Modulation of the action of insulin by angiotensin-(1–7)

2014 ◽  
Vol 126 (9) ◽  
pp. 613-630 ◽  
Author(s):  
Fernando P. Dominici ◽  
Valeria Burghi ◽  
Marina C. Muñoz ◽  
Jorge F. Giani
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Molecular Mechanisms ◽  
Insulin Signalling ◽  
Pathological Condition ◽  
Signalling Pathway ◽  
Systemic Hypertension ◽  
The Metabolic Syndrome ◽  
Insulin Signalling Pathway ◽  
Cardiovascular Morbidity And Mortality

The prevalence of Type 2 diabetes mellitus is predicted to increase dramatically over the coming years and the clinical implications and healthcare costs from this disease are overwhelming. In many cases, this pathological condition is linked to a cluster of metabolic disorders, such as obesity, systemic hypertension and dyslipidaemia, defined as the metabolic syndrome. Insulin resistance has been proposed as the key mediator of all of these features and contributes to the associated high cardiovascular morbidity and mortality. Although the molecular mechanisms behind insulin resistance are not completely understood, a negative cross-talk between AngII (angiotensin II) and the insulin signalling pathway has been the focus of great interest in the last decade. Indeed, substantial evidence has shown that anti-hypertensive drugs that block the RAS (renin–angiotensin system) may also act to prevent diabetes. Despite its long history, new components within the RAS continue to be discovered. Among them, Ang-(1–7) [angiotensin-(1–7)] has gained special attention as a counter-regulatory hormone opposing many of the AngII-related deleterious effects. Specifically, we and others have demonstrated that Ang-(1–7) improves the action of insulin and opposes the negative effect that AngII exerts at this level. In the present review, we provide evidence showing that insulin and Ang-(1–7) share a common intracellular signalling pathway. We also address the molecular mechanisms behind the beneficial effects of Ang-(1–7) on AngII-mediated insulin resistance. Finally, we discuss potential therapeutic approaches leading to modulation of the ACE2 (angiotensin-converting enzyme 2)/Ang-(1–7)/Mas receptor axis as a very attractive strategy in the therapy of the metabolic syndrome and diabetes-associated diseases.

scholarly journals Mir-338-3p Mediates Tnf-A-Induced Hepatic Insulin Resistance by Targeting PP4r1 to Regulate PP4 Expression

2017 ◽  
Vol 41 (6) ◽  
pp. 2419-2431 ◽  
Author(s):  
Lin Dou ◽  
Shuyue Wang ◽  
Libo Sun ◽  
Xiuqing Huang ◽  
Yang Zhang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Phosphatase ◽  
Insulin Signalling ◽  
Critical Role ◽  
Transcriptional Regulator ◽  
Signalling Pathway ◽  
Hepatic Insulin Resistance ◽  
Luciferase Assay ◽  
Insulin Signalling Pathway ◽  
Tnf Α

Objective: Insulin resistance is a critical factor contributing to the pathogenesis of type 2 diabetes and other metabolic diseases. Recent studies have indicated that miR-338-3p plays an important role in cancer. Here, we investigated whether miR-338-3p mediates tumour necrosis factor-α (TNF-α)-induced hepatic insulin resistance. Methods: The activation of the insulin signalling pathway and the level of glycogenesis were examined in the livers of the db/db and high fat diet (HFD)-fed mice and in HEP1-6 cells transfected with miR-338-3p mimic or inhibitor. Computational prediction of microRNA target, luciferase assay and Western blot were used to assess the miR-338-3p target. Chromatin immunoprecipitation (ChIP) assay was used to determine the transcriptional regulator of miR-338-3p. Results: miR-338-3p was down-regulated in the livers of the db/db, HFD-fed and TNF-α-treated C57BL/6J mice, as well as in mouse HEP1-6 hepatocytes treated with TNF-α. Importantly the down-regulation of miR-338-3p induced insulin resistance, as indicated by impaired glucose tolerance and insulin tolerance. Further research showed that the down-regulated miR-338-3p resulted in the impaired AKT/ glycogen synthase kinase 3 beta (GSl·Gβ) signalling pathway and glycogen synthesis. In contrast, hepatic over-expression of miR-338-3p rescued the TNF-α-induced insulin resistance. Moreover, protein phosphatase 4 regulator subunit 1 (PP4R1) was identified as a direct target of miR-338-3p that mediated hepatic insulin signalling by regulating protein phosphatase 4 (PP4). Finally we identified hepatic nuclear factor 4 alpha (HNF-4α) as the transcriptional regulator of miRNA-338-3p. Conclusions: Our studies provide novel insight into the critical role and molecular mechanism by which miR-338-3p is involved in TNF-α-induced hepatic insulin resistance. miR-338-3p might mediate TNF-α-induced hepatic insulin resistance by targeting PP4R1 to regulate PP4 expression.

scholarly journals The Role of TGFβ Ligands and Signalling on Insulin Resistance in Skeletal Muscle in Women With PCOS

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A443-A444
Author(s):  
Alba Moreno-Asso ◽  
Luke C McIlvenna ◽  
Rhiannon K Patten ◽  
Andrew J McAinch ◽  
Raymond J Rodgers ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Insulin Signalling ◽  
Signalling Pathway ◽  
Whole Body ◽  
Insulin Signalling Pathway ◽  
Cultured Myotubes ◽  
Tgfβ Superfamily

Abstract Polycystic ovary syndrome (PCOS) is the most common female endocrinopathy affecting metabolic and reproductive health of 8–13% of reproductive-age women. Insulin resistance (IR) appears to underpin the pathophysiology of PCOS and is present in approximately 38–95% of women with PCOS. This underlying IR has been identified as unique from, but synergistic with, obesity-induced IR (1). Skeletal muscle accounts for up to 85% of whole-body insulin-stimulated glucose uptake; however, in PCOS this is reduced by about 27% when assessed by a euglycaemic-hyperinsulinaemic clamp (2). Interestingly, this reduced insulin-stimulated glucose uptake observed in skeletal muscle tissue is not retained in cultured myotubes (3), suggesting that in vivo environmental factors may play a role in this PCOS-specific IR. Yet, the molecular mechanisms regulating IR remain unclear (4). A potential environmental mechanism contributing to the development of peripheral IR may be the extracellular matrix remodelling and aberrant transforming growth factor beta (TGFβ) signalling. Previous work demonstrated that TGFβ superfamily ligands are involved in the increased collagen deposition and fibrotic tissue in the ovaries, and suggested that these ligands may be involved in the metabolic morbidity associated with PCOS (5). In this study, we investigated the effects of TGFβ1 (1, 5 ng/ml), and the Anti-Müllerian hormone (AMH; 5, 10, 30 ng/ml), a TGFβ superfamily ligand elevated in women with PCOS, as causal factors of IR in cultured myotubes from women with PCOS (n=5) and healthy controls (n=5). TGFβ1 did not have a significant effect on insulin signalling but induced expression of some ECM related genes and proteins, and increased glucose uptake via Smad2/3 signalling in myotubes from both groups. Conversely, AMH did not appear to activate the TGFβ/Smad signalling pathway and had no significant impact on insulin signalling or glucose uptake in any of the groups. In conclusion, these findings suggest that TGFβ1, but not AMH, may play a role in skeletal muscle ECM remodelling/fibrosis and glucose metabolism in PCOS but does not have a direct effect on insulin signalling pathway. Further research is required to elucidate its contribution to the development of in vivo skeletal muscle IR and broader impact in this syndrome. References: (1) Stepto et al., Hum Reprod 2013 Mar;28(3):777–784. (2) Cassar et al., Hum Reprod 2016 Nov;31(11):2619–2631. (3) Corbould et al., Am J Physiol-Endoc 2005 May;88(5):E1047-54. (4) Stepto et al., J Clin Endocrinol Metab, 2019 Nov 1;104(11):5372–5381. (5) Raja-Khan et al., Reprod Sci 2014 Jan;21(1):20–31.

The effect of aging on insulin signalling pathway is tissue dependent: Central role of adipose tissue in the insulin resistance of aging

2009 ◽  
Vol 130 (3) ◽  
pp. 189-197 ◽  
Author(s):  
Rosario Serrano ◽  
Margarita Villar ◽  
Nilda Gallardo ◽  
José M. Carrascosa ◽  
Carmen Martinez ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Signalling ◽  
Signalling Pathway ◽  
Insulin Signalling Pathway

scholarly journals Grape seed extract supplementation prevents high-fructose diet-induced insulin resistance in rats by improving insulin and adiponectin signalling pathways

2011 ◽  
Vol 106 (8) ◽  
pp. 1173-1181 ◽  
Author(s):  
Aramsri Meeprom ◽  
Weerachat Sompong ◽  
Wannaporn Suwannaphet ◽  
Sirintorn Yibchok-anun ◽  
Sirichai Adisakwattana
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Mrna Expression ◽  
Glycogen Synthase ◽  
Insulin Signalling ◽  
Grape Seed ◽  
Signalling Pathway ◽  
Signalling Pathways ◽  
High Fructose ◽  
Insulin Signalling Pathway

Recent evidence strongly supports the contention that grape seed extract (GSE) improves hyperglycaemia and hyperinsulinaemia in high-fructose-fed rats. To explore the underlying molecular mechanisms of action, we examined the effects of GSE on the expression of muscle proteins related to the insulin signalling pathway and of mRNA for genes involved in the adiponectin signalling pathway. Compared with rats fed on a normal diet, high-fructose-fed rats developed pathological changes, including insulin resistance, hyperinsulinaemia, hypertriacylglycerolaemia, a low level of plasma adiponectin and a high level of plasma fructosamine. These disorders were effectively attenuated in high-fructose-fed rats supplemented with GSE. A high-fructose diet causes insulin resistance by significantly reducing the protein expression of insulin receptor, insulin receptor substrate-1, Akt and GLUT4, and the mRNA expression of adiponectin, adiponectin receptor R1 (AdipoR1) and AMP-activated protein kinase (AMPK)-α in the skeletal muscle. Supplementation of GSE enhanced the expression of insulin signalling pathway-related proteins, including Akt and GLUT4. GSE also increased the mRNA expression of adiponectin, AdipoR1 and AMPK-α. In addition, GSE increased the mRNA levels of glycogen synthase and suppressed the mRNA expression of glycogen synthase kinase-3-α, causing an increase in glycogen accumulation in the skeletal muscle. These results suggest that GSE ameliorates the defective insulin and adiponectin signalling pathways in the skeletal muscle, resulting in improved insulin resistance in fructose-fed rats.

scholarly journals HYPERTENSION MANAGEMENT IN METABOLIC SYNDROME

2019 ◽  
Vol 9 (5) ◽  
pp. 327-347
Author(s):  
E. V. Reznik ◽  
I. G. Nikitin
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Metabolic Syndrome ◽  
Insulin Resistance Syndrome ◽  
Effective Control ◽  
Peripheral Tissues ◽  
The Metabolic Syndrome ◽  
Cardiovascular Morbidity And Mortality ◽  
Therapy Target ◽  
Based Medicine

Hypertension is one of the key risk factors for cardiovascular morbidity and mortality. Metabolic syndrome (synonyms: syndrome X, insulin resistance syndrome) is characterized by increased visceral fat mass, decreased sensitivity of peripheral tissues to insulin (insulin resistance) and hyperinsulinemia, which cause disorders of carbohydrate, lipid, and purine metabolism. Hypertension is an integral component of the metabolic syndrome. The severity of hypertension in patients with metabolic syndrome is higher in comparison with patients without metabolic disorders. In patients with metabolic syndrome, the probability of cardiac and brain damage increases fivefold, kidney damage threefold, and the vessels twofold. The presence of diabetes reduces the likelihood of achieving effective control of blood pressure by 1.4 times, hypercholesterolemia — by 1.5 times, obesity — by 1.7 times. In the presence of any three factors, the effectiveness of treatment is reduced twofold. In this article, approaches to the management of patients with hypertension and metabolic syndrome, aspects of non-drug therapy, target blood pressure levels, and the choice of drugs are presented in accordance with evidence-based medicine and current recommendations.

scholarly journals Gynura divaricata ameliorates hepatic insulin resistance by modulating insulin signalling, maintaining glycolipid homeostasis and reducing inflammation in type 2 diabetic mice

2019 ◽  
Vol 8 (6) ◽  
pp. 928-938 ◽  
Author(s):  
Xuan Dong ◽  
Shu-Xiang Zhao ◽  
Bing-Qing Xu ◽  
Yu-Qing Zhang
Keyword(s):  
Insulin Resistance ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Molecular Mechanisms ◽  
Insulin Signalling ◽  
Fasting Blood Glucose ◽  
Hepatic Insulin Resistance ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Insulin Signalling Pathway

Abstract Diabetes mellitus, one of the fastest growing epidemics worldwide, has become a serious health problem in modern society. Gynura divaricata (GD), an edible medicinal plant, has been shown to have hypoglycaemic effects. The molecular mechanisms by which GD improves hepatic insulin resistance (IR) in mice with type 2 diabetes (T2D) remain largely unknown. The aerial parts of GD were prepared in a lyophilized powder, which was added into the diet of T2D mice for 4 weeks. GD could result in an obvious decrease in fasting blood glucose and insulin levels in T2D mice. Meanwhile, the underlying mechanisms involved in the insulin-signalling pathway, glucose metabolism, lipid metabolism and inflammatory reaction in the liver tissue were also investigated by western blot, which indicated that GD further ameliorated hepatic IR by activating the PI3K/p-AKT pathway, decreasing the levels of hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase and increasing the levels of glucokinase and peroxisome proliferator-activated receptor-γ in the livers of T2D mice. GD has the potential to alleviate both hyperglycaemia and hepatic IR in T2D mice. Therefore, GD might be a promising functional food or medicine for T2D treatment.

Molecular mechanisms for myocardial mitochondrial dysfunction in the metabolic syndrome

2008 ◽  
Vol 114 (3) ◽  
pp. 195-210 ◽  
Author(s):  
Heiko Bugger ◽  
E. Dale Abel
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Coronary Artery Disease ◽  
Metabolic Syndrome ◽  
Molecular Mechanisms ◽  
Contractile Dysfunction ◽  
The Metabolic Syndrome ◽  
Artery Disease

The metabolic syndrome represents a cluster of abnormalities, including obesity, insulin resistance, dyslipidaemia and Type 2 diabetes, that increases the risk of developing cardiovascular diseases, such as coronary artery disease and heart failure. The heart failure risk is increased even after adjusting for coronary artery disease and hypertension, and evidence is emerging that changes in cardiac energy metabolism might contribute to the development of contractile dysfunction. Recent findings suggest that myocardial mitochondrial dysfunction may play an important role in the pathogenesis of cardiac contractile dysfunction in obesity, insulin resistance and Type 2 diabetes. This review will discuss potential molecular mechanisms for these mitochondrial abnormalities.

scholarly journals Natriuretic peptides and cardiovascular damage in the metabolic syndrome: molecular mechanisms and clinical implications

2009 ◽  
Vol 118 (4) ◽  
pp. 231-240 ◽  
Author(s):  
Carmine Savoia ◽  
Massimo Volpe ◽  
Alessandro Alonzo ◽  
Chiara Rossi ◽  
Speranza Rubattu
Keyword(s):  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Metabolic Syndrome ◽  
Natriuretic Peptide ◽  
Natriuretic Peptides ◽  
Molecular Mechanisms ◽  
Vascular Inflammation ◽  
Visceral Obesity ◽  
Blood Pressure Elevation ◽  
The Metabolic Syndrome

Natriuretic peptides are endogenous antagonists of vasoconstrictor and salt- and water-retaining systems in the body's defence against blood pressure elevation and plasma volume expansion, through direct vasodilator, diuretic and natriuretic properties. In addition, natriuretic peptides may play a role in the modulation of the molecular mechanisms involved in metabolic regulation and cardiovascular remodelling. The metabolic syndrome is characterized by visceral obesity, hyperlipidaemia, vascular inflammation and hypertension, which are linked by peripheral insulin resistance. Increased visceral adiposity may contribute to the reduction in the circulating levels of natriuretic peptides. The dysregulation of neurohormonal systems, including the renin–angiotensin and the natriuretic peptide systems, may in turn contribute to the development of insulin resistance in dysmetabolic patients. In obese subjects with the metabolic syndrome, reduced levels of natriuretic peptides may be involved in the development of hypertension, vascular inflammation and cardio vascular remodelling, and this may predispose to the development of cardiovascular disease. The present review summarizes the regulation and function of the natriuretic peptide system in obese patients with the metabolic syndrome and the involvement of altered bioactive levels of natriuretic peptides in the pathophysiology of cardiovascular disease in patients with metabolic abnormalities.

Sign in / Sign up

Export Citation Format

Share Document