Decreased Glucagon-Like Peptide 1 Fasting Levels in Type 2 Diabetes

The significance of over- or underproduction of glucagon-like peptide 1 (GLP-1) (7–36) amide in diabetes remains controversial (1,2). Although it has been proposed that at least one factor contributing to the pathogenesis of type 2 diabetes is desensitization of the GLP-1 receptor on β-cells (2), exogenous administration of GLP-1 in patients with type 2 diabetes fully normalizes fasting hyperglycemia and reduces postprandial glycemic increments (3). Also, the GLP-1 response to oral glucose is not altered in postmenopausal women with impaired glucose tolerance (2). The purpose of the present study was to establish any difference in the fasting state concentration of GLP-1 in type 2 diabetes as compared with the normal state.

We examined 26 subjects (12 men and 14 women) with type 2 diabetes who were aged 67.6 ± 10.09 years (means ± SD) and had a BMI of 29.2 ± 3.5 kg/m² and a diabetes duration of 137.0 ± 23.7 months. As a control group, we included 15 normal subjects (9 women and 6 men) who were aged 65.8 ± 8.01 years and had a BMI of 28.1 ± 3.7 kg/m². Patients with type 2 diabetes were treated by diet and were on metformin and/or sulfonylurea therapy with HbA_1c 6.81 ± 1.37% and fasting glucose 87.30 ± 5.20 mg/dl. Written consent was obtained from all participants. Blood samples were obtained at rest between 8:00 and 9:00 a.m. after an overnight fast and 24 h alcohol abstention. Insulin and GLP-1 were measured using an enzyme-linked immunosorbent assay (AxSYM; Abbott Lab, North Abbott, IL) and competitive radioimmunoassay (Peninsula Lab, Belmont, CA), respectively.

Interestingly, GLP-1, displaying a normal distribution, exhibited a statistically significant decrease (P < 0.001) in type 2 diabetic patients (23.8 ± 3.17 pg/ml) compared with control subjects (76.4 ± 4.47), whereas the plasma insulin concentration was higher in type 2 diabetic subjects (20.9 ± 13.4 ÌU/ml) than in control subjects (9.8 ± 1.3), with the difference being statistically significant (P < 0.03).

Using linear regression analysis, we found that GLP-1 was more negatively correlated with insulin in the type 2 diabetic patients than in the normal subjects (r = −0.64, P < 0.001 vs. r = −0.43, P = 0.040). In addition, GLP-1 was also negatively correlated with HbA_1c in type 2 diabetic subjects at a statistical level (r = −0.43, P = 0.037). Interestingly, the results were independent of diabetes duration.

The physiological importance of the decreased fasting level of GLP-1 in type 2 diabetic patients requires further clarification. If it is a reflection of increased sensitivity of β-cell responsitivity to secretagogues, then this study further confirms previous findings on the existence of a negative feedback loop between GLP-1 and insulin secretion and provides further evidence for the importance of the entero-insular axis in the regulation of insulin secretion. Moreover, the dissociation of GLP-1 levels with the duration of the disease suggests an early impairment of the entero-insular axis.