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Sirtuin (SirT), a family of conserved histone deacetylases and transferases, has been proposed to function in inflammatory, cancer, and metabolic diseases. However, it is unclear how SirT modulates these processes. In this study, the effect of metformin on senescence and antisenescence mediators (SirT1-7, p53, and p16(INK4a)) mRNA expression in white blood cells (WBCs) following lipopolysaccharides (LPS)-induced inflammation in mice was examined.C57BL/6 mice were treated with metformin in their drinking water (2 mg/mL) for 1 week followed by intraperitoneal injection of LPS from Escherichia coli serotype 0111:B4 at 2 mg/kg. Blood was collected at the basal level and 1, 2, and 3 hr after LPS injection. SirT1-7, p53, and p16(INK4a) mRNA expression in WBCs was measured by real-time quantitative polymerase chain reaction (RT-qPCR).SirT7 at 2 hr, SirT1 at 3 hr, and p16(INK4a) at 1 hr were inhibited significantly in WBCs following LPS injection. There were no significant changes in other SirT nor p53 mRNA expression in WBCs after LPS injection. Metformin inhibited SirT2 expression in WBCs significantly (P0.05) and did not induce any significant changes in other SirT forms and p53, whereas it induced p16(INK4a) mRNA expression in WBCs (P0.05) at the basal levels. Additionally, metformin treatment significantly inhibited SirT7, SirT1, and p16(INK4a) mRNA expression in WBCs at 1, 2, and 3 hr, whereas p53 was inhibited significantly at 2 hr after LPS injection.SirT7 and SirT1 are stress responsive proteins that may mediate inflammation. The data suggest that metformin may exert its potential antisenescence and anti-inflammatory effects by targeting SirT7 and SirT1 pathways. SirT7 inhibition may allow the healing process and prevention of tissue damage by enabling cells to survive through inhibition of cytokines and inflammatory mediators under severe stress conditions.

The normal endothelium produces a number of vasodilator substances such as nitric oxide (NO) and prostacyclin (PGI2) that regulate vasomotor tone, reduce platelet aggregation, and inhibit the recruitment and activity of inflammatory cells. The functions of vascular endothelial cells are disturbed in diabetic patients. The major cause for mortality and a great percent of morbidity in patients with diabetes mellitus is atherosclerosis. Insulin has recently been shown to stimulate NO release and the expression of NO synthase by the endothelium. Insulin is thus a vasodilator, has anti-platelet activity, and now has been shown to be anti-inflammatory and thus, potentially anti-atherogenic. Similar anti-inflammatory effects of thiazolidenediones (TZDs), troglitazone, and rosiglitazone suggest that they too may have potential anti-atherogenic effects. These effects of insulin and TZDs are of importance since the two major states of insulin resistance, obesity and type 2 diabetes, are associated with a marked increase in atherosclerosis, coronary heart disease, and stroke. These recent observations have extremely important implications for the understanding of the pathogenesis of atherosclerosis in insulin-resistant states and for a rational approach to their comprehensive treatment, including the prevention of atherosclerosis and its complications. This review challenges the previously proposed hypothesis that hyperinsulinemia represents a common pathophysiological pathway of diabetic complications and advances our hypothesis that insulin, through its effect on the endothelium, leucocytes, and platelets, has anti-inflammatory and thus potentially anti-atherogenic properties. Furthermore, through its anti-inflammatory effects, its use improves clinical outcomes in at least two clinical states characterized by profound inflammation-acute myocardial infarction and sepsis.

The major cause of heart attack and stroke is atherosclerosis. Because the atherosclerotic lesion contains lipid, and because elevated cholesterol levels are epidemiologically associated with heart attack, the major thrust of dietary research in relation to heart disease has been toward fats in the diet. Decades of research in this area have led to the clear conclusions that (1) an increase in low-density lipoprotein cholesterol (LDL-C) predicts the risk of coronary heart disease (CHD) and stroke; (2) the risk of CHD is inversely related to the circulating level of high-density lipoprotein cholesterol (HDL-C); and that (3) the level of very-low-density lipoprotein cholesterol (VLDL-C) does not directly predict heart-attack risk but that an increase in this cholesterol fraction appears to enhance the risk posed by LDL-C. Additionally, the subclass of lipid known as small dense LDL-C has, over the past decade, been shown to predict pathology related to atherosclerosis. Prospective, randomized studies of the beneficial effect of lowering blood cholesterol levels through the use of a variety of drugs have conclusively shown that reducing the level of LDL-C markedly lowers the risk of CHD morbidity and mortality. A recent study directed at increasing the circulating level of HDL has also shown an improved outcome in CHD,1 and another study aimed at reducing triglycerides and raising the level of HDL in diabetic subjects has also shown improved outcome.2 Clearly, therefore, decreasing LDL-C and increasing HDL-C with or without a concomitant decrease in triglycerides improves cardiovascular outcomes.

Fasting hyperinsulinemia is associated with an increased risk of atherosclerotic complications of heart attack and stroke. This has resulted in the concept that insulin may promote atherosclerosis in spite of the absence of any evidence that insulin is atherogenic either in the human or in experimental models. Recent evidence shows that insulin exerts vasodilatory, anti-platelet and anti-inflammatory effects at the cellular level in vitro and in the human in vivo. Since atherosclerosis is a chronic inflammatory process of the arterial wall, insulin may be potentially anti-atherosclerotic in the long term. More recent data on experimental atherosclerosis in the mouse shows that (1) insulin administration reduces the number and the size of atherosclerotic lesions in apo E null mice and (2) in IRS-2 null mice, the interruption in insulin signal transduction results in enhanced atherogenicity. Finally, the use of a low dose of insulin infusion in patients with acute myocardial infarction has been shown to markedly improve clinical outcomes, both in diabetic and nondiabetic patients. Our own most recent data show that a low dose infusion of insulin in patients with acute myocardial infarction induces a reduction in inflammation (C-reactive protein and serum amyloid A) and oxidative stress, and promotes fibrinolysis. We conclude that insulin is anti-inflammatory and potentially antiatherogenic and may be of use in the treatment of cardiovascular inflammatory conditions.

The metabolic syndrome, as described by Reaven, is a combination of obesity, insulin resistance, hypertension, hypertriglyceridemia, low HDL cholesterol, and hyperinsulinemia. The syndrome was recognized as a very high pro-atherogenic risk causing coronary heart disease. More recently, other features like an elevated plasma PAI -1 and CRP have been added to the syndrome. In view of the recent data demonstrating that insulin exerts an anti-inflammatory effect while macronutrients exert a pro-inflammatory effect, we are in a better position to explain not only why an insulin resistant state like the metabolic syndrome is pro-inflammatory but also to explain how it develops. This review discusses the relevance of these recent observations and puts into perspective the pathogenesis of various features of the metabolic syndrome and also predicts some features which may get incorporated into it in the future.