scholarly journals Defective nitric oxide synthesis: a link between metabolic insulin resistance, sympathetic overactivity and cardiovascular morbidity

2000 ◽  
pp. 315-323 ◽  
Author(s):  
U Scherrer ◽  
C Sartori
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Epidemiological Studies ◽  
Cardiovascular Morbidity ◽  
Metabolic Effects ◽  
Nitric Oxide Synthesis ◽  
Insulin Resistant ◽  
The Past ◽  
Regulatory Systems ◽  
Underlying Mechanisms

Epidemiological studies demonstrate an association between insulin resistance, hypertension and cardiovascular morbidity. In addition to its metabolic effects, insulin also has important cardiovascular actions. The sympathetic nervous system and the nitric oxide-l-arginine pathway have emerged as central players in the mediation of these actions. Over the past decade, the underlying mechanisms and the factors that may govern the interaction between insulin and these two major cardiovascular regulatory systems have been studied extensively in healthy people and insulin-resistant individuals. Here we summarize the current understanding and gaps in knowledge on these interactions. We propose that a genetic and/or acquired defect of nitric oxide synthesis could represent a central defect triggering many of the metabolic, vascular and sympathetic abnormalities characteristic of insulin-resistant states, all of which may predispose to cardiovascular disease.

scholarly journals Exercise, heat shock proteins and insulin resistance

2017 ◽  
Vol 373 (1738) ◽  
pp. 20160529 ◽  
Author(s):  
Ashley E. Archer ◽  
Alex T. Von Schulze ◽  
Paige C. Geiger
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Metabolic Effects ◽  
Diabetic Patients ◽  
Alcoholic Fatty Liver ◽  
Insulin Resistant ◽  
Exercise Induced ◽  
Shock Proteins

Best known as chaperones, heat shock proteins (HSPs) also have roles in cell signalling and regulation of metabolism. Rodent studies demonstrate that heat treatment, transgenic overexpression and pharmacological induction of HSP72 prevent high-fat diet-induced glucose intolerance and skeletal muscle insulin resistance. Overexpression of skeletal muscle HSP72 in mice has been shown to increase endurance running capacity nearly twofold and increase mitochondrial content by 50%. A positive correlation between HSP72 mRNA expression and mitochondrial enzyme activity has been observed in human skeletal muscle, and HSP72 expression is markedly decreased in skeletal muscle of insulin resistant and type 2 diabetic patients. In addition, decreased levels of HSP72 correlate with insulin resistance and non-alcoholic fatty liver disease progression in livers from obese patients. These data suggest the targeted induction of HSPs could be a therapeutic approach for preventing metabolic disease by maintaining the body's natural stress response. Exercise elicits a number of metabolic adaptations and is a powerful tool in the prevention and treatment of insulin resistance. Exercise training is also a stimulus for increased HSP expression. Although the underlying mechanism(s) for exercise-induced HSP expression are currently unknown, the HSP response may be critical for the beneficial metabolic effects of exercise. Exercise-induced extracellular HSP release may also contribute to metabolic homeostasis by actively restoring HSP72 content in insulin resistant tissues containing low endogenous levels of HSPs. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.

Hemodynamic actions of insulin

1994 ◽  
Vol 267 (2) ◽  
pp. E187-E202 ◽  
Author(s):  
A. D. Baron
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Pressor Response ◽  
Physiological Role ◽  
Oxide System ◽  
Maximal Response ◽  
Insulin Resistant ◽  
The Right

There is accumulating evidence that insulin has a physiological role to vasodilate skeletal muscle vasculature in humans. This effect occurs in a dose-dependent fashion within a half-maximal response of approximately 40 microU/ml. This vasodilating action is impaired in states of insulin resistance such as obesity, non-insulin-dependent diabetes, and elevated blood pressure. The precise physiological role of insulin-mediated vasodilation is not known. Data indicate that the degree of skeletal muscle perfusion can be an important determinant of insulin-mediated glucose uptake. Therefore, it is possible that insulin-mediated vasodilation is an integral aspect of insulin's overall action to stimulate glucose uptake; thus defective vasodilation could potentially contribute to insulin resistance. In addition, insulin-mediated vasodilation may play a role in the regulation of vascular tone. Data are provided to indicate that the pressor response to systemic norepinephrine infusions is increased in obese insulin-resistant subjects. Moreover, the normal effect of insulin to shift the norepinephrine pressor dose-response curve to the right is impaired in these patients. Therefore, impaired insulin-mediated vasodilation could further contribute to the increased prevalence of hypertension observed in states of insulin resistance. Finally, data are presented to indicate that, via a yet unknown interaction with the endothelium, insulin is able to increase nitric oxide synthesis and release and through this mechanism vasodilate. It is interesting to speculate that states of insulin resistance might also be associated with a defect in insulin's action to modulate the nitric oxide system.(ABSTRACT TRUNCATED AT 250 WORDS)

Pioglitazone and exenatide enhance cognition and downregulate hippocampal beta amyloid oligomer and microglia expression in insulin-resistant rats

2016 ◽  
Vol 94 (8) ◽  
pp. 819-828 ◽  
Author(s):  
Enas S. Gad ◽  
Sawsan A. Zaitone ◽  
Yasser M. Moustafa
Keyword(s):  
Insulin Resistance ◽  
Learning And Memory ◽  
Insulin Signaling ◽  
Beta Amyloid ◽  
Male Rats ◽  
Insulin Resistant ◽  
Ppar Γ ◽  
Glucagon Like Peptide 1 ◽  
Underlying Mechanisms ◽  
Amyloid Oligomer

Insulin resistance is known to be a risk factor for cognitive impairment, most likely linked to insulin signaling, microglia overactivation, and beta amyloid (Aβ) deposition in the brain. Exenatide, a long lasting glucagon-like peptide-1 (GLP-1) analogue, enhances insulin signaling and shows neuroprotective properties. Pioglitazone, a peroxisome proliferated-activated receptor-γ (PPAR-γ) agonist, was previously reported to enhance cognition through its effect on Aβ accumulation and clearance. In the present study, insulin resistance was induced in male rats by drinking fructose for 12 weeks. The effect of monotherapy with pioglitazone (10 mg·kg−1) and exenatide or their combination on memory dysfunction was determined and some of the probable underlying mechanisms were studied. The current results confirmed that (1) feeding male rats with fructose syrup for 12 weeks resulted in a decline of learning and memory registered in eight-arm radial maze test; (2) treatment with pioglitazone or exenatide enhanced cognition, reduced hippocampal neurodegeneration, and reduced hippocampal microglia expression and beta amyloid oligomer deposition in a manner that is equal to monotherapies. These results may give promise for the use of pioglitazone or exenatide for ameliorating the learning and memory deficits associated with insulin resistance in clinical setting.

scholarly journals Melatonin Improves Glucose Homeostasis and Endothelial Vascular Function in High-Fat Diet-Fed Insulin-Resistant Mice

Endocrinology ◽  
2009 ◽  
Vol 150 (12) ◽  
pp. 5311-5317 ◽  
Author(s):  
Claudio Sartori ◽  
Pierre Dessen ◽  
Caroline Mathieu ◽  
Anita Monney ◽  
Jonathan Bloch ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Signal Transduction ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
High Fat Diet ◽  
High Fat ◽  
Insulin Resistant ◽  
Normal Chow ◽  
Underlying Mechanisms

Abstract Obesity and insulin resistance represent a problem of utmost clinical significance worldwide. Insulin-resistant states are characterized by the inability of insulin to induce proper signal transduction leading to defective glucose uptake in skeletal muscle tissue and impaired insulin-induced vasodilation. In various pathophysiological models, melatonin interacts with crucial molecules of the insulin signaling pathway, but its effects on glucose homeostasis are not known. In a diet-induced mouse model of insulin resistance and normal chow-fed control mice, we sought to assess the effects of an 8-wk oral treatment with melatonin on insulin and glucose tolerance and to understand underlying mechanisms. In high-fat diet-fed mice, but not in normal chow-fed control mice, melatonin significantly improved insulin sensitivity and glucose tolerance, as evidenced by a higher rate of glucose infusion to maintain euglycemia during hyperinsulinemic clamp studies and an attenuated hyperglycemic response to an ip glucose challenge. Regarding underlying mechanisms, we found that melatonin restored insulin-induced vasodilation to skeletal muscle, a major site of glucose utilization. This was due, at least in part, to the improvement of insulin signal transduction in the vasculature, as evidenced by increased insulin-induced phosphorylation of Akt and endoethelial nitric oxide synthase in aortas harvested from melatonin-treated high-fat diet-fed mice. In contrast, melatonin had no effect on the ability of insulin to promote glucose uptake in skeletal muscle tissue in vitro. These data demonstrate for the first time that in a diet-induced rodent model of insulin resistance, melatonin improves glucose homeostasis by restoring the vascular action of insulin.

Metabolic responses of horses and ponies to high and low glycaemic feeds: implications for laminitis

2013 ◽  
Vol 53 (11) ◽  
pp. 1182 ◽  
Author(s):  
S. R. Bailey ◽  
N. J. Bamford
Keyword(s):  
Insulin Resistance ◽  
Peak Plasma ◽  
Glycaemic Index ◽  
Dietary Factors ◽  
Metabolic Effects ◽  
Painful Condition ◽  
Insulin Resistant ◽  
Breed Type ◽  
Glycaemic Load ◽  
Equine Metabolic Syndrome

Equine laminitis is the painful condition resulting from disruption of the laminar bonds within the foot. Understanding the dietary triggers may facilitate strategies to prevent laminitis in susceptible animals. The purpose of this review is to examine how dietary factors may lead to insulin resistance and/or excessive insulin production from the pancreas, and why certain breeds or types of horses are more predisposed to this form of laminitis than others. Understanding these relationships will be very important when considering appropriate feeds and the dietary countermeasures necessary for preventing this condition. It is important to note the breed type when considering the likely metabolic effects of dietary carbohydrate, because there are major differences between the Thoroughbred/Standardbred type and some other breeds of horses and ponies. Ponies and certain breeds of horses produce excessive amounts of insulin in response to dietary carbohydrates and this may lead to the development of the three main features of the equine metabolic syndrome, namely obesity, insulin resistance and laminitis. Relative glycaemic index or glycaemic load may be useful in predicting peak plasma insulin (with due consideration for breed type), but carbohydrates such as starch and fructans may have particularly marked effects on insulin sensitivity. Although it is normal for ponies and certain horse breeds to be relatively insulin resistant, it may be possible to reduce the likelihood of exacerbating insulin resistance in obese animals with careful dietary modification. This may help to some extent in reducing hyperinsulinaemia and thereby reducing the risk of laminitis.

scholarly journals Inducible Nitric Oxide Synthase Deficiency in Myeloid Cells Does Not Prevent Diet-Induced Insulin Resistance

2010 ◽  
Vol 24 (7) ◽  
pp. 1413-1422 ◽  
Author(s):  
Min Lu ◽  
PingPing Li ◽  
Jan Pferdekamper ◽  
WuQiang Fan ◽  
Maziyar Saberi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Myeloid Cells ◽  
Mixed Effect ◽  
Insulin Resistant ◽  
Oxide Synthase ◽  
Inos Inhibition ◽  
Inducible Nitric Oxide

Abstract Recent findings denote an important contribution of macrophage inflammatory pathways in causing obesity-related insulin resistance. Inducible nitric oxide synthase (iNOS) is activated in proinflammatory macrophages and modestly elevated in insulin-responsive tissues. Although the benefits of systemic iNOS inhibition in insulin-resistant models have been demonstrated, the role of macrophage iNOS in metabolic disorders is not clear. In the current work, we used bone marrow transplantation (BMT) to generate mice with myeloid iNOS deficiency [iNOS BMT knockout (KO)]. Interestingly, disruption of iNOS in myeloid cells did not protect mice from high-fat diet-induced obesity and insulin resistance. When mice were treated with the iNOS inhibitor, N6-(1-Iminoethyl)-L-lysine hydrochloride (L-NIL), we observed a significant and comparable improvement of glucose homeostasis and insulin sensitivity in both wild-type and iNOS BMT KO mice. We further demonstrated that absence of iNOS in primary macrophages did not affect acute TLR4 signaling pathways and had only a modest and mixed effect on inflammatory gene expression. With respect to TNFα treatment, iNOS KO macrophages showed, if anything, a greater inflammatory response. In summary, we conclude that iNOS inhibition in tissues other than myeloid cells is responsible for the beneficial effects in obesity/insulin resistance.

scholarly journals Differential vulnerability of skeletal muscle feed arteries to dysfunction in insulin resistance: impact of fiber type and daily activity

2011 ◽  
Vol 300 (4) ◽  
pp. H1434-H1441 ◽  
Author(s):  
Shawn B. Bender ◽  
Sean C. Newcomer ◽  
M. Harold Laughlin
Keyword(s):  
Physical Activity ◽  
Nitric Oxide ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Sodium Nitroprusside ◽  
Fiber Type ◽  
Vascular Dysfunction ◽  
Insulin Resistant ◽  
Long Evans ◽  
Feed Arteries

Functional and structural heterogeneity exists among skeletal muscle vascular beds related, in part, to muscle fiber type composition. This study was designed to delineate whether the vulnerability to vascular dysfunction in insulin resistance is uniformly distributed among skeletal muscle vasculatures and whether physical activity modifies this vulnerability. Obese, hyperphagic Otsuka Long-Evans Tokushima fatty rats (20 wk old) were sedentary (OSED) or physically active (OPA; access to running wheels) and compared with age-matched sedentary Long-Evans Tokushima Otsuka (LSED) rats. Vascular responses were determined in isolated, pressurized feed arteries from fast-twitch gastrocnemius (GFAs) and slow-twitch soleus (SFAs) muscles. OSED animals were obese, insulin resistant, and hypertriglyceridemic, traits absent in LSED and OPA rats. GFAs from OSED animals exhibited depressed dilation to ACh, but not sodium nitroprusside, and enhanced vasoconstriction to endothelin-1 (ET-1), but not phenylephrine, compared with those in LSED. Immunoblot analysis suggests reduced endothelial nitric oxide synthase phosphorylation at Ser1177 and endothelin subtype A receptor expression in OSED GFAs. Physical activity prevented reduced nitric oxide-dependent dilation to ACh, but not enhanced ET-1 vasoconstriction, in GFA from OPA animals. Conversely, vasoreactivity of SFAs to ACh and ET-1 were principally similar in all groups, whereas dilation to sodium nitroprusside was enhanced in OSED and OPA rats. These data demonstrate, for the first time, that SFAs from insulin-resistant rats exhibit reduced vulnerability to dysfunction versus GFAs and that physical activity largely prevents GFA dysfunction. We conclude that these results demonstrate that vascular dysfunction associated with insulin resistance is heterogeneously distributed across skeletal muscle vasculatures related, in part, to muscle fiber type and activity level.

Modulation of vasomotion in resistance arteries of JCR:LA-cp rats: a model of insulin resistance

1999 ◽  
Vol 77 (1) ◽  
pp. 71-74 ◽  
Author(s):  
Sheila F O'Brien ◽  
James C Russell ◽  
Sandra T Davidge
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Mesenteric Arteries ◽  
Resistance Arteries ◽  
Nitric Oxide Synthase Inhibitor ◽  
Insulin Resistant ◽  
Increased Risk ◽  
Prostaglandin H ◽  
Synthase Inhibitor ◽  
Oxide Synthase

Obesity and insulin resistance are strongly associated with an increased risk of vascular disease. Vasomotion is the cyclic variation in the diameter of arteries and is a general feature of the vasculature that may have important physiological consequences. We tested the hypothesis that obesity - insulin resistance is associated with abnormal vasomotion by comparing obese, insulin-resistant JCR:LA-cp rats, known to develop vasculopathy, atherosclerosis, and ischemic lesions of the heart, with lean insulin-sensitive animals from the same strain. Vasomotion was assessed using isolated mesenteric arteries on a myograph system after preconstriction to 50% of maximal constriction with norepinephrine. The amplitude of vasomotion was enhanced by the presence of meclofenamate, a prostaglandin H synthase inhibitor, and was diminished by NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. Removal of the endothelium essentially abolished vasomotion, and meclofenamate had no effect on de-endothelialized arteries. Frequency was not altered by either L-NAME or meclofenamate. Although pharmacological inhibition of nitric oxide and eicosanoid production clearly altered vasomotion, there was no difference in the amplitude or frequency of vasomotion in arteries from obese rats compared with lean rats. These results indicate that the endothelium plays a central role in modulating vasomotion, involving both enhancing and inhibiting effects, and that vasomotion is similar between obese, insulin-resistant and lean, insulin-sensitive rats.Key words: insulin resistance, vasomotion, resistance arteries, JCR:LA-cp rats.

Sign in / Sign up

Export Citation Format

Share Document