Role of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in HypoglycemiaGlucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the post translational processing are reviewed.
GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor.
Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions.
The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the "ileal brake" mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake.
Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia. See figure 1 and 2 below.
A relatively recent addition to the arsenal of antidiabetic drugs used for the treatment of type 2 diabetes mellitus (T2DM) has been the “incretin mimetics,” a group of drugs that work on the glucagon-like peptide-1 (GLP-1) receptor and enhance insulin secretion from the pancreatic β-cells in a glucose-dependent manner, more potently in hyperglycemic conditions, while suppressing glucagon secretion at the same time.
Therefore, it was assumed that this class of drugs would have a lower risk of hypoglycemia than insulin secretagogues like sulphonylureas. However, GLP-1 receptor agonists have been proposed to cause hypoglycemia in healthy normoglycemic subjects implying that their action is not as glucose-dependent as once thought. Other studies concluded that they might not induce hypoglycemia and the risk is dependent on other individual factors. However, the FDA announced that the 12 GLP-1 receptor agonists currently available on the market had potential safety signs and evaluated the need for regulatory action.
In this review, researchers provide an overview of the studies that investigated the possible hypoglycemic effect of GLP-1 receptor agonists. In addition, the review describes other adverse effects of GLP-1 receptor agonist treatment.
To date, there is no clear evidence supporting the probability of sole GLP-1 agonist-induced hypoglycemia. GLP-1 receptor agonists have shown effective outcomes of glycemic control in type 2 diabetic patients especially in the elderly patients who are already taking other drugs for different conditions. GLP-1 receptor agonists have not been linked to weight gain and the possible risk of hypoglycemia has not been demonstrated.
Our review suggests that hypoglycemia cannot occur in type 2 diabetic patients because of their insulin resistance and impaired insulin response. However, 1 clinical trial,11 reported 3 instances of hypoglycemia out of 10 healthy patients.
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Daria Ja’arah, Mazhar Salim Al Zoubi, Gamal Abdelhady, Firas Rabi,and Murtaza M Tambuwala. Role of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Hypoglycemia. Clinical Medicine Insights: Endocrinology and Diabetes Volume 14: 1–10 (2021), doi: doi/10.1177/11795514211051697