Review ArticleImpaired Glucose Tolerance and Insulin Resistance in Heart Failure: Underrecognized and Undertreated?
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.
References (72)
- et al.
Role of diabetes in congestive heart failure: The Framingham study
Am J Cardiol
(1974) - et al.
Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE)
Am Heart J
(2005) - et al.
The effect of diabetes on outcomes of patients with advanced heart failure in the BEST trial
J Am Coll Cardiol
(2003) - et al.
Diabetes mellitus, a predictor of morbidity and mortality in the Studies of Left Ventricular Dysfunction (SOLVD) Trials and Registry
Am J Cardiol
(1996) - et al.
Insulin resistance in idiopathic dilated cardiomyopathy: a possible etiologic link
J Am Coll Cardiol
(2004) - et al.
Insulin resistance in chronic heart failure: relation to severity and etiology of heart failure
J Am Coll Cardiol
(1997) - et al.
Usefulness of preoperative oral glucose tolerance testing for perioperative risk stratification in patients scheduled for elective vascular surgery
Am J Cardiol
(2008) - et al.
The value of glycosylated haemoglobin as a substitute for the oral glucose tolerance test in the detection of impaired glucose tolerance (IGT)
Diabetes Res Clin Pract
(1992) - et al.
Impaired insulin sensitivity as an independent risk factor for mortality in patients with stable chronic heart failure
J Am Coll Cardiol
(2005) - et al.
Functional class in patients with heart failure is associated with the development of diabetes
Am J Med
(2003)
Insulin-resistant cardiomyopathy clinical evidence, mechanisms, and treatment options
J Am Coll Cardiol
Resistin, adiponectin, and risk of heart failure the Framingham offspring study
J Am Coll Cardiol
Role of resistin in cardiac contractility and hypertrophy
J Mol Cell Cardiol
Peroxisome proliferator-activated receptor alpha (PPARalpha) signaling in the gene regulatory control of energy metabolism in the normal and diseased heart
J Mol Cell Cardiol
Decreased myocardial free fatty acid uptake in patients with idiopathic dilated cardiomyopathy: evidence of relationship with insulin resistance and left ventricular dysfunction
J Card Fail.
Improvement of long-term preservation of the isolated arrested rat heart by trimetazidine: effects on the energy state and mitochondrial function
Am J Cardiol
A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure
J Am Coll Cardiol
Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure
J Card Fail
Asthma and diabetes mellitus
Zeutschr Klin Med
The association between glucose abnormalities and heart failure in the population-based Reykjavik study
Diabetes Care
Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey1988-1994
Diabetes Care
EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population
Eur Heart J
Diabetes, left ventricular systolic dysfunction, and chronic heart failure
Eur Heart J
Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme
Eur Heart J
Glucose and insulin abnormalities relate to functional capacity in patients with congestive heart failure
Eur Heart J
Elevated glycated haemoglobin is a strong predictor of mortality in patients with left ventricular systolic dysfunction who are not receiving treatment for diabetes mellitus
Heart
Nature and prognostic importance of abnormal glucose tolerance and diabetes in acute heart failure
Heart
High prevalence of undiagnosed impaired glucose regulation and diabetes mellitus in patients scheduled for an elective coronary angiography
Clin Res Cardiol
Is admission hyperglycemia in non-diabetic patients with acute myocardial infarction a surrogate for previously undiagnosed abnormal glucose tolerance?
Eur Heart J
The glucose tolerance test, but not HbA(1c), remains the gold standard in identifying unrecognized diabetes mellitus and impaired glucose tolerance in hypertensive subjects
Angiology
Fasting plasma glucose and glycated haemoglobin in the screening of diabetes and impaired glucose tolerance
Acta Diabetol
B-type natriuretic peptide levels and insulin resistance in patients with severe ischemic myocardial dysfunction
J Endocrinol Invest
The hemoglobin A1c level as a progressive risk factor for cardiovascular death, hospitalization for heart failure, or death in patients with chronic heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program
Arch Intern Med
Elevated admission glucose and mortality in elderly patients hospitalized with heart failure
Circulation
Abnormal glucose regulation in patients with acute ST-elevation myocardial infarction—a cohort study on 224 patients
Cardiovasc Diabetol
Insulin resistance and risk of congestive heart failure
JAMA
Cited by (37)
Friedreich's Ataxia related Diabetes: Epidemiology and management practices
2022, Diabetes Research and Clinical PracticeCitation Excerpt :In adults without FRDA, DM is a risk factor for non-ischemic cardiomyopathy and heart failure [23]. In adults without FRDA, impaired glucose tolerance is prevalent in heart failure and correlates with heart failure severity [24]. Finally, the chronic stress of cardiomyopathy could contribute to abnormal glucose metabolism.
Insulin Resistance and Risk for Incident Heart Failure<sup>*</sup>
2013, JACC: Heart FailureImpact of the renin-angiotensin system on cardiac energy metabolism in heart failure
2013, Journal of Molecular and Cellular CardiologyInsulin Resistance Is Associated With Heart Failure With Recovered Ejection Fraction in Patients Without Diabetes
2022, Journal of the American Heart AssociationSystems Pharmacology-Based Strategy to Investigate Pharmacological Mechanisms of Total Flavonoids in Dracocephalum moldavica on Chronic Heart Failure
2022, International Journal of Molecular Sciences
See page 766 for disclosure information.