Role Of Glucose Research Articles

Characterization of the SWEET Gene Family in Blueberry (Vaccinium corymbosum L.) and the Role of VcSWEET6 Related to Sugar Accumulation in Fruit Development

Sugars will eventually be exported transporters (SWEETs) are essential transmembrane proteins involved in plant growth, stress responses, and plant–pathogen interactions. Despite their importance, systematic studies on SWEETs in blueberries (Vaccinium corymbosum L.) are limited. Blueberries are recognized for their rapid growth and the significant impact of sugar content on fruit flavor, yet the role of the SWEET gene family in sugar accumulation during fruit development remains unclear. In this study, 23 SWEET genes were identified in blueberry, and their phylogenetic relationships, duplication events, gene structures, cis-regulatory elements, and expression profiles were systematically analyzed. The VcSWEET gene family was classified into four clades. Structural and motif analysis revealed conserved exon–intron organization within each clade. RT-qPCR analysis showed widespread expression of VcSWEETs across various tissues and developmental stages, correlating with promoter cis-elements. VcSWEET6a, in particular, was specifically expressed in fruit and showed reduced expression during fruit maturation. Subcellular localization indicated that VcSWEET6a is located in the endoplasmic reticulum. Functional assays in yeast confirmed its role in glucose and fructose uptake, with transport activity inhibited at higher sugar concentrations. Overexpression of VcSWEET6a in blueberries resulted in reduced sugar accumulation. These findings offer valuable insights into the role of VcSWEETs in blueberry sugar metabolism.

Long-Term Aerobic Exercise Enhances Hepatoprotection in MAFLD by Modulating Exosomal miR-324 via ROCK1.

Insulin resistance (IR) is central to the progression of non-alcoholic fatty liver disease (MAFLD). While aerobic exercise reduces hepatic fat and enhances insulin sensitivity, the specific mechanisms-particularly those involving exosomal pathways-are not fully elucidated. Exosomes were isolated from 15 MAFLD patients' plasma following the final session of a 12-week aerobic exercise intervention. Liver fat content was measured using MRI-PDFF, and metabolic parameters were assessed via OGTT, HOMA-IR, QUICKI, and VO2 max. Co-culture experiments evaluated the effects of exercise-derived exosomes on IR signaling pathways. miRNA microarray analysis identified miR-324, which was quantified in high-fat diet (HFD) mice with and without exercise and compared between athletes and sedentary controls. Functional assays assessed miR-324's role in glucose and lipid metabolism, while luciferase reporter and Western blot assays confirmed ROCK1 as its direct target. Aerobic exercise significantly reduced liver fat and improved insulin sensitivity in both MAFLD patients and HFD mice. Notably, exosomal miR-324 levels were lower in athletes than sedentary controls, indicating an inverse association with insulin sensitivity. Post-exercise, precursor and mature miR-324 increased in adipose tissue and decreased in muscle, suggesting its adipose origin and inverse regulation. Functional assays demonstrated that miR-324 modulates insulin resistance by targeting ROCK1. Exercise-induced exosomal miR-324 from adipose tissue targets ROCK1, revealing a novel mechanism by which aerobic exercise confers hepatoprotection against insulin resistance in MAFLD. These findings enhance our understanding of how exercise influences metabolic health and may inform future therapeutic strategies for managing MAFLD and related conditions.

Effects of dechlorane plus on hepatic pathology, metabolic health and gut microbiota in male mice.

Dechlorane plus (DP), a widely used flame retardant, was added to Annex A of the Stockholm Convention on Persistent Organic Pollutants in 2023. This study aimed to investigate the effects of DP on glucose and lipid metabolism by orally exposing eight-week-old male mice to environmentally relevant concentrations of DP (0.5, 1, and 5mg/kg/day) for six weeks. The in vivo effects of DP on liver histomorphology, glucose and lipid metabolism, intestinal microbiota, and the associated molecular mechanisms were assessed. Pathological examination revealed that exposure to 1 and 5mg/kg/day DP induced hepatic damage, characterized by structural disarray of the hepatic cords and vacuolar degeneration of liver cells, while 0.5 and 1mg/kg/day DP exposure led to significant triglycerides (TG) accumulation in the liver. Metabolite analysis showed a marked increase in hepatic pyruvate, glycogen, and TG in mice exposed to 0.5 and 1mg/kg/day DP, while 5mg/kg/day exposure resulted in elevated glycogen levels and reduced pyruvate and glucose concentrations. The underlying mechanisms involved the transcriptional regulation of key enzymes related to glucose and lipid metabolism, as well as the activation of the PI3K/AKT pathway. Exposure to 5mg/kg/day DP upregulated genes associated with glycogenesis (GK), glycolysis (HK1 and PK), and fatty acid synthesis (SREBP1, FAS, and ACC1), while downregulating genes involved in gluconeogenesis (PCK1) and fatty acid β-oxidation (CPT1 and PPARA). The activated PI3K/AKT pathway regulated key proteins (GLUT4, GSK3β, and FoxO1), playing distinct roles in glucose and lipid metabolism. High-throughput 16S rDNA sequencing revealed that 5mg/kg/day DP exposure altered the composition and diversity of intestinal microbiota, reducing the relative abundance of beneficial probiotics at both the phylum and genus levels. These findings offer new insights into the complex mechanisms through which DP affects glucose and lipid metabolism in mammals, contributing to a more comprehensive evaluation of its toxicity.

Discovering the therapeutic potential of Naringenin in diabetes related to GLUT-4 and its regulatory factors: A computational approach

This study explores the therapeutic potential of Naringenin, a natural flavonoid, in managing Type 2 Diabetes Mellitus (T2DM) by focusing on Glucose Transporter 4 (GLUT4) and related regulatory proteins that play a role in glucose and lipid metabolism. Through bioinformatics analysis, key proteins such as Carnitine palmitoyltransferase I, mitochondrial carnitine/acylcarnitine carrier protein, and PPARγ were identified, highlighting their importance in insulin sensitivity. Molecular docking results indicated that Naringenin has a strong binding affinity for GLUT4 and PPARγ, with binding energies of -8.18 kcal/mol and -8.21 kcal/mol, respectively. This suggests that Naringenin may modulate these proteins to enhance insulin sensitivity. In contrast, its weaker binding with Enhancer-Binding Protein Alpha points to Naringenin's selective efficacy among various targets. Molecular dynamics (MD) simulations conducted over 100 ns confirmed the stability of the GLUT4-Naringenin complex, showing a reduced RMSD of 1.25 nm and a more compact structure with a Radius of Gyration (Rg) value of 2.14 nm. However, Rho-related GTP exhibited increased instability upon Naringenin binding, indicating a potential inhibitory effect. Additionally, an in silico ADMET profile revealed Naringenin's favorable pharmacokinetics, including low hepatotoxicity, no mutagenic effects, and a high maximum tolerated dose, which supports its safety for drug development. In conclusion, Naringenin shows promising potential in enhancing glucose metabolism and insulin sensitivity, positioning it as a viable candidate for future preclinical and clinical studies in T2DM management. Future research should aim to validate these computational findings through experimental methods and investigate possible synergistic effects with existing antidiabetic medications to improve treatment outcomes.

Liver adrenoceptor alpha-1b plays a key role in energy and glucose homeostasis in female mice.

The liver plays a major role in glucose and lipid homeostasis and acts as a key organ in the pathophysiology of metabolic diseases. Intriguingly, increased sympathetic nervous system (SNS) activity to the liver has been associated with the development and progression of type 2 diabetes and obesity. However, the precise mechanisms by which the SNS regulates hepatic metabolism remain to be defined. Although liver α1-adrenoceptors were suggested to play a role in glucose homeostasis, the specific subtypes involved are unknown mainly because of the limitations of pharmacological tools. Here, we generated and validated a novel mouse model allowing tissue-specific deletion of α-1b adrenoceptor (Adra1b) in hepatocytes to investigate the role of liver ADRA1B in energy and glucose metabolism. We found that selective deletion of Adra1b in mouse liver has limited metabolic impact in lean mice. However, loss of Adra1b in hepatocytes exacerbated diet-induced obesity, insulin resistance, and glucose intolerance in female, but not in male mice. In obese females, this was accompanied by reduced hepatic gluconeogenic capacity and reprogramming of gonadal adipose tissue with hyperleptinemia. Our data highlight sex-dependent mechanisms by which the SNS regulates energy and glucose homeostasis through liver ADRA1B.NEW & NOTEWORTHY The sympathetic nervous system plays an important role in regulating hepatic physiology and metabolism. However, the identity of the adrenoceptors involved in these effects is still elusive. Using CRISPR-Cas9, we developed a novel transgenic tool to study the role of liver α-1b adrenoceptor (ADRA1B). We show that ADRA1B plays a key role in mediating the effects of the sympathetic nervous system on hepatic metabolism, particularly in female mice.

Fibroblast Growth Factors in Cardiovascular Disease.

Despite advancements in managing traditional cardiovascular risk factors, many cardiovascular diseases (CVDs) persist. Fibroblast growth factors (FGFs) have emerged as potential diagnostic markers and therapeutic targets for CVDs. FGF1, FGF2, and FGF4 are primarily used for therapeutic angiogenesis. Clinical applications are being explored based on animal studies using approaches such as recombinant protein administration and adenovirus-mediated gene delivery, targeting patients with coronary artery disease and lower extremity arterial disease. Although promising results have been observed in animal models and early-stage clinical trials, further studies are required to assess their therapeutic potential. The FGF19 subfamily, consisting of FGF19, FGF21, and FGF23, act via endocrine signaling in various organs. FGF19, primarily expressed in the small intestine, plays important roles in glucose, lipid, and bile acid metabolism and has therapeutic potential for metabolic disorders. FGF21, found in various tissues, improves glucose metabolism and insulin sensitivity, suggesting potential for treating obesity and diabetes. FGF23, primarily secreted by osteocytes, regulates vitamin D and phosphate metabolism and serves as an important biomarker for chronic kidney disease and CVDs. Thus, FGFs holds promise for both therapeutic and diagnostic applications in metabolic and cardiovascular diseases. Understanding the mechanisms of FGF may pave the way for novel strategies to prevent and manage CVDs, potentially addressing the limitations of current treatments. This review explores the roles of FGF1, FGF2, FGF4, and the FGF19 subfamily in maintaining cardiovascular health. Further research and clinical trials are crucial to fully understand the therapeutic potential of FGFs in managing cardiovascular health.

Is the HNF4A gene variant paradoxically associated with better prognostic in CAD patients?

Abstract Background The Hepatocyte nuclear factor 4 A (HNF4A) gene was considered to be associated with susceptibility to atherosclerosis and coronary artery disease (CAD). It encodes a protein HNF4α, a genetic transcription factor regulating the genetic expression of thousands of genes playing essential roles in glucose and lipid metabolism. Its abnormal expression is emerging as a critical factor in diabetes, dyslipidemia, and cancer. Loss of function of specific mutations could attenuate its role in CAD pathogenesis and the progression of atherosclerosis. Aim To investigate whether a genetic variant (HNF4α rs1884613 C>G) could be associated with a low genetic function and, paradoxically, a better prognostic in CAD patients. Methods A cohort of 1,718 patients with coronary angiography (>70% stenosis of at least one main coronary vessel) from the GENEMACOR Study was investigated. Thirty-three genetic variants were genotyped using TaqMan assay methodology and HNF4A rs1884613 C>G genotype models were individually studied regarding the occurrence of Major Adverse Cardiovascular Events (MACEs). We used bivariate analysis to evaluate genotypic and allelic differences. Multivariate Cox regression analysis estimated variables independently associated with MACE, and Kaplan-Meier estimate methodology assessed the survival. Results Of the 1,718 CAD patients with the CC wild type, 73.4% had MACE, compared with 66.5% without. CG had 25.2% compared with 30.5% without. Finally, in the GG genotype, only 1.4% had events compared with 3.0% without (p=0.004). Cox regression analysis showed that GG genotype (mutated) is significantly and independently associated with 56% of MACE protection with a hazard ratio (HR) of 0.436; p=0.014. Physical inactivity and type-2 Diabetes remained independently associated with MACE occurrence (Fig.1). Kaplan-Meier cumulative event analysis disclosed that the carriers of the GG genotype were significantly associated with a better event-free time, and CC discloses a worse event-free time (Breslow test, p=0.001) (Fig.2). Conclusions The rs1884613 genetic variant of HNF4A is associated with a better CAD prognosis. This variant could probably induce gene downregulation and HNF4A gene function loss. Modifying and modulating hepatic lipase and lipid metabolism positively affected atherosclerosis progression. Future bioactive modulators for HNF4A variants could raise the possibility that diseases involving diabetes, lipid disorders, and cancer might be amenable to pharmacologic intervention.

Role of glucose in regulating menstrual cycle

Goal of the study: To find correlation between estrogen hormone and glucose intake. Introduction: The main estrogens: estradiol, estrone and their acyl-esters have been studied essentially related to their classical estrogenic functions. However their main effect in the body is probably the sustained control of core energy metabolism. With regard to energy, the estrogen molecular species act through control of glucose availability. Material and methods: There were analyzed articles from the PubMed database, from the last 5 years 2019-2024, mentioning such words as “estrogen”, “glucose”, “ menstrual cycle” [1]. Results: Estrogens play a paramount and continued regulatory role, to maintain energy (lipid / glucose) homeostasis. Estrogens have extensive and powerful control of energy homeostasis. Premenopausal women exhibit enhanced insulin sensitivity and reduced incidence of type 2 diabetes, compared with age matched men, but this advantage disappears after menopause with disrupted glucose homeostasis, in part owing to a reduction in circulating 17 β –estradiol (E2). Moreover a study shows the efficacy of a glucagon like peptide-1 and estrogen dual agonist (GLP1-E2) in pancreatic islet protection. The enzymes that are involved in the menstrual cycle are β-glucoronidase, thought to be involved in the final stages of mucopolysaccharide breakdown. Conclusion: So far there is limited information on the major role played by different forms of physiological estrogens in the control of energy metabolism at the whole body level. E2 protects the functionality of the pancreatic β cells, preventing apoptosis, adapting their function to insulin resistance and maintaining their insulin content. The lack of E2 availability also increases hepatic insulin clearance. Estrogen receptor α plays a crucial role in regulating glucose. However, the underlying mechanisms remain incompletely understood and therefore studies on the maintenance of (lipid / glucose) homeostasis are ongoing [2-10] in various neuro-endocrine and visceral multisystem biomedical areas, where the diagnostic role of markers is essential [11,12].

Metabolic Syndrome, Thyroid Dysfunction, and Cardiovascular Risk: The Triptych of Evil

The triad formed by thyroid dysfunction, metabolic syndrome (MetS), and cardiovascular (CV) risk forms a network with many connections that aggravates health outcomes. Thyroid hormones (THs) play an important role in glucose and lipid metabolism and hemodynamic regulation at the molecular level. It is noteworthy that a bidirectional association between THs and MetS and their components likely exists as MetS leads to thyroid dysfunction, whereas thyroid alterations may cause a higher incidence of MetS. Thyroid dysfunction increases insulin resistance, the circulating levels of lipids, in particular LDL-C, VLDL-C, and triglycerides, and induces endothelial dysfunction. Furthermore, THs are important regulators of both white and brown adipose tissue. Moreover, the pathophysiological relationship between MetS and TH dysfunction is made even tighter considering that these conditions are usually associated with inflammatory activation and increased oxidative stress. Therefore, the role of THs takes place starting from the molecular level, then manifesting itself at the clinical level, through an increased risk of CV events in the general population as well as in patients with heart failure or acute myocardial infarction. Thus, MetS is frequently associated with thyroid dysfunction, which supports the need to assess thyroid function in this group, and when clinically indicated, to correct it to maintain euthyroidism. However, there are still several critical points to be further investigated both at the molecular and clinical level, in particular considering the need to treat subclinical dysthyroidism in MetS patients.

Targeting ketone body metabolism to treat fatty liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a metabolic disorder marked by excessive accumulation of lipids within the liver. If untreated, this condition can progress to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and ultimately, hepatocellular carcinoma (HCC). Given the liver's pivotal role in glucose and fatty acid metabolism, disruptions in these processes are commonly observed in MASLD. Ketone bodies, crucial energy metabolites primarily produced in the liver, are also closely related to the progression of MASLD. Recent studies have demonstrated that disrupted ketogenesis not only accompanies MASLD, but may also play a causal role in its development and progression. Moreover, activation of the ketogenic pathway has been suggested as a promising strategy for reducing excessive hepatic fat accumulation. This review focuses on the regulation of ketogenesis in MASLD, emphasizing the significance of dietary and pharmacological interventions as potential therapeutic approaches to treat fatty liver disease.

MTOR Dysregulation, Insulin Resistance, and Hypertension.

Worldwide, diabetes mellitus (DM) and cardiovascular diseases (CVDs) represent serious health problems associated with unhealthy diet and sedentarism. Metabolic syndrome (MetS) is characterized by obesity, dyslipidemia, hyperglycemia, insulin resistance (IR) and hypertension. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase with key roles in glucose and lipid metabolism, cell growth, survival and proliferation. mTOR hyperactivation disturbs glucose metabolism, leading to hyperglycemia and further to IR, with a higher incidence in the Western population. Metformin is one of the most used hypoglycemic drugs, with anti-inflammatory, antioxidant and antitumoral properties, having also the capacity to inhibit mTOR. mTOR inhibitors such as rapamycin and its analogs everolimus and temsirolimus block mTOR activity, decrease the levels of glucose and triglycerides, and reduce body weight. The link between mTOR dysregulation, IR, hypertension and mTOR inhibitors has not been fully described. Therefore, the main aim of this narrative review is to present the mechanism by which nutrients, proinflammatory cytokines, increased salt intake and renin-angiotensin-aldosterone system (RAAS) dysregulation induce mTOR overactivation, associated further with IR and hypertension development, and also mTOR inhibitors with higher potential to block the activity of this protein kinase.

The Role of Glucose, Insulin and Body Fat in Assessment of Bone Mineral Density and Trabecular Bone Score in Women with Functional Hypothalamic Amenorrhea.

Background: For years, bone mineral density (BMD) has played a key role in assessing bone health, but the trabecular bone score (TBS) is emerging as an equivalent measure. However, BMD alone may not fully measure bone quality or predict osteoporosis risk. To evaluate the usefulness of TBS and BMD in estimating the risk of bone fracture in young women with FHA, this study examined the association between metabolic parameters and bone quality, which was measured using TBS and BMD. Methods: We analyzed the association of metabolic factors with tests assessing bone quality-TBS and BMD. Patients were checked for BMI, measured body fat, and determined serum glucose levels and insulin levels in a 75g glucose load test. Spearman correlation analysis was used. Results: Significant positive correlations were found between BMD and age (p < 0.001) and body fat (p < 0.001), as well as between TBS values and BMI (p < 0.001) and TBS and percent body fat (p < 0.001). Of the variables analyzed in the multivariate analysis, the only independent predictor of higher bone mineral density in the lumbar spine was found to be higher values of the trabecular bone index in the same segment (p < 0.001). Conclusions: The use of TBS provides a simple tool for estimating the risk of bone damage. Ultimately, early screening, diagnosis and treatment of patients with FHA may help prevent osteoporosis and fragility fractures in the long term.

Endurance exercise boosts Sirtuin 1 and PGC1α in mouse skeletal muscle amid nitric oxide synthesis inhibition

Abstract Sarcopenia is an age-related condition characterised by muscle atrophy and loss of muscle mass. The degradation of myofibrils (atrophy) caused by the activation of myofibrillar degradation proteins, e.g. due to a decrease in nitric oxide (NO) associated with aging, contributes to sarcopenia. NO is involved in glucose and lipid metabolism and mitochondrial proliferation; however, whether endurance exercise increases NO production remains unclear. Therefore, in this study, we examined whether endurance exercise promotes metabolic signalling in muscles during continuous suppression of NO production. Mice were assigned to three groups: control, nitric oxide synthase inhibitor administration (L-NAME), and L-NAME administration plus endurance exercise (L-NAME + Ex). The L-NAME group was administered an NO synthesis inhibitor, and the L-NAME + Ex group was administered the inhibitor and performed exercise. The relative amounts of calmodulin (CaM) and nitric oxide synthase (nNOS) in the soleus muscle were significantly increased in the L-NAME + Ex group compared with those in the control and L-NAME groups. In addition, the relative amounts of Sirtuin 1 (Sirt1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) in the L-NAME + Ex group were significantly higher than those in the L-NAME group and similar to those in the control group. CaM and nNOS are involved in NO production, whereas Sirt1 and PGC1α play facilitatory roles in glucose and lipid metabolism. These findings suggest that endurance exercise may enhance muscle metabolic signalling by increasing NO production, even with the suppression of NO synthesis.

Glucagon agonism in the treatment of metabolic diseases including type 2 diabetes mellitus and obesity.

Type 2 diabetes mellitus (T2DM) is associated with obesity and, therefore, it is important to target both overweight and hyperglycaemia. Glucagon plays important roles in glucose, amino acid and fat metabolism and may also regulate appetite and energy expenditure. These physiological properties are currently being exploited therapeutically in several compounds, most often in combination with glucagon-like peptide-1 (GLP-1) agonism in the form of dual agonists. With this combination, increases in hepatic glucose production and hyperglycaemia, which would be counterproductive, are largely avoided. In multiple randomized trials, the co-agonists have been demonstrated to lead to significant weight loss and, in participants with T2DM, even improved glycated haemoglobin (HbA1c) levels. In addition, significant reductions in hepatic fat content have been observed. Here, we review and discuss the studies so far available. Twenty-six randomized trials of seven different GLP-1 receptor (GLP-1R)/glucagon receptor (GCGR) co-agonists were identified and reviewed. GLP-1R/GCGR co-agonists generally provided significant weight loss, reductions in hepatic fat content, improved lipid profiles, insulin secretion and sensitivity, and in some cases, improved HbA1c levels. A higher incidence of adverse effects was present with GLP-1R/GCGR co-agonist treatment than with GLP-1 agonist monotherapy or placebo. Possible additional risks associated with glucagon agonism are also discussed. A delicate balance between GLP-1 and glucagon agonism seems to be of particular importance. Further studies exploring the optimal ratio of GLP-1 and glucagon receptor activation and dosage and titration regimens are needed to ensure a sufficient safety profile while providing clinical benefits.

Exploring Folklore Ecuadorian Medicinal Plants and Their Bioactive Components Focusing on Antidiabetic Potential: An Overview.

Diabetes mellitus (DM) is a global health concern characterized by a deficiency in insulin production. Considering the systemic toxicity and limited efficacy associated with current antidiabetic medications, there is the utmost need for natural, plant-based alternatives. Herbal medicines have experienced exponential growth in popularity globally in recent years for their natural origins and minimal side effects. Ecuador has a rich cultural history in ethnobotany that plays a crucial role in its people's lives. This study identifies 27 Ecuadorian medicinal plants that are traditionally used for diabetes treatment and are prepared through infusion, decoction, or juice, or are ingested in their raw forms. Among them, 22 plants have demonstrated hypoglycemic or anti-hyperglycemic properties that are rich with bioactive phytochemicals, which was confirmed in several in vitro and in vivo studies. However, Bryophyllum gastonis-bonnieri, Costus villosissimus, Juglans neotropica, Pithecellobium excelsum, and Myroxylon peruiferum, which were extensively used in traditional medicine preparation in Ecuador for many decades to treat diabetes, are lacking in pharmacological elucidation. The Ecuadorian medicinal plants used to treat diabetes have been found to have several bioactive compounds such as flavonoids, phenolics, fatty acids, aldehydes, and terpenoids that are mainly responsible for reducing blood sugar levels and oxidative stress, regulating intestinal function, improving insulin resistance, inhibiting α-amylase and α-glucosidase, lowering gluconeogenic enzymes, stimulating glucose uptake mechanisms, and playing an important role in glucose and lipid metabolism. However, there is a substantial lack of integrated approaches between the existing ethnomedicinal practices and pharmacological research. Therefore, this review aims to discuss and explore the traditional medicinal plants used in Ecuador for treating DM and their bioactive phytochemicals, which are mainly responsible for their antidiabetic properties. We believe that the use of Ecuadorian herbal medicine in a scientifically sound way can substantially benefit the local economy and industries seeking natural products.

Inhibition of SGL2 Prevents Albumin Induced Proximal Tubule Inflammation

Albuminuria is an independent risk factor for cardiovascular disease and renal damage in hypertension. It is associated with a higher risk of cardiovascular morbidity and mortality, and with declining kidney function. The Na+-glucose cotransporter-2 (SGLT2) plays a crucial role in glucose and sodium reabsorption in the proximal tubule. Clinical trials have shown that SGLT2 inhibitors can reduce cardiovascular events, lower blood pressure, and decrease the risk of end-stage kidney disease in individuals with type 2 diabetes mellitus. These trials have also demonstrated the potential of SGLT2 inhibitors to provide additional benefits beyond their glucose control, including decreased albuminuria. In this study, we hypothesized that exposure to elevated albumin causes proximal tubule injury and the release of cytokines from the basolateral membrane. We propose that by reducing transport in the proximal tubule, SGLT2 inhibitors may alleviate kidney damage by reducing cytokine production and subsequently renal inflammation. To test our hypothesis, we conducted experiments using Dahl salt-sensitive (SS) rats and immortalized human proximal tubule cells (RPTEC-TERT1). To determine how early albuminuria and proximal injury occur in the development of salt-sensitive hypertension, 24-hour urine was collected from SS rats fed either a control salt (CS, 0.4% NaCl, n=10) or a high salt (HS, 4.0% NaCl, n=11) diet for 7 days. Significant increases in albuminuria were observed after 1 day of HS (CS: 25±7 vs. HS: 59±13 mg/day p=0.016). This was followed by significant increases in urinary kidney injury molecule-1 (Kim-1) after 2 days of HS (CS: 13±2 vs. HS: 23±3 pg/day p=0.021). Preliminary analysis found substantial increases in urinary CCL2 after 4 days of HS (CS: 58±7 vs. HS: 135±25 pg/mg, n=5). To investigate whether the renoprotective effects of SGLT2 inhibitors are in part due to their ability to reduce inflammation in the proximal tubule, we exposed the apical membrane of RPTEC-TERT1 cells to human serum albumin (HSA, 10mg/ml, n=6) with and without Dapagliflozin (Dapa, 15ng/ml, n=5) for 24-hours and measured the levels of CCL2 in the basolateral media. HSA caused a significant increase in CCL2 levels relative to control cells (Control: 42.5±5.6 vs. HSA: 84.1±8.7 pg/mg, p=0.00). This increase was prevented by co-treatment with Dapa and CCL2 levels were equivalent to those in the control cells (HSA+Dapa: 44.0±4.5 pg/mg, p=0.988). In conclusion, our findings support the hypothesis that albuminuria precedes proximal tubule injury and may contribute to the development of renal inflammation in salt-sensitive hypertension. The ability of Dapa to reduce prevent albumin induced CCL2 production in RPTEC-TERT1 cells suggests that SGLT2 inhibitors may reduce renal inflammation in salt-sensitive hypertension and is an area of ongoing studies. Studies funded by R01HL152166 to LE. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Mechanisms of PAK1-Induced Skeletal Muscle Myokines in Improving Islet β-Cell Function

The critical role of skeletal muscle in regulating metabolic homeostasis is well-acknowledged. The p21-activated kinase (PAK1), a prominent signaling molecule in skeletal muscle, has garnered attention for its potential modulatory role in glucose and mitochondrial metabolism. By applying conditioned media derived from PAK1-enriched L6 Glut4 myc myotubes or myoblasts to INS-1 832/13 clonal β-cells, we confirmed that a muscle-derived circulating factor(s) could enhance β-cell function. Furthermore, our mass spectrometry analysis in the conditioned media (CM) collected from PAK1 enriched L6.GLUT4myc myotubes revealed elevated levels of one protein in particular, hepatocyte growth factor activator (HGFAC), which is categorized as a secreted myokine. HGFAC is secreted into the circulation, where, upon activation, it can act in a paracrine or endocrine fashion to proteolytically cleave and activate HGF. It has been reported that HGF has a vital role in islet β-cell mass and function and HNFα, a transcription factor that is expressed in pancreatic β-cells regulates β-cell mass or function by modulating HGFAC expression. Thus, we hypothesize that PAK1-enriched skeletal muscle releases HGFAC into the serum-free conditioned medium and the medium carrying HGFAC when applied to islet β-cells enhances insulin secretion. Elevated levels of HGFAC protein were detected in the cells and their associated CM from PAK1-enriched skeletal myotubes, as compared with that of GFP-transduced control myotubes, using sandwich ELISA to quantify HGFAC. Notably, these cells were incubated in a serum-free medium, a means to eliminate serum factors that might impact HGFAC levels or detection capacity. Given this, we tested the effect of this serum-free CM collected from PAK1-enriched L6.GLUT4myc myotubes application to species-matched (rat) clonal β-cells functional capacity. Indeed, CM from PAK1-enriched myotubes significantly enhanced glucose-stimulated insulin secretion (GSIS), as compared that of the control CM. The presence of elevated HGFAC levels in PAK1-enriched cells, and the beneficial impact of this HGFAC-enriched CM upon beta cell function, reveals a new mechanism by which PAK1-enrichment in skeletal muscle imparts improved overall whole-body glucose homeostasis. further hints at a possible intricate relationship between muscle-pancreas crosstalk in the regulation of islet β-cell insulin secretion. Future investigations into possible autocrine functions of PAK1-enriched skeletal muscle are underway. This research was funded by the National Institutes of Health to D.C.T. (DK067912, DK112917, and DK102233), and an American Heart Association Postdoctoral fellowship to R.B. (#905770). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Role of C1q/TNF-Related Protein 6 for the Evaluation of Coronary Heart Disease Associated with Type 2 Diabetes.

Coronary artery disease (CAD) and type 2 diabetes (T2DM) are closely associated with increased rate of death. C1q/TNF-related protein 6 (CTRP6) is a novel adipocytokine which plays an important role in glucose and lipid metabolism. Little is known about the function of CTRP6 in CAD and T2DM patients. Herein, we aimed to study the association of CTRP6 level with CAD and T2DM. This study included 51 CAD, 44 CAD+T2DM and 65 non-CAD+T2DM patients from Affiliated Aoyang Hospital of Jiangsu University. Serum CTRP6 concentrations were detected by ELISA. Multiple logistic regression was used to analyze the association of serum CTRP6 with CAD and T2DM. Serum CTRP6 concentrations were significantly lower in CAD patients than controls. However, there is no significant statistical difference between CAD+T2DM patients and non-CAD+T2DM patients. Serum CTRP6 was negatively correlated with low-density lipoprotein cholesterol (LDL-C) (ρ=-0.2769, p=0.028) in controls. Serum CTRP6 was positively correlated with age (ρ=0.4121, p=0.0027), systolic blood pressure (SBP) (ρ=0.4012, p=0.0035), Creatinine (ρ=0.3295, p=0.0194), uric acid (UA) (ρ=0.3386, p=0.0162), and left ventricular end diastolic diameter (LVD) (ρ=0.4277, p=0.0042) and negatively correlated with ejection fraction (EF) (ρ=-0.3237, p=0.0342) in CAD patients. Serum CTRP6 was negatively correlated with high-density lipoprotein cholesterol (HDL-C) (ρ=-0.3164, p=0.0387) in CAD+T2DM patients. Multiple logistic regression showed that the decrease of CTRP6 was significantly related to the increased prevalence of CAD. What is more, CTRP6 increased prevalence of T2DM in CAD patients. Lower serum CTRP6 could be a risk factor of CAD. However, higher circulating CTRP6 associated with the increased prevalence of T2DM in CAD patients.

The regulation of AMPK pathway in liver abnormal lipid deposition caused by high carbohydrate diet in rice field eel

AMP-activated protein kinase-alpha 1 (AMPKα1) plays a vital role in glucose and lipid metabolism. Five isonitrogenous and isolipid diets with starch levels (15%, 20%, 25%, 30% and 35%) were formulated to study the modulation of AMPKα1 in hepatic lipid deposition induced by high gelatinized starch diet in rice field eel (Monopterus albus) (initial body weight, 30.00 ± 0.10 g) and the growth trial lasted for 8 weeks. The results showed that dietary gelatinized starch did not affect the growth performance of rice filed eel compared with S15 group. High gelatinized starch could induce AMPKα1 expression and glucose catabolism, and inhibit hepatic glycogen synthesis without effecting glucose content. Dietary ≥ 30% gelatinized starch began to dramatically suppress gluconeogenesis and promote the lipid synthesis, followed by a higher triglyceride (TG) and hepatic crude lipid. Dietary 20–30% gelatinized starch induced phosphorylation of AMPKα compared to 15% gelatinized starch diet, whereas 35% starch dramatically suppressed AMPKα phosphorylation together with unnormal increase in phosphorylation of forkhead box O1 A (FOXO1A) and acetyl-CoA carboxylase (ACC), TG content compared to 30% starch. In short, high gelatinized starch could induce AMPKα1 expression and promoted systemic metabolism, whereas dietary ≥ 25% gelatinized starch initially suppressed AMPKα1 activation and caused abnormal lipid deposition in liver of rice field eel.

The association of serum irisin with anthropometric, metabolic, and bone parameters in obese children and adolescents.

Irisin is an adipomyokine secreted by muscle and adipose cells, and it plays a role in glucose, fat, and bone metabolism. This study aimed to determine the correlation of serum irisin levels with anthropometric, metabolic, and bone parameters in obese children and adolescents. This single-center study included 103 Korean children and adolescents: 54 (52.4%) obese participants with a body mass index (BMI) ≥95th percentile and 49 (47.6%) healthy controls with BMI within the 15th to 85th percentile. Various parameters were measured, including fasting blood glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride and glucose (TyG) index, lipid profile, alkaline phosphatase (ALP), osteocalcin, and 25(OH)-Vitamin D levels. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DEXA) in 33 healthy subjects. Serum irisin was significantly higher in the obese group than in the control group (mean 18.1 ± 3.5 vs. 16.2 ± 2.0 ng/mL; p = 0.001). Serum irisin level was positively correlated with chronological age (r = 0.28; p = 0.004), height SDS (r = 0.24; p = 0.02), BMI SDS (r = 0.37; p < 0. 001), fasting glucose (r = 0.27; p = 0.007), fasting insulin (r = 0.23; p = 0.03), HOMA-IR (r = 0.21; p = 0.04), osteocalcin (r = 0.27; p = 0.006) and negatively correlated with HDL cholesterol (r = -0.29; p = 0.005). All these correlations were evident in obese subjects but not in healthy subjects. ALP and 25(OH)-Vitamin D were unrelated to irisin levels. Among 33 healthy subjects, total body-less head (TBLH) BMD Z-score was positively correlated with serum irisin (r = 0.39; p = 0.03), osteocalcin (r = 0.40; p = 0.02), fasting insulin (r = 0.39; p = 0.04), and HOMA-IR (r = 0.38; p = 0.047). This study demonstrated an association between irisin levels and glucose, lipid, and bone parameters in children and adolescents. Our findings suggest that irisin has a potential role in metabolic disorders and bone health in obese children and adolescents.