The main result of this study is that insulin-stimulated endothelial function remained preserved during treatment with carvedilol and blunted during treatment with metoprolol, whereas endothelium-dependent and endothelium-independent vasodilation was unchanged in both groups.
The lack of effect of carvedilol in endothelial function in the absence of stimulation with insulin, is somehow in contrast with a recent study where carvedilol has shown to improve endothelial function assessed by measures on albuminuria and measures on brachial reactivity by ultrasound, compared with metoprolol . It cannot be ruled out that we could have demonstrated an improvement of the serotonin-stimulated flow in a larger population but intra-arterial co-infusion of insulin and serotonin provides a unique possibility to assess specifically insulin sensitivity of the endothelium , whereby it further supports that an improved vascular nitric oxide reactivity is the main mechanism that accounts for the beneficial effects of carvedilol. This is additionally supported by the observation in our study that co-infusion of serotonin, insulin and L-NMMA totally abolished vasodilation both before and after treatment with either of the two beta blockers. These findings could not be explained by changes in either blood pressure or metabolic glucose control. Furthermore, it is possible that a lower CRP measured at baseline in the carvedilol group accounts for the lack of potential to improve serotonin response (Table 1). Nevertheless, this difference at baseline rather strengthens our study, since in spite of a "healthier" condition of the carvedilol group it was possible to improve the insulin-stimulated serotonin response. Insulin resistance is an independent risk factor of developing cardiovascular disease . Diabetes is a condition with insulin resistance including vascular insulin resistance . This was also found in our study. By improving metabolic glucose control in patients with type 2 diabetes, vascular insulin resistance also improves . Insulin stimulated vasodilation has been found to be NO dependent . A blunted insulin stimulated vasodilation itself leads to vasoconstriction and is thereby proatherogenic. Co-morbidity with hypertension, ischemic heart disease or heart failure is common in patients with type 2 diabetes. Treatment with beta adrenergic blockers is therefore often necessary to reduce their total risk of cardiovascular disease. As insulin resistance serves as a key role between diabetes and cardiovascular disease, it is of importance that beta blocker treatment does not aggravate insulin resistance. Vascular insulin resistance deteriorates glucose supply and thereby utilization in peripheral tissue. Vascular insulin resistance may therefore be an important factor when treating patients with type 2 diabetes or metabolic syndrome. The importance of the findings in this study for the prognosis of patients is unknown, but the result could inspire to further studies of the importance of vascular insulin sensitivity given the favorable effects of carvedilol compared to metoprolol observed in the COMET study (The Carvedilol or Metoprolol European Trial) [3, 4].
Carvedilol has been found superior to metoprolol in the control of glucose metabolism in patients with type 2 diabetes and hypertension . Also studies show that carvedilol does not deteriorate insulin resistance, as it was found in a direct comparison with metoprolol . In the study by Jacob et al, insulin sensitivity was measured by use of the euglycemic hyperinsulinaemic clamp method and the study included patients with hypertension, but not diabetes. Compared to atenolol, a selective beta-1 adrenergic receptor blocker, carvedilol has also shown a more favorable effect on systemic glucose metabolism , whereas atenolol and metoprolol both decreased insulin sensitivity to a similar level, when compared directly with an euglycemic hyperinsulinaemic clamp . These studies all show a systemic change in insulin resistance, whereas our study shows that the two beta-blockers, metoprolol and carvedilol, have a differential effect on vascular insulin sensitivity, with an advantage in favor of carvedilol.
In the group of patients treated with metoprolol we found an increase in body weight of 1.8 kg (p = 0.02) after 2 months of treatment. In contrast to this, no significant weight gain was found in the group of patients treated with carvedilol. This is in accordance with the weight gain seen after treatment with beta-blockers in large clinical trials . In the GEMINI trial, a significant weight gain of 1.2 kg was found in the metoprolol arm compared to a non-significant weight gain in the carvedilol arm ; whether this can explain the general metabolic disadvantages seen with metoprolol in large clinical trials is uncertain. Whether the weight gain in the metoprolol group seen in our study is associated with deterioration of insulin-stimulated endothelial function is also not known. An inverse association between weight and adiponectin level has been found  and low plasma-adiponectin levels are considered to be a predictor of cardiovascular disease in patients with type 2 diabetes . In a recent study, metoprolol was found to decrease adiponectin level in hypertensive patients . Adiponectin could play a role in the relationship between vascular insulin resistance and treatment with metoprolol found in our study, and the weight-gain seen could also be an important factor.
The beta-1 adrenergic receptor blocker atenolol causes enhancement of endothelium-dependent vasodilation during short time infusion and during 3 months treatment [25, 26]. In contrast, the non-selective beta-blocker propranolol causes attenuation of endothelial function during direct intra-arterial infusion and causes coronary artery vasoconstriction [25, 27, 28]. Four months treatment with carvedilol in patients with coronary artery disease improved endothelial function whereas no change was seen after short term treatment of 2 hours . The long term effect on endothelial reactivity therefore seems to be dependent on the properties of the beta-blockers.
Carvedilol has additional adrenergic receptor blocking properties, beta-1, beta-2 and alfa-1, along with antioxidative properties  compared to metoprolol, a beta-blocker with beta-1 adrenergic receptor blocking properties. The effect of carvedilol on the endothelium may be explained by either increased endothelial NO-production or decreased NO-breakdown. Carvedilol stimulates endothelial nitric oxide production  and its hemodynamic effects are blunted during complete inhibition of NO-production . In type 2 diabetes, an increased production of free radicals leads to an increased oxidative stress to the vascular wall . Therefore carvedilol may have beneficial effects on endothelial dysfunction caused by oxidative stress in patients with type 2 diabetes.
Vascular studies of long-term treatment with carvedilol have shown to improve endothelial function in patients with coronary artery disease which was attributed to the antioxidative properties of carvedilol , but in a recent study improvement of endothelial function after treatment with carvedilol in patients with diabetes, no changes in markers of oxidative stress could be found .
As described, studies show inconclusive effects of the anti-oxidant property of carvedilol on endothelial function. We have not been able to demonstrate a benefit on endothelial function from treatment with carvedilol in patients with type 2 diabetes, despite the increased oxidative stress in this group of patients . But our study indicates that carvedilol has supplemental effects and this might be of importance when treating diabetic vascular diseases; to our knowledge, this is the first study to demonstrate a direct effect on insulin-stimulated endothelial function in patients with type 2 diabetes, when treated with different generations of beta-blockers.
Limitations to the study
The lack of changes in serotonin stimulated endothelial function after treatment with carvedilol or metoprolol might be caused by the small number of patients included in the study. Nevertheless we were able to demonstrate a difference between the insulin stimulated endothelial function in the group of patients treated with carvedilol and not even a trend of change in serotonin stimulated endothelial function. The number of patients included in the study might not be the only explanation to the lack of change after beta blocker treatment.
This a small interventional study with the purpose of finding changes in endothelial function between groups. Therefore changes in baseline characteristics could not be expected to be found with a statistical significance in this study. A large interventional study is needed to find the actual differences in endothelial function after treatment with either carvedilol or metoprolol with correction for the baseline characteristics and changes found in this study.