Role Of Glucose Research Articles

Determination of a possible relationship between a single nucleotide polymorphism (SNP) in the promoter region of the SIRT1 gene and production and reproduction traits in the Agerolese cattle breed.

Sirtuins (sir2-like proteins) belong to the family of class III NAD-dependent histone deacetylases. Among them, SIRT1 is the most studied sirtuin. It plays a key role in many biological processes in the liver, adipose tissue, muscle, pancreas, testis, ovary and mammary gland. It has an important function in endocrine signaling, with a specific role in glucose and fat metabolism. To date, in bovine species, only few SIRT1 single nucleotide polymorphisms (SNPs) have been reported in the literature. Thus, the aims of the present study were to estimate the allele and genotype frequencies at the g.-274C G locus in the promoter region of the SIRT1 gene and to investigate, for the first time, the relationship among different genotypes and milk production and some reproduction traits in a sample of cows belonging to the Agerolese breed. All the animals were genotyped at the abovementioned locus using the PCR-RFLP technique. The investigated population was found to be polymorphic at the investigated locus. Concerning milk production performances, significant differences between genotypes were found in daily milk yield (DMY), fat percentage (FC), lactation length (LL), peak daily milk yield (PY) and 305-day milk yield (305MY). Moreover, the effect of the g.-274C G genotype on age at first calving and calving period was significant. In conclusion, our findings are promising and should encourage scientists to further investigate the effect of genetic polymorphism of sirtuins on milk performance and reproductive traits.

Levels of chemerin and asymmetric dimethylarginine (ADMA) in obese type 2 diabetic patients.

Diabetes Mellitus (D.M) has reached epidemic proportion and has become one of the most challenging health problems of the 21st century. Moreover, it is the 4th leading cause of death by disease globally, where every 10 seconds a person dies from diabetes-related causes. Obesity, insulin resistance, dyslipidemia and hypertension are associated with (T2DM) termed together as a metabolic syndrome. Mobilization of free fatty acids and secretion of certain inflammatory adipokines from adipose tissue promote insulin resistance in obese diabetics by interfere with insulin sensitivity, glucose and lipid metabolism. Chemerin, a specific adipokine, has an essential role in glucose and lipid metabolism. It plays a role in pathogenesis of obesity and T2DM also has important roles in energy metabolism, adipogenesis, and inflammation. Asymmetric dimethyl arginine (ADMA) consider a natural analogue of the essential amino acid arginine and a metabolic by-product obtained from processes of protein turnover of all human cells cytoplasm.

Increased serum/plasma fibroblast growth factor 21 in type 2 diabetes mellitus: a systematic review and meta-analysis

ObjectivesFibroblast growth factor-21 (FGF-21) plays an important role in glucose and lipid metabolism. This study aims to systemically review the evidence regarding the relationship between the FGF-21 levels and type...

Mobilization of fat body glycogen and haemolymph trehalose under nutritional stress in Bombyx mori larvae in relation to their physiological age and the duration of food deprivation

In insects, fat body glycogen and haemolymph trehalose are principal carbohydrate reserves. Here, in Bombyx mori (Linnaeus, 1758), we report an accelerated fat body glycogen accumulation in feeding 5th instar larvae, when they reach the terminal growth period (TGP). Haemolymph trehalose and glucose levels, however, fluctuated between 7–21 mM and 0.8–10 mM, respectively, depending on the larval physiological age. Food deprivation triggered a dramatic increase in mobilization of glycogen in larvae at TGP than at active growth period (AGP), mobilized almost 78% of stored glycogen at an initial 12 h of food deprivation, possibly by increasing the percentage of active glycogen phosphorylase, as observed. This rapid glycogen mobilization, along with meeting the energy demand of starving tissues, might also have provided glucose for trehalose synthesis, as evident by observed hypertrehalosemia. A prolonged food deprivation (24–48 h) triggered hypotrehalosemia along with an increase in the enzyme activity of trehalase, and the transcript level of trehalase-2, indicating the utilization of trehalose as an energy source for the demanding tissues. Further, in TGP larvae, a prolonged food deprivation increased the level of haemolymph glucose (1.8–3.5 mM) as well as glucose/trehalose ratio, and this suggests that the fat body might have released the glucose molecules directly into the haemolymph, instead of utilizing it for trehalose synthesis, possibly to minimize the expenditure of energy. Thus, short-term food deprivation triggered an initial glycogen mobilization whereas, prolonged food deprivation led to the utilization of trehalose as an energy source. Hence, mobilization of carbohydrate reserves varied depending on the larval physiological age and the extent of food deprivation period. The future investigation can expand our understanding on the role of glucose as an important haemolymph sugar along with trehalose.

Long-Term Impact of Neonatal Intake of Oleanolic Acid on the Expression of AMP-Activated Protein Kinase, Adiponectin and Inflammatory Cytokines in Rats Fed with a High Fructose Diet.

AMP-activated protein kinase (AMPK) is known to regulate both glucose and lipid metabolism, which play vital roles in the development of metabolic syndrome. One way of regulating AMPK is through hormonal activation using adiponectin. Patients diagnosed with type-2 diabetes (T2D) and obesity exhibit low adiponectin concentration levels in their blood. Moreover, studies have also shown that inflammatory processes play a significant role in the etiology of these metabolic diseases. In this study, the long-term effects of neonatal intake of oleanolic acid (OA) on the AMPK gene, genes associated with glucose transport and lipid metabolism, adiponectin levels, and inflammatory biomarkers in rats fed with a high fructose diet were investigated. Seven day old pups were randomly divided into five groups and treated as follows; 0.5% dimethylsulphoxide v/v in distilled water vehicle control (CON), oleanolic acid (OA, 60 mg/kg), high fructose diet (HF, 20% w/v), high fructose diet combined with oleanolic acid (HF+OA), and high fructose diet combined with metformin (HF+MET, 500 mg/kg). The treatments were administered once daily until day 14. The rats were then weaned at day 21 and fed standard rat chow and had ad libitum access to plain drinking water until day 112. The quantitative polymerase chain reaction (qPCR) was used to analyze the gene expressions of AMPK, Glut-4, Cpt-1, AdipoR1, AdipoR2, TNF-α, and IL-6 in the skeletal muscles. Bio-Plex Pro magnetic bead-based assay was used to measure plasma levels of inflammatory markers (TNF-α, IL-6, VEGF, and MCP-1) while ELISA kits were used to measure adiponectin concentration in blood plasma. The results obtained in this study showed that neonatal supplementation with OA significantly increased AMPK gene expression approximately ~4-fold in OA fed rats compared to those that were fed with HF alone. In addition, glut-4 gene expression was also significantly higher in the OA treatment group compared to all the other experimental groups except the CON group whereas Cpt-1 gene was more expressed when OA was administered alone. Together, these results indicated that OA can play a role in glucose and lipid metabolism gene regulation. Furthermore, the results showed that the OA group had ~1.5-fold increase in adiponectin concentration when comparedto the HF group. Moreover, HF increased levels of inflammatory cytokines, which was attenuated by neonatal administration of OA. Plasma concentration and gene expression in the skeletal muscle for TNF-α and IL-6 were significantly increased in rats that were treated with HF alone when compared to all the other groups. On the contrary, the high levels of TNF-α and IL-6 were reduced when OA was administered. These findings suggest that intake of oleanolic acid during the neonatal stage of development could be a potential strategic intervention for the long-term prevention of metabolic diseases such as T2D and obesity.

Genetic variants and haplotype combination in the bovine CRTC3 affected conformation traits in two Chinese native cattle breeds (Bos Taurus)

CREB-regulated transcription coactivator 3 (CRTC3) plays an extensive role in glucose and lipid metabolism. This study investigated the genetic variation and haplotype combination in CRTC3 and verified their contribution to bovine growth traits. Firstly, investigated the mRNA expression of CRTC3 in adult Qinchuan cattle and evaluated the effects that genetic variation of CRTC3 had on conformation and carcass traits in two Chinese cattle breeds (Qinchuan and Jiaxian). Four SNPs (single nucleotide polymorphisms) were identified including two in introns (SNP1: g.62652 A > G and SNP4: g.91297C > T) and two in exons (SNP2 g.62730C > T and SNP3: g.66478G > C). The association and haplotype combination results showed that there was an association with some growth and carcass traits(P < 0.05). Individuals with haplotype combination H1H1 (-AACCCCTT-) were associated with a conformation of a larger framed animal and an animal that produced a larger loin area. Variations in the CRTC3 genes and the haplotype combination H1H1 may be considered as molecular markers for carcass traits that are associated with more lean meat yield for use in cattle breeding programs in China.

Effect of Metabolic Reprogramming on the Biological Activity of Acute Myeloid Leukemia Cells

ABSTRACTMetabolic reprogramming of acute myeloid leukemia (AML) cell lines has been described as a compensatory adaptation to fulfill their energy requirements for its rapid proliferation. In this study,we examined the role of the glutamine (Gln) removal or inhibition of glutaminase by GLS inhibitor bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol- 2-yl) ethyl sulfide(BPTES) in AML cell lines SKM-1 to Observe whether it has an effect on the biological activity of SKM-1 cells. Our results indicated that inhibit glutamine uptake or utilization can inhibit cell growth and induce apoptosis in AML. we used Long non-coding RNAs (LncRNAs) Gene Microarray to analyze gene expression after Gln deprivation treatment. We found that the expression of MT2A, MT1X, MT3, MT1H, MT1F and MT1E in the metallothionein (MT) gene family was significantly upregulated and the expression of AGT、CSF1R、PAK7、MYCN、ARG1 was significantly downregulated . We further analysed the expression of MT isogenes by quantitative real-time PCR (RT-PCR). The results showed that the gene expression of the MT gene family was upregulated, consistent with the results of the Gene Microarray. These findings indicate that metallothionein may play an important role in the glutamine metabolic pathway of AML cells. metformin, a commonly used antidiabetic drug, play an important role in Glucose Metabolism.We observed that Metformin alone exhibited a dose-dependent anti-leukemic activity in SKM-1 cell lines and its anti-leukemic activity was enhanced when used in combination with Gln deprivation or Cytarabine. These findings show that Gln deprivation or Metformin enhance the sensitivity of SKM-1 cell line to chemotherapeutic agents. Taken together , targeting amino acid metabolism and glucose metabolism are promising new therapeutic strategies to enhance the efficacy of chemotherapeutic agents in AML.Conflict of interestNo relevant conflicts of interest to declare.Acknowledgments:Tongyuan Liu analyzed the data, plotted the tables and figures and wrote the paper; Dengju Li designed projects and revised the paper. This work was supported by the National Natural Science Foundation of China (Grant no. 81770168). DisclosuresNo relevant conflicts of interest to declare.

Association of elevated circulating fibroblast growth factor 21 levels with prevalent and incident metabolic syndrome: The Multi-Ethnic Study of Atherosclerosis

Background and aimsFibroblast growth factor 21 (FGF21) plays an important role in glucose and lipid metabolism. We have investigated the relationship of plasma FGF21 levels with both prevalent and incident metabolic syndrome (MetS) in participants from the Multi-Ethnic Study of Atherosclerosis (MESA). Methods5783 participants from four major ethnic groups (non-Hispanic white, African American, Hispanic American, and Chinese American) were included in the cross-sectional analysis. Longitudinal analysis involved 3479 participants without MetS at baseline, of whom 1100 participants developed incident MetS over 9.2 years. ResultsElevated FGF21 levels were found in participants with prevalent MetS (median [interquartile range] = 189.4 [114.4–302.1] vs. 123.7 [65.9–210.3] pg/mL, p < 0.001) or incident MetS (145.6 [84.9–240.8] vs 112.0 [57.0–194.5] pg/mL, p < 0.001), compared to those without. After adjusting for baseline demographic, socioeconomic and lifestyle factors, as well as cardiovascular risk factors and biomarkers, and compared to the lowest quartile, the highest FGF21 quartile was associated with prevalent MetS (odds ratio 2.80; 95% confidence interval, 2.30–3.40, p < 0.001). Among participants without MetS at baseline, the highest FGF21 quartile was associated with higher risk of incident MetS (hazards ratio 1.76; 95% confidence interval, 1.46–2.12, p < 0.001). Similar results were obtained when assessing ln-transformed FGF21 levels. Overall, no significant interaction was found with age, sex, and race/ethnicity for both prevalent and incident MetS. ConclusionsHigher FGF21 levels significantly predict the development of MetS in an ethnically diverse population followed long term. Further studies are needed to confirm the potential role of FGF21 as a biomarker for MetS.

Pleiotrophin deletion alters glucose homeostasis, energy metabolism and brown fat thermogenic function in mice.

Pleiotrophin, a developmentally regulated and highly conserved cytokine, exerts different functions including regulation of cell growth and survival. Here, we hypothesise that this cytokine can play a regulatory role in glucose and lipid homeostasis. To test this hypothesis, we performed a longitudinal study characterising the metabolic profile (circulating variables and tissue mRNA expression) of gene-targeted Ptn-deficient female mice and their corresponding wild-type counterparts at different ages from young adulthood (3months) to older age (15months). Metabolic cages were used to investigate the respiratory exchange ratio and energy expenditure, at both 24°C and 30°C. Undifferentiated immortalised mouse brown adipocytes (mBAs) were treated with 0.1μg/ml pleiotrophin until day 6 of differentiation, and markers of mBA differentiation were analysed by quantitative real-time PCR (qPCR). Ptn deletion was associated with a reduction in total body fat (20.2% in Ptn+/+ vs 13.9% in Ptn-/- mice) and an enhanced lipolytic response to isoprenaline in isolated adipocytes from 15-month-old mice (189% in Ptn+/+ vs 273% in Ptn-/- mice). We found that Ptn-/- mice exhibited a significantly lower QUICKI value and an altered lipid profile; plasma triacylglycerols and NEFA did not increase with age, as happens in Ptn+/+ mice. Furthermore, the contribution of cold-induced thermogenesis to energy expenditure was greater in Ptn-/- than Ptn+/+ mice (42.6% and 33.6%, respectively). Body temperature and the activity and expression of deiodinase, T3 and mitochondrial uncoupling protein-1 in the brown adipose tissue of Ptn-/- mice were higher than in wild-type controls. Finally, supplementing brown pre-adipocytes with pleiotrophin decreased the expression of the brown adipocyte markers Cidea (20% reduction), Prdm16 (21% reduction), and Pgc1-α (also known as Ppargc1a, 11% reduction). Our results reveal for the first time that pleiotrophin is a key player in preserving insulin sensitivity, driving the dynamics of adipose tissue lipid turnover and plasticity, and regulating energy metabolism and thermogenesis. These findings open therapeutic avenues for the treatment of metabolic disorders by targeting pleiotrophin in the crosstalk between white and brown adipose tissue.

Glucose suppresses IL-1β-induced MMP-1 expression through the FAK, MEK, ERK, and AP-1 signaling pathways.

Osteoarthritis (OA) commonly affects the synovial joint and is characterized by degradation of articular cartilage. Increased matrix metalloproteinase (MMP) activity plays a major role in this degradation. Dextrose (D-glucose) prolotherapy has shown promising activity in the treatment of different musculoskeletal disorders, including OA. However, little is known about the role of glucose on MMP inhibition in OA therapy. We found that stimulating chondrocytes with the proinflammatory cytokine interleukin-1β (IL-1β) increased the expression of MMP-1, MMP-3, and MMP-13. Glucose reduced this increase in MMP-1 expression, but had no effect upon MMP-3 or MMP-13 expression. Analyses using a focal adhesion kinase (FAK) inhibitor, MEK inhibitors (U0126 and PD98059), an ERK inhibitor, AP-1 inhibitors (curcumin and tanshinone), or siRNAs demonstrated that the FAK, MEK, ERK, and AP-1 pathways mediate IL-1β-induced increases in MMP-1 expression. Glucose antagonized IL-1β-promoted phosphorylation of FAK, MEK, ERK, and c-Jun. Thus, glucose decreased IL-1β-induced MMP-1 expression through the FAK, MEK, ERK, and AP-1 signaling cascades. These findings may provide a better understanding of the mechanisms of prolotherapy on inhibiting MMP expression.

Abstract 274: Regulation of Myocardial Ketone Body Oxidation Capacity by Increased Protein O-GlcNAcylation in Diabetic Heart

Diabetes increases the risk of heart failure independently of underlying coronary artery disease. Perturbations in myocardial substrate utilization have been proposed to contribute to the pathogenesis of cardiac dysfunction. However, the exact mechanisms linking impaired substrate utilization to disease progression remain elusive. Compared to the well-established roles of glucose and fatty acids metabolism in cardiac physiology and pathology, the importance of ketone body (KB) metabolism is less well understood. Several findings suggest the importance of KB in the cardiac health and disease. More recently, two independent studies have simultaneously demonstrated increased reliance on KB utilization by the failing heart in the absence of diabetes. Despite these observations, our understanding of the importance of KB metabolism in a diabetic heart is incomplete. Interestingly, our findings from the hearts of streptozotocin-induced diabetic mice confirmed elevated cardiac β-hydroxybutyrate (a major KB) levels and transcriptional suppression of Oxct1 gene expression that encodes for SCOT (succinyl-CoA:3-oxoacid CoA transferase; a rate limiting enzyme of KB oxidation), consistent with a mismatch between KB availability and utilization. To determine a specific role for glucose delivery in this regulation we used an inducible transgenic mouse model with cardiac-restricted expression of the glucose transporter 4 (GLUT4; mG4H). Interestingly, mG4H mice had reduced cardiac SCOT protein levels and oxidation of KB in isolated working heart suggesting that glucose is sufficient to regulate the ketone metabolic pathway. Hyperglycemia associated with diabetes alter protein function via post-translational O -GlcNAcylation. Interestingly, we found that myocardial SCOT expression was also reduced in a third mouse model with increased cardiac O -GlcNAc levels (overexpression of a dominant negative form of O -GlcNAcase, which normally removes O -GlcNAc; dnOGAh) suggesting that increased protein O -GlcNAcylation is directly involved. Collectively, these studies establish a novel role of glucose and its downstream regulator, O -GlcNAc, in attenuation of KB metabolism in the diabetic heart.

Feasibility of chromium measurement in skin using a portable hand-held XRF system

Abstract Chromium (III) is a trace mineral that plays an important role in glucose and lipid metabolism in the body, in addition to being used in clinical formulations for the treatment of hypoglycemia. Chromium (Cr) deficiency in humans is known to cause insulin resistance and diabetes, however, effects of over exposure are not well studied or understood. This study aims to determine the feasibility of measuring Cr in skin using a portable InnovX XRF system at 40 kVp and 100 μA with a mean beam energy of 20 keV. Calibration lines were developed for K α and K β X-ray peaks using fiberglass resin phantoms with 1000 mg/L Cr(III) atomic standard solution, assuming a homogeneous distribution of Cr in skin. This assumption was validated through previously acquired XRF data from tissue cross-sections. Analysis of these data not only showed the presence of Cr in tissue samples, but also that Cr was distributed evenly across the tissue cross-section. Phantom concentrations were validated using delayed neutron activation analysis of fragments of each phantom via the neutron capture reaction 50Cr(n,γ)51Cr. Minimum detection limit (MDL) of the XRF system was determined using these calibration lines to be 5 ± 1 μg/g. This system was used to acquire data from the skin surface of five different parts of the body on four cadavers through a 300 s acquisition at each location. Cr was measurable at the 95% confidence level in 90% of the cadaver skin sites. The effective dose was determined to be 0.013 μSv which is small compared to a dental X-ray. However, the beam was very narrow so the skin dose delivered at the central axis of the beam was 201 mSv. Although the Cr levels did not vary significantly between the cadavers, the different parts of the body showed statistically significant differences in Cr levels. The XRF system used for this study shows promise as an effective monitoring tool for quantifying Cr levels in skin, although adjustments to produce a less collimated beam, and interrogate a larger area of skin, will be preferable so that the central dose is not as intense.

FKBP5 expression in human adipose tissue: potential role in glucose and lipid metabolism, adipogenesis and type 2 diabetes

PurposeHere, we explore the involvement of FKBP51 in glucocorticoid-induced insulin resistance (IR) in human subcutaneous adipose tissue (SAT), including its potential role in type 2 diabetes (T2D). Moreover, we assess the metabolic effects of reducing the activity of FKBP51 using the specific inhibitor SAFit1.MethodsHuman SAT was obtained by needle biopsies of the lower abdominal region. FKBP5 gene expression was assessed in fresh SAT explants from a cohort of 20 T2D subjects group-wise matched by gender, age and BMI to 20 non-diabetic subjects. In addition, human SAT was obtained from non-diabetic volunteers (20F/9M). SAT was incubated for 24 h with or without the synthetic glucocorticoid dexamethasone and SAFit1. Incubated SAT was used to measure the glucose uptake rate in isolated adipocytes.ResultsFKBP5 gene expression levels in SAT positively correlated with several indices of IR as well as glucose area under the curve during oral glucose tolerance test (r = 0.33, p < 0.05). FKBP5 gene expression levels tended to be higher in T2D subjects compared to non-diabetic subjects (p = 0.088). Moreover, FKBP5 gene expression levels were found to inversely correlate with lipolytic, lipogenic and adipogenic genes. SAFit1 partly prevented the inhibitory effects of dexamethasone on glucose uptake.ConclusionsFKBP5 gene expression in human SAT tends to be increased in T2D subjects and is related to elevated glucose levels. Moreover, FKBP5 gene expression is inversely associated with the expression of lipolytic, lipogenic and adipogenic genes. SAFit1 can partly prevent glucose uptake impairment by glucocorticoids, suggesting that FKBP51 might be a key factor in glucocorticoid-induced IR.

Transcription factor 7-like 2 single nucleotide polymorphisms are associated with lipid profile in the Balinese.

Transcription factor 7-like 2 (TCF7L2) protein plays an important role in glucose and lipid metabolisms. Single nucleotide polymorphisms (SNPs) in the TCF7L2 gene contribute to increased fasting plasma glucose (FPG) and body mass index (BMI), and altered lipid concentrations in various population. We investigated whether the TCF7L2 SNPs were associated with obesity, high FPG and altered lipid profile in the Balinese. A total of 608 Balinese from rural and urban Bali, Indonesia, were recruited. Triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC) and FPG were measured, and BMI was calculated. Ratios of TG/HDL-C, LDL-C/HDL-C, and TC/HDL-C were determined. Genotyping of SNPs rs7903146, rs10885406, and rs12255372 were done in all samples. Genetic association analyses under a dominant model showed that the rs7903146 (OR 5.50, 95% CI 2.34-12.91, p = 8.5 × 10-5), rs12255372 (OR 4.15, 95% CI 1.66-10.33, p = 0.003) and rs10885406 (OR 2.43, 95% CI 1.39-4.25, p = 0.003) were significantly associated with high TC/HDL-C ratio. The rs10885406 also presented a significant association with high TG (OR 2.21, 95% CI 1.29-3.81, p = 0.004) and low HDL-C (OR 3.02, 95% CI 1.58-5.80, p = 0.001) concentrations, as well as high TG/HDL-C ratio (OR 1.95, 95% CI 1.16-3.27, p = 0.013). None of the SNPs exhibited significant association with obesity or high FPG. SNPs in the TCF7L2 gene are associated with altered lipid profile in the Balinese.

Visceral fat accumulation is associated with increased plasma sphingosine-1-phosphate levels in type 2 diabetes mellitus

ObjectiveAccumulating evidence has shown that sphingosine-1-phosphate (S1P) plays roles in glucose and fat metabolism. However, the association between plasma S1P levels and fat mass, especially visceral fat mass, remains unknown. MethodsIn this cross-sectional study, 80 men with type 2 diabetes mellitus (T2DM) were recruited to investigate the association of plasma S1P levels with body fat parameters. Visceral (VFA) and subcutaneous fat (SFA) areas were evaluated by performing computed tomography scan, and fat mass (FM) and lean body mass (LBM) were examined by whole body dual-energy X-ray absorptiometry. ResultsMultiple regression analysis adjusted for age, T2DM duration, serum creatinine, and body mass index (BMI) showed that S1P was significantly and positively associated with fasting plasma glucose (β = 0.25, p = 0.027), HbA1c (β = 0.28, p = 0.012), and urine C-peptide (β = 0.29, p = 0.014). Moreover, multiple regression analysis adjusted for age, T2DM duration, serum creatinine, HbA1c, and urine C-peptide showed that BMI (β = 0.32, p = 0.008), VFA (β = 0.33, p = 0.008), SFA (β = 0.26, p = 0.039), FM (β = 0.37, p = 0.003), and LBM (β = 0.35, p = 0.01). FM was significantly and positively associated with S1P after additional adjustment for LBM (β = 0.29, p = 0.028), whereas LBM was not after adjustment for FM. Moreover, VFA was significantly and positively associated with S1P after additional adjustment for SFA (β = 0.27, p = 0.039), whereas SFA was not after adjustment for VFA. ConclusionThis is the first study to show that increased plasma S1P levels are associated with blood glucose levels and accumulation of fat mass, especially visceral fat mass, in men with T2DM.

Abstract 4417: MicroRNA 181a-5p reprogrammed glucose and lipid metabolism in lung cancer though regulating SIRT1 and ACSL4

Abstract Changes in metabolism are key contributors to tumorigenesis and metastasis. Micro RNAs (miRNA) play critical roles in glucose and lipid metabolism. In previous studies, miRNA 181a-5p (miR-181a-5p) was shown to be a significant component in down regulation of lung cancer tissue and mesenchymal-like lung cancer cell lines. To define the role of endogenous miR-181a-5p in cancer metabolism, we performed assays for luciferase, Lactate Dehydrogenase (LDH), glucose uptake and mitochondrial ATP synthase inhibitor. It was demonstrated that miR-181a-5p inhibited aerobic glycolysis and lipid metabolism and overexpression decreased LDH and lipid content in lung cancer. Furthermore, the overexpression of miR-181a-5p diminished invasion and migration by inhibition of Sirtuin 1 (SIRT1) and acyl-CoA synthetase long-chain family member 4 (ACSL4). Together these findings suggest that miR-181a-5p might be involved with reprograming lung cancer metabolism. Citation Format: Ji Woong Son, Seul-Gi Kim, In Beom Jeong, Sun Jung Kwon. MicroRNA 181a-5p reprogrammed glucose and lipid metabolism in lung cancer though regulating SIRT1 and ACSL4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4417.

Metabolomics Shows an Association of Betatrophin with Bile Acids, Suggesting an Involvement of Betatrophin in Bile Acid–Mediated Metabolic Control

Betatrophin, also known as ANGPTL8, is secreted by liver and adipose tissue and plays an important role in glucose and lipid metabolism, but the mechanisms behind this remain unclear. Betatrophin is highly activated by active triiodothyronine (T3), a key player in metabolic control, which in turn is activated by bile acids (BA) via the BA-G-protein-coupled receptor TGR5-cAMP-deiodinase (D2), mediating the conversion of prohormone thyroxine to T3. We here measured betatrophin by ELISA and also applied GWAS and targeted metabolomic profiling in 233 serum samples of coronary angiographied patients. We found a correlation between betatrophin and BMI (r=0.142, p&amp;lt;0.001), fasting glucose (r=0.133, p=0.002), insulin (r=0.221, p&amp;lt;0.001), triglycerides (r=0.233, p&amp;lt;0.001), HDL (-0.122, p=0.004), and oxLDL (r=0.247, p&amp;lt;0.001). GWAs also found a genome wide-association between betatrophin and genomic variants in sterol transporter genes ABCG5/G8 and ABCA1. In the metabolomic assay we identified BA as the top metabolites to be associated with betatrophin concentration in serum (CDCA, r=0.234, p&amp;lt;0.001; GDCA, r=0.247, p&amp;lt;0.001; GCA, r=0.269, p&amp;lt;0.001; GCDCA, r=0.268, p&amp;lt;0.001; GLCA, r=0.211, p=0.002; TDCA, r=0.184, p=0.006). In conclusion, this study for the first time describes the association between betatrophin and BA. As (i) T3 is activated by BA via the BA-TGR5-cAMP-D2 signalling pathway and (ii) T3 is a strong activator of betatrophin, the link between betatrophin concentration and BA suggests that, at least in part, the impact of BA on energy homeostasis and metabolic control may be mediated via betatrophin. Moreover, TGR5 receptors have also been identified on pancreatic islet α- and β-cells and are stimulating insulin secretion in β-cells and able to restore β-cell mass and function under hyperglycemic conditions. Altogether, this may elucidate the impact of betatrophin on lipid and glucose metabolism. Disclosure A. Leiherer: None. A. Muendlein: None. K. Geiger: None. C.H. Saely: None. E. Brandtner: None. J. Ebner: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. H. Drexel: None.

Metabolic effects of genetic variation in the human REPIN1 gene.

Replication initiator 1 (Repin1) is a zinc finger protein highly expressed in liver and adipose tissue. The Repin1 resides within a quantitative trait locus (QTL) for body weight and triglyceride levels in the rat, and its hepatic deletion in mice results in improved insulin sensitivity and lower body weight. Here, we analyzed whether genetic variation within the Repin1 affects parameters of glucose and lipid metabolism. We sequenced REPIN1 in 48 non-related Caucasian subjects. We discovered a 12 base pair deletion (12 bp del; rs3832490), which was subsequently genotyped in two well-characterized cohorts (N = 3013) to test for associations with metabolic traits. Functional consequences of the variant were investigated in HepG2 cells in vitro. In human cohorts, we show that the 12 bp del associates with improved glucose metabolism (lower fasting plasma glucose, fasting plasma insulin, and HOMA IR). Cells transfected with the plasmid carrying the 12 bp del variant are characterized by increased GLUT2 and fatty acid translocase CD36 expression and more lipid droplets. Our data suggest that genetic variation in human REPIN1 plays a role in glucose and lipid metabolism by differentially affecting the expression of REPIN1 target genes including glucose and fatty acid transporters.

In vitro corrosion of magnesium alloy AZ31 — a synergetic influence of glucose and Tris

Biodegradable Mg alloys have generated great interest for biomedical applications. Accurate predictions of in vivo degradation of Mg alloys through cost-effective in vivo evaluations require the latter to be conducted in an environment close to that of physiological scenarios. However, the roles of glucose and buffering agents in regulating the in vivo degradation performance of Mg alloys has not been elucidated. Herein, degradation behavior of AZ31 alloy is investigated by hydrogen evolution measurements, pH monitoring and electrochemical tests. Results indicate that glucose plays a content-dependent role in degradation of AZ31 alloy in buffer-free saline solution. The presence of a low concentration of glucose, i.e. 1.0 g/L, decreases the corrosion rate of Mg alloy AZ31, whereas the presence of 2.0 and 3.0 g/L glucose accelerates the corrosion rate during long term immersion in saline solution. In terms of Tris-buffered saline solution, the addition of glucose increases pH value and promotes pitting corrosion or general corrosion of AZ31 alloy. This study provides a novel perspective to understand the bio-corrosion of Mg alloys in buffering agents and glucose containing solutions.

CREBH Regulates Systemic Glucose and Lipid Metabolism.

The cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CREBH, encoded by CREB3L3) is a membrane-bound transcriptional factor that primarily localizes in the liver and small intestine. CREBH governs triglyceride metabolism in the liver, which mediates the changes in gene expression governing fatty acid oxidation, ketogenesis, and apolipoproteins related to lipoprotein lipase (LPL) activation. CREBH in the small intestine reduces cholesterol transporter gene Npc1l1 and suppresses cholesterol absorption from diet. A deficiency of CREBH in mice leads to severe hypertriglyceridemia, fatty liver, and atherosclerosis. CREBH, in synergy with peroxisome proliferator-activated receptor α (PPARα), has a crucial role in upregulating Fgf21 expression, which is implicated in metabolic homeostasis including glucose and lipid metabolism. CREBH binds to and functions as a co-activator for both PPARα and liver X receptor alpha (LXRα) in regulating gene expression of lipid metabolism. Therefore, CREBH has a crucial role in glucose and lipid metabolism in the liver and small intestine.