PREDICTORS OF INCRETIN CONCENTRATIONS IN SUBJECTS WITH NORMAL, IMPAIRED, AND DIABETIC GLUCOSE TOLERANCE

Abstract

Introduction: Defects in GLP-1 secretion have been reported in some patients with type 2 diabetes after meal ingestion. We addressed the questions: (1) Is the quantitative impairment in GLP-1 levels different after mixed meal or isolated glucose ingestion? (2) Which endogenous factors are associated with the concentrations of GLP-1, and in particular do elevated fasting glucose or glucagon levels diminish GLP-1 responses.

Patients and methods: 17 patients with mild type 2 diabetes, 17 subjects with impaired glucose tolerance and 14 matched controls participated in an oral glucose tolerance test (75 g) and a mixed meal challenge (820 kcal), both carried out over 240 min on separate occasions. Plasma levels of glucose, insulin, C-peptide, glucagon, triglycerides, free fatty acids, GIP and GLP-1 were determined.

Results: GIP and GLP-1 levels increased significantly in both experiments (p < 0.0001). In patients with type 2 diabetes, the initial GIP response was exaggerated compared to controls after mixed meal (p < 0.001), but not oral glucose ingestion (p = 0.98). GLP-1 levels were similar in all three groups in both experiments. GIP responses were 186 ± 17 % higher after mixed meal ingestion than after the oral glucose load (p < 0.0001), whereas GLP-1 levels were similar in both experiments. There was a strong negative association between fasting glucagon and integrated FFA levels and subsequent GLP-1 concentrations. In contrast, fasting FFA and integrated glucagon levels after glucose or meal ingestion as well as female gender were positively related to GLP-1 concentrations. Incretin levels were unrelated to measures of glucose control or insulin secretion.

Conclusions: Deteriorations in glucose homeostasis can develop in the absence of any impairment in GIP or GLP-1 levels. This suggests that the defects in GLP-1 concentrations previously described in patients with long-standing type 2 diabetes are likely secondary to other hormonal and metabolic alterations, such as hyperglucagonaemia. GIP and GLP-1 concentrations appear to be regulated by different factors and are independent of each other.