Novel nonmetabolic actions of insulin

The nonmetabolic actions of insulin are readily explained by the recent observations that insulin is an anti-inflammatory hormone and that macronutrient intake is pro-inflammatory. Insulin has been shown to suppress several pro-inflammatory transcription factors such as nuclear factor kappa-B (NFkB), early growth response-

1 (Egr-1), activator protein-1 (AP-1), and the corresponding genes they regulate that mediate inflammation.1617 An impairment of the action of insulin due to insulin resistance would thus result in the activation of these pro-inflammatory transcription factors and an increase in the expression of the corresponding genes.

Insulin has been shown to suppress NFkB binding activity, reactive oxygen species (ROS) generation, p47phox expression, increase inhibitor kappa-B (IkB) expression in mononuclear cells (MNCs), and suppress plasma concentrations of intracellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1).16 In addition, insulin suppresses AP-1 and Egr-1, two pro-inflammatory transcription factors and their respective genes, matrix metalloproteinase-9 (MMP-9), tissue factor (TF), and PAI-1.17-19 Thus, insulin exerts comprehensive anti-inflammatory effects and also has anti-oxidant effects as reflected in the suppression of ROS generation and p47phox expression (Figure 2.1).1620

Two further pieces of evidence demonstrating the anti-inflammatory action of insulin have emerged recently. First, the treatment of type 2 diabetes with insulin for

2 weeks caused reductions in CRP and MCP-1.21 Second, the treatment of severe hyperglycemia associated with marked increases in inflammatory mediators with insulin resulted in rapid marked decreases in the concentrations of inflammatory mediators.22 Most recently, in a rat model in which inflammation was induced with endotoxin, insulin suppressed the concentration of inflammatory mediators including

Novel Biological Action of Insulin

Platelet Inhibition t t NO release in platelets t e-AMP

Vasodilation t NO release t eNOS expression t


Animals, human t

Vascular (other) actions


Heart, other issues

Anti-oxidant Anti-inflammatory

J ROS generation J NFkB, t IkB i MCP J ICAM-1 J CRP

Anti-thrombotic i TF

Profibrinolytic i PAI-1


Apo E null mouse IRS-1 null mouse IRS-2 null mouse

FIGURE 2.1 Novel biological effects of insulin targeted at endothelial cells, platelets, and leucocytes resulting in vasodilation, anti-aggregatory effects on platelets, antiinflammatory effects, and other related effects. (Source: From Dandona, P. et al., Circulation 111, 1448, 2005.)

interleukin-1 beta (IL-1p), IL-6, macrophage inhibitory factor (MIF), and tumor necrosis factor alpha (TNFa).23 Insulin also suppressed the expression of pro-inflammatory transcription factor CEBP and cytokines in the livers of the experimental animals. Similar reductions in inflammatory mediators were observed in rats with thermal injuries treated with insulin.24 Finally, insulin has been shown to suppress the increases in cytokine concentrations in pigs challenged with endotoxin.23

The anti-inflammatory, anti-oxidant (ROS-suppressive), anti-thrombotic, and pro-fibrinolytic effects of insulin have recently been shown to occur in patients with acute myocardial infarctions when they were treated with low dose infusions of insulin independently of decreases in glucose concentrations. These patients demonstrated impressive 40% reductions in plasma CRP and serum amyloid A (SAA) concentrations at 24 hours. This reduction was maintained at 48 hours of insulin infusion.25

These anti-inflammatory effects of insulin have also been shown in patients undergoing coronary artery bypass grafts in association with extracorporeal cir-culation.26 The increase in plasma CRP concentration occurring within 16 hours of surgery is 30 times greater than that in patients with ST-Elevation Myocardial Infarction (STEMI).26 The reduction in the magnitude of increase in CRP and SAA is 40% — very similar to that observed following insulin infusion in patients with STEMI.26

Another novel anti-apoptotic effect of insulin has recently been described. In experimental acute myocardial infarction in the rat heart, the addition of insulin to the reperfusion fluid led to a 50% reduction in infarct size.27 More recently, a similar cardio-protective effect of insulin was shown in human acute myocardial infarction when insulin at a low dose was infused with a thrombolytic agent and heparin.20 Conversely, insulin-resistant states of obesity and type 2 diabetes have been shown to be associated with larger infarcts than those observed in non-diabetic subjects. Further work is required to establish this feature as an integral component of metabolic syndrome.

It should also be mentioned that insulin administration suppresses atherogen-esis in apolipoprotein E null mice.28 Conversely, interference with insulin signal transduction, as in IRS-2 null mice, resulted in atherosclerosis.29 The IRS-1 null mouse also has a tendency toward atherosclerosis. It is relevant that a mutation of IRS-1 (arginine at 792) leads to abnormal vascular reactivity, a decrease in eNOS expression in endothelial cells, and an increased incidence of coronary heart disease.30 It is interesting that the pro-atherogenic effects of insulin proposed primarily on the basis of in vitro studies are being challenged by evidence generated in the past 6 years.7 This debate has been further fueled by two recent articles showing that knocking out the insulin receptor in myelogenic cells that are precursors of MNCs (cells that play a crucial role in the pathogenesis of atherosclerosis) is anti-atherogenic in the background of LDL receptor deficiency and pro-atherogenic in apo E-deficient animals.3132

Consistent with the anti-inflammatory effects of insulin, insulin sensitizers of the thiazolidinediones class (troglitazone33,34 and rosiglitazone35) have been shown to exert anti-inflammatory effects in addition to their glucose lowering effects in patients with diabetes. Troglitazone has been shown to suppress the development of diabetes in patients at high risk of developing this condition.36 Trials are under way to determine whether rosiglitazone and pioglitazone prevent both type 2 diabetes and atherosclerotic complications. Positive results from those trials would support the concept that inflammatory mechanisms underlie the pathogenesis both of insulin resistance and atherosclerosis. It is of interest in this regard that metformin causes reductions in plasma concentrations of MIF in obese subjects.37 Obese individuals have elevated plasma concentrations of this cytokine and increases in the expression of this cytokine in MNCs.37 While evidence indicates that TZDs exert direct anti-inflammatory effects on macrophages in vitro, it is possible that their effects in vivo may arise through insulin sensitization.

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