Glucose Metabolic Rate Research Articles

Significantly Decreased Islet β Cell Function is Closely Associated with Hyperglycemia in Chronic Hepatitis B Patients.

Aim This study is aimed at the characteristics of glucose metabolism and islet β cell function evaluated by the homeostasis model assessment of β cell function (HOMA-β) value and its risk factors in chronic hepatitis B (CHB) patients. Method This cross-sectional study recruited 110 CHB patients (CHB group) and 110 patients without hepatitis B virus (non-HBV group); the groups were matched according to sex, age, and body mass index under the same glucose metabolism status. The risk factors, characteristics, and differences in glucose metabolism and HOMA-β values between the two groups were analyzed. Results The abnormal glucose metabolism rate was higher in CHB patients with liver cirrhosis (LC) or hepatitis B envelope antigen (HBeAg) (−) status. In addition, under the same glucose metabolism status, the fasting plasma glucose (FPG) levels and 2-hour postprandial plasma glucose (2h-PG) levels in the CHB group were higher, while the HOMA-β values were significantly lower and the homeostasis model assessment of insulin resistance (HOMA-IR) value was not higher than that in the non-HBV group (all P < 0.0001). Further analyses revealed that the main risk factors for abnormal glucose metabolism were HBeAg (−) status and hepatitis B envelope antibody levels. But HBV serological and virological indicators had no effects on the HOMA-β values. Conclusion Islet β cell function in patients with CHB was compromised, which is closely associated with fasting and postprandial hyperglycemia in chronic hepatitis B patients. Further research should be done to verify the compromised islet β cell function and then to investigate the mechanisms behind the effect of hepatitis B virus infection on islet β cell function in CHB patients.

Residual deficits in functional brain activity after chronic cocaine self-administration in rhesus monkeys.

Previous studies in humans and in animals have shown dramatic effects of cocaine on measures of brain function that persist into abstinence. The purpose of this study was to examine the neurobiological consequences of abstinence from cocaine, using a model that removes the potential confound of cocaine cues. Adult male rhesus monkeys self-administered cocaine (0.3 mg/kg/injection; N = 8) during daily sessions or served as food-reinforcement controls (N = 4). Two times per week, monkeys were placed in a neutral environment and presented with a cartoon video for ~30 min, sometimes pre- and sometimes post-operant session, but no reinforcement was presented during the video. After ~100 sessions and when the cocaine groups had self-administered 900 mg/kg cocaine, the final experimental condition was a terminal 2-[14C]-deoxyglucose procedure, which occurred in the neutral (cartoon video) environment; for half of the monkeys in each group, this occurred after 1 day of abstinence and for the others after 30 days of abstinence. Rates of local cerebral glucose metabolism were measured in 57 brain regions. Global rates of cerebral metabolism were significantly lower in animals 1 day and 30 days post-cocaine self-administration when compared to those of food-reinforced controls. Effects were larger in 30- vs. 1-day cocaine abstinence, especially in prefrontal, parietal and cingulate cortex, as well as dorsal striatum and thalamus. Because these measures were obtained from monkeys while in a neutral environment, the deficits in glucose utilization can be attributed to the consequences of cocaine exposure and not to effects of conditioned stimuli associated with cocaine.

Likely Common Role of Hypoxia in Driving 18F-FDG Uptake in Cancer, Myocardial Ischemia, Inflammation and Infection.

First introduced in 1976, 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) has become an indispensable tool for diagnosis and prognostic evaluation of tumors, heart disease, as well as other conditions, including inflammation and infection. Because 18F-FDG can accurately reflect the glucose metabolism level of organs and tissues, it is known as a "century molecule" and is currently the main agent for PET imaging. The degree of 18F-FDG uptake by cells is related to both the rate of glucose metabolism and glucose transporter expression. These, in turn, are strongly influenced by hypoxia, in which cells meet their energy needs through glycolysis, and 18F-FDG uptake increased due to hypoxia. 18F-FDG uptake is a complex process, and hypoxia may be one of the fundamental driving forces. The correct interpretation of 18F-FDG uptake in PET imaging can help clinics make treatment decisions more accurately and effectively. In this article, we review the application of 18F-FDG PET in tumors, myocardium, and inflammation. We discuss the relationship between 18F-FDG uptake and hypoxia, the possible mechanism of 18F-FDG uptake caused by hypoxia, and the associated clinical implications.

LncRNA XIST Contributes to Cisplatin Resistance of Lung Cancer Cells by Promoting Cellular Glycolysis through Sponging miR-101-3p

Background: Non-small-cell lung carcinoma is one of the most frequently diagnosed cancers. Cisplatin (CDDP) is a currently applied standard anticancer agent for advanced lung cancers. Although effectively clinical response was achieved initially, a large fraction of lung cancer patients developed cisplatin resistance. Therefore, understanding the molecular mechanisms of chemoresistance is crucial for anti-lung cancer therapy. Long non-coding RNA (lncRNA)-X-inactive-specific transcript (XIST) has been reported to be positively associated with multiple cancers. Currently, the precise role and mechanism of XIST in cisplatin resistance of lung cancer have not been elucidated. Methods: The expression levels of miR-101-3p and lncRNA XIST were detected by qRT-PCR. Cisplatin-resistant lung cancer cell line was established by selecting the survival cells under gradually increased cisplatin treatments. The cell proliferation was detected by MTT assay, and the cellular glucose metabolism rate was evaluated by Seahorse metabolic flux analysis and glucose uptake and lactate product assays. Glycolysis-related protein expression levels were detected by Western blot. Dual luciferase reporter was constructed to determine the lncRNA-miRNA interaction. Results: Here, we report XIST is significantly upregulated in lung cancer tissues compared with normal lung tissues. In addition, cisplatin-resistant lung cancer cells displayed remarkably elevated XIST expression. We demonstrated that miR-101-3p functioned as a tumor suppressor in lung cancer and sensitized lung cancer cells to cisplatin. Bioinformatics analysis predicted miR-101-3p could be a potential target of XIST through direct binding with it as a competing endogenous RNA, which was further validated from lung tumor tissues and cell lines by luciferase assay. Intriguingly, XIST significantly promoted cellular glycolysis rate of lung cancer cells. The extracellular acidification rate, glucose uptake, and lactate product were elevated by XIST overexpression. On the contrary, miR-101-3p effectively suppressed glycolysis rate. Finally, we demonstrated silencing XIST significantly recovered miR-101-3p expression and downregulated expression of glycolysis key enzymes, a phenotype could be further overridden by miR-101-3p inhibition. Conclusions: This study reveals a new molecular mechanism for the lncRNA-XIST-promoted cisplatin resistance via sponging miR-101-3p, leading to de-repression of cellular glycolysis. Moreover, these findings warrant further in vivo investigations to study XIST as a potential target to overcome cisplatin resistance.

PET/MRI of glucose metabolic rate, lipid content and perfusion in human brown adipose tissue

This study evaluated the MRI-derived fat fraction (FF), from a Cooling-reheating protocol, for estimating the cold-induced brown adipose tissue (BAT) metabolic rate of glucose (MRglu) and changes in lipid content, perfusion and arterial blood volume (VA) within cervical-supraclavicular fat (sBAT). Twelve volunteers underwent PET/MRI at baseline, during cold exposure and reheating. For each temperature condition, perfusion and VA were quantified with dynamic [15O]water-PET, and FF, with water-fat MRI. MRglu was assessed with dynamic [18F]fluorodeoxyglucose-PET during cold exposure. sBAT was defined using anatomical criteria, and its subregion sBATHI, by MRglu > 11 μmol/100 cm3/min. For all temperature conditions, sBAT-FF correlated negatively with sBAT-MRglu (ρ ≤ − 0.87). After 3 h of cold, sBAT-FF decreased (− 2.13 percentage points) but tended to normalize during reheating although sBATHI-FF remained low. sBAT-perfusion and sBAT-VA increased during cold exposure (perfusion: + 5.2 ml/100 cm3/min, VA: + 4.0 ml/100 cm3). sBAT-perfusion remained elevated and sBAT-VA normalized during reheating. Regardless of temperature condition during the Cooling-reheating protocol, sBAT-FF could predict the cold-induced sBAT-MRglu. The FF decreases observed after reheating were mainly due to lipid consumption, but could potentially be underestimated due to intracellular lipid replenishment. The influence of perfusion and VA, on the changes in FF observed during cold exposure, could not be ruled out.

Measuring Glycolytic Activity with Hyperpolarized [2H7, U-13C6] D-Glucose in the Naive Mouse Brain under Different Anesthetic Conditions.

Glucose is the primary fuel for the brain; its metabolism is linked with cerebral function. Different magnetic resonance spectroscopy (MRS) techniques are available to assess glucose metabolism, providing complementary information. Our first aim was to investigate the difference between hyperpolarized 13C-glucose MRS and non-hyperpolarized 2H-glucose MRS to interrogate cerebral glycolysis. Isoflurane anesthesia is commonly employed in preclinical MRS, but it affects cerebral hemodynamics and functional connectivity. A combination of low doses of isoflurane and medetomidine is routinely used in rodent functional magnetic resonance imaging (fMRI) and shows similar functional connectivity, as in awake animals. As glucose metabolism is tightly linked to neuronal activity, our second aim was to assess the impact of these two anesthetic conditions on the cerebral metabolism of glucose. Brain metabolism of hyperpolarized 13C-glucose and non-hyperpolaized 2H-glucose was monitored in two groups of mice in a 9.4 T MRI system. We found that the very different duration and temporal resolution of the two techniques enable highlighting the different aspects in glucose metabolism. We demonstrate (by numerical simulations) that hyperpolarized 13C-glucose reports on de novo lactate synthesis and is sensitive to cerebral metabolic rate of glucose (CMRGlc). We show that variations in cerebral glucose metabolism, under different anesthesia, are reflected differently in hyperpolarized and non-hyperpolarized X-nuclei glucose MRS.

The cerebral hypometabolism model of Alzheimer's disease explored: can a ketogenic diet improve cognition in Alzheimer's disease? A review of the literature

Background: Much research supports the emerging theory that Alzheimer's disease originates from a pathological cerebral metabolic disturbance in glucose metabolism, analogous to insulin resistance in type 2 diabetes. This has led to the theory that ketone bodies may provide an alternative neuronal fuel, correcting, in part, the neuronal energy deficiency and improving cognition in Alzheimer's disease. Aims: To evaluate the literature of human studies on the effectiveness of improving cognition in Alzheimer's disease through a low-carbohydrate diet or administration of exogenous ketones. Methods: A literature review was conducted, with the PRISMA guidelines used to guide this review. The PICO (Population, Intervention, Comparison, Outcome) concept tool was used to search for terms generated through background research. Full-text, peer-reviewed English articles from SocINDEX, Medline, CINAHL, PsychInfo and ScienceDirect were selected, using exclusion and inclusion criteria. Six human studies in which cognition was assessed following a low-carbohydrate diet or administration of exogenous ketones were evaluated. Findings: Some cognitive improvements were demonstrated in all studies in participants with mild-moderate Alzheimer's disease, but not in all cognitive tests and not at all time points. Cognitive improvements returned to baseline after the intervention. Two studies included genetic data and found that cognitive improvement was most notable in those without an E4 allele. Conclusions: This review provides some preliminary support for the potential therapeutic use of ketones in Alzheimer's disease. However, considerable future research is needed, as this is a relatively novel research area. The findings support the suggestion of a gene-environment interaction in the aetiology of Alzheimer's disease, and may contribute to an understanding of how the E4 allele is linked to the pathology of Alzheimer's disease. This review provides suggestions for improving screening for Alzheimer's disease from a nursing perspective—for example, by screening for risk factors, such as hyperinsulinemia and reduced cerebral metabolic rate of glucose.

Analgesic and Antidepressant Effects of the Clinical Glutamate Modulators Acetyl-L-Carnitine and Ketamine.

Pain and depression are leading causes of disability and of profound social and economic burden. Their impact is aggravated by their chronicity and comorbidity and the insufficient efficacy of current treatments. Morphological and functional metabolism studies link chronic pain and depressive disorders to dysfunctional neuroplastic changes in fronto-limbic brain regions that control emotional responses to painful injuries and stressful events. Glutamate modulators are emerging new therapies targeting dysfunctional brain areas implicated in the generation and maintenance of chronic pain and depression. Here, we report the effects of two clinically approved glutamate modulators: acetyl-L-carnitine (ALCAR) and S, R(±)ketamine (KET). ALCAR is a natural neurotrophic compound currently marketed for the treatment of neuropathies. KET is the prototypical non-competitive antagonist at N-methyl-D-aspartate glutamate receptors and a clinically approved anesthetic. Although they differ in pharmacological profiles, ALCAR and KET both modulate aminergic and glutamatergic neurotransmissions and pain and mood. We assessed in rats the effects of ALCAR and KET on cerebral metabolic rates for glucose (rCMRglc) and assessed clinically the effects of ALCAR in chronic pain and of KET in post-operative pain. ALCAR and KET increased rCMRglc at similar degrees in prefrontal, somatosensory, and cingulate cortices, and KET increased rCMRglc at a different, much larger, degree in limbic and dopaminergic areas. While rCMRglc increases in prefrontal cortical areas have been associated with analgesic and antidepressant effects of ALCAR and KET, the marked metabolic increases KET induces in limbic and dopaminergic areas have been related to its psychotomimetic and abuse properties. In patients with chronic neuropathic pain, ALCAR (1,000 mg/day) yielded to a fast (2 weeks) improvement of mood and then of pain and quality of life. In day-surgery patients, KET improved dischargeability and satisfaction. In obese patients undergoing bariatric surgery, a single, low dose of KET (0.5 mg/kg) at induction of anesthesia determined a very fast (hours) amelioration of post-operative depression and pain and an opioid-sparing effect. These findings indicate that ALCAR and KET, two non-selective glutamate modulators, still offer viable therapeutic options in comorbid pain and depression.

Tissue-specific glucose partitioning and fat content in prediabetes and type 2 diabetes: whole-body PET/MRI during hyperinsulinemia.

To obtain direct quantifications of glucose turnover, volumes and fat content of several tissues in the development of type 2 diabetes (T2D) using a novel integrated approach for whole-body imaging. Hyperinsulinemic-euglycemic clamps and simultaneous whole-body integrated [18F]FDG-PET/MRI with automated analyses were performed in control (n = 12), prediabetes (n = 16) and T2D (n = 13) subjects matched for age, sex and BMI. Whole-body glucose uptake (Rd) was reduced by approximately 25% in T2D vs control subjects, and partitioning to brain was increased from 3.8% of total Rd in controls to 7.1% in T2D. In liver, subcutaneous AT, thigh muscle, total tissue glucose metabolic rates (MRglu) and their % of total Rd were reduced in T2D compared to control subjects. The prediabetes group had intermediate findings. Total MRglu in heart, visceral AT, gluteus and calf muscle was similar across groups. Whole-body insulin sensitivity assessed as glucose infusion rate correlated with liver MRglu but inversely with brain MRglu. Liver fat content correlated with MRglu in brain but inversely with MRglu in other tissues. Calf muscle fat was inversely associated with MRglu only in the same muscle group. This integrated imaging approach provides detailed quantification of tissue-specific glucose metabolism. During T2D development, insulin-stimulated glucose disposal is impaired and increasingly shifted away from muscle, liver and fat toward the brain. Altered glucose handling in the brain and liver fat accumulation may aggravate insulin resistance in several organs.

Conscious rat PET imaging with soft immobilization for quantitation of brain functions: comprehensive assessment of anesthesia effects on cerebral blood flow and metabolism

BackgroundAnimal brain functions evaluated by in vivo imaging under anesthesia can be affected by anesthetic agents, resulting in incorrect assessment of physiological brain function. We therefore performed dynamic positron emission tomography (PET) imaging of conscious rats using recently reported soft immobilization to validate the efficacy of the immobilization for brain function assessments. We also determined the effects of six anesthetic agents—a mixed anesthetic agent (MMB), ketamine + xylazine (KX), chloral hydrate (Chloral), pentobarbital (PTB), propofol (PF), and isoflurane (IFL)—on brain function by comparison with conscious rats.ResultsThe immobilization enabled 45-min dynamic [18F]FDG-PET acquisition with arterial blood sampling using conscious rats without the use of special techniques or invasive surgery. The spatial resolution and quantitativity of [18F]FDG-PET were not significantly lower for conscious rats than for anesthetized rats. While MMB, Chloral, PTB, and PF showed ubiquitous reduction in the cerebral metabolic rates of glucose (CMRglu) in brain regions, KX and IFL showed higher reductions in cerebellum and interbrain, and cerebellum, respectively. Cerebral blood flow (CBF) was reduced by MMB, KX, PTB, and PF; increased by IFL; and unaltered by Chloral. The magnitude of decrease in CMRglu and CBF for MMB were not larger than for other five anesthetic agents, although blood glucose levels and body temperature can be easily affected by MMB.ConclusionThe six anesthetic agents induced various effects on CMRglu and CBF. The immobilization technique presented here is a promising tool for noninvasive brain functional imaging using conscious rats to avoid the effects of anesthetic agents.

Metabolomic profiles are reflective of hypoxia-induced insulin resistance during exercise in healthy young adult males.

Hypoxia-induced insulin resistance appears to suppress exogenous glucose oxidation during metabolically matched aerobic exercise during acute (<8 h) high-altitude (HA) exposure. However, a better understanding of this metabolic dysregulation is needed to identify interventions to mitigate these effects. The objective of this study was to determine if differences in metabolomic profiles during exercise at sea level (SL) and HA are reflective of hypoxia-induced insulin resistance. Native lowlanders (n = 8 males) consumed 145 g (1.8 g/min) of glucose while performing 80-min of metabolically matched treadmill exercise at SL (757 mmHg) and HA (460 mmHg) after 5-h exposure. Exogenous glucose oxidation and glucose turnover were determined using indirect calorimetry and dual tracer technique ([13C]glucose and [6,6-2H2]glucose). Metabolite profiles were analyzed in serum as change (Δ), calculated by subtracting postprandial/exercised state SL (ΔSL) and HA (ΔHA) from fasted, rested conditions at SL. Compared with SL, exogenous glucose oxidation, glucose rate of disappearance, and glucose metabolic clearance rate (MCR) were lower (P < 0.05) during exercise at HA. One hundred and eighteen metabolites differed between ΔSL and ΔHA (P < 0.05, Q < 0.10). Differences in metabolites indicated increased glycolysis, tricarboxylic acid cycle, amino acid catabolism, oxidative stress, and fatty acid storage, and decreased fatty acid mobilization for ΔHA. Branched-chain amino acids and oxidative stress metabolites, Δ3-methyl-2-oxobutyrate (r = −0.738) and Δγ-glutamylalanine (r = −0.810), were inversely associated (P < 0.05) with Δexogenous glucose oxidation. Δ3-Hydroxyisobutyrate (r = −0.762) and Δ2-hydroxybutyrate/2-hydroxyisobutyrate (r = −0.738) were inversely associated (P < 0.05) with glucose MCR. Coupling global metabolomics and glucose kinetic data suggest that the underlying cause for diminished exogenous glucose oxidative capacity during aerobic exercise is acute hypoxia-mediated peripheral insulin resistance.

Cerebral Metabolism Related to Cognitive Impairments in Multiple System Atrophy.

Objective: We aimed to characterize the cognitive profiles in multiple system atrophy (MSA) and explore the cerebral metabolism related to the cognitive decline in MSA using 18F-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography (PET).Methods: In this study, 105 MSA patients were included for cognitive assessment and 84 of them were enrolled for 18F-FDG PET analysis. The comprehensive neuropsychological tests covered five main domains including execution, attention, memory, language, and visuospatial function. The cognitive statuses were classified to MSA with normal cognition (MSA-NC) and MSA with cognitive impairment (MSA-CI), including dementia (MSA-D), and mild cognitive impairment (MSA-MCI). With 18F-FDG PET imaging, the cerebral metabolism differences among different cognitive statuses were analyzed using statistical parametric mapping and post-hoc analysis.Results: Among 84 MSA patients, 52 patients were found with MSA-CI, including 36 patients as MSA-MCI and 16 patients as MSA-D. In detail, the cognitive impairments were observed in all the five domains, primarily in attention, executive function and memory. In 18F-FDG PET imaging, MSA-D and MSA-MCI patients exhibited hypometabolism in left middle and superior frontal lobe compared with MSA-NC (p < 0.001). The normalized regional cerebral metabolic rate of glucose (rCMRglc) in left middle frontal lobe showed relative accuracy in discriminating MSA-CI and MSA-NC [areas under the curve (AUC) = 0.750; 95%CI = 0.6391–0.8609].Conclusions: Cognitive impairments were not rare in MSA, and the hypometabolism in frontal lobe may contribute to such impairments.

Plasma Apolipoprotein E3 and Glucose Levels Are Associated in APOE ɛ3/ɛ4 Carriers

Background:Altered cerebral glucose metabolism, especially prominent in APOE ɛ4 carriers, occurs years prior to symptoms in Alzheimer’s disease (AD). We recently found an association between a higher ratio of plasma apolipoprotein E4 (apoE4) over apoE3, and cerebral glucose hypometabolism in cognitively healthy APOE ɛ3/ɛ4 subjects. Plasma apoE does not cross the blood-brain barrier, hence we speculate that apoE is linked to peripheral glucose metabolism which is known to affect glucose metabolism in the brain.Objective:Explore potential associations between levels of plasma insulin and glucose with previously acquired plasma apoE, cerebral metabolic rate of glucose (CMRgl), gray matter volume, and neuropsychological test scores.Methods:Plasma insulin and glucose levels were determined by ELISA and a glucose oxidase assay whereas apoE levels were earlier quantified by mass-spectrometry in 128 cognitively healthy APOE ɛ3/ɛ4 subjects. Twenty-five study subjects had previously undergone FDG-PET and structural MRI.Results:Lower plasma apoE3 associated with higher plasma glucose but not insulin in male subjects and subjects with a body mass index above 25. Negative correlations were found between plasma glucose and CMRgl in the left prefrontal and bilateral occipital regions. These associations may have functional implications since glucose levels in turn were negatively associated with neuropsychological test scores.Conclusion:Plasma apoE3 but not apoE4 may be involved in insulin-independent processes governing plasma glucose levels. Higher plasma glucose, which negatively affects brain glucose metabolism, was associated with lower plasma apoE levels in APOE ɛ3/ɛ4 subjects. High plasma glucose and low apoE levels may be a hazardous combination leading to an increased risk of AD.

BIMG-21. DEUTERIUM METABOLIC IMAGING (DMI), A NEW, MRI-BASED TECHNIQUE FOR MAPPING BRAIN TUMOR METABOLISM IN VIVO

Deuterium Metabolic Imaging (DMI) combines 3D deuterium (2H) magnetic resonance spectroscopic imaging (MRSI) with administration of a 2H-labeled substrate to map uptake and metabolism of the substrate. DMI has been implemented on a 4 Tesla clinical research MRI scanner, and on an 11.7 Tesla preclinical MRI scanner, and has been used with 2H-labeled glucose, acetate and choline. DMI data are presented as color maps of concentration of the 2H-labeled substrate and its metabolites, overlaid on anatomical MR images. In rat and mouse models of glioblastoma, DMI data acquired at 5 to 8 uL resolution following intravenous 2H-glucose infusion clearly showed the Warburg effect in the tumor lesions. The Warburg effect is indicated by the ratio of 2H-labeled lactate/glutamate+glutamine (Glx). High levels of 2H-labeled lactate and low levels of 2H-labeled Glx are the result of a high rate of glycolysis and low rate of oxidative glucose metabolism. Because DMI detects both glucose and its downstream metabolism, the technique does not suffer from low image contrast with normal brain, as is the case with FDG-PET that detects glucose uptake only. For clinical research studies patients orally consumed 0.75g/kg of 2H-glucose dissolved in water. The observations made in the animal models were confirmed in several patients with recurrent GBM, showing hotspots in the lac/Glx maps (8 mL resolution), coinciding with the area of the tumor lesion. In patients with meningioma, no Warburg effect was detected using DMI. Furthermore, DMI data acquired in a patient with GBM one week after finishing 30 days of radiation therapy, also showed no high levels of 2H-labeled lactate in the lesion. These data indicate that the presence of the Warburg effect could correlate with tumor grade and/or aggressiveness, and that DMI of glucose metabolism could potentially be a biomarker of therapy effect.

The Obesity Risk SNP (rs17782313) near the MC4R Gene Is Not Associated with Brain Glucose Uptake during Insulin Clamp-A Study in Finns.

The melanocortin system is involved in the control of adiposity through modulation of food intake and energy expenditure. The single nucleotide polymorphism (SNP) rs17782313 near the MC4R gene has been linked to obesity, and a previous study using magnetoencephalography has shown that carriers of the mutant allele have decreased cerebrocortical response to insulin. Thus, in this study, we addressed whether rs17782313 associates with brain glucose uptake (BGU). Here, [18F]-fluorodeoxyglucose positron emission tomography (PET) data from 113 Finnish subjects scanned under insulin clamp conditions who also had the rs17782313 determined were compiled from a single-center cohort. BGU was quantified by the fractional uptake rate. Statistical analysis was performed with statistical parametric mapping. There was no difference in age, BMI, and insulin sensitivity as indexed by the M value between the rs17782313-C allele carriers and non-carriers. Brain glucose uptake during insulin clamp was not different by gene allele, and it correlated with the M value, in both the rs17782313-C allele carriers and non-carriers. The obesity risk SNP rs17782313 near the MC4R gene is not associated with brain glucose uptake during insulin clamp in humans, and this frequent mutation cannot explain the enhanced brain glucose metabolic rates in insulin resistance.

Dynamic FDG PET Imaging to Probe for Cardiac Metabolic Remodeling in Adults Born Premature.

Individuals born very premature have an increased cardiometabolic and heart failure risk. While the structural differences of the preterm heart are now well-described, metabolic insights into the physiologic mechanisms underpinning this risk are needed. Here, we used dynamic fluorodeoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET-MRI) in young adults born term and preterm during normoxic (N = 28 preterm; 18 term) and hypoxic exposure (12% O2; N = 26 preterm; 17 term) to measure the myocardial metabolic rate of glucose (MMRglc) in young adults born term (N = 18) and preterm (N = 32), hypothesizing that young adults born preterm would have higher rates of MMRglc under normoxic conditions and a reduced ability to augment glucose metabolism under hypoxic conditions. MMRglc was calculated from the myocardial and blood pool time-activity curves by fitting the measured activities to the 3-compartment model of FDG kinetics. MMRglc was similar at rest between term and preterm subjects, and decreased during hypoxia exposure in both groups (p = 0.02 for MMRglc hypoxia effect). There were no differences observed between groups in the metabolic response to hypoxia, either globally (serum glucose and lactate measures) or within the myocardium. Thus, we did not find evidence of altered myocardial metabolism in the otherwise healthy preterm-born adult. However, whether subtle changes in myocardial metabolism may preceed or predict heart failure in this population remains to be determined.

Scutellarin resensitizes oxaliplatin-resistant colorectal cancer cells to oxaliplatin treatment through inhibition of PKM2

Although oxaliplatin is an effective chemotherapeutic drug commonly used for colorectal cancer (CRC) treatment, drug resistance usually occurs during the long-term use of it. It is urgent to create strategies to reduce the resistance of CRC cells to oxaliplatin. Oxaliplatin-resistant CRC cells (OR-SW480 and OR-HT29) were acquired through long-term exposure of CRC cells to oxaliplatin. It was found that OR-SW480 and OR-HT29 cells exhibited obvious lower sensitivity and a higher metabolism rate of glucose compared to their parental SW480 and HT29 cells, respectively. However, combination with scutellarin significantly resensitized the OR-SW480 and OR-HT29 cells to oxaliplatin-induced cytotoxicity. Mechanically, overexpression of pyruvate kinase isoenzyme M2 (PKM2) was responsible for the resistance to oxaliplatin in OR-SW480 and OR-HT29. Combination with scutellarin was able to inhibit the PKM2 activity and thus reduced the production of adenosine triphosphate (ATP) to sensitize the oxaliplatin-induced mitochondrial apoptosis pathway in both OR-SW480 and OR-HT29 cells. It was indicated that scutellarin resensitizes oxaliplatin-resistant CRC cells to oxaliplatin treatment through inhibition of PKM2.

Prediabetes Is Associated With Brain Hypometabolism and Cognitive Decline in a Sex-Dependent Manner: A Longitudinal Study of Nondemented Older Adults.

Although type 2 diabetes is a well-known risk factor for Alzheimer's disease (AD), little is known about how its precursor—prediabetes—impacts neuropsychological function and brain health. Thus, we examined the relationship between prediabetes and AD-related biological and cognitive/clinical markers in a well-characterized sample drawn from the Alzheimer's Disease Neuroimaging Initiative. Additionally, because women show higher rates of AD and generally more atherogenic lipid profiles than men, particularly in the context of diabetes, we examined whether sex moderates any observed associations. The total sample of 911 nondemented and non-diabetic participants [normal control = 540; mild cognitive impairment (MCI) = 371] included 391 prediabetic (fasting blood glucose: 100–125 mg/dL) and 520 normoglycemic individuals (age range: 55–91). Linear mixed effects models, adjusted for demographics and vascular and AD risk factors, examined the independent and interactive effects of prediabetes and sex on 2–6 year trajectories of FDG-PET measured cerebral metabolic glucose rate (CMRglu), hippocampal/intracranial volume ratio (HV/IV), cerebrospinal fluid phosphorylated tau-181/amyloid-β1−42 ratio (p-tau181/Aβ1−42), cognitive function (executive function, language, and episodic memory) and the development of dementia. Analyses were repeated in the MCI subsample. In the total sample, prediabetic status had an adverse effect on CMRglu across time regardless of sex, whereas prediabetes had an adverse effect on executive function across time in women only. Within the MCI subsample, prediabetic status was associated with lower CMRglu and poorer executive function and language performance across time within women, whereas these associations were not seen within men. In the total sample and MCI subsample, prediabetes did not relate to HV/IV, p-tau181/Aβ1−42, memory function or dementia risk regardless of sex; however, among incident dementia cases, prediabetic status related to earlier age of dementia onset in women but not in men. Results suggest that prediabetes may affect cognition through altered brain metabolism, and that women may be more vulnerable to the negative effects of glucose intolerance.

Does insulin resistance influence neurodegeneration in non-diabetic Alzheimer\u2019s subjects?

BackgroundType 2 diabetes is a risk factor for Alzheimer’s disease (AD), and AD brain shows impaired insulin signalling. The role of peripheral insulin resistance on AD aetiopathogenesis in non-diabetic patients is still debated. Here we evaluated the influence of insulin resistance on brain glucose metabolism, grey matter volume and white matter lesions (WMLs) in non-diabetic AD subjects.MethodsIn total, 130 non-diabetic AD subjects underwent MRI and [18F]FDG PET scans with arterial cannula insertion for radioactivity measurement. T1 Volumetric and FLAIR sequences were acquired on a 3-T MRI scanner. These subjects also had measurement of glucose and insulin levels after a 4-h fast on the same day of the scan. Insulin resistance was calculated by the updated homeostatic model assessment (HOMA2). For [18F]FDG analysis, cerebral glucose metabolic rate (rCMRGlc) parametric images were generated using spectral analysis with arterial plasma input function.ResultsIn this non-diabetic AD population, HOMA2 was negatively associated with hippocampal rCMRGlc, along with total grey matter volumes. No significant correlation was observed between HOMA2, hippocampal volume and WMLs.ConclusionsIn non-diabetic AD, peripheral insulin resistance is independently associated with reduced hippocampal glucose metabolism and with lower grey matter volume, suggesting that peripheral insulin resistance might influence AD pathology by its action on cerebral glucose metabolism and on neurodegeneration.

736 Comparing neonatal outcomes among patients undergoing intravenous glucose tolerance testing for diagnosis of gestational diabetes

To assess neonatal outcomes associated with abnormal intravenous glucose tolerance test (IV GTT) results in a cohort of patients unable to tolerate the standard oral glucose tolerance test for diagnosis of gestational diabetes (GDM). Patients who could not tolerate an oral glucose load, were > 24 weeks gestation, had a viable singleton or multifetal gestation, and spoke English or Spanish were enrolled prospectively between February 2019 and February 2020. Patients with pre-existing diabetes mellitus (DM) or clinically significant hemoglobinopathies were excluded. Enrolled patients underwent an IV GTT and glucose monitoring was initiated if the IV GTT resulted in a glucose metabolism rate below trimester-specific normative values. The primary outcome of interest was large for gestational age (LGA) infants. The study was powered to detect a 25% difference in LGA infants between patients with an abnormal IV GTT result compared to those with a normal IV GTT result. Of the 120 patients consented, 115 completed glucose testing and 13 (11.3%) had an abnormal IV GTT. Age, race/ethnicity, parity, family history of DM, insurance status, gestational age at testing, and body mass index did not differ between those with abnormal compared to normal IV GTT results. Participants with an abnormal IV GTT result were more likely to have multifetal pregnancies (15.4% vs 0%, p=0.01). Infants delivered to patients with an abnormal IV GTT result were more likely to be LGA, have lower mean neonatal blood glucose nadirs, and require treatment with supplemental glucose (Table). Participants with an abnormal IV GTT result were more likely to have an LGA neonate and clinically significant hypoglycemia. The IV GTT is a reasonable diagnostic test for GDM-related morbidities when an oral glucose load cannot be tolerated.