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GLP-1 Slows Hypoglycemia

Glucagon-like peptide 1 (GLP-1) slows the accelerated gastric emptying associated with hypoglycemia, according to a crossover study….

According to Dr. Mark P. Plummer from University of Adelaide in Australia, “The physiological response to hypoglycemia in health involves a dramatic acceleration in gastric emptying to increase nutrient delivery to the small intestine.”

“We were surprised that, in contrast to the islet cell effects, exogenous GLP-1 attenuated such a powerful counter-regulatory mechanism,” he said.

During the postprandial phase, GLP-1 lowers glucose primarily by slowing gastric emptying. Whether this happens during hypoglycemia has not been studied before.

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The team enrolled 10 healthy volunteers aged 50 to 75 years in a randomized crossover study. The participants underwent concurrent measurements of gastric emptying, blood glucose concentrations, and glucose absorption twice with blood glucose concentrations maintained at euglycemia and twice during a period of insulin-induced hypoglycemia. They received infusions of GLP-1 or placebo during each period.

Gastric retention was less during both periods of hypoglycemia (with and without GLP-1) than during euglycemia, consistent with more rapid gastric emptying, according to researchers.

Administration of GLP-1, however, was associated with a profound slowing of gastric emptying during euglycemia and a significant but less dramatic slowing of gastric emptying during hypoglycemia (compared with placebo).

GLP-1 also significantly reduced glucose absorption during both hypoglycemia and euglycemia. Glucose absorption was strongly and inversely correlated with gastric emptying.

The current American Diabetes Association guidelines for the management of type 2 diabetes support the combination of a GLP-1 agonist with a sulfonylurea or insulin. While GLP-1 agonists have a low risk of hypoglycemia, the risk is, not surprisingly, increased by this combination. Given that hypoglycemia in the community is managed with an oral carbohydrate load and accelerating gastric emptying is an important counter-regulatory response to expedite glucose absorption, it was important to establish whether GLP-1 agonists would inappropriately slow gastric emptying in this setting.

“From the study we found that exogenous GLP-1 attenuates, but does not abolish, this response,” Dr. Plummer said.” “We should emphasize that the research environment is ‘artificial’ in that the blood glucose was ‘clamped’ at hypoglycemia whereas in practice it would rise spontaneously following the meal. It is also reassuring that in large clinical trials of combined GLP-1 agonist and basal insulin, the occurrence of severe hypoglycemia such as loss of consciousness or seizure has been very low.”

“The results of our study have highlighted a potential safety implication for the combination of GLP-1 agonists with agents known to induce hypoglycemia,” Dr. Plummer said. “We would view these results as hypothesis generating and supportive of ongoing research into the gastrokinetic properties of GLP-1 agonists during hypoglycemia in patients with type 2 diabetes.”

Published online before print March 5, 2014, doi: 10.2337/dc13-1813 Diabetes Care March 5, 2014