Stimulation Of Glucose Utilization Research Articles

Near-Physiological Concentrations of Extracellular Pyruvate Stimulated Glucose Utilization along with Triglyceride Accumulation and Mitochondrial Activity in HepG2 Cells

Near-Physiological Concentrations of Extracellular Pyruvate Stimulated Glucose Utilization along with Triglyceride Accumulation and Mitochondrial Activity in HepG2 Cells

In vivo antioxidant and hypoglycaemic potentials of Rivina humilis extract against streptozotocin induced diabetes and its complications in wistar rats.

This current research study was designed to investigate beneficial effects of R. humilis (Rivina humilis) against streptozotocin-induced diabetic rats. The R. humilis ethanol extract was prepared using soxhlet and its phenol content was determined. The type-2 diabetes was induced in rats by giving fructose mixed drinking water and single dose of streptozotocin. Oral glucose tolerance test (OGTT) was performed after 72h of streptozotocin to check ability of extract to utilize oral glucose load with 2h. The extract was also tested for its potentials to reduce blood glucose (BGL) and diabetic complications by administering to diabetic rats for 21 days. Blood glucose was determined on day 1, 7, 14 and 21. At 21st day, blood samples were collected from experimental rats were euthanized to collect pancreas and liver. Liver and kidney function tests, HbAc1 and lipid profile was established from blood samples. Pancreas was subjected to histopathological examination and liver was used to determine antioxidant enzymes. In vitro study was done to investigate the effect of extract on glucose utilization by rat hemidiaphragm. In OGTT, administration of extract could stimulate glucose utilization which was witnessed by significant BGL reduction at 90 and 120min in therapeutic groups compare to diabetics. In chronic study, we observed significant reduction in BGL on 21st day and all tests performed to determine liver and kidney function, HbAc1, vitamin E were normal in extract treated groups. There was significant increase in liver antioxidant enzymes in therapeutic groups which revealed regeneration of β-cells in therapeutic groups. The results of research demonstrated significant antidiabetic potentials in R. humilis. The online version contains supplementary material available at 10.1007/s40200-023-01258-6.

Abstract P6-11-09: Effects of a 12 Week Breast Cancer Exercise Program on the Mitochondrial Derived Peptide MOTS-c

Abstract Background: Breast cancer survivors have an increased risk for comorbid conditions such as cardiovascular disease, diabetes, and hypertension. In addition, cancer related treatments negatively affect bone health, muscular strength, and quality of life. Exercise is an effective strategy to combat cancer related symptoms (fatigue, anxiety) and common comorbid conditions. MOTS-c is a Mitochondrial Derived Peptide (MDP) that has a number of beneficial effects on metabolism, insulin sensitivity, and exercise capacity. Previously published preclinical studies have shown that MOTS-c treatment improves physical performance in young, middle-age, and old mice. In humans, it has been implicated to promote metabolic homeostasis, stimulate glucose utilization, fat-oxidation, reduce inflammation, and protect against both cardiovascular and metabolic disease. We implemented a 12-week exercise program in breast cancer survivors. We evaluated changes in baseline and post12-week MOTS-c levels and corresponding body composition changes. Methods: We evaluated 25 participant paired samples at baseline and post 12-weeks of exercise. Participants engaged in a 12-week exercise program, 3 times a week for 90 minutes/session. At baseline and post 12-weeks, participants underwent a DXA scan, body composition analysis, and a blood draw. The blood samples were analyzed using an in-house ELISA and compared to various clinical and body composition metrics. Results: The median age was lowest for the high responders (56.7 years) compared to moderate responders (57 years) and reduced MOTS-c (61.5 years). We found 3 distinct groups: reduced MOTS-c with exercise (n=8), increased MOTS-c moderate responders (0-10pg/ml; n=2), and increased MOTS-c high responders (>10 pg/ml; n=15). MOTS-c had an inverse relationship with almost all tested metrics including: age, weight, BMI, waist to hip ratio, body composition—visceral (fat area, fat mass, fat volume), subcutaneous fat mass, whole body (body lean, body mass, body percent fat, bone mineral content (BMC), and bone mineral density (BMD). Although the majority of the metrics improved and had inverse relationships for MOTS-c, the reduced MOTS-c group had increased BMC and BMD. Interestingly, despite a higher MOTS-c value, there was an increase in visceral fat as well as an increase in whole body fat across all groups. Of the 25 participants, 22 were Asian, two were Caucasian, and one was Native Hawaiian/Pacific Islander. Given the small number of participants, there does not appear to be any correlation between MOTS-c and ethnicity in our study. Summary: We found significant changes in MOTS-c according to clinical and body composition metrics after a 12-week exercise program. The findings in this study support previous findings on MOTS-c metrics including MOTS-c levels decreasing with age. However, there are few clinical trials evaluating MOTS-c in cancer survivors. MOTS-c is a potential biomarker related to exercise in cancer survivors. Our study was predominantly conducted in Asian women where there is limited data. This emphasizes the need for more clinical trials to be conducted with racially/ethnically diverse populations to better understand MOTS-c’s role in our varied cancer populations. Citation Format: Chloe Shen, Kirsten Baron, Matthew Toyama, Pinchas Cohen, Junxiang Wan, Hiroshi Kumagai, Ian Pagano, Paulette Yamada, Cheri Teranishi-Hashimoto, Jami Fukui. Effects of a 12 Week Breast Cancer Exercise Program on the Mitochondrial Derived Peptide MOTS-c [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-09.

Pregnane-Oximino-Alkyl-Amino-Ether Compound as a Novel Class of TGR5 Receptor Agonist Exhibiting Antidiabetic and Anti-Dyslipidemic Activities

Introduction: The present study deals with the synthesis of pregnane-oximino-amino-alkyl-ethers and their evaluation for antidiabetic and anti-dyslipidemic activities in validated animal and cell culture models. Methods: The effect on glucose tolerance was measured in sucrose-loaded rats; antidiabetic activity was evaluated in streptozotocin (STZ)-induced diabetic rats and genetically diabetic db/db mice; the anti-dyslipidemic effect was characterized in high-fructose, high-fat diet (HFD)-fed dyslipidemic hamsters. The effect on glucose production and glucose utilization was analyzed in HepG2 liver and L6 skeletal muscle cells, respectively. Results: From the synthesized molecules, pregnane-oximino-amino-alkyl-ether (compound 14b) improved glucose clearance in sucrose-loaded rats and exerted antihyperglycemic activity on STZ-induced diabetic rats. Further evaluation in genetically diabetic db/db mice showed temporal decrease in blood glucose, and improvement in glucose tolerance and lipid parameters, associated with mild improvement in the serum insulin level. Moreover, compound 14b treatment displayed an anti-dyslipidemic effect characterized by significant improvement in altered lipid parameters of the high-fructose, HFD-fed dyslipidemic hamster model. In vitro analysis in the cellular system suggested that compound 14b decreased glucose production in liver cells and stimulated glucose utilization in skeletal muscle cells. These beneficial effects of compound 14b were associated with the activation of the G-protein-coupled bile acid receptor TGR5. Conclusion: Compound 14b exhibits antidiabetic and anti-dyslipidemic activities through activating the TGR5 receptor system and can be developed as a lead for the management of type II diabetes and related metabolic complications.

Abstract 415: Effect of aerobic and resistance exercise on the mitochondrial peptide MOTSc in Hispanic and non-Hispanic breast cancer survivors

Abstract Background MOTS-c is a mitochondrial derived peptide with exercise mimetic activity that elicits beneficial effects on metabolism and exercise capacity. MOTS-c stimulates glucose utilization, fat-oxidization, reduces inflammation, and protects against experimental models of metabolic disease. Furthermore, MOTS-c effects in humans are affected by race, potentially via ethnic-specific mtDNA variations. Women treated for breast cancer are at an increased risk for risk for cardiovascular disease, diabetes and obesity, due to side effects of cancer-treatments. Exercise mitigates many of these side effects, but the role of MOTS-c regulation by exercise among breast cancer survivors (BCS) of varying ethnicities is unknown. We examined the effects of a 16-week aerobic and resistance exercise intervention on MOTS-c in Hispanic and Non-Hispanic BCS. Methods BCS (Stage I-III) were randomized to exercise (n=50) or standard care (n=50). The intervention promoted supervised, progressive moderate-vigorous aerobic and resistance exercise thrice weekly for 16 weeks. Aerobic exercise was performed at 65-85% maximum heart rate. Resistance exercise was performed in circuit-fashion with 3 sets of 10-15 repetitions including upper and lower body exercises at 65-70% 1-repetition maximum. Fasting blood draws were obtained at baseline and post-intervention (4 months). Body composition was assessed by dual energy x-ray absorptiometry. MOTS-c was analyzed in plasma using an in-house ELISA. Within and between group differences were assessed by paired t-test and repeated measures ANOVA. Pearson's correlation was computed to assess the association between MOTS-c and metabolic biomarkers. ResultsTwenty-five Hispanic BCS and 24 non-Hispanic BCS (age 53.5±10.4 years) and BMI of 33.5±5.5 kg/m2 were included. Hispanic BCS were younger, of greater adiposity, had higher stage cancers, and had worse metabolic profiles at baseline compared to non-Hispanic BCS (p<0.001). Post-exercise, MOTS-c levels significantly increased when compared to baseline and the usual care group among NHBCS (p<0.01). Post-exercise levels of MOTS-c among non-Hispanic BCS were significantly associated with reductions in fat mass, body weight, HOMA-IR, CRP, and an increase in lean mass (p<0.01). MOTS-c did not significantly change following exercise among Hispanic BCS (p>0.05). Conclusions A 16-week aerobic and resistance intervention increased MOTS-c levels among non-Hispanic BCS but not Hispanic BCS. Non-Hispanic BCS who experience exercise-induced improvements in MOTS-c may also experience improved insulin sensitivity thereby reducing the risk for comorbid conditions. Despite poorer metabolic profiles, Hispanic BCS may not experience exercise-induced benefits on MOTS-c. Future trials should aim for reducing potential ethnic differences in cardiometabolic health. Citation Format: Christina M. Dieli-Conwright, Nathalie Sami, Mary K. Norris, Junxiang Wan, Hiroshi Kumagai, Pinchas Cohen. Effect of aerobic and resistance exercise on the mitochondrial peptide MOTSc in Hispanic and non-Hispanic breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 415.

β-Sitosterol-D-Glucopyranoside Mimics Estrogenic Properties and Stimulates Glucose Utilization in Skeletal Muscle Cells.

Estrogenic molecules have been reported to regulate glucose homeostasis and may be beneficial for diabetes management. Here, we investigated the estrogenic effect of β-sitosterol-3-O-D-glucopyranoside (BSD), isolated from the fruits of Cupressus sempervirens and monitored its ability to regulate glucose utilization in skeletal muscle cells. BSD stimulated ERE-mediated luciferase activity in both ERα and ERβ-ERE luc expression system with greater response through ERβ in HEK-293T cells, and induced the expression of estrogen-regulated genes in estrogen responsive MCF-7 cells. In silico docking and molecular interaction studies revealed the affinity and interaction of BSD with ERβ through hydrophobic interaction and hydrogen bond pairing. Furthermore, prolonged exposure of L6-GLUT4myc myotubes to BSD raised the glucose uptake under basal conditions without affecting the insulin-stimulated glucose uptake, the effect associated with enhanced translocation of GLUT4 to the cell periphery. The BSD-mediated biological response to increase GLUT4 translocation was obliterated by PI-3-K inhibitor wortmannin, and BSD significantly increased the phosphorylation of AKT (Ser-473). Moreover, BSD-induced GLUT4 translocation was prevented in the presence of fulvestrant. Our findings reveal the estrogenic activity of BSD to stimulate glucose utilization in skeletal muscle cells via PI-3K/AKT-dependent mechanism.

Short-term administration of C. aronia stimulates insulin signaling, suppresses fatty acids metabolism, and increases glucose uptake and utilization in the hearts of healthy rats.

This study evaluated the effect of Crataegus aronia (C. aronia) aqueous extract on cardiac substrate utilization and insulin signaling in adult male healthy Wistar rats. Rats (n=18/group) were either administered normal saline (vehicle) or treated with C. aronia aqueous extract (200mg/kg) for 7days, daily. Fasting plasma glucose and insulin levels were not significantly changed in C. aronia-treated rats but were significantly reduced after both the intraperitoneal glucose or insulin tolerance tests. Besides, C. aronia significantly increased the left ventricular (LV) activities of phosphofructokinase (PFK) and pyruvate dehydrogenase (PDH), two markers of glycolysis and glucose oxidation, respectively, and suppressed the levels of pyruvate dehydrogenase kinase 4 (PDK4), an inhibitor of PDH. Concomitantly, it significantly reduced the LV levels of carnitine palmitoyltransferase 1 (CPT1) and PPARα, two markers of fatty acid (FAs) oxidations. Under basal and insulin stimulation, C. aronia aqueous extract boosted insulin signaling in the LV of rats by increasing the protein levels of p-IRS (Tyr612) and p-Akt (Ser473) and suppressing protein levels of p-mTOR (Ser 2448) and p-IRS (Ser307). In parallel, C. aronia also increased the protein levels of GLUT-4 in the membrane fraction of the treated LVs. All these effects were also associated with a significant increase in AMPK activity (phosphorylation at Thr172), a major energy modulator that stimulates glucose utilization. In conclusion, short-term administration of C. aronia aqueous extract shifts the cardiac metabolism toward glucose utilization, thus making this plant a potential therapeutic medication in cardiac disorders with impaired metabolism.

COMPARISON OF INSULIN RESISTANCE WITH THE SEVERITY OF METABOLIC SYNDROME

Objective: Insulin resistance (IR) means a reduced ability of insulin to stimulate glucose utilization. IR is related to cardiovascular disease (CVD) risk as the IR forms the basis for atherogenesis and acts as a major risk factor for atherosclerotic CVD.
 Methods: Total of 195 participants were recruited divided into three groups based on the presence of metabolic abnormalities as control Group I (with <3 components of metabolic syndrome [MS]), MS group as Group II (with any 3 components of MS), and severe MS as Group III (with more than three components of MS).
 Results: Results showed that fasting blood sugar (FBS) and glycated hemoglobin showed a significant difference between the groups (p<0.001), whereas fasting insulin and IR were higher in severe MS which showed statistically significant difference (p<0.001) in comparison with control and MS group.
 Conclusion: IR is one of the principal factors for the development of MS and further threw light that the increase in the IR level proportionately increases the severity of MS.

Mitochondrial oxidants, but not respiration, are sensitive to glucose in adipocytes

Insulin action in adipose tissue is crucial for whole-body glucose homeostasis, with insulin resistance being a major risk factor for metabolic diseases such as type 2 diabetes. Recent studies have proposed mitochondrial oxidants as a unifying driver of adipose insulin resistance, serving as a signal of nutrient excess. However, neither the substrates for nor sites of oxidant production are known. Because insulin stimulates glucose utilization, we hypothesized that glucose oxidation would fuel respiration, in turn generating mitochondrial oxidants. This would impair insulin action, limiting further glucose uptake in a negative feedback loop of "glucose-dependent" insulin resistance. Using primary rat adipocytes and cultured 3T3-L1 adipocytes, we observed that insulin increased respiration, but notably this occurred independently of glucose supply. In contrast, glucose was required for insulin to increase mitochondrial oxidants. Despite rising to similar levels as when treated with other agents that cause insulin resistance, glucose-dependent mitochondrial oxidants failed to cause insulin resistance. Subsequent studies revealed a temporal relationship whereby mitochondrial oxidants needed to increase before the insulin stimulus to induce insulin resistance. Together, these data reveal that (a) adipocyte respiration is principally fueled from nonglucose sources; (b) there is a disconnect between respiration and oxidative stress, whereby mitochondrial oxidant levels do not rise with increased respiration unless glucose is present; and (c) mitochondrial oxidative stress must precede the insulin stimulus to cause insulin resistance, explaining why short-term, insulin-dependent glucose utilization does not promote insulin resistance. These data provide additional clues to mechanistically link nutrient excess to adipose insulin resistance.

Syntheses, crystal structures and biological activity of oxidovanadium(V) complexes with tridentate aroylhydrazone ligands

A series of oxidovanadium(V) complexes, [VOLa-cL′] (L′ = ethyl maltolate), were synthesized by reaction of VOSO4 with the aroylhydrazones 2-amino-N'-(2-hydroxybenzylidene)benzohydrazide (H2La), N'-(3-bromo-2-hydroxybenzylidene)-3-hydroxylbenzohydrazide (H2Lb) and N′-(2-hydroxy-5-nitrobenzylidene) pivalohydrazide (H2Lc), respectively. The complexes were characterized by physico-chemical methods. Molecular structures of the complexes were further characterized by single crystal X-ray diffraction. The V ions in the three complexes are coordinated by three donor atoms of the aroylhydrazone ligands, two donor atoms of the ethyl maltolate ligand, and one oxo group. Biological study of the complexes indicates that they are insulin-like agents, which stimulated glucose utilization in a dose dependent manner over the concentration range 125 μM to 1 mM.

Glycolytic genes expression, proapoptotic potential in relation to the total content of bioactive compounds in durian fruits.

The properties of durian fruit at five stages of ripeness were evaluated and compared. The physicochemical parameters such as titratable acidity (TA) and total soluble solids (TSS) increased, whereas the pH slightly decreased during the ripening process. The highest contents of polyphenols, flavonoids, flavanols, tannins, vitamin C and the antioxidant capacities, measured by radical scavenging assays, were found in ripe and overripe fruits. The structural properties of extracted polyphenols were evaluated by Fourier transform infrared spectroscopy (FTIR) and fluorescence spectroscopy. The interaction of polyphenols with the main drug carrier in blood human serum albumin (HSA) showed decrease in its fluorescence intensity. The binding properties of polyphenols were in direct correlation with the antioxidant capacities of the investigated fruits. HepG2 cells evaluated cytotoxic effect and the mechanism of cell death after treatment with durian. The metabolism of carbohydrates was examined on the expression of glycolysis-related genes (hexokinase 2 (HK2); 6-phosphofructo-2-kinase 4 (PFKFB4); facilitated glucose transporter member 1 (SLC2A1 (Glut1)) and lactate dehydrogenase A and utilization of glucose in the hepatocytes with durian treatment. Durian in immature stage had stronger cytotoxic effect and weak proapoptotic potential on HepG2 cells than the mature and overripe ones. The ripe and overripe fruits increased the expression of hepatic HK2 and PFKFB4 glycolytic genes and stimulated glucose utilization in HepG2 cells. The present results indicate that durians reveal different biological activity and may provide their broad and extensive use as medicinal or functional foods.

The relationship of arterial hypertension with the disturbance of glucose tolerance

Arterial hypertension and impaired glucose tolerance are in many ways interdependent and often precede a more pronounced pathology, the metabolic syndrome. In this regard, it is an actual problem of modern medicine, as the timely diagnosis and treatment of this combination can reduce the disability and mortality in this cohort of patients, prolonging their life and preserving their working capacity. Clinical features of hypertension with concomitant metabolic disorders are: frequent formation of refractory hypertension, early damage to target organs-development of LVH (left ventricular hypertrophy), quickly leading to myocardial dysfunction, renal hyper filtration and MAU, reduction of aortic and arteries elasticity. It has been established that impairment of insulin's ability to suppress glucose production in the liver and/or stimulate glucose uptake by peripheral tissues can underlie a decrease in insulin sensitivity. Since in healthy people 75–80% of glucose is utilized by skeletal muscles, it is more likely that its main cause of IR is impaired insulin stimulated glucose utilization [8]. A certain value in the development of hypertrophy and proliferation of smooth muscle cells and fibroblasts of the vascular wall in hypertension has a stimulating effect of insulin on collagen synthesis. It has been established that the thickness of the intima media complex of the carotid artery and the number of desquamated endotheliocytes circulating in the blood of patients with hypertension with IGT closely correlate with elevated insulin levels [5]. Thus, hypertension and IGT are largely interdependent conditions, significantly affect health and often precede a more pronounced pathology-the metabolic syndrome. Timely diagnosis and correction of this combination can reduce disability and premature death, prolong and improve their quality of life, and maintain their efficiency.

EVALUATION OF THE OF INSULIN RESISTANCE EFFECTS ON OBESITY AND RELATED PARAMETERS

Obesity, especially abdominal obesity, is one of the most important underlying risk factors for metabolic syndrome and increases the risk of developing various pathological conditions like Type 2 Diabetes Mellitus, dyslipidemia, hypertension and Non Alcoholic Fatty Liver Disease. Insulin resistance means that the ability of insulin to stimulate glucose utilization is reduced, it is an integral feature of the metabolic syndrome and an important predictor of Type 2 Diabetes Mellitus development. It is well known that obesity is associated with diabetes mellitus, and the main basis of this link is thought to be the ability of obesity to stimulate insulin resistance. In this study, we aimed to evaluate the relationship between insulin resistance and obesity, related biochemical parameters, body analysis data. In this retrospective case control study, the insulin resistance status of 120 volunteers in Samsun Buyuk Anadolu Hospital's Nutrition and Diet Policlinic was determined by calculating the Homeostatic Model Assessment-Insulin Resistance formula. Biochemical values and body analysis results of individuals with and without insulin resistance were compared. Insulin resistance was detected in 56 (%46,7) of the subjects participating in the study. Insulin resistance was significantly related with weight, body mass index, body fat mass, abdominal fat mass (p 0,05). Fasting plasma glucose, HbA1c percentages, insulin, triglyceride and ALT levels were found to be higher in individuals with insulin resistance (p 0,05). In conclusion, considering the risks of diseases caused by insulin resistance, findings of this study emphasizes the importance of detecting insulin resistance. Determining the presence of insulin resistance can help prevent a variety of diseases by regulating nutrition. Detection of insulin resistance and regulation of nutrition can help prevent various diseases.

NOD1 Mediates Insulin Resistance in Response to Circulating Free Fatty Acids

Insulin resistance (IR) in type 2 diabetes (T2D) is associated with chronic low-grade inflammation. We have shown that nucleotide binding oligomerization domain (NOD)1, an intracellular pattern recognition receptor for bacterial wall peptidoglycans, is a factor linking the innate immune system to the development of high fat diet-induced IR. Although high fat diet may result in NOD1 activation via increased intestinal absorption of bacterial products, NOD1 has also been shown to be activated by saturated fatty acids in intestinal cells and adipocytes. We hypothesize that NOD1 plays a role in IR caused by chronic high levels of circulating free fatty acids (FFA) as found in obesity and T2D. Wild type (WT) and NOD1-/- mice were infused with ethylpalmitate (resulting in raised circulating palmitate) or ethanol vehicle as a control, for 48 hours to model prolonged elevation of circulating FFA in vivo. Hyperinsulinemic-euglycemic clamp with tracer methodology was then used to assess peripheral and hepatic insulin sensitivity. WT mice treated with ethylpalmitate had decreased peripheral and hepatic insulin sensitivity expressed as stimulation of glucose utilization (Control= 123%±30 and Ethylpalmitate= 25%±25, p<.05) and suppression of glucose production (Control= 51%±10 and Ethylpamitate= 22%±2, p<.05). NOD1-/- mice were protected from palmitate induced IR, showing no difference in stimulation of glucose utilization (Control= 289%±27 and Ethylpalmitate= 352%±64) and suppression of glucose production (Control= 63%±16 and Ethylpalmitate= 95%±25) with or without palmitate. Thus, our data provide compelling evidence that NOD1 activation via elevated plasma FFA contributes to the development of peripheral and hepatic IR. Disclosure S.L. Rivers: None. L. Yeung: None. K.L. Chan: None. Y. Mori: None. D. Philpott: None. A. Klip: None. A. Giacca: None.

Isoalantolactone derivative promotes glucose utilization in skeletal muscle cells and increases energy expenditure in db/db mice via activating AMPK-dependent signaling

Augmenting glucose utilization and energy expenditure in skeletal muscle via AMP-activated protein kinase (AMPK) is an imperative mechanism for the management of type 2 diabetes. Chemical derivatives (2a-2h, 3, 4a-4d, 5) of the isoalantolactone (K007), a bioactive molecule from roots of Inula racemosa were synthesized to optimize the bioactivity profile to stimulate glucose utilization in skeletal muscle cells. Interestingly, 4a augmented glucose uptake, driven by enhanced translocation of glucose transporter 4 (GLUT4) to cell periphery in L6 rat skeletal muscle cells. The effect of 4a was independent to phosphatidylinositide-3-kinase (PI-3-K)/Akt pathway, but mediated through Liver kinase B1 (LKB1)/AMPK-dependent signaling, leading to activation of downstream targets acetyl coenzyme A carboxylase (ACC) and sterol regulatory element binding protein 1c (SREBP-1c). In db/db mice, 4a administration decreased blood glucose level and improved body mass index, lipid parameters and glucose tolerance associated with elevation of GLUT4 expression in skeletal muscle. Moreover, 4a increased energy expenditure via activating substrate utilization and upregulated the expression of thermogenic transcription factors and mitochondrial proteins in skeletal muscle, suggesting the regulation of energy balance. These findings suggest the potential implication of isoalantolactone derivatives for the management of diabetes.

6-Paradol and 6-Shogaol, the Pungent Compounds of Ginger, Promote Glucose Utilization in Adipocytes and Myotubes, and 6-Paradol Reduces Blood Glucose in High-Fat Diet-Fed Mice.

The anti-diabetic activity of ginger powder (Zingiber officinale) has been recently promoted, with the recommendation to be included as one of the dietary supplements for diabetic patients. However, previous studies presented different results, which may be caused by degradation and metabolic changes of ginger components, gingerols, shogaols and paradols. Therefore, we prepared 10 ginger active components, namely 6-, 8-, 10-paradols, 6-, 8-, 10-shogaols, 6-, 8-, 10-gingerols and zingerone, and evaluated their anti-hyperglycemic activity. Among the tested compounds, 6-paradol and 6-shogaol showed potent activity in stimulating glucose utilization by 3T3-L1 adipocytes and C2C12 myotubes. The effects were attributed to the increase in 5′ adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in 3T3-L1 adipocytes. 6-Paradol, the major metabolite of 6-shogaol, was utilized in an in vivo assay and significantly reduced blood glucose, cholesterol and body weight in high-fat diet-fed mice.

Glial Excitatory Amino Acid Transporters and Glucose Incorporation.

Excitatory amino acid transporters (EAATs) expressed in astrocytes remove the glutamate released by neurons in and around the synaptic cleft. In this manner, astrocytes preserve the signaling functions mediated by glutamate on synapses and prevent excitotoxicity. Additionally, EAAT activation stimulates glucose utilization in astrocytes, linking neuronal activity with astrocyte metabolism. In this chapter, we briefly review the characteristics of the EAATs and the glucose transporters (GLUTs) expressed in the brain. Thereafter, we focus on the effect of EAATs activation and its association with glucose utilization in astrocytes, specifically addressing the role played by Na+ and Ca2+ ions. Next, we analyze evidence that proposes mechanisms by which the activity of GLUTs could be modulated after EAAT activation (e.g., kinases altering GLUTs traffic to cell membrane). Finally, we analyzed the current knowledge on EAAT function during energy deficiency as a possible inducer of GLUT expression to prevent neuronal damage.

Effect of Peripheral Electrical Stimulation (PES) on Nocturnal Blood Glucose in Type 2 Diabetes: A Randomized Crossover Pilot Study.

BackgroundRegulation of hepatic glucose production has been a target for antidiabetic drug development, due to its major contribution to glucose homeostasis. Previous pre-clinical study demonstrated that peripheral electrical stimulation (PES) may stimulate glucose utilization and improve hepatic insulin sensitivity. The aim of the present study was to evaluate safety, tolerability, and the glucose-lowering effect of this approach in patients with type 2 diabetes (T2DM).MethodsTwelve patients with T2DM were recruited for an open label, interventional, randomized trial. Eleven patients underwent, in a crossover design, an active, and a no-intervention control periods, separated with a two-week washout phase. During the active period, the patients received a daily lower extremity PES treatment (1.33Hz/16Hz burst mode), for 14 days. Study endpoints included changes in glucose levels, number of hypoglycemic episodes, and other potential side effects. Endpoints were analyzed based on continuous glucose meter readings, and laboratory evaluation.ResultsWe found that during the active period, the most significant effect was on nocturnal glucose control (P < 0.0004), as well as on pre-meal mean glucose levels (P < 0.02). The mean daily glucose levels were also decreased although it did not reach clinical significance (P = 0.07). A reduction in serum cortisol (P < 0.01) but not in insulin was also detected after 2 weeks of treatment. No adverse events were recorded.ConclusionsThese results indicate that repeated PES treatment, even for a very short duration, can improve blood glucose control, possibly by suppressing hepatic glucose production. This effect may be mediated via hypothalamic-pituitary-adrenal axis modulation.Trial registrationClinicalTrials.gov NCT02727790

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

The Wnt signaling pathway is critical for a number of functions in the central nervous system, including regulation of the synaptic cleft structure and neuroprotection against injury. Deregulation of Wnt signaling has been associated with several brain pathologies, including Alzheimer's disease. In recent years, it has been suggested that the Wnt pathway might act as a central integrator of metabolic signals from peripheral organs to the brain, which would represent a new role for Wnt signaling in cell metabolism. Energy metabolism is critical for normal neuronal function, which mainly depends on glucose utilization. Brain energy metabolism is important in almost all neurological disorders, to which a decrease in the capacity of the brain to utilize glucose has been linked. However, little is known about the relationship between Wnt signaling and neuronal glucose metabolism in the cellular context. In the present study, we found that acute treatment with the Wnt3a ligand induced a large increase in glucose uptake, without changes in the expression or localization of glucose transporter type 3. In addition, we observed that Wnt3a treatment increased the activation of the metabolic sensor Akt. Moreover, we observed an increase in the activity of hexokinase and in the glycolytic rate, and both processes were dependent on activation of the Akt pathway. Furthermore, we did not observe changes in the activity of glucose-6-phosphate dehydrogenase or in the pentose phosphate pathway. The effect of Wnt3a was independent of both the transcription of Wnt target genes and synaptic effects of Wnt3a. Together, our results suggest that Wnt signaling stimulates glucose utilization in cortical neurons through glycolysis to satisfy the high energy demand of these cells.

Apelin/APJ system as a therapeutic target in diabetes and its complications.

The G-protein-coupled receptor APJ and its endogenous ligand apelin are widely expressed in many peripheral tissues and central nervous system, including adipose tissue, skeletal muscles and hypothalamus. Apelin/APJ system, involved in numerous physiological functions like angiogenesis, fluid homeostasis and energy metabolism regulation, is notably implicated in the development of different pathologies such as diabetes and its complications. Increasing evidence suggests that apelin regulates insulin sensitivity, stimulates glucose utilization and enhances brown adipogenesis in different tissues associated with diabetes. Moreover, apelin is also involved in the regulation of diabetic complications via binding to APJ receptor. Apelin improves diabetes-induced kidney hypertrophia, normalizes obesity-associated cardiac hypertrophy and negatively promotes retinal angiogenesis in diabetic retinopathy. In this review, we provide a comprehensive overview about the role of apelin/APJ system in different tissues related with diabetes. Furthermore, we describe the pathogenesis of diabetic complications associated with apelin/APJ system. Finally, agonists and antagonists targeted to APJ receptor are described in the literature. Thus, we highlight apelin/APJ system as a novel therapeutic target for pharmacological intervention in treating diabetes and its complications.