GLP-1 secretion: No acute affect on insulin

Take another look at the popular hypothesis that suggests type 2 diabetes has an acute effect on the secretion of GLP-1 and that lower GLP-1 secretion has an acute effect on insulin. It doesn't work that way, said Michael Nauck, MD, PhD, Diabeteszentrum Bad Lauterberg, Bad Lauterberg, Germany. Decreased GLP-1 secretion is not part of the pathophysiology of type 2 diabetes.

"The majority of papers show very close to normal secretions of GLP-1 and GIP compared to controls," Dr. Nauck explained. "GLP-1 probably does not have a significant impact on insulin in the short term."

The key is timing, Dr. Nauck continued. Total GLP-1 secretion is reduced by about 53% in patients with type 2 diabetes. But the decrease in secretion compared to normal control subjects does not begin until about an hour after eating, either a mixed meal or oral glucose. The ramp up of GLP-1 secretion is nearly identical in diabetic patients and controls for the first 30 to 60 minutes after eating.

Four factors in GLP-1 secretion
More detailed analysis shows that GLP-1 secretion is dependent on four factors: age, body mass index (BMI), glucagon levels, and free fatty acids.

Increasing age and increasing levels of free fatty acids are both associated with increased levels of GLP-1. Higher BMI and higher glucagon levels are associated with decreased levels of GLP-1.

Patients with diabetes are typically older and heavier, with elevated glucagon and elevated free fatty acids, Dr. Nauck said. The different interaction among these four factors in each individual seems to control GLP-1 secretion.

"There is no general abnormality of GLP-1 secretion in type 2 diabetes," he said. It is the individual variation that makes the difference."

Multiple drugs can affect GLP-1 secretion, he added, including metformin, sitagliptin and voglibose. Trials with other agents are under way, including human GLP-1 analogs.