Regulation Of Glucose Uptake Research Articles

Ubiquitin-like processing of TUG proteins as a mechanism to regulate glucose uptake and energy metabolism in fat and muscle.

In response to insulin stimulation, fat and muscle cells mobilize GLUT4 glucose transporters to the cell surface to enhance glucose uptake. Ubiquitin-like processing of TUG (Aspscr1, UBXD9) proteins is a central mechanism to regulate this process. Here, recent advances in this area are reviewed. The data support a model in which intact TUG traps insulin-responsive “GLUT4 storage vesicles” at the Golgi matrix by binding vesicle cargoes with its N-terminus and matrix proteins with its C-terminus. Insulin stimulation liberates these vesicles by triggering endoproteolytic cleavage of TUG, mediated by the Usp25m protease. Cleavage occurs in fat and muscle cells, but not in fibroblasts or other cell types. Proteolytic processing of intact TUG generates TUGUL, a ubiquitin-like protein modifier, as the N-terminal cleavage product. In adipocytes, TUGUL modifies a single protein, the KIF5B kinesin motor, which carries GLUT4 and other vesicle cargoes to the cell surface. In muscle, this or another motor may be modified. After cleavage of intact TUG, the TUG C-terminal product is extracted from the Golgi matrix by the p97 (VCP) ATPase. In both muscle and fat, this cleavage product enters the nucleus, binds PPARγ and PGC-1α, and regulates gene expression to promote fatty acid oxidation and thermogenesis. The stability of the TUG C-terminal product is regulated by an Ate1 arginyltransferase-dependent N-degron pathway, which may create a feedback mechanism to control oxidative metabolism. Although it is now clear that TUG processing coordinates glucose uptake with other aspects of physiology and metabolism, many questions remain about how this pathway is regulated and how it is altered in metabolic disease in humans.

Signaling and Gene Expression in Skeletal Muscles in Type 2 Diabetes: Current Results and OMICS Perspectives.

Skeletal muscles mainly contribute to the emergence of insulin resistance, impaired glucose tolerance and the development of type 2 diabetes. Molecular mechanisms that regulate glucose uptake are diverse, including the insulin-dependent as most important, and others as also significant. They involve a wide range of proteins that control intracellular traffic and exposure of glucose transporters on the cell surface to create an extensive regulatory network. Here, we highlight advantages of the omics approaches to explore the insulin-regulated proteins and genes in human skeletal muscle with varying degrees of metabolic disorders. We discuss methodological aspects of the assessment of metabolic dysregulation and molecular responses of human skeletal muscle to insulin. The known molecular mechanisms of glucose uptake regulation and the first results of phosphoproteomic and transcriptomic studies are reviewed, which unveiled a large-scale array of insulin targets in muscle cells. They demonstrate that a clear depiction of changes that occur during metabolic dysfunction requires systemic and combined analysis at different levels of regulation, including signaling pathways, transcription factors, and gene expression. Such analysis seems promising to explore yet undescribed regulatory mechanisms of glucose uptake by skeletal muscle and identify the key regulators as potential therapeutic targets.

Measurement of skeletal muscle glucose uptake in mice in response to acute treadmill running.

Skeletal muscle contractions stimulate glucose uptake into the working muscles during exercise. Because this signaling pathway is independent of insulin, exercise constitutes an important alternative pathway to increase glucose uptake, also in insulin-resistant muscle. Therefore, much effort is being put into understanding the molecular regulation of exercise-stimulated glucose uptake by skeletal muscle. To delineate the causal molecular mechanisms whereby muscle contraction or exercise regulate glucose uptake, the investigation of genetically manipulated rodents is necessary. Presented here is a modified and optimized protocol assessing exercise-induced muscle glucose uptake in mice in response to acute treadmill running. Using this high-throughput protocol, running capacity can accurately and reproducibly be determined in mice, and basal- and exercise-stimulated skeletal muscle glucose uptake and intracellular signaling can precisely and dose-dependently be measured in awake mice in vivo without the need for catheterization and with minimal loss of blood.

Geranylgeranyl pyrophosphate depletion by statins compromises skeletal muscle insulin sensitivity.

Statins are widely prescribed cholesterol-lowering drugs but have been shown to increase the risk of type 2 diabetes mellitus. However, the molecular mechanisms underlying the diabetogenic effect of statins are still not fully understood. The effects of geranylgeranyl transferase I and II (GGTase I and II) inhibition on insulin-stimulated glucose uptake and GLUT4 translocation, and the dependence of these effects on insulin signalling were investigated in skeletal muscle cells. The protective effects of geranylgeranyl pyrophosphate (GGPP) and its precursor geranylgeraniol (GGOH) on simvastatin-induced insulin resistance were evaluated in vitro and in vivo. The effect of GGTase II inhibition in skeletal muscle on insulin sensitivity in vivo was confirmed by adeno-associated virus serotype 9 (AAV9)-mediated knockdown of the specific subunit of GGTase II, RABGGTA. The regulatory mechanisms of GGTase I on insulin signalling and GGTase II on insulin-stimulated GLUT4 translocation were investigated by knockdown of RhoA, TAZ, IRS1, geranylgeranylation site mutation of RhoA, RAB8A, and RAB13. Both inhibition of GGTase I and II mimicked simvastatin-induced insulin resistance in skeletal muscle cells. GGPP and GGOH were able to prevent simvastatin-induced skeletal muscle insulin resistance in vitro and in vivo. GGTase I inhibition suppressed the phosphorylation of AKT (Ser473) (-51.3%, P<0.01), while GGTase II inhibition had no effect on it. AAV9-mediated knockdown of RABGGTA in skeletal muscle impaired glucose disposal without disrupting insulin signalling in vivo (-46.2% for gastrocnemius glucose uptake, P<0.001; -52.5% for tibialis anterior glucose uptake, P<0.001; -17.8% for soleus glucose uptake, P<0.05; -31.4% for extensor digitorum longus glucose uptake, P<0.01). Inhibition of RhoA, TAZ, IRS1, or geranylgeranylation deficiency of RhoA attenuated the beneficial effect of GGPP on insulin signalling in skeletal muscle cells. Geranylgeranylation deficiency of RAB8A inhibited insulin-stimulated GLUT4 translocation and concomitant glucose uptake in skeletal muscle cells (-42.8% for GLUT4 translocation, P<0.01; -50.6% for glucose uptake, P<0.001). Geranylgeranyl pyrophosphate regulates glucose uptake via GGTase I-mediated insulin signalling-dependent way and GGTase II-mediated insulin signalling-independent way in skeletal muscle. Supplementation of GGPP/GGOH could be a potential therapeutic strategy for statin-induced insulin resistance.

A Nodal enhanced micropeptide NEMEP regulates glucose uptake during mesendoderm differentiation of embryonic stem cells

TGF-β family proteins including Nodal are known as central regulators of early development in metazoans, yet our understanding of the scope of Nodal signaling’s downstream targets and associated physiological mechanisms in specifying developmentally appropriate cell fates is far from complete. Here, we identified a highly conserved, transmembrane micropeptide—NEMEP—as a direct target of Nodal signaling in mesendoderm differentiation of mouse embryonic stem cells (mESCs), and this micropeptide is essential for mesendoderm differentiation. We showed that NEMEP interacts with the glucose transporters GLUT1/GLUT3 and promotes glucose uptake likely through these interactions. Thus, beyond expanding the scope of known Nodal signaling targets in early development and showing that this target micropeptide augments the glucose uptake during mesendoderm differentiation, our study provides a clear example for the direct functional impact of altered glucose metabolism on cell fate determination.

Evaluation of the Influence of Biosurface Design on the Interaction between the Regulatory Peptide RS1-reg and ODC1 Reveals a Membrane-Dependent Affinity Increase.

The regulatory solute carrier protein, family 1, member 1 (RS1) modulates via its N-terminal domain RS1-reg the activity of Na+ -d-glucose cotransporter 1 (SGLT1) and thereby the glucose uptake in the small intestine by blocking the release of SGLT1-containing vesicles at the trans-Golgi network (TGN). The antidiabetic activity of RS1 is mediated by ornithindecarboxylase 1 (ODC1), catalyzing the conversion of ornithine to putrescine. Putrescine can bind to a buddying protein complex for SGLT1-containing vesicles at the membrane of the TGN, triggering vesicle release. In this report, a first in-depth analysis of the important binding process between ODC1 and RS1-reg for regulating glucose uptake in the human organism is described by comparing results from the surface-based methods, "surface plasmon resonance" (SPR) and "surface acoustic wave" (SAW) with findings by isothermal titration calorimetry (ITC). In cases of SAW and SPR, three different assay surface setups are compared, resulting in small but significant differences in KD values for different surfaces. Noteworthy, an affinity increase by the factor of about 100 for the interaction is detected and herewith described for the first time in the presence of biological membranes that may be relevant in vivo for the biological function of RS1 and future bespoken antidiabetic drug development.

1303-P: Decreased Hepatic HMGB1 in Type 2 Diabetes Increases Mitochondrial Glucose Uptake by Regulating Insulin/AKT Signaling

Introduction: High Mobility Group Box-1 (HMGB1) is strongly associated with Type 2 Diabetes (T2D) and hepatocyte function. HMGB1 can regulate mitochondrial function under high glucose conditions. Our group has shown that knockdown of HMGB1 reduces hyperglycemia with decrease insulin activity. We want to further understand the role of HMGB1 in hepatocyte mitochondrial function and the insulin/AKT signaling, a vital pathway in glucose hemostasis. We hypothesize that by decreasing HMGB1, hepatocytes increase glucose uptake by regulating mitochondrial function with more effective Insulin/AKT signaling. Methods: Primary hepatocytes and liver lysates were isolated from inducible HMGB1 KO (iHMGB1 KO) and HMGB1 Flox (wildtype) mice after Tamoxifen and Streptozotocin IP injections for HMGB1 knockout and T2D-10-weeks development. HMGB1 knockdown and insulin/AKT signaling were assessed by RT-PCR and immunoblot. Flow cytometry was performed on primary hepatocyte cell suspension for mitochondrial function/mass (TMRE, Mitotracker) and glucose uptake (NDBG) cellular markers. Results: Liver lysates showed significant decreased expression/activity of HMGB1, Insulin Receptor-B, phosphorylated AKT, PDK and SIRT3 in iHMGB1 KO T2D mice. A counter regulator of metabolic and glucose activity, phosphorylated PDH, was found increased in iHMGB1 KO mice. Flow cytometry of isolated hepatocytes showed that iHMGB1 KO T2D animals had significantly less mitochondrial mass and functioning mitochondria, however showed increased glucose uptake. Conclusion: We found a potential mechanism by which HMGB1 regulates glucose uptake by regulating mitochondrial function and mass potentially by regulating the effectiveness of the Insulin/Akt signaling in T2D. Future studies will be directed to test glucose transport/metabolism in HMGB1 KO hepatocytes guided by more effective Insulin activity in the mediation of mitochondria function at the different stages of T2D progression. Disclosure Z.Liu: None. C.Kaltenmeier: None. R.I.Mota alvidrez: None. Funding This work was funded by department of surgery support for RIMA

Circulating Ism1 Reduces the Risk of Type 2 Diabetes but not Diabetes-Associated NAFLD.

PurposeTo examine the association of serum Ism1, a new adipokine that can regulate glucose uptake, with type 2 diabetes (T2D) in a Chinese population. Considering high prevalence of Nonalcoholic Fatty Liver Disease in patients with type 2 diabetes and the regulating role of Ism1 on glucose uptake of peripheral tissues, we further explored the association between Ism1 and diabetes-associated nonalcoholic fatty liver disease.MethodsA total of 120 newly diagnosed T2D patients and 60 control subjects with normal glucose were recruited in the case-control study. Serum Ism1 concentrations were determined by ELISA. Multivariate logistic regression analysis was used to evaluate the independent association of serum Ism1 concentration with the risk of T2D. The 120 newly diagnosed T2D patients were divided into uncomplicated T2D group and diabetes-associated NAFLD group according to the FLI score.ResultsThe Ism1 level of normoglycemic controls was higher than that of T2D patients (3.91 ± 0.24 ng/ml vs 3.01 ± 0.16 ng/ml, P=0.001). Based on quartile analysis of Ism1 level, the proportion of high circulating Ism1 levels in the control group increased while T2D group decreased, and the distribution difference was statistically significant (P=0.015). Logistic regression analysis indicated that the serum Ism1 level was an independent protective factor of type 2 diabetes (OR=0.69, 95%CI: 0.54-0.89). The decrease of Ism1 level did not increase the risk of non-alcoholic fatty liver disease in diabetic patients by Binary logistic regression analysis (OR=1.08, 95% CI: 0.69-1.69).ConclusionsThe increase of serum Ism1 was associated with a decreased risk of diabetes, and it did not reduce the risk of non-alcoholic fatty liver disease in diabetic patients.

Metabolic changes induced by DNA damage in Ramos cells: exploring the role of mTORC1 complex.

DNA damage induces the activation of many different signals associated with repair or cell death, but it is also connected with physiological events, such as adult neurogenesis and B‐cell differentiation. DNA damage induces different signaling pathways, some of them linked to important metabolic changes. The mTORC1 pathway has a central role in the regulation of growth processes and cell division in response to environmental changes and also controls protein synthesis, lipid biogenesis, nucleotide synthesis, and expression of glycolytic genes. Here, we report that double‐strand breaks induced with etoposide affect the expression of genes encoding different enzymes associated with specific metabolic pathways in Ramos cells. We also analyzed the role of mTOR signaling, demonstrating that double‐strand breaks induce downregulation of mTOR signaling. Specific inhibition of mTORC1 using rapamycin also induced changes in the expression of metabolic genes. Finally, we demonstrated that DNA damage and rapamycin can regulate glucose uptake. In summary, our findings show that etoposide and rapamycin affect the expression of metabolic genes as well as apoptotic and proliferation markers in Ramos cells, increasing our understanding of cancer metabolism.

Phenolics from Chrozophora oblongifolia Aerial Parts as Inhibitors of α-Glucosidases and Advanced Glycation End Products: In-Vitro Assessment, Molecular Docking and Dynamics Studies

Simple SummaryThe chemical investigation of Chrozophora oblongifolia aerial parts resulted in the isolation of five phenolic compounds. The isolated metabolites were tested for their antioxidant and advanced glycation end-products (AGEs) formation, α-glucosidase, and lipase inhibitory activities. 1,3,6-Trigalloyl glucose exhibited the highest activity as an antioxidant and AGEs inhibitor as well as an α-glucosidase inhibitor. It showed promising binding affinity and stability towards the human intestinal maltase-glucoamylase α-glucosidases, as revealed through coupled molecular docking and dynamics studies that could encourage the utilization of this compound in the management of diabetes and its complications.Modern life is associated with low physical activity that leads to the accumulation of fats, gaining more weight, and obesity. Accumulation of fat in the abdomen region contributes to diabetes via insulin resistance and hyperglycemia. Polyphenols are major plant constituents that exert antidiabetic activity through different mechanisms, including radicle scavenging activity, regulation of glucose uptake, and inhibition of fat and polysaccharide hydrolysis in addition to their inhibitory role regarding the formation of advanced glycation end products (AGEs). Chemical investigation of C. oblongifolia aerial parts resulted in the isolation of five major compounds: apeginin-7-O-β-D-glucoside (1), quercetin-3-O-β-D-glucuronic acid (2), quercetin-3-O-β-D-galacturonic acid (3), rutin (4), and 1,3,6-trigalloyl glucose (5). The isolated compounds were tested for their antioxidant and AGEs formation, α-glucosidase, and lipase inhibitory activities. Compound 5 revealed the highest antioxidant and AGEs inhibitory activity in bovine serum albumin (BSA)-methylglyoxal, BSA-fructose, and arginine-methylglyoxal models. Moreover, it exhibited a potent inhibitory profile on Saccharomyces cerevisiae α-glucosidases compared to the positive control, acarbose. Compound (5) further depicted promising binding affinity and stability towards the human intestinal maltase-glucoamylase α-glucosidases, which is a diabetes-related therapeutic target, through coupled molecular docking and dynamics studies. The obtained results encourage the usage of 1,3,6-trigalloyl glucose in the management of diabetes and its complications. However, detailed in-vivo studies for this compound should be performed.

Design and characterization of a FGF1‐FGF21 chimeric protein with increased stability and enhanced antidiabetic activities

Fibroblast growth factor (FGF) family is consisted of 22 proteins that regulate a wide variety of biological functions such as wound healing, tissue repairs, and angiogenesis. FGF family follows three main modes of action: paracrine, intracrine or endocrine. One member of the paracrine FGFs is FGF1, which works locally through interaction with heparin or heparin sulfate (HS). With its mitogenic and cell survival activities, FGF1 participates in many developmental processes, cell growth and differentiation, tissue repairs, and tumor growth and invasion. A representative of endocrine FGFs is FGF21, which is often used in long range physiological processes, but does not require HS. FGF21 engages in many functions across various organs like liver, pancreas, adipose tissues. One of FGF21’s abilities is the regulation of glucose uptake in adipocytes through upregulating the transcription of glucose transporter‐1. Thus, FGF21 is a potential treatment for metabolic diseases such as Type‐2 Diabetes. However, FGF21 has been reported to possess an inherently unstable core with low thermal stability and receptor affinity. Herein, we designed a structure‐based chimera protein by replacing the core of FGF21 with a thermally stable paracrine FGF1 (sFGF1). Using techniques such as fluorescence spectroscopy, and circular dichroism, we show that the chimera protein sFGF1‐FGF21 adopts a β‐trefoil core. Intrinsic fluorescence spectra of the chimera protein shows an emission maximum centered at 307 nm indicating that the emission of the conserved tryptophan is quenched similar to wildtype FGF1. Differential calorimetry data suggests that chimera sFGF1‐FGF21 is significantly more stable than wild type FGF21. The findings of this study provide valuable clues for the rational design of FGF21‐based therapeutic against hyperglycemia and obesity.

IP3R-mediated Ca2+ signaling controls B cell proliferation through metabolic reprogramming

SummaryEmerging evidence shows that metabolic regulation may be a critical mechanism in B cell activation and function. As targets of several most widely used immunosuppressants, Ca2+ signaling and calcineurin may play an important role in regulating B cell metabolism. Here, we demonstrate that IP3R-mediated Ca2+ signaling and calcineurin regulate B cell proliferation and survival by activating metabolic reprogramming in response to B cell receptor (BCR) stimulation. Both IP3R-triple-knockout (IP3R-TKO) and calcineurin inhibition dramatically suppress the metabolic switch in oxidative phosphorylation and glycolysis of stimulated B cells through regulation of glucose uptake, glycolytic enzyme expression, and mitochondrial remodeling, leading to impaired cell-cycle entry and survival. In addition, IP3R-Ca2+ acts as a master regulator of the calcineurin-MEF2C-Myc pathway in driving B cell metabolic adaptations. As genetic defects of IP3Rs were recently identified as a new class of inborn errors of immunity, these results have important implications for understanding the pathogenesis of such diseases.

Effects of Adiponectin on Glucose Metabolism in the Hepatopancreas of Grass Carp (Ctenopharyngodon idella)

Adiponectin plays critical roles in the regulation of energy metabolism in mammals. However, its roles in fish remain to be evaluated. In this study, we examined the tissue distribution characteristics of two adiponectin genes, namely, adipoqa and adipoqb, at transcriptional level, and detected the changes of their mRNA expressions during oral glucose tolerance test (OGTT). Furthermore, we prepared recombinant proteins of grass carp adiponectin A and adiponectin B and studied their roles in the regulation of glucose metabolism in the hepatopancreas of grass carp in vivo. The results showed that adipoqa mRNA was mainly expressed in the heart of grass carp, followed by red muscle, white muscle, and adipose tissue, while adipoqb mRNA was highly expressed in adipose tissue, red muscle, and white muscle. The mRNA levels of adipoqa and adipoqb in the white muscle and heart were significantly decreased at 1 h post OGTT, and their expressions in the heart were also suppressed at 3 h, whereas the transcriptional levels of adipoqa and adipoqb in the red muscle were elevated significantly at 12 h after glucose load. Intraperitoneal injection of adiponectin A or adiponectin B reduced basal serum glucose levels of grass carp and caused an increase of glycogen content in the hepatopancreas. Adiponectin A upregulated the expression of enzyme genes related to glycolysis (gk and pk) and glycogen synthesis (gys) in the hepatopancreas, and adiponectin B promoted the expression of pk and gys, as well as g6pase in the glycogenetic pathway. Besides, adiponectin A and adiponectin B have opposite regulatory effects on glut2 mRNA expression. These results suggested that adiponectin A and adiponectin B promoted glycolysis, gluconeogenesis, and glycogen synthesis, increased glycogen content of hepatopancreas, and reduced basal blood glucose level, and they may have an antagonistic regulatory mechanism in regulating glucose uptake.

Epiregulin as an Alternative Ligand for Leptin Receptor Alleviates Glucose Intolerance without Change in Obesity.

The leptin receptor (LepR) acts as a signaling nexus for the regulation of glucose uptake and obesity, among other metabolic responses. The functional role of LepR under leptin-deficient conditions remains unclear. This study reports that epiregulin (EREG) governed glucose uptake in vitro and in vivo in Lepob mice by activating LepR under leptin-deficient conditions. Single and long-term treatment with EREG effectively rescued glucose intolerance in comparative insulin and EREG tolerance tests in Lepob mice. The immunoprecipitation study revealed binding between EREG and LepR in adipose tissue of Lepob mice. EREG/LepR regulated glucose uptake without changes in obesity in Lepob mice via mechanisms, including ERK activation and translocation of GLUT4 to the cell surface. EREG-dependent glucose uptake was abolished in Leprdb mice which supports a key role of LepR in this process. In contrast, inhibition of the canonical epidermal growth factor receptor (EGFR) pathway implicated in other EREG responses, increased glucose uptake. Our data provide a basis for understanding glycemic responses of EREG that are dependent on LepR unlike functions mediated by EGFR, including leptin secretion, thermogenesis, pain, growth, and other responses. The computational analysis identified a conserved amino acid sequence, supporting an evolutionary role of EREG as an alternative LepR ligand.

Effect of Taurine on the Regulation of Glucose Uptake in the Skeletal Muscle.

Diabetes is so common in Japan as to be called a national disease. Taurine, a free amino acid found abundantly in mammalian tissues that is also a key ingredient of many "energy drinks," has been shown to be effective in improving the hyperglycemic state caused by diabetes. Taurine administration is associated with increased insulin secretion from the pancreas, higher levels of insulin signaling-related factors, and higher expression of the glucose transporter, GLUT4. Skeletal muscle is the main target organ of insulin: Via cell surface GLUT4 molecules, myocytes take up blood glucose, enabling skeletal muscle contraction. The enhancing effect of taurine on blood glucose uptake in skeletal muscle has not been fully studied, and little is known about its mechanism. This review article summarizes what is known about the effects of taurine on insulin secretion from the pancreas and especially blood glucose uptake in skeletal muscle.

Amino Acid Nanofibers Improve Glycemia and Confer Cognitive Therapeutic Efficacy to Bound Insulin.

Diabetes poses a high risk for debilitating complications in neural tissues, regulating glucose uptake through insulin-dependent and predominantly insulin-independent pathways. Supramolecular nanostructures provide a flexible strategy for combinatorial regulation of glycemia. Here, we compare the effects of free insulin to insulin bound to positively charged nanofibers comprised of self-assembling amino acid compounds (AACs) with an antioxidant-modified side chain moiety (AAC2) in both in vitro and in vivo models of type 1 diabetes. Free AAC2, free human insulin (hINS) and AAC2-bound-human insulin (AAC2-hINS) were tested in streptozotocin (STZ)-induced mouse model of type 1 diabetes. AAC2-hINS acted as a complex and exhibited different properties compared to free AAC2 or hINS. Mice treated with the AAC2-hINS complex were devoid of hypoglycemic episodes, had improved levels of insulin in circulation and in the brain, and increased expression of neurotransmitter taurine transporter, Slc6a6. Consequently, treatment with AAC2-hINS markedly advanced both physical and cognitive performance in mice with STZ-induced and genetic type 1 diabetes compared to treatments with free AAC2 or hINS. This study demonstrates that the flexible nanofiber AAC2 can serve as a therapeutic platform for the combinatorial treatment of diabetes and its complications.

Effect of photobiomodulation therapy on the regulation of glucose uptake by lymphocytes in diabetes mellitus (Review)

For most cells, including lymphocytes, glucose is a primary energy source, and, therefore, it is vital to understand the regulatory mechanisms that control the work of glucose transporters. Lymphocytes are pivotal for mediation of immune and inflammatory responses. A feature of lymphocytes is increasing glucose utilization during activation of the immune function, which is strongly dependent on glucose uptake. Some studies show that elevated glucose concentration in diabetes mellitus affects lymphocytes’ glucose transporters expression, whichcorrelates with impaired immune functions and may become one of the predisposing factors of contracting infectious diseases. Recent studies have focused on glucose transporters as therapeutic targets for a variety of diseases, including diabetes mellitus. This review demonstrates the effect of photobiomodulationtherapy on glucose uptake by Na+-coupled glucose carrier SGLT1 and facilitated diffusion glucose carriers of the GLUT family (GLUT1, GLUT3, GLUT4) in normal and diabetic lymphocytes.

The “Levine effect” and the father of modern diabetes research

The “Levine effect” and the father of modern diabetes research

LIGHT (TNFSF14) inhibits glucose uptake of adipocytes by downregulating GLUT4 expression via AKT signaling pathway

Glucose homeostasis of adipocytes could be regulated by immune-adipose crosstalk. In order to investigate the effects of Lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells (LIGHT) on glucose metabolism, we performed the present study. Our results showed that LIGHT deficiency improved glucose tolerance and enhanced glucose consumption of inguinal white adipose tissue (iWAT) under high fat diet. Consistently, Light overexpression could inhibit glucose uptake during the process of white adipogenesis. Mechanistically, LIGHT interacted with lymphotoxin-β receptor (LTβR) to attenuate AKT pathway leading to downregulation of glucose transporter-4 (GLUT4) expression, which resulted in glucose uptake inhibition. In summary, our findings revealed LIGHT-LTβR-AKT-GLUT4 axis as a regulator of glucose uptake in adipose tissue, which suggested the pivotal role of LIGHT in maintaining glucose homeostasis.

Impact of germline polymorphisms in genes regulating glucose uptake on positron emission tomography findings and outcome in diffuse large B-cell lymphoma: results from the PETAL trial

Background[18F]Fluoro-deoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is the standard imaging procedure in diffuse large B-cell lymphoma (DLBCL). Disease presentation, FDG-PET/CT performance, and outcome may be influenced by germline single nucleotide polymorphisms (SNP) in genes regulating glucose uptake.MethodsClinical variables, FDG-PET findings, and outcome were analysed in relation to SNPs in 342 DLBCL patients participating in the ‘Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas’ (PETAL) trial. Genes analysed included SLC2A1 (SNPs rs1385129, referred to as HaeIII; rs710218, HpyCH4V; rs841853, XbaI), VEGFA (rs3025039), HIF1A (rs11549465, P582S; rs11549467, A588T), and APEX1 (rs1130409, D148E). Statistical significance was assumed at p ≤ 0.05.ResultsThe SLC2A1 HaeIII and HpyCH4V SNPs were tightly linked and statistically significantly associated with baseline maximum standardized uptake value (SUVmax) and Ann Arbor stage, with slightly lower SUVmax (HaeIII, median 18.9, interquartile range [IQR] 11.5–26.6, versus 21.6, IQR 14.4–29.7; p = 0.019) and more frequent stage IV disease (HaeIII, 44.5% versus 30.8%; p = 0.011) in minor allele carriers. As previously reported for lung cancer, the association was dependent upon the coexistent APEX1 D148E genotype. The HIF1A A588T SNP was associated with total metabolic tumour volume (TMTV) and time-to-progression, with significantly lower TMTV (median 16 cm3, IQR 7–210, versus 146 cm3, IQR 34–510; p = 0.034) and longer time-to-progression in minor allele carriers (log-rank p = 0.094). Time-to-progression was also associated with the SLC2A1 XbaI and APEX1 D148E SNPs, with shorter time-to-progression in homozygous and heterozygous SLC2A1 XbaI (HR 1.456; CI 0.930–2.280; p = 0.099) and homozygous APEX1 D148E minor allele carriers (HR 1.6; CI 1.005–2.545; p = 0.046). In multivariable analyses including SNPs, International Prognostic Index factors, sex, and B symptoms, HIF1A A588T, SLC2A1 XbaI, and APEX1 D148E retained statistical significance for time-to-progression, and SLC2A1 XbaI was also significantly associated with overall survival.ConclusionsCommon SNPs in genes regulating glucose uptake may impact SUVmax, tumour distribution, tumour volume, and outcome in DLBCL. The effects on SUVmax are of low magnitude and appear clinically negligible. The results are consistent with findings in other types of cancer. They need to be confirmed in an independent DLBCL population of sufficient size.Trial registrationTrial registration: ClinicalTrials.gov NCT00554164; EudraCT 2006-001641-33. Registration date November 5, 2007, https://www.clinicaltrials.gov/ct2/show/NCT00554164