Glucose Uptake In Tissue Research Articles

Differential Impact of Medical Therapies for Acromegaly on Glucose Metabolism.

Acromegaly is a rare endocrine disorder caused by excessive growth hormone (GH) production, due, in the vast majority of cases, to the presence of a GH-secreting pituitary tumour. The chronic elevation of GH and the resulting high circulating levels of insulin-like growth factor-1 (IGF-1) cause the characteristic tissue overgrowth and a number of associated comorbidities, including several metabolic changes, such as glucose intolerance and overt diabetes mellitus (DM). Elevated GH concentrations directly attenuate insulin signalling and stimulate lipolysis, decreasing glucose uptake in peripheral tissues, thus leading to the development of impaired glucose tolerance and DM. Acromegaly treatment aims to normalize plasma GH and IGF-1 levels using surgery, medical treatment, or radiotherapy. The effect of the different medical therapies on glucose homeostasis varies. This literature review explores the impact of the currently available pharmacological therapies for acromegaly (first- and second-generation somatostatin receptor ligands, a GH receptor antagonist, and dopamine agonists) on glucose homeostasis. We also discuss the underlying biological mechanisms through which they impact glucose metabolism.

A Mechanism-Based Comparative Review on Functional Food with Phytomolecules and Marketed Formulation for Type II Diabetes Mellitus

Abstract: Type II diabetes mellitus is a chronic disorder characterized by pancreatic beta cell dysfunction, insulin resistance, and hyperglycemia. Administration of different classes of anti-diabetic drugs over the long term is essential to maintain normoglycemic levels in affected individuals. This study is focused on natural analogs as substitutes for the most marketed synthetic and semi-synthetic anti-diabetic drugs. This study aimed to review phytoconstituents with their mechanism of action, which are comparatively equivalent to that of the allopathic anti-diabetic marketed drugs, like biguanides, sulphonylurea, and thiazolidinediones. The methodology used for the review involved using the keywords collected from online sites, like PubMed, ScienceDirect, and Google Scholar. At present, different drugs are available for the treatment of diabetes and work with different mechanisms, like metformin induces the AMPK pathway in hepatocytes and muscle fibers with increased glucose uptake in peripheral tissues, whereas the phytoconstituents, like quercetin (flavonoid), mahanimbine, and koenidine (carbazole alkaloids) involve same mechanism as metformin. Sulfonylureas drugs bind to specific receptors in hepatocytes, resulting in glucose-independent insulin release. The phytomolecule amyrins (pentacyclic triterpenoid) and kaempferol (flavonoid) have similar effects as that of sulphonylureas. Thiazoglinediones target adipocytes and cause GLUT-4 translocation and up-regulation of PPAR and adiponectin gene expression. Phytoconstituents, like cyanidin-3-glucoside (anthocyanin) and protocatechuic acid (tannin), exhibit a similar mechanism of action to that of thiazolidinediones. In this review, it can be concluded that the selected compounds have the same antidiabetic activity as the synthetic drugs. In the future, a new polyherbal formulation can be developed with these selected molecules having the same mechanisms of action, with significant therapeutic value without side effects.

Role of Abscisic Acid in the Whole-Body Regulation of Glucose Uptake and Metabolism.

Abscisic acid (ABA) is a hormone with a long evolutionary history, dating back to the earliest living organisms, of which modern (ABA-producing) cyanobacteria are likely descendants, which existed long before the separation of the plant and animal kingdoms, with a conserved role as signals regulating cell responses to environmental challenges. In mammals, along with the anti-inflammatory and neuroprotective function of ABA, nanomolar ABA regulates the metabolic response to glucose availability by stimulating glucose uptake in skeletal muscle and adipose tissue via an insulin-independent mechanism and increasing metabolic energy production and also dissipation in brown and white adipocytes. Chronic ABA intake of micrograms per Kg body weight improves blood glucose, lipids, and morphometric parameters (waist circumference and body mass index) in borderline subjects for prediabetes and metabolic syndrome. This review summarizes the most recent in vitro and in vivo data obtained with nanomolar ABA, the involvement of the receptors LANCL1 and LANCL2 in the hormone's action, and the importance of mammals' endowment with two distinct hormones governing the metabolic response to glucose availability. Finally, unresolved issues and future directions for the clinical use of ABA in diabetes are discussed.

Machine learning-based prognostic model of lactylation-related genes for predicting prognosis and immune infiltration in patients with lung adenocarcinoma

BackgroundHistone lactylation is a novel epigenetic modification that is involved in a variety of critical biological regulations. However, the role of lactylation-related genes in lung adenocarcinoma has yet to be investigated.MethodsRNA-seq data and clinical information of LUAD were downloaded from TCGA and GEO datasets. Unsupervised consistent cluster analysis was performed to identify differentially expressed genes (DEGs) between the two clusters, and risk prediction models were constructed by Cox regression analysis and LASSO analysis. Kaplan–Meier (KM) survival analysis, ROC curves and nomograms were used to validate the accuracy of the models. We also explored the differences in risk scores in terms of immune cell infiltration, immune cell function, TMB, TIDE, and anticancer drug sensitivity. In addition, single-cell clustering and trajectory analysis were performed to further understand the significance of lactylation-related genes. We further analyzed lactate content and glucose uptake in lung adenocarcinoma cells and tissues. Changes in LUAD cell function after knockdown of lactate dehydrogenase (LDHA) by CCK-8, colony formation and transwell assays. Finally, we analyzed the expression of KRT81 in LUAD tissues and cell lines using qRT-PCR, WB, and IHC. Changes in KRT81 function in LUAD cells were detected by CCK-8, colony formation, wound healing, transwell, and flow cytometry. A nude mouse xenograft model and a KrasLSL-G12D in situ lung adenocarcinoma mouse model were used to elucidate the role of KRT81 in LUAD.ResultsAfter identifying 26 lactylation-associated DEGs, we constructed 10 lactylation-associated lung adenocarcinoma prognostic models with prognostic value for LUAD patients. A high score indicates a poor prognosis. There were significant differences between the high-risk and low-risk groups in the phenotypes of immune cell infiltration rate, immune cell function, gene mutation frequency, and anticancer drug sensitivity. TMB and TIDE scores were higher in high-risk score patients than in low-risk score patients. MS4A1 was predominantly expressed in B-cell clusters and was identified to play a key role in B-cell differentiation. We further found that lactate content was abnormally elevated in lung adenocarcinoma cells and cancer tissues, and glucose uptake by lung adenocarcinoma cells was significantly increased. Down-regulation of LDHA inhibits tumor cell proliferation, migration and invasion. Finally, we verified that the model gene KRT81 is highly expressed in LUAD tissues and cell lines. Knockdown of KRT81 inhibited cell proliferation, migration, and invasion, leading to cell cycle arrest in the G0/G1 phase and increased apoptosis. KRT81 may play a tumorigenic role in LUAD through the EMT and PI3K/AKT pathways. In vivo, KRT81 knockdown inhibited tumor growth.ConclusionWe successfully constructed a new prognostic model for lactylation-related genes. Lactate content and glucose uptake are significantly higher in lung adenocarcinoma cells and cancer tissues. In addition, KRT81 was validated at cellular and animal levels as a possible new target for the treatment of LUAD, and this study provides a new perspective for the individualized treatment of LUAD.

UBXN9 governs GLUT4-mediated spatial confinement of RIG-I-like receptors and signaling.

The cytoplasmic RIG-I-like receptors (RLRs) recognize viral RNA and initiate innate antiviral immunity. RLR signaling also triggers glycolytic reprogramming through glucose transporters (GLUTs), whose role in antiviral immunity is elusive. Here, we unveil that insulin-responsive GLUT4 inhibits RLR signaling independently of glucose uptake in adipose and muscle tissues. At steady state, GLUT4 is trapped at the Golgi matrix by ubiquitin regulatory X domain 9 (UBXN9, TUG). Following RNA virus infection, GLUT4 is released and translocated to the cell surface where it spatially segregates a significant pool of cytosolic RLRs, preventing them from activating IFN-β responses. UBXN9 deletion prompts constitutive GLUT4 translocation, sequestration of RLRs and attenuation of antiviral immunity, whereas GLUT4 deletion heightens RLR signaling. Notably, reduced GLUT4 expression is uniquely associated with human inflammatory myopathies characterized by hyperactive interferon responses. Overall, our results demonstrate a noncanonical UBXN9-GLUT4 axis that controls antiviral immunity via plasma membrane tethering of cytosolic RLRs.

Effects of metformin supplementation in high-carbohydrate diets on growth performance, glucose metabolism, intestinal flora, and PI3K/AKT signaling pathway of hybrid grouper (Epinephelus fuscoguttatus♀×Epinephelus lanceolatu♂)

Metformin, or 1,1-dimethylbiguanide, is a hypoglycemic drug that lowers blood glucose by reducing glycogen synthesis and increasing glucose uptake in peripheral tissues. Six diets with iso-nitrogenous and iso-lipid compositions were prepared, including a positive control (20 % carbohydrate, PC) and a negative control (30 % carbohydrate, T0). The experimental diets contained 0.2 % (T2), 0.4 % (T4), 0.6 % (T6), and 0.8 % (T8) metformin based on the negative control diet. A total of 540 hybrid groupers, with consistent size and health conditions, were randomly assigned to six groups. Each group contained 30 fish, with three replicates per group, and they were fed for eight weeks. The high-carbohydrate diet reduced weight gain, digestive enzyme activities and specific growth rates (P>0.05), while significantly increasing hepatosomatic indices (P<0.05). Metformin supplementation reduced both hepatosomatic and viscerosomatic indices (P<0.05). The high-carbohydrate diet led to increased levels of glucose, triglycerides, low-density lipoprotein, hepatic fructose 1,6-bisphosphatase, and glucose-6-phosphatase in the serum (P<0.05). In contrast, metformin supplementation significantly lowered glucose, insulin, triglycerides, and low-density lipoprotein levels (P<0.05), while enhancing the activities of hepatic glucokinase, phosphofructokinase-1, and pyruvate kinase (P<0.05). It significantly reduced the activities of PEPCK and G6Pase and downregulated the expression of ir, pi3k, pdk, ampkα1, and gs in fish on high-carbohydrate diets, while metformin supplementation upregulated the expression of ir, pi3k, pdk, ampkα1, and gs genes compared to the T0 group (P<0.05). In terms of microbiota, a high-carbohydrate diet increased pathogenic bacteria like Proteobacteria and Photobacterium, while metformin boosted beneficial bacteria such as Firmicutes and Brevibacillus. Overall, the high-carbohydrate diet impaired growth and insulin sensitivity, while metformin improved glucose metabolism, promoted beneficial bacteria, and supported intestinal health.

Baicalein Ameliorates Insulin Resistance of HFD/STZ Mice Through Activating PI3K/AKT Signal Pathway of Liver and Skeletal Muscle in a GLP-1R-Dependent Manner.

Insulin resistance (IR) is the principal pathophysiological change occurring in diabetes mellitus (DM). Baicalein, a bioactive flavonoid primarily extracted from the medicinal plant Scutellaria baicalensis Georgi, has been shown in our previous research to be a potential natural glucagon-like peptide-1 receptor (GLP-1R) agonist. However, the exact therapeutic effect of baicalein on DM and its underlying mechanisms remain elusive. In this study, we investigated the therapeutic effects of baicalein on diabetes and sought to clarify its underlying molecular mechanisms. Our results demonstrated that baicalein improves hyperglycemic, hyperinsulinemic, and glucometabolic disorders in mice with induced diabetes via GLP-1R. This was confirmed by the finding that baicalein's effects on improving IR were largely diminished in mice with whole-body Glp1r ablation. Complementarily, network pharmacology analysis highlighted the pivotal involvement of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) insulin signaling pathway in the therapeutic actions of baicalein on IR. Our mechanism research significantly confirmed that baicalein mitigates hepatic and muscular IR through the PI3K/AKT signal pathway, both in vitro and in vivo. Furthermore, we demonstrated that baicalein enhances glucose uptake in skeletal muscle cells under IR conditions through the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-adenosine 5'-monophosphate-activated protein kinase (AMPK)-glucose transporter 4 (GLUT4) signaling pathway in a GLP-1R-dependent manner. In conclusion, our findings confirm the therapeutic effects of baicalein on IR and reveal that it improves IR in liver and muscle tissues through the PI3K/AKT insulin signaling pathway in a GLP-1R dependent manner. Moreover, we clarified that baicalein enhances the glucose uptake in skeletal muscle tissue through the Ca2+/CaMKII-AMPK-GLUT4 signal pathway.

Effects Of Reduced Sedentary Time On Adipose Tissue Glucose Uptake In Adults With Metabolic Syndrome

Effects Of Reduced Sedentary Time On Adipose Tissue Glucose Uptake In Adults With Metabolic Syndrome

HOXD9 Enhances the Release of HMGB1 and Boosts Glycolysis in Glioblastoma under Hypoxic Conditions, Leading to Tumor Growth by Activating the Transcription of PFKFB3.

Glioblastoma (GBM) is an aggressive primary brain tumor. The HOX gene family has been implicated in the pathogenesis of different types of tumors. This research aimed to examine the impact of homeobox D9 (HOXD9) in GBM under hypoxic conditions, as well as to elucidate its underlying molecular mechanisms. The study assessed the differential expression of nine HOXD genes in GBM using the Mann-Whitney U test and identified genes with high correlation with the cancer genome atlas (TCGA)-GBM dataset using receiver operating characteristic (ROC) curves. Prognostic genes of GBM patients were identified through a combination of prognostic Kaplan-Meier (KM) curve and Cox analysis. In vitro experiments were conducted using U87-MG and U251-MG cells, and an animal GBM model was constructed. The study also measured the secretion level of high mobility group box 1 (HMGB1) using enzyme-linked immunosorbent assay (ELISA). Glucose uptake and lactate production levels in cells and tissues were analyzed using kits. The expressions of HOXD9 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) were detected by immunofluorescence, and chromatin immunoprecipitation (ChIP) validated their relationship. HOXD9 was identified as the target gene, showing a significant correlation between HOXD9 expression and prognostic clinical outcomes. Overexpression of HMGB1 enhanced cell proliferation, migration, and the expression levels of HOXD9 and PFKFB3 and promoted HMGB1 secretion, glucose uptake, and lactate generation. HOXD9 bound to the PFKFB3 promoter region in U87-MG and U251-MG cells. Furthermore, PFKFB3 overexpression partially counteracted the suppressive effects of HOXD9 silencing on tumor formation. HOXD9 promoted hypoxia-induced HMGB1 secretion and glycolysis in GBM through the transcriptional activation of PFKFB3, which in turn promoted tumorigenesis.

A Randomized Trial of the Efficacy of Three Weight Loss Diet Interventions in Overweight/Obese with Polycystic Ovary Syndrome.

Polycystic Ovary Syndrome (PCOS) is a highly prevalent, complex, heterogeneous, polygenic endocrine disorder characterized by metabolic and reproductive dysfunction that affects 8-13% of women of reproductive age worldwide. The pathogenesis of PCOS has not been fully clarified and includes genetics, obesity, and insulin resistance (IR). Oxidative stress (OS) of PCOS is independent of obesity. It can induce IR through post-insulin receptor defects, impair glucose uptake in muscle and adipose tissue, and exacerbate IR by reducing insulin secretion from pancreatic β-cells. To investigate the effects of Calorie Restricted Diet (CRD), High Protein Diet (HPD), and High Protein and High Dietary Fiber Diet (HPD+HDF) on body composition, insulin resistance, and oxidative stress in overweight/obese PCOS patients. A total of 90 overweight/obese patients with PCOS were selected to receive an 8- week medical nutrition weight loss intervention at our First Hospital of Peking University, and we randomly divided them into the CRD group (group A), the HPD group (group B), and the HPD+HDF group (group C), with 30 patients in each group. We measured their body composition, HOMA-IR index, and oxidative stress indicators. The t-test, Mann-Whitney U test, analysis of variance (ANOVA), and Kruskal-Wallis H test were used to compare the efficacy of the three methods. After eight weeks, the body weights of the three groups decreased by 6.32%, 5.70% and 7.24%, respectively, and the Visceral Fat Area (VFA) values decreased by 6.8 cm2, 13.4 cm2 and 23.45 cm2, respectively, especially in group C (p <0.05). The lean body mass (LBM), also known as the Fat-Free Mass (FFM) values of group B and group C after weight loss, were higher than that of group A (p <0.05). After weight loss, the homeostatic model assessment of insulin resistance (HOMA-IR) index and malondialdehyde (MDA) were decreased. Superoxide dismutase (SOD) was increased in all three groups (p <0.05), and the changes in SOD and MDA in group B and group C were more significant (p <0.05). HOMA-IR index positively correlated with body mass index (BMI) (r=0.195; p <0.05); MDA positively correlated with percent of body fat (PBF) (r=0.186; p <0.05) and HOMA-IR index (r=0.422; p <0.01); SOD positively correlated with LMI/FFMI (r=0.195; p <0.05), negatively correlated with HOMA-IR index (r=-0.433; p <0.01). All three diets were effective in reducing the body weight of overweight/obese patients with PCOS by more than 5% within 8 weeks and could improve both insulin resistance and oxidative stress damage. Compared with CRD, HPD and HPD+HDF diets could better retain lean body mass and significantly improve oxidative stress damage.

Insulin-Independent Regulation of Type 1 Diabetes via Brown Adipocyte-Secreted Proteins and the Novel Glucagon Regulator Nidogen-2.

The large molecular weight brown adipocyte-secreted protein fraction suppresses glucagon secretion and normalizes glycemia in mouse models of type 1 diabetes (T1D), independent of insulin, offering a novel therapeutic strategy for disease management.Nidogen-2, a critical component of this fraction, is identified as an inhibitor of glucagon secretion in pancreatic α-cells by regulating intracellular messenger activities.The large-secreted protein fraction prevents T1D-related whitening of brown adipose tissue, promotes adipocyte differentiation, and enhances browning of inguinal white adipose tissue.This fraction enhances glucose uptake in adipose tissue, skeletal muscle, and liver through an insulin receptor-dependent pathway.

Effect of abdominal adipose tissue glucose uptake on brain aging.

Abdominal adipose tissue (AT) mass has adverse effects on the brain. This study aimed to investigate the effect of glucose uptake by abdominal AT on brain aging. Three-hundred twenty-five participants underwent total-body positron emission tomography scan. Brain age was estimated in an independent test set (n=98) using a support vector regression model that was built using a training set (n=227). Effects of abdominal subcutaneous and visceral AT (SAT/VAT) glucose uptake on brain age delta were evaluated using linear regression. Higher VAT glucose uptake was linked to negative brain age delta across all subgroups. Higher SAT glucose uptake was associated with negative brain age delta in lean individuals. In contrast, increased SAT glucose uptake demonstrated positive trends with brain age delta in female and overweight/obese participants. Increased glucose uptake of the abdominal VAT has positive influences on the brain, while SAT may not have such influences, except for lean individuals. Higher glucose uptake of the visceral adipose tissue was linked to decelerated brain aging. Higher glucose uptake of the subcutaneous adipose tissue (SAT) was associated with negative brain age delta in lean individuals. Faster brain aging was associated with increased glucose uptake of the SAT in female and overweight and obese individuals.

The metabolic consequences of 'yo-yo' dieting are markedly influenced by genetic diversity.

Weight loss can improve the metabolic complications of obesity. However, it is unclear whether insulin resistance persists despite weight loss and whether any protective benefits are preserved following weight regain (weight cycling). The impact of genetic background on weight cycling is undocumented. We aimed to investigate the effects of weight loss and weight cycling on metabolic outcomes and sought to clarify the role of genetics in this relationship. Both C57BL/6 J and genetically heterogeneous Diversity Outbred Australia (DOz) mice were alternately fed high fat Western-style diet (WD) and a chow diet at 8-week intervals. Metabolic measures including body composition, glucose tolerance, pancreatic beta cell activity, liver lipid levels and adipose tissue insulin sensitivity were determined. After diet switch from WD (8-week) to chow (8-week), C57BL/6 J mice displayed a rapid normalisation of body weight, adiposity, hyperinsulinemia, liver lipid levels and glucose uptake into adipose tissue comparable to chow-fed controls. In response to the same dietary intervention, genetically diverse DOz mice conversely maintained significantly higher fat mass and insulin levels compared to chow-fed controls and exhibited much more profound interindividual variability than C57BL/6 J mice. Weight cycled (WC) animals were re-exposed to WD (8-week) and compared to age-matched controls fed 8-week WD for the first time (LOb). In C57BL/6 J but not DOz mice, WC animals had significantly higher blood insulin levels than LOb controls. All WC animals exhibited significantly greater beta cell activity than LOb controls despite similar fat mass, glucose tolerance, liver lipid levels and insulin-stimulated glucose uptake in adipose tissue. Following weight loss, metabolic outcomes return to baseline in C57BL/6 J mice with obesity. However, genetic diversity significantly impacts this response. A period of weight loss does not provide lasting benefits after weight regain, and weight cycling is detrimental and associated with hyperinsulinemia and elevated basal insulin secretion.

Unraveling the Complex Role of Zinc, Boron, Chromium, and Selenium in the Pathogenesis of Diabetes Mellitus: A Review

Trace elements are micronutrient components that are only required in small amounts but are critical for the biological functions of many human body tissues. Studies in multiple settings found significant connections between diabetic mellitus (DM) and trace elements caused by disturbances of overlapping cellular metabolic systems. Zinc, boron, chromium, and selenium at either extremely high or low levels could elicit some alteration in cellular metabolism. These lead to the development of DM. The changes include 1) the disturbance in the efficient release of insulin secretory granules, 2) the production of proinflammatory cytokines and oxidative stress state, 3) the failure of insulin signalling pathway, and 4) the reduction of glucose tissue uptake secondary to the downregulation of glucose transporters. Both significantly high and low concentrations have been linked to the development of insulin resistance. Nevertheless, conflicting evidence makes their optimum nutritional levels difficult to establish. For example, lead at a trace concentration may accelerate the development of insulin resistance. The purpose of this review is to emphasise the metabolic role of the 4 trace elements and their influence on the pathogenesis of diabetes when body levels are below optimal. Understanding the consequences of these elements could pave the way for therapeutic possibilities and breakthroughs in personalised DM management.

Diabetes mellitus in patients with acromegaly: pathophysiology, clinical challenges and management.

Acromegaly is a rare endocrine disease caused by hypersecretion of growth hormone, most commonly arising due to a pituitary adenoma. Diabetes mellitus is a common complication of acromegaly, occurring in approximately one-third of patients. The risk of diabetes mellitus in acromegaly is driven by increased exposure to growth hormone, which directly attenuates insulin signalling and stimulates lipolysis, leading to decreased glucose uptake in peripheral tissues. Acromegaly is a unique human model, where insulin resistance occurs independently of obesity and is paradoxically associated with a lean phenotype and reduced body adipose tissue mass. Diabetes mellitus in patients with acromegaly is associated with an increased risk of cardiovascular morbidity and mortality. Therefore, preventive measures and optimized treatment of diabetes mellitus are essential in these patients. However, specific recommendations for the management of diabetes mellitus secondary to acromegaly are lacking due to limited research on this subject. This Review explores the underlying mechanisms for diabetes mellitus in acromegaly and its effect on morbidity and mortality. We also discuss treatment modalities for diabetes mellitus that are suited for patients with acromegaly. Improved understanding of these issues will lead to better management of acromegaly and its associated metabolic complications.

UBXN9 governs GLUT4-mediated spatial confinement of RIG-I-like receptors and signaling.

The cytoplasmic RIG-I-like receptors (RLRs) recognize viral RNA and initiate innate antiviral immunity. RLR signaling also triggers glycolytic reprogramming through glucose transporters (GLUTs), whose role in antiviral immunity is elusive. Here, we unveil that insulin-responsive GLUT4 inhibits RLR signaling independently of glucose uptake in adipose and muscle tissues. At steady state, GLUT4 is docked at the Golgi matrix by ubiquitin regulatory X domain 9 (UBXN9, TUG). Following RNA virus infection, GLUT4 is released and translocated to the cell surface where it spatially segregates a significant pool of cytosolic RLRs, preventing them from activating IFN-β responses. UBXN9 deletion prompts constitutive GLUT4 trafficking, sequestration of RLRs, and attenuation of antiviral immunity, whereas GLUT4 deletion heightens RLR signaling. Notably, reduced GLUT4 expression is uniquely associated with human inflammatory myopathies characterized by hyperactive interferon responses. Overall, our results demonstrate a noncanonical UBXN9-GLUT4 axis that controls antiviral immunity via plasma membrane tethering of cytosolic RLRs.

The thermoneutral zone in women takes an “arctic” shift compared to men

Conventionally, women are perceived to feel colder than men, but controlled comparisons are sparse. We measured the response of healthy, lean, young women and men to a range of ambient temperatures typical of the daily environment (17 to 31 °C). The Scholander model of thermoregulation defines the lower critical temperature as threshold of the thermoneutral zone, below which additional heat production is required to defend core body temperature. This parameter can be used to characterize the thermoregulatory phenotypes of endotherms on a spectrum from "arctic" to "tropical." We found that women had a cooler lower critical temperature (mean ± SD: 21.9 ± 1.3 °C vs. 22.9 ± 1.2 °C, P = 0.047), resembling an "arctic" shift compared to men. The more arctic profile of women was predominantly driven by higher insulation associated with more body fat compared to men, countering the lower basal metabolic rate associated with their smaller body size, which typically favors a "tropical" shift. We did not detect sex-based differences in secondary measures of thermoregulation including brown adipose tissue glucose uptake, muscle electrical activity, skin temperatures, cold-induced thermogenesis, or self-reported thermal comfort. In conclusion, the principal contributors to individual differences in human thermoregulation are physical attributes, including body size and composition, which may be partly mediated by sex.

Unique features of β-cell metabolism are lost in type 2 diabetes.

Pancreatic β cells play an essential role in the control of systemic glucose homeostasis as they sense blood glucose levels and respond by secreting insulin. Upon stimulating glucose uptake in insulin-sensitive tissues post-prandially, this anabolic hormone restores blood glucose levels to pre-prandial levels. Maintaining physiological glucose levels thus relies on proper β-cell function. To fulfill this highly specialized nutrient sensor role, β cells have evolved a unique genetic program that shapes its distinct cellular metabolism. In this review, the unique genetic and metabolic features of β cells will be outlined, including their alterations in type 2 diabetes (T2D). β cells selectively express a set of genes in a cell type-specific manner; for instance, the glucose activating hexokinase IV enzyme or Glucokinase (GCK), whereas other genes are selectively "disallowed", including lactate dehydrogenase A (LDHA) and monocarboxylate transporter 1 (MCT1). This selective gene program equips β cells with a unique metabolic apparatus to ensure that nutrient metabolism is coupled to appropriate insulin secretion, thereby avoiding hyperglycemia, as well as life-threatening hypoglycemia. Unlike most cell types, β cells exhibit specialized bioenergetic features, including supply-driven rather than demand-driven metabolism and a high basal mitochondrial proton leak respiration. The understanding of these unique genetically programmed metabolic features and their alterations that lead to β-cell dysfunction is crucial for a comprehensive understanding of T2D pathophysiology and the development of innovative therapeutic approaches for T2D patients.

Fungal Depsidones Stimulate AKT-Dependent Glucose Uptake in 3T3-L1 Adipocytes.

Enhanced glucose uptake in insulin-sensitive tissues is one of the therapeutic strategies to ameliorate hyperglycemia and maintain glucose homeostasis in type 2 diabetes. This study disclosed the role of fungal depsidones in glucose uptake and the underlying mechanism in 3T3-L1 adipocytes. Depsidones, including nidulin, nornidulin, and unguinol, isolated from Aspergillus unguis, stimulate glucose uptake in adipocytes. Compared to the others, nidulin exhibited an upward trend in glucose uptake. The effect of nidulin was found to be dose- and time-dependent. Nidulin also enhanced insulin- and metformin-stimulated glucose uptake. Upregulation of GLUT4 expression and AKT and AMPK phosphorylation were observed with nidulin treatment. Blockage of AKT, but not AMPK, phosphorylation was largely accompanied by diminished glucose uptake. In agreement, nidulin triggered the translocation of GLUT4 to the plasma membrane. Importantly, nidulin elevated glucose uptake associated with increased AKT phosphorylation in insulin-resistant adipocytes. Taken together, nidulin could stimulate glucose uptake mainly through AKT-dependent GLUT4 translocation, serving as a seed compound in drug discovery for type 2 diabetes.

Effect of Dapagliflozin on Renal and Hepatic Glucose Kinetics in T2D and NGT Subjects.

Acute and chronic SGLT-2 inhibition increase endogenous glucose production (EGP). However, the organ - liver versus kidney - responsible for the increase in EGP has not been identified. 20 T2DM and 12 NGT subjects received [3-3H]-glucose infusion (to measure total EGP) in combination with arterial and renal vein catheterization and PAH infusion for determination of renal blood flow. Total EGP, net renal arteriovenous balance, and renal glucose production were measured before and 4 hours after dapagliflozin and placebo administration. Following DAPA, EGP increased in both T2D and NGT from baseline to 240 minutes, while there was a significant time-related decrease after placebo in T2D. Renal glucose production at baseline was <5% of basal EGP in both groups and did not change significantly following DAPA in either NGT and T2D. Renal glucose uptake (sum of tissue glucose uptake plus glucosuria) increased in both T2D and NGT following DAPA (P<0.05 vs placebo). The increase in RGU was entirely explained by the increase in glucosuria. Single dose of dapagliflozin significantly increased EGP, which primarily is explained by an increase in hepatic glucose production, establishing the existence of a novel renal-hepatic axis.