Increased Glucose Utilization Research Articles

Evaluation of the effects of dietary cinnamaldehyde on growth and nutrient use in Nile Tilapia (Oreochromis niloticus)

Cinnamaldehyde is an active organic compound and an aromatic aldehyde substance found in cinnamon oil. It is a new feed supplement for animals that can improve growth, nutrient digestion and absorption, lipid use, and immunity. The present study evaluated the effects of dietary trans-cinnamaldehyde 98 % (CIN) on nutrient utilization, antioxidant capacity, and growth performance in Nile tilapia (Oreochromis niloticus). Juveniles used was weighing at about 19.77 ± 0.10 g received dietary CIN at different doses (0, 0.25, 0.5, 0.75, and 1.0 g/kg feed). The fish were maintained in a glass aquarium of 95 × 45 × 35 cm3 in size at a stocking density of 20 fish per aquarium and fed three times a day to clear satiation. Dietary carbohydrate digestion and absorption were significantly improved in fish fed 0.75 g/kg CIN, as indicated by increased amylase activity and glucose tolerance test. The latter was subsequently confirmed by increases in relative ir, glut4, hx and gs expression that indicated the increase in glucose absorption led to an increase in glucose utilization as an energy source and the synthesis of glycogen as an energy reserve. Interestingly, dietary CIN supplementation also resulted in the downregulation of fas, which facilitates the conversion of glucose to fatty acids, and the upregulation of cpt1a and hsl, indicating increased fatty acid oxidation for energy. CIN at a range of 0.5–0.75 g/kg improved the antioxidant status in the liver, as illustrated by elevated glutathione peroxidase and superoxide dismutase activities (both P < 0.05). Final weight, feed consumption, the specific growth rate, feed efficiency, and protein retention increased were significantly in all CIN groups, with the highest values reached in the 0.5 g/kg CIN (all P < 0.05). Based on a polynomial orthogonal analysis of the fish-specific growth rate, the optimum dosage of CIN inclusion is 0.42 g/kg.

Development of Syringaldehyde as an Agonist of the GLP-1 Receptor to Alleviate Diabetic Disorders in Animal Models.

The phenolic aldehyde syringaldehyde (SA) has been shown to have an antihyperglycemic effect in diabetic rats due to increased glucose utilization and insulin sensitivity. To understand the direct effect of SA on the GLP-1 receptor, STZ-induced diabetic rats were used. The levels of pro-inflammatory cytokines, liver enzymes, and renal function were measured using specific ELISA kits. The mechanisms of SA effects were investigated using CHO-K1 cells, pancreatic Min-6 cells, and cardiomyocyte H9c2 cells. The results indicated that the antihyperglycemic effect of SA in diabetic rats was abolished by blocking the GLP-1 receptor with an antagonist. SA has a direct effect on the GLP-1 receptor when using CHO-K1 cells transfected with the exogenous GLP-1 receptor gene. In addition, SA stimulated insulin production in Min-6 cells by activating GLP-1 receptors. SA caused a dose-dependent rise in GLP-1 receptor mRNA levels in cardiac H9c2 cells. These in vitro results support the notion that SA has a direct effect on the GLP-1 receptor. Otherwise, SA inhibited the increase of pro-inflammatory cytokines, including interleukins and tumor TNF-α, in type 1 diabetic rats in a dose-dependent manner. Moreover, as with liraglutide, SA reduced plasma lipid profiles, including total cholesterol and triglyceride, in mixed diet-induced type 2 diabetic rats. Intriguingly, chronic treatment with SA (as with liraglutide) reversed the functions of both the liver and the kidney in these diabetic rats. SA displayed less efficiency in reducing body weight and food consumption compared to liraglutide. In conclusion, SA effectively activates GLP-1 receptors, resulting in a reduction in diabetic-related complications in rats. Therefore, it is beneficial to develop SA as a chemical agonist for clinical applications in the future.

Bovine serum albumin uptake and polypeptide disaggregation studies of hypoglycemic ruthenium(II) uracil Schiff-base complexes

Our prior studies have illustrated that the uracil ruthenium(II) diimino complex, [Ru(H3ucp)Cl(PPh3)] (1) (H4ucp = 2,6-bis-((6-amino-1,3-dimethyluracilimino)methylene)pyridine) displayed high hypoglycemic effects in diet-induced diabetic rats. To rationalize the anti-diabetic effects of 1, three new derivatives have been prepared, cis-[Ru(bpy)2(urdp)]Cl2 (2) (urdp = 2,6-bis-((uracilimino)methylene)pyridine), trans-[RuCl2(PPh3)(urdp)] (3), and cis-[Ru(bpy)2(H4ucp)](PF6)2 (4). Various physicochemical techniques were utilized to characterize the structures of the novel ruthenium compounds. Prior to biomolecular interactions or in vitro studies, the stabilities of 1–4 were monitored in anhydrous DMSO, aqueous phosphate buffer containing 2% DMSO, and dichloromethane (DCM) via UV–Vis spectrophotometry. Time-dependent stability studies showed ligand exchange between DMSO nucleophiles and chloride co-ligands of 1 and 3, which was suppressed in the presence of an excess amount of chloride ions. In addition, the metal complexes 1 and 3 are stable in both DCM and an aqueous phosphate buffer containing 2% DMSO. In the case of compounds 2 and 4 with no chloride co-ligands within their coordination spheres, high stability in aqueous phosphate buffer containing 2% DMSO was observed. Fluorescence emission titrations of the individual ruthenium compounds with bovine serum albumin (BSA) showed that the metal compounds interact non-discriminately within the protein's hydrophobic cavities as moderate to strong binders. The metal complexes were capable of disintegrating mature amylin amyloid fibrils. In vivo glucose metabolism studies in liver (Chang) cell lines confirmed enhanced glucose metabolism as evidenced by the increased glucose utilization and glycogen synthesis in liver cell lines in the presence of complexes 2–4.

Endothelial-specific telomerase inactivation causes telomere-independent cell senescence and multi-organ dysfunction characteristic of aging.

It has remained unclear how aging of endothelial cells (EC) contributes to pathophysiology of individual organs. Cell senescence results in part from inactivation of telomerase (TERT). Here, we analyzed mice with Tert knockout specifically in EC. Tert loss in EC induced transcriptional changes indicative of senescence and tissue hypoxia in EC and in other cells. We demonstrate that EC-Tert-KO mice have leaky blood vessels. The blood-brain barrier of EC-Tert-KO mice is compromised, and their cognitive function is impaired. EC-Tert-KO mice display reduced muscle endurance and decreased expression of enzymes responsible for oxidative metabolism. Our data indicate that Tert-KO EC have reduced mitochondrial content and function, which results in increased dependence on glycolysis. Consistent with this, EC-Tert-KO mice have metabolism changes indicative of increased glucose utilization. In EC-Tert-KO mice, expedited telomere attrition is observed for EC of adipose tissue (AT), while brain and skeletal muscle EC have normal telomere length but still display features of senescence. Our data indicate that the loss of Tert causes EC senescence in part through a telomere length-independent mechanism undermining mitochondrial function. We conclude that EC-Tert-KO mice is a model of expedited vascular senescence recapitulating the hallmarks aging, which can be useful for developing revitalization therapies.

Positron Emission Tomography Imaging of Tumor Proliferation and DNA Repair.

Positron emission tomography (PET) is an established tool for molecular imaging of cancers, and its role in diagnosis, staging, and phenotyping continues to evolve and expand rapidly. PET imaging of increased glucose utilization with 18F-fluorodeoxyglucose is now entrenched in clinical oncology practice for improving prognostication and treatment response assessment. Additional critical processes for cancer cell survival can also be imaged by PET, helping to inform individualized treatment selections for patients by improving our understanding of cell survival mechanisms and identifying relevant active mechanisms in each patient. The critical importance of quantifying cell proliferation and DNA repair pathways for prognosis and treatment selection is highlighted by the nearly ubiquitous use of the Ki-67 index, an established histological quantitative measure of cell proliferation, and BRCA mutation testing for treatment selection. This review focuses on PET advances in imaging and quantifying cell proliferation and poly(ADP-ribose)polymerase expression that can be used to complement cancer phenotyping approaches that will identify the most effective treatments for each individual patient.

Cardiometabolic rewiring in the context of doxorubicin-induced cardiotoxicity: fuel preference changes from fatty acids to glucose oxidation

Abstract Background Doxorubicin (DOX) is a chemotherapeutic drug administered to treat a wide spectrum of tumours. However, its clinical use is hampered by the onset of cardiotoxic effects, with a reduction of LVEF that occurs within the first year from the treatment initiation. Recently it has been demonstrated that DOX accumulates into mitochondria, with metabolic perturbation and energetic imbalance. We previously described that phosphoinositide 3-kinase γ (PI3Kγ) contributes to DOX-induced cardiotoxicity, with the inhibition of autophagy and accumulation of damaged mitochondria into cardiac cells. Objective Here we intend to better understand the maladaptive metabolic rewiring occurring in DOX-treated hearts and the contribution of PI3Kg signalling to this process. Methods 10 weeks-old wild-type (WT) and knock-in mice expressing a kinase-inactive PI3Kγ (kinase-dead; KD) were treated with DOX (4 mg/Kg) at day 0, 7 and 14 (cumulative dose 12 mg/Kg). To explore the contribution of PI3Kγ on the early cardiac metabolic rewiring, metabolomic analysis were performed on animals sacrificed at day 3. Mitochondria respiration capacity and glycolytic enzymes activity were evaluated at day 3 and 42. To investigate the role of autophagy, 8 weeks-old mice were infected with an adeno-associated virus 9 (AAV9) carrying a vector expressing a short-hairpin RNA against ATG7 (ATG7sh). To test the role of PI3Kγ in glycolysis regulation, glucose uptake and plasma membrane exposure of GLUT-4 were measured in neonatal mouse cardiomyocytes (NMCs) with DOX acute treatment (1µM for 3h). To evaluate oxygen consumption with the administration of different substrates OROBOROS analysis were performed on myocardial slices from mice sacrificed at day 3. Results Metabolomic analysis of DOX-treated hearts revealed an accumulation of TCA cycle metabolites, with reduced levels of pyruvate, unchanged abundance of lactate but increased quantity of Acetyl-CoA, indicative of increased glucose oxidation and accelerated TCA cycle flux. Moreover, the activity of glycolytic enzymes was upregulated and fatty acid oxidation downregulated after DOX. In agreement, oxygen consumption was significantly increased in DOX-treated WT after pyruvate supplementation, with the formation of cytotoxic ROS rather than energy production. These metabolic changes were fully prevented in KD hearts. Interestingly, they failed to increase glucose oxidation in response to DOX even with autophagy inhibition, indicating that PI3Kγ likely controls the fuel preference after DOX through an autophagy-independent mechanism. In vitro experiments showed that genetic and pharmacological inhibition of PI3Kγ significantly prevented DOX-induced mobilization of GLUT-4-carrying vesicles to the plasma membrane and reduced glucose uptake. Conclusion These results demonstrate that PI3Kγ promotes a maladaptive metabolic rewiring in the heart in response to DOX, with an increased glucose utilization via a GLUT4-dependent mechanism.

FRI663 A Rare Case Of Igf-2 Induced Hypoglycemia Associated With Metastatic Colon Cancer

Abstract Disclosure: A. Alshaakh Mohd Mari: None. A. Varshney: None. A. Sidhu: None. M. Matos: None. M. Kinaan: None. Introduction: The diagnosis of hypoglycemia in patients without diabetes is uncommon and nonislet cell tumor hypoglycemia (NICTH) represent a minority of these cases. The most common mechanism is related to IGF-2 production from tumor cells. Case description: A 66-year-old man with a history of stage IV colon cancer presented to the hospital due to breathlessness while receiving chemotherapy (Bevacizumab plus FOLFOX4). He had partial colectomy and chemotherapy 3 years earlier but was recently found to have metastatic disease to the liver. A CT abdomen during hospitalization showed a 15 cm hepatic mass occupying the entire right hepatic lobe. Endocrinology was consulted due to persistent postprandial and fasting hypoglycemia despite dextrose infusion. He had no history of diabetes and denied taking any diabetes medications. Plasma blood glucose (BG) was noted to be 74 mg/dl (74-106) while on dextrose. An 8AM cortisol was checked to exclude adrenal insufficiency and was 8.08 mcg/dL (4.30-22.40). A 72 hour fast was done but discontinued at 8 hours when plasma BG dropped to 48 and patient became symptomatic. At the time C-peptide and Insulin levels were low &amp;lt;0.05 ng/mL (0.48-5.05) and &amp;lt;1.0 mU/L (3.0-25) respectively, with normal Beta-hydroxybutyrate (BHB) 1.1 mg/dL (0.2-2.8). At the end of the fast 1 mg of glucagon was administered and his BG increased to 112 mg/dl in 2 hrs. IGF-1 levels were undetectable &amp;lt;15 ng/mL and IGF-2 levels were found to be 175 ng/mL. The IGF2:IG1 ratio was at 11 confirming IGF-2 mediated NICTH. Dexamethasone 10 mg daily was started, and BG were maintained &amp;gt; 70mg/dl without dextrose infusion. Discussion: In approximately 50% of NICTH, the tumor is identified prior to the onset of hypoglycemia, but up to 50% of these patients may be asymptomatic despite hypoglycemia. Our patient had a known hepatic lesion and was minimally symptomatic despite very low BG. The mechanism for NICTH can include insulin secretion from the tumor, replacement of hepatic tissue and increased glucose utilization by the tumor, or most commonly, IGF-2 secretion. In the case of IGF-2 mediated hypoglycemia insulin, proinsulin, C-peptide, and β-hydroxybutyrate levels are low. An elevated IGF-2:IGF-1 ratio (&amp;gt;10) confirms the diagnosis. The primary treatment is through surgical removal or debulking of the tumor. Neoadjuvant therapies such as radiation and chemotherapy may reduce occurrences of hypoglycemia, but only temporarily. Glucocorticoids may be used when the underlying malignancy cannot be treated. Presentation: Friday, June 16, 2023

Analysis of multi-disease targeting effect of phytochemicals by AMPK stimulation– diabetes: A computational approach

Diabetes is a silent killer and a metabolic syndrome characterized by hyperglycemia that has been exponentially increasing in recent years. There is a need to develop therapeutic agents to control hyperglycemia and its secondary complications as well as protect and revive beta cells in diabetic patients. The target for first-line diabetes treatment is the adenosine monophosphate protein kinase (AMPK), which participates in cellular energy metabolism through phosphorylation of metabolic enzymes and transcription regulators. This study examined the drug-related properties as well as lead preparation of Catharanthus roseus alkaloids and testing molecular interaction at the AMPK targets to confirm their anti-diabetic effect. A control drug metformin and a library of 85 molecules of C. roseus alkaloids were crossed with the ADMET test, followed by the investigation of molecular interaction tested on AMPK1 and AMPK2 targets through an in silico docking process. Vindolinine (CID: 24148538), vindoline (CID: 425978), (+)-vindorosine (CID: 261578), Cr-1 (CID: 5315746), and Cr-2 (CID: 59908094) had passed the ADMET test. Molecular interaction of the tested C. roseus alkaloids on AMPK1 and AMPK2 targets had potential energy that varied from &amp;minus;7.4 to &amp;minus;5.3 kcal/mol, whereas binding energies of &amp;minus;4.0 kcal/mol for AMPK1-metformin interaction and &amp;minus;4.2 kcal/mol for AMPK2-metformin interaction were observed. The tested C. roseus alkaloids were shown to be more potent activators of AMPK than the control drug. All five biomolecules of C. roseus acted as modulators that have the potential to stimulate AMPK, reduce glucose production, and increase glucose utilization in hepatocytes. In addition, they diminished insulin resistance and secondary complications of diabetes by inhibiting acetyl-CoA carboxylase, regulating cholesterol levels and macrophage, and reviving beta cells in Type 2 diabetes. These results provided the foundation for developing new multi-disease-targeting drugs that can treat diabetes, obesity, cardiovascular disease, cancer, and other diseases by the stimulation of AMPK1 and AMPK2 targets.

Oral Carbohydrate Administration was Suitable for Cesarean Section–A Systematic Review and Meta-Analysis of Randomized Trials

The use of carbohydrate (CHO) drinks prior to elective cesarean section has gained momentum, but its effect on maternal and neonatal outcomes remains controversial. The aim of this meta-analysis was to assess the effect of an oral CHO load prior to cesarean delivery on insulin sensitivity, insulin resistance, maternal glycemia, neonatal glycemia, and breastfeeding. As of May 21, 2023, we searched through five databases for English-language experimental studies on pre-cesarean oral CHO. A total of 3,940 citations were received, of which seven were selected. The concentrations of CHO used in these studies ranged from 5.9% to 14.2%, and the amounts used were 300-400 ml. We found that pre-cesarean CHO loading reduced maternal insulin resistance and increased maternal glucose levels. CHO loading activates the insulin pathway of critical en-zymes to some extent, increasing glucose utilization by peripheral tissues and ultimately reducing postop-erative insulin resistance. Of course, this is also beneficial in improving maternal blood sugar. We did not find that CHO increased maternal insulin sensitivity or neonatal blood glucose levels. Future prospective randomized controlled trials can use nutritional load to increase colostrum production after Caesarean sec-tion to enhance the confidence of these mothers in breastfeeding. In addition, our preoperative beverage could be more individualized to accommodate diabetic women.

Appearance of aseptic vascular grafts after endovascular aortic repair on [(18)F]fluorodeoxyglucose positron emission tomography/computed tomography.

Diagnosis of prosthetic vascular graft infection with [(18)F]fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) allows for early detection of functional changes associated with infection, based on increased glucose utilization by activated macrophages and granulocytes. Aseptic vascular grafts, like all foreign bodies, can stimulate an inflammatory response, which can present as increased activity on 18F-FDG PET/CT. Consequently, distinguishing aseptic inflammation from graft infection, though important, can be difficult. In the case of endovascular aneurysm repair (EVAR), a minimally invasive procedure involving the transfemoral insertion of an endoprosthetic stent graft, the normal postoperative appearance of these grafts on 18F-FDG PET/CT can vary over time, potentially confounding study interpretation. To investigate the visual, semiquantitative, and temporal characteristics of aseptic vascular grafts in patients status post EVAR. In this observational retrospective cohort study, patients with history of EVAR who underwent 18F-FDG PET/CT for indications other than infection were identified retrospectively. All patients were asymptomatic for graft infection - no abdominal pain, fever of unknown origin, sepsis, or leukocytosis - at the time of imaging and for ≥ 2 mo after each PET/CT. Imaging studies such as CT for each patient were also reviewed, and any patients with suspected or confirmed vascular graft infection were excluded. One hundred two scans performed on 43 patients (34 males; 9 females; age = 77 ± 8 years at the time of the final PET/CT) were retrospectively reviewed. All 43 patients had an abdominal aortic (AA) vascular graft, 40 patients had a right iliac (RI) limb graft, and 41 patients had a left iliac (LI) limb graft. Twenty-two patients had 1 PET/CT and 21 patients had from 2 to 9 PET/CTs. Grafts were imaged between 2 mo to 168 mo (about 14 years) post placement. Eight grafts were imaged within 6 mo of placement, including three that were imaged within three months of placement. The mean interval between graft placement and PET/CT for all 102 scans was 51 ± 39 mo. PET/CT data was reconstructed with region-of-interest analysis of proximal, mid and distal portions of the grafts and background ascending aorta. Maximum standardized uptake value (SUVmax) was recorded for each region. SUVmax-to-background uptake ratios (URs) were calculated. Visual assessment was performed using a 2-pattern grading scale: Diffuse (homogeneous uptake less than liver uptake) and focal (one or more areas of focal uptake in any part of the graft). Statistical analysis was performed. In total, there were 306 AA grafts, 285 LI grafts, 282 RI grafts, and 306 ascending aorta background SUVmax measurements. For all 102 scans, mean SUVmax values for AA grafts were 2.8-3.0 along proximal, mid, and distal segments. Mean SUVmax values for LI grafts and RI grafts were 2.7-2.8. Mean SUVmax values for background were 2.5 ± 0.5. Mean URs were 1.1-1.2. Visual analysis of the scans reflected results of quantitative analysis. On visual inspection, 98% revealed diffuse, homogeneous 18F-FDG uptake less than liver. Graft URs and visual pattern categories were significantly associated for AA graft URs (F-ratio = 21.5, P < 0.001), LI graft URs (F-ratio = 20.4, P < 0.001), and RI graft URs (F-ratio = 30.4, P < 0.001). Thus, visual patterns of 18F-FDG uptake corresponded statistically significantly to semiquantitative URs. The age of grafts showing focal patterns was greater than grafts showing diffuse patterns, 87 ± 89 vs 50 ± 37 mo, respectively (P = 0.02). URs were significantly associated with graft age for AA grafts (r = 0.19, P = 0.001). URs were also significantly associated with graft age for LI grafts (r = 0.25, P < 0.0001), and RI grafts (r = 0.31, P < 0.001). Quartiles of similar numbers of graft (n = 25-27) grouped by graft age indicated that URs were significantly higher for 4th quartile vs 2nd quartile URs (F-ratio = 19.5, P < 0.001). When evaluating URs, graft SUVmax values within 10%-20% of the ascending aorta SUVmax is evident in aseptic grafts, except for grafts in the oldest quartiles. In this study, grafts in the oldest quartiles (> 7 years post EVAR) showed SUVmax up to 30% higher than the ascending aorta SUVmax. Characteristics of an aseptic vascular stent graft in the aorta and iliac vessels on 18F-FDG PET/CT include graft SUVmax values within 10%-20% of the ascending aorta background SUVmax. The SUVmax of older aseptic grafts can be as much as 30% above background. The visual uptake pattern of diffuse, homogeneous uptake less than liver was seen in 98% of aseptic vascular grafts, making this pattern particularly reassuring for clinicians.

Abstract P2161: Stem Cell-derived Exosome Nebulization Therapy (SCENT) Improves Cardiac Function And Tissue Repair In Mice And Pigs

Stem cell-derived exosomes show promise as therapeutics for cardiac repair after injury. However, due to their short half-life in vivo, effective treatment typically requires repeated dosing. Previous methods for delivering exosomes to the heart involve invasive injection routes. Here, we report a noninvasive and repeatable approach to exosome delivery via inhalation after myocardial infarction (MI), called Stem Cell-derived Exosome Nebulization Therapy (SCENT). In a mouse model of MI, exosomes were recruited to the ischemic heart after repeated dosing via nebulization. SCENT ameliorated cardiac repair by significantly improving left ventricular function, reducing infarct size, and promoting cardiomyocyte proliferation. Further investigation via single-cell RNA sequencing of the mouse heart after SCENT revealed a significant downregulation of CD36 in endothelial cells (ECs). In an EC- Cd36 fl/- mouse model, we found that inhibiting CD36, a fatty acid transporter in ECs, led to a compensatory increase in glucose utilization in the heart and higher ATP generation, resulting in enhanced cardiac contractility. In a pig model of acute MI, we evaluated functional outcomes using cardiac magnetic resonance imaging (MRI) and found that SCENT led to reduced left ventricular (LV) end-systolic volume (ESV) at day 28 (19.07 ± 3.22 ml) compared to controls (23.60 ± 3.06 ml). Additionally, pigs treated with SCENT exhibited increased LV ejection fraction (EF) (59.36 ±2.84%) and fractional shortening (FS) (29.56 ± 1.25%), further confirming cardioprotection in pigs. Our results pave the way for development of a non-invasive exosome delivery method for rescuing heart injury.

Quantifying Insulin-Mediated and Non-Insulin-Mediated Changes in Glucose Dynamics during Resistance Exercise in Type 1 Diabetes.

Exercise can cause dangerous fluctuations in blood glucose in people living with type 1 diabetes (T1D). Aerobic exercise, for example, can cause acute hypoglycemia secondary to increased insulin-mediated and non-insulin-mediated glucose utilization. Less is known about how resistance exercise (RE) impacts glucose dynamics. Twenty-five people with T1D underwent three sessions of either moderate or high intensity RE at three insulin infusion rates during a glucose tracer clamp. We calculated time-varying rates of endogenous glucose production (EGP) and glucose disposal (Rd) across all sessions and used linear regression and extrapolation to estimate insulin- and non-insulin-mediated components of glucose utilization. Blood glucose did not change on average during exercise. The area under the curve (AUC) for EGP increased by 1.04 mM during RE (95% CI: 0.65-1.43, p < 0.001) and decreased proportionally to insulin infusion rate (0.003 mM per percent above basal rate, 95% CI: 0.001-0.006, p = 0.003). The AUC for Rd rose by 1.26 mM during RE (95% CI: 0.41-2.10, p = 0.004) and increased proportionally with insulin infusion rate (0.04 mM per percent above basal rate, CI: 0.03-0.04, p < 0.001). No differences were observed between the moderate and high resistance groups. Non-insulin-mediated glucose utilization rose significantly during exercise before returning to baseline roughly 30-minutes post-exercise. Insulin-mediated glucose utilization remained unchanged during exercise sessions. Circulating catecholamines and lactate rose during exercise despite relatively small changes observed in Rd. Results provide an explanation why RE may pose a lower overall risk for hypoglycemia.

Manipulating mitochondrial dynamics in the NTS prevents diet-induced deficits in brown fat morphology and glucose uptake

AimsBrown adipose tissue (BAT) can produce heat by metabolizing glucose and fatty acids. Activation of BAT is controlled by the central nervous system (CNS) through sympathetic innervation. Dysregulation of signalling molecules in selective CNS areas such as the nucleus of tractus solitarius (NTS) are linked with altered BAT activity, obesity and diabetes. High-fat diet (HFD)-feeding increases mitochondrial fragmentation in the NTS, triggering insulin resistance, hyperphagia and weight gain. Here we sought to determine whether changes in mitochondrial dynamics in the NTS can affect BAT glucose uptake. Main methodsRats received DVC stereotactic surgery for local brain administration of viruses that express mutated Drp1 genes. BAT glucose uptake was measured with PET/CT scans. Biochemical assays and immunohistochemistry determined altered levels of key signalling molecules and neural innervation of BAT. Key findingsWe show that short-term HFD-feeding decreases BAT glucose uptake. However, inhibiting mitochondrial fragmentation in NTS-astrocytes of HFD-fed rats partially restores BAT glucose uptake accompanied by lower blood glucose and insulin levels. Tyrosine Hydroxylase (TH) revealed that rats with inhibited mitochondrial fragmentation in NTS astrocytes had higher levels of catecholaminergic innervation in BAT compared to HFD-fed rats, and did not exhibit HFD-dependent infiltration of enlarged white fat droplets in the BAT. In regular chow-fed rats, increasing mitochondrial fragmentation in the NTS-astrocytes reduced BAT glucose uptake, TH immune-positive boutons and β3-adrenergic receptor levels. SignificanceOur data suggest that targeting mitochondrial dynamics in the NTS-astrocytes could be a beneficial strategy to increase glucose utilization and protect from developing obesity and diabetes.

M2 isoform of pyruvate kinase rewires glucose metabolism during radiation therapy to promote an antioxidant response and glioblastoma radioresistance.

Resistance to existing therapies is a significant challenge in improving outcomes for glioblastoma (GBM) patients. Metabolic plasticity has emerged as an important contributor to therapy resistance, including radiation therapy (RT). Here, we investigated how GBM cells reprogram their glucose metabolism in response to RT to promote radiation resistance. Effects of radiation on glucose metabolism of human GBM specimens were examined in vitro and in vivo with the use of metabolic and enzymatic assays, targeted metabolomics, and FDG-PET. Radiosensitization potential of interfering with M2 isoform of pyruvate kinase (PKM2) activity was tested via gliomasphere formation assays and in vivo human GBM models. Here, we show that RT induces increased glucose utilization by GBM cells, and this is accompanied with translocation of GLUT3 transporters to the cell membrane. Irradiated GBM cells route glucose carbons through the pentose phosphate pathway (PPP) to harness the antioxidant power of the PPP and support survival after radiation. This response is regulated in part by the PKM2. Activators of PKM2 can antagonize the radiation-induced rewiring of glucose metabolism and radiosensitize GBM cells in vitro and in vivo. These findings open the possibility that interventions designed to target cancer-specific regulators of metabolic plasticity, such as PKM2, rather than specific metabolic pathways, have the potential to improve the radiotherapeutic outcomes in GBM patients.

Epigenetically altered macrophages promote development of diabetes-associated atherosclerosis.

Atherosclerosis (AS) risk is elevated in diabetic patients, but the underlying mechanism such as involvement of epigenetic control of foam macrophages remains unclear. We have previously shown the importance of immune regulation on endothelial cells to AS development in diabetes. In this study, we examined the hypothesis that diabetes may promote AS through modification of the epigenetic status of macrophages. We employed the Laser Capture Microdissection (LCM) method to evaluate the expression levels of key epigenetic regulators in both endothelial cells and macrophages at the AS lesions of patients. We then assessed the correlation between the significantly altered epigenetic regulator and serum levels of low-density Lipoprotein (LDL), triglycerides (TRIG) and high-density Lipoprotein (HDL) in patients. In vitro, the effects of high glucose on glucose utilization, lactate production, succinate levels, oxygen consumption and polarization in either undifferentiated or differentiated bone marrow-derived macrophages (BMDMs) were analyzed. The effects of depleting this significantly altered epigenetic regulator in macrophages on AS development were assessed in AS-prone diabetic mice. Histone deacetylase 3 (HDAC3) was identified as the most significantly altered epigenetic regulator in macrophages from the AS lesions in human diabetic patients. The levels of HDAC3 positively correlated with high serum LDL and TRIG, as well as low serum HDL. High glucose significantly increased glucose utilization, lactate production, succinate levels and oxygen consumption in cultured macrophages, and induced proinflammatory M1-like polarization. Macrophage depletion of HDAC3 significantly attenuated AS severity in AS-prone diabetic mice. Epigenetically altered macrophages promote development of diabetes-associated AS, which could be prevented through HDAC3 depletion.

Abstract 3209: Metabolic characterization of radiation-induced cardiotoxicity

Abstract Background: Approximately 50% of all cancer patients receive radiation therapy as a component of their cancer care. While radiation therapy has demonstrable benefit in improving survival in patients, radiation-induced heart disease (RIHD) is a major contributor to morbidity and mortality in cancer survivors with history of thoracic radiation. Understanding metabolic changes underlying RIHD may enable development of novel diagnostic and therapeutic approaches for early detection and treatment of RIHD. The high energetic demands of the heart require properly functioning mitochondria to meet the ATP production needs. Fatty acids are the primary metabolic substrates for energy production in a healthy heart. However, under conditions of stress, the cardiac metabolism shifts towards increased glucose utilization. In this study, we characterize the impact of radiation of cardiac substrate utilization and energy production. Methods: Pre-clinical RIHD models were established by administering whole heart radiation (8Gy x 5) in mice and rats followed by structural and biochemical characterization. Transmission electron microscopy and western blot analyses were used to characterize structural and biochemical changes in the heart in response to radiation. Spectrophotometric assays and Western blot analyses were used to characterize changes in pyruvate dehydrogenase (PDH) activity and function in the heart in response to radiation. Results: Our studies identified myocardial mitochondrial dysfunction as an early event following exposure of heart to radiation. Cardiac irradiation resulted in increased mitochondrial fusion and higher expression of MFN1, a key protein that mediates mitochondrial fusion. The pathological structural and biochemical changes in the myocardial mitochondria are associated with reduced glucose metabolism due to impaired PDH activity. This decline was mediated by increased phosphorylation of PDH in irradiated hearts, which inhibits its activity. Conclusion: Cardiac irradiation results in early metabolic dysregulation, especially in glucose metabolism, which may be exploited for early detection and mitigation of radiation-induced cardiotoxicity. Citation Format: Sarah C. Elliott, Jayesh Sharma, Elizabeth R. Zhang-Velten, Abdallah Elnwasany, Chantal Vidal, Luke Szweda, Prasanna Alluri. Metabolic characterization of radiation-induced cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3209.

The SWGEDWGEIW from Soybean Peptides Reduces Insulin Resistance in 3T3-L1 Adipocytes by Activating p-Akt/GLUT4 Signaling Pathway.

Diabetes mellitus, a group of metabolic disorders characterized by persistent hyperglycemia, affects millions of people worldwide and is on the rise. Dietary proteins, from a wide range of food sources, are rich in bioactive peptides with anti-diabetic properties. Notably, the protective mechanism of the single peptide SWGEDWGEIW (TSP) from soybean peptides (SBPs) on insulin resistance of adipocytes in an inflammatory state was investigated by detecting the lipolysis and glucose absorption and utilization of adipocytes. The results showed that different concentrations of TSP (5, 10, 20 µg/mL) intervention can reduce 3T3-L1 adipocytes' insulin resistance induced by inflammatory factors in a dose-dependent manner and increase glucose utilization by 34.2 ± 4.6%, 74.5 ± 5.2%, and 86.7 ± 6.1%, respectively. Thus, TSP can significantly alleviate the lipolysis of adipocytes caused by inflammatory factors. Further mechanism analysis found that inflammatory factors significantly reduced the phosphorylation (p-Akt) of Akt, two critical proteins of glucose metabolism in adipocytes, and the expression of GLUT4 protein downstream, resulting in impaired glucose utilization, while TSP intervention significantly increased the expression of these two proteins. After pretreatment of adipocytes with PI3K inhibitor (LY294002), TSP failed to reduce the inhibition of p-Akt and GLUT4 expression in adipocytes. Meanwhile, the corresponding significant decrease in glucose absorption and the increase in the fat decomposition of adipocytes indicated that TSP reduced 3T3-L1 adipocytes' insulin resistance by specifically activating the p-Akt/GLUT4 signal pathway. Therefore, TSP has the potential to prevent obesity-induced adipose inflammation and insulin resistance.

Antidiabetic and Anticancer Potentials of Mangifera indica L. from Different Geographical Origins.

Mango fruit is well known for its nutritional and health benefits due to the presence of a plethora of phytochemical classes. The quality of mango fruit and its biological activities may change depending upon the variation in geographical factors. For the first time, this study comprehensively screened the biological activities of all four parts of the mango fruit from twelve different origins. Various cell lines (MCF7, HCT116, HepG2, MRC5) were used to screen the extracts for their cytotoxicity, glucose uptake, glutathione peroxidase activity, and α-amylase inhibition. MTT assays were carried out to calculate the IC50 values for the most effective extracts. The seed part from Kenya and Sri Lanka origins exhibited an IC50 value of 14.44 ± 3.61 (HCT116) and 17.19 ± 1.60 (MCF7). The seed part for Yemen Badami (119 ± 0.08) and epicarp part of Thailand (119 ± 0.11) mango fruit showed a significant increase in glucose utilization (50 μg/mL) as compared to the standard drug metformin (123 ± 0.07). The seed extracts of Yemen Taimoor seed (0.46 ± 0.05) and Yemen Badami (0.62 ± 0.13) produced a significant reduction in GPx activity (50 μg/mL) compared to the control cells (100 μg/mL). For α-amylase inhibition, the lowest IC50 value was observed for the endocarp part of Yemen Kalabathoor (108.8 ± 0.70 μg/mL). PCA, ANOVA, and Pearson's statistical models revealed a significant correlation for the fruit part vs. biological activities, and seed part vs. cytotoxicity and α-amylase activity (p = 0.05). The seed of mango fruit exhibited significant biological activities; hence, further in-depth metabolomic and in vivo studies are essential to effectively utilize the seed part for the treatment of various diseases.

Targeting first trimester trophoblast cell metabolism modulates its susceptibility to Zika virus infection.

In the last 15 years Zika virus (ZIKV) caused several outbreaks of increasing scale in Micronesia, South Pacific islands, and more recently in the Caribbean and South America. The severity of the clinical presentation in neonates from pregnant women infected with ZIKV during the last outbreak supports the relevance of unraveling the mechanism of infection and viral persistence in the placenta with local viral isolates. Here, we investigated the relevance of trophoblast metabolic rewiring for viral multiplication and the role of the vasoactive intestinal peptide (VIP) as an endogenous factor associated with placental restriction to ZIKV infection at early pregnancy. Our in vitro model demonstrated that ZIKV triggers metabolic rewiring in first trimester cytotrophoblast-derived cells by increasing glucose utilization as fuel to sustain its replication, decreasing long-chain polyunsaturated fatty acid uptake, and promoting lipid droplets accumulation to favor its multiplication. Of note, variations in nutrient availability modulated viral spread in trophoblast cultures. The presence of VIP during trophoblast infection impaired ZIKV infective particle production and viral replication, restoring cell migration and metabolism. Moreover, the blockade of endogenous VIP signaling increased viral particle production and the viral entry receptor AXL expression. These results highlight the potential role of VIP as an endogenous antiviral factor related to trophoblast cell permissiveness to ZIKV infection at early pregnancy.

Substituent effects of sulfonamide derivatives of metformin that can dually improve cellular glucose utilization and anti-coagulation

Metformin, the most frequently prescribed medicine for the management of type 2 diabetes, has been shown to reduce cardiovascular events in diabetic patients in pre-clinical and clinical studies. The present work reports the design, synthesis, and biological assessment of the impact of six benzenesulfonamide biguanides on various aspects of hemostasis, cell function, red blood cell integrity (RBC), and their ability to uptake glucose in human umbilical endothelial cells (HUVECs). It was found that all synthesized o- and m-benzenesulfonamides, particularly derivatives with nitro (3) and amino groups (4), are characterized by a good safety profile in HUVECs, which was further confirmed in the cellular integrity studies. The biguanide analogues with methoxy group (1, 2) and an amino substituent (5, 6) significantly increased glucose utilization in HUVECs, similarly to the parent drug. Intriguingly, compounds 1, 3, and 6 favourably influenced some of the coagulation parameters. Furthermore, derivative 3 also slowed the process of fibrin polymerization, indicating more beneficial anti-coagulant properties than metformin. None of the novel metformin analogues interact strongly with the erythrocyte lipid-protein bilayer. Our findings indicate that derivative 3 has highly desirable anti-coagulant properties, and compounds 1 and 6 have potential dual-action activity, including anti-hyperglycaemic properties and anti-coagulant activity. As such, these derivatives can be used as lead molecules for further development of anti-diabetic agents with a beneficial effect on hypercoagulability.