Search Results (210)

Insulin is an anabolic hormone involved in the regulation of several processes, such as the storage of glucose into glycogen, decrease of glucose output, stimulation of glucose transport into cells, etc. The hormone binds to its receptor, thereby activating an intracellular signaling cascade. Once activated, the insulin receptor (INSR) phosphorylates multiple intracellular substrates, which initiate the downstream signaling pathway. The nature of insulin signaling pathways may vary depending on the organ or tissue. In the central nervous system (CNS), INSRs are expressed in all cell types. This observation may suggest that insulin signaling is involved in important and diverse processes. It regulates glucose metabolism, supports cognitive functions, enhances the outgrowth of neurons, as well as plays a role in the modulation of release and uptake of catecholamine, among other roles. Importantly, insulin can freely cross the blood–brain barrier (BBB) from the circulation and is also synthesized locally within the brain. Insulin resistance (IR) impairs insulin signaling, which may accelerate brain aging, affect plasticity, and potentially contribute to neurodegeneration. Dysregulation of insulin signaling has been implicated in several diseases, including diabetes mellitus, metabolic syndrome, certain cancers, and neurodegenerative diseases, such as Alzheimer’s disease. There are two principal insulin signaling pathways: the PI3K/AKT pathway, primarily associated with metabolic effects, and the MAPK pathway, which is involved in cell growth, survival, and gene expression. Our review describes the role of insulin in the human brain, as well as the disturbances in insulin signaling resulting from brain insulin resistance, with a particular focus on its association with Alzheimer’s disease. Full article

Objective: β-cell dysfunction and loss are major pathological determinants of impaired islet function and hyperglycemia in diabetes. Given the inability of current therapies to restore β-cell viability or glucose-responsive insulin secretion, this study aimed to investigate whether a cell-permeable PBX1 fusion protein (TAT-PBX1) could rescue streptozotocin (STZ)-induced β-cell injury and restore β-cell functional integrity. Methods: A TAT-PBX1 recombinant fusion protein was produced using a prokaryotic expression system. Its protective effects were assessed in STZ-treated MIN6 β cells and in a mouse model of STZ-induced diabetes, with the glucokinase (GK) activator dorzagliatin included as a positive control. We evaluated β-cell apoptosis, DNA damage, ATP and NAD⁺/NADH levels, insulin signaling (IRS1/PI3K/Akt), and the expression of PDX1 and GK. Glucose-stimulated insulin secretion (GSIS), glucose tolerance, islet morphology, and β-cell proliferation were also examined in vivo. Results: TAT-PBX1 was detectable and significantly enriched in pancreatic tissue and mitigated STZ-induced cytotoxicity by reducing DNA damage, PARP1-associated energy depletion, and β-cell apoptosis. It restored intracellular ATP and NAD⁺/NADH ratios and reactivated IRS1/PI3K/Akt signaling. TAT-PBX1 further enhanced PDX1 protein levels and upregulated GK, resulting in improved glucose uptake and GSIS. In addition, it increased Ki67⁺ β-cell proliferation. In diabetic mice, TAT-PBX1 improved glucose tolerance, preserved islet morphology and number, and improved insulin signaling responsiveness. Conclusions: TAT-PBX1 restores β-cell function through coordinated protection of cellular metabolism and insulin signaling, leading to improved β-cell survival, glucose responsiveness, and regenerative capacity. These findings support TAT-PBX1 as a promising molecular strategy for β-cell-protective and β-cell-restorative diabetes therapy. Full article

Taste receptor type 1 member 3 (TAS1R3) is a class C G protein-coupled receptor (GPCR) traditionally associated with taste perception. While its role in insulin secretion is established, its contribution to skeletal muscle glucose uptake, a process responsible for 70–80% of postprandial glucose disposal, remains unclear. TAS1R3 expression was assessed in skeletal muscle biopsies from non-diabetic and type 2 diabetes (T2D) donors using qPCR and immunoblotting. Functional studies in human LHCN-M2 myotubes involved TAS1R3 inhibition with lactisole or siRNA-mediated knockdown, followed by the measurement of insulin-stimulated glucose uptake using radiolabeled glucose assays. Rac1 activation and phospho-cofilin were analyzed by G-LISA and Western blotting, and Gαq/11 involvement was tested using YM-254890. TAS1R3 mRNA and protein levels were significantly reduced in T2D skeletal muscle. Pharmacological inhibition or the knockdown of TAS1R3 impaired insulin-stimulated glucose uptake in myotubes. TAS1R3 regulates skeletal muscle glucose uptake through a non-canonical insulin signaling pathway involving Rac1 and phospho-cofilin, independent of IRS1-AKT and Gαq/11 signaling. These findings identify TAS1R3 as a key determinant of Rac1-mediated glucose uptake and a potential therapeutic target for improving insulin sensitivity in T2D. Full article

Background: Diabetes mellitus is a multifactorial disease characterized by complex metabolic dysfunctions and chronic complications induced by hyperglycaemia. The design of multitarget ligands, capable of simultaneously controlling different pathogenic processes, was proposed as a promising approach to identify novel antidiabetic drugs endowed with improved efficacy. Methods: (5-Arylidene-4-oxothiazolidin-3-yl)alkanoic acid derivatives 1a–g and 2a–g were synthesized as potential multitarget antidiabetic agents. They were tested in vitro as inhibitors of both human recombinant AKR1B1 and PTP1B, and kinetic studies and molecular docking simulations for both enzymes were performed. Their effects on cellular glucose uptake, insulin signalling, and mitochondrial potential were assayed in cultures of murine C2C12 myocytes. A lipid accumulation assay was performed in HepG2 liver cells. The effects on high glucose-induced sorbitol accumulation were evaluated in lens HLE and retinal MIO-M1 cells. Results: All compounds displayed excellent AKR1B1 inhibitory activity (IC₅₀ 0.03–0.46 μM 1a–g; IC₅₀ 0.48–6.30 μM 2a–g); 1g and 2e–g also appreciably inhibited PTP1B at micromolar concentrations. Propanoic derivatives 2e–g significantly stimulated glucose uptake in C2C12 myocytes, in an insulin-independent way, reduced lipid accumulation in HepG2 liver cells, and caused hyperpolarization of C2C12 mitochondria at 10 μM concentration. Derivative 2e significantly reduced sorbitol accumulation in both HLE and MIO-M1 cells at a 5 μM concentration. Conclusions: The results reported here provided new insights into the mechanisms of action and structure/activity relationships of 4-thiazolidinone derivatives, underscoring the capability of compounds 2e–g of eliciting insulin-mimetic effects independent of hormone signalling. Among them, compound 2e also proved to inhibit AKR1B1-dependent sorbitol accumulation and, thus, emerged as a promising multitarget agent that can be considered for further investigations. Full article

This study aimed to investigate the chemical composition, antioxidant activity, and in vitro antidiabetic properties of extracts obtained from ripe, unripe, and fermented (unripe) cornelian cherry (Cornus mas L.) fruits. Polyphenols were identified using UPLC-ESI-qTOF-MS/MS and quantified by HPLC-PDA. Antioxidant activity was evaluated using ABTS, DPPH, and FRAP assays, while enzyme inhibitory activity was determined for α-glucosidase and α-amylase. Additionally, the effects of C. mas extracts on insulin sensitivity in adipocytes were investigated. The study’s results showed that each of the extracts tested contained varying proportions of substances with proven health-promoting properties. The extract from ripe fruits was characterized by the highest loganic acid content, whereas the extract from fermented unripe fruits contained a high amount of gallic acid, released through the hydrolysis of tannins during fermentation. The extract from unripe fruits exhibited the highest tannin content and the strongest antioxidant activity. All extracts inhibited α-glucosidase and α-amylase to a similar extent and improved insulin-stimulated glucose uptake in 3T3-L1 adipocytes without affecting INSR or SLC2A4 expression. In conclusion, extracts from unripe and fermented C. mas fruits may represent promising agents for alleviating insulin resistance and preventing type 2 diabetes. Full article

Obesity is a chronic systemic disease characterised by insulin resistance, inflammation, and mitochondrial dysfunction. Hyperbaric oxygen therapy (HBOT), which involves the administration of 100% oxygen under elevated atmospheric pressure, has a well-established clinical application in the treatment of non-healing wounds and ischemia, and it is currently being investigated as an adjunctive therapy for obesity and metabolic disorders. The aim of this review is to provide a critical synthesis of recent (2012–2025) evidence regarding the mechanisms of HBOT action in the human body. Furthermore, it examines the metabolic effects and safety profile of HBOT in the context of obesity, with particular attention to experimental and preliminary clinical research. Preclinical studies have demonstrated that HBOT enhances insulin sensitivity, reduces adipose tissue inflammation, and modulates lipid metabolism. The proposed mechanisms include activation of Akt/AMPK signalling and GLUT4 translocation in skeletal muscle, resulting in improved glucose uptake and oxidation, as well as stimulation of thermogenesis in brown adipose tissue. In rodent models of obesity, HBOT has been shown to reduce adipose tissue mass, improve lipid profiles, and restore normal β-oxidation of fatty acids by normalising the expression of peroxisome proliferator-activated receptor-α and carnitine palmitoyl transferase 1B in muscle tissue. Preliminary clinical studies in humans indicate that HBOT enhances both systemic and tissue insulin sensitivity, accompanied by improved mitochondrial function and reduced endoplasmic reticulum stress. Despite these promising findings, data on the long-term efficacy, optimal treatment protocols, and safety of HBOT in obese individuals remain limited. In conclusion, HBOT appears to be a promising adjunctive approach in the management of obesity through the multidirectional improvement in metabolic functions. However, high-quality clinical trials are required to confirm its effectiveness, durability of outcomes, and safety profile across diverse patient populations. Full article

Background/Objectives: Skeletal muscle plays a pivotal role in whole-body glucose metabolism and is a major target in the pathogenesis and treatment of insulin resistance and type 2 diabetes. The C2C12 myotube cell line is one of the most used in vitro models to investigate mechanisms of insulin resistance. This systematic review (1) summarizes the most common experimental conditions including palmitate concentrations and treatment durations used to induce insulin resistance in C2C12 myotubes; (2) characterizes outcomes related to insulin resistance; and (3) discusses strengths and limitations associated with this model. Methods: A systematic search of PubMed and Scopus was conducted using terms “C2C12 AND palmitate AND insulin resistance” and related variations. A total of 191 articles met inclusion criteria. Results: The most frequently used palmitate concentrations were 0.25 mM, 0.5 mM, and 0.75 mM for at least 16 h, which consistently led to decreased insulin-stimulated pAkt expression, GLUT4 abundance, and insulin-stimulated glucose uptake. Conclusions: The high volume and consistency of primary findings is a key strength of this article which demonstrated reduced insulin signaling across various culture conditions, treatment durations, and insulin co-stimulation protocols. Full article

AMP-activated protein kinase (AMPK) is activated by reduced cellular energy charge and mimics the action of insulin in muscle by stimulating increased trafficking of GLUT4 to the plasma membrane. In contrast, we have previously reported that short-term activation of AMPK in adipocytes has no effect on glucose uptake. Whether prolonged AMPK activation influences adipocyte glucose uptake remains poorly characterised. To investigate the effect of sustained AMPK activation on glucose uptake in adipocytes, glucose uptake and insulin signalling were assessed in 3T3-L1 adipocytes stimulated with AICAR and 991, which activate AMPK by different mechanisms, for 24 h. Furthermore, glucose uptake and GLUT4 levels were assessed in adipocytes or adipose tissue from mice lacking AMPKα1 as a model of prolonged AMPK downregulation. AICAR, but not 991, markedly inhibited insulin-stimulated glucose uptake in 3T3-L1 adipocytes. This effect of AICAR was associated with impaired trafficking of GLUT4 to the plasma membrane but did not alter cellular GLUT4 levels or insulin signalling via AKT. The effect of AICAR did, however, require phosphorylation to the nucleotide ZMP and was associated with altered insulin-stimulated MEK1/2-ERK1/2 phosphorylation. Sustained AMPK downregulation had no effect on adipocyte glucose uptake or GLUT4 levels. Taken together, these data demonstrate that sustained changes in AMPK activity do not alter adipocyte glucose uptake. Furthermore, AICAR reduces insulin-stimulated GLUT4 translocation and glucose uptake in adipocytes by a mechanism that is independent of AMPK but requires phosphorylation of AICAR to ZMP. Full article

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

Obesity is characterized by chronic low-grade inflammation, largely driven by macrophage infiltration into adipose tissue, which contributes to the development of insulin resistance. All-trans retinoic acid (ATRA), a biologically active metabolite of vitamin A, has demonstrated anti-inflammatory properties. This study examined the effects of ATRA on inflammation and insulin resistance using a coculture model comprising hypertrophied 3T3-L1 adipocytes and RAW264.7 macrophages. Coculture markedly elevated the production of pro-inflammatory mediators—including nitric oxide, monocyte chemoattractant protein-1, tumor necrosis factor-alpha, and interleukin-6—and increased free fatty acid release while suppressing the secretion of anti-inflammatory adiponectin. Treatment with ATRA (0.1, 1, and 10 μM) significantly reversed these coculture-induced alterations (p < 0.001). ATRA also inhibited the nuclear translocation of NF-κB and downregulated the expression of retinol-binding protein 4 (RBP4). Moreover, ATRA improved insulin-stimulated glucose uptake in adipocytes rendered insulin-resistant by coculture (p < 0.01), an effect associated with the restoration of glucose transporter 4 (GLUT4) and insulin receptor substrate-2 (IRS-2) expression. These findings suggest that ATRA effectively mitigates inflammation and insulin resistance arising from adipocyte–macrophage interactions, highlighting its potential as a therapeutic agent for obesity-related metabolic disorders. Full article

Influenced by various physical, chemical, and microbial factors, the aging process of Citri Reticulatae ‘Chachiensis’ Pericarpium (CRCP) poses a complex scientific challenge. Drawing inspiration from the perspective of traditional Chinese medicine, volatile oils were extracted from CRCP aged 1, 3, 5, and 7 years by steam distillation and subsequently analyzed by GC-MS. The results revealed that the relative percentage of 4-vinylguaiacol (4-VG) increased progressively with aging. Nineteen volatile oil components were further assessed for their glucose metabolism-enhancing activities, with 4-VG emerging as a key active compound. Notably, 4-VG remarkably enhanced insulin-stimulated glucose uptake in C2C12 myotubes. Moreover, 4-VG demonstrated potent antihyperglycemic effects by upregulating IRS-1/Akt/GSK-3β phosphorylation in the insulin signaling pathway on a high-fat diet and STZ-induced diabetic mouse model. In addition, the metabolic pathway of 4-VG, from ferulic acid and then to vanillin and guaiacol, was verified via HPLC-UV, metabolomics, and microbiome analyses, which confirmed the microbial conversion of 4-VG within CRCP. The metabolic pathway was ultimately validated by isolating and identifying Priestia aryabhattai, Bacillus velezensis, and Aspergillus fumigatus from CRCP, with further in vitro culture and biotransformation experiments confirming its functionality and efficiency. These findings provide new insights and experimental evidence that deepen our understanding of the aging process of CRCP. Full article

Background: Small-molecule tyrosine kinase inhibitors (SMTKIs), widely used in cancer chemotherapy, have been reported to variably affect glycaemic control and metabolism, with some agents demonstrating hypoglycaemic effects while others show hyperglycaemic properties. This study aims to elucidate how small-molecule tyrosine kinase inhibitors affect glucose metabolism in C2C12 cells in vitro. Specifically, this study investigated their impact on glucose uptake, AKT expression, GLUT4 expression and translocation, and IL-6 expression. Methods: In this study, skeletal muscle (C2C12) preparations were separately treated with small-molecule tyrosine kinase inhibitors; imatinib, dasatinib, axitinib, and erlotinib for 24 h. Thereafter, the effect of the test drugs was assessed on cell viability using the MTT assay, while glucose uptake was determined by measuring residual glucose concentrations in the culture medium with a glucometer. The expression of AKT, GLUT4, and IL-6 and translocation of GLUT4 were evaluated using ELISA. Furthermore, the effect of the drugs was assessed on insulin-stimulated AKT phosphorylation and GLUT4 translocation. Imatinib, dasatinib, axitinib, and erlotinib were selected due to their effect of glucose metabolism, highlighted in the literature. Results and Discussion: C2C12 cells treated with SMTKIs were viable after 24 h. A concentration-dependent increase in glucose uptake in C2C12 cells treated with imatinib was observed as the concentration of imatinib increased. Axitinib, dasatinib, and erlotinib demonstrated glucose uptake levels comparable to the control across all concentrations. SMTKIs demonstrated an increase in GLUT4 translocation in the absence of insulin. GLUT4 expression was unchanged in cells treated with small-molecule tyrosine kinase inhibitors compared to the control. Small-molecule tyrosine kinase inhibitors showed an increase in AKT expression. C2C12 cells treated with SMTKI were observed to have elevated IL-6 expression compared to the control. Conclusions: The results show that SMTKIs, in particular dasatinib, impact glucose metabolism in C2C12 cells via their effect on GLUT4 translocation and expression and AKT expression. Dasatinib shows promising potential with regard to antidiabetic capabilities. Further research is needed to better understand SMKI effects on metabolic homeostasis, which can perhaps inform future therapeutic strategies. Full article

Obesity is closely associated with the development of insulin resistance (IR) and type 2 diabetes mellitus (T2DM), primarily due to dysfunctional adipose tissue expansion and the secretion of pro-inflammatory cytokines such as interleukin-1β (IL-1β). 14-Deoxy-11,12-didehydroandrographolide (deAND), a major diterpenoid component of Andrographis paniculata, has demonstrated notable antioxidant and anti-inflammatory activities. This study aimed to investigate the protective effects and mechanisms of deAND against IL-1β-induced IR in 3T3-L1 adipocytes. Network pharmacology analysis indicated that deAND targets several IR-related signaling pathways, particularly the MAPK and IRS-1/AKT pathways. The experimental results show that IL-1β stimulated p67phox membrane translocation and reactive oxygen species (ROS) production, contributing to impaired insulin signaling by activating ERK and JNK and reducing IRS-1/AKT phosphorylation, which ultimately decreased insulin-stimulated glucose uptake. Pretreatment with deAND effectively inhibited NOX2-derived ROS generation, suppressed ERK/JNK activation, restored IRS-1/AKT phosphorylation, and reversed the reduction in glucose uptake caused by IL-1β. These findings suggest that deAND can alleviate IR by inhibiting NOX2-mediated oxidative stress, restoring insulin signaling and improving glucose uptake, highlighting its potential as a therapeutic agent for obesity-related IR. Full article

Background/Objectives: Stimulation of glucose uptake in response to ischemic stress is important for cardiomyocyte post-ischemic function and survival. In the diabetic myocardium chronically exposed to an excess of circulating lipids, this mechanism is impaired, making the myocardium more sensitive to ischemia–reperfusion injury (IRI). In vitro studies have shown that exposure to fatty acids (FAs) reduces basal and stimulated glucose uptake in cardiomyocytes. Preliminary results indicate reduced NAD⁺ levels and increased protein lysine acetylation in FA-exposed cardiomyocytes. This study aims to investigate whether intracellular NAD⁺ reduction is responsible for FA-induced increase in protein acetylation and impaired glucose uptake. Methods: Primary rat cardiomyocytes were chronically treated with the sirtuin deacetylase inhibitor nicotinamide (NAM) in absence of FAs to induce protein acetylation. Conversely, we replenished NAD⁺ concentration using nicotinamide riboside (NR) to induce protein deacetylation in FA-exposed cardiomyocytes. Results: Similar to FA exposure, NAM treatment increased protein acetylation and impaired metabolic-stress-stimulated glucose uptake in cardiomyocytes. In contrast, NR supplementation reduced protein acetylation and improved metabolic-stress-stimulated glucose uptake in FA-exposed cardiomyocytes. Neither NAM nor NR influenced insulin-stimulated glucose uptake. Both NAM and FAs induced hydroxyacyl-CoA dehydrogenase trifunctional enzyme subunit α (HADHA) acetylation on lysine residues K¹⁶⁶ and K²¹⁴ and enhanced palmitate oxidation. Conversely, NR treatment induced HADHA deacetylation and reduced palmitate uptake and oxidation in FA-exposed cardiomyocytes. Conclusions: In cardiomyocytes, protein hyperacetylation, resulting from either FA exposure or sirtuin inhibition, impairs metabolic-stress-stimulated glucose uptake and is associated with increased FA oxidation. Full article

Chlorophyll, the green pigment essential for photosynthesis, abundantly found in green vegetables and algae, has attracted growing scientific interest for its potential therapeutic effects, particularly in diabetes management. Recent research highlighted that chlorophyll and its derivatives may beneficially influence glucose metabolism and oxidative stress, key factors in diabetes. This review examines current knowledge on how chlorophyll compounds could aid diabetes control. Chlorophyll and its derivatives appear to support glucose regulation primarily through actions in the gastrointestinal tract. They modulate gut microbiota, improve glucose tolerance, reduce inflammation, and alleviate obesity-related markers. While chlorophyll itself does not directly inhibit digestive enzymes like α-glucosidase, its derivatives such as pheophorbide a, pheophytin a, and pyropheophytin a may slow carbohydrate digestion, acting as α-amylase and α-glucosidase inhibitors, reducing postprandial glucose spikes. Additionally, chlorophyll enhances resistant starch content, further controlling glucose absorption. Beyond digestion, chlorophyll derivatives show promise in inhibiting glycation processes, improving insulin sensitivity through nuclear receptor modulation, and lowering oxidative stress. However, some compounds pose risks due to photosensitizing effects and toxicity, warranting careful consideration. Chlorophyllin, a stable semi-synthetic derivative, also shows potential in improving glucose and lipid metabolism. Notably, pheophorbide a demonstrates insulin-mimetic activity by stimulating glucose uptake via glucose transporters, offering a novel therapeutic avenue. Overall, the antioxidant, anti-inflammatory, and insulin-mimicking properties of chlorophyll derivatives suggest a multifaceted approach to diabetes management. While promising, these findings require further clinical validation to establish effective therapeutic applications. Full article