Beneficial effects of insulin on endothelial function, inflammation, and atherogenesis and their implications

Journal of Family Practice, June, 2005 by Louis Kuritzky, Scott E. Nelson

With 221 million people predicted to have diabetes by 2010, (1) increasing numbers of patients will require insulin to maintain glycemic control. Patients with type 2 diabetes are at increased risk for cardiovascular (CV) mortality (2) independent of classic risk factors such as smoking, dyslipidemia, and hypertension. Despite not having the problem of severe insulin resistance, patients with type 1 diabetes are also at increased risk for coronary artery disease (CAD). Clearly, this would suggest that hyperglycemia plays a more fundamental role in worsening CV risk than insulin resistance in patients with diabetes.

Inflammation is considered to be a significant contributor to the pathogenesis of atherosclerosis and ultimately to adverse CV events. The recent REVERSAL study demonstrated that progression of coronary atherosclerosis was decreased in patients with CAD who received an intensive regimen of atorvastatin (80 mg/day). This outcome may be a result of atorvastatin's combined effects on atherogenic lipoproteins and inflammation (reflected by C-reactive protein, a non-specific marker of inflammation). (3) Because of these results and the increased risk for CV mortality seen in patients with type 2 diabetes, the effect of insulin on atherogenesis is also important. In fact, insulin has also been studied to determine its possible anti-inflammatory and antiatherogenic roles.

The effects of insulin resistance on platelets

Insulin resistance has also been shown to affect platelets. Normally, insulin prevents platelet adherence to collagen; insulin resistance reduces insulin's effect on platelets and contributes to a potentially atherogenic state. This interaction has been studied in vitro after in vivo exposure of platelets to insulin in insulin-sensitive (nonobese) and insulin-resistant (obese) patients. Following in vivo insulin infusion, insulin inhibited platelet deposition upon collagen in insulin-sensitive individuals (P < .05), but failed to do so in patients with insulin resistance. (4) Insulin resistance, then, favors an atherothrombotic status, by adversely affecting platelet function (ie, enhancing aggregability).

Notably, in patients with type 2 diabetes, platelets are hyperactive, resulting in a provasoconstrictive and proaggregation state. The progressive nature of this process is clearly depicted in FIGURE 1. Moreover, the fibrinolytic side of normal hemostasis may also be impaired in patients with type 2 diabetes. Patients with type 2 diabetes demonstrate hypofibrinolysis. (5) In fact, a recent study demonstrated altered structures of fibrin clots obtained from patients with type 2 diabetes, and those alterations were related to an individual's glycemic control. These structural differences might increase resistance to fibrinolysis in the setting of thrombosis and also contribute to increased CV risk in the setting of type 2 diabetes. (6)

[FIGURE 1 OMITTED]

Endothelium vasodilation: CV risk and effect of insulin

Endothelial dysfunction, which results in pathologic coagulant, inflammatory, and vascular growth patterns, is often demonstrated by measuring impaired endothelium-dependent vasorelaxation resulting from a loss of nitric oxide (NO) bioactivity in the vessel wall. (7)

Endothelial cells produce a variety of vasodilators, NO being the most important. NO is produced from L-arginine in a reaction catalyzed by endothelial nitric oxide synthase (eNOS). It then diffuses to the vascular smooth-muscle cells and stimulates guanylate cyclase to catalyze the production of cyclic guanosine monophosphate (cGMP)--a potent vascular smooth-muscle relaxing agent--resulting in vasodilation and increased blood flow. Endothelial function can be studied using agents such as acetylcholine (ACh); ACh stimulates parasympathetic receptors to increase eNOS in an endothelium-dependent manner, the impact of which may be quantified by measuring forearm blood flow. Blunted increments of forearm blood flow indicate endothelial dysfunction. In a study of patients with essential hypertension, the blunted production of NO in response to ACh predicted CV events; (8) similar results were seen in patients with CAD. (9)

Insulin mediates the production of potent vasodilators including NO (FIGURE 2). In vitro insulin has stimulated the production of eNOS and NO in a receptor kinasemediated manner. (10) Clinical studies have substantiated the acute activation of endothelium-dependent vasodilation in subjects by either regular human insulin or insulin glargine, as long as the vasculature is healthy. (11) However, in diabetic subjects or others with vascular disease there is consistent blunting of endothelial blood flow in response to ACh. (12) Ultimately, insulin treatment may improve endothelial function in patients with diabetes (see below).

[FIGURE 2 OMITTED]

The effect of chronic insulin therapy on endothelial function

Studies of the effect of chronic insulin use on endothelial function in patients with type 2 diabetes have demonstrated that insulin enhances ACh-induced vasodilation. (13-15) A Finnish study assessed the effect of chronic insulin glargine therapy on endothelial function in patients with type 2 diabetes. Eleven insulin-naive patients with diabetes (aged 59 [ or -] 2 years) had insulin glargine added to their oral hypoglycemic therapy for 3.5 years. Compared with baseline, significant improvements in blood flow response to high-dose ACh were demonstrated at 0.5 years and 3.5 years, with an 86% improvement in blood flow at 3.5 years. (16)