Myocardial Insulin Resistance: An Overview of Its Causes, Effects, and Potential Therapy

Abstract: Insulin resistance ensues when normal physiological concentrations of insulin are unable to induce effective cellular insulin signalling and glucose uptake by insulin sensitive tissues. It is caused by several abnormalities that include; 1) an overabundance of circulating free fatty acids (and dyslipidaemia), 2) systemic inflammation caused by increased tissue and circulating pro-inflammatory cytokines, and, 3) over activation of the systemic and organ specific renin-angiotensin systems. Although usually associated with obesity, insulin resistance is not a condition that only afflicts obese individuals. Dyslipidaemia which is implicated in the aetiology of insulin resistance can be caused by adipose tissue expansion (obesity) or the increased consumption of lipogenic fructose which has profound effects on liver metabolism and serum lipid profiles. The primary reason fructose is implicated in insulin resistance is because it induces hepatic lipogenesis which would directly contribute to dyslipidaemia and increased lipid deposition in adipose tissue, muscle (heart and skeletal) and the liver. These changes in tissue lipid content and utilisation are thought to compromise tissue insulin signalling and induce insulin resistance. Myocardial insulin resistance not only influences myocardial metabolism and mechanical function in the normoxic heart but also compromises myocardial tolerance to ischaemia/reperfusion and post-ischaemic outcomes. Once insulin sensitive organs become insulin resistant, their substrate metabolism is altered and in the case of the heart, cardiac mechanical function is compromised which could potentially contribute to heart failure. Insulin resistance also decreases myocardial tolerance to ischaemia and reperfusion by compromising myocardial metabolism during ischaemic/reperfusion. Recently emerged evidence also suggests that insulin resistance reduces myocardial tolerance to ischaemia and reperfusion by altering the functionality of the intrinsic pro-survival Reperfusion Injury Salvage Kinase (RISK) pathways that protect against ischaemia/reperfusion injury. The authors and others have demonstrated strong links between reduced expression and activation (phosphorylation) of components of the RISK pathway and increased myocardial susceptibility to ischaemia/reperfusion injury. Lifestyle changes are known to improve insulin sensitivity while several pharmacological interventions using metabolic modulators and insulin sensitizer are currently being investigated and have shown promise in the treatment of animals and patients with myocardial insulin resistance. This review will identify and highlight some of the proposed causes of insulin resistance with particular reference to the role of dyslipidaemia, inflammation and the rennin-angiotensin system in the aetiology of this condition. We will also explore the possible effects of high dietary fructose consumption on circulating lipids and inflammation and the implications of these changes on skeletal and cardiac muscle insulin sensitivity. We will briefly reflect on the adverse effects of myocardial insulin resistance on myocardial metabolism and mechanical function and assess the effects of insulin resistance on myocardial tolerance to ischaemia and reperfusion. The proposed cellular causes of this decreased myocardial tolerance to ischaemia will be identified and current lifestyle and pharmacological interventions utilised to alleviate these adverse effects of insulin resistance will be reviewed. Keywords: Insulin resistance, Dyslipidaemia, Lipotoxicity, Adipocytokines, Renin-angiotensin system, Myocardial ischaemia/reperfusion.Griffith Health, School of Medical ScienceFull Tex

Impact of dietary-induced obesity on adrenergic-induced cardiomyocyte damage in rats

Although obesity is an independent risk factor for heart failure and even mild-to-moderate forms of obesity are associated with myocardial systolic dysfunction the mechanisms of the myocardial dysfunction have not been identifi ed. We assessed whether dietary-induced obesity is associated with an increased sensitivity of the myocardium to ß-adrenergic-induced cardiomyocyte apoptosis or fibrosis. To induce obesity, rats were fed a diet that promotes an increased caloric intake. Adrenergic-induced cardiomyocyte apoptosis was determined by injecting rats for 5 days with isoproterenol (0.01 mg/kg/day for 3 days and 0.02 mg/kg/day for 2 days) and then studying the degree of cardiomyocyte damage using a TUNEL assay and assessing the pathological score. Five months of feeding rats a diet that promoted the development of an increased body weight (Control=481±4.3 g, Diet=550±7.8 g, p‹0.001) and visceral fat content (Control=19.6±0.8 g, Diet=33.0±1.2 g, p‹0.0001), did not alter baseline cardiomyocyte apoptosis. However, 5 days of ß-adrenergic activation resulted in an enhanced cardiomyocyte apoptosis in rats receiving the experimental diet as compared to rats receiving a normal diet (p‹0.01). No changes in the myocardial pathological score (fibrosis) were noted. The enhanced adrenergic-induced cardiomyocyte apoptosis in obese rats could not be explained by dietary-induced increases in baseline left ventricular internal diameters, decreases in systolic function (endocardial or midwall fractional shortening) or differences in the response of the heart to adrenergic-induced increases in inotropic or chronotropic function. In conclusion, the present study suggests that obesity may contribute to myocardial dysfunction by increasing the sensitivity of the myocardium to adrenergic-induced cardiomyocyte damage

The effect of dietary red palm oil on the functional recovery of the ischaemic/reperfused isolated rat heart: the involvement of the PI3-Kinase signaling pathway

We have previously shown that dietary red palm oil (RPO) supplementation improves functional recovery in hearts subjected to ischaemia/reperfusion-induced injury. Unfortunately, the cellular and molecular mechanisms responsible for this phenomenon are still poorly understood and no knowledge exists regarding the effects of RPO supplementation on the phosphoinositide 3-kinase (PI3-K) signaling pathway and apoptosis during ischaemia/reperfusion injury. Therefore, the aims of the present study were three fold: (i) to establish the effect of RPO on the functional recovery of the heart after ischaemia/reperfuion injury; (ii) to determine the effect of the PI3-K pathway in RPO-induced protection with the aid of an inhibitor (wortmannin); and (iii) to evaluate apoptosis in our model. Wistar rats were fed a standard rat chow control diet or a control diet plus 7 g RPO/kg for six weeks. Hearts were excised and mounted on a Langendorff perfusion apparatus. Mechanical function was measured after a 25 min period of total global ischaemia followed by 30 minutes of reperfusion. Hearts subjected to the same conditions were freeze-clamped for biochemical analysis at 10 min during reperfusion to determine the involvement of the PI3-Kinase signaling pathway and apoptosis in our model. Dietary RPO supplementation significantly increased % rate pressure product recovery during reperfusion (71.0 ± 6.3% in control vs 92.36 ± 4.489% in RPO; p < 0.05). The % rate pressure product recovery was significantly reduced when wortmannin was added during perfusion (92.36 ± 4.489% in the RPO group vs 75.21 ± 5.26% in RPO + Wm). RPO + Wm also significantly attenuated PI3-K induction compared with the RPO group (59.2 ± 2.8 pixels in RPO vs 37.9 ± 3.4 pixels in RPO + Wm). We have also demonstrated that PI3-K inhibition induced PARP cleavage (marker of apoptosis) in the hearts during ischaemia/reperfusion injury and that RPO supplementation counteracted this effect

Creatine and exercise – strong evidence for stronger heart muscle

The original publication is available at http://www.asep.org/journals/JEPonlinePublication of this article was funded by the Stellenbosch University Open Access Fund.BibliographyThere has been a dramatic increase in the use of dietary creatine supplementation among sports men and women, and by clinicians as a therapeutic agent in muscular and neurological diseases. The effects on skeletal muscles have been documented and reviewed extensively. However, this review looks at another important muscle – the heart – and both the advantages and disadvantages to creatine supplementation, exercise, and the combination. The proposed mechanisms of each are examined and explained.Stellenbosch University Open Access FundPublishers' Versio

THE EFFECT OF LONG TERM SWIM TRAININ G ON PHYSIOLOGICA L STRESS LEVELS IN THE RAT

http://www.mtsaj.co.za/index.php/mtsaj/article/view/12post prin

Obesity improves myocardial ischaemic tolerance and RISK signalling in insulin-insensitive rats

SUMMARY Obesity with associated metabolic disturbances worsens ischaemic heart disease outcomes, and rodent studies confirm that obesity with insulin-resistance impairs myocardial resistance to ischemia-reperfusion (I-R) injury. However, the effects of obesity per se are unclear, with some evidence for paradoxic cardioprotection (particularly in older subjects). We tested the impact of dietary obesity on I-R tolerance and reperfusion injury salvage kinase (RISK) signalling in hearts from middle-aged (10 months old) insulin-insensitive rats. Hearts from Wistar rats on either a 32-week control (CD) or high carbohydrate obesogenic (OB) diet were assessed for I-R resistance in vivo (45 minutes left anterior descending artery occlusion and 120 minutes reperfusion) and ex vivo (25 minutes ischemia and 60 minutes reperfusion). Expression and δ-opioid receptor (δ-OR) phospho-regulation of pro-survival (Akt/PKB, Erk1/2, eNOS) and pro-injury (GSK3β) enzymes were also examined. OB rats were heavier (764±25 versus 657±22 g for CD; P<0.05), hyperleptinaemic (11.1±0.7 versus 5.0±0.7 for CD; P<0.01) and comparably insulin-insensitive (HOMA-IR of 63.2±3.3 versus 63.2±1.6 for CD). In vivo infarction was more than halved in OB (20±3%) versus CD rats (45±6% P<0.05), as was post-ischaemic lactate dehydrogenase efflux (0.4±0.3 mU/ml versus 5.6±0.5 mU/ml; P<0.02) and ex vivo contractile dysfunction (62±2% versus 44±6% recovery of ventricular force; P<0.05). OB hearts exhibited up to 60% higher Akt expression, with increased phosphorylation of eNOS (+100%), GSK3β (+45%) and Erk1/2 (+15%). Pre-ischaemic δ-OR agonism with BW373U86 improved recoveries in CD hearts in association with phosphorylation of Akt (+40%), eNOS (+75%) and GSK3β (+30%), yet failed to further enhance RISK-NOS activation or I-R outcomes in OB hearts. In summary, dietary obesity in the context of age-related insulin-insensitivity paradoxically improves myocardial I-R tolerance, in association with moderate hyperleptinaemic and enhanced RISK expression and phospho-regulation. However, OB hearts are resistant to further RISK modulation and cardioprotection via acute δ-OR agonism

Opioid receptors and cardioprotection - 'opioidergic conditioning' of the heart

Ischaemic heart disease (IHD) remains a major cause of morbidity/mortality globally, firmly established in Westernized or developed' countries and rising in prevalence in developing nations. Thus, cardioprotective therapies to limit myocardial damage with associated ischaemia-reperfusion (I-R), during infarction or surgical ischaemia, is a very important, although still elusive, clinical goal. The opioid receptor system, encompassing the (vas etocyclazocine) and (orphine) opioid receptors and their endogenous opioid ligands (endorphins, dynorphins, enkephalins), appears as a logical candidate for such exploitation. This regulatory system may orchestrate organism and organ responses to stress, induces mammalian hibernation and associated metabolic protection, triggers powerful adaptive stress resistance in response to ischaemia/hypoxia (preconditioning), and mediates cardiac benefit stemming from physical activity. In addition to direct myocardial actions, central opioid receptor signalling may also enhance the ability of the heart to withstand I-R injury. The - and -opioid receptors are strongly implicated in cardioprotection across models and species (including anti-infarct and anti-arrhythmic actions), with mixed evidence for opioid receptor-dependent protection in animal and human tissues. A small number of clinical trials have provided evidence of cardiac benefit from morphine or remifentanil in cardiopulmonary bypass or coronary angioplasty patients, although further trials of subtype-specific opioid receptor agonists are needed. The precise roles and utility of this GPCR family in healthy and diseased human myocardium, and in mediating central and peripheral survival responses, warrant further investigation, as do the putative negative influences of ageing, IHD co-morbidities, and relevant drugs on opioid receptor signalling and protective responses