Cardiomyopathy in Type 2 Diabetes

Abstract

Type 2 diabetes mellitus (DM) is associated with increased risk for developing heart failure (HF) and worse outcomes once HF is present. While the exact mechanisms underpinning these observations remain poorly understood, several metabolic perturbations associated with DM have been implicated as contributors to the HF risk, including alterations of cardiomyocyte metabolic substrate switching between free fatty acid (FFA) and glucose metabolism; increased FFA exposure and cellular accumulation; and alterations in peroxisome proliferator-activated receptor-(PPAR-)alpha activity, among others. The commonly coincident conditions of left ventricular hypertrophy and ischemic heart disease likely confound the metabolic derangements further increasing HF risk. Continued investigation into these mechanistic connections is necessary to better understand the pathophysiology and ideally inform the pursuit of novel therapeutic targets and strategies to intervene on the HF associated with DM.

Cardiovascular Risk in Diabetes Mellitus: Complication of the Disease or of Antihyperglycemic Medications

“…Common co-morbidities in patients with DM directly contribute to this association, such as prevalent ischemic heart disease and hypertension, with additional contribution to cardiac dysfunction underpinned by derangements of myocardial energy substrate metabolism. (49) The potential effects of anti-hyperglycemic medications on ventricular function and mass gained much attention after TZD-related increases in the risk for HF were observed in clinical trials. (4) The effects of troglitazone versus placebo on cardiac structure and function were assessed in a randomized trial of 48-weeks duration in patients with T2DM.…”

Heart Failure Considerations of Antihyperglycemic Medications for Type 2 Diabetes

“…2,3 They constitute an ominous octet in the often unrecognized transformation of the heart in T2DM from ailing to failing ( Figure 1). Observations on HF risks of antihyperglycemic therapies in patients with T2DM derive from many cohort studies and randomized clinical trials (RCTs) and highlight the importance of HF in the context of T2DM, as well as the effects of various antihyperglycemic medications on HF risk.…”

Diabetic cardiomyopathy: signaling defects and therapeutic approaches

“…FAs, endogenous ligands of PPAR-α, induce a positive feedback loop when present in high concentrations, in which the expression and activity of PPAR-α itself is upregulated. The result is a profound increase in both uptake and oxidation of FAs [15]. In addition, PGC-1α also fosters the expression of electron transport genes and promotes mitochondrial biogenesis to accommodate the oxidation of abundant FAs [16].…”

“…Interestingly, PPAR-α appears to be downregulated in late diabetes, after the cardiomyocyte has been exposed to high levels of circulating FAs for many years. Concomitantly, PPAR-β, an isoform most abundantly expressed in liver, is upregulated [15]. Although the downregulation of PPAR-α may be compensatory, the isoform switch to PPAR-β promotes lipogenesis, which some see as evidence of a ‘second hit’ leading to lipotoxicity [15].…”

“…Recent studies in humans and rodents have reported increased FA oxidation rates in the obese, the insulin resistant and those with T2DM [10,26]. However, as diabetes progresses, upregulation of oxidation fails to keep pace with the increase in uptake [15]. In addition, PPAR isoform switching from PPAR-α to PPAR-β leads to cardiac lipogenesis [27].…”