Editorial Commentary Hypertension and Insulin Resistance

Diminished tissue sensitivity to the metabolic actions of insulin is a characteristic feature of various pathological conditions termed the “cardiometabolic syndrome.”1–3 Factors that contribute to the complex interaction of genetic and environmental factors required for impaired insulin signaling include obesity, inactivity, and aging. Recent research has underscored the importance of heightened activation of the renin-angiotensin-aldosterone system and sympathetic nervous system, oxidative stress, inflammation, and mitochondrial functional abnormalities in promoting insulin resistance.1–3 In addition to the negative effects of these factors on insulin metabolic signaling in conventionally insulin-sensitive tissue, such as skeletal muscle, there is a contemporaneous negative effect on metabolic signaling in cardiovascular tissue. These negative effects include reduced insulin stimulation of endothelial cell NO production and increased NO destruction with resulting endothelial dysfunction and hypertension.1,2 Indeed, both pharmacological and nonpharmacological strategies to improve insulin metabolic signaling generally also improve endothelial function and lower blood pressure. In this regard, the current report from Ruggenenti et al4 is an important translational contribution that provides a potential mechanism by which oral provision of a critical mitochondrial substrate, L-carnitine, can correct insulin resistance and lower blood pressure through improvements in mitochondrial free fatty acid use. This investigative team prospectively studied 2 cohorts of insulin-resistant subjects with the presence of other cardiometabolic risk factors, such as body mass index 25 kg/m and hypertension. Eligible subjects underwent a euglycemic, hyperinsulinemic clamp to determine glucose disposal rate (GDR) and were divided into those with and without a low GDR ( 7.9 or 7.9 mg/kg per minute). The 2 groups underwent an oral glucose tolerance test and measurement of blood pressure, as well as other metabolic markers. Subjects were then given 24 weeks of acetyl-Lcarnitine treatment, followed by a 16-week recovery period off of treatment, and metabolic and blood pressure measurements were repeated after acetyl-L-carnitine treatment and recovery. Their work was based on the premise that the product of metabolism of acetyl-L-carnitine, L-carnitine, improves glucose use through improved intracellular free fatty acid and lipid metabolism and facilitates glycolysis in skeletal muscle tissue.5–7 L-Carnitine serves as an obligatory cofactor for mitochondrial -fatty acid oxidation to facilitate transport of long-chain fatty acids across the mitochondrial membrane, thus resulting in more efficient mitochondrial oxidative phosphorylation and glucose use. This improved mitochondrial function, in turn, would also improve both endothelial cell and skeletal muscle insulin-stimulated NO bioavailability and glucose use and ultimately improve endothelial function and systemic insulin sensitivity (Figure). The authors report that the subjects with a lower GDR ( 7.9 mg/kg per minute) displayed characteristics of the cardiometabolic syndrome and consistently had higher systolic blood pressures when compared to those with a higher GDR ( 7.9 mg/kg per minute). Treatment with acetyl-L-carnitine over 24 weeks resulted in improvement in GDR (insulin sensitivity) only in those with low GDR but lowered systolic blood pressure in both study groups. These effects in these overweight/obese subjects occurred independent of changes in diet and body weight. Interestingly, the authors observed that, in the recovery period off of therapy, systolic blood pressure in both groups returned to baseline, suggesting that acetyl-L-carnitine may have an effect on BP reduction partly independent of its actions on insulin sensitivity. Endothelial dysfunction is commonly present in concert with insulin resistance. Several vascular metabolic abnormalities have been documented in obese, insulin-resistant subjects. These abnormalities include impaired insulinstimulated glucose uptake, similar to what is seen in traditional insulin-sensitive tissues (eg, skeletal muscle, fat, and liver). Typically, insulin-dependent glucose use is partly dependent on insulin-mediated increases in blood flow and substrate delivery to tissues. In insulin resistance, there is decreased insulin stimulation of NO bioactivity (decreased endothelial NO synthase activation and increased NO destruction), diminished vasodilatation, and substrate delivery.8 Increased generation of reactive oxygen species plays an important role in this decrease in insulin metabolic signaling, in part by increasing redoxsensitive serine kinase activation. These activated kinases decrease insulin receptor 1 levels and engagement with phosphoinositol 3-kinase, with resulting diminution of protein kinase B and atypical protein kinase activation of glucose transport (Figure).1,8 As a result, insulin-resistant individuals with obesity are more prone to endothelial dysfunction and subsequent development of hypertension. The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Diabetes and Cardiovascular Center, Department of Medicine and Physiology, University of Missouri-Columbia School of Medicine, Columbia, Mo; Harry S. Truman Veterans’ Affairs Medical Center, Columbia, Mo. Correspondence to James R. Sowers, D109 HSC Diabetes Center, One Hospital Drive, Columbia, MO 65212. E-mail sowersj@health. missouri.edu (Hypertension. 2009;54:462-464.) © 2009 American Heart Association, Inc.