In a 19th century poem by John Godfrey Saxe (1), a group of blind men touch an elephant to learn what it is like. Each one touches a different part, but only 1 part, obtaining varying views that depend on their perspectives, unable to conceive of the entirety. Although knowing that we are in the midst of an epidemic of glucose intolerance and diabetes that has developed as a consequence of excessive caloric intake and diminished activity, we remain unsure of its exact nature, defaulting to the analysis of its parts from various perspectives. What is not in dispute is its impact on ischemic heart disease and heart failure.

From one perspective, the epidemic is diabetes, where in the U.S. alone, more than 19 million people, or >9% of the population, are affected (2), carrying with them an average 2-fold independent increased risk of heart failure (3). Although, as physicians, we often prefer to examine risk factors as categorical phenomena, glycemia is a continuous variable like blood pressure and low-density lipoprotein cholesterol. For instance, we have known for some time that among those with diagnosed diabetes, long-term glycemic control correlates closely with heart failure risk so that, after adjusting for associated risk factors, a 1% increase in hemoglobin A1c is associated with a 16% increase in heart failure risk over a 10-year period (4). More recently, we have also come to appreciate that just being nondiabetic does not mean normoglycemia. The intermediate category, variably called dysglycemia or pre-diabetes, encompasses impaired fasting glucose and impaired glucose tolerance, and sometimes even includes those patients with a high-normal fasting plasma glucose. Such dysglycemic patients are at a higher risk of heart failure than their normoglycemic counterparts whose fasting plasma glucose is <5.0 mmol/l (5).

Furthermore, those who view our burgeoning waistlines as the primary problem will note that, among adult Americans, 66% are overweight or obese (32% obese) (6). Alterations in cardiac structure and function are being increasingly recognized, not only among the morbidly obese, but also in those with mild to moderate obesity, with clinical correlates that vary from asymptomatic left ventricular dysfunction to overt heart failure (7). Indeed, these findings have led to the proposal to recognize obesity cardiomyopathy as a diagnostic entity in obese individuals with heart failure where other etiologies such as coronary artery disease, diabetes, and hypertension are absent (7).

From another perspective, insulin resistance, manifested clinically as the variably defined metabolic syndrome, is the prime mover. Like dysglycemia and obesity, metabolic syndrome is highly prevalent, affecting 27% of the U.S. population (8). Complicating the relationship between heart failure and the metabolic syndrome is the finding that heart failure itself is also an insulin-resistant state (9). Two papers in this issue of the Journal ([10] and [11]) explore these complex inter-relationships further.

To examine the prevalence of insulin resistance among heart failure patients, AlZadjali et al. (10) studied 129 patients who had been diagnosed with stable symptomatic systolic heart failure, after excluding those with a previous diagnosis of diabetes or a fasting plasma glucose >7.0 mmol/l (126 mg/dl), the current threshold for the diagnosis of diabetes. Impaired glucose tolerance was not assessed during screening. Of the 525 patients approached to participate in the study, 281 (54%) were excluded because of a current diagnosis of diabetes, a prevalence that is much higher than the more customary 25% to 35% reported in most series (12). Among this study cohort recruited from inpatients, outpatient clinics, and community general practice, 61% were found to be insulin resistant, and this was associated with increased waist circumference and serum leptin. Insulin resistance was also independently associated with worsening New York Heart Association functional class, a decrease in peak oxygen consumption, decrease in exercise time, and endothelial dysfunction.

Adipose tissue, although initially regarded as a simple repository of stored energy, has come to be recognized as a complex organ system, consisting of a range of cell types that include not only adipocytes but also macrophages with which they share a common precursor. Although well known for its ability to extrude various lipid moieties, adipose tissue is also responsible for the secretion of an array of polypeptides that modulate inflammatory and metabolic pathways by both paracrine and endocrine mechanisms. Included among them are 4 principal adipokines: leptin and adiponectin, which augment insulin sensitivity, along with resistin and retinol-binding protein 4, which diminish it (13). Resistin is a 12.5-kDa cysteine-rich protein, named for its ability to induce insulin resistance in rodents. However, more recent studies in humans suggest that it may also have a prominent role in inflammation, providing a pathophysiological link between inflammation and insulin resistance (14). For instance, among its activities, resistin induces p38 mitogen-activated protein kinase, a stress-related signaling cascade that has been implicated in the development of heart failure following myocardial infarction (15). Consistent with this, a cross-sectional 126-patient study from Japan found that serum resistin was elevated in heart failure patients when compared with 18 control subjects and that it increased in association with higher New York Heart Association functional class (16).

The second paper reported in this issue by Frankel et al. (11) explores this new scientific front of the adipokines resistin and adiponectin, and the associated risk of developing heart failure. The paper is particularly instructive, as it is a prospective study from the Framingham Offspring Study in which 2,739 subjects without heart failure at baseline were followed for 6 years, during which time 58 participants (2%) developed new-onset heart failure. Dividing circulating resistin concentrations into tertiles and using a nested series of Cox proportional-hazards regression models, the investigators found a hazard ratio for developing heart failure of 2.89 for the middle tertile and 4.01 for the upper tertile relative to the lowest tertile. Moreover, this relationship persisted after accounting for coronary artery disease, body mass index, insulin resistance, C-reactive protein, and B-type natriuretic peptide.

Heart failure, like the elephant to a blind person, has many different ways in which it can be understood, depending on where you stand. Numerous drug and nondrug strategies have been developed over the last 20 years, based on the prevailing mechanistic understanding at the time. These advances have successfully improved patient outcomes. Nonetheless, quality and quantity of life remain poor for many patients. At the present time, we still have much to learn about the complex inter-relationships between dysglycemia, obesity, and insulin resistance. However, their impact on heart failure and the cardiovascular system is becoming clearer, with inflammation emerging as a possible unifying mechanism ([13] and [17]). Clinical management of diabetes, obesity, and heart failure each requires a multidisciplinary team approach. Ongoing interdisciplinary research will hopefully provide us with a better understanding of these emerging risk factors and potential therapeutic targets that will allow us to see the full and correct picture rather than just individual parts.

“And so these men of Indostan
Disputed loud and long,
Each in his own opinion
Exceeding stiff and strong,
Though each was partly in the right,
And all were in the wrong!”

John Godfrey Saxe (1816–1887) (1)

References

1 J.G. Saxe, The Blind Men and the Elephant, The Poems of John Godfrey Saxe (Complete Edition), James R. Osgood and Company, Boston, MA (1873), pp. 77–78.

2 C.C. Cowie, K.F. Rust and D.D. Byrd-Holt et al., Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population: National Health And Nutrition Examination Survey 1999–2002, Diabetes Care 29 (2006), pp. 1263–1268.

3 G.A. Nichols, T.A. Hillier, J.R. Erbey and J.B. Brown, Congestive heart failure in type 2 diabetes: prevalence, incidence, and risk factors, Diabetes Care 24 (2001), pp. 1614–1619.

4 I.M. Stratton, A.I. Adler and H.A. Neil et al., Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study, BMJ 321 (2000), pp. 405–412.

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8 E.S. Ford, W.H. Giles and A.H. Mokdad, Increasing prevalence of the metabolic syndrome among U.S. adults, Diabetes Care 27 (2004), pp. 2444–2449.

9 A.J. Coats and S.D. Anker, Insulin resistance in chronic heart failure, J Cardiovasc Pharmacol 35 (2000), pp. S9–S14.

10 M.A. ALZadjali, V. Godfrey and F. Khan et al., Insulin resistance is highly prevalent and is associated with reduced exercise tolerance in nondiabetic patients with heart failure, J Am Coll Cardiol 53 (2009), pp. 747–753.

11 D.S. Frankel, R.S. Vasan and R.B. D'Agostino et al., Resistin, adiponectin, and risk of heart failure: the Framingham Offspring study, J Am Coll Cardiol 53 (2009), pp. 754–762.

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13 S. Schenk, M. Saberi and J.M. Olefsky, Insulin sensitivity: modulation by nutrients and inflammation, J Clin Invest 118 (2008), pp. 2992–3002.

14 Y.H. Shen, L. Zhang and Y. Gan et al., Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) mediates p38 MAPK stress signal-induced inhibition of insulin signaling: A cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells, J Biol Chem 281 (2006), pp. 7727–7736.

15 F. See, W. Thomas and K. Way et al., p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat, J Am Coll Cardiol 44 (2004), pp. 1679–1689.

16 Y. Takeishi, T. Niizeki and T. Arimoto et al., Serum resistin is associated with high risk in patients with congestive heart failure—a novel link between metabolic signals and heart failure, Circ J 71 (2007), pp. 460–464.

17 A. Pradhan, Obesity, metabolic syndrome, and type 2 diabetes: inflammatory basis of glucose metabolic disorders, Nutr Rev 65 (2007), pp. S152–S156.