Dysregulated hepatic gluconeogenesis driven by glucagon is a key contributor to hyperglycemia in diabetes, yet the molecular mechanisms that restrain this pathway remain incompletely understood. This study reveals neuraminidase 1 (NEU1) as a suppressor of hepatic glucagon-driven gluconeogenesis in diabetes. We found that glucagon challenge downregulates hepatic NEU1 expression, inversely correlating with fasting blood glucose levels in individuals with diabetes. Functionally, liver-specific NEU1 overexpression antagonizes hepatic gluconeogenesis in glucagon-challenged mice and high fat diet (HFD)-fed mice, while NEU1 knockout augments glucagon response. Additionally, NEU1 inhibits hepatic gluconeogenesis in a non-enzymatic manner. Mechanistically, NEU1 interacts with SAM68 to activate GCN5 promoter, leading to increase of PGC-1α acetylation. The inhibitory effect of NEU1 overexpression on gluconeogenesis is abrogated by GCN5 knockdown in HFD-fed mice. A NEU1-targeted screening strategy identified α-hederin and oleanolic acid as synergistic inhibitors of hepatic glucagon response through NEU1 stabilization and SAM68 binding enhancement. Here we show an inhibitory role of NEU1 in the hepatic glucagon response and suggest a potential avenue for targeting NEU1 to treat diabetes.

Incretin hormones, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), serve as crucial mediators of postprandial glucose homeostasis by primarily enhancing glucose-stimulated insulin secretion. Research indicates that the incretin effect accounts for approximately 50% of insulin secretion in individuals without diabetes, which is significantly reduced to 30% or less in those with Type 2 Diabetes Mellitus (T2DM). The mechanisms underlying this incretin resistance have emerged as critical causes of postprandial hyperglycemia. Incretin-based therapies, including GLP-1 receptor agonists (GLP-1RAs) and DPP-4 inhibitors, have demonstrated efficacy in managing T2DM; however, intrinsic resistance mechanisms may limit their effectiveness. Understanding the processes by which T2DM affects incretin action, from hormone secretion to the modulation of signal transduction, is essential for optimizing current therapies and developing new interventions to enhance β-cell responsiveness and improve glycemic control. The concept of incretin resistance has a well-established history in literature, dating back to at least the early 1990 s. It is used to describe a reduced insulinotropic responsiveness to incretin hormones in individuals diagnosed with T2DM. This review examines how hyperglycemia, chronic inflammation, and genetic susceptibility collectively inhibit incretin signaling through distinct yet interconnected molecular pathways. This impairment exacerbates postprandial hyperglycemia and accelerates β-cell dysfunction. We propose novel hypotheses regarding selective β-arrestin signaling, enhancers, epigenetic regulation, interactions between gut microbiota and incretins, inflammation-induced endoplasmic reticulum (ER) stress, and genotype-specific therapeutic responses. The hypotheses presented in this review serve as a framework for future research and therapeutic development to combat the phenomenon of incretin resistance and improve the clinical management of T2DM.

The intertwined global epidemics of chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) pose an increasing challenge in chronic disease management, constituting a clinically significant bidirectional threat. This review integrates current evidence to propose a pathological interactive axis underlying this comorbidity, driven by shared risk factors such as smoking, obesity, and physical inactivity, and mediated through interconnected inflammatory signaling (e.g. IL-6/NF-κB and NLRP3/IL-1β), metabolic dysregulation, and oxidative stress. Within this framework, pulmonary inflammation in COPD may exacerbate systemic metabolic abnormalities, whereas chronic hyperglycemia and insulin resistance in T2DM may, in turn, aggravate lung injury, sustaining a self-perpetuating cycle of multi-organ dysfunction. Against this background, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a pharmacological class of interest due to their pleiotropic metabolic and anti-inflammatory properties. Experimental and indirect clinical evidence suggests that SGLT2i may modulate key inflammatory and oxidative stress pathways, including macrophage polarization, AMPK/NF-κB/NLRP3 signaling, mitochondrial protection, and Nrf2-SIRT1 activation. In addition, SGLT2i-associated improvements in body weight, metabolic efficiency, and cardiopulmonary loading may indirectly influence pulmonary-metabolic interactions. However, evidence for direct benefits on COPD-specific clinical outcomes remains limited and largely hypothesis-generating. Despite these mechanistic insights, substantial gaps remain regarding cross-organ molecular interactions, the role of hypoxia, and translational limitations of current models. Future research should prioritize dedicated randomized controlled trials, advanced single-cell and spatial omics approaches, and integrated digital health strategies to refine individualized SGLT2i-based interventions and advance multi-organ protective therapies in this complex patient population.

Glucose serves not only as an energy source but also as a signaling molecule for organ growth. Intrauterine hyperglycemia elevates the risk of congenital heart defects independently of genetic factors, although its underlying mechanisms remain unclear. In this study, we investigated the impact of maternal hyperglycemia on cardiac development using a diabetic pregnancy mouse model and pluripotent stem cell-derived cardiomyocytes. Multi-modal analysis revealed that hyperglycemia disrupts mitochondrial structure and function in fetal hearts even before overt malformations appear, indicating that mitochondrial immaturity is an early signature of diabetic embryopathy. Metabolomic profiling revealed nucleotide imbalance and subsequent AMP-activated protein kinase (AMPK) suppression-contrasting with reports of increased AMPK activity observed in hyperglycemic neural tube defects. Notably, pharmacological activation of AMPK restored cardiomyocyte and mitochondrial function under high-glucose conditions in vitro. Our findings demonstrate that high glucose inhibits cardiomyocyte maturation through dysregulated nucleotide metabolism and AMPK suppression, advancing understanding of hyperglycemia-induced cardiac developmental defects.

Axonal regeneration in the central nervous system is imperative for functional restoration following spinal cord injury (SCI). Myeloid cells are key regulators of axonal regeneration, yet their roles are not fully revealed. SCI perturbs glucose metabolism; however, its precise impact on axonal regeneration remains undefined. Moreover, whether myeloid cells orchestrate glucose metabolic responses to facilitate regeneration is unclear. Here, using the zebrafish Mauthner cell axon transection model, we demonstrate that following SCI, myeloid cell deficiency leads to a late-stage glucose surge, which leads to impaired axonal regeneration. We further identify glucagon signalling as a critical molecular determinant of this metabolic dysregulation and show that targeted mutations in gcga or its receptors (gcgra, gcgrb) rescue the axonal regeneration defects caused by myeloid cell deficiency. Finally, cell-depletion experiments demonstrated that macrophages are responsible for the late-stage hyperglycemia and defective axon regeneration of Mauthner cells. These findings suggest that glucose metabolism plays a critical role in macrophage-warranted axon regeneration in the spinal cord, positioning glucose homeostasis as a potential therapeutic target for enhancing axon regeneration and recovery.

Effective healing of diabetic wounds remains a major clinical challenge due to persistent hyperglycemia, bacterial infections, and hypoxia. In this study, a multifunctional self-healing hydrogel by embedding Fe3O4 nanoparticles (NPs) immobilized with glucose oxidase (Fe3O4/GOD) into a dynamic Schiff base-crosslinked hydrogel matrix of composed of oxidized bacterial nanocellulose (OBNC-D), carboxymethyl chitosan (CMC), and ε-poly-L-lysine (ε-PL) is developed. The resulting Fe3O4/GOD@H hydrogel exhibited excellent injectability, mechanical robustness, and self-healing capability, attributed to dynamic imine bond formation. Functionally, the embedded Fe3O4/GOD nanozyme enabled glucose-responsive cascade reactions, generating hydroxyl radicals (·OH) under mildly acidic conditions for potent antibacterial activity, and producing oxygen under neutral conditions to alleviate local hypoxia. In vitro experiments confirmed efficient ·OH generation, sustained oxygen release, and significant antibacterial efficacy against Staphylococcus aureus and Escherichia coli. The hydrogel also exhibited good hemocompatibility and cytocompatibility, particularly at optimized nanozyme concentrations. In a diabetic rat model, Fe3O4/GOD@H markedly accelerated wound closure and achieved complete re-epithelialization within 14 days, with minimal tissue toxicity. This intelligently responsive hydrogel provides a promising strategy for diabetic wound treatment by integrating glucose regulation, antibacterial action, and oxygen delivery to overcome multiple healing barriers.

Diabetes mellitus (DM) is a chronic metabolic disorder associated with hyperglycemia, dyslipidemia, oxidative stress, inflammation, apoptosis, and renal dysfunction. Although phlorizin (PHL) possesses well-documented antidiabetic properties, its clinical applicability is limited by poor bioavailability and rapid metabolism, which may restrict its therapeutic efficacy. This study evaluated the therapeutic potential of phlorizin (PHL) and its chitosan nanoparticle formulation (PHL-CSNPs) in streptozotocin (STZ)-induced type 1 diabetic rats. Ninety adult male albino rats were randomly divided into six groups (n = 15 each): non-diabetic control, non-diabetic treated with crude PHL, non-diabetic treated with PHL-CSNPs, diabetic untreated (STZ-induced T1DM), diabetic treated with crude PHL, and diabetic treated with PHL-CSNPs. STZ-induced T1DM caused significant reductions in serum insulin, body weight gain, renal antioxidant defences, and mitochondrial function, accompanied by marked elevations in fasting blood glucose, dyslipidemia, oxidative stress markers, pro-inflammatory cytokines, apoptotic markers, and renal fibrotic mediators, as well as pronounced histopathological and ultrastructural kidney damage. In diabetic rats, treatment with PHL-CSNPs significantly improved insulin levels, glucose homeostasis, and body weight, restored lipid profiles and antioxidant enzyme activities, enhanced mitochondrial respiratory complex activities and ATP production, suppressed NF-κB-mediated inflammation, upregulated Nrf2/HO-1 signalling, decreased Bax and caspase-3 levels, increased Bcl-2 levels, and reduced TGF-β1-mediated fibrosis. Crude PHL provided moderate protective effects but was consistently less effective than the nanoparticle formulation. Importantly, the chitosan nanoparticle formulation markedly enhanced the therapeutic efficacy of PHL, likely by improving its stability, bioavailability, and renal tissue delivery, thereby producing stronger antioxidant, anti-inflammatory, and anti-apoptotic effects than crude PHL. Non-diabetic rats treated with either PHL or PHL-CSNPs maintained normal metabolic and renal parameters, confirming the safety of the treatments. Histopathological and ultrastructural analyses further confirmed the preservation of renal architecture in PHL-CSNP-treated diabetic rats. Collectively, this study demonstrates that nanoencapsulation significantly potentiates the biological activity of PHL, providing a clear therapeutic advantage over the crude compound. Overall, these findings demonstrate that PHL-CSNPs provide superior nephroprotective, antioxidant, anti-inflammatory, and metabolic benefits, highlighting their potential as a promising therapeutic strategy for managing type 1 diabetes-induced metabolic and renal complications.

Metabolic diseases, particularly type 2 diabetes mellitus (T2DM) and obesity, have been traditionally understood through glucose-centric models. However, hyperglycaemia is a downstream consequence of systemic immune-metabolic dysregulation, with the gut microbiota acting as a central upstream regulator through defined molecular signalling pathways. This review examines four principal microbiota-host signalling axes through which ecological disruption drives systemic metabolic disease: short-chain fatty acid (SCFA) depletion impairing free fatty acid receptor (FFAR2/FFAR3) and AMP-activated protein kinase (AMPK) signalling; altered bile acid (BA) biotransformation perturbing farnesoid X receptor (FXR) and TGR5 signalling; increased intestinal permeability facilitating lipopolysaccharide (LPS) translocation and Toll-like receptor 4 (TLR4)-nuclear factor kappa B (NF-κB) activation; and diminished indole production reducing aryl hydrocarbon receptor (AhR)-driven interleukin-22 (IL-22) secretion. Therapeutic strategies targeting these pathways, including SCFA prodrugs, FXR modulators, TGR5 agonists, and next-generation probiotics, offer disease-modifying potential beyond glycaemic lowering and highlight the need for a multidimensional clinical endpoint framework spanning inflammatory, hepatic, and barrier biomarkers to enable comprehensive translational evaluation of microbiota-directed therapies.

Diabetic cardiomyopathy (DCM) is a major contributor to heart failure in patients with diabetes. Although berberine (BBR) exhibits broad metabolic and cardiovascular benefits, its mechanistic role in DCM remains incompletely defined. Cardiovascular function was assessed using arterial blood pressure (ABP), electrocardiography (ECG), and echocardiography. Biochemical analyses included glycemic indices, lipid profile, oxidative stress markers, inflammatory cytokines, and cardiac injury biomarkers. Cardiac and aortic tissues were evaluated for calcium (Ca[2][+]) content, gene expression by RT-PCR, and immunohistochemical changes. DCM rats exhibited significant increases in ABP, left ventricular internal diameter, fasting glucose, HbA1c, cholesterol, triglycerides, LDL-C, malondialdehyde, tumor necrosis factor-α, interleukin-17, cardiac enzymes, Caspase-3 expression, and myocardial and aortic fibrosis, accompanied by marked ECG abnormalities. Conversely, ejection fraction, fractional shortening, serum insulin, HDL-C, superoxide dismutase activity, interleukin-10 levels, cardiac Ca[2][+] content, and expression of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), nuclear factor erythroid 2-related factor 2 (Nrf2), and PTEN-induced putative kinase protein 1 (PINK1) were significantly reduced. Combined insulin and BBR treatment produced greater improvement in cardiac structure, function, and molecular signaling than either treatment alone. Berberine, particularly as an adjunct to insulin therapy, effectively attenuates DCM by reducing hyperglycemia, dyslipidemia, oxidative stress, inflammation, fibrosis, and apoptosis, while enhancing mitophagy and cardiac Ca[2][+] homeostasis. These effects are mediated, at least in part, through the coordinated modulation of the PI3K/Akt/mTOR and Nrf2 signaling pathways.