Decreased Glucose Utilization Research Articles

Prostate cancer cell-derived exosomal IL-8 fosters immune evasion by disturbing glucolipid metabolism of CD8+ T cell

Depletion of CD8+ Tcells is a major obstacle in immunotherapy; however, the relevant mechanisms remain largely unknown. Here, we showed that prostate cancer (PCa) cell-derived exosomes hamper CD8+ Tcell function by transporting interleukin-8 (IL-8). Compared to the low IL-8 levels detected in immune cells, PCa cells secreted the abundance of IL-8 and further accumulated in exosomes. The delivery of PCa cell-derived exosomes into CD8+ Tcells exhausted the cells through enhanced starvation. Mechanistically, exosomal IL-8 overactivated PPARα in recipient cells, thereby decreasing glucose utilization by downregulating GLUT1 and HK2 but increasing fatty acid catabolism via upregulation of CPT1A and ACOX1. PPARα further activates uncoupling protein 1 (UCP1), leading to fatty acid catabolism for thermogenesis rather than ATP synthesis. Consequently, inhibition of PPARα and UCP1 restores CD8+ Tcell proliferation by counteracting the effect of exosomal IL-8. This study revealed that the tumor exosome-activated IL-8-PPARα-UCP1 axis harms tumor-infiltrating CD8+ Tcells by interfering with energy metabolism.

Effects of two different angiotensin receptor blockers on blood glucose level and HbA1c in type-2 diabetes mellitus patients with hypertension

Diabetes mellitus is a common metabolic disorder characterized by chronic hyperglycemia and disturbance of carbohydrate, fats, and protein metabolism. Type 2 diabetes mellitus results from reduced insulin secretion, decreased glucose utilization, and increased glucose production, which results in hyperglycemia. Hypertension further increases the risk of cardiovascular diseases, including coronary heart disease (CHD), congestive heart failure (CHF), ischemic and hemorrhagic stroke, renal failure, and peripheral arterial disease (PAD). Angiotensin receptor blockers (ARBs) are very effective antihypertensive drugs. This study was done to find the effects of two different angiotensin receptor blockers on various biochemical markers in type-2 diabetes mellitus patients.MethodsThis was a prospective interventional study, comparing two ARBs Azilsartan and telmisartan, involving 76 patients with type 2 diabetes mellitus and hypertension.ResultsBoth drugs controlled blood pressure equally. The study showed that improvement in fasting plasma glucose was more with Azilsartan as compared to Telmisartan but their mean difference is not statistically significant (p > 0.05). The improvement in post-prandial plasma glucose and HbA1C was more with Telmisartan as compared to Azilsartan but only mean HbA1C was statistically significant (p < 0.05).ConclusionsTelmisartan has a better impact on HbA1c reduction than Azilsartan, as a part of the pleotropic effect of ARBs.

Membrane Phenotypic, Metabolic and Genotypic Adaptations of Streptococcus oralis Strains Destined to Rapidly Develop Stable, High-Level Daptomycin Resistance during Daptomycin Exposures.

The Streptococcus mitis-oralis subgroup of viridans group streptococci are important human pathogens. We previously showed that a substantial portion of S. mitis-oralis strains (>25%) are 'destined' to develop rapid, high-level, and stable daptomycin (DAP) resistance (DAP-R) during DAP exposures in vitro. Such DAP-R is often accompanied by perturbations in distinct membrane phenotypes and metabolic pathways. The current study evaluated two S. oralis bloodstream isolates, 73 and 205. Strain 73 developed stable, high-level DAP-R (minimum inhibitory concentration [MIC] > 256 µg/mL) within 2 days of in vitro DAP passage ("high level" DAP-R [HLDR]). In contrast, strain 205 evolved low-level and unstable DAP-R (MIC = 8 µg/mL) under the same exposure conditions in vitro ("non-HLDR"). Comparing the parental 73 vs. 73-D2 (HLDR) strain-pair, we observed the 73-D2 had the following major differences: (i) altered cell membrane (CM) phospholipid profiles, featuring the disappearance of phosphatidylglycerol (PG) and cardiolipin (CL), with accumulation of the PG-CL pathway precursor, phosphatidic acid (PA); (ii) enhanced CM fluidity; (iii) increased DAP surface binding; (iv) reduced growth rates; (v) decreased glucose utilization and lactate accumulation; and (vi) increased enzymatic activity within the glycolytic (i.e., lactate dehydrogenase [LDH]) and lipid biosynthetic (glycerol-3-phosphate dehydrogenase [GPDH]) pathways. In contrast, the 205 (non-HLDR) strain-pair did not show these same phenotypic or metabolic changes over the 2-day DAP exposure. WGS analyses confirmed the presence of mutations in genes involved in the above glycolytic and phospholipid biosynthetic pathways in the 73-D2 passage variant. These data suggest that S. oralis strains which are 'destined' to rapidly develop HLDR do so via a conserved cadre of genotypic, membrane phenotypic, and metabolic adaptations.

Risk of Developing Insulin Resistance in Adult Subjects with Phenylketonuria: Machine Learning Model Reveals an Association with Phenylalanine Concentrations in Dried Blood Spots.

Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism where high phenylalanine (Phe) concentrations cause irreversible intellectual disability that can be prevented by newborn screening and early treatment. Evidence suggests that PKU subjects not adherent to treatment could be at risk of insulin resistance (IR). We studied how Phe concentrations (PheCs) relate to IR using machine learning (ML) and derived potential biomarkers. In our cross-sectional study, we analyzed subjects with neonatal diagnoses of PKU, grouped as follows: 10 subjects who adhered to treatment (G1); 14 subjects who suspended treatment (G2); and 24 control subjects (G3). We analyzed plasma biochemical variables, as well as profiles of amino acids and acylcarnitines in dried blood spots (DBSs). Higher PheCs and plasma insulin levels were observed in the G2 group compared to the other groups. Additionally, a positive correlation between the PheCs and homeostatic measurement assessments (HOMA-IRs) was found, as well as a negative correlation between the HOMA-Sensitivity (%) and quantitative insulin sensitivity check index (QUICKI) scores. An ML model was then trained to predict abnormal HOMA-IRs using the panel of metabolites measured from DBSs. Notably, ranking the features' importance placed PheCs as the second most important feature after BMI for predicting abnormal HOMA-IRs. Our results indicate that low adherence to PKU treatment could affect insulin signaling, decrease glucose utilization, and lead to IR.

The metabolic state of the heart regulates mitochondrial supercomplex abundance in mice

Mitochondrial supercomplexes are observed in mammalian tissues with high energy demand and may influence metabolism and redox signaling. Nevertheless, the mechanisms that regulate supercomplex abundance remain unclear. In this study, we examined the composition of supercomplexes derived from murine cardiac mitochondria and determined how their abundance changes with substrate provision or by genetically induced changes to the cardiac glucose-fatty acid cycle. Protein complexes from digitonin-solubilized cardiac mitochondria were resolved by blue-native polyacrylamide gel electrophoresis and were identified by mass spectrometry and immunoblotting to contain constituents of Complexes I, III, IV, and V as well as accessory proteins involved in supercomplex assembly and stability, cristae architecture, carbohydrate and fat oxidation, and oxidant detoxification. Respiratory analysis of high molecular mass supercomplexes confirmed the presence of intact respirasomes, capable of transferring electrons from NADH to O2. Provision of respiratory substrates to isolated mitochondria augmented supercomplex abundance, with fatty acyl substrate (octanoylcarnitine) promoting higher supercomplex abundance than carbohydrate-derived substrate (pyruvate). Mitochondria isolated from transgenic hearts that express kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (GlycoLo), which decreases glucose utilization and increases reliance on fatty acid oxidation for energy, had higher mitochondrial supercomplex abundance and activity compared with mitochondria from wild-type or phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-expressing hearts (GlycoHi), the latter of which encourages reliance on glucose catabolism for energy. These findings indicate that high energetic reliance on fatty acid catabolism bolsters levels of mitochondrial supercomplexes, supporting the idea that the energetic state of the heart is regulatory factor in supercomplex assembly or stability.

O‐GlcNAcylation modulates GLUT1 levels at the blood‐brain barrier

AbstractBackgroundGlucose transporter 1 (GLUT1) at the blood‐brain barrier (BBB) is essential for glucose uptake into the brain. Previous studies have shown that GLUT1 levels are reduced at the BBB in Alzheimer’s disease (AD) post‐mortem brain, and perhaps explains the decreased glucose utilization observed in AD (Sweeney et al., Nat Rev Neurol, 2018). Individuals with a genetic reduction of GLUT1, known as GLUT1‐deficiency syndrome, were treated with increased blood glucose with no long‐lasting increase in brain glucose. Diabetes is a risk factor for AD and AD is sometimes referred to as Type‐3 diabetes due to elevated blood glucose levels. Taken together, these ideas provoked us to investigate connections between glucose and GLUT1 levels. Here, we tested if the glucose‐dependent post‐translational modification, O‐linked‐N‐acetylglucosaminylation (O‐GlcNAcylation), is the missing link. We hypothesized that increasing glucose concentrations will elevate O‐GlcNAcylation and decrease GLUT1 levels at the BBB. Furthermore, previous studies have shown that decreased GLUT1 levels result in reduced levels of the low‐density lipoprotein receptor‐related protein‐1 (LRP‐1) (Winkler, Nat Neurosci, 2015). Thus, we also are determining if altering glucose levels not only changes GLUT1 levels, but also other key BBB receptors implicated in AD.MethodsMouse brain endothelial (bEnd.3) cells were treated with vehicle (glucose 5.6 mmol), DMSO, the O‐GlcNAcase inhibitor Thiamet‐G (TMG, 1 µM), or the O‐GlcNAc transferase inhibitor OSMI‐1 (20 µM), for 24 and 48 hours. Next, the protein expression of O‐GlcNAc and GLUT1 were measured by western blot.ResultsAs previously reported, TMG increased and OSMI‐1 decreased O‐GlcNAcylation at both 24 and 48 h, compared to vehicle. Notably, TMG treatment significantly reduced and OSMI‐1 increased GLUT1 expression at both time points.ConclusionGLUT1 levels are modulated through O‐GlcNAcylation at BBB. When blood glucose levels are high, O‐GlcNAcylation will be high, thereby reducing GLUT1 at the BBB and brain glucose uptake. This is likely a homeostatic mechanism to prevent spikes in brain glucose levels when blood sugar levels are elevated.

Uremic Myopathy and Mitochondrial Dysfunction in Kidney Disease.

Alterations in muscle structure and function in chronic kidney disease (CKD) patients are associated with poor outcomes. As key organelles in muscle cell homeostasis, mitochondrial metabolism has been studied in the context of muscle dysfunction in CKD. We conducted a study to determine the contribution of oxidative metabolism, glycolysis and fatty acid oxidation to the muscle metabolism in CKD. Mice developed CKD by exposure to adenine in the diet. Muscle of CKD mice showed significant weight loss compared to non-CKD mice, but only extensor digitorum longus (EDL) muscle showed a decreased number of fibers. There was no difference in the proportion of the various muscle fibers in CKD and non-CKD mice. Muscle of CKD mice had decreased expression of proteins associated with oxidative phosphorylation but increased expression of enzymes and transporters associated with glycolysis. In cell culture, myotubes exposed to uremic serum demonstrated decreased oxygen consumption rates (OCR) when glucose was used as substrate, conserved OCR when fatty acids were used and increased lactate production. In conclusion, mice with adenine-induced CKD developed sarcopenia and with increased glycolytic metabolism but without gross changes in fiber structure. In vitro models of uremic myopathy suggest fatty acid utilization is preserved compared to decreased glucose utilization.

Glucagon-like peptide-1 receptor mediates the improvement in glycolipid metabolism disorder via AKT and AMPK signalling pathways in L02 cells with insulin resistance

Glucagon-like peptide 1 (GLP-1) has previously been found to regulate glycolipid metabolism in the liver by promoting insulin secretion. However, the presence of GLP-1 receptors (GLP-1R) in the human liver has not been determined. In this research, GLP-1R was found to be expressed in L02 cells and decreased in insulin resistant (IR) cells. Compared with LG treatment group, GLP-1R knockdown significantly decreased glucose utilization (from 143.13% to 118.41%.) and intracellular glycogen content (from 122.77% to 105.72%). Furthermore, the transcription levels of PEPCK and G6Pase increased, and the phosphorylation levels of AKT, FOXO1 and GSK3β decreased in siGLP-1R group. Similarly, the contents of triglyceride and total cholesterol in siGLP-1R group increased by 43.23% and 24.19%, respectively. PCR and WB results showed that knockdown of GLP-1R increased the levels of ACC, FAS, and SREBP-1c, and decreased the levels of CPT-1 via AMPK pathway. GLP-1R knockdown changed the LG-induced promotion of glucose utilization and inhibition of lipid synthesis. These findings demonstrated that GLP-1R is the molecular basis for GLP-1 to improve glycolipid metabolism in L02 cells.

PSVI-4 Serum Metabolomic Characterization of Birth Weight and Neonatal Nutrient Restriction on Piglet Growth and Development

Abstract The objective was to characterize developmental differences in low birth weight (LBW) and normal birth weight (NBW) piglets with or without nutrient restriction using serum metabolomic profile analysis. After farrowing, 112 piglets were selected as LBW (1.22 ± 0.28 kg) or NBW (1.70 ± 0.27 kg) and were categorized to receive normal nutrition (NN) or restricted nutrition (RN - 6 h/day no suckling) until d 28 when the pigs were weaned onto a common diet until d 56. Blood samples were taken on d 28 and d 56 (n=8 pigs/treatment) and were analyzed using quantitative metabolomics via a combination of direct injection mass spectrometry with a reverse-phase LC-MS/MS custom assay (TMIC prime). Data were normalized using logarithmic transformation and auto-scaling. Partial least squares discriminant analysis (PLS-DA) was carried out to further explore the differential metabolites among the treatments (metaboanalyst.ca) with an integrated enrichment and pathway topography analysis. The results suggest that at d 28, LBW piglets had decreased metabolites associated with fatty acid oxidation, glycolysis and TCA cycle metabolites, and essential amino acids such as valine, leucine, arginine. These indicate a decrease utilization of gluconeogenic, and TCA cycle pathways compared with the NBW group. On d 56, LBW piglets had increased utilization of fatty acids, exhibited by increased production of serum acetoacetate, B-hydroxybutyrate, glycerol, compared with NBW. Additionally, the LBW piglets had decreased glucose utilization, pyruvate, succinate, citrate, a-ketoglutaric acid, and lactate compared with the NBW piglets. Due to low utilization of glycolysis and the TCA cycle, associated amino acids were less in LBW piglets, except for a increased glycerol which may indicate impairments in glucose tolerance. In summary, LBW piglets appear to have more metabolic deficiencies in early life, which is not resolved with nutrition in early life, but may be responsive to a tailored nutritional intervention post-weaning.

Catestatin regulates core bioenergetic and metabolic functions of the myocardium

ObjectiveHypertension is a global pandemic, affecting more than one billion people. We have recently reported that chromogranin A (CgA) peptide catestatin (CST: human CgA352‐372) decreases blood pressure in hypertensive CST knockout (CST‐KO) mice by inhibiting catecholamine secretion and decreasing inflammation. Using CST‐KO mice we show here that CST regulates core bioenergetic and metabolic functions of the myocardium.Methods and ResultsWe carried out transcriptomic analyses (gene microarray) of the left ventricles of wild‐type (WT) and CST‐KO mice. Analysis revealed altered expression. Downregulated genes, which were most enriched in pathways that impact muscle conduction and contractility include, among other genes, Glo1 (glyoxylase 1). Upregulated genes include, among others, Gm7120 (predicted gene 7120), Astn2 (astrotactin 2), and Defa20 (defensin a‐20). We validated several of these up‐ and downregulated genes by qPCR and found that CST supplementation reversed these aberrant expressions in all cases. Targeted qPCR analysis of sarcomeric genes revealed reduced expression of Tnni3 (cardiac troponin I), Tnnt2 (cardiac troponin T), Myl4(atrial light chain‐1) and Myl7 (atrial light chain‐2) genes in CST‐KO mice. CST treatment increased expression of Tnni3, Tnnt2, Actc1 (cardiac a‐actin), Myl4 and Myl7 in both WT and CST‐KO mice albeit to a much higher level in CST‐KO mice. An analysis of mitochondrial genes revealed reduced expression of Ndufa3 (complex I), Sdhc (complex II) and Atp5j (complex V) genes in CST‐KO mice. CST treatment increased the expression of all three genes in WT and CST‐KO mice. Taken together, these unbiased approaches and qPCR validation studies provide insight into how an inflamed dysfunctional heart in the absence of CST may impact muscle function (contractility), rhythm, mitochondrial bioenergetics, and conduction.CST‐KO mice showed decreased uptake of 2‐deoxy glucose in the left ventricle compared to WT mice. Furthermore, glucose‐6‐phosphate utilization was significantly lower in CST‐KO compared to WT mice. We also found that compared to WT mice, CST‐KO mice show a significantly higher uptake of fatty acids. Furthermore, 14C‐labeled acid soluble metabolites were significantly higher in CST‐KO compared to WT mice, suggesting that increased dependence on fatty acids for energy needs make CST‐KO hearts resistant to insulin.ConclusionsTaken together with the cardiometabolic shifts (decreased glucose utilization with a concomitant increase in the utilization of fatty acids), these findings indicate that CST maintains cardiometabolic homeostasis; it does so at least in part by acting as an insulin‐sensitizing peptide which regulates myocardial choice of substrates for generating energy (i.e., ATP).

Tissue-specific responses that constrain glucose oxidation and increase lactate production with the severity of hypoxemia in fetal sheep.

Fetal hypoxemia decreases insulin and increases cortisol and norepinephrine concentrations and may restrict growth by decreasing glucose utilization and altering substrate oxidation. Specifically, we hypothesized that hypoxemia would decrease fetal glucose oxidation and increase lactate and pyruvate production. We tested this by measuring whole body glucose oxidation and lactate production, and molecular pathways in liver, muscle, adipose, and pancreas tissues of fetuses exposed to maternal hypoxemia for 9 days (HOX) compared with control fetal sheep (CON) in late gestation. Fetuses with more severe hypoxemia had lower whole body glucose oxidation rates, and HOX fetuses had increased lactate production from glucose. In muscle and adipose tissue, expression of the glucose transporter GLUT4 was decreased. In muscle, pyruvate kinase (PKM) and lactate dehydrogenase B (LDHB) expression was decreased. In adipose tissue, LDHA and lactate transporter (MCT1) expression was increased. In liver, there was decreased gene expression of PKLR and MPC2 and phosphorylation of PDH, and increased LDHA gene and LDH protein abundance. LDH activity, however, was decreased only in HOX skeletal muscle. There were no differences in basal insulin signaling across tissues, nor differences in pancreatic tissue insulin content, β-cell area, or genes regulating β-cell function. Collectively, these results demonstrate coordinated metabolic responses across tissues in the hypoxemic fetus that limit glucose oxidation and increase lactate and pyruvate production. These responses may be mediated by hypoxemia-induced endocrine responses including increased norepinephrine and cortisol, which inhibit pancreatic insulin secretion resulting in lower insulin concentrations and decreased stimulation of glucose utilization.NEW & NOTEWORTHY Hypoxemia lowered fetal glucose oxidation rates, based on severity of hypoxemia, and increased lactate production. This was supported by tissue-specific metabolic responses that may result from increased norepinephrine and cortisol concentrations, which decrease pancreatic insulin secretion and insulin concentrations and decrease glucose utilization. This highlights the vulnerability of metabolic pathways in the fetus and demonstrates that constrained glucose oxidation may represent an early event in response to sustained hypoxemia and fetal growth restriction.

CTNI-14. EVALUATING METABOLIC ALTERATIONS IN PATIENTS WITH EGFR ACTIVATED RECURRENT GLIOBLASTOMA (RGBM) BY INHIBITING EGFR WITH OSIMERTINIB

Abstract BACKGROUND EGFR activated GBM is highly metabolically active and effective targeting with EGFR TKis in human-tumor models rapidly attenuates glucose metabolism engaging apoptotic machinery. Rapid changes in glucose uptake using 18F-FDG-PET is an effective predictive biomarker of therapeutic response in these models. Clinical 18F-FDG-PET may allow investigators to obtain early readout on EGFR TKi in this patient population. We explore this approach using osimertinib in EGFRamp/p53wt rGBM. METHODS EGFRamp/p53wt rGBM patients were treated with oral osimertinib 240mg for three days followed by 160mg/day until progression. F18-FDG-PET scan was obtained as a double baseline, 24 hours apart, prior to dosing with osimertinib. Third scan was obtained after 3 doses of 240mg. Primary objective defines test-retest variance of tumor FDG uptake before osimertinib and to evaluate if osimertinib significantly decreases glucose utilization after three doses. Study-drug and funding provided by AstraZeneca. RESULTS 12 pts were evaluated, 10 female, median age 57.5 years (44-61). Volumetric mRANO showed no responses, 6 SD, 5 PD, and one NE. Median PFS was 31 days, no patient achieved 6-month-PFS and median OS was 5.5 months. No new adverse event signal appeared. Double baseline PET SUV mean was 0.97 (normalized to whole cerebellum) with upward trend from first to second scan with mean percent change of 2.8 and 95% CI(0.7,5.1). Change in PET from 2nd to 3rd showed mean percent change -3.2 with 95% CI (-11.1,4.8). Preclinical models suggest 15-20% attenuation is needed to predict improved outcomes in patients treated with EGFR-TKi. CONCLUSION F18-FDG-PET has little variance with test-retest showing upward trend with second scan. Post osimertinib F18-FDG-PET shows limited attenuation of tumor FDG uptake. No clinical signal was seen in study. Deeper attenuation of FDG uptake may be needed to show clinical effect from EGFR inhibitors. F18-FDG-PET can be used to evaluate change in tumor glucose utilization.

Glomerular basement membrane damage and leaking of structural proteins in among different stages of type 2 diabetes mellitus patients

Type 2 Diabetes mellitus (T2DM) is a syndrome of disorders characterized by hyperglycemia caused due to a relative or absolute deficiency of insulin, decreased glucose utilization. The metabolic derangements in diabetes lead to secondary complications that affect multiple organ systems particularly on kidney. For early detection of kidney damage in T2DM patients are important by using certain type of urinary proteins. We aimed to evaluate the glomerular basement membrane damage and leaking of structural proteins in among different stages of type 2 diabetes mellitus patients. A total 150 type 2 diabetes mellitus patients were included in the present study and again sub classified into 2 types (Normoalbuminuria 50, Microalbuminuria 50) based on their urinary ACR and also included 50 age, gender matched healthy controls. The FBS, PPBS, Urea, Creatinine, HbA1C, Urinary Albumin was analysed by using laboratory standard methods and Urinary Adiponectin was measured by using were collected from the all subjects. A statistical was performed by using SPSS Version 21.0 and P value considers &amp;#60; 0.05 is statistically significant. The significantly elevated levels of plasma FBS, PPBS, Serum Urea, Creatinine, HbA1c, Urinary albuminuria and Urinary Adiponectin observed in two groups of type 2 diabetes mellitus when compared to healthy controls. The Urinary Adiponectin was positively correlated with blood sugar levels and urinary albumin in two groups of diabetes mellitus. The data showed a significantly damaged foot process of podocytes and glomerular basement membrane leads to leaking of certain urinary proteins.The elevated levels of Urinary Proteins and HbA1c, Urinary Albuminuria directly indicate the damage of podocytes and glomerular basement membrane in the kidney. These studies suggest continuous monitoring of these parameters may helpful for progression of type 2 diabetes mellitus complications.

Orexin receptors 1 and 2 in serotonergic neurons differentially regulate peripheral glucose metabolism in obesity

The wake-active orexin system plays a central role in the dynamic regulation of glucose homeostasis. Here we show orexin receptor type 1 and 2 are predominantly expressed in dorsal raphe nucleus-dorsal and -ventral, respectively. Serotonergic neurons in ventral median raphe nucleus and raphe pallidus selectively express orexin receptor type 1. Inactivation of orexin receptor type 1 in serotonin transporter-expressing cells of mice reduced insulin sensitivity in diet-induced obesity, mainly by decreasing glucose utilization in brown adipose tissue and skeletal muscle. Selective inactivation of orexin receptor type 2 improved glucose tolerance and insulin sensitivity in obese mice, mainly through a decrease in hepatic gluconeogenesis. Optogenetic activation of orexin neurons in lateral hypothalamus or orexinergic fibers innervating raphe pallidus impaired or improved glucose tolerance, respectively. Collectively, the present study assigns orexin signaling in serotonergic neurons critical, yet differential orexin receptor type 1- and 2-dependent functions in the regulation of systemic glucose homeostasis.

Tryptophan, kynurenine pathway, and diabetic ketoacidosis in type 1 diabetes.

Diabetic ketoacidosis (DKA) is a serious complication of complete insulin deficiency and insulin resistance in Type 1 diabetes (T1D). This results in the body producing high levels of serum ketones in an attempt to compensate for the insulin deficiency and decreased glucose utilization. DKA’s metabolic and immunologic dysregulation results in gradual increase of systemic and cerebral oxidative stress, along with low grade systemic and cerebral inflammation and the development of pretreatment subclinical BE. During treatment the early progression of oxidative stress and inflammation is hypothesized to advance the possibility of occurrence of crisis of clinical brain edema (BE), which is the most important cause of morbidity and mortality in pediatric DKA. Longitudinal neurocognitive studies after DKA treatment show progressive and latent deficits of cognition and emphasize the need for more effective DKA treatment of this long-standing conundrum of clinical BE, in the presence of systemic osmotic dehydration, metabolic acidosis and immune dysregulation. Candidate biomarkers of several systemic and neuroinflammatory pathways prior to treatment also progress during treatment, such as the neurotoxic and neuroprotective molecules in the well-recognized tryptophan (TRP)/kynurenine pathway (KP) that have not been investigated in DKA. We used LC-MS/MS targeted mass spectrometry analysis to determine the presence and initiation of the TRP/KP at three time points: A) 6–12 hours after initiation of treatment; B) 2 weeks; and C) 3 months following DKA treatment to determine if they might be involved in the pathogenesis of the acute vasogenic complication of DKA/BE. The Trp/KP metabolites TRP, KYN, quinolinic acid (QA), xanthurnenic acid (XA), and picolinic acid (PA) followed a similar pattern of lower levels in early treatment, with subsequent increases. Time point A compared to Time points B and C were similar to the pattern of sRAGE, lactate and pyruvic acid. The serotonin/melatonin metabolites also followed a similar pattern of lower quantities at the early stages of treatment compared to 3 months after treatment. In addition, glutamate, n-acetylglutamate, glutamine, and taurine were all lower at early treatment compared to 3 months, while the ketones 3-hydroxybutaric acid and acetoacetate were significantly higher in the early treatment compared to 3 months. The two major fat metabolites, L-carnitine and acetyl-L-carnitine (ALC) changed inversely, with ALC significantly decreasing at 2 weeks and 3 months compared to the early stages of treatment. Both anthranilic acid (AA) and 3-OH-anthranilic acid (3OH-AA) had overall higher levels in the early stages of treatment (A) compared to Time points (B and C). Interestingly, the levels of AA and 3OH-AA early in treatment were higher in Caucasian females compared to African American females. There were also differences in the metabolite levels of QA and kynurenic acid (KA) between genders and between races that may be important for further development of custom targeted treatments. We hypothesize that the TRP/KP, along with the other inflammatory pathways, is an active participant in the metabolic and immunologic pathogenesis of DKA’s acute and chronic insults.

Effect of metformin on serum level of vitamin B12 and folate in patients of type-2 diabetes mellitus

Background: Several types of DM are caused by a complex interaction of genetic and environmental factors. Depending on the etiology of the DM, factors contributing to hyperglycaemia include- reduced insulin secretion, decreased glucose utilization, and increased glucose production.Objective of the current study was to study the effect of metformin on the level of vitamin B12 and folate in patients of type 2 DM.Methods: This is hospital based study before and after metformin therapy randomized controlled trial was conducted in medicine ward of M. B. hospital, Udaipur. Baseline serum vitamin B12 and folate level of all patients were measured and treatment with metformin 500 mg twice a day was given for 6 months. After 6 months serum vitamin B12 and folate level of all patients were re-evaluated.Results: There was a significant positive correlation (r=0.824, p&lt;0.001) between decrease in vitamin B12 and decrease in folate level after metformin treatment. When analysis for change in vitamin B12 is compared with change in MCV values after 6 months, negative correlation (r=-0.08, p&gt;0.05) was obtained. A non significant correlation (r=-0.08, p&gt;0.05) with change in level of serum folate and change in MCV values or haemoglobin level was obtained.Conclusions: Low serum vitamin B12 level is associated with longer duration and higher dose of metformin use. Routine determination of vitamin B12 level in patients with type 2 DM on high dose of metformin and those with prolonged use of metformin might help in identifying patients that would benefit from vitamin B12 supplements.

AGE-RELATED CHANGES IN BLOOD CONCENTRATIONS OF GLUCOSE, PROINSULIN AND INSULIN AMONG RESIDENTS OF THE RUSSIAN ARCTIC

Introduction: Extreme natural and climatic conditions of the Arctic have led to development of a special type of glucose metabolism and its regulating links, although the evidence on age-related changes in these mechanisms among Arctic residents is still scarce. Aim: To study age-related changes in blood concentrations of glucose, proinsulin and insulin in residents of Russian circumpolar territories. Methods: In total 1 058 healthy individuals of both genders aged 16-74 years took part in a multicenter cross-sectional study. Of them, 629 permanently lived in the Arctic region while 429 were residents of the Subarctic areas. By age the participants were classified as 16-21, 22-35, 36-45, 46-60 and 61-74 years old. Concentrations of proinsulin and insulin were determined by the enzyme immunoassay methods while glucose level was assessed by spectrophotometric analysis. Between group differences in numeric characteristics were analyzed using Mann-Whitney tests with Bonferroni correction. Associations between variables were studied by non-parametric correlation analysis. Results. Blood glucose concentration increased with age. Among the 16-21-year-olds, higher concentrations of glucose was observed among Subarctic residents. Regional differences reduced in parallel with age. In the Arctic region, an increase in blood glucose in comparison with the youngest group began from 22-35 years while in the Subarctic region. The proportion of people with high glucose levels in age-groups 46-60 and 61-74 years was greater among the Arctic residents compared with their Subarctic counterparts (22.5% and 33.3 % vs. 14.7% and 27.9 %). This was combined with greater proportions of people in the AR with increased proinsulin levels (37.5% and 33.3 % vs. 24.7% and 28.8%) and decreased levels of insulin (57.5% and 53.8 % vs. 74.0 and 36.8 %). Conclusion: A gradual decrease in glucose utilization with age seems to be associated with a decrease in the intensity of proinsulin processing into insulin suggesting early depletion of the functional and receptor activity of pancreatic p-cells. The changes were more pronounced among the residents of the Arctic areas compared to their Subarctic counterparts.

PET imaging of neural activity, β-amyloid, and tau in normal brain aging.

Normal brain aging is commonly associated with neural activity alteration, β-amyloid (Aβ) deposition, and tau aggregation, driving a progressive cognitive decline in normal elderly individuals. Positron emission tomography (PET) with radiotracers targeting these age-related changes has been increasingly employed to clarify the sequence of their occurrence and the evolution of clinically cognitive deficits. Herein, we reviewed recent literature on PET-based imaging of normal human brain aging in terms of neural activity, Aβ, and tau. Neural hypoactivity reflected by decreased glucose utilization with PET imaging has been predominately reported in the frontal, cingulate, and temporal lobes of the normal aging brain. Aβ PET imaging uncovers the pathophysiological association of Aβ deposition with cognitive aging, as well as the potential mechanisms. Tau-associated cognitive changes in normal aging are likely independent of but facilitated by Aβ as indicated by tau and Aβ PET imaging. Future longitudinal studies using multi-radiotracer PET imaging combined with other neuroimaging modalities, such as magnetic resonance imaging (MRI) morphometry, functional MRI, and magnetoencephalography, are essential to elucidate the neuropathological underpinnings and interactions in normal brain aging.

Possible value of galectin-3 on follow-up of cardiac remodeling during glucocorticoid treatment.

Glucocorticoids are among the most prescribed drugs globally due to their potent anti-inflammatory and immunosuppressive properties. Although they have positive effects on the treatment of various disease states; long-term administration is associated with high blood pressure, insulin resistance, and susceptibility to type 2 diabetes. The heart attempts to cope with increased blood pressure and a decrease in glucose utilization by developing pathological cardiac remodeling. However, in this process, cardiac fibrosis formation and deterioration in heart structure and functions occur. Galectin-3, a member of the β-galactoside binding lectins, is consistently associated with inflammation and fibrosis in the pathogenesis of various disease states including insulin resistance and heart failure. Galectin-3 expression is markedly increased in activated macrophages and a subset of activated fibroblasts and vascular cells. Also, failing and remodeling myocardium show increased Gal-3 expression and elevated Gal-3 levels are related to heart failure severity and prognosis. Furthermore, Gal-3-related pathways are recently suggested as therapeutic targets both pharmacologically and genetically to increase insulin sensitivity in vivo. The objective of this review is to provide a summary of our current understanding of the role of glucocorticoid-associated insulin resistance, which is important for some cardiac events, and the potential role of galectin in this pathophysiological process.

Hepatic nNOS impaired hepatic insulin sensitivity through the activation of p38 MAPK.

Neuronal nitric oxide synthase (nNOS) interacts with its adaptor protein NOS1AP through its PZD domain in the neurons. Previously, we had reported that NOS1AP enhanced hepatic insulin sensitivity through its PZD-binding domain, which suggested that nNOS might mediate the effect of NOS1AP. This study aimed to examine the role and underlying mechanisms of nNOS in regulating hepatic insulin sensitivity. nNOS co-localized with NOS1AP in mouse liver. The overexpression of NOS1AP in mouse liver decreased the level of phosphorylated nNOS (p-nNOS (Ser1417)), the active form of nNOS. Conversely, the liver-specific deletion of NOS1AP increased the level of p-nNOS (Ser1417). The overexpression of nNOS in the liver of high-fat diet-induced obese mice exacerbated glucose intolerance, enhanced intrahepatic lipid accumulation, decreased glycogen storage, and blunted insulin-induced phosphorylation of IRbeta and Akt in the liver. Similarly, nNOS overexpression increased triglyceride production, decreased glucose utilization, and downregulated insulin-induced expression of p-IRbeta, p-Akt, and p-GSK3beta in the HepG2 cells. In contrast, treatment with Nω-propyl-L-arginine (L-NPA), a selective nNOS inhibitor, improved glucose tolerance and upregulated insulin-induced phosphorylation of IRbeta and Akt in the liver of ob/ob mice. Furthermore, overexpression of nNOS increased p38MAPK phosphorylation in the HepG2 cells. In contrast, inhibition of p38MAPK with SB203580 significantly reversed the nNOS-induced inhibition of insulin-signaling activity (all P < 0.05). This indicated that hepatic nNOS inhibited the insulin-signaling pathway through the activation of p38MAPK. These findings suggest that nNOS is involved in the development of hepatic insulin resistance and that nNOS might be a potential therapeutic target for diabetes.