Excess Glucose Research Articles

Injectable Multifunctional Hyaluronan based Hydrogel Suppressing the Excessive Glucose and Reactive Oxygen Species in Diabetic Wound Treatment

In diabetic wounds, the overlapping presence of excessive glucose and reactive oxygen species (ROS) forming a vicious cycle that severely impedes the wound healing process. Despite advancements in wound care, current treatments often limit in addressing these two critical factors simultaneously. To address these challenges, this study introduces a multifunctional hydrogel system capable of dual regulation of excessive glucose and ROS levels in a hyperglycemic environment, while also provide a platform with favorable properties that support wound healing. First, by modifying hyaluronic acid (HA) chains with vinyl sulfone and thiol functional groups, the resulting hydrogel exhibited tunable gelation time, elastic modulus, and degradation rates, making it adaptable for diabetic wound management. Notably, this hydrogel allows for precise glucose and ROS regulation by encapsulating glucose oxidase (GOx), horseradish peroxidase (HRP), and tannic acid (TA) within the HA hydrogel matrix. It was verified that the hydrogels could reduce the glucose levels to desired concentration by varying the encapsulated GOx content. Simultaneously, the combined ROS-scavenging effect of HRP and TA effectively addressed the excessive ROS problem. Specifically, H2O2 generated from the GOx-glucose reaction was consumed in the HRP-mediated polymerization of TA, and free radicals (OH•, DPPH) were scavenged up to 70% by TA. Due to the glucose and ROS regulation properties, this hydrogel system was able to promote the proliferation and migration of human dermal fibroblast in a hyperglycemic environment. Overall, this study offers a simple and effective approach to regulate the excessive levels of glucose and ROS in a hyperglycemic condition, which has potential in creating a multifunctional platform for diabetic wound treatment.

Postprandial hypoglycaemia after gastric bypass in type 2 diabetes: pathophysiological mechanisms and clinical implications.

Postprandial hypoglycaemia (PPHG) is a frequent late complication of Roux-en-Y gastric bypass (RYGB) in people without diabetes. We aimed to examine the pathogenetic mechanisms of PPHG and its clinical consequences in people with a history of type 2 diabetes. In this case-control study, 24 participants with type 2 diabetes treated with RYGB (14 women; median [IQR] age 53.5 [13.8] years, BMI 29.3 [6.3] kg/m2, HbA1c 36.0 [6.2] mmol/mol [5.4% (0.6%)]) underwent a dual-tracer, frequently sampled, 300 min, 75 g OGTT for the diagnosis of PPHG (glucose nadir <3.0 mmol/l, or <3.3 mmol/l with symptoms). Plasma glucose, glucose tracers, insulin, C-peptide, glucagon-like peptide-1, gastric inhibitory polypeptide, glucagon, adrenaline (epinephrine), noradrenaline (norepinephrine), cortisol and NEFAs were measured. Mathematical models were implemented to estimate glucose metabolic fluxes and beta cell function. ECG recordings, cognitive testing and hypoglycaemia awareness assessments were repeated during the OGTT. Glycaemic levels and dietary habits were assessed under free-living conditions. PPHG occurred in 12 (50%) participants, mostly without symptoms, due to excessive tracer-derived glucose clearance (mean group difference ± SE in AUC0-180 min +261±72 ml min-1 kg-1 × min) driven by higher whole-body insulin sensitivity and early glucose-stimulated hyperinsulinaemia, the latter depending on lower insulin clearance and enhanced beta cell function, regardless of incretin hormones. PPHG participants also had defective counterregulatory hormone responses to hypoglycaemia, preventing a physiological increase in endogenous glucose production and the appearance of symptoms and signs of sympathetic cardiovascular activation and neuroglycopenia. PPHG was associated with more frequent and prolonged hypoglycaemia on 14 day continuous glucose monitoring and alterations in free-living dietary habits. Our results demonstrate that post-bypass PPHG occurs frequently in individuals with a history of type 2 diabetes, often without warning symptoms, and expose its complex pathogenetic mechanisms, revealing potential therapeutic targets.

Postprandial regulation of glucose metabolism and insulin signaling pathways in Macrobrachium rosenbergii

To better understand postprandial glucose metabolic mechanisms in crustaceans, the pathways involved in glucose transport, breakdown, synthesis, and regulation were investigated in the giant freshwater prawn Macrobrachium rosenbergii after feeding. Prawns were fasted for 48 hours and then refed to satiation. Glucose and glycogen contents, along with the transcriptional levels of glucose metabolism-related genes, were measured at 0, 1, 3, 6, and 10 hours after feeding (HAF). Plasma glucose levels peaked at 3 HAF and returned to basal levels by 6–10 HAF. Hepatopancreas glucose followed a similar trend, except for a notable increase at 10 HAF, suggesting gluconeogenesis at this time point. Expression analysis of glucose transporter genes in hepatopancreas revealed a significant upregulation of GLUT1 at 3, 6, and 10 HAF, while GLUT2 showed significant decreases only at 6 HAF. Glycolysis-related genes (GK and PK) exhibited transient increases post-feeding, whereas the gluconeogenesis-related gene FBP was initially suppressed, with expression recovering from 6 HAF onward. The glycogenesis-related gene GS was significantly upregulated at 3, 6, and 10 HAF, correlating with increased glycogen levels in the hepatopancreas. Conversely, the expression of the glycogenolysis-related gene GDE was inhibited after feeding, along with a decrease in the glycogenesis inhibitory gene GSK3. Genes in the insulin signaling pathway (ILP, PI3KCa, and AKT) were upregulated post-feeding, peaking at 3 HAF and subsequently declining. These results suggest that feeding stimulates the insulin signaling pathway and GLUT1 to transport excess glucose, inducing glycolysis and hepatopancreatic glycogenesis, while inhibiting gluconeogenesis and glycogenolysis.

Measuring Cell Dimensions in Fission Yeast Using Machine Learning.

In fission yeast (Schizosaccharomyces pombe), cell length is a crucial indicator of cell cycle progression. Microscopy screens that examine the effect of agents or genotypes suspected of altering genomic or metabolic stability and thus cell size are crucial for studying disruptions to cell cycle dynamics. This method is based on using an automated cell segmentation algorithm to measure S. pombe cells imaged by brightfield (BF) microscopy methods. PhotoPhenosizer (PP) is a machine learning-based tool designed for automated cell measuring and dimensional analysis of morphology frequency distributions. Integration of this method into large-scale pipelines for tracking cell dimension change streamlines morphological measurements, which facilitates the examination of cellular responses to genomic and metabolic stresses. In this protocol, we use PP to observe the effect of genomic instability on cell size dynamics over a 12-day chronological lifespan assay. Our results show that relative to wild-type cells, a replication stress mutant shows larger cells during chronological aging in excess glucose media. Our results are consistent with activation of checkpoints that regulate cell morphology in response to DNA damage. This method's application highlights the relevance of its incorporation in experimental routines that require large-scale image processing and its adoption by users with routine needs in S. pombe molecular research projects.

The Warburg Effect is the result of faster ATP production by glycolysis than respiration

Many prokaryotic and eukaryotic cells metabolize glucose to organism-specific by-products instead of fully oxidizing it to carbon dioxide and water-a phenomenon referred to as the Warburg Effect. The benefit to a cell is not fully understood, given that partial metabolism of glucose yields an order of magnitude less adenosine triphosphate (ATP) per molecule of glucose than complete oxidation. Here, we test a previously formulated hypothesis that the benefit of the Warburg Effect is to increase ATP production rate by switching from high-yielding respiration to faster glycolysis when excess glucose is available and respiration rate becomes limited by proteome occupancy. We show that glycolysis produces ATP faster per gram of pathway protein than respiration in Escherichia coli, Saccharomyces cerevisiae, and mammalian cells. We then develop a simple mathematical model of energy metabolism that uses five experimentally estimated parameters and show that this model can accurately predict absolute rates of glycolysis and respiration in all three organisms under diverse conditions, providing strong support for the validity of the ATP production rate maximization hypothesis. In addition, our measurements show that mammalian respiration produces ATP up to 10-fold slower than respiration in E. coli or S. cerevisiae, suggesting that the ATP production rate per gram of pathway protein is a highly evolvable trait that is heavily optimized in microbes. We also find that E. coli respiration is faster than fermentation, explaining the observation that E. coli, unlike S. cerevisiae or mammalian cells, never switch to pure fermentation in the presence of oxygen.

Effectiveness and mechanisms of sodium-dependent glucose transporter 2 inhibitors in type 2 diabetes and heart failure patients.

We comment on an article by Grubić Rotkvić et al published in the recent issue of the World Journal of Cardiology. We specifically focused on possible factors affecting the therapeutic effectiveness of sodium-dependent glucose transporter inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) and their impact on comorbidities. SGLT2i inhibits SGLT2 in the proximal tubules of the kidneys, lowering blood glucose levels by inhibiting glucose reabsorption by the kidneys and causing excess glucose to be excreted in the urine. Previous studies have demonstrated a role of SGLT2i in cardiovascular function in patients with diabetes who take metformin but still have poor glycemic control. In addition, SGLT2i has been shown to be effective in anti-apoptosis, weight loss, and cardiovascular protection. Accordingly, it is feasible to treat patients with T2DM with cardiovascular or renal diseases using SGLT2i.

Glucotoxicity suppresses function of pancreatic beta and duct cells via miR-335-targeted Runx2 and insulin-mediated mechanism.

Pancreatic cell dynamics have important contributions to the development of type 2 diabetes and related diseases such as nonalcoholic fatty pancreas disease. The aim of this study was to investigate the effects of prolonged excessive glucose exposure on the functions of pancreatic beta cells and duct cells in single and co-culture conditions. In this study, we focused on the effects of glucotoxicity on insulin secretion which is the main function of beta cells and on progenitor functions of duct cells. Rat primary INS1 beta cells and ARIP duct cells were exposed to glucose (25mM) for 72h under single or indirect co-culture conditions. Glucotoxicity stimuli increased insulin secretion and decreased insulin expression in single beta cells while stimulating beta-cell differentiation and adipogenesis in single duct cells. On the other hand, glucotoxicity caused functional loss and increased proliferation and apoptosis in beta cells while increasing proliferation but suppressed beta-cell differentiation and adipogenesis in duct cells under co-culture conditions. The expression level of miR-335, a microRNA known to be upregulated by leptin and target Runx2, was measured. As a result, unlike single-cell culture, glucotoxicity upregulated miR-335, downregulated Runx2, and decreased insulin signaling in beta cells while downregulating miR-335 and upregulating Runx2, and decreased insulin signaling in duct cells under co-culture conditions. When the results of single and co-culture experiments are compared, insulin and miR-335 may be seen as important mediators for setting up the relation between beta and duct cells. Our findings are important for preventing the development of type 2 diabetes and nonalcoholic fatty pancreas disease, even developing new diagnosis and treatment strategies.

Excess glucose alone induces hepatocyte damage due to oxidative stress and endoplasmic reticulum stress

Type 2 diabetes mellitus (DM) is a significant risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). With the increasing prevalence of type 2 DM and MASLD due to lifestyle changes, understanding their impact on liver health is crucial. However, the hepatocellular damage caused by glucose alone is unknown. This study investigates the effect of excess glucose on hepatocytes, focusing on oxidative stress, endoplasmic reticulum stress (ER stress), apoptosis, autophagy, and cell proliferation. We treated an immortalized-human hepatocyte cell line with excess glucose and analyzed. Excess glucose induced oxidative stress and ER stress in a time- and concentration-dependent manner, leading to apoptosis. Oxidative stress and ER stress were independently induced by excess glucose. Proteasome inhibitors and palmitic acid exacerbated glucose-induced stress, leading to the formation of Mallory-Denk body-like inclusion bodies. Despite these stresses, autophagic flux was not altered. Excess glucose also caused DNA damage but did not affect cell proliferation. This suggests that glucose itself can contribute to the progression of metabolic dysfunction-associated steatohepatitis (MASH) and carcinogenesis of HCC in patients with type 2 DM. Managing blood glucose levels is crucial to prevent hepatocyte damage and associated complications.

Abstract C109: Identifying a novel metabolic reprogramming strategy to inhibit diabetes-associated TNBC in African American

Abstract Cancer cells have an increased glucose metabolism, primarily characterized by augmented glucose uptake and aerobic glycolysis, converting glucose into pyruvate, eventually producing lactate. Breast cancer (BC) is the most commonly diagnosed cancer and the second leading cause of death among women in the United States. The triple-negative breast cancer (TNBC) subgroup is the most aggressive, metastatic, and refractory because of the absence of the three characteristic receptors: Estrogen (ER), progesterone (PR), and human epidermal growth factor (Her2/neu), representing approximately 10-15% of all BC cases. Racial disparities analysis demonstrates that African American (AA) has a higher incidence of TNBC subtype, with an earlier onset, more advanced stage, more aggressive histologic features, and poor survival, compared to other ethnic groups. Hyperglycemia affects the cancer progression through metabolic reprogramming and molecular alterations. AA women with Type 2 diabetes (T2D) are at increased risk of developing ER-negative BC. The reasonable combination therapy of metformin with NF-𝜅Bi and MCT4i, is promising because it can rapidly disable tumor cell growth but with a minor effect on normal cells, holding promise as an anti-BC treatment. Because of the potential side effects of MCT4 inhibitors and the potent inhibitory effect of microRNA on target genes, we consider using microRNA instead of inhibitors to suppress MCT4 expression. We will investigate the anti-diabetes-associated TNBC effect of the MRS, consisting of blocking lactate export via MCT4 degradation by miR-206, in combination with promoting lactate production via forcing glycolysis with metformin and NF-𝜅Bi treatment, in a preclinical study of AA women. Moreover, our previous study and other studies have also shown an elevated expression of Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) in BC tissues and cells, particularly in metastatic TNBC. We will also explore the molecular mechanisms by which high glucose (HG) leads to lactate accumulation in BC cells. Our overall strategy is that excessive glucose uptake upregulates the MCT4 through a MALAT1/miR-206/MCT4 axis, miR-206-directed MRS shifts glucose metabolism from Oxidative phosphorylation (OXPHOS) to glycolysis, increasing lactate production. Meanwhile, blocking the export of excessive lactate through MCT4 degradation causes high intracellular lactate accumulation and a decrease in intracellular pH (pHi), resulting in metabolic crisis and BC cell death. Due to a complex interplay between hyperglycemia and cancer, antihyperglycemic drugs have often been devised in combination with anticancer drugs for cancer treatment. Our proposed approach will broadly impact the field by providing a novel idea for therapies targeting cancer cell lactate metabolism. In the long term, these studies may reveal an effective therapeutic strategy for diabetes-associated BC, especially in AA women. Citation Format: Qiongyu Hao, Yong Wu, Yanyuan Wu, Jaydutt Vadgama. Identifying a novel metabolic reprogramming strategy to inhibit diabetes-associated TNBC in African American [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C109.

Exploring the Biological Effects of Anti-Diabetic Vanadium Compounds in the Liver, Heart and Brain.

The prevalence of diabetes mellitus and diabetes-related complications is rapidly increasing worldwide, placing a substantial financial burden on healthcare systems. Approximately 537 million adults are currently diagnosed with type 1 or type 2 diabetes globally. However, interestingly, the increasing morbidity rate is primarily influenced by the effects of long-term hyperglycemia on vital organs such as the brain, the liver and the heart rather than the ability of the body to use glucose effectively. This can be attributed to the summation of the detrimental effects of excessive glucose on major vascular systems and the harmful side effects attributed to the current treatment associated with managing the disease. These drugs have been implicated in the onset and progression of cardiovascular disease, hepatocyte injury and cognitive dysfunction, thereby warranting extensive research into alternative treatment strategies. Literature has shown significant progress in utilizing metal-based compounds, specifically those containing transition metals such as zinc, magnesium and vanadium, in managing hyperglycaemia. Amongst these metals, research carried out on vanadium reflected the most promising anti-diabetic efficacy in cell culture and animal studies. This was attributed to the ability to improve glucose management in the bloodstream by enhancing its uptake and metabolism in the kidney, brain, skeletal muscle, heart and liver. Despite this, organic vanadium was considered toxic due to its accumulative characteristics. To alleviate vanadium's toxic nature while subsequently manipulating its therapeutic properties, vanadium complexes were synthesized using either vanadate or vanadyl as a base compound. This review attempts to evaluate organic vanadium salts' therapeutic and toxic effects, highlight vanadium complexes' research and provide insight into the novel dioxidovanadium complex synthesized in our laboratory to alleviate hyperglycaemia-associated macrovascular complications in the brain, heart and liver.

From Hyperinsulinemia to Cancer Progression: How Diminishing Glucose Storage Capacity Fuels Insulin Resistance

ABSTRACTBackgroundType 2 diabetes (T2D) is a complex metabolic disorder characterized by insulin resistance, hyperglycemia, and hyperinsulinemia. A significant portion of individuals with T2D are unaware of their condition until it has reached advanced stages. T2D is also associated with an increased risk and worse prognosis of cardiovascular disease, cognitive decline, and cancer. Understanding the mechanisms underlying the emergence of insulin resistance is critical for improving early detection and therapeutic interventions.MethodsAn updated framework is proposed to describe the emergence of insulin resistance that precedes the development of T2D. The model focuses on the impact of diminishing capacity to store excess glucose, which can occur due to a multitude of factors, including age‐related muscle loss. The model is used to simulate responses to oral glucose tolerance tests (OGTTs) to capture the transition from a normal to a diabetic phenotype, as defined by the Kraft criteria. Additionally, the model is used to explore how the metabolic environment influences tumor progression, drawing on experimental data regarding the impact of transient diabetic phenotypes and hyperinsulinemia on cancer therapy efficacy.ResultsThe model successfully demonstrates that reduced glucose storage capacity can qualitatively reproduce the progression from normal to diabetic phenotypes observed in OGTT responses. Furthermore, it shows that tumor progression or regression is highly dependent on the host's metabolic environment, particularly hyperinsulinemia. This aligns with experimental results that connect drug‐induced hyperinsulinemia to a loss of therapeutic efficacy against tumors, whereas the reversal of the diabetic phenotype could restore drug sensitivity and treatment response.ConclusionsThis study highlights the critical role of hyperinsulinemia, even in normoglycemic individuals, in both the progression of T2D and the modulation of cancer therapy outcomes. Addressing hyperinsulinemia emerges as a promising strategy to enhance cancer treatment efficacy and improve overall health outcomes in patients with or at risk for T2D.

Endothelin 3/EDNRB signaling induces thermogenic differentiation of white adipose tissue

Thermogenic adipose tissue, consisting of brown and beige fat, regulates nutrient utilization and energy metabolism. Human brown fat is relatively scarce and decreases with obesity and aging. Hence, inducing thermogenic differentiation of white fat offers an attractive way to enhance whole-body metabolic capacity. Here, we show the role of endothelin 3 (EDN3) and endothelin receptor type B (EDNRB) in promoting the browning of white adipose tissue (WAT). EDNRB overexpression stimulates thermogenic differentiation of human white preadipocytes through cAMP-EPAC1-ERK activation. In mice, cold induces the expression of EDN3 and EDNRB in WAT. Deletion of EDNRB in adipose progenitor cells impairs cold-induced beige adipocyte formation in WAT, leading to excessive weight gain, glucose intolerance, and insulin resistance upon high-fat feeding. Injection of EDN3 into WAT promotes browning and improved whole-body glucose metabolism. The findings shed light on the mechanism of WAT browning and offer potential therapeutics for obesity and metabolic disorders.

Diet and physical exercise as key players to tackle MASLD through improvement of insulin resistance and metabolic flexibility.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has emerged as a prevalent health concern, encompassing a wide spectrum of liver-related disorders. Insulin resistance, a key pathophysiological feature of MASLD, can be effectively ameliorated through dietary interventions. The Mediterranean diet, rich in whole grains, fruits, vegetables, legumes, and healthy fats, has shown promising results in improving insulin sensitivity. Several components of the Mediterranean diet, such as monounsaturated fats and polyphenols, exert anti-inflammatory and antioxidant effects, thereby reducing hepatic steatosis and inflammation. Furthermore, this dietary pattern has been associated with a higher likelihood of achieving MASLD remission. In addition to dietary modifications, physical exercise, particularly resistance exercise, plays a crucial role in enhancing metabolic flexibility. Resistance exercise training promotes the utilization of fatty acids as an energy source. It enhances muscle glucose uptake and glycogen storage, thus reducing the burden on the liver to uptake excess blood glucose. Furthermore, resistance exercise stimulates muscle protein synthesis, contributing to an improved muscle-to-fat ratio and overall metabolic health. When implemented synergistically, the Mediterranean diet and resistance exercise can elicit complementary effects in combating MASLD. Combined interventions have demonstrated additive benefits, including greater improvements in insulin resistance, increased metabolic flexibility, and enhanced potential for MASLD remission. This underscores the importance of adopting a multifaceted approach encompassing dietary modifications and regular physical exercise to effectively manage MASLD. This narrative review explores the biological mechanisms of diet and physical exercise in addressing MASLD by targeting insulin resistance and decreased metabolic flexibility.

The Synergistic Effects of Polyol Pathway-Induced Oxidative and Osmotic Stress in the Aetiology of Diabetic Cataracts.

Cataracts are the world's leading cause of blindness, and diabetes is the second leading risk factor for cataracts after old age. Despite this, no preventative treatment exists for cataracts. The altered metabolism of excess glucose during hyperglycaemia is known to be the underlying cause of diabetic cataractogenesis, resulting in localised disruptions to fibre cell morphology and cell swelling in the outer cortex of the lens. In rat models of diabetic cataracts, this damage has been shown to result from osmotic stress and oxidative stress due to the accumulation of intracellular sorbitol, the depletion of NADPH which is used to regenerate glutathione, and the generation of fructose metabolites via the polyol pathway. However, differences in lens physiology and the metabolism of glucose in the lenses of different species have prevented the translation of successful treatments in animal models into effective treatments in humans. Here, we review the stresses that arise from hyperglycaemic glucose metabolism and link these to the regionally distinct metabolic and physiological adaptations in the lens that are vulnerable to these stressors, highlighting the evidence that chronic oxidative stress together with osmotic stress underlies the aetiology of human diabetic cortical cataracts. With this information, we also highlight fundamental gaps in the knowledge that could help to inform new avenues of research if effective anti-diabetic cataract therapies are to be developed in the future.

Relation between possible under-diagnosed/treated glucose dysmetabolism, delayed villous maturation, and lethal fetal pneumonia

BackgroundGestational diabetes mellitus (GDM) is a known risk factor for stillbirth (Rosenstein et al., 2012) [1]. Delayed villous maturation (DVM), predominantly seen in term placentas in pregnancies complicated with glucose dysmetabolism, may in part be a consequence of excessive maternal glucose leading to release of fetal insulin and other growth factors that promote excessive placental growth at the expense of villous maturation (Redline, 2012) [2]. CasesWe present three cases of under-diagnosed/treated glucose dysmetabolism in women in their first pregnancies cared for in other hospitals in the United Kingdom (UK) with the fatal fetal/neonatal outcomes and confirmed DVM in the placenta and congenital pneumonia on post-mortem examination in all three cases. ConclusionThis cluster supports a hypothesis that DVM and glucose dysmentabolism may make babies more susceptible to severe perinatal infection. All three cases received the antenatal care in their subsequent pregnancies in our unit and had confirmed glucose dysmetabolism which was treated and resulted in healthy babies.

Development of the CaCO3-coated passive film on Mg alloy densified by glucose/sodium gluconate via the assistance of ultrasound with a regrowth feature in Portland cement

To address the limitations of non-dense chemical conversion coatings on Mg alloys, glucose and sodium gluconate were employed to facilitate the creation of dual-layered CaCO3 coated MgO passive layers via ultrasound-assisted chemical conversion. Results indicate that the addition of an appropriate quantity of glucose enhances the corrosion resistance of CaCO3/MgO coatings, whereas excessive glucose compromises coating density. Furthermore, higher concentrations of sodium gluconate contribute to improving coating density. Significantly, the immersion in simulated concrete pore solutions with 0.6 M NaCl reveals a re-growth phenomenon instead of corrosion. This observation stems from the increased CaCO3 production, including calcite and aragonite during the immersion process.

N-Glycosylation of MRS2 balances aerobic and anaerobic energy production by reducing rapid mitochondrial Mg2+ influx in conditions of high glucose or impaired respiratory chain function.

N-linked glycoproteins function in numerous biological processes, modulating enzyme activities as well as protein folding, stability, oligomerization, and trafficking. While N-glycosylation of mitochondrial proteins has been detected by untargeted MS-analyses, the physiological existence and roles of mitochondrial protein N-linked glycosylation remain under debate. Here, we report that MRS2, a mitochondrial inner membrane protein that functions as the high flux magnesium transporter, is N-glycosylated to various extents depending on cellular bioenergetic status. Both N-glycosylated and unglycosylated isoforms were consistently detected in mitochondria isolated from mouse liver, rat and mouse liver fibroblast cells (BRL 3A and AFT024, respectively) as well as human skin fibroblast cells. Immunoblotting of MRS2 showed it was bound to, and required stringent elution conditions to remove from, lectin affinity columns with covalently bound concanavalin A or Lens culinaris agglutinin. Following peptide:N-glycosidase F (PNGase F) digestion of the stringently eluted proteins, the higher Mr MRS2 bands gel-shifted to lower Mr and loss of lectin affinity was seen. BRL 3A cells treated with two different N-linked glycosylation inhibitors, tunicamycin or 6-diazo-5-oxo-l-norleucine, resulted in decreased intensity or loss of the higher Mr MRS2 isoform. To investigate the possible functional role of MRS2 N- glycosylation, we measured rapid Mg2+ influx capacity in intact mitochondria isolated from BRL 3A cells in control media or following treatment with tunicamycin or 6-diazo-5-oxo-l-norleucine. Interestingly, rapid Mg2+ influx capacity increased in mitochondria isolated from BRL 3A cells treated with either N-glycosylation inhibitor. Forcing reliance on mitochondrial respiration by treatment with either galactose media or the glycolytic inhibitor 2-deoxyglucose or by minimizing glucose concentration similarly reduced the N-glycosylated isoform of MRS2, with a correlated concomitant increase in rapid Mg2+ influx capacity. Conversely, inhibiting mitochondrial energy production in BRL 3A cells with either rotenone or oligomycin resulted in an increased fraction of N-glycosylated MRS2, with decreased rapid Mg2+ influx capacity. Collectively, these data provide strong evidence that MRS2 N-glycosylation is directly involved in the regulation of mitochondrial matrix Mg2+, dynamically communicating relative cellular nutrient status and bioenergetic capacity by serving as a physiologic brake on the influx of mitochondrial matrix Mg2+ under conditions of glucose excess or mitochondrial bioenergetic impairment.

The Functional Role of microRNAs and mRNAs in Diabetic Kidney Disease: A Review.

Diabetes is a group of diseases marked by poor control of blood glucose levels. Diabetes mellitus (DM) occurs when pancreatic cells fail to make insulin, which is required to keep blood glucose levels stable, disorders, and so on. High glucose levels in the blood induce diabetic effects, which can cause catastrophic damage to bodily organs such as the eyes and lower extremities. Diabetes is classified into many forms, one of which is controlled by hyperglycemia or Diabetic Kidney Disease (DKD), and another that is not controlled by hyperglycemia (nondiabetic kidney disease or NDKD) and is caused by other factors such as hypertension, hereditary. DKD is associated with diabetic nephropathy (DN), a leading cause of chronic kidney disease (CKD) and end-stage renal failure. The disease is characterized by glomerular basement membrane thickening, glomerular sclerosis, and mesangial expansion, resulting in a progressive decrease in glomerular filtration rate, glomerular hypertension, and renal failure or nephrotic syndrome. It is also represented by some microvascular complications such as nerve ischemia produced by intracellular metabolic changes, microvascular illness, and the direct impact of excessive blood glucose on neuronal activity. Therefore, DKD-induced nephrotic failure is worse than NDKD. MicroRNAs (miRNAs) are important in the development and progression of several diseases, including diabetic kidney disease (DKD). These dysregulated miRNAs can impact various cellular processes, including inflammation, fibrosis, oxidative stress, and apoptosis, all of which are implicated during DKD. MiRNAs can alter the course of DKD by targeting several essential mechanisms. Understanding the miRNAs implicated in DKD and their involvement in disease development might lead to identifying possible therapeutic targets for DKD prevention and therapy. Therefore, this review focuses specifically on DKD-associated DN, as well as how in-silico approaches may aid in improving the management of the disease.

Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors and Cardiovascular Outcomes: A Review of Literature.

Coronary arterial diseases are a major contributor to disease and death worldwide and are most often compounded by several other underlying medical conditions. A key concern is type 2 diabetes mellitus (T2DM). Despite progress in medical advancements, these life-threatening illnesses are still underdiagnosed and undermanaged. A relatively newer class of anti-diabetic drugs, the sodium-glucose cotransporter-2 inhibitors (SGL2-Is), also termed gliflozins, have shown promising results in reducing cardiovascular risk, regardless of diabetic status. These drugs have on-target (promoting renal glycosuria and diuresis by acting on the SGLT-2 channels in the proximal convoluted tubule) and off-target effects contributing to the reported cardiovascular benefit. Some emerging theories about its impact on myocardial energetics, calcium balance, and renal physiology exist. In this review article, we explored three major cardiovascular outcome trials: the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, the CANagliflozin cardioVascular Assessment Study (CANVAS) program, and the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 DiabetesMellitus Patients-Removing Excess Glucose(EMPA-REG OUTCOME) trial to evaluate the cardiovascular effects of SGLT2-Is.

Obesity-related neuropathy: the new epidemic.

To examine the evidence evaluating the association between obesity and neuropathy as well as potential interventions. Although diabetes has long been associated with neuropathy, additional metabolic syndrome components, including obesity, are increasingly linked to neuropathy development, regardless of glycemic status. Preclinical rodent models as well as clinical studies are shedding light on the mechanisms of obesity-related neuropathy as well as challenges associated with slowing progression. Dietary and surgical weight loss and exercise interventions are promising, but more data is needed. High-fat-diet rodent models have shown that obesity-related neuropathy is a product of excess glucose and lipid accumulation leading to inflammation and cell death. Clinical studies consistently demonstrate obesity is independently associated with neuropathy; therefore, likely a causal risk factor. Dietary weight loss improves neuropathy symptoms but not examination scores. Bariatric surgery and exercise are promising interventions, but larger, more rigorous studies are needed. Further research is also needed to determine the utility of weight loss medications and ideal timing for obesity interventions to prevent neuropathy.