scholarly journals Metformin Targets Foxo1 to Control Glucose Homeostasis

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 873
Author(s):  
Xiaoqin Guo ◽  
Xiaopeng Li ◽  
Wanbao Yang ◽  
Wang Liao ◽  
James Zheng Shen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Blood Glucose ◽  
Signaling Pathway ◽  
Glucose Homeostasis ◽  
Molecular Mechanisms ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Suppressive Effect ◽  
Dependent Manner ◽  
Glucose Lowering Effect

Metformin is the first-line pharmacotherapy for type 2 diabetes mellitus (T2D). Metformin exerts its glucose-lowering effect primarily through decreasing hepatic glucose production (HGP). However, the precise molecular mechanisms of metformin remain unclear due to supra-pharmacological concentration of metformin used in the study. Here, we investigated the role of Foxo1 in metformin action in control of glucose homeostasis and its mechanism via the transcription factor Foxo1 in mice, as well as the clinical relevance with co-treatment of aspirin. We showed that metformin inhibits HGP and blood glucose in a Foxo1-dependent manner. Furthermore, we identified that metformin suppresses glucagon-induced HGP through inhibiting the PKA→Foxo1 signaling pathway. In both cells and mice, Foxo1-S273D or A mutation abolished the suppressive effect of metformin on glucagon or fasting-induced HGP. We further showed that metformin attenuates PKA activity, decreases Foxo1-S273 phosphorylation, and improves glucose homeostasis in diet-induced obese mice. We also provided evidence that salicylate suppresses HGP and blood glucose through the PKA→Foxo1 signaling pathway, but it has no further additive improvement with metformin in control of glucose homeostasis. Our study demonstrates that metformin inhibits HGP through PKA-regulated transcription factor Foxo1 and its S273 phosphorylation.

scholarly journals P0950EFFECT OF THYROID HORMONE TREATMENT ON RENAL REABSORPTION OF GLUCOSE IN ALLOXAN-INDUCED DIABETIC RATS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Gireesh Dayma
Keyword(s):  
Blood Glucose ◽  
Thyroid Hormone ◽  
Glucose Homeostasis ◽  
Hepatic Glucose Production ◽  
Liver Perfusion ◽  
Glucose Production ◽  
Diabetic Rats ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Renal Expression

Abstract Background and Aims The thyroid hormone (TH) plays an important role in glucose metabolism. Recently, we showed that the TH improves glycemia control by decreasing cytokines expression in the adipose tissue and skeletal muscle of alloxan-induced diabetic rats, which were also shown to present primary hypothyroidism. In this context, this study aims to investigate whether the chronic treatment of diabetic rats with T3 could affect other tissues that are involved in the control of glucose homeostasis, as the liver and kidney. Method Adult male Wistar rats were divided into nondiabetic, diabetic, and diabetic treated with T3 (1.5 ?g/100 g BW for 4 weeks). Diabetes was induced by alloxan monohydrate (150 mg/kg, BW, i.p.). Animals showing fasting blood glucose levels greater than 250 mg/dL were selected for the study. Results After treatment, we measured the blood glucose, serum T3, T4, TSH, and insulin concentration, hepatic glucose production by liver perfusion, liver PEPCK, GAPDH, and pAKT expression, as well as urine glucose concentration and renal expression of SGLT2 and GLUT2. T3 reduced blood glucose, hepatic glucose production, liver PEPCK, GAPDH, and pAKT content and the renal expression of SGLT2 and increased glycosuria. Conclusion Results suggest that the decreased hepatic glucose output and increased glucose excretion induced by T3 treatment are important mechanisms that contribute to reduce serum concentration of glucose, accounting for the improvement of glucose homeostasis control in diabetic rats.

scholarly journals Transcription Factor HMG Box-Containing Protein 1 (HBP1) Regulates Glycemic Homeostasis Through Modulation of Gluconeogenesis

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1247-1247
Author(s):  
Chin-Ming Chang ◽  
Chun-Yin Huang
Keyword(s):  
Transcription Factor ◽  
Blood Glucose ◽  
Glucose Homeostasis ◽  
Molecular Mechanisms ◽  
Ectopic Expression ◽  
Tolerance Test ◽  
Public Health Issue ◽  
Oral Glucose ◽  
Hmg Box ◽  
Blood Glucose Homeostasis

Abstract Objectives Glycemic dysregulation is one of the major metabolic disorders, which has long been a significant public health issue. The liver plays a pivotal role in the maintenance of blood glucose homeostasis. Previous studies indicate that upon refeeding a high carbohydrate diet, the expression of transcription factor HMG box-containing protein 1 (HBP1) was elevated in mice livers, suggesting a role of HBP1 in carbohydrate metabolism. Therefore, the objective of the current study was to understand the molecular mechanisms through which HBP1 regulates glucose generation in the liver. Methods Both in vivo HBP1 knockdown mice and in vitro HepG2 cell line were employed as the experimental models. Results First, we observed that overnight fasting led to increased PEPCK but decreased HBP1 expression in mice livers, and subsequent addition of insulin reversed the expression pattern. More importantly, HBP1 knockout (KO) mice displayed a significantly higher blood glucose level (173 mg/dL) than that of the controls (98 mg/dL). Also, HBP1 KO led to impaired OGTT (oral glucose tolerance test) and ITT (insulin tolerance test). These data suggest that HBP1 might have a role in the regulation of gluconeogenesis in the liver. To unveil the molecular mechanism by which HBP1 regulates glucose homeostasis, we examined its role in gluconeogenesis. Administration of gluconeogenic stimulators glucagon (100 nM) and cAMP (0.5 ng/mL) resulted in increased expression of Phosphoenolpyruvate carboxykinase (PEPCK; encoded by the PCK1 gene), a key enzyme in gluconeogenesis, but decreased HBP1 expression in HepG2 cells. Last, HBP1 siRNA-mediated mRNA disruption led to elevated PEPCK expression, whereas ectopic expression of HBP1 (pcDNA3-HBP1-Flag) significantly suppressed it. Conclusions In conclusion, our data indicate that HBP1 might negatively regulate glucose production and support HBP1 as a novel biological regulator of blood glucose homeostasis. Funding Sources This work was supported by the grant to MOST 108–2320-B-039–051-MY3 C-Y Huang.

scholarly journals Dietary supplementation of inulin alleviates metabolism disorders in gestational diabetes mellitus mice via RENT/AKT/IRS/GLUT4 pathway

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Miao Miao ◽  
Yongmei Dai ◽  
Can Rui ◽  
Yuru Fan ◽  
Xinyan Wang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Blood Glucose ◽  
Gestational Diabetes ◽  
Glucose Tolerance ◽  
Gestational Diabetes Mellitus ◽  
Glucose Homeostasis ◽  
Molecular Mechanisms ◽  
Fasting Blood Glucose ◽  
High Dose ◽  
Dependent Manner

Abstract Background Gestational diabetes mellitus (GDM) has significant short and long-term health consequences for both the mother and child. There is limited but suggestive evidence that inulin could improve glucose tolerance during pregnancy. This study assessed the effect of inulin on glucose homeostasis and elucidated the molecular mechanisms underlying the inulin-induced antidiabetic effects during pregnancy. Method Female C57BL/6 mice were randomized to receive either no treatment, high-dose inulin and low-dose inulin for 7 weeks with measurement of biochemical profiles. A real-time2 (RT2) profiler polymerase chain reaction (PCR) array involved in glycolipid metabolism was measured. Results Inulin treatment facilitated glucose homeostasis in a dose-dependent manner by decreasing fasting blood glucose, advanced glycation end products and total cholesterol, and improving glucose tolerance. Suppressing resistin (RETN) expression was observed in the inulin treatment group and the expression was significantly correlated with fasting blood glucose levels. The ratios of p-IRS to IRS and p-Akt to Akt in liver tissue and the ratio of p-Akt to Akt in adipose tissue as well as the expression level of GLUT4 increased significantly after inulin treatment. Conclusions Our findings indicated improvement of glucose and lipid metabolism by inulin was to activate glucose transport through the translocation of GLUT4 which was mediated by insulin signaling pathway repairment due to decreased expression of RETN and enhanced phosphorylation of IRS and Akt in GDM mice.

scholarly journals Phosphorylation of Forkhead Protein FoxO1 at S253 Regulates Glucose Homeostasis in Mice

Endocrinology ◽  
2019 ◽  
Vol 160 (5) ◽  
pp. 1333-1347 ◽  
Author(s):  
Kebin Zhang ◽  
Xiaoqin Guo ◽  
Hui Yan ◽  
Yuxin Wu ◽  
Quan Pan ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Glucose Homeostasis ◽  
Target Genes ◽  
Cell Function ◽  
Hepatic Glucose Production ◽  
Fasting Blood Glucose ◽  
Phosphorylation Site ◽  
Glucose Production ◽  
Β Cell Function

Abstract The transcription factor forkhead box O1 (FoxO1) is a key mediator in the insulin signaling pathway and controls multiple physiological functions, including hepatic glucose production (HGP) and pancreatic β-cell function. We previously demonstrated that S256 in human FOXO1 (FOXO1-S256), equivalent to S253 in mouse FoxO1 (FoxO1-S253), is a key phosphorylation site mediating the effect of insulin as a target of protein kinase B on suppression of FOXO1 activity and expression of target genes responsible for gluconeogenesis. Here, we investigated the role of FoxO1-S253 phosphorylation in control of glucose homeostasis in vivo by generating global FoxO1-S253A/A knockin mice, in which FoxO1-S253 alleles were replaced with alanine (A substitution) blocking FoxO1-S253 phosphorylation. FoxO1-S253A/A mice displayed mild increases in feeding blood glucose and insulin levels but decreases in fasting blood glucose and glucagon concentrations, as well as a reduction in the ratio of pancreatic α-cells/β-cells per islet. FoxO1-S253A/A mice exhibited a slight increase in energy expenditure but barely altered food intake and glucose uptake among tissues. Further analyses revealed that FoxO1-S253A/A enhances FoxO1 nuclear localization and promotes the effect of glucagon on HGP. We conclude that dephosphorylation of S253 in FoxO1 may reflect a molecular basis of pancreatic plasticity during the development of insulin resistance.

scholarly journals Glucagon regulates hepatic mitochondrial function and biogenesis through FOXO1

2019 ◽  
Vol 241 (3) ◽  
pp. 265-278
Author(s):  
Wanbao Yang ◽  
Hui Yan ◽  
Quan Pan ◽  
James Zheng Shen ◽  
Fenghua Zhou ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Mitochondrial Function ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Complex Iii ◽  
Dependent Manner ◽  
Hepatic Glucose ◽  
Patients With Diabetes ◽  
High Level

Glucagon promotes hepatic glucose production maintaining glucose homeostasis in the fasting state. Glucagon maintains at high level in both diabetic animals and human, contributing to hyperglycemia. Mitochondria, a major place for glucose oxidation, are dysfunctional in diabetic condition. However, whether hepatic mitochondrial function can be affected by glucagon remains unknown. Recently, we reported that FOXO1 is an important mediator in glucagon signaling in control of glucose homeostasis. In this study, we further assessed the role of FOXO1 in the action of glucagon in the regulation of hepatic mitochondrial function. We found that glucagon decreased the heme production in a FOXO1-dependent manner, suppressed heme-dependent complex III (UQCRC1) and complex IV (MT-CO1) and inhibited hepatic mitochondrial function. However, the suppression of mitochondrial function by glucagon was largely rescued by deleting the Foxo1 gene in hepatocytes. Glucagon tends to reduce hepatic mitochondrial biogenesis by attenuating the expression of NRF1, TFAM and MFN2, which is mediated by FOXO1. In db/db mice, we found that hepatic mitochondrial function was suppressed and expression levels of UQCRC1, MT-CO1, NRF1 and TFAM were downregulated in the liver. These findings suggest that hepatic mitochondrial function can be impaired when hyperglucagonemia occurs in the patients with diabetes mellitus, resulting in organ failure.

scholarly journals The CNS glucagon-like peptide-2 receptor in the control of energy balance and glucose homeostasis

2014 ◽  
Vol 307 (6) ◽  
pp. R585-R596 ◽  
Author(s):  
Xinfu Guan
Keyword(s):  
Energy Balance ◽  
Food Intake ◽  
Signaling Pathway ◽  
Glucose Homeostasis ◽  
Hepatic Glucose Production ◽  
Physiological Role ◽  
Glucose Production ◽  
Short Chain Fatty Acids ◽  
Hepatic Insulin Resistance ◽  
Membrane Excitability

The gut-brain axis plays a key role in the control of energy balance and glucose homeostasis. In response to luminal stimulation of macronutrients and microbiota-derived metabolites (secondary bile acids and short chain fatty acids), glucagon-like peptides (GLP-1 and -2) are cosecreted from endocrine L cells in the gut and coreleased from preproglucagonergic neurons in the brain stem. Glucagon-like peptides are proposed as key mediators for bariatric surgery-improved glycemic control and energy balance. Little is known about the GLP-2 receptor (Glp2r)-mediated physiological roles in the control of food intake and glucose homeostasis, yet Glp1r has been studied extensively. This review will highlight the physiological relevance of the central nervous system (CNS) Glp2r in the control of energy balance and glucose homeostasis and focuses on cellular mechanisms underlying the CNS Glp2r-mediated neural circuitry and intracellular PI3K signaling pathway. New evidence (obtained from Glp2r tissue-specific KO mice) indicates that the Glp2r in POMC neurons is essential for suppressing feeding behavior, gastrointestinal motility, and hepatic glucose production. Mice with Glp2r deletion selectively in POMC neurons exhibit hyperphagic behavior, accelerated gastric emptying, glucose intolerance, and hepatic insulin resistance. GLP-2 differentially modulates postsynaptic membrane excitability of hypothalamic POMC neurons in Glp2r- and PI3K-dependent manners. GLP-2 activates the PI3K-Akt-FoxO1 signaling pathway in POMC neurons by Glp2r-p85α interaction. Intracerebroventricular GLP-2 augments glucose tolerance, suppresses glucose production, and enhances insulin sensitivity, which require PI3K (p110α) activation in POMC neurons. Thus, the CNS Glp2r plays a physiological role in the control of food intake and glucose homeostasis. This review will also discuss key questions for future studies.

Insulin as a physiological modulator of glucagon secretion

2008 ◽  
Vol 295 (4) ◽  
pp. E751-E761 ◽  
Author(s):  
Pritpal Bansal ◽  
Qinghua Wang
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucagon Secretion ◽  
Suppressive Effect ◽  
Inhibitory Effect ◽  
Β Cells ◽  
Receptor System ◽  
Glucose Levels

Glucose homeostasis is regulated primarily by the opposing actions of insulin and glucagon, hormones that are secreted by pancreatic islets from β-cells and α-cells, respectively. Insulin secretion is increased in response to elevated blood glucose to maintain normoglycemia by stimulating glucose transport in muscle and adipocytes and reducing glucose production by inhibiting gluconeogenesis in the liver. Whereas glucagon secretion is suppressed by hyperglycemia, it is stimulated during hypoglycemia, promoting hepatic glucose production and ultimately raising blood glucose levels. Diabetic hyperglycemia occurs as the result of insufficient insulin secretion from the β-cells and/or lack of insulin action due to peripheral insulin resistance. Remarkably, excessive secretion of glucagon from the α-cells is also a major contributor to the development of diabetic hyperglycemia. Insulin is a physiological suppressor of glucagon secretion; however, at the cellular and molecular levels, how intraislet insulin exerts its suppressive effect on the α-cells is not very clear. Although the inhibitory effect of insulin on glucagon gene expression is an important means to regulate glucagon secretion, recent studies suggest that the underlying mechanisms of the intraislet insulin on suppression of glucagon secretion involve the modulation of KATP channel activity and the activation of the GABA-GABAA receptor system. Nevertheless, regulation of glucagon secretion is multifactorial and yet to be fully understood.

Pisosterol Induces G2/M Cell Cycle Arrest and Apoptosis via the ATM/ATR Signaling Pathway in Human Glioma Cells

2020 ◽  
Vol 20 (6) ◽  
pp. 734-750
Author(s):  
Wallax A.S. Ferreira ◽  
Rommel R. Burbano ◽  
Claudia do Ó. Pessoa ◽  
Maria L. Harada ◽  
Bárbara do Nascimento Borges ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Signaling Pathway ◽  
Glioma Cell ◽  
Molecular Mechanisms ◽  
Glioma Cells ◽  
Dependent Manner ◽  
M Cell ◽  
Trypan Blue Exclusion ◽  
Cycle Arrest

Background: Pisosterol, a triterpene derived from Pisolithus tinctorius, exhibits potential antitumor activity in various malignancies. However, the molecular mechanisms that mediate the pisosterol-specific effects on glioma cells remain unknown. Objective: This study aimed to evaluate the antitumoral effects of pisosterol on glioma cell lines. Methods: The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and trypan blue exclusion assays were used to evaluate the effect of pisosterol on cell proliferation and viability in glioma cells. The effect of pisosterol on the distribution of the cells in the cell cycle was performed by flow cytometry. The expression and methylation pattern of the promoter region of MYC, ATM, BCL2, BMI1, CASP3, CDK1, CDKN1A, CDKN2A, CDKN2B, CHEK1, MDM2, p14ARF and TP53 was analyzed by RT-qPCR, western blotting and bisulfite sequencing PCR (BSP-PCR). Results: Here, it has been reported that pisosterol markedly induced G2/M arrest and apoptosis and decreased the cell viability and proliferation potential of glioma cells in a dose-dependent manner by increasing the expression of ATM, CASP3, CDK1, CDKN1A, CDKN2A, CDKN2B, CHEK1, p14ARF and TP53 and decreasing the expression of MYC, BCL2, BMI1 and MDM2. Pisosterol also triggered both caspase-independent and caspase-dependent apoptotic pathways by regulating the expression of Bcl-2 and activating caspase-3 and p53. Conclusions: It has been, for the first time, confirmed that the ATM/ATR signaling pathway is a critical mechanism for G2/M arrest in pisosterol-induced glioma cell cycle arrest and suggests that this compound might be a promising anticancer candidate for further investigation.

scholarly journals The Hormetic Effect of Metformin: “Less Is More”?

2021 ◽  
Vol 22 (12) ◽  
pp. 6297
Author(s):  
Isabella Panfoli ◽  
Alessandra Puddu ◽  
Nadia Bertola ◽  
Silvia Ravera ◽  
Davide Maggi
Keyword(s):  
Complex I ◽  
Molecular Mechanisms ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Target Tissue ◽  
Atp Production ◽  
Less Is More ◽  
First Line Therapy ◽  
Hormetic Effect ◽  
Intracellular Content

Metformin (MTF) is the first-line therapy for type 2 diabetes (T2DM). The euglycemic effect of MTF is due to the inhibition of hepatic glucose production. Literature reports that the principal molecular mechanism of MTF is the activation of 5′-AMP-activated protein kinase (AMPK) due to the decrement of ATP intracellular content consequent to the inhibition of Complex I, although this effect is obtained only at millimolar concentrations. Conversely, micromolar MTF seems to activate the mitochondrial electron transport chain, increasing ATP production and limiting oxidative stress. This evidence sustains the idea that MTF exerts a hormetic effect based on its concentration in the target tissue. Therefore, in this review we describe the effects of MTF on T2DM on the principal target organs, such as liver, gut, adipose tissue, endothelium, heart, and skeletal muscle. In particular, data indicate that all organs, except the gut, accumulate MTF in the micromolar range when administered in therapeutic doses, unmasking molecular mechanisms that do not depend on Complex I inhibition.

TRAF6-mediated ubiquitination of APPL1 enhances hepatic actions of insulin by promoting the membrane translocation of Akt

2013 ◽  
Vol 455 (2) ◽  
pp. 207-216 ◽  
Author(s):  
Kenneth K. Y. Cheng ◽  
Karen S. L. Lam ◽  
Yu Wang ◽  
Donghai Wu ◽  
Mingliang Zhang ◽  
...  
Keyword(s):  
Hepatic Glucose Production ◽  
Adaptor Protein ◽  
Glucose Production ◽  
Membrane Localization ◽  
Dependent Manner ◽  
Membrane Translocation ◽  
Insulin Stimulation ◽  
Akt Activation ◽  
Hepatic Glucose ◽  
Impaired Insulin

The adaptor protein APPL1 undergoes ubiquitination upon insulin stimulation in a TRAF6-dependent manner. Abrogation of APPL1 ubiquitination blocks insulin-evoked membrane localization of the APPL1–Akt complex, leading to impaired insulin actions on Akt activation and suppression of hepatic glucose production.

Sign in / Sign up

Export Citation Format

Share Document