The glucose transporter 4 (GLUT4) is a high-affinity glucose transporter that is predominantly expressed in the skeletal muscle, myocardium, and adipose tissue, and is the rate-limiting transporter of insulin-stimulated glucose uptake. Compounds that enhance the process of GLUT4 translocation in skeletal muscle would provide a novel treatment for type 2 diabetes mellitus. After a high-throughput screening (HTS) campaign and medicinal chemistry efforts, we identified the xanthene compound DS-1150b (16·tBuNH2) as a novel potent GLUT4 translocation enhancer. DS-1150b was found to promote GLUT4 translocation in L6-myotubes in rats and showed a glucose-lowering effect in an oral glucose tolerance test (oGTT) in a Zucker fatty rat model. Identification of naphthalene analog DS20060511 is also briefly described.

The connecting peptide (C-peptide), once relegated as an epiphenomenon in insulin biosynthesis, has now been recognized for its capacity to instigate molecular effects along with important physiological functions. These findings suggest that C-peptide is a hormonally active molecule responsible for controlling a number of diabetes-related complications, in addition to proinsulin processing. Notably, it demonstrates cellular responsiveness and acts as a robust biomarker for beta cell functions, with a half-life longer than that of insulin. Herein, we investigated the effect of some synthetic C-peptide mimics on glucose homeostasis, specifically focusing on glucose uptake, GLUT4 translocation and associated membrane trafficking processes. The glucose utilization potential of some of the C-peptide mimics in L6 muscle myotubes was significantly better than that of the human C-peptide. One of the synthesized C-peptide mimics, CP8, showed glucose metabolism akin to insulin, including potential for Akt phosphorylation and IRβ autophosphorylation. Also, it showed the ability to mitigate intramolecular reactive oxygen species production. The results obtained here highlight the potential of C-peptide mimics on glucose metabolism, as well as interaction with Akt and IRβ, positioning them as promising candidates for future diabetes research.

The impact of obesity on female reproductive health is considerable; despite the well-established association between nutritional status, obesity, and reproductive health, the mechanisms through which obesity impacts the reproductive axis remain poorly understood. For this reason, this study aims to investigate the expression of protein glucose transporter 4 (GLUT4) in the ovary and their association with morphophysiological alterations in the ovaries and uterus in a genetic obesity model, the Zucker fatty (fa/fa) rat. Various parameters were evaluated, including zoometric and metabolic measurements, estrous cyclicity, ovulation, and follicular development. The ovaries and uterus were histologically analyzed using hematoxylin-eosin staining. Furthermore, ovarian GLUT4 protein levels were estimated by Western blotting and fluorescence microscopy to investigate its association with metabolic and reproductive dysfunctions observed in this model. Zucker fatty rats exhibited significant body weight and adiposity index increases, accompanied by elevated cholesterol, triglycerides, and insulin levels. Conversely, progesterone levels were found to be significantly reduced. Histological analysis of ovarian morphology revealed pre-cystic follicles, a diminished follicular population, and a reduced number of corpora lutea. Additionally, a decrease in ovarian GLUT4 protein expression was observed. The uterine analysis demonstrated a smaller overall area, with notable reductions in both endometrial and myometrial thickness and fewer uterine glands. These findings indicate that in Zucker fatty rats, decreased ovarian GLUT4 protein expression and impaired glucose homeostasis are strongly associated with significant morphological alterations in the ovaries and uterus.

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been proposed to benefit cardiometabolic health. However, the relationship between the intake of DHA and EPA and type 2 diabetes (T2D) risk remains equivocal, and the effects of DHA and EPA on skeletal muscle, the primary organ for glucose metabolism, merit further investigation. Here, we show that habitual fish oil supplementation was associated with a 9% lower T2D risk and significantly interacted with variants at GLUT4 in a prospective cohort of 48,358 people with prediabetes. Muscular metabolome analysis in the animal study revealed that DHA and EPA altered branched-chain amino acids, creatine, and glucose oxidation-related metabolites, concurrently with elevated muscular glycogen synthase and pyruvate dehydrogenase contents that promoted glucose disposal. Further myotube investigation revealed that DHA and EPA promoted muscular GLUT4 translocation by elevating Rab GTPases and target-SNARE expression. Together, DHA and EPA supplementation provides a promising approach for T2D prevention through targeting muscular glucose homeostasis, including enhancing GLUT4 translocation, glycogen synthesis, and aerobic glycolysis.

Alzheimer's disease (AD) is an age-associated neurodegenerative disorder with a complex etiology. While emerging AD therapeutics can slow cognitive decline, they may worsen dementia in certain groups of individuals. Therefore, alternative treatments are much needed. Microglia, the brain resident macrophages, have the potential to be novel therapeutic targets as they regulate many facets of AD, including lipid droplet (LD) accumulation, amyloid beta (Aβ) clearance, and neuroinflammation. To carry out such functions, microglia undergo phenotypic changes, which are linked to shifts in metabolism and substrate utilization. While homeostatic microglia are driven by oxidative phosphorylation (OXPHOS) and glycolysis, in aging and AD, microglia shift further towards glycolysis. Interestingly, this "metabolic reprogramming" may be linked to an increase in fructose metabolism. In the brain, microglia predominantly express the fructose transporter SLC2A5 (GLUT5), and enzymes involved in fructolysis and endogenous fructose production, with their expression being upregulated in aging and disease. Here, we review evidence for fructose uptake, breakdown, and production in microglia. We also evaluate emerging literature targeting fructose metabolism in the brain and periphery to assess its ability to modulate microglial function in AD. The ability of microglia to transport and utilize fructose, coupled with the well-established role of fructose in metabolic dysfunction, supports the notion that microglial fructose metabolism may be a novel potential therapeutic target for AD.

Endocrine-disrupting chemicals (EDCs) play an important role in the incidence of type-2 diabetes. Di-2-ethyl hexyl Phthalate (DEHP) is one of the endocrine-disrupting chemicals used as a plasticizer to impart flexibility and softness to plastic-containing materials. Mono-2-ethylhexyl Phthalate (MEHP), a DEHP's primary metabolite, is preferentially absorbed once metabolized. A previous study from our laboratory showed that DEHP and MEHP altered the key proteins such as insulin receptor (INSR) and glucose transporter-4 (GLUT4) in L6 myotubes. In a sequel to the previous study, the present study hypothesized that DEHP and its metabolite MEHP may alter the Insr and Glut4 gene expression in L6 myotubes. Therefore, to find out the molecular mechanism behind the decreased INSR and GLUT4 protein levels in the previous study, the direct effect of DEHP and its metabolite MEHP in regulating Insr and Glut4 gene transcription in L6 myotubes was studied. The L6 myotubes were exposed to 50 and 100 μM DEHP and MEHP for 24 h, followed by insulin stimulation for 20 min. We observed decreased Insr and Glut4 mRNA levels in DEHP and MEHP-treated groups. Western blot data showed decreased protein levels of MEF2A and MyoD in treated groups. ChIP assay detected a decreased association of MEF2A and MyoD to the Glut4 gene promoter and HMGA1 to the Insr gene promoter. The study revealed that DEHP and MEHP diminished the Insr and Glut4 gene expression through weakened interaction of their transcription factors on the respective promoter.

Diabetes mellitus (DM) and its various complications, including diabetic nephropathy, retinopathy, neuropathy, cardiovascular disease, and ulcers, pose significant challenges to global health. This review investigates the potential of procyanidins (PCs), a natural polyphenolic compound, in preventing and managing diabetes and its complications. PCs, recognized for their strong antioxidant, anti-inflammatory, and anti-hyperglycemic properties, play a crucial role in reducing oxidative stress and enhancing endothelial function, which are essential for managing diabetic complications. This review elucidates the molecular mechanisms by which PCs improve insulin sensitivity and endothelial health, thereby providing protection against the various complications of diabetes. The comprehensive analysis underscores the promising therapeutic role of PCs in diabetes care, indicating the need for further clinical studies to confirm and leverage their potential in comprehensive diabetes management strategies.

The effects of wheat and oat dietary fiber (DF) alone or combined on T2DM remain unclear. In this research, db/db diabetic mice were fed with diets containing 10% insoluble wheat dietary fiber (WDF), 10% insoluble oat dietary fiber (ODF), and 10% WODF (mixture of WDF and ODF, WDF : ODF = 1 : 1) for 8 weeks. The results showed that WDF, ODF, and WODF all reduced the body weight and fasting blood glucose (FBG) and improved oral glucose tolerance in db/db mice. WDF and ODF alone further relieved insulin resistance and decreased the levels of glycated hemoglobin A1c (GHbA1c), and glycosylated serum protein (GSP). In addition, WDF and ODF alone decreased the levels of TNF-α, IL-6, and IL-1β in serum. The colon function was improved and similar changes were observed in the gut microbiota structure and abundance in all the DF groups. The change of gut microbiota mainly manifested as reducing F/B ratio at the phylum level, while at the genus level as decreasing Enterococcus, Escherichia-Shigella, Erysipelatoclostridium, and unclassified_f_Lachnospiraceae and increase of norank_f_Muribaculaceae, Bacteroides, and Alistipes. Further testing of colonic bile acids (BAs) revealed that WDF, ODF, and WODF all significantly changed the composition of BAs, mainly reducing the levels of UDCA, HDCA, and 3β-UDCA. WODF further decreased DCA and increased β-MCA, LCA-3S, and 12-KCDCA. Importantly, WODF reduced the values of 12-OH-BAs/non-12-OH-BAs. Moreover, the TGR5 level was up-regulated in both the liver and colon, and the FXR level was up-regulated in the liver while down-regulated in the colon in all the DF groups. Furthermore, for the protein level, IRS-1, p-PI3K/PI3K, and AKT were up-regulated in the liver in all the DF groups, while for the mRNA expression level, GLUT4 was up-regulated, and FOXO1, GSK3β, PEPCK, and PGC-1α were down-regulated. WDF and WODF further up-regulated the mRNA expression levels of GYS and down-regulated that of G6Pase. These results suggested that WDF, ODF, and WODF all can alleviate T2DM through the gutmicrobiota-BAs-TGR5/FXR axis and liver IRS-1/PI3K/AKT pathway in db/db mice. WDF and ODF alone are beneficial for improving glucose metabolism and inflammation indicators, while WODF helps improve BAs' profile more in the colon.

Insulin resistance is a primary feature of type 2 diabetes. This study compared the effects of curcumin and its nanoformulation on insulin resistance, fasting blood sugar, liver function, GLUT4, lipid profile, and oxidative stress in the liver and pancreas in a diabetic model.

Thirty male Wistar rats were divided into five groups: a control group, a diabetic group, a diabetic group treated with metformin (40 mg/kg), a diabetic group treated with curcumin (100 mg/kg), and a diabetic group treated with curcumin NPs (100 mg/kg). Diabetes was induced by injecting dexamethasone daily for 14 days. Treatment with curcumin and curcumin NPs was administered by gavage for 14 days. Body weight and fasting blood sugar levels were measured on days 1, 14, and 28.

The metformin, curcumin, and curcumin NPs groups showed significantly greater body weight gain than the untreated diabetic group (P < 0.001). In diabetic rats treated with curcumin and curcumin NPs, insulin resistance decreased by approximately 40 %, while fasting blood sugar levels dropped by 35-40 % (P < 0.001). The levels of liver enzymes (AST, ALT), cholesterol, triglycerides, LDL, and the oxidative stress marker MDA in liver and pancreatic tissues were reduced by 30-50 %. Additionally, beneficial markers such as albumin, HDL, antioxidants (GSH, SOD), and GLUT4 levels were increased by 25-45 % (P < 0.001). Nano-curcumin consistently showed greater improvements than curcumin, especially in reducing oxidative stress and supporting liver and pancreatic health.

This study demonstrates that curcumin NPs has a superior effect on reducing oxidative stress and improving metabolic parameters in diabetes compared to curcumin. by enhancing the bioavailability and stability of curcumin, the nanoformulation showed stronger therapeutic potential for managing high blood sugar, cholesterol issues, and liver health, positioning curcumin NPs as a promising alternative to conventional treatments for diabetes and its complications.

Recent discoveries demonstrated the skeleton's role as an endocrine organ regulating whole-body glucose homeostasis. Glucose metabolism is critical for rapid cell proliferation and tumour growth through increasing glucose uptake and fermentation of glucose to lactate despite being in an aerobic environment. This hypothesis paper discusses emerging evidence on how bones can regulate whole-body glucose homeostasis with potential to impact on tumour growth and proliferation. Moreover, it proposes a clinical link between bone glucose metabolism and prognosis of cancer based on recent clinical trial data. Targeting metabolic pathways related with classic glucose metabolism and also bone metabolism, novel methods of cancer therapy and treatment could be developed. This paper objective is to highlight the need for future research on this altered metabolism with potential to change future management of cancer patients.

The insulin-regulated aminopeptidase (IRAP; oxytocinase) is part of the M1 aminopeptidase family and is highly expressed in many tissues, including the neocortex and hippocampus of the brain. IRAP is involved in various physiological functions and has been identified as a receptor for the endogenous hexapeptide Angiotensin IV (Ang IV). The binding of Ang IV inhibits the enzymatic activity of IRAP and has been proven to enhance learning and memory in animal models. The macrocyclic compound 9 (C9) is a potent synthetic IRAP inhibitor developed from the previously reported inhibitor HA08. In this study, we have examined compound C9 and its effects on cognitive markers drebrin, microtubule-associated protein 2 (MAP2), and glial fibrillary acidic protein (GFAP) in primary hippocampal and cortical cultures. Cells from Sprague Dawley rats were cultured for 14 days before treatment with C9 for 4 consecutive days. The cells were analysed for protein expression of drebrin, MAP2, GFAP, glucose transporter type 4 (GLUT4), vesicular glutamate transporter 1 (vGluT1), and synapsin I using immunocytochemistry. The gene expression of related proteins was determined using qPCR, and viability assays were performed to evaluate toxicity. The results showed that protein expression of drebrin and MAP2 was increased, and the corresponding mRNA levels were decreased after treatment with C9 in the hippocampal cultures. The ratio of MAP2-positive neurons and GFAP-positive astrocytes was altered and there were no toxic effects observed. In conclusion, the IRAP inhibitor compound C9 enhances the expression of the pro-cognitive markers drebrin and MAP2, which further confirms IRAP as a relevant pharmaceutical target and C9 as a promising candidate for further investigation.

The thyroid function test (free triiodothyronine [FT3], free thyroxine [FT4], and thyroid-stimulating hormone [TSH]) is one of the key determinant of glucose homeostasis by regulating the balance of insulin. Thyroid dysfunction alters glucose metabolism, leading to insulin resistance (IR). This study aimed to assess the association between thyroid function and IR in pregnant Sudanese women.

A cross-sectional study was conducted in Saad Abuelela Hospital, Khartoum-Sudan, from January to April 2021. Obstetric/sociodemographic characteristics were gathered through questionnaires. Serum TSH, FT3, FT4, fasting plasma glucose (FPG), and fasting insulin levels were measured and evaluated, and IR was estimated using the homeostatic model assessment for insulin resistance (HOMA-IR) equation.

In total, the study included 127 pregnant women with a median age of 27.0 years (interquartile range [IQR] 23.0‒31.2) and a median gestational (IQR) age of 25.0 (IQR 25.0‒27.0) weeks. The medians (IQRs) of the TSH, FT3, and FT4 were 1.600 (1.162‒2.092) IU/ml, 2.020(1.772‒2.240) nmol/l, and 10.70 (9.60‒11.90) pmol/l, respectively. The median (IQR) of the FPG and fasting blood insulin level was [69.0 (62.00‒78.00) mg/dl] and [5.68(2.99‒11.66) IU/ml], respectively. The median (IQR) of the HOMA-IR level was 0.9407 (0.4356‒2.1410). There was a positive correlation between HOMA -IR and FT3 levels (r = 0.375; P < 0.001) and a negative correlation with FT4 levels (r= -0.312; P < 0.001). Also, a significant positive correlation was found between fasting insulin levels and FT3 levels (r = 0.438; P < 0.001) and a negative correlation with FT4 levels (r= -0.305; P < 0.001).

This study indicated that FT3 has positive correlation with HOMA-IR, while FT4 has negative correlation among healthy pregnant women without a history of thyroid dysfunction. This may indicate screening of euthyroid pregnant women for thyroid dysfunction and IR. Further studies are needed.

We planned to explore the protective activities of extract of Phyllanthus emblica L. (EPE) on insulin resistance and metabolic disorders including hyperlipidemia, visceral obesity, and renal dysfunction in high-fat diet (HFD)-progressed T2DM mice. Mice treatments included 7 weeks of HFD induction followed by EPE, fenofibrate (Feno), or metformin (Metf) treatment daily for another 4-week HFD in HFD-fed mice. Finally, we harvested blood to analyze some tests on circulating glycemia and blood lipid levels. Western blotting analysis was performed on target gene expressions in peripheral tissues. The present findings indicated that EPE treatment reversed the HFD-induced increases in blood glucose, glycosylated HbA1C, and insulin levels. Our findings proved that treatment with EPE in HFD mice effectively controls hyperglycemia and hyperinsulinemia. Our results showed that EPE reduced blood lipid levels, including a reduction in blood triglyceride (TG), total cholesterol (TC), and free fatty acid (FFA); moreover, EPE reduced blood leptin levels and enhanced adiponectin concentrations. EPE treatment in HFD mice reduced BUN and creatinine in both blood and urine and lowered albumin levels in urine; moreover, EPE decreased circulating concentrations of inflammatory NLR family pyrin domain containing 3 (NLRP3) and kidney injury molecule-1 (KIM-1). These results indicated that EPE displayed antihyperglycemic and antihyperlipidemic activities but alleviated renal dysfunction in HFD mice. The histology examinations indicated that EPE treatment decreased adipose hypertrophy and hepatic ballooning, thus contributing to amelioration of lipid accumulation. EPE treatment decreased visceral fat amounts and led to improved systemic insulin resistance. For target gene expression levels, EPE enhanced AMP-activated protein kinase (AMPK) phosphorylation expressions both in livers and skeletal muscles and elevated the muscular membrane glucose transporter 4 (GLUT4) expressions. Treatment with EPE reduced hepatic glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) expressions to suppress glucose production in the livers and decreased phosphorylation of glycogen synthase kinase 3β (GSK3β) expressions to affect hepatic glycogen synthesis, thus convergently contributing to an antidiabetic effect and improving insulin resistance. The mechanism of the antihyperlipidemic activity of EPE involved a decrease in the hepatic phosphorylation of mammalian target of rapamycin complex C1 (mTORC1) and p70 S6 kinase 1 (S6K1) expressions to improve insulin resistance but also a reduction in hepatic sterol regulatory element binding protein (SREBP)-1c expressions, and suppression of ACC activity, thus resulting in the decreased fatty acid synthesis but elevated hepatic peroxisome proliferator-activated receptor (PPAR) α and SREBP-2 expressions, resulting in lowering TG and TC concentrations. Our results demonstrated that EPE improves insulin resistance and ameliorates hyperlipidemia in HFD mice.

Tyrosine protein phosphatase non-receptor type 1 (PTP1B; also known as protein tyrosine phosphatase 1B) is a member of the protein tyrosine phosphatase (PTP) family and is a soluble enzyme that plays an essential role in different physiological processes, including the regulation of metabolism, specifically in insulin and leptin sensitivity. PTP1B is crucial in the pathogenesis of type 2 diabetes mellitus and obesity. These biological functions have made PTP1B validated as an antidiabetic and anti-obesity, and potentially anticancer, molecular target. Four main approaches aim to inhibit PTP1B: orthosteric, allosteric, bidentate inhibition, and PTPN1 gene silencing. Developing a potent and selective PTP1B inhibitor is still challenging due to the enzyme's ubiquitous expression, subcellular location, and structural properties. This article reviews the main advances in the study of PTP1B since it was first isolated in 1988, as well as recent contextual information related to the PTP family to which this protein belongs. Furthermore, we offer an overview of the role of PTP1B in diabetes and obesity, and the challenges to developing selective, effective, potent, bioavailable, and cell-permeable compounds that can inhibit the enzyme.

In fat and skeletal muscle cells, insulin causes plasma membrane translocation of specialized insulin-responsive vesicles, or IRVs. These vesicles consist of multiple copies of Glut4, sortilin, IRAP, and LRP1 as well as several auxiliary components. Major IRV proteins have relatively long half-life inside the cell and survive multiple rounds of translocation to and from the cell surface. Here, we summarize evidence showing how the IRVs are self-assembled from pre-synthesized Glut4, sortilin, IRAP, and LRP1 after each translocation event. Furthermore, the cytoplasmic tail of sortilin binds Akt while cytoplasmic tails of IRAP and LRP1 interact with the Akt target, TBC1D4. Recruitment of signaling proteins to the IRVs may render insulin responsiveness to this compartment and thus distinguish it from other intracellular membrane vesicles.

This study aims to investigate the influence of socioeconomic status (SES) on variations in physical activity (PA) levels and diabetes-related cognitive dysfunction and impairment amidst disruptions caused by the COVID-19 pandemic.

With the sample of old population, comprising about 20 thousand from the Fact-Finding Survey on the Status of Senior Citizens (FSSSC) released by Ministry of Health and Welfare of South Korea in 2017 and 2020, we empirically tested the direct and indirect effects of SES on cognitive dysfunction using structural equation modeling (SEM). Two SEMs provided the comparison on the effects of COVID-19.

Household income had a negative impact on the likelihood of dementia diagnosis via PA related diabetes during the pandemic (p < 0.001), whereas no effects of household income on dementia diagnosis were found in 2017, due to no direct effect of PA on diabetes confirmation in 2017. The disparity in PA based on SES becomes more prominent among the older individuals during the pandemic (z = 11.7) than 2017 (z = 6.0), emphasizing the significance of PA in mitigating diabetes-induced cognitive dysfunction during the pandemic. SES affects access to PA, contributing to diabetes-induced cognitive dysfunctions in the older population with lower SES during the pandemic.

PA may serve as a preventive measure against diabetes-induced cognitive dysfunction and dementia in the older population. Thorough investigation of these mechanisms is imperative to establish the role of PA in preventing diabetes-induced cognitive impairment, particularly among the older population with lower SES.

The skeletal muscle is a pivotal organ involved in the regulation of both energy metabolism and exercise capacity. There is no doubt that exercise contributes to a healthy life through the consumption of excessive energy or the release of myokines. Skeletal muscles exhibit insulin sensitivity and can rapidly uptake blood glucose. In addition, they can undergo non-shivering thermogenesis through actions of both the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) and small peptide, sarcolipin, resulting in systemic energy metabolism. Accordingly, the maintenance of skeletal muscles is important for both metabolism and exercise. Prolyl isomerase Pin1 is an enzyme that converts the cis-trans form of proline residues and controls substrate function. We have previously reported that Pin1 plays important roles in insulin release, thermogenesis, and lipolysis. However, the roles of Pin1 in skeletal muscles remains unknown. To clarify this issue, we generated skeletal muscle-specific Pin1 knockout mice. Pin1 deficiency had no effects on muscle weights, morphology and ratio of fiber types. However, they showed exacerbated obesity or insulin resistance when fed with a high-fat diet. They also showed a lower ability to exercise than wild type mice did. We also found that Pin1 interacted with SERCA and elevated its activity, resulting in the upregulation of oxygen consumption. Overall, our study reveals that Pin1 in skeletal muscles contributes to both systemic energy metabolism and exercise capacity.

Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC), associated with obesity and insulin resistance. The FDA prohibited the use of BPA-based polycarbonate resins in infant formula packaging; thus, its analogs, viz. Bisphenol S (BPS) and Bisphenol F (BPF) were considered alternatives in epoxy resins, plastics, and food cans. As these analogs might evoke a similar response, we investigated the role of Bisphenols (BPA, BPF, and BPS), on insulin signaling in CHO-HIRc-myc-GLUT4eGFP cells at environmentally relevant concentrations of 2 nM and 200 nM. Insulin signaling demonstrated that Bisphenols reduced phosphorylation of IR and AKT2, GLUT4 translocation, and glucose uptake. This was accompanied by increased oxidative stress. Furthermore, SWATH-MS-based proteomics of 3T3-L1 cells demonstrated that Bisphenol-treated cells regulate proteins in insulin resistance, adipogenesis, and fatty acid metabolism pathways differently. All three Bisphenols induced differentially expressed proteins enriched similar pathways, although their abundance differed for each Bisphenol. This might be due to their varying toxicity level, structural differences, and estrogen-mimetic activity. This study has important implications in addressing health concerns related to EDCs. Given that the analogs of BPA are considered alternatives to BPA, the findings of this study suggest they are equally potent in altering fatty acid metabolism and inducing insulin resistance.

The vagus nerve belongs to the parasympathetic nervous system, which is involved in the regulation of organs throughout the body. Since the discovery of the non-neuronal cardiac cholinergic system (NNCCS), several studies have provided evidence for the positive role of acetylcholine (ACh) released from cardiomyocytes against cardiovascular diseases, such as sympathetic hyperreactivity-induced cardiac remodeling and dysfunction as well as myocardial infarction. Non-neuronal ACh released from cardiomyocytes is believed to regulate key physiological functions of the heart, such as attenuating heart rate, offsetting hypertrophic signals, maintaining action potential propagation, and modulating cardiac energy metabolism through the muscarinic ACh receptor in an auto/paracrine manner. Moreover, the NNCCS may also affect peripheral remote organs (e.g., liver) through the vagus nerve. Remote ischemic preconditioning (RIPC) and NNCCS activate the central nervous system and afferent vagus nerve. RIPC affects hepatic glucose and energy metabolism through the central nervous system and vagus nerve. In this review, we discuss the mechanisms and potential factors responsible for NNCCS in glucose and energy metabolism in the liver.

Lysophosphatidylserine (lyso-PS) has emerged as yet another important signaling lysophospholipid in mammals, and deregulation in its metabolism has been directly linked to an array of human autoimmune and neurological disorders. It has an indispensable role in several biological processes in humans, and therefore, cellular concentrations of lyso-PS are tightly regulated to ensure optimal signaling and functioning in physiological settings. Given its biological importance, the past two decades have seen an explosion in the available literature toward our understanding of diverse aspects of lyso-PS metabolism and signaling and its association with human diseases. In this Review, we aim to comprehensively summarize different aspects of lyso-PS, such as its structure, biodistribution, chemical synthesis, and SAR studies with some synthetic analogs. From a biochemical perspective, we provide an exhaustive coverage of the diverse biological activities modulated by lyso-PSs, such as its metabolism and the receptors that respond to them in humans. We also briefly discuss the human diseases associated with aberrant lyso-PS metabolism and signaling and posit some future directions that may advance our understanding of lyso-PS-mediated mammalian physiology.

Cancer cells reprogram their metabolism to become "glycolysis-dominant," which enables them to meet their energy and macromolecule needs and enhancing their rate of survival. This glycolytic-dominancy is known as the "Warburg effect", a significant factor in the growth and invasion of malignant tumors. Many studies confirmed that members of the GLUT family, specifically HK-II from the HK family play a pivotal role in the Warburg effect, and are closely associated with glucose transportation followed by glucose metabolism in cancer cells. Overexpression of GLUTs and HK-II correlates with aggressive tumor behaviour and tumor microenvironment making them attractive therapeutic targets. Several studies have proven that the regulation of GLUTs and HK-II expression improves the treatment outcome for various tumors. Therefore, small molecule inhibitors targeting GLUT and HK-II show promise in sensitizing cancer cells to treatment, either alone or in combination with existing therapies including chemotherapy, radiotherapy, immunotherapy, and photodynamic therapy. Despite existing therapies, viable methods to target the glycolysis of cancer cells are currently lacking to increase the effectiveness of cancer treatment. This review explores the current understanding of GLUT and HK-II in cancer metabolism, recent inhibitor developments, and strategies for future drug development, offering insights into improving cancer treatment efficacy.

Fatty acids have been shown to modulate glucose metabolism in vitro and in vivo. However, there is still a need for substantial evidence and mechanistic understanding in many cell types whether both saturated and unsaturated fatty acids (SFAs and UFAs) pose a similar effect and, if not, what determines the net effect of fatty acid mixes on glucose metabolism. In the present study, we asked these questions by treating granulosa cells (GCs) with the most abundant non-esterified fatty acid species in bovine follicular fluid. Results revealed that oleic and alpha-linolenic acids (UFAs) significantly increased glucose consumption compared to palmitic and stearic acids (SFAs). A significant increase in lactate production, extracellular acidification rate, and decreased mitochondrial activity indicate glucose channeling through aerobic glycolysis in UFA treated GCs. We show that insulin independent glucose transporter GLUT10 is essential for UFA driven glucose consumption, and the induction of AKT and ERK signaling pathways necessary for GLUT10 expression. To mimic the physiological conditions, we co-treated GCs with mixes of SFAs and UFAs. Interestingly, co-treatments abolished the UFA induced glucose uptake and metabolism by inhibiting AKT and ERK phosphorylation and GLUT10 expression. These data suggest that the net effect of fatty acid induced glucose uptake in GCs is determined by SFAs under physiological conditions.

Cancer reprogramming is an important facilitator of cancer development and survival, with tumor cells exhibiting a preference for aerobic glycolysis beyond oxidative phosphorylation, even under sufficient oxygen supply condition. This metabolic alteration, known as the Warburg effect, serves as a significant indicator of malignant tumor transformation. The Warburg effect primarily impacts cancer occurrence by influencing the aerobic glycolysis pathway in cancer cells. Key enzymes involved in this process include glucose transporters (GLUTs), HKs, PFKs, LDHs, and PKM2. Moreover, the expression of transcriptional regulatory factors and proteins, such as FOXM1, p53, NF-κB, HIF1α, and c-Myc, can also influence cancer progression. Furthermore, lncRNAs, miRNAs, and circular RNAs play a vital role in directly regulating the Warburg effect. Additionally, gene mutations, tumor microenvironment remodeling, and immune system interactions are closely associated with the Warburg effect. Notably, the development of drugs targeting the Warburg effect has exhibited promising potential in tumor treatment. This comprehensive review presents novel directions and approaches for the early diagnosis and treatment of cancer patients by conducting in-depth research and summarizing the bright prospects of targeting the Warburg effect in cancer.

In light of the expected increase in the prevalence of diabetes mellitus due to an aging population, sedentary lifestyles, an increase in obesity, and unhealthy diets, there is a need to identify potential pharmacological agents that can heighten the risk of developing diabetes. Similarly, it is equally important to also identify those agents that show blood glucose-lowering properties. Amongst these agents are tyrosine kinase inhibitors used to treat certain types of cancers. Over the last two decades, there has been an increase in the use of targeted chemotherapy for cancers such as renal cell carcinoma, chronic leukaemia, and gastrointestinal stromal tumours. Small molecule tyrosine kinase inhibitors have been at the forefront of targeted chemotherapy. Studies have shown that small molecule tyrosine kinase inhibitors can alter glycaemic control and glucose metabolism, with some demonstrating hypoglycaemic activities whilst others showing hyperglycaemic properties. The mechanism by which small molecule tyrosine kinase inhibitors cause glycaemic dysregulation is not well understood, therefore, the clinical significance of these chemotherapeutic agents on glucose handling is also poorly documented. In this review, the effort is directed at mapping mechanistic insights into the effect of various small molecule tyrosine kinase inhibitors on glycaemic dysregulation envisaged to provide a deeper understanding of these chemotherapeutic agents on glucose metabolism. Small molecule tyrosine kinase inhibitors may elicit these observed glycaemic effects through preservation of β-cell function, improving insulin sensitivity and insulin secretion. These compounds bind to a spectrum of receptors and proteins implicated in glucose regulation for example, non-receptor tyrosine kinase SRC and ABL. Then receptor tyrosine kinase EGFR, PDGFR, and FGFR.

Diabetes belongs to the most prevalent metabolic diseases worldwide, which is featured with insulin resistance, closely associated with obesity and urgently needs to be treated. Baicalin, belonging to natural flavonoids, has been reported to inhibit oxidative stress or inflammatoin.

This study investigated the properties of baicalin on modulating abnormal glucolipid metabolism, as well as the underlying in-vitro and in-vivo mechanisms.

Insulin-resistant (IR)-HepG2 cells were stimulated by dexamethasone (20 µM) and high glucose (50 mM) for 48 h and incubated with or without baicalin or metformin for another 16 h. Male C57BL/6 J mice were fed with a high-fat diet (HFD, 60 % kcal% fat) during the total 14 weeks. Obese mice were then administered with baicalin (50 and 100 mg/kg) or vehicle solution everyday through oral gavage during the last 4-week period. Moreover, baicalin metabolisms in vitro and in vivo were determined using UPLC/MS/MS to study its metabolism situation.

Exposure to dexamethasone and high glucose damaged the abilities of glycogen synthesis and glucose uptake with elevated oxidative stress and increased generation levels of advanced glycation end-products (AGEs) in HepG2 cells. These impairments were basically reversed by baicalin treatment. Four-week oral administration with baicalin ameliorated hyperglycemia and dyslipidemia in HFD-induced obese and pre-diabetic mice. Downregulation of IRS/PI3K/Akt signaling pathway accomplished with reduced GLUT4 expression and enhanced GSK-3β activity was observed in insulin resistant HepG2 cells as well as liver tissues from pre-diabetic mice; and such effect was prevented by baicalin. Moreover, baicalin and its matabolites were detected in IR-HepG2 cells and mouse plasma.

The study illustrated that baicalin alleviated insulin resistance by activating insulin signaling pathways and inhibiting oxidative stress and AGEs production, revealing the potential of baicalin to be a therapeutic natural flavonoid against hepatic insulin and glucose-lipid metabolic disturbance in pre-diabetes accompanied with obesity.

The triglyceride glucose (TyG) index was suggested as a novel reliable surrogate marker for insulin resistance and related cardiovascular-metabolic diseases. We aimed to evaluate the association between the TyG index and environmental exposure to lead (Pb), mercury (Hg), and cadmium (Cd). A total of 9645 adults who enrolled in the Korea National Health and Nutrition Examination Survey in 2005, 2008-2013, and 2016 were included. Fasting plasma glucose and triglyceride levels were used to calculate the TyG index. Multivariate logistic regression model was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). We noted an increasing trend in the TyG index with increment of blood Pb and Cd concentrations. Participants in the highest quartile of blood Pb and Cd concentrations had higher TyG index values than those in the lowest quartile, with ORs (95% CIs) of 1.32 (1.07-1.63) and 1.29 (1.04-1.59) for Pb and Cd, respectively. Strong associations between blood Pb and Cd concentrations and the TyG index were found in men. Blood Hg concentrations did not show a significant association with the TyG index. Our study suggests that public health strategies for cardiovascular-metabolic disorder prevention should be directed toward individuals exposed to priority heavy metals.

In embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), the expression of an RNA-binding pluripotency-relevant protein, LIN28, and the absence of its antagonist, the tumor-suppressor microRNA (miRNA) let-7, play a key role in maintaining pluripotency. Muse cells are non-tumorigenic pluripotent-like stem cells residing in the bone marrow, peripheral blood, and organ connective tissues as pluripotent surface marker SSEA-3(+). They express pluripotency genes, differentiate into triploblastic-lineage cells, and self-renew at the single cell level. Muse cells do not express LIN28 but do express let-7 at higher levels than in iPSCs. In Muse cells, we demonstrated that let-7 inhibited the PI3K-AKT pathway, leading to sustainable expression of the key pluripotency regulator KLF4 as well as its downstream genes, POU5F1, SOX2, and NANOG. Let-7 also suppressed proliferation and glycolysis by inhibiting the PI3K-AKT pathway, suggesting its involvement in non-tumorigenicity. Furthermore, the MEK/ERK pathway is not controlled by let-7 and may have a pivotal role in maintaining self-renewal and suppression of senescence. The system found in Muse cells, in which the tumor suppressor let-7, but not LIN28, tunes the expression of pluripotency genes, might be a rational cell system conferring both pluripotency-like properties and a low risk for tumorigenicity.

Dorper and Tan sheep are renowned for their rapid growth and exceptional meat quality, respectively. Previous research has provided evidence of the impact of gut microbiota on breed characteristics. The precise correlation between the gastrointestinal tract and peripheral organs in each breed is still unclear. Investigating the metabolic network of the intestinal organ has the potential to improve animal growth performance and enhance economic benefits through the regulation of intestinal metabolites.

In this study, we identified the growth advantage of Dorper sheep and the high fat content of Tan sheep. A transcriptome study of the brain, liver, skeletal muscle, and intestinal tissues of both breeds revealed 3,750 differentially expressed genes (DEGs). The genes PPARGC1A, LPL, and PHGDH were found to be highly expressed in Doper, resulting in the up-regulation of pathways related to lipid oxidation, glycerophospholipid metabolism, and amino acid anabolism. Tan sheep highly express the BSEP, LDLR, and ACHE genes, which up-regulate the pathways involved in bile transport and cholesterol homeostasis. Hindgut content analysis identified 200 differentially accumulated metabolites (DAMs). Purines, pyrimidines, bile acids, and fatty acid substances were more abundant in Dorper sheep. Based on combined gene and metabolite analyses, we have identified glycine, serine, and threonine metabolism, tryptophan metabolism, bile secretion, cholesterol metabolism, and neuroactive ligand-receptor interaction as key factors contributing to the differences among the breeds.

This study indicates that different breeds of sheep exhibit unique breed characteristics through various physiological regulatory methods. Dorper sheep upregulate metabolic signals related to glycine, serine, and threonine, resulting in an increase in purine and pyrimidine substances. This, in turn, promotes the synthesis of amino acids and facilitates body development, resulting in a faster rate of weight gain. Tan sheep accelerate bile transport, reduce bile accumulation in the intestine, and upregulate cholesterol homeostasis signals in skeletal muscles. This promotes the accumulation of peripheral and intramuscular fat, resulting in improved meat quality. This work adopts a joint analysis method of multi-tissue transcriptome and gut metabolome, providing a successful case for analyzing the mechanisms underlying the formation of various traits.

Glucose metabolism is of critical importance for cell growth and proliferation, the disorders of which have been widely implicated in cancer progression. Glucose uptake is achieved differently by normal cells and cancer cells. Even in an aerobic environment, cancer cells tend to undergo metabolism through glycolysis rather than the oxidative phosphorylation pathway. Disordered metabolic syndrome is characterized by elevated levels of metabolites that can cause changes in the tumor microenvironment, thereby promoting tumor recurrence and metastasis. The activation of glycolysis-related proteins and transcription factors is involved in the regulation of cellular glucose metabolism. Changes in glucose metabolism activity are closely related to activation of protein kinase B (PKB/AKT). This review discusses recent findings on the regulation of glucose metabolism by AKT in tumors. Furthermore, the review summarizes the potential importance of AKT in the regulation of each process throughout glucose metabolism to provide a theoretical basis for AKT as a target for cancers.

Brown adipose tissue (BAT) converts chemical energy into heat to maintain body temperature. Although fatty acids (FAs) represent a primary substrate for uncoupling protein 1 (UCP1)-dependent thermogenesis, BAT also utilizes glucose for the same purpose. Considering that estrous cycle effects on BAT are not greatly explored, we examined those of 6-h fasting on interscapular BAT (iBAT) thermogenic markers in proestrus and diestrus. We found that the percentage of multilocular adipocytes was lower in proestrus than in diestrus, although it was increased after fasting in both analyzed estrous cycle stages. Furthermore, the percentage of paucilocular adipocytes was increased by fasting, unlike the percentage of unilocular cells, which decreased in both analyzed stages of the estrous cycle. The UCP1 amount was lower in proestrus irrespectively of the examined dietary regimens. Regarding FA transporters, it was shown that iBAT CD36 content was increased in fasted rats in diestrus. In contrast to GLUT1, the level of GLUT4 was interactively modulated by selected estrous cycle phases and fasting. There was no change in insulin receptor and ERK1/2 activation, while AKT activation was interactively modulated by fasting and estrous cycle stages. Our study showed that iBAT exhibits morphological and functional changes in proestrus and diestrus. Moreover, iBAT undergoes additional dynamic functional and morphological changes during short-term fasting to modulate nutrient utilization and adjust energy expenditure.

Obesity has become a global health concern with an increasing prevalence as years pass by but the researchers have not come to a consensus on the exact pathophysiological mechanism underlying this disease. In the past three decades, Monoamine Oxidases (MAO), has come into limelight for a possible involvement in orchestrating the genesis of obesity but the exact mechanism is not well elucidated. MAO is essentially an enzyme involved in the catabolism of neurotransmitters and other biogenic amines to form a corresponding aldehyde, hydrogen peroxide (H2O2) and ammonia. This review aims to highlight the repercussions of MAO's catabolic activity on the redox balance, carbohydrate metabolism and lipid metabolism of adipocytes which ultimately leads to obesity. The H2O2 produced by these enzymes seems to be the culprit causing oxidative stress in pre-adipocytes and goes on to mimic insulin's activity independent of its presence via the Protein Kinase B Pathway facilitating glucose influx. The H2O2 activates Sterol regulatory-element binding protein-1c and peroxisome proliferator activated receptor gamma crucial for encoding enzymes like fatty acid synthase, acetyl CoA carboxylase 1, Adenosine triphosphate-citrate lyase, phosphoenol pyruvate carboxykinase etc., which helps promoting lipogenesis at the same time inhibits lipolysis. More reactive oxygen species production occurs via NADPH Oxidases enzymes and is also able activate Nuclear Factor kappa B leading to inflammation in the adipocyte microenvironment. This chronic inflammation is the seed for insulin resistance.

A major consequence of insulin binding its receptor on fat and muscle cells is the stimulation of glucose transport into these tissues. This is achieved through an increase in the exocytic trafficking rate of the facilitative glucose transporter GLUT4 from intracellular stores to the cell surface. Delivery of GLUT4 to the cell surface requires the formation of functional SNARE complexes containing Syntaxin 4, SNAP23, and VAMP2. Insulin stimulates the formation of these complexes and concomitantly causes phosphorylation of Syntaxin 4. Here, we use a combination of biochemistry and cell biological approaches to provide a mechanistic link between these observations. We present data to support the hypothesis that Tyr-115 and Tyr-251 of Syntaxin 4 are direct substrates of activated insulin receptors, and that these residues modulate the protein's conformation and thus regulate the rate at which Syntaxin 4 forms SNARE complexes that deliver GLUT4 to the cell surface. This report provides molecular details on how the cell regulates SNARE-mediated membrane traffic in response to an external stimulus.

Lysiphyllum strychnifolium (Craib) A. Schmitz (LS) (Fabaceae) has traditionally been used to treat diabetes mellitus.

This study demonstrates the antidiabetic and antioxidant effects of aqueous extract of LS leaves in vivo and in vitro.

The effects of aqueous LS leaf extract on glucose uptake, sodium-dependent glucose cotransporter 1 (SGLT1) and glucose transporter 2 (GLUT2) mRNA expression in Caco-2 cells, α-glucosidase, and lipid peroxidation were evaluated in vitro. The antidiabetic effects were evaluated using an oral glucose tolerance test (OGTT) and a 28-day consecutive administration to streptozotocin (STZ)-nicotinamide (NA)-induced type 2 diabetic mice.

The extract significantly inhibited glucose uptake (IC₅₀: 236.2 ± 36.05 µg/mL) and downregulated SGLT1 and GLUT2 mRNA expression by approximately 90% in Caco-2 cells. Furthermore, it non-competitively inhibited α-glucosidase in a concentration-dependent manner with the IC₅₀ and K_i of 6.52 ± 0.42 and 1.32 µg/mL, respectively. The extract at 1000 mg/kg significantly reduced fasting blood glucose levels in both the OGTT and 28-day consecutive administration models as compared with untreated STZ-NA-induced diabetic mice (p < 0.05). Significant improvements of serum insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and GLUT4 levels were observed. Furthermore, the extract markedly decreased oxidative stress markers by 37-53% reduction of superoxide dismutase 1 (SOD1) in muscle and malondialdehyde (MDA) in muscle and pancreas, which correlated with the reduction of MDA production in vitro (IC₅₀: 24.80 ± 7.24 µg/mL).

The LS extract has potent antihyperglycemic activity to be used as alternative medicine to treat diabetes mellitus.

Magnesium (Mg) has a pivotal role in upholding skeletal muscle health and optimizing performance. Its deficiency decreases muscle strength, and an association has been reported between Mg intake and sarcopenia. To gain a comprehensive understanding of the repercussions arising from low Mg concentrations on muscle behavior, we employed an in vitro model utilizing C2C12-derived myotubes. Myotubes cultured in low Mg show a significant reduction of thickness and a concomitant down-regulation of myosin heavy chain (MyHC), Myog and Myomixer. In parallel, myotubes shape their metabolism. Glycolysis is inhibited and beta-oxidation increases. These metabolic changes are consistent with the increase of MyHC I (slow) vs. MyHC II (fast) expression. We identified an essential player in these changes, namely nitric oxide (NO), as the increase in NO production appeared to orchestrate the observed modifications in myotube behavior and metabolism under low Mg conditions. Understanding these underlying mechanisms may pave the way for targeted interventions to ameliorate muscle-related conditions associated with Mg deficiency and contribute to enhancing overall muscle health and function.

Cell membrane phosphatidylcholine (PC) composition is regulated by lysophosphatidylcholine acyltransferase (LPCAT); changes in membrane PC saturation are implicated in metabolic disorders. Here, we identified LPCAT3 as the major isoform of LPCAT in adipose tissue and created adipocyte-specific Lpcat3-knockout mice to study adipose tissue lipid metabolism. Transcriptome sequencing and plasma adipokine profiling were used to investigate how LPCAT3 regulates adipose tissue insulin signaling. LPCAT3 deficiency reduced polyunsaturated PCs in adipocyte plasma membranes, increasing insulin sensitivity. LPCAT3 deficiency influenced membrane lipid rafts, which activated insulin receptors and AKT in adipose tissue, and attenuated diet-induced insulin resistance. Conversely, higher LPCAT3 activity in adipose tissue from ob/ob, db/db, and high-fat diet-fed mice reduced insulin signaling. Adding polyunsaturated PCs to mature human or mouse adipocytes in vitro worsened insulin signaling. We suggest that targeting LPCAT3 in adipose tissue to manipulate membrane phospholipid saturation is a new strategy to treat insulin resistance.

Glucose transporters (GLUTs) are responsible for transporting hexose molecules across cellular membranes. In adipocytes, insulin stimulates glucose uptake by redistributing GLUT4 to the plasma membrane. In unstimulated adipose-like mouse cell lines, GLUT4 is known to be retained intracellularly by binding to TUG protein, while upon insulin stimulation, GLUT4 dissociates from TUG. Here, we report that the TUG homolog in human, ASPL, exerts similar properties, i.e., forms a complex with GLUT4. We describe the structural details of complex formation by combining biochemical assays with cross-linking mass spectrometry and computational modeling. Combined, the data suggest that the intracellular domain of GLUT4 binds to the helical lariat of ASPL and contributes to the regulation of GLUT4 trafficking by cooperative binding.

Adipocyte dysfunction is a crucial driver of insulin resistance and type 2 diabetes. We identified EH domain-containing protein 2 (EHD2) as one of the most highly upregulated genes at the early stage of adipose-tissue expansion. EHD2 is a dynamin-related ATPase influencing several cellular processes, including membrane recycling, caveolae dynamics, and lipid metabolism. Here, we investigated the role of EHD2 in adipocyte insulin signaling and glucose transport. Using C57BL6/N EHD2 knockout mice under short-term high-fat diet conditions and 3T3-L1 adipocytes we demonstrate that EHD2 deficiency is associated with deterioration of insulin signal transduction and impaired insulin-stimulated GLUT4 translocation. Furthermore, we show that lack of EHD2 is linked with altered plasma membrane lipid and protein composition, reduced insulin receptor expression, and diminished insulin-dependent SNARE protein complex formation. In conclusion, these data highlight the importance of EHD2 for the integrity of the plasma membrane milieu, insulin receptor stability, and downstream insulin receptor signaling events, involved in glucose uptake and ultimately underscore its role in insulin resistance and obesity.

In adipose tissue, insulin stimulates glucose uptake by mediating the translocation of GLUT4 from intracellular vesicles to the plasma membrane. In 2010, insulin was revealed to also have a fundamental impact on the spatial distribution of GLUT4 within the plasma membrane, with the existence of two GLUT4 populations at the plasma membrane being defined: (1) as stationary clusters and (2) as diffusible monomers. In this model, in the absence of insulin, plasma membrane-fused GLUT4 are found to behave as clusters. These clusters are thought to arise from exocytic events that retain GLUT4 at their fusion sites; this has been proposed to function as an intermediate hub between GLUT4 exocytosis and re-internalisation. By contrast, insulin stimulation induces the dispersal of GLUT4 clusters into monomers and favours a distinct type of GLUT4-vesicle fusion event, known as fusion-with-release exocytosis. Here, we review how super-resolution microscopy approaches have allowed investigation of the characteristics of plasma membrane-fused GLUT4 and further discuss regulatory step(s) involved in the GLUT4 dispersal machinery, introducing the scaffold protein EFR3 which facilitates localisation of phosphatidylinositol 4-kinase type IIIα (PI4KIIIα) to the cell surface. We consider how dispersal may be linked to the control of transporter activity, consider whether macro-organisation may be a widely used phenomenon to control proteins within the plasma membrane, and speculate on the origin of different forms of GLUT4-vesicle exocytosis.

The discovery of insulin in 1921 introduced a new branch of research into insulin activity and insulin resistance. Many discoveries in this field have been applied to diagnosing and treating diseases related to insulin resistance. In this mini-review, the authors attempt to synthesize the updated discoveries to unravel the related mechanisms and inform the development of novel applications. Firstly, we depict the insulin signaling pathway to explain the physiology of insulin action starting at the receptor sites of insulin and downstream the signaling of the insulin signaling pathway. Based on this, the next part will analyze the mechanisms of insulin resistance with two major provenances: the defects caused by receptors and the defects due to extra-receptor causes, but in this study, we focus on post-receptor causes. Finally, we discuss the recent applications including the diseases related to insulin resistance (obesity, cardiovascular disease, Alzheimer's disease, and cancer) and the potential treatment of those based on insulin resistance mechanisms.

The estrogen receptor (ER) designated ERα has actions in many cell and tissue types that impact glucose homeostasis. It is unknown if these include mechanisms in endothelial cells, which have the potential to influence relative obesity, and processes in adipose tissue and skeletal muscle that impact glucose control. Here we show that independent of impact on events in adipose tissue, endothelial ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle. Endothelial ERα-deficient male mice are glucose intolerant and insulin resistant, and in females the antidiabetogenic actions of estradiol (E2) are absent. The glucose dysregulation is due to impaired skeletal muscle glucose disposal that results from attenuated muscle insulin delivery. Endothelial ERα activation stimulates insulin transcytosis by skeletal muscle microvascular endothelial cells. Mechanistically this involves nuclear ERα-dependent upregulation of vesicular trafficking regulator sorting nexin 5 (SNX5) expression, and PI3 kinase activation that drives plasma membrane recruitment of SNX5. Thus, coupled nuclear and non-nuclear actions of ERα promote endothelial insulin transport to skeletal muscle to foster normal glucose homeostasis.

Cerebellar ataxia is often the first and irreversible outcome in the disease of ataxia-telangiectasia (A-T), as a consequence of selective cerebellar Purkinje neuronal degeneration. A-T is an autosomal recessive disorder resulting from the loss-of-function mutations of the ataxia-telangiectasia-mutated ATM gene. Over years of research, it now becomes clear that functional ATM-a serine/threonine kinase protein product of the ATM gene-plays critical roles in regulating both cellular DNA damage response and central carbon metabolic network in multiple subcellular locations. The key question arises is how cerebellar Purkinje neurons become selectively vulnerable when all other cell types in the brain are suffering from the very same defects in ATM function. This review intended to comprehensively elaborate the unexpected linkages between these two seemingly independent cellular functions and the regulatory roles of ATM involved, their integrated impacts on both physical and functional properties, hence the introduction of selective vulnerability to Purkinje neurons in the disease will be addressed.