CORRESPONDENCE: LETTER TO THE EDITOR
Caloric Restriction Models Reverse Metabolic Syndrome
Lionel H. Opie, MD, DPhil, FRCP, FACC*
* Director, Hatter Cardiovascular Research Institute, Department of Medicine, University of Cape Town Faculty of Health Sciences, Observatory 7925, South Africa (Email: Lionel.opie{at}uct.ac.za).
The major metabolic effects of substantial weight loss in obese patients with type 2 diabetes mellitus (1) provide a novel insight into the mechanisms postulated to underlie the metabolic syndrome. The diagnosis of metabolic syndrome requires the presence of 3 of 5 characteristics: increased abdominal waist, hyperglycemia, high blood triglycerides, high blood pressure, and low high-density lipoprotein (HDL) cholesterol. To tie these apparently disparate manifestations together, an interesting hypothesis is that the crucial initial event is the increased concentrations of circulating free fatty acids (FFAs) and cytokines derived from the excess visceral abdominal fat (2). Although there are well-established links whereby increased circulating FFAs decrease the uptake of glucose by heart (3) and skeletal muscle (4), it has been much more difficult to link chronically increased circulating FFAs to increased blood triglycerides and decreased HDL cholesterol in humans.
The data of Hammer et al. (1) lead to the novel concept of the "reverse metabolic syndrome," which can link excess circulating FFAs to the other metabolic changes in humans. Substantial weight loss in obese patients with type 2 diabetes led to decreased waist measurement (Fig. 1 of Hammer et al. [1]), decreased circulating concentrations of glucose and triglycerides (and, hence, by inference, increased HDL cholesterol), and decreased concentrations of the adverse cytokine, leptin. Another example of reversed metabolic syndrome is the acute inhibition of lipolysis by acipimox, which abruptly reduced circulating FFAs in obese patients with type 2 diabetes, with rapid falls in plasma glucose and insulin, and decreases in muscle content of long-chain fatty acid (as derivatives) (5). Furthermore, Hammer et al. (1) showed that as plasma FFAs decrease, so do myocardial triglycerides. Conversely, chronically increased circulating FFAs, when taken up by the heart, form excess myocardial triglycerides (6), the basis of the diastolic dysfunction that can extend to lipotoxic cardiomyopathy, described in humans by Taegtmeyer's group (6,7). These novel concepts add a potentially new dimension to the adverse effects of excessively high blood FFAs in metabolic syndrome.
Overall, the study by Hammer et al. (1) shows that unloading the human body of adipose tissue induces a "reverse metabolic syndrome." This study provides additional data to support the concept that excess circulating FFA, as associated with abdominal visceral obesity, is fundamental in the genesis of an increasingly common human disease, namely, metabolic syndrome.
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1. Hammer S, Snel M, Lamb HJ, et al. Prolonged caloric restriction in obese patients with type 2 diabetes mellitus decreases myocardial triglyceride content and improves myocardial function J Am Coll Cardiol 2008;52:1006-1012.[Abstract/Free Full Text]2. Opie LH. Metabolic syndrome Circulation 2007;115:e32-e35.[Free Full Text] 3. Shipp J, Opie LH, Challoner DR. Fatty acid and glucose metabolism in the perfused heart Nature 1961;189:1018-1019.[CrossRef][Web of Science] 4. Randle PJ, Garland PB, Hales CN, et al. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963;1:785-789.[Web of Science][Medline] 5. Bajaj M, Suraamornkul S, Romanelli A, et al. Effect of a sustained reduction in plasma free fatty acid concentration on intramuscular long-chain fatty Acyl-CoAs and insulin action in type 2 diabetic patients Diabetes 2005;54:3148-3153.[Abstract/Free Full Text] 6. Taegtmeyer H, Harmancey R. Virchow's metamorphosis revealed triglycerides in the heart J Am Coll Cardiol 2008;52:1013-1014.[Free Full Text] 7. Sharma S, Adrogue JV, Golfman L, et al. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart FASEB J 2004;18:1692-1700.[Abstract/Free Full Text]
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