Improvement of Glycemic Control by 1 Year of Insulin Therapy Leads to a Sustained Decrease in sE-Selectin Concentrations in Type 2 Diabetes

Abstract

OBJECTIVE -To examine whether and how improvement of glycemic control by long-term insulin therapy decreases endothelial activation as measured by serum levels of the soluble adhesion molecules sE-selectin and vascular cell adhesion molecule (VCAM-1) and whether the drug used to lower blood glucose in addition to insulin influences such a response.RESEARCH DESIGN AND METHODS -Circulating adhesion molecules were measured before and after 3 and 12 months of therapy in 81 patients with type 2 diabetes and 41 subjects without diabetes. The patients were treated with bedtime administration of NPH insulin combined with either glibenclamide (n ϭ 19), metformin (n ϭ 17), glibenclamide and metformin (n ϭ 17), or morning administration of NPH insulin (n ϭ 23).RESULTS -Before insulin therapy, serum sE-selectin level was 71% higher in the patients with type 2 diabetes (77 Ϯ 4 ng/ml) than in the normal subjects (45 Ϯ 3 ng/ml, P Ͻ 0.001), whereas levels of sVCAM-1 were comparable (420 Ϯ 25 vs. 400 Ϯ 11 ng/ml, respectively). Glycemic control in all patients improved as judged from a decrease in HbA 1c from 9.7 Ϯ 0.2 to 7.6 Ϯ 0.1% (P Ͻ 0.001). sE-selectin decreased to 67 Ϯ 4 ng/ml by 3 months (P Ͻ 0.001 vs. 0 months) and then remained unchanged until 12 months (70 Ϯ 4 ng/ml, P Ͻ 0.001 vs. 0 months). sVCAM-1 levels at 12 months was similar to those at 0 months (416 Ϯ 25 ng/ml). The change in glycemic control, measured by HbA 1c , but not in other parameters, was correlated with the change of sE-selectin (r ϭ 0.41, P Ͻ 0.001) within the patients with type 2 diabetes. The decreases in sE-selectin were not different between the various treatment groups.CONCLUSIONS -We conclude that improvement in glycemic control by administration of insulin alone or insulin combined with either glibenclamide, metformin, or both agents induces a sustained decrease in sE-selectin, the magnitude of which seems to be dependent on the degree of improvement in glycemia. These data suggest that sE-selectin might provide a marker of effects of treatment of chronic hyperglycemia on endothelial activation. Diabetes Care 24:549 -554, 2001H yperglycemia promotes leukocyte adhesion to endothelial cells through upregulation of cell-surface expression of E-selectin, intercellular adhesion molecule (ICAM-1), and vascular cell adhesion molecule (VCAM-1) (1). Stimulation of endothelial cells with glycated albumin (advanced glycation end product/bovine serum albumin) also increases expression of these adhesion molecules (1,2), which can be detected in soluble (3) forms (sE-selectin, sICAM-1, and sVCAM-1) in the circulation (4,5). In patients with type 2 diabetes, concentrations of serum sE-selectin, which is expressed exclusively on endothelial cells, have been increased in most (3,6 -11) but not all (12,13) comparisons and have correlated with glycemia in five studies (6 -10). Serum sICAM-1 concentrations have been increased in most comparisons between groups of patients with type 2 diabetes and normal subjects (8,9,(11)(12)(13)(14). A positive correlation with gly...

Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes

“…In fact, several CVD biomarkers (e.g. TNF-a, adhesion molecules, vWf, t-PA-ag and PAI-1-ag) have been associated with phenotypes of the metabolic syndrome (16)(17)(18). From the present study, we have previously reported a non-significant difference in levels of HbA 1c (0.17 percentage points), significantly lower body weight (1.58 kg) and significantly lower fasting serum insulin levels (13%) during metformin than repaglinide treatments (33).…”

“…Here, we collectively term these non-conventional CVD risk markers 'CVD biomarkers'. Interrelations between the CVD biomarkers and the glycaemic variables have been suggested (16)(17)(18). Thus, biological mechanisms both dependent and independent of glycaemia might influence the CVD biomarkers.…”

“…Thus, biological mechanisms both dependent and independent of glycaemia might influence the CVD biomarkers. As yet, few studies have compared the effect of various anti-hyperglycaemic treatment regimens on CVD biomarkers, and most studies were in obese patients with T2DM (17,(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

Metformin therapy and clinical uses

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The effects of short-term, rapid glycemic control on the peroneal nerve function and serum VCAM-1 and AGE in type 2 diabetic patients in Malaysia

“…Additionally, only serum VCAM-1 was measured, which may be less sensitive than other soluble CAMs in predicting in vivo endothelial dysfunction. [23] This could partly explain the lack of signiÞ cant changes in the VCAM-1 levels despite signiÞ cant improvements in glycemic control and peroneal nerve function following treatment.…”