“Heart failure, whole-body insulin resistance and myocardial insulin resistance: An intriguing puzzle”

Excerpt

Type 2 diabetes mellitus (DM) is not only a causative factor of heart failure (HF),1 but the co-existence of DM in HF patients is also responsible for more severe prognosis.2 DM cause functional, metabolic, and structural alterations that ultimately generate myocardial damage and HF progression. In particular, abnormalities in contractile proteins and impaired relaxation,3 change in substrate utilization,4 cellular injury,5 microvascular dysfunction,6,7 neurohormonal, and sympathetic nervous systems activation8,9 are main features that accompany DM in HF (Figure 1). As recently reported,10 these alterations can be recognized not only in DM, but also in patients with insulin resistance (IR). IR is highly prevalent (up to 60%) in patients affected by HF,11 and a complex pathophysiological interaction exists between these two conditions, since IR may represent, at the same time, cause and consequence of HF. In HF patients, not only the presence of established DM but also presence of minimal glycemic profile alteration, such as those recognized in prediabetic and newly diagnosed DM patients, can induce more aggressive form of HF.12 Perturbation in myocardial metabolism and energetics in patients with IR is one of underlying mechanisms likely involved. Although whole-body IR is a central feature of prediabetes and DM, the insulin sensitivity of the heart in patients with DM is subject of debate. Some studies using positron emission tomography (PET) with F-fluorodeoxyglucose (FDG) reported reduced myocardial glucose uptake (MGU) during hyperinsulinemia in patients with DM;13,14 however, other evidences documented absence of myocardial IR in patients with DM.15 In this issue of Journal of Nuclear Cardiology, Nielsen et al16 reported the results of their study looking at the relationship between abnormal response to oral glucose tolerance test (OGTT) that is a reliable method to test patients with possible DM,17 and MGU, assessed by FDG-PET in HF patients without overt DM. The study is a substudy of the clinical, randomised LIVE study,18 enrolling HF patients with reduced left ventricular ejection fraction, initiated to elucidate the effect of a glucagon-like peptide 1 analog (liraglutide) on left ventricular function. It involved 35 patients that underwent OGTT, insulin sensitivity, free fatty acid estimation, echocardiographic measurement, 18F-FDG/15O-H2O PET/CT scan. For each patient, they measured global and regional MGU, myocardial blood flow (MBF) at rest and during adenosine-induced hyperemia, and global myocardial flow reserve (MFR), as the ratio between adenosine-induced hyperaemia MBF and resting MBF. Myocardial segments were defined based on a combination of WMS and FDG-PET examinations and grouped into those who had preserved function (Wall Motion Score (WMS = 2)) and were dysfunctional viable (WMS < 2, normal FDG uptake) and dysfunctional nonviable (WMS < 2, low FDG uptake). From methodological point of view, differently from other studies exploring the role of whole-body glucose metabolism alterations on myocardial IR, authors use OGTT to stimulate MGU. During OGTT values of glycaemia and insulinemia are not stable, differently from those obtainable with hyperisulinemic-euglycemic clamp technique; however, insulin levels achieved are more physiological and, likely, more representative of a daily postprandial condition.19

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