Elsevier

Journal of Cardiac Failure

Volume 16, Issue 9, September 2010, Pages 761-768
Journal of Cardiac Failure

Review Article
Impaired Glucose Tolerance and Insulin Resistance in Heart Failure: Underrecognized and Undertreated?

https://doi.org/10.1016/j.cardfail.2010.05.027Get rights and content

Abstract

Background

A link between diabetes mellitus (DM) and heart failure (HF) has been well-recognized for more than a century. HF is also closely linked to abnormal glucose regulation (AGR) and insulin resistance (IR) in patients without DM and, similarly, these conditions commonly coexist. In epidemiological studies, each condition appears to predict the other. The prevalence of AGR/IR in HF patients without DM is significantly underrecognized and, as yet, the optimal method for screening for these abnormalities in the outpatient setting is unclear.

Methods and Results

The purpose of this review is to overview the prevalence and prognostic impact of AGR and IR in HF patients without DM and discuss potential pathophysiological pathways that link these conditions with HF. The severity of glucose intolerance in patients with HF correlates with functional and clinical severity of HF and is an independent predictor of an adverse outcome. It is thought that changes in cardiac metabolism, including a switch from glucose metabolism toward fatty acid metabolism, may in part contribute to the pathophysiological processes associated with HF patients with AGR/IR.

Conclusions

We discuss how pharmacological targeting of metabolic pathways in the myocardium of these patients with HF may represent novel therapeutic strategies in these at-risk patients.

Section snippets

Abnormalities of Glucose Regulation in HF

Abnormalities in glucose regulation are commonly observed in nondiabetic patients with HF. In the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) Pilot Study,11 23% of nondiabetic patients had impaired fasting glucose (IFG), 11% had fasting glucose concentrations in the diabetic range, whereas 33% had IR as assessed by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Similarly, Witteles et al12 demonstrated that 48% of nondiabetic patients with

Severity of HF and Abnormalities in Glucose Regulation

Insulin resistance and abnormalities in glucose regulation appear to correlate with functional, clinical, and biochemical severity of heart failure in nondiabetic HF cohorts studied. Data from the RESOLVD study in patients without known DM have shown that NYHA Class III/IV patients compared with Class I/II patients were more likely to have IFG (32% versus 18%, P < .005), hyperinsulinemia (45% versus 28%, P < .005), or IR assessed by HOMA-IR (44% versus 28%, P < .005).11

In a prospective study of

Abnormalities of Glucose Regulation and Prognosis

Recent data suggest that IGT or IR in HF patients are independent predictors of adverse outcomes (Table 1). Data from 2412 CHARM study subjects showed that HbA1C was an independent predictor of CV death, hospitalization for worsening HF, and total mortality.24 Similarly, in the Reykjavik study, IGT was an independent predictor of all-cause mortality (OR 1.9; 95% CI 1.5–2.5) that was of similar magnitude to that associated with the presence of DM (OR 2.1; 95% CI 1.5–2.9).

In the study of Doehner

The Chicken or the Egg: Insulin Resistance or HF?

Epidemiological studies such as those presented here have the inherent limitation that the associations observed do not necessarily indicate causality. For example, it is unclear whether IR causes HF, whether HF causes IR, or whether HF is simply associated with IR through other variables. In reality, some combination of all 3 possibilities seems likely. Although the conclusions drawn from prospective studies may also be limited by residual confounding and reverse causation, there are some

Mechanisms

It is not clear what intrinsically ties systemic IR/glucose intolerance to HF so closely and how 1 condition may predispose to the other. Recently, it has been shown that adipose tissue is able to release a large number of cytokines and bioactive mediators that influence several aspects of the pathogenesis of insulin resistance and cardiovascular disease33; these mediators may provide the link between IR and HF. Furthermore, metabolic changes in cardiac muscle occurring as a consequence of IR

A Role for Resistin?

There is growing evidence that adipose tissue is a biologically active tissue that secretes a number of biologically active molecules including interferon-γ, interleukin-6, tumor necrosis factor, C-reactive protein, and adiponectin that have important roles in the development of a systemic inflammatory state, are able to influence insulin resistance and increase cardiovascular risk.33, 37, 38, 39 One such adipose tissue-derived mediator that may provide a link between HF development and IR is

Insulin Resistance, Myocardial Substrate Metabolism, and Cardiac Function

Insulin has an important role in regulating cardiac function through regulation of cardiac metabolism and integration of both glucose and fatty acid metabolism.34, 36, 49 Under physiological conditions, glucose is the main carbohydrate metabolized by the cardiac muscle. An overview of glucose metabolism is presented in Fig. 1. Glucose is transported into myocardial cells by 2 membrane transporter systems: a basal GLUT-1 transporter system and GLUT-4, which is the dominant glucose transport

Targeting Insulin Resistance/Cardiac Metabolism

It is clear that the presence of AGT and IR in nondiabetic patients is associated with an adverse prognosis. Furthermore, from the previous information presented here, changes in cardiac metabolism occurring as a consequence of IR may in part contribute to the pathophysiological processes that underlie IR and abnormal glucose regulation (AGR) in HF patients. Does targeting this insulin resistance or cardiac metabolism in patients with heart failure have the potential for improving outcomes in

Conclusion

HF is closely linked to AGR/IR. In clinical practice, these conditions commonly coexist and, in epidemiological studies, each condition appears to predict the other. The severity of glucose intolerance/IR in patients with HF correlates with severity of HF and is an independent predictor of an adverse outcome. Adipose tissue derived mediators such as resistin may contribute to IR and are independent predictors of incidents HF. Furthermore, changes in cardiac metabolism including a switch from

Acknowledgments

The authors acknowledge the support of the Biomedical Research Centre (BRC), Manchester Academy of Health Sciences (MAHSC), and the Collaboration for Leadership in Applied Health Research and Care for Greater Manchester (CLAHRC).

Disclosures

None.

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