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GLP-1 Agonist Interaction with Insulin-Induced Hypoglycemia

A study shows GLP-1 agonists slow the acceleration of gastric emptying that occurs as a result of insulin-induced hypoglycemia….

Glucagon-like peptide 1 (GLP-1) receptor agonists are used as monotherapy, secondary therapy with other oral agents, and in combination with basal insulin for management of type 2 diabetes. Though they are unlikely to cause hypoglycemia when used alone, they have a greater potential to do so when used in combination with other medications known to cause hypoglycemia, such as insulin or sulfonylureas. Hypoglycemia is known to accelerate gastric emptying in both healthy and diabetic patients, while hyperglycemia slows gastric emptying. In healthy subjects, GLP-1 agonists have no effect on the counterregulatory hormonal response to insulin-induced hypoglycemia, though their effect on gastric emptying during periods of hypoglycemia is yet to be studied. Researchers therefore designed a study to determine whether GLP-1 agonists will slow the acceleration of gastric emptying that occurs as a result of acute hypoglycemia in healthy patients.

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A total of 10 participants were included in this study, all age 50-75 years. Patients were required to be healthy, and were excluded if they had diabetes, BMI ≥30kg/m2, impaired renal function, anemia, were smokers, consume >20g/day of alcohol, receive any meds known to affect GI motility or glycemia, or if they have a history of gastric or small intestinal surgery. The study was randomized and double-blind, and involved observing the participants on four separate days. Researchers stabilized the patient’s blood glucose at hypoglycemia or euglycemia using a glucose/insulin clamp after the patient had been in the corresponding ranges for hypoglycemia or euglycemia for 15-45 minutes. Participants then received intravenous GLP-1 agonist or placebo. At time T=0, study subjects then ingested 100g beef mince labeled with 20 MBq99Tc-sulfur-colloid and 3g of 3-O-methyl-glucose (a marker of glucose absorption) dissolved in 150mL of water. Scintigraphy was used from T=0 to T=180 minutes to observe gastric emptying, and serum 3-OMG was taken at 15-minute intervals.

Results showed gastric emptying to be accelerated during hypoglycemia, as was expected. Glucose absorption was also accelerated during hypoglycemia. Administration of GLP-1 agonist resulted in slowed gastric emptying in the participants with euglycemia, while in the patients with hypoglycemia, acceleration of gastric emptying was markedly diminished in the patients administered the GLP-1 agonist when compared to the placebo. Glucose absorption also decreased substantially in the hypoglycemic patients given GLP-1 agonists.

In conclusion, this study showed that in healthy patients, exogenous GLP-1 agonists, when administered acutely, attenuate the acceleration of gastric emptying that occurs secondary to insulin-induced hypoglycemia. In doing so, they also lower the rate of small intestinal carbohydrate absorption. This is new information as previously, this was only known to occur at “normal” blood glucose concentrations. The mechanism by which this occurs is still unknown, requiring further studies to determine the contribution of peripheral and central mechanisms.

Practice Pearls:
  • GLP-1 agonists attenuate, but do not eliminate, the acceleration of gastric emptying that occurs as a result of hypoglycemia in healthy patients.
  • This effect of GLP-1 agonists should be considered when prescribing other medications that influence gastric emptying to patients using this drug class.

Plummer, MP et al. “Glucagon-Like Peptide 1 Attenuates the Acceleration of Gastric Emptying Induced by Hypoglycemia in Healthy Subjects” Diabetes Care. 2014; 38:7p.