Number 25, 2004
Heart failure in diabetes

Metabolic imaging and diabetes

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Juhani Knuuti
Turku PET Centre, Turku University Central Hospital, Turku, Finland
Correspondence: Juhani Knuuti, Turku PET Centre, Turku University Central Hospital, P.O. Box 52 FI-20521, Turku, Finland.
Tel: +35823132842, fax: +35822318191, e-mail: juhani.knuuti@utu.fi

Introduction
It has long been known that patients with diabetes have myocardial dysfunction and heart failure not necessarily attributable to any known cardiac disease [1]. Abnormal intracellular calcium metabolism and coronary regulation, autonomic neuropathy, and defective glucose and fatty acid metabolism have been proposed to contribute to the pathogenic mechanism [2,3].
Diabetes is a major risk factor for atherosclerotic vascular disease and individuals with diabetes have a 2- to 4-fold increased risk of developing coronary artery disease [4]. Metabolic alterations may be involved in the pathogenesis of diabetic cardiomyopathy. Glucose is an important substrate for the myocardial cells, especially during ischemia, and preserved myocardial glucose uptake appears to be crucial to the viability of the jeopardized myocardium. This is supported also by the finding that, in high-risk patients, intense insulin therapy improves prognosis in those with type 2 (noninsulin-dependent) diabetes with acute myocardial infarction [5].
Metabolic imaging studies have been able to increase our knowledge of the physiology and pathophysiology of cardiac disease in diabetes. Until now, most studies have focused on the characterization of metabolic abnormalities in the diabetic heart.

Myocardial substrate metabolism
Free fatty acids (FFAs), glucose, and lactate are the main fuels of the heart [6]. Under normal resting conditions, metabolism is mainly oxidative, with FFA being the major source, whereas glycolysis contributes only about 30% of substrate to the tricarboxylic acid cycle.
Ischemia is associated with increased glycolysis, with glucose transporters translocated to the cell membrane. During states of mild ischemia, lactate continues to be removed from the myocardium by the residual blood flow, but accumulates in tissue when blood flow decreases further during more severe states of ischemia. Increased tissue concentrations of lactate and hydrogen ions impair glycolysis, leading to loss of transmembrane ion concentration gradients, disruption of cell membranes and, ultimately, to cell death [6].
As diabetes has significant effects on the concentrations of circulating substrate, it can be assumed that cardiac substrate metabolism is directly altered in diabetes (Table I). In addition to potential changes in glucose and FFA metabolism, there are changes in concentrations of lactate and ketone bodies, leading to their increased uptake in uncontrolled diabetes [6].

Table 1. Is diabetes associated with changes in myocardial substrate metabolism? Summary of myocardial energy metabolism in diabetes during different physiological and pathophysiological conditions.

Application of metabolic imaging
Noninvasive quantification of perfusion, oxygen consumption, glucose utilization, and fatty acid metabolism are possible using positron emission tomography (PET). The most commonly applied metabolic imaging has been measurement of glucose uptake using fluorine-18 ([¹⁸F])-labeled deoxyglucose [7]. Recently, the use of carbon-11 ([¹¹C])-labeled glucose has been reintroduced and has been shown to provide accurate quantification of glucose uptake [8].
Two PET tracers have been used to measure free fatty acid metabolism: [¹¹C]palmitic acid has been traditionally used, allowing both FFA uptake and oxidative metabolism to be quantified [6,7], and [¹⁸F]-6-thia-heptadecanoic acid has also been used recently to study fatty acid metabolism in humans [9]. The tracers [¹¹C]acetate and [¹⁵O]oxygen have been used to measure myocardial oxygen consumption with PET in humans [10]. Lactate also has been labeled with [¹¹C], and human studies have been successfully performed.
Myocardial scintigraphy using γ-emitting tracers has also been applied to the investigation of myocardial FFA metabolism. The limitation of this technique is that it does not allow absolute quantification of metabolic processes.

Cardiac metabolic imaging in diabetes
Most cardiac metabolic studies in diabetes have focused on the characterization of metabolic abnormalities in the diabetic heart [11–19]. It is well known that resistance to the action of insulin in peripheral tissues characterizes diabetic patients and, thus, an apparent question is whether similar insulin resistance exists in the diabetic heart.
In patients with type 1 (insulin-dependent) diabetes, two studies have reported preserved myocardial glucose uptake despite peripheral insulin resistance and reduced glucose uptake in skeletal muscle [11,12]. These studies were performed during euglycemia and controlled infusion of insulin.
In patients with type 2 diabetes, the results are more controversial. In some studies reduced myocardial glucose uptake was observed [13–15], whereas in others no such difference was found [16–19]. As several factors affect myocardial substrate metabolism, the metabolic imaging should be performed under standardized metabolic conditions. Most of those studies that were performed during euglycemic hyperinsulinemic clamps with comparable insulin, glucose and FFA concentrations revealed myocardial glucose uptakes that were similar in those with type 2 diabetes and in nondiabetic individuals. In the study by Utriainen et al [17], concentrations of insulin were used that were 5-fold greater than in the physiological range, but in the other studies insulin concentrations were within the physiological range. In patients with type 2 diabetes, other diseases such as coronary heart disease, renal disease, and obesity are common and may also confound the findings.
Serum FFA concentrations are usually increased in patients with type 2 diabetes, as a result of enhanced rates of lipolysis, impaired suppression of lipolysis by insulin, and defective clearance of FFA [20]. An attractive hypothesis has been that increased availability and oxidation of FFAs leads to impaired insulin-mediated glucose uptake and causes insulin resistance in type 2 diabetes. In one previous study, myocardial fatty acid uptake and indices of β-oxidation (measured with scintigraphy and iodine-123-labeled heptadecanoic acid) were reduced in individuals with impaired glucose tolerance.
A recent study applying a PET technique demonstrated that FFA uptake in the femoral muscle was decreased by about 25% in a glucose-intolerant group, whereas no differences were observed with respect to myocardial uptake of FFA [21] (Figure 1). Thus, in individuals with disturbed glucose tolerance, heart and skeletal muscle may differ with respect to substrate utilization. The findings of this study also argued against the hypothesis that excessive FFA utilization per se is the key explanation for impaired glucose utilization. This idea was also supported by another PET study using [¹¹C]palmitate, which demonstrated that, in the presence of comparable FFA concentrations, myocardial FFA uptake and oxidation are similar in diabetic and nondiabetic individuals [22].

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REFERENCES

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