Poor GLP-1 Response Seen Before Type 2 Diabetes Develops


A Danish study found reduced endogenous levels of glucagon-like peptide-1 in persons with prediabetes. Perhaps the incretin system defect comes first.

Results of a Danish study have found that response to glucagon-like peptide-1 (GLP-1), which plays an important role in glucose regulation, begins to decrease prior to the development of type 2 diabetes and obesity.

“This finding indicates that alterations in GLP-1 release contribute to dysregulation of glucose metabolism and appetite rather than being a consequence of type 2 diabetes or obesity,” wrote researchers led by Kristine Fræch, of Steno Diabetes Center, Getofte, Denmark. “Since we found reduced endogenous GLP-1 levels and response in pre-diabetes, treatment with GLP-1 analogues could be relevant as part of a prevention strategy if weight loss attempts are unsuccessful.”

The ADDITION-PRO study included 1,462 participants who had normal glucose tolerance (n=774), pre-diabetes (n=523), or screen-detected type 2 diabetes (n=163). The researchers measured participants for circulating concentrations of glucose, insulin, and GLP-1 using oral glucose tolerance tests.

Compared with participants with a normal glucose tolerance, women characterized as having pre-diabetes or type 2 diabetes had a 25% lower GLP-1 response on the oral glucose tolerance test. In addition, both men and women with pre-diabetes or type 2 diabetes had between a 16% to 21% lower 120-minute GLP-1 concentration, and this finding was independent of the participant’s age and obesity.

Looking at those participants characterized as overweight or obese, the researchers found a 20% reduced GLP-1 response to oral glucose compared with normal weight individuals. This finding was independent of the participant’s glucose tolerance status.

Finally, study data also indicated that GLP-1 response had a positive association with insulin sensitivity, beta cell function, and age, but had an inverse association with body mass index and waist circumference.

“It should also be mentioned that any reduced GLP-1 response observed in our study population can either reflect an impaired release or an increased elimination of GLP-1,” the researchers noted. “However, as other studies have found similar elimination rates and gastric emptying rates of GLP-1 in individuals with and without diabetes, our findings of reduced GLP-1 response in pre-diabetes and diabetes are likely to reflect an impaired release of GLP-1.”


Fræch K, Torekov SS, Vistisen D, et al. Glucagon-like peptide-1 (GLP-1) response in oral glucose is reduced in pre-diabetes, screen-detected type 2 diabetes and obesity, and influenced by sex: the ADDITION-PRO study. Diabetes. Epub 2015 Feb 12.

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