Myocyte membrane and microdomain modifications in diabetes: determinants of ischemic tolerance and cardioprotection

Abstract

Cardiovascular disease, predominantly ischemic heart disease (IHD), is the leading cause of death in diabetes mellitus (DM). In addition to eliciting cardiomyopathy, DM induces a ‘wicked triumvirate’: (i) increasing the risk and incidence of IHD and myocardial ischemia; (ii) decreasing myocardial tolerance to ischemia–reperfusion (I–R) injury; and (iii) inhibiting or eliminating responses to cardioprotective stimuli. Changes in ischemic tolerance and cardioprotective signaling may contribute to substantially higher mortality and morbidity following ischemic insult in DM patients. Among the diverse mechanisms implicated in diabetic impairment of ischemic tolerance and cardioprotection, changes in sarcolemmal makeup may play an overarching role and are considered in detail in the current review. Observations predominantly in animal models reveal DM-dependent changes in membrane lipid composition (cholesterol and triglyceride accumulation, fatty acid saturation vs. reduced desaturation, phospholipid remodeling) that contribute to modulation of caveolar domains, gap junctions and T-tubules. These modifications influence sarcolemmal biophysical properties, receptor and phospholipid signaling, ion channel and transporter functions, contributing to contractile and electrophysiological dysfunction, cardiomyopathy, ischemic intolerance and suppression of protective signaling. A better understanding of these sarcolemmal abnormalities in types I and II DM (T1DM, T2DM) can inform approaches to limiting cardiomyopathy, associated IHD and their consequences. Key knowledge gaps include details of sarcolemmal changes in models of T2DM, temporal patterns of lipid, microdomain and T-tubule changes during disease development, and the precise impacts of these diverse sarcolemmal modifications. Importantly, exercise, dietary, pharmacological and gene approaches have potential for improving sarcolemmal makeup, and thus myocyte function and stress-resistance in this ubiquitous metabolic disorder.

Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity

“…Various mechanisms underlying the detrimental influence of hyperglycemia under diabetic and/or insulin-resistant conditions on the myocardial function, structure, and energy metabolism have been intensively investigated [34][35][36][37]. One key point to note in the present isolated heart perfusion study is that the detrimental effects of HFD on these parameters became evident after ischemia-reperfusion, not being noted at baseline before ischemia.…”

“…Furthermore, we obtained the new finding that the GLUT4 upregulation in response to IRI insult was significantly attenuated in HFD mice, in association with the decreased myocardial glucose uptake after IRI. The impaired GLUT4 expression and translocation in diabetic subjects may involve not only disturbance of insulin signaling but also increased membrane cholesterol, reductions in membrane fluidity, and disruption of caveolae and caveolin-3 [34]. These findings may, at least in part, account for the impaired cardiac functional recovery and increased myocardial injury after ischemiareperfusion in HFD hearts.…”

Impact of intravenous exenatide infusion for perioperative blood glucose control on myocardial ischemia-reperfusion injuries after coronary artery bypass graft surgery: sub study of the phase II/III ExSTRESS randomized trial

“…Combining the GLP-1 agonist liraglutide and insulin did not appear to provide any additional effect compared to liraglutide or insulin alone in type 2 diabetes mellitus [ 41 ]. Moreover, a low overall baseline insulin resistance in non-diabetic patients in one hand, and desensitized cardioprotective pathways related to altered sarcolemma function of cardiomyocytes in long-standing diabetes mellitus in the other hand, could contribute to an impaired response to exenatide in the present study [ 42 , 43 ]. Furthermore, early and prolonged exenatide administration, and the use of a long-acting GLP-1 agonist, such as liraglutide, could provide a higher cardioprotective effect, as reported by Chen et al [ 44 ] in myocardial infarction.…”

Isopulegol Ameliorates Dyslipidemia by Modulating Adipokine Secretion in High Fat Diet / Streptozotocin Induced Diabetic Rats

“…PLs are susceptible substrates for oxygen and hydroxyl free radicals generated in diabetic state. In DM, chronic hyperglycemia alters fatty acids, lipids and decreases the activities of membrane-bound enzymes [24].We observed an increase in cholesterol, phospholipids and HMG CoA reductase activity in plasma and liver tissue of diabetic rats.…”