The possible protective role of glucagon-like peptide 1 on endothelium during the meal and evidence for an "endothelial resistance" to glucagon-like peptide 1 in diabetes

Abstract

Objective: Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion. However, GLP-1 also improves endothelial function in diabetes.

Research design and methods: Sixteen type 2 diabetic patients and 12 control subjects received a meal, an oral glucose tolerance test (OGTT), and two hyperglycemic clamps, with or without GLP-1. The clamps were repeated in diabetic patients after 2 months of strict glycemic control.

Results: During the meal, glycemia, nitrotyrosine, and plasma 8-iso prostaglandin F2α (8-iso-PGF2a) remained unchanged in the control subjects, whereas they increased in diabetic patients. Flow-mediated vasodilation (FMD) decreased in diabetes, whereas GLP-1 increased in both groups. During the OGTT, an increase in glycemia, nitrotyrosine, and 8-iso-PGF2a and a decrease in FMD were observed at 1 h in the control subjects and at 1 and 2 h in the diabetic patients. In the same way, GLP-1 increased in both groups at the same levels of the meal. During the clamps, in both the control subjects and the diabetic patients, a significant increase in nitrotyrosine and 8-iso-PGF2a and a decrease in FMD were observed, effects that were significantly reduced by GLP-1. After improved glycemic control, hyperglycemia during the clamps was less effective in producing oxidative stress and endothelial dysfunction and the GLP-1 administration was most effective in reducing these effects.

Conclusions: Our data suggest that during the meal GLP-1 can simultaneously exert an incretin effect on insulin secretion and a protective effect on endothelial function, reasonably controlling oxidative stress generation. The ability of GLP-1 in protecting endothelial function seems to depend on the level of glycemia, a phenomenon already described for insulin secretion.

Figure 1

Changes of glycemia, GLP-1, FMD, plasma nitrotyrosine, 8-iso-PGF2a, and insulin during the meal and the OGTT in normal healthy control subjects and type 2 diabetic patients. Data are expressed as mean ± SE; △, meal test controls; ▲, OGTT controls; ○, meal test type 2 diabetes; ●, OGTT type 2 diabetes; *P < 0.001 vs. basal; †P < 0.01 vs. basal; ‡P < 0.05 vs. basal; §P < 0.01 vs. OGTT; ||P < 0.05 vs. OGTT.

Figure 2

Changes of glycemia, GLP-1, FMD, plasma nitrotyrosine, 8-iso-PGF2a, and insulin during the hyperglycemic clamp with or without GLP-1 infusion in normal healthy control subjects and type 2 diabetic patients. Data are expressed as mean ± SE; △, hyperglycemic clamp + placebo control subjects; ▲, hyperglycemic clamp + GLP-1 control subjects; ○, hyperglycemic clamp + placebo type 2 diabetes; ●, hyperglycemic clamp + GLP-1 type 2 diabetes; *P < 0.001 vs. basal; †P < 0.01 vs. basal; ‡P < 0.05 vs. basal; §P < 0.01 vs. placebo; ||P < 0.05 vs. placebo.

Figure 3

Changes of glycemia, GLP-1, FMD, plasma nitrotyrosine, 8-iso-PGF2a, and insulin during the hyperglycemic clamp with or without GLP-1 infusion in normal healthy control subjects and type 2 diabetic patients at baseline and after 2 months of optimized glycemic control. For the comparisons between baseline and after 2 months of optimized glycemic control, see the results section. Data are expressed as mean ± SE; △, hyperglycemic clamp + placebo; ○, hyperglycemic clamp + placebo after 2 months of optimized glycemic control; ▲, hyperglycemic clamp + GLP-1; ●, hyperglycemic clamp + GLP-1 after 2 months of optimized glycemic control; *P < 0.001 vs. basal; †P < 0.01 vs. basal; ‡P < 0.05 vs. basal.