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Mechanisms of metformin influence on the nitrogen oxide system investigation at experimental insulin resistance in rats

DOI:10.24959/ubphj.17.103
Authors:
Andriy Zagayko at National University of Pharmacy
Andriy Zagayko
Tetiana Briukhanova at Kharkiv National Medical University
Tetiana Briukhanova
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Abstract

Topicality. Cardiovascular complications are among the leading causes of death in the world. It is known that diseases associated with insulin resistance, are often accompanied by endothelial dysfunction and cardiovascular continuum. Aim. It is reasonable to investigate metformin mechanisms effect on the functional state of endothelium at experimental insulin resistance. Materials and methods. The syndrome of insulin resistance was designed on Wistar rats – males by mass of a 180-220 g and age 3 months in the beginning of experiment, by daily long period intraperitoneal Dexamethazonum injections in low doses (15 mg/kg) in low-calorie diet conditions (29 % fats – predominantly saturated lipids ), rich in fructose (1 g per day per 100 g of body weight) (water solution ) over 5 weeks. Results and discussion. The results indicate that in a model pathology group on 5 week of experiment, metformin significantly increases the total content of nitrates and nitrites and mediates a moderate, but significant increase in levels of citrulline, with a slight decrease in the arginine content. Conclusions. The article presents the biochemical results mechanisms of influence on the nitrogen oxide system by the oral hypoglycemic agent metformin experimental investigation at experimental insulin resistance in rats. This pattern of changes suggests a clinically significant influence of metformin on endothelium functional state that can be interpreted as a manifestation of endothelium protection properties.
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Ukraïns’kij bìofarmacevtičnij žurnal, No. 2 (49) 2017 ISSN 2311-715X (Print)ISSN 2519-8750 (Online)
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Національний фармацевтичний університет
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Ключові слова: інсулінорезистентність; метформін; ендотелій; Нітроген (ІІ) оксид
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
  
 
     

Key words: insulin resistance; metformin; endothelium; nitric oxide



 













Ключевые слова: инсулинорезистентность; метформин; эндотелий; оксид азота (II)
[24] Фармакологія, фармакоекономіка та біохімія
Український біофармацевтичний журнал, № 2 (49) 2017ISSN 2311-715X (Print) ISSN 2519-8750 (Online)
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






 


  
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

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 
 













   

  






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
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


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  






 


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 



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


  

   

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 
 



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
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
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
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

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
in vitro
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






a




 





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Ukraïns’kij bìofarmacevtičnij žurnal, No. 2 (49) 2017 ISSN 2311-715X (Print)ISSN 2519-8750 (Online)
  

 





 
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   


 








   
   
   
   





   


   
   
   


[26] Фармакологія, фармакоекономіка та біохімія
Український біофармацевтичний журнал, № 2 (49) 2017ISSN 2311-715X (Print) ISSN 2519-8750 (Online)











   

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

 Journal of Endo-
crinology, 220 (2), 
 
Reviews in Endocrine and Metabolic Disorders,
14 (1), 
      
Hypertension, 64 (6),
 
Nutrition, Metabolism and Cardiovascular Diseases, 20 (2),
     Cell Metabolism, 20 (6),

 
Journal of Clinical Investigation, 108 (8),
 Diabetologia, 56 (9),

 
Diabetes, 51 (8),
 Clini-
cal Science, 122 (6),
Ukrainskyi tsentr naukovoi medychnoi informatsii ta patentno–litsenziinoi roboty (Ukrmed-
patentinform), 86.

Diabetologia, 28 (7),
Spravochnik po klinicheskoi pharmatcii.
Biokhimicheskie analizy v klinike.



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Molecular mechanism of action of metformin: Old or new insights?
Article
Full-text available
Metformin is the first-line drug treatment for type 2 diabetes. Globally, over 100 million patients are prescribed this drug annually. Metformin was discovered before the era of target-based drug discovery and its molecular mechanism of action remains an area of vigorous diabetes research. An improvement in our understanding of metformin's molecular targets is likely to enable target-based identification of second-generation drugs with similar properties, a development that has been impossible up to now. The notion that 5' AMP-activated protein kinase (AMPK) mediates the anti-hyperglycaemic action of metformin has recently been challenged by genetic loss-of-function studies, thrusting the AMPK-independent effects of the drug into the spotlight for the first time in more than a decade. Key AMPK-independent effects of the drug include the mitochondrial actions that have been known for many years and which are still thought to be the primary site of action of metformin. Coupled with recent evidence of AMPK-independent effects on the counter-regulatory hormone glucagon, new paradigms of AMPK-independent drug action are beginning to take shape. In this review we summarise the recent research developments on the molecular action of metformin.
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Endothelial dysfunction in (pre)diabetes: Characteristics, causative mechanisms and pathogenic role in type 2 diabetes
Article
Full-text available
Endothelial dysfunction associated with diabetes and cardiovascular disease is characterized by changes in vasoregulation, enhanced generation of reactive oxygen intermediates, inflammatory activation, and altered barrier function. These endothelial alterations contribute to excess cardiovascular disease in diabetes, but may also play a role in the pathogenesis of diabetes, especially type 2. The mechanisms underlying endothelial dysfunction in diabetes differ between type 1 (T1D) and type 2 diabetes (T2D): hyperglycemia contributes to endothelial dysfunction in all individuals with diabetes, whereas the causative mechanisms in T2D also include impaired insulin signaling in endothelial cells, dyslipidemia and altered secretion of bioactive substances (adipokines) by adipose tissue. The close association of so-called perivascular adipose tissue with arteries and arterioles facilitates the exposure of vascular endothelium to adipokines, particularly if inflammation activates the adipose tissue. Glucose and adipokines activate specific intracellular signaling pathways in endothelium, which in concert result in endothelial dysfunction in diabetes. Here, we review the characteristics of endothelial dysfunction in diabetes, the causative mechanisms involved and the role of endothelial dysfunction(s) in the pathogenesis of T2D. Finally, we will discuss the therapeutic potential of endothelial dysfunction in T2D.
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Cellular and molecular mechanisms of metformin: An overview
Article
Full-text available
Considerable efforts have been made since the 1950s to better understand the cellular and molecular mechanisms of action of metformin, a potent antihyperglycaemic agent now recommended as the first-line oral therapy for T2D (Type 2 diabetes). The main effect of this drug from the biguanide family is to acutely decrease hepatic glucose production, mostly through a mild and transient inhibition of the mitochondrial respiratory chain complex I. In addition, the resulting decrease in hepatic energy status activates AMPK (AMP-activated protein kinase), a cellular metabolic sensor, providing a generally accepted mechanism for the action of metformin on hepatic gluconeogenesis. The demonstration that respiratory chain complex I, but not AMPK, is the primary target of metformin was recently strengthened by showing that the metabolic effect of the drug is preserved in liver-specific AMPK-deficient mice. Beyond its effect on glucose metabolism, metformin has been reported to restore ovarian function in PCOS (polycystic ovary syndrome), reduce fatty liver, and to lower microvascular and macrovascular complications associated with T2D. Its use has also recently been suggested as an adjuvant treatment for cancer or gestational diabetes and for the prevention in pre-diabetic populations. These emerging new therapeutic areas for metformin will be reviewed together with recent findings from pharmacogenetic studies linking genetic variations to drug response, a promising new step towards personalized medicine in the treatment of T2D.
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The Antidiabetic Drug Metformin Activates the AMP-Activated Protein Kinase Cascade via an Adenine Nucleotide-Independent Mechanism
Article
Full-text available
Metformin, a drug widely used to treat type 2 diabetes, was recently shown to activate the AMP-activated protein kinase (AMPK) in intact cells and in vivo. In this study we addressed the mechanism for this effect. In intact cells, metformin stimulated phosphorylation of the key regulatory site (Thr-172) on the catalytic (alpha) subunit of AMPK. It did not affect phosphorylation of this site by either of two upstream kinases in cell-free assays, although we were able to detect an increase in upstream kinase activity in extracts of metformin-treated cells. Metformin has been reported to be an inhibitor of complex 1 of the respiratory chain, but we present evidence that activation of AMPK in two different cell types is not a consequence of depletion of cellular energy charge via this mechanism. Whereas we have not established the definitive mechanism by which metformin activates AMPK, our results show that the mechanism is different from that of the existing AMPK-activating agent, 5-aminoimidazole-4-carboxamide (AICA) riboside. Metformin therefore represents a useful new tool to study the consequences of AMPK activation in intact cells and in vivo. Our results also show that AMPK can be activated by mechanisms other than changes in the cellular AMP-to-ATP ratio.
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Metformin: From Mechanisms of Action to Therapies
Article
Metformin is currently the first-line drug treatment for type 2 diabetes. Besides its glucose-lowering effect, there is interest in actions of the drug of potential relevance to cardiovascular diseases and cancer. However, the underlying mechanisms of action remain elusive. Convincing data place energy metabolism at the center of metformin's mechanism of action in diabetes and may also be of importance in cardiovascular diseases and cancer. Metformin-induced activation of the energy-sensor AMPK is well documented, but may not account for all actions of the drug. Here, we summarize current knowledge about the different AMPK-dependent and AMPK-independent mechanisms underlying metformin action. Copyright © 2014 Elsevier Inc. All rights reserved.
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Endothelial Dysfunction Potentially Interacts With Impaired Glucose Metabolism to Increase Cardiovascular Risk
Article
  • Sep 2014
See related article, pp 1299–1305 The term endothelial dysfunction generally refers to a maladapted endothelial phenotype characterized by reduced nitric oxide (NO) bioavailability, increased oxidative stress, elevated expression of proinflammatory and prothrombotic factors, and reduced endothelial-derived vasodilation.1 Hyperglycemia, insulin resistance, dyslipidemia, hyperuricemia, increased dietary fructose, and fat are conditions that predispose endothelial dysfunction, an early precursor to increased vascular and cardiac stiffness and atherosclerosis, all risk factors for hypertension, myocardial infarction, stroke, limb ischemia, and heart failure. Thus, endothelial dysfunction is an important risk factor for cardiovascular disease (CVD)–related morbidity and mortality.2 Recently, cross-sectional studies suggested that endothelial dysfunction also independently predicts the incidence of type 2 diabetes mellitus (T2D). For example, a prospective study of the children and spouses of children from the original Framingham Heart Study cohort found that high levels of endothelial cell (EC)–derived Willebrand factor increased the risk of developing T2D independent of other risk factors for diabetes mellitus, including obesity, abnormal glucose metabolism, and inflammation.3 Similarly, in a large, prospective, nested case–control study from an ethnically diverse cohort of US postmenopausal women (Women’s Health Initiative Observational Study), higher levels of circulating E-selectin and intercellular adhesion molecule-1 were consistently associated with increased risk of developing T2D.4 …
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Insulin signaling, resistance, and metabolic syndrome: Insights from mouse models into disease mechanisms
Article
Insulin resistance is a major underlying mechanism for the 'metabolic syndrome', which is also known as insulin resistance syndrome. Metabolic syndrome is increasing at an alarming rate, becoming a major public and clinical problem worldwide. Metabolic syndrome is represented by a group of interrelated disorders, including obesity, hyperglycemia, hyperlipidemia, and hypertension. It is also a significant risk factor for cardiovascular disease and increased morbidity and mortality. Animal studies demonstrate that insulin and its signaling cascade normally control cell growth, metabolism and survival through activation of mitogen-activated protein kinases (MAPKs) and phosphotidylinositide-3-kinase (PI3K), of which activation of PI-3K-associated with insulin receptor substrate-1 and -2 (IRS1, 2) and subsequent Akt→Foxo1 phosphorylation cascade has a central role in control of nutrient homeostasis and organ survival. Inactivation of Akt and activation of Foxo1, through suppression IRS1 and IRS2 in different organs following hyperinsulinemia, metabolic inflammation, and over nutrition may provide the underlying mechanisms for metabolic syndrome in humans. Targeting the IRS→Akt→Foxo1 signaling cascade will likely provide a strategy for therapeutic intervention in the treatment of type 2 diabetes and its complications. This review discusses the basis of insulin signaling, insulin resistance in different mouse models, and how a deficiency of insulin signaling components in different organs contributes to the feature of the metabolic syndrome. Emphasis will be placed on the role of IRS1, IRS2, and associated signaling pathways that couple to Akt and the forkhead/winged helix transcription factor Foxo1.
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Endothelial dysfunction in metabolic syndrome: Prevalence, pathogenesis and management
Article
  • Oct 2009
The metabolic syndrome (MetS) is characterized by the presence of central obesity, impaired glucose metabolism, dyslipidemia and hypertension. Several studies showed that MetS is associated with increased risk for type 2 diabetes mellitus (T2DM) and vascular events. All components of MetS have adverse effects on the endothelium. Endothelial dysfunction plays a role in the pathogenesis of atherosclerosis and might also increase the risk for insulin resistance and T2DM. We review the prevalence and pathogenesis of endothelial dysfunction in MetS. We also discuss the potential effects of lifestyle measures and pharmacological interventions on endothelial function in these patients. It remains to be established whether improving endothelial function in MetS will reduce the risk for T2DM and vascular events.
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Homeostatis model assessment - Insulin Resistance and Beta-Cell Function From Fasting Plasma-Glucose and insulin concentration in man
Article
  • Aug 1985
The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
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Homeostasis model assessment: insulin resistance and b–cell function from fasting plasma glucose and insulin concentrations in man
  • Jan 1985
  • 7-412
  • D Matthews
  • J Matthews
  • A Hosker
  • Rudenski
Matthews, D. Homeostasis model assessment: insulin resistance and b–cell function from fasting plasma glucose and insulin concentrations in man / D. Matthews, J. Hosker, A. Rudenski // Diabetol. – 1985. – Vol. 28, Issue 7. – С. 412–419. doi : 10.1007/bf00280883.