal muscle metabolic homeostasis, and targeting this pathway provides a robust theoretical foundation and broad application prospects for the prevention and treatment of skeletal muscle-related diseases.
2026-07-01 | Metabolomics and cardiovascular risk factors in autoimmune-mediated connective tissue diseases – an exploratory, hypothesis-generating study
Abstract Background Autoimmune connective tissue diseases (ACTD), including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren’s disease (SD), and idiopathic inflammatory myopathies (IIM), are associated with markedly increased cardiovascular risk (CVR) that is insufficiently captured by conventional risk scores. Reliable biomarkers for CVR stratification in ACTD are lacking. This exploratory, hypothesis-generatig study aimed to investigate whether metabolomic alterations reflect CVR across ACTD subtypes. Methods In this cross-sectional, exploratory study, patients with SLE (n = 33), SSc (n = 18), SD (n = 16), and IIM (n = 9) were recruited from a tertiary rheumatology center. Serum metabolomic profiling was performed using ¹H-NMR spectroscopy. Associations between 113 quantified metabolites and clinical CVR parameters (including age, sex, body mass index, glucocorticoid use, Framingham score, hypertension, diabetes, lipid parameters, and lifestyle factors) were analyzed using non-parametric statistics with false discovery rate correction. Correlation analyses were conducted using Spearman coefficients. Results Metabolomic alterations varied substantially across ACTD subtypes and CVR factors. Lipid metabolites showed the strongest and most consistent associations with CVR parameters. The Framingham score correlated with 11 metabolites in SLE, 1 in SSc, 2 in SD, and 93 in IIM, predominantly involving lipid components. Diabetes mellitus was associated with extensive metabolomic changes, particularly in SSc (n = 62 metabolites), followed by SD (n = 20) and SLE (n = 5). In contrast, arterial hypertension showed minimal metabolomic differentiation across most ACTD, except in IIM. Body mass index correlated mainly with lipid metabolites in SSc, but not in SLE. Glucocorticoid therapy and dosage were strongly associated with alterations in lipid metabolism, especially in SLE and SSc. Across all entities, correlations with total cholesterol, LDL, and HDL were dominated by lipid metabolites. Associations with renal markers (UACR) were limited. Conclusions ACTD are characterized by heterogeneous metabolomic signatures associated with cardiovascular risk factors. Larger, longitudinal studies are required to validate these findings and to determine their clinical utility in cardiovascular risk stratification in ACTD.
2026-06-01 | Therapeutic Effects of Lycopene and Aerobic Exercise in Skeletal Muscles Myopathy in Type 2 Diabetic Rat Model
Abstract Type 2 diabetes mellitus (T2DM) causes metabolic disturbances and skeletal muscle pathology. Aerobic training (AT) improves insulin sensitivity, while lycopene (LYC) has antidiabetic and anti-inflammatory properties. This study evaluated the individual and combined therapeutic effects of AT and LYC on skeletal muscle alterations in a T2DM rat model. Forty-eight adult male Albino rats were divided into six groups (n = 8): negative control, LYC control, T2DM, T2DM-AT, T2DM-LYC, and T2DM-AT-LYC. T2DM was induced using a high-fat/high-fructose diet followed by Streptozotocin injection. Interventions were applied for 8 weeks. Body weight, food intake, gastrocnemius muscle (GCM) weight, fasting blood glucose, fasting insulin, lipid profile, C-reactive protein (CRP), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) were assessed. Muscle histology, collagen deposition, and expression of LC3A-II (autophagy marker) and apoptosis-inducing factor (AIF) were evaluated. T2DM induced hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, inflammation, elevated muscle enzymes, and reduced GCM mass. Histologically, diabetic muscles showed fiber distortion and increased collagen deposition, with elevated autophagy and apoptosis markers. AT and/or LYC significantly improved metabolic parameters, reduced inflammation and muscle enzyme levels, preserved muscle mass, and improved muscle architecture. LYC mainly improved metabolic, inflammatory, and enzymatic disturbances, whereas AT more effectively suppressed autophagy and apoptosis. Combined AT-LYC treatment produced additive and superior benefits across all outcomes. In conclusion, Aerobic training and lycopene, individually and synergistically, protect against T2DM-induced skeletal muscle pathology by improving metabolic control, reducing inflammation, and attenuating autophagy and apoptosis, supporting combined lifestyle and nutraceutical interventions in diabetes management.
2026-05-28 | Real-World Safety and Efficacy of a Pitavastatin-Ezetimibe Combination Therapy in Taiwanese Patients after PCI.
Patients undergoing percutaneous coronary intervention (PCI) have a higher risk of recurrence. While lipid and glucose control can improve the prognosis, concerns remain about side effects such as myopathy, liver dysfunction, and potential new-onset diabetes mellitus. This study aimed to evaluate the real-world safety and efficacy of dual lipid-lowering therapy with pitavastatin 4 mg/day (P4) and ezetimibe 10 mg/day (E10), hereafter referred to as P4/E10 in post-PCI patients in Taiwan. The retrospective cohort study enrolled patients who underwent PCI between 2008 and 2021 at two institutes in Taiwan and received P4/E10 combination therapy for longer than a year. The primary endpoint was the overall adverse event rate associated with P4/E10. Efficacy evaluations included changes from baseline in lipid profile and glycemic markers. A total of 120 patients were enrolled. No adverse events were recorded during the study period. After 12 months of therapy, the average low-density lipoprotein cholesterol level decreased by 32.54% from baseline, and there were decreases in glycated hemoglobin and triglyceride glucose index (-0.40% and -0.23, respectively) in diabetic patients. In this real-world study of Taiwanese patients, P4/E10 combination therapy was safe and effective in both lipid and glycemic index control. Nevertheless, further large-scale studies are warranted to validate our findings.
2026-04-26 | Mitochondrial dysfunction-driven inflammation and β-Cell apoptosis in type 2 diabetes mellitus: mechanistic insights and therapeutic implications.
Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic syndrome characterized by chronic hyperglycemia, progressive pancreatic β-cell malfunction, and peripheral insulin resistance. There is growing evidence suggesting that mitochondrial dysfunction and apoptosis play a critical role in the development and advancement of T2DM. Mitochondria are essential for cellular energy metabolism and redox homeostasis. It is the metabolic stress and apoptotic cell death in insulin-producing β-cells and insulin-sensitive tissues induced by mitochondrial dysfunction caused by excessive reactive oxygen species (ROS) production, imbalanced mitochondrial dynamics, impaired mitophagy, mitochondrial fission-fusion imbalance, and defective biogenesis. This review summarizes the molecular pathways by which mitochondrial dysfunction triggers inflammatory responses, such as activation of NLRP3 inflammasomes, cytokine release, and mitochondria-mediated intrinsic apoptotic signaling. We describe the role of these pathways in insulin resistance and in the emergence of diabetic complications like neuropathy, nephropathy, myopathy, and hepatopathy. New treatment approaches aimed at mitochondrial integrity and apoptotic signaling are promising. These are AMPK/PGC-1α pathway activators, mitochondria-targeted antioxidants (MitoQ, SS-31), and mitophagy and ferroptosis modulators. But poor tissue specificity, poor bioavailability, and patient-to-patient variability are limitations in clinical translation. Lastly, the review highlights the possibilities of personalized medicine strategies that incorporate the use of mitochondrial profiling to maximize therapeutic outcomes. Collectively, available evidence suggests that therapeutic strategies restoring mitochondrial quality control in β-cells may offer greater disease-modifying potential than glucose-centric interventions alone.
proteins
2025-07-03 | Incretin-based therapy: An update focusing on the major revolution in cardiovascular-kidney-metabolic health.
Type 2 diabetes mellitus and obesity have become the rising burden across various geographic and economic regions, and they are also the common causes of chronic kidney disease, which further contributes to the development and progression of cardiovascular disease. The recently proposed cardiovascular-kidney-metabolic syndrome-the new paradigm of recognizing excess or dysfunctional adipose tissue as the shared pathophysiology-has signaled the interconnection of type 2 diabetes mellitus, obesity, chronic kidney disease, and cardiovascular disease beyond the disturbance of glucose homeostasis, for which recently developed incretin-based therapy has offered an avenue of holistic management. Glucagon-like peptide-1 (GLP1) is one of the incretins and potentiates insulin secretion after food intake, additionally offering extra-pancreatic metabolic effects-reduced hepatic gluconeogenesis and steatosis, increased muscular glucose uptake, and increased lipolysis and glucose uptake in the adipose tissue. Seven different GLP1 receptor agonists have been licensed globally. For those with type 2 diabetes mellitus, GLP1 receptor agonists overall reduce major adverse cardiovascular events by 14% (hazard ratio 0.86, 95% confidence interval 0.80-0.93) and all-cause death by 18% (hazard ratio 0.82, 95% confidence interval 0.82-0.94), and semaglutide, a long-acting GLP1 receptor agonist for once weekly injection, reduces major renal events by 24% (hazard ratio 0.76, 95% confidence interval 0.66-0.88). For obese patients without diabetes mellitus, semaglutide results in a 12.4% (95% confidence interval -13.4 to -11.5) reduction in body weight and 20% lower in the risk of major adverse cardiovascular events (hazard ratio 0.80, 95% confidence interval 0.72-0.90), while the burden of heart failure can also be improved by 7.8 points (95% confidence interval 4.8-10.9) in those with heart failure with preserved ejection fraction and obesity. These findings highlight the transformative role of GLP1 receptor agonists in the management of cardiovascular-kidney-metabolic syndrome. We reviewed the updated clinical evidence of incretin-based therapy and summarized its outcome benefits.
2024-07-11 | Diabetes with GLP-1R polymorphism (rs3765467) accompanied by myotonic dystrophy: A case of myotonic dystrophy with p.R131Q polymorphism at the glucagon-like peptide-1 receptor (rs3765467) resulting in marked effects of its agonist, dulaglutide.
A 47-year-old woman was diagnosed with myotonic dystrophy when admitted for traumatic subarachnoid hemorrhage. Her glycemic control was poor despite administration of pioglitazone, a PPARɤ agonist, and subcutaneous insulin infusion. However, adding a GLP-1 receptor (GLP-1R) agonist markedly improved blood glucose levels, resulting in eventual insulin withdrawal. Genetic testing revealed a heterozygous variant, p.R131Q, in the GLP1R (rs3765467), a common variant in Asia. This variant is known to be associated with increased endogenous insulin from beta cells in response to exogenous GLP-1 infusion. This is the first report and short review of a Japanese case of myotonic dystrophy accompanied by GLP-1R gene polymorphism.
2024-06-27 | Current research trends on the effect of diabetes mellitus on rotator cuff tendon healing/tendinopathy.
Rotator cuff tendon tears are a leading cause of shoulder pain. They are challenging to treat, and tendon-bone healing has a high failure rate despite successful surgery. Tendons connect the muscles and bones, which make them important for the body's overall mobility and stability. Metabolic diseases, including diabetes or high blood pressure, can affect the healing process after repair of a damaged tendon. With a global incidence of 9.3%, diabetes is considered as a significant risk factor for rotator cuff tendon healing because it causes structural, inflammatory, and vascular changes in the tendon. However, the mechanisms of how diabetes affects tendon healing remain unknown. Several factors have been suggested, including glycation product accumulation, adipokine dysregulation, increased levels of reactive oxygen species, apoptosis, inflammatory cytokines, imbalanced matrix-metalloproteinase-to-tissue-inhibitor ratio, and impaired angiogenesis and differentiation of the tendon sheath. Despite the effects of diabetes on tendon function and healing, few treatments are available to improve recovery in these patients. This review summarizes the current literature on the pathophysiological changes of the tendon in diabetes and hyperlipidemia. Preclinical and clinical evidence regarding the association between diabetes and tendon healing is presented. Moreover, current approaches to improve tendon healing in patients with diabetes are reviewed.
2024-04-27 | Targeting Molecular Mechanisms of Obesity- and Type 2 Diabetes Mellitus-Induced Skeletal Muscle Atrophy with Nerve Growth Factor.
Skeletal muscle plays a critical role in metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM). Muscle atrophy, characterized by a decrease in muscle mass and function, occurs due to an imbalance between the rates of muscle protein synthesis and degradation. This study aimed to investigate the molecular mechanisms that lead to muscle atrophy in obese and T2DM mouse models. Additionally, the effect of nerve growth factor (NGF) on the protein synthesis and degradation pathways was examined. Male mice were divided into three groups: a control group that was fed a standard chow diet, and two experimental groups that were fed a Western diet. After 8 weeks, the diabetic group was injected with streptozotocin to induce T2DM. Each group was then further divided into NGF-treated or non-treated control group. In the gastrocnemius muscles of the Western diet group, increased expressions of myostatin, autophagy markers, and ubiquitin ligases were observed. Skeletal muscle tissue morphology indicated signs of muscle atrophy in both obese and diabetic mice. The NGF-treated group showed a prominent decrease in the protein levels of myostatin and autophagy markers. Furthermore, the NGF-treated group showed an increased Cyclin D1 level. Western diet-induced obesity and T2DM may be linked to muscle atrophy through upregulation of myostatin and subsequent increase in the ubiquitin and autophagy systems. Moreover, NGF treatment may improve muscle protein synthesis and cell cycling.
2023-12-25 | Beyond the Cardiovascular Effects of Glucagon-like Peptide-1 Receptor Agonists: Body Slimming and Plaque Stabilization. Are New Statins Born?
Atherosclerosis is a chronic inflammatory disease characterized by lipid and inflammatory cell deposits in the inner layer of large- and medium-sized elastic and muscular arteries. Diabetes mellitus (DM) significantly increases the risk of cardiovascular diseases and the overall and cardiovascular mortality, and it is a pro-atherogenic factor that induces atherosclerosis development and/or accelerates its progression through a multifactorial process. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a new class of drugs, belonging to the armamentarium to fight type 2 DM, that have shown robust reductions in atherosclerotic events and all-cause mortality in all studies. Preclinical studies have shown that GLP-1RAs play a role in the immunomodulation of atherosclerosis, affecting multiple pathways involved in plaque development and progression. In this review, we wanted to explore the translational power of such preclinical studies by analyzing the most recent clinical trials investigating the atheroprotective effect of GLP-1RAs.
gene therapies
2024-07-18 | Systemic Deletion of ARRDC4 Improves Cardiac Reserve and Exercise Capacity in Diabetes.
Exercise intolerance is an independent predictor of poor prognosis in diabetes. The underlying mechanism of the association between hyperglycemia and exercise intolerance remains undefined. We recently demonstrated that the interaction between ARRDC4 (arrestin domain-containing protein 4) and GLUT1 (glucose transporter 1) regulates cardiac metabolism. To determine whether this mechanism broadly impacts diabetic complications, we investigated the role of ARRDC4 in the pathogenesis of diabetic cardiac/skeletal myopathy using cellular and animal models. High glucose promoted translocation of MondoA into the nucleus, which upregulated Arrdc4 transcriptional expression, increased lysosomal GLUT1 trafficking, and blocked glucose transport in cardiomyocytes, forming a feedback mechanism. This role of ARRDC4 was confirmed in human muscular cells from type 2 diabetic patients. Prolonged hyperglycemia upregulated myocardial Arrdc4 expression in multiple types of mouse models of diabetes. We analyzed hyperglycemia-induced cardiac and skeletal muscle abnormalities in insulin-deficient mice. Hyperglycemia increased advanced glycation end-products and elicited oxidative and endoplasmic reticulum stress leading to apoptosis in the heart and peripheral muscle. Deletion of Arrdc4 augmented tissue glucose transport and mitochondrial respiration, protecting the heart and muscle from tissue damage. Stress hemodynamic analysis and treadmill exhaustion test uncovered that Arrdc4-knockout mice had greater cardiac inotropic/chronotropic reserve with higher exercise endurance than wild-type animals under diabetes. While multiple organs were involved in the mechanism, cardiac-specific overexpression using an adenoassociated virus suggests that high levels of myocardial ARRDC4 have the potential to contribute to exercise intolerance by interfering with cardiac metabolism through its interaction with GLUT1 in diabetes. Importantly, the ARRDC4 mutation mouse line exhibited greater exercise tolerance, showing the potential therapeutic impact on diabetic cardiomyopathy by disrupting the interaction between ARRDC4 and GLUT1. ARRDC4 regulates hyperglycemia-induced toxicities toward cardiac and skeletal muscle, revealing a new molecular framework that connects hyperglycemia to cardiac/skeletal myopathy to exercise intolerance.
2022-10-11 | 11β-HSD1 contributes to age-related metabolic decline in male mice.
The aged phenotype shares several metabolic similarities with that of circulatory glucocorticoid excess (Cushing's syndrome), including type 2 diabetes, obesity, hypertension, and myopathy. We hypothesise that local tissue generation of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts 11-dehydrocorticosterone to active corticosterone in rodents (corticosterone to cortisol in man), plays a role in driving age-related chronic disease. In this study, we have examined the impact of ageing on glucocorticoid metabolism, insulin tolerance, adiposity, muscle strength, and blood pressure in both wildtype (WT) and transgenic male mice with a global deletion of 11β-HSD1 (11β-HSD1-/-) following 4 months high-fat feeding. We found that high fat-fed 11β-HSD1-/- mice were protected from age-related glucose intolerance and hyperinsulinemia when compared to age/diet-matched WTs. By contrast, aged 11β-HSD1-/- mice were not protected from the onset of sarcopenia observed in the aged WTs. Young 11β-HSD1-/- mice were partially protected from diet-induced obesity; however, this partial protection was lost with age. Despite greater overall obesity, the aged 11β-HSD1-/- animals stored fat in more metabolically safer adipose depots as compared to the aged WTs. Serum analysis revealed both WT and 11β-HSD1-/- mice had an age-related increase in morning corticosterone. Surprisingly, 11β-HSD1 oxo-reductase activity in the liver and skeletal muscle was unchanged with age in WT mice and decreased in gonadal adipose tissue. These data suggest that deletion of 11β-HSD1 in high fat-fed, but not chow-fed, male mice protects from age-related insulin resistance and supports a metabolically favourable fat distribution.
2022-03-31 | Sirtuin 3 overexpression preserves maximal sarco(endo)plasmic reticulum calcium ATPase activity in the skeletal muscle of mice subjected to high fat - high sucrose feeding.
Sarco(endo)plasmic reticulum calcium (Ca2+) ATPase (SERCA) transports Ca2+ in muscle. Impaired SERCA activity may contribute to diabetic myopathy. Sirtuin (SIRT) 3 regulates muscle metabolism and function; however, it is unknown if SIRT3 regulates muscle SERCA activity or acetylation. We determined if SIRT3 overexpression enhances SERCA activity in mouse gastrocnemius muscle and if SIRT3 overexpression preserves gastrocnemius SERCA activity in a model of type 2 diabetes, induced by high fat - high sucrose (HFHS) feeding. We also determined if the acetylation status of SERCA proteins in mouse gastrocnemius is altered by SIRT3 overexpression or HFHS feeding. Wild-type (WT) and SIRT3 transgenic (SIRT3TG) mice, overexpressing SIRT3 in skeletal muscle, were fed a standard or HFHS diet for 4 months. SIRT3TG and WT mice developed obesity and glucose intolerance after 4 months of HFHS feeding. SERCA Vmax was higher in gastrocnemius of SIRT3TG mice compared with WT mice. HFHS-fed mice had lower SERCA1a protein levels and lower SERCA Vmax in their gastrocnemius than control-fed mice. The decrease in SERCA Vmax in gastrocnemius muscle due to HFHS feeding was attenuated by SIRT3 overexpression in HFHS-fed SIRT3TG mice. SERCA1a and SERCA2a acetylation in mouse gastrocnemius was not altered by genotype or diet. These findings suggest SIRT3 overexpression improves SERCA function in mouse skeletal muscle.
2019-11-06 | A fully human transgene switch to regulate therapeutic protein production by cooling sensation.
The ability to safely control transgene expression with simple synthetic gene switches is critical for effective gene- and cell-based therapies. In the present study, the signaling pathway controlled by human transient receptor potential (TRP) melastatin 8 (hTRPM8), a TRP channel family member1, is harnessed to control transgene expression. Human TRPM8 signaling is stimulated by menthol, an innocuous, natural, cooling compound, or by exposure to a cool environment (15-18 °C). By functionally linking hTRPM8-induced signaling to a synthetic promoter containing elements that bind nuclear factor of activated T cells, a synthetic gene circuit was designed that can be adjusted by exposure to either a cool environment or menthol. It was shown that this gene switch is functional in various cell types and human primary cells, as well as in mice implanted with engineered cells. In response to transdermal delivery of menthol, microencapsulated cell implants harboring this gene circuit, coupled to expression of either of two therapeutic proteins, insulin or a modified, activin type IIB, receptor ligand trap protein (mActRIIBECD-hFc), could alleviate hyperglycemia in alloxan-treated mice (a model of type 1 diabetes) or reverse muscle atrophy in dexamethasone-treated mice (a model of muscle wasting), respectively. This fully human-derived orthogonal transgene switch should be amenable to a wide range of clinical applications.
2018-11-05 | Generation and Phenotype Identification of PAX4 Gene Knockout Rabbit by CRISPR/Cas9 System.
Paired-homeodomain transcription factor 4 (PAX4) gene encodes a transcription factor which plays an important role in the generation, differentiation, development, and survival of insulin-producing β-cells during mammalian pancreas development. PAX4 is a key diabetes mellitus (DM) susceptibility gene, which is associated with many different types of DM, including T1DM, T2DM, maturity onset diabetes of the young 9 (MODY9) and ketosis prone diabetes. In this study, a novel PAX4 gene knockout (KO) model was generated through co-injection of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) mRNA/sgRNA into rabbit zygotes. Typical phenotypes of growth retardation, persistent hyperglycemia, decreased number of insulin-producing β cells and increased number of glucagon-producing α cells were observed in the homozygous PAX4 KO rabbits. Furthermore, DM associated phenotypes including diabetic nephropathy, hepatopathy, myopathy and cardiomyopathy were also observed in the homozygous PAX4 KO rabbits but not in the wild type (WT) controls and the heterozygous PAX4 KO rabbits. In summary, this is the first PAX4 gene KO rabbit model generated by CRISPR/Cas9 system. This novel rabbit model may provide a new platform for function study of PAX4 gene in rabbit and gene therapy of human DM in clinical trails.
antibodies
2026-06-17 | Successful corticosteroid-free management of anti-HMG-CoA reductase immune-mediated necrotizing myopathy with subcutaneous immunoglobulins monotherapy: a case report.
Given the high rate of cardiovascular comorbidities in anti-HMG-CoA reductase (HMGCR)-immune-mediated necrotizing myopathy (IMNM), a glucocorticosteroids (GC)-free treatment approach remains an appealing strategy. While intravenous immunoglobulins (IVIg) represents an effective therapy in most subgroups of idiopathic inflammatory myositis (IIM), there remains limited evidence supporting the use subcutaneous immunoglobulins (SCIg), a potentially safer, more convenient and cost-effective alternative. We present a case of a 68-year-old male of European descent with a 2-year history of progressive proximal bilateral lower extremity weakness. He had been treated for his dyslipidemia with atorvastatin for 2 years, then with rosuvastatin for 2 additional years until discontinued a year before our assessment. His other comorbidities included hypertension and diabetes mellitus type II. Physical examination demonstrated proximal weakness of his bilateral hip flexors and deltoids, and no rash. His creatine kinase (CK) was elevated at 1644 IU/L. Electromyography revealed a generalized myopathic disorder with proximal predominance and muscle biopsy of the right quadriceps showed typical findings of an IMNM. Serum HMG-CoA reductase antibody was positive. Due to accumulating evidence supporting the effectiveness of IVIg in anti-HMGCR-IMNM, even without concomitant GC or other immunosuppressive agent, we opted for a GC-free approach through shared-decision making in light of patient's preference regarding potential GC side effects with his comorbidities. As he lived a considerable distance from any center, where IVIg infusions could be offered, and given the patient was unable to drive himself due to his symptoms we opted for SCIg (0.5 g/kg/week). Within 1 month, his CK decreased and weakness resolved. SCIg monotherapy was tapered over 3 years and this patient remains in remission 7 years after SCIg initiation. The patient did not have any adverse effects related to SCIg use. To our knowledge, this is the first case report describing a successful corticosteroid-free management of anti-HMGCR immune-mediated necrotizing myopathy using SCIg as monotherapy. This case highlights the potential for steroids-free induction and maintenance strategies in IMNM. Larger studies are required to confirm the effectiveness and safety of SCIg in IMNM and other subtypes of IIM, and to provide guidelines for dosing recommendations.
2025-03-28 | Beyond Bone Remodeling: Denosumab's Multisystemic Benefits in Musculoskeletal Health, Metabolism, and Age-Related Diseases-A Narrative Review.
Background: Denosumab, a receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitor, demonstrates therapeutic effects beyond traditional osteoporosis management through the RANK/RANKL/osteoprotegerin pathway. Methods: This narrative review analyzed 37 studies (2018-2024) examining denosumab's broader physiological effects and clinical applications. Results: Long-term safety data spanning 10 years showed sustained fracture prevention efficacy with a favorable benefit/risk profile. Compared to bisphosphonates, denosumab demonstrated superior outcomes in bone mineral density improvement and fracture risk reduction, particularly in elderly and frail populations. It enhanced muscular function by improving appendicular lean mass and grip strength while reducing fall risk. The drug showed potential cardiovascular benefits through its effects on cardiac and smooth muscle function. Notably, denosumab use was associated with reduced Type II diabetes mellitus risk through improved glucose metabolism. Additionally, it demonstrated promise in osteoarthritis treatment by suppressing osteoclast activity and chondrocyte apoptosis. While there are multisystem benefits, vigilance is required regarding adverse events, including hypocalcemia, infection risk, cutaneous reactions, and osteonecrosis of the jaw. Conclusions: Denosumab exhibits potential benefits in bone and systemic metabolism. Further research is needed to fully understand its therapeutic potential beyond osteoporosis and optimize clinical applications across different populations.
2025-01-20 | ICAM1 blockade improves ischemic muscle reperfusion in diabetic mice.
Chronic Limb-Threatening Ischemia (CLTI) represents the most advanced stage of Peripheral Artery Disease (PAD) and is associated with dire prognosis, characterized by a substantial risk of limb amputation and diminished life expectancy. Despite significant advancements in therapeutic interventions, the underlying mechanisms precipitating the progression of PAD to CLTI remain elusive. Considering diabetes is one of the main risk factors contributing to PAD exacerbation into CLTI, we compared hind limb ischemia recovery in HFD STZ vs. non-HFD STZ mice to identify new mechanisms responsible for the exacerbation of PAD. We used three different mouse models of diabetes and found that blood flow recovery in HFD STZ mice is altered only from day 14 post-surgery. Consistent with this kinetics, we found that angiogenesis and myogenesis which typically occur between day five and day 14 post-surgery are not impaired in mice in which diabetes was induced by a high fat diet and streptozotocin injections (HFD STZ mice). On the contrary, we found that capillary functionality e.i. acquisition of functional intercellular junctions and immune quiescence is impaired in HFD + STZ mice. Notably, 28 days after hind limb ischemia surgery, HFD + STZ mice display significantly increased capillary permeability to IgG and significantly increased levels of ICAM1. This was associated with an increased macrophage infiltration and an impaired myocyte differentiation. Importantly, we used ICAM1-blocking antibodies to demonstrate that increased ICAM1 expression in HFD + STZ mice decreases white blood cell circulation velocity within the microcirculation, which impairs its perfusion. Notably anti-ICAM1 therapy did diminish macrophage infiltration and oxidative stress but not myopathy suggesting that myopathy characterized by small myocytes expressing higher level of MYH2 could be responsible for microangiopathy. ICAM1 expression by the microvasculature impairs ischemic muscle reperfusion in HFD + STZ mice. Importantly, the increase in blood flow between day 14 and day 90 post-HLI surgery is not associated with an increased capillary density but with an improved functionality of capillaries.
2023-08-03 | Neural gut-to-brain communication for postprandial control of satiation and glucose metabolism.
The brain is tuned to integrate food-derived signals from the gut, allowing it to accurately adjust behavioral and physiological responses in accordance with nutrient availability. A key element of gut-to-brain communication is the relay of neural cues via peripheral sensory neurons (PSN) which harbor functionally specialized peripheral endings innervating the muscular and mucosal layers of gastrointestinal (GI) tract organs. In this review, we detail the properties of GI tract innervating PSN and describe their roles in regulating satiation and glucose metabolism in response to food consumption. We discuss the complex anatomical organization of vagal and spinal PSN subtypes, their peripheral and central projection patterns, and describe the limitations of unselective lesion and ablation approaches to investigate them. We then highlight the recent identification of molecular markers that allow selective targeting of PSN subtypes that innervate GI tract organs. This has facilitated accurately determining their projections, monitoring their responses to gut stimuli, and manipulating their activity. We contend that these recent developments have significantly improved our understanding of PSN-mediated gut-to-brain communication, which may open new therapeutic windows for the treatment of metabolic disorders, such as obesity and type 2 diabetes.
2022-01-26 | A new therapeutic approach with tocilizumab in a 39-year-old patient with recurrent diabetic myonecrosis.
We report the case of a 39-year-old female patient with acute painful swelling of the left thigh and symmetric muscle weakness in both upper legs. The patient had a history of long-standing, poorly controlled type 1 diabetes which required dialysis. Serum inflammatory markers were highly elevated. Magnetic resonance imaging (MRI) indicated necrotic or inflammatory colliquation. As antibiotic therapy did not lead to clinical improvement, a successful anti-inflammatory therapy with prednisolone was initiated. Three months later, the patient presented with a new onset of progressive and painful muscle swelling of the right thigh. MRI showed pronounced swelling of the right adductor muscles and inflammatory markers were massively elevated. In the absence of autoantibodies or any infectious agents and the recurrent symptomatology, relapsing diabetogenic myonecrosis was diagnosed. Initially, clinical improvement could only be achieved with high-dose glucocorticosteroids. Intravenous immunoglobulins did not show an effect, whereas serological and clinical remission was achieved after we administered tocilizumab intravenously. Diabetic myonecrosis is a rare complication of long-term, poorly controlled diabetes mellitus. Acute muscle pain and elevated inflammatory markers should prompt suspicion. Contralateral muscle involvement is also suggestive of the disease. The optimisation of diabetes treatment is crucial in order to prevent further disease complications.
other
2025-11-28 | Anemarrhena asphodeloides-derived small extracellular vesicle ameliorate diabetes-induced muscle atrophy via activating Pink1-mediated mitophagy.
Diabetes-induced muscle atrophy, characterized by progressive loss of skeletal muscle mass and function, poses a major challenge in diabetes management. To address this, we developed a phyto-exosomal formulation derived from Anemarrhena asphodeloides small extracellular vesicle (AA-sEV) and evaluated its therapeutic potential against diabetic muscle atrophy. AA-sEV were isolated by ultracentrifugation and characterized for exosomal morphology. The therapeutic efficacy of AA-sEV was assessed through in vivo studies in diabetic db/db mice and in vitro assays using C2C12 myoblasts exposed to high glucose conditions. Fluorescently labeled AA-sEV efficiently accumulated in skeletal muscle tissue and myoblasts. Oral administration of AA-sEV enhanced muscle performance, as indicated by increased grip strength and hanging endurance, restoration of myofiber cross-sectional area, and upregulation of FNDC5 expression. Transcriptomic analysis revealed that mitophagy served as the central mechanism mediating AA-sEV's therapeutic effects. Specifically, AA-sEV activated the Pink1/Parkin-dependent mitophagy pathway, reducing mitochondrial reactive oxygen species accumulation. This restoration of mitochondrial quality control promoted the MyoG/MyoD1-driven anabolic program while suppressing the MuRF1/MAFbx-mediated catabolic response. Treatment with the mitophagy inhibitor 3-methyladenine abolished the anabolic and catabolic regulatory effects of AA-sEV under hyperglycemic conditions. Our findings demonstrate that AA-sEV mitigate diabetes-induced muscle atrophy by restoring protein anabolic-catabolic balance via Pink1-mediated mitophagy. These results highlight a novel extracellular vesicle-based therapeutic strategy for managing diabetic myopathy and related complications.
2025-02-26 | New Insights on the miRNA Role in Diabetic Tendinopathy: Adipose-Derived Mesenchymal Stem Cell Conditioned Medium as a Potential Innovative Epigenetic-Based Therapy for Tendon Healing.
Adipose-derived mesenchymal stem cell conditioned medium (ASC-CM) improved the viability and wound closure of human tenocytes (HTCN) exposed to high glucose (HG) by activating the transforming growth factor beta 1 (TGF-β1) pathway. Since ASC-CM can also modulate microRNAs (miRNAs) in recipient cells, this study investigated the effects of ASC-CM on the miRNAs regulating tendon repair (miR-29a-3p, miR-210-3p and miR-21-5p) in HG-HTNC. ASC-CM was obtained by ASCs isolated from the abdominal fat tissue of seven non-diabetic patients. HTNC were cultured in HG for 20 days, then scratched and exposed for 24 h to ASC-CM. qRT-PCR and ELISAs assessed miRNA and target levels. HG-HTNC exhibited a significant downregulation of miRNAs. ASC-CM restored the levels of miRNAs and their related targets involved in tendon repair. The epigenetic modulation observed in HG-HTNC exposed to ASC-CM could be an innovative option in the management of diabetic tendinopathy.
2025-01-28 | Aptamer-Conjugated Exosomes Ameliorate Diabetes-Induced Muscle Atrophy by Enhancing SIRT1/FoxO1/3a-Mediated Mitochondrial Function.
Muscle atrophy is associated with Type 2 diabetes mellitus, which reduces the quality of life and lacks effective treatment strategies. Previously, it was determined that human umbilical cord mesenchymal stromal cell (hucMSC)-derived exosomes (EXOs) ameliorate diabetes-induced muscle atrophy. However, the systemic application of EXOs is less selective for diseased tissues, which reduces their efficacy and safety associated with their nonspecific biological distribution in vivo. Therefore, improving exosomal targeting is imperative. In this study, a skeletal muscle-specific aptamer (Apt) was used to explore the effects of Apt-functionalized EXOs derived from hucMSCs in diabetes-associated muscle atrophy and its specific mechanisms. Diabetic db/db mice and C2C12 myotubes were used to explore the effects of MSC-EXOs or Apt-EXOs in alleviating muscle atrophy. Grip strength, muscle weight and muscle fibre cross-sectional area (CSA) were used to evaluate skeletal muscle strength and muscle mass. Western blot analysis of muscle atrophy signalling, including MuRF1 and Atrogin 1 and the mitochondrial complex and Seahorse analysis were performed to investigate the underlying mechanisms of MSC-EXOs or Apt-EXOs on muscle atrophy. MSC-EXOs increased grip strength (p = 0.0002) and muscle mass (p = 0.0044 for tibialis anterior (TA) muscle, p = 0.002 for soleus (SO) muscle) in db/db mice. It also increased the CSA of muscle fibres (p = 0.0011 for all fibres, p = 0.0036 for slow muscle fibres and p = 0.0089 for fast muscle fibres) and the percentage of slow-to-fast muscle fibres (p = 0.0109). However, Atrogin 1 (p = 0.0455) and MuRF1 expression (p = 0.0168) was reduced. MSC-EXOs activated SIRT1/FoxO1/3a signalling and enhanced mitochondrial function in db/db mice and C2C12 myotubes. SIRT1 knockdown decreased the beneficial antiatrophic effects of MSC-EXOs. Additionally, Apt conjugation increased the effect of MSC-EXOs on muscle atrophy and myofiber-type transition (p = 0.0133 for grip strength, p = 0.0124 for TA muscle weight, p = 0.0008 for SO muscle weight, p < 0.0001 for CSA of all muscle fibres, p = 0.0198 for CSA of slow muscle fibres, p = 0.0213 for CSA of fast muscle fibres, p = 0.011 for percentage of slow-fast muscle fibres, p = 0.0141 for Atrogin 1 expression and p = 0.005 for MuRF1 expression). The results suggest that hucMSC-derived exosomes ameliorate diabetes-associated muscle atrophy by enhancing SIRT1/FoxO1/3a-mediated mitochondrial function and that Apt conjugation strengthens the effects of MSC-EXOs on muscle atrophy. These findings demonstrate the therapeutic potential of muscle-targeted MSC-EXOs for the treatment of muscle atrophy.
2025-01-25 | The Role of microRNA-22 in Metabolism.
microRNA-22 (miR-22) plays a pivotal role in the regulation of metabolic processes and has emerged as a therapeutic target in metabolic disorders, including obesity, type 2 diabetes, and metabolic-associated liver diseases. While miR-22 exhibits context-dependent effects, promoting or inhibiting metabolic pathways depending on tissue and condition, current research highlights its therapeutic potential, particularly through inhibition strategies using chemically modified antisense oligonucleotides. This review examines the dual regulatory functions of miR-22 across key metabolic pathways, offering perspectives on its integration into next-generation diagnostic and therapeutic approaches while acknowledging the complexities of its roles in metabolic homeostasis.
2024-12-18 | Development of a natural rubber latex-based biodevice with mesenchymal stem cells as a potential treatment for skeletal muscle regeneration in gestational diabetes-induced myopathy.
Women with gestational diabetes mellitus show a high risk of developing Gestational Diabetes Induced Myopathy (GDiM). GDiM is characterized by significant pelvic floor skeletal muscle atrophy and urinary incontinence. This study aimed to develop a natural rubber latex (NRL) based biodevice with mesenchymal/stromal stem cells (MSCs) for skeletal muscle regeneration for women with GDiM. NRL showed porosity, roughness, biocompatibility, and bioactivity. MSCs adhesion on the NRL scaffold surface was assessed by scanning electron microscopy (SEM), confocal microscopy, and zymography. The scaffold's physicochemical and biological properties were carried out by Fourier transform infrared spectroscopy (FTIR), swelling and degradation studies, hemolytic activity, and antioxidant activity (AA), using Electronic Paramagnetic Resonance (EPR). MSCs in culture expressed CD90, adhered to plastic, differentiated, and produced fibroblast colonies. A high rate of cell proliferation was seen in MSCs on the NRL scaffold. FTIR analysis confirmed protein structures and polyisoprene in the scaffold. Swelling and degradation showed low water uptake and weight loss. Furthermore, NRL presented a hemolytic rate of 2.90 ± 0.26 % for 24 h, and EPR revealed the scaffold's strong AA. The generated biodevice has potential for muscle regeneration and may be useful as a therapeutic option for skeletal muscle disorders in GDiM or urinary incontinence.
small molecules
2026-07-08 | The Central Role of the AMPK/SIRT1/PGC-1α Signaling Axis in Skeletal Muscle Physiology and Pathology and Its Targeted Therapeutic Strategies
Considered by some to be the largest metabolic organ of the body, the functional integrity of skeletal muscle is highly dependent on its exceptional plasticity, which is primarily governed by mitochondrial quality control. The signaling axis composed of AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) serves as a critical hub that senses cellular energy status, coordinates mitochondrial biogenesis, regulates muscle fiber type switching, and maintains protein homeostasis. This review systematically delineates the structural functions and synergistic regulatory network of the AMPK/SIRT1/PGC-1α signaling axis. It further elucidates the regulatory roles of this pathway under physiological conditions—such as exercise adaptation and muscle fiber-type transformation—and its dysregulated mechanisms in the pathogenesis of various skeletal muscle disorders, including sarcopenia, disuse atrophy, cachexia, neurogenic atrophy, muscular dystrophy, and type 2 diabetes mellitus-related myopathy. Building on this foundation, this review critically analyzes current multifaceted therapeutic strategies targeting this pathway, encompassing exercise and physical therapy, nutritional and natural products, and small molecule drugs, as well as gene and cell-based therapies. Finally, this review delves into the challenges facing clinical translation in this field, such as the complexity of the signaling network, individual variability, and bioavailability issues. It also proposes future research directions focused on developing precision intervention tools, establishing effective biomarker systems, and exploring combination intervention strategies. Collectively, the AMPK/SIRT1/PGC-1α signaling axis is central to maintaining skeletal muscle metabolic homeostasis, and targeting this pathway provides a robust theoretical foundation and broad application prospects for the prevention and treatment of skeletal muscle-related diseases.
2026-07-01 | Metabolomics and cardiovascular risk factors in autoimmune-mediated connective tissue diseases – an exploratory, hypothesis-generating study
Abstract Background Autoimmune connective tissue diseases (ACTD), including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren’s disease (SD), and idiopathic inflammatory myopathies (IIM), are associated with markedly increased cardiovascular risk (CVR) that is insufficiently captured by conventional risk scores. Reliable biomarkers for CVR stratification in ACTD are lacking. This exploratory, hypothesis-generatig study aimed to investigate whether metabolomic alterations reflect CVR across ACTD subtypes. Methods In this cross-sectional, exploratory study, patients with SLE (n = 33), SSc (n = 18), SD (n = 16), and IIM (n = 9) were recruited from a tertiary rheumatology center. Serum metabolomic profiling was performed using ¹H-NMR spectroscopy. Associations between 113 quantified metabolites and clinical CVR parameters (including age, sex, body mass index, glucocorticoid use, Framingham score, hypertension, diabetes, lipid parameters, and lifestyle factors) were analyzed using non-parametric statistics with false discovery rate correction. Correlation analyses were conducted using Spearman coefficients. Results Metabolomic alterations varied substantially across ACTD subtypes and CVR factors. Lipid metabolites showed the strongest and most consistent associations with CVR parameters. The Framingham score correlated with 11 metabolites in SLE, 1 in SSc, 2 in SD, and 93 in IIM, predominantly involving lipid components. Diabetes mellitus was associated with extensive metabolomic changes, particularly in SSc (n = 62 metabolites), followed by SD (n = 20) and SLE (n = 5). In contrast, arterial hypertension showed minimal metabolomic differentiation across most ACTD, except in IIM. Body mass index correlated mainly with lipid metabolites in SSc, but not in SLE. Glucocorticoid therapy and dosage were strongly associated with alterations in lipid metabolism, especially in SLE and SSc. Across all entities, correlations with total cholesterol, LDL, and HDL were dominated by lipid metabolites. Associations with renal markers (UACR) were limited. Conclusions ACTD are characterized by heterogeneous metabolomic signatures associated with cardiovascular risk factors. Larger, longitudinal studies are required to validate these findings and to determine their clinical utility in cardiovascular risk stratification in ACTD.
2026-06-01 | Therapeutic Effects of Lycopene and Aerobic Exercise in Skeletal Muscles Myopathy in Type 2 Diabetic Rat Model
Abstract Type 2 diabetes mellitus (T2DM) causes metabolic disturbances and skeletal muscle pathology. Aerobic training (AT) improves insulin sensitivity, while lycopene (LYC) has antidiabetic and anti-inflammatory properties. This study evaluated the individual and combined therapeutic effects of AT and LYC on skeletal muscle alterations in a T2DM rat model. Forty-eight adult male Albino rats were divided into six groups (n = 8): negative control, LYC control, T2DM, T2DM-AT, T2DM-LYC, and T2DM-AT-LYC. T2DM was induced using a high-fat/high-fructose diet followed by Streptozotocin injection. Interventions were applied for 8 weeks. Body weight, food intake, gastrocnemius muscle (GCM) weight, fasting blood glucose, fasting insulin, lipid profile, C-reactive protein (CRP), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) were assessed. Muscle histology, collagen deposition, and expression of LC3A-II (autophagy marker) and apoptosis-inducing factor (AIF) were evaluated. T2DM induced hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, inflammation, elevated muscle enzymes, and reduced GCM mass. Histologically, diabetic muscles showed fiber distortion and increased collagen deposition, with elevated autophagy and apoptosis markers. AT and/or LYC significantly improved metabolic parameters, reduced inflammation and muscle enzyme levels, preserved muscle mass, and improved muscle architecture. LYC mainly improved metabolic, inflammatory, and enzymatic disturbances, whereas AT more effectively suppressed autophagy and apoptosis. Combined AT-LYC treatment produced additive and superior benefits across all outcomes. In conclusion, Aerobic training and lycopene, individually and synergistically, protect against T2DM-induced skeletal muscle pathology by improving metabolic control, reducing inflammation, and attenuating autophagy and apoptosis, supporting combined lifestyle and nutraceutical interventions in diabetes management.
2026-05-28 | Real-World Safety and Efficacy of a Pitavastatin-Ezetimibe Combination Therapy in Taiwanese Patients after PCI.
Patients undergoing percutaneous coronary intervention (PCI) have a higher risk of recurrence. While lipid and glucose control can improve the prognosis, concerns remain about side effects such as myopathy, liver dysfunction, and potential new-onset diabetes mellitus. This study aimed to evaluate the real-world safety and efficacy of dual lipid-lowering therapy with pitavastatin 4 mg/day (P4) and ezetimibe 10 mg/day (E10), hereafter referred to as P4/E10 in post-PCI patients in Taiwan. The retrospective cohort study enrolled patients who underwent PCI between 2008 and 2021 at two institutes in Taiwan and received P4/E10 combination therapy for longer than a year. The primary endpoint was the overall adverse event rate associated with P4/E10. Efficacy evaluations included changes from baseline in lipid profile and glycemic markers. A total of 120 patients were enrolled. No adverse events were recorded during the study period. After 12 months of therapy, the average low-density lipoprotein cholesterol level decreased by 32.54% from baseline, and there were decreases in glycated hemoglobin and triglyceride glucose index (-0.40% and -0.23, respectively) in diabetic patients. In this real-world study of Taiwanese patients, P4/E10 combination therapy was safe and effective in both lipid and glycemic index control. Nevertheless, further large-scale studies are warranted to validate our findings.
2026-04-26 | Mitochondrial dysfunction-driven inflammation and β-Cell apoptosis in type 2 diabetes mellitus: mechanistic insights and therapeutic implications.
Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic syndrome characterized by chronic hyperglycemia, progressive pancreatic β-cell malfunction, and peripheral insulin resistance. There is growing evidence suggesting that mitochondrial dysfunction and apoptosis play a critical role in the development and advancement of T2DM. Mitochondria are essential for cellular energy metabolism and redox homeostasis. It is the metabolic stress and apoptotic cell death in insulin-producing β-cells and insulin-sensitive tissues induced by mitochondrial dysfunction caused by excessive reactive oxygen species (ROS) production, imbalanced mitochondrial dynamics, impaired mitophagy, mitochondrial fission-fusion imbalance, and defective biogenesis. This review summarizes the molecular pathways by which mitochondrial dysfunction triggers inflammatory responses, such as activation of NLRP3 inflammasomes, cytokine release, and mitochondria-mediated intrinsic apoptotic signaling. We describe the role of these pathways in insulin resistance and in the emergence of diabetic complications like neuropathy, nephropathy, myopathy, and hepatopathy. New treatment approaches aimed at mitochondrial integrity and apoptotic signaling are promising. These are AMPK/PGC-1α pathway activators, mitochondria-targeted antioxidants (MitoQ, SS-31), and mitophagy and ferroptosis modulators. But poor tissue specificity, poor bioavailability, and patient-to-patient variability are limitations in clinical translation. Lastly, the review highlights the possibilities of personalized medicine strategies that incorporate the use of mitochondrial profiling to maximize therapeutic outcomes. Collectively, available evidence suggests that therapeutic strategies restoring mitochondrial quality control in β-cells may offer greater disease-modifying potential than glucose-centric interventions alone.
proteins
2025-07-03 | Incretin-based therapy: An update focusing on the major revolution in cardiovascular-kidney-metabolic health.
Type 2 diabetes mellitus and obesity have become the rising burden across various geographic and economic regions, and they are also the common causes of chronic kidney disease, which further contributes to the development and progression of cardiovascular disease. The recently proposed cardiovascular-kidney-metabolic syndrome-the new paradigm of recognizing excess or dysfunctional adipose tissue as the shared pathophysiology-has signaled the interconnection of type 2 diabetes mellitus, obesity, chronic kidney disease, and cardiovascular disease beyond the disturbance of glucose homeostasis, for which recently developed incretin-based therapy has offered an avenue of holistic management. Glucagon-like peptide-1 (GLP1) is one of the incretins and potentiates insulin secretion after food intake, additionally offering extra-pancreatic metabolic effects-reduced hepatic gluconeogenesis and steatosis, increased muscular glucose uptake, and increased lipolysis and glucose uptake in the adipose tissue. Seven different GLP1 receptor agonists have been licensed globally. For those with type 2 diabetes mellitus, GLP1 receptor agonists overall reduce major adverse cardiovascular events by 14% (hazard ratio 0.86, 95% confidence interval 0.80-0.93) and all-cause death by 18% (hazard ratio 0.82, 95% confidence interval 0.82-0.94), and semaglutide, a long-acting GLP1 receptor agonist for once weekly injection, reduces major renal events by 24% (hazard ratio 0.76, 95% confidence interval 0.66-0.88). For obese patients without diabetes mellitus, semaglutide results in a 12.4% (95% confidence interval -13.4 to -11.5) reduction in body weight and 20% lower in the risk of major adverse cardiovascular events (hazard ratio 0.80, 95% confidence interval 0.72-0.90), while the burden of heart failure can also be improved by 7.8 points (95% confidence interval 4.8-10.9) in those with heart failure with preserved ejection fraction and obesity. These findings highlight the transformative role of GLP1 receptor agonists in the management of cardiovascular-kidney-metabolic syndrome. We reviewed the updated clinical evidence of incretin-based therapy and summarized its outcome benefits.
2024-07-11 | Diabetes with GLP-1R polymorphism (rs3765467) accompanied by myotonic dystrophy: A case of myotonic dystrophy with p.R131Q polymorphism at the glucagon-like peptide-1 receptor (rs3765467) resulting in marked effects of its agonist, dulaglutide.
A 47-year-old woman was diagnosed with myotonic dystrophy when admitted for traumatic subarachnoid hemorrhage. Her glycemic control was poor despite administration of pioglitazone, a PPARɤ agonist, and subcutaneous insulin infusion. However, adding a GLP-1 receptor (GLP-1R) agonist markedly improved blood glucose levels, resulting in eventual insulin withdrawal. Genetic testing revealed a heterozygous variant, p.R131Q, in the GLP1R (rs3765467), a common variant in Asia. This variant is known to be associated with increased endogenous insulin from beta cells in response to exogenous GLP-1 infusion. This is the first report and short review of a Japanese case of myotonic dystrophy accompanied by GLP-1R gene polymorphism.
2024-06-27 | Current research trends on the effect of diabetes mellitus on rotator cuff tendon healing/tendinopathy.
Rotator cuff tendon tears are a leading cause of shoulder pain. They are challenging to treat, and tendon-bone healing has a high failure rate despite successful surgery. Tendons connect the muscles and bones, which make them important for the body's overall mobility and stability. Metabolic diseases, including diabetes or high blood pressure, can affect the healing process after repair of a damaged tendon. With a global incidence of 9.3%, diabetes is considered as a significant risk factor for rotator cuff tendon healing because it causes structural, inflammatory, and vascular changes in the tendon. However, the mechanisms of how diabetes affects tendon healing remain unknown. Several factors have been suggested, including glycation product accumulation, adipokine dysregulation, increased levels of reactive oxygen species, apoptosis, inflammatory cytokines, imbalanced matrix-metalloproteinase-to-tissue-inhibitor ratio, and impaired angiogenesis and differentiation of the tendon sheath. Despite the effects of diabetes on tendon function and healing, few treatments are available to improve recovery in these patients. This review summarizes the current literature on the pathophysiological changes of the tendon in diabetes and hyperlipidemia. Preclinical and clinical evidence regarding the association between diabetes and tendon healing is presented. Moreover, current approaches to improve tendon healing in patients with diabetes are reviewed.
2024-04-27 | Targeting Molecular Mechanisms of Obesity- and Type 2 Diabetes Mellitus-Induced Skeletal Muscle Atrophy with Nerve Growth Factor.
Skeletal muscle plays a critical role in metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM). Muscle atrophy, characterized by a decrease in muscle mass and function, occurs due to an imbalance between the rates of muscle protein synthesis and degradation. This study aimed to investigate the molecular mechanisms that lead to muscle atrophy in obese and T2DM mouse models. Additionally, the effect of nerve growth factor (NGF) on the protein synthesis and degradation pathways was examined. Male mice were divided into three groups: a control group that was fed a standard chow diet, and two experimental groups that were fed a Western diet. After 8 weeks, the diabetic group was injected with streptozotocin to induce T2DM. Each group was then further divided into NGF-treated or non-treated control group. In the gastrocnemius muscles of the Western diet group, increased expressions of myostatin, autophagy markers, and ubiquitin ligases were observed. Skeletal muscle tissue morphology indicated signs of muscle atrophy in both obese and diabetic mice. The NGF-treated group showed a prominent decrease in the protein levels of myostatin and autophagy markers. Furthermore, the NGF-treated group showed an increased Cyclin D1 level. Western diet-induced obesity and T2DM may be linked to muscle atrophy through upregulation of myostatin and subsequent increase in the ubiquitin and autophagy systems. Moreover, NGF treatment may improve muscle protein synthesis and cell cycling.
2023-12-25 | Beyond the Cardiovascular Effects of Glucagon-like Peptide-1 Receptor Agonists: Body Slimming and Plaque Stabilization. Are New Statins Born?
Atherosclerosis is a chronic inflammatory disease characterized by lipid and inflammatory cell deposits in the inner layer of large- and medium-sized elastic and muscular arteries. Diabetes mellitus (DM) significantly increases the risk of cardiovascular diseases and the overall and cardiovascular mortality, and it is a pro-atherogenic factor that induces atherosclerosis development and/or accelerates its progression through a multifactorial process. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a new class of drugs, belonging to the armamentarium to fight type 2 DM, that have shown robust reductions in atherosclerotic events and all-cause mortality in all studies. Preclinical studies have shown that GLP-1RAs play a role in the immunomodulation of atherosclerosis, affecting multiple pathways involved in plaque development and progression. In this review, we wanted to explore the translational power of such preclinical studies by analyzing the most recent clinical trials investigating the atheroprotective effect of GLP-1RAs.
gene therapies
2024-07-18 | Systemic Deletion of ARRDC4 Improves Cardiac Reserve and Exercise Capacity in Diabetes.
Exercise intolerance is an independent predictor of poor prognosis in diabetes. The underlying mechanism of the association between hyperglycemia and exercise intolerance remains undefined. We recently demonstrated that the interaction between ARRDC4 (arrestin domain-containing protein 4) and GLUT1 (glucose transporter 1) regulates cardiac metabolism. To determine whether this mechanism broadly impacts diabetic complications, we investigated the role of ARRDC4 in the pathogenesis of diabetic cardiac/skeletal myopathy using cellular and animal models. High glucose promoted translocation of MondoA into the nucleus, which upregulated Arrdc4 transcriptional expression, increased lysosomal GLUT1 trafficking, and blocked glucose transport in cardiomyocytes, forming a feedback mechanism. This role of ARRDC4 was confirmed in human muscular cells from type 2 diabetic patients. Prolonged hyperglycemia upregulated myocardial Arrdc4 expression in multiple types of mouse models of diabetes. We analyzed hyperglycemia-induced cardiac and skeletal muscle abnormalities in insulin-deficient mice. Hyperglycemia increased advanced glycation end-products and elicited oxidative and endoplasmic reticulum stress leading to apoptosis in the heart and peripheral muscle. Deletion of Arrdc4 augmented tissue glucose transport and mitochondrial respiration, protecting the heart and muscle from tissue damage. Stress hemodynamic analysis and treadmill exhaustion test uncovered that Arrdc4-knockout mice had greater cardiac inotropic/chronotropic reserve with higher exercise endurance than wild-type animals under diabetes. While multiple organs were involved in the mechanism, cardiac-specific overexpression using an adenoassociated virus suggests that high levels of myocardial ARRDC4 have the potential to contribute to exercise intolerance by interfering with cardiac metabolism through its interaction with GLUT1 in diabetes. Importantly, the ARRDC4 mutation mouse line exhibited greater exercise tolerance, showing the potential therapeutic impact on diabetic cardiomyopathy by disrupting the interaction between ARRDC4 and GLUT1. ARRDC4 regulates hyperglycemia-induced toxicities toward cardiac and skeletal muscle, revealing a new molecular framework that connects hyperglycemia to cardiac/skeletal myopathy to exercise intolerance.
2022-10-11 | 11β-HSD1 contributes to age-related metabolic decline in male mice.
The aged phenotype shares several metabolic similarities with that of circulatory glucocorticoid excess (Cushing's syndrome), including type 2 diabetes, obesity, hypertension, and myopathy. We hypothesise that local tissue generation of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts 11-dehydrocorticosterone to active corticosterone in rodents (corticosterone to cortisol in man), plays a role in driving age-related chronic disease. In this study, we have examined the impact of ageing on glucocorticoid metabolism, insulin tolerance, adiposity, muscle strength, and blood pressure in both wildtype (WT) and transgenic male mice with a global deletion of 11β-HSD1 (11β-HSD1-/-) following 4 months high-fat feeding. We found that high fat-fed 11β-HSD1-/- mice were protected from age-related glucose intolerance and hyperinsulinemia when compared to age/diet-matched WTs. By contrast, aged 11β-HSD1-/- mice were not protected from the onset of sarcopenia observed in the aged WTs. Young 11β-HSD1-/- mice were partially protected from diet-induced obesity; however, this partial protection was lost with age. Despite greater overall obesity, the aged 11β-HSD1-/- animals stored fat in more metabolically safer adipose depots as compared to the aged WTs. Serum analysis revealed both WT and 11β-HSD1-/- mice had an age-related increase in morning corticosterone. Surprisingly, 11β-HSD1 oxo-reductase activity in the liver and skeletal muscle was unchanged with age in WT mice and decreased in gonadal adipose tissue. These data suggest that deletion of 11β-HSD1 in high fat-fed, but not chow-fed, male mice protects from age-related insulin resistance and supports a metabolically favourable fat distribution.
2022-03-31 | Sirtuin 3 overexpression preserves maximal sarco(endo)plasmic reticulum calcium ATPase activity in the skeletal muscle of mice subjected to high fat - high sucrose feeding.
Sarco(endo)plasmic reticulum calcium (Ca2+) ATPase (SERCA) transports Ca2+ in muscle. Impaired SERCA activity may contribute to diabetic myopathy. Sirtuin (SIRT) 3 regulates muscle metabolism and function; however, it is unknown if SIRT3 regulates muscle SERCA activity or acetylation. We determined if SIRT3 overexpression enhances SERCA activity in mouse gastrocnemius muscle and if SIRT3 overexpression preserves gastrocnemius SERCA activity in a model of type 2 diabetes, induced by high fat - high sucrose (HFHS) feeding. We also determined if the acetylation status of SERCA proteins in mouse gastrocnemius is altered by SIRT3 overexpression or HFHS feeding. Wild-type (WT) and SIRT3 transgenic (SIRT3TG) mice, overexpressing SIRT3 in skeletal muscle, were fed a standard or HFHS diet for 4 months. SIRT3TG and WT mice developed obesity and glucose intolerance after 4 months of HFHS feeding. SERCA Vmax was higher in gastrocnemius of SIRT3TG mice compared with WT mice. HFHS-fed mice had lower SERCA1a protein levels and lower SERCA Vmax in their gastrocnemius than control-fed mice. The decrease in SERCA Vmax in gastrocnemius muscle due to HFHS feeding was attenuated by SIRT3 overexpression in HFHS-fed SIRT3TG mice. SERCA1a and SERCA2a acetylation in mouse gastrocnemius was not altered by genotype or diet. These findings suggest SIRT3 overexpression improves SERCA function in mouse skeletal muscle.
2019-11-06 | A fully human transgene switch to regulate therapeutic protein production by cooling sensation.
The ability to safely control transgene expression with simple synthetic gene switches is critical for effective gene- and cell-based therapies. In the present study, the signaling pathway controlled by human transient receptor potential (TRP) melastatin 8 (hTRPM8), a TRP channel family member1, is harnessed to control transgene expression. Human TRPM8 signaling is stimulated by menthol, an innocuous, natural, cooling compound, or by exposure to a cool environment (15-18 °C). By functionally linking hTRPM8-induced signaling to a synthetic promoter containing elements that bind nuclear factor of activated T cells, a synthetic gene circuit was designed that can be adjusted by exposure to either a cool environment or menthol. It was shown that this gene switch is functional in various cell types and human primary cells, as well as in mice implanted with engineered cells. In response to transdermal delivery of menthol, microencapsulated cell implants harboring this gene circuit, coupled to expression of either of two therapeutic proteins, insulin or a modified, activin type IIB, receptor ligand trap protein (mActRIIBECD-hFc), could alleviate hyperglycemia in alloxan-treated mice (a model of type 1 diabetes) or reverse muscle atrophy in dexamethasone-treated mice (a model of muscle wasting), respectively. This fully human-derived orthogonal transgene switch should be amenable to a wide range of clinical applications.
2018-11-05 | Generation and Phenotype Identification of PAX4 Gene Knockout Rabbit by CRISPR/Cas9 System.
Paired-homeodomain transcription factor 4 (PAX4) gene encodes a transcription factor which plays an important role in the generation, differentiation, development, and survival of insulin-producing β-cells during mammalian pancreas development. PAX4 is a key diabetes mellitus (DM) susceptibility gene, which is associated with many different types of DM, including T1DM, T2DM, maturity onset diabetes of the young 9 (MODY9) and ketosis prone diabetes. In this study, a novel PAX4 gene knockout (KO) model was generated through co-injection of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) mRNA/sgRNA into rabbit zygotes. Typical phenotypes of growth retardation, persistent hyperglycemia, decreased number of insulin-producing β cells and increased number of glucagon-producing α cells were observed in the homozygous PAX4 KO rabbits. Furthermore, DM associated phenotypes including diabetic nephropathy, hepatopathy, myopathy and cardiomyopathy were also observed in the homozygous PAX4 KO rabbits but not in the wild type (WT) controls and the heterozygous PAX4 KO rabbits. In summary, this is the first PAX4 gene KO rabbit model generated by CRISPR/Cas9 system. This novel rabbit model may provide a new platform for function study of PAX4 gene in rabbit and gene therapy of human DM in clinical trails.
antibodies
2026-06-17 | Successful corticosteroid-free management of anti-HMG-CoA reductase immune-mediated necrotizing myopathy with subcutaneous immunoglobulins monotherapy: a case report.
Given the high rate of cardiovascular comorbidities in anti-HMG-CoA reductase (HMGCR)-immune-mediated necrotizing myopathy (IMNM), a glucocorticosteroids (GC)-free treatment approach remains an appealing strategy. While intravenous immunoglobulins (IVIg) represents an effective therapy in most subgroups of idiopathic inflammatory myositis (IIM), there remains limited evidence supporting the use subcutaneous immunoglobulins (SCIg), a potentially safer, more convenient and cost-effective alternative. We present a case of a 68-year-old male of European descent with a 2-year history of progressive proximal bilateral lower extremity weakness. He had been treated for his dyslipidemia with atorvastatin for 2 years, then with rosuvastatin for 2 additional years until discontinued a year before our assessment. His other comorbidities included hypertension and diabetes mellitus type II. Physical examination demonstrated proximal weakness of his bilateral hip flexors and deltoids, and no rash. His creatine kinase (CK) was elevated at 1644 IU/L. Electromyography revealed a generalized myopathic disorder with proximal predominance and muscle biopsy of the right quadriceps showed typical findings of an IMNM. Serum HMG-CoA reductase antibody was positive. Due to accumulating evidence supporting the effectiveness of IVIg in anti-HMGCR-IMNM, even without concomitant GC or other immunosuppressive agent, we opted for a GC-free approach through shared-decision making in light of patient's preference regarding potential GC side effects with his comorbidities. As he lived a considerable distance from any center, where IVIg infusions could be offered, and given the patient was unable to drive himself due to his symptoms we opted for SCIg (0.5 g/kg/week). Within 1 month, his CK decreased and weakness resolved. SCIg monotherapy was tapered over 3 years and this patient remains in remission 7 years after SCIg initiation. The patient did not have any adverse effects related to SCIg use. To our knowledge, this is the first case report describing a successful corticosteroid-free management of anti-HMGCR immune-mediated necrotizing myopathy using SCIg as monotherapy. This case highlights the potential for steroids-free induction and maintenance strategies in IMNM. Larger studies are required to confirm the effectiveness and safety of SCIg in IMNM and other subtypes of IIM, and to provide guidelines for dosing recommendations.
2025-03-28 | Beyond Bone Remodeling: Denosumab's Multisystemic Benefits in Musculoskeletal Health, Metabolism, and Age-Related Diseases-A Narrative Review.
Background: Denosumab, a receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitor, demonstrates therapeutic effects beyond traditional osteoporosis management through the RANK/RANKL/osteoprotegerin pathway. Methods: This narrative review analyzed 37 studies (2018-2024) examining denosumab's broader physiological effects and clinical applications. Results: Long-term safety data spanning 10 years showed sustained fracture prevention efficacy with a favorable benefit/risk profile. Compared to bisphosphonates, denosumab demonstrated superior outcomes in bone mineral density improvement and fracture risk reduction, particularly in elderly and frail populations. It enhanced muscular function by improving appendicular lean mass and grip strength while reducing fall risk. The drug showed potential cardiovascular benefits through its effects on cardiac and smooth muscle function. Notably, denosumab use was associated with reduced Type II diabetes mellitus risk through improved glucose metabolism. Additionally, it demonstrated promise in osteoarthritis treatment by suppressing osteoclast activity and chondrocyte apoptosis. While there are multisystem benefits, vigilance is required regarding adverse events, including hypocalcemia, infection risk, cutaneous reactions, and osteonecrosis of the jaw. Conclusions: Denosumab exhibits potential benefits in bone and systemic metabolism. Further research is needed to fully understand its therapeutic potential beyond osteoporosis and optimize clinical applications across different populations.
2025-01-20 | ICAM1 blockade improves ischemic muscle reperfusion in diabetic mice.
Chronic Limb-Threatening Ischemia (CLTI) represents the most advanced stage of Peripheral Artery Disease (PAD) and is associated with dire prognosis, characterized by a substantial risk of limb amputation and diminished life expectancy. Despite significant advancements in therapeutic interventions, the underlying mechanisms precipitating the progression of PAD to CLTI remain elusive. Considering diabetes is one of the main risk factors contributing to PAD exacerbation into CLTI, we compared hind limb ischemia recovery in HFD STZ vs. non-HFD STZ mice to identify new mechanisms responsible for the exacerbation of PAD. We used three different mouse models of diabetes and found that blood flow recovery in HFD STZ mice is altered only from day 14 post-surgery. Consistent with this kinetics, we found that angiogenesis and myogenesis which typically occur between day five and day 14 post-surgery are not impaired in mice in which diabetes was induced by a high fat diet and streptozotocin injections (HFD STZ mice). On the contrary, we found that capillary functionality e.i. acquisition of functional intercellular junctions and immune quiescence is impaired in HFD + STZ mice. Notably, 28 days after hind limb ischemia surgery, HFD + STZ mice display significantly increased capillary permeability to IgG and significantly increased levels of ICAM1. This was associated with an increased macrophage infiltration and an impaired myocyte differentiation. Importantly, we used ICAM1-blocking antibodies to demonstrate that increased ICAM1 expression in HFD + STZ mice decreases white blood cell circulation velocity within the microcirculation, which impairs its perfusion. Notably anti-ICAM1 therapy did diminish macrophage infiltration and oxidative stress but not myopathy suggesting that myopathy characterized by small myocytes expressing higher level of MYH2 could be responsible for microangiopathy. ICAM1 expression by the microvasculature impairs ischemic muscle reperfusion in HFD + STZ mice. Importantly, the increase in blood flow between day 14 and day 90 post-HLI surgery is not associated with an increased capillary density but with an improved functionality of capillaries.
2023-08-03 | Neural gut-to-brain communication for postprandial control of satiation and glucose metabolism.
The brain is tuned to integrate food-derived signals from the gut, allowing it to accurately adjust behavioral and physiological responses in accordance with nutrient availability. A key element of gut-to-brain communication is the relay of neural cues via peripheral sensory neurons (PSN) which harbor functionally specialized peripheral endings innervating the muscular and mucosal layers of gastrointestinal (GI) tract organs. In this review, we detail the properties of GI tract innervating PSN and describe their roles in regulating satiation and glucose metabolism in response to food consumption. We discuss the complex anatomical organization of vagal and spinal PSN subtypes, their peripheral and central projection patterns, and describe the limitations of unselective lesion and ablation approaches to investigate them. We then highlight the recent identification of molecular markers that allow selective targeting of PSN subtypes that innervate GI tract organs. This has facilitated accurately determining their projections, monitoring their responses to gut stimuli, and manipulating their activity. We contend that these recent developments have significantly improved our understanding of PSN-mediated gut-to-brain communication, which may open new therapeutic windows for the treatment of metabolic disorders, such as obesity and type 2 diabetes.
2022-01-26 | A new therapeutic approach with tocilizumab in a 39-year-old patient with recurrent diabetic myonecrosis.
We report the case of a 39-year-old female patient with acute painful swelling of the left thigh and symmetric muscle weakness in both upper legs. The patient had a history of long-standing, poorly controlled type 1 diabetes which required dialysis. Serum inflammatory markers were highly elevated. Magnetic resonance imaging (MRI) indicated necrotic or inflammatory colliquation. As antibiotic therapy did not lead to clinical improvement, a successful anti-inflammatory therapy with prednisolone was initiated. Three months later, the patient presented with a new onset of progressive and painful muscle swelling of the right thigh. MRI showed pronounced swelling of the right adductor muscles and inflammatory markers were massively elevated. In the absence of autoantibodies or any infectious agents and the recurrent symptomatology, relapsing diabetogenic myonecrosis was diagnosed. Initially, clinical improvement could only be achieved with high-dose glucocorticosteroids. Intravenous immunoglobulins did not show an effect, whereas serological and clinical remission was achieved after we administered tocilizumab intravenously. Diabetic myonecrosis is a rare complication of long-term, poorly controlled diabetes mellitus. Acute muscle pain and elevated inflammatory markers should prompt suspicion. Contralateral muscle involvement is also suggestive of the disease. The optimisation of diabetes treatment is crucial in order to prevent further disease complications.
other
2025-11-28 | Anemarrhena asphodeloides-derived small extracellular vesicle ameliorate diabetes-induced muscle atrophy via activating Pink1-mediated mitophagy.
Diabetes-induced muscle atrophy, characterized by progressive loss of skeletal muscle mass and function, poses a major challenge in diabetes management. To address this, we developed a phyto-exosomal formulation derived from Anemarrhena asphodeloides small extracellular vesicle (AA-sEV) and evaluated its therapeutic potential against diabetic muscle atrophy. AA-sEV were isolated by ultracentrifugation and characterized for exosomal morphology. The therapeutic efficacy of AA-sEV was assessed through in vivo studies in diabetic db/db mice and in vitro assays using C2C12 myoblasts exposed to high glucose conditions. Fluorescently labeled AA-sEV efficiently accumulated in skeletal muscle tissue and myoblasts. Oral administration of AA-sEV enhanced muscle performance, as indicated by increased grip strength and hanging endurance, restoration of myofiber cross-sectional area, and upregulation of FNDC5 expression. Transcriptomic analysis revealed that mitophagy served as the central mechanism mediating AA-sEV's therapeutic effects. Specifically, AA-sEV activated the Pink1/Parkin-dependent mitophagy pathway, reducing mitochondrial reactive oxygen species accumulation. This restoration of mitochondrial quality control promoted the MyoG/MyoD1-driven anabolic program while suppressing the MuRF1/MAFbx-mediated catabolic response. Treatment with the mitophagy inhibitor 3-methyladenine abolished the anabolic and catabolic regulatory effects of AA-sEV under hyperglycemic conditions. Our findings demonstrate that AA-sEV mitigate diabetes-induced muscle atrophy by restoring protein anabolic-catabolic balance via Pink1-mediated mitophagy. These results highlight a novel extracellular vesicle-based therapeutic strategy for managing diabetic myopathy and related complications.
2025-02-26 | New Insights on the miRNA Role in Diabetic Tendinopathy: Adipose-Derived Mesenchymal Stem Cell Conditioned Medium as a Potential Innovative Epigenetic-Based Therapy for Tendon Healing.
Adipose-derived mesenchymal stem cell conditioned medium (ASC-CM) improved the viability and wound closure of human tenocytes (HTCN) exposed to high glucose (HG) by activating the transforming growth factor beta 1 (TGF-β1) pathway. Since ASC-CM can also modulate microRNAs (miRNAs) in recipient cells, this study investigated the effects of ASC-CM on the miRNAs regulating tendon repair (miR-29a-3p, miR-210-3p and miR-21-5p) in HG-HTNC. ASC-CM was obtained by ASCs isolated from the abdominal fat tissue of seven non-diabetic patients. HTNC were cultured in HG for 20 days, then scratched and exposed for 24 h to ASC-CM. qRT-PCR and ELISAs assessed miRNA and target levels. HG-HTNC exhibited a significant downregulation of miRNAs. ASC-CM restored the levels of miRNAs and their related targets involved in tendon repair. The epigenetic modulation observed in HG-HTNC exposed to ASC-CM could be an innovative option in the management of diabetic tendinopathy.
2025-01-28 | Aptamer-Conjugated Exosomes Ameliorate Diabetes-Induced Muscle Atrophy by Enhancing SIRT1/FoxO1/3a-Mediated Mitochondrial Function.
Muscle atrophy is associated with Type 2 diabetes mellitus, which reduces the quality of life and lacks effective treatment strategies. Previously, it was determined that human umbilical cord mesenchymal stromal cell (hucMSC)-derived exosomes (EXOs) ameliorate diabetes-induced muscle atrophy. However, the systemic application of EXOs is less selective for diseased tissues, which reduces their efficacy and safety associated with their nonspecific biological distribution in vivo. Therefore, improving exosomal targeting is imperative. In this study, a skeletal muscle-specific aptamer (Apt) was used to explore the effects of Apt-functionalized EXOs derived from hucMSCs in diabetes-associated muscle atrophy and its specific mechanisms. Diabetic db/db mice and C2C12 myotubes were used to explore the effects of MSC-EXOs or Apt-EXOs in alleviating muscle atrophy. Grip strength, muscle weight and muscle fibre cross-sectional area (CSA) were used to evaluate skeletal muscle strength and muscle mass. Western blot analysis of muscle atrophy signalling, including MuRF1 and Atrogin 1 and the mitochondrial complex and Seahorse analysis were performed to investigate the underlying mechanisms of MSC-EXOs or Apt-EXOs on muscle atrophy. MSC-EXOs increased grip strength (p = 0.0002) and muscle mass (p = 0.0044 for tibialis anterior (TA) muscle, p = 0.002 for soleus (SO) muscle) in db/db mice. It also increased the CSA of muscle fibres (p = 0.0011 for all fibres, p = 0.0036 for slow muscle fibres and p = 0.0089 for fast muscle fibres) and the percentage of slow-to-fast muscle fibres (p = 0.0109). However, Atrogin 1 (p = 0.0455) and MuRF1 expression (p = 0.0168) was reduced. MSC-EXOs activated SIRT1/FoxO1/3a signalling and enhanced mitochondrial function in db/db mice and C2C12 myotubes. SIRT1 knockdown decreased the beneficial antiatrophic effects of MSC-EXOs. Additionally, Apt conjugation increased the effect of MSC-EXOs on muscle atrophy and myofiber-type transition (p = 0.0133 for grip strength, p = 0.0124 for TA muscle weight, p = 0.0008 for SO muscle weight, p < 0.0001 for CSA of all muscle fibres, p = 0.0198 for CSA of slow muscle fibres, p = 0.0213 for CSA of fast muscle fibres, p = 0.011 for percentage of slow-fast muscle fibres, p = 0.0141 for Atrogin 1 expression and p = 0.005 for MuRF1 expression). The results suggest that hucMSC-derived exosomes ameliorate diabetes-associated muscle atrophy by enhancing SIRT1/FoxO1/3a-mediated mitochondrial function and that Apt conjugation strengthens the effects of MSC-EXOs on muscle atrophy. These findings demonstrate the therapeutic potential of muscle-targeted MSC-EXOs for the treatment of muscle atrophy.
2025-01-25 | The Role of microRNA-22 in Metabolism.
microRNA-22 (miR-22) plays a pivotal role in the regulation of metabolic processes and has emerged as a therapeutic target in metabolic disorders, including obesity, type 2 diabetes, and metabolic-associated liver diseases. While miR-22 exhibits context-dependent effects, promoting or inhibiting metabolic pathways depending on tissue and condition, current research highlights its therapeutic potential, particularly through inhibition strategies using chemically modified antisense oligonucleotides. This review examines the dual regulatory functions of miR-22 across key metabolic pathways, offering perspectives on its integration into next-generation diagnostic and therapeutic approaches while acknowledging the complexities of its roles in metabolic homeostasis.
2024-12-18 | Development of a natural rubber latex-based biodevice with mesenchymal stem cells as a potential treatment for skeletal muscle regeneration in gestational diabetes-induced myopathy.
Women with gestational diabetes mellitus show a high risk of developing Gestational Diabetes Induced Myopathy (GDiM). GDiM is characterized by significant pelvic floor skeletal muscle atrophy and urinary incontinence. This study aimed to develop a natural rubber latex (NRL) based biodevice with mesenchymal/stromal stem cells (MSCs) for skeletal muscle regeneration for women with GDiM. NRL showed porosity, roughness, biocompatibility, and bioactivity. MSCs adhesion on the NRL scaffold surface was assessed by scanning electron microscopy (SEM), confocal microscopy, and zymography. The scaffold's physicochemical and biological properties were carried out by Fourier transform infrared spectroscopy (FTIR), swelling and degradation studies, hemolytic activity, and antioxidant activity (AA), using Electronic Paramagnetic Resonance (EPR). MSCs in culture expressed CD90, adhered to plastic, differentiated, and produced fibroblast colonies. A high rate of cell proliferation was seen in MSCs on the NRL scaffold. FTIR analysis confirmed protein structures and polyisoprene in the scaffold. Swelling and degradation showed low water uptake and weight loss. Furthermore, NRL presented a hemolytic rate of 2.90 ± 0.26 % for 24 h, and EPR revealed the scaffold's strong AA. The generated biodevice has potential for muscle regeneration and may be useful as a therapeutic option for skeletal muscle disorders in GDiM or urinary incontinence.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
0 orphan drug designations.
0 orphan drug designations.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.