Hypoglycemia and Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists

Glucagon-like peptide 1 (GLP-1) is a hormone of 30 amino acids produced in intestinal epithelial endocrine L-cells by differential processing of the proglucagon gene. The present state of knowledge on the processes responsible for post-translational processing and regulating proglucagon gene expression in the brain and the intestines is reviewed.

The article delves into the molecular processes and cues that trigger the production of GLP-1 in response to food consumption. Sensory neurons in the intestine and liver that express the GLP-1 receptor may convey the potential of GLP-1 since the hormone is quickly degraded and inactive by the enzyme dipeptidyl peptidase IV even before it leaves the stomach.

So, it’s crucial to differentiate between hormone measures (representing endocrine actions) and hormone measurements (representing total L-cell secretion and, by extension, potential neuronal actions), which includes both the intact hormone and its metabolites.

In order to prevent postprandial glucose excursions, GLP-1 has been hypothesized to primarily act as an incretin hormone by stimulating insulin production and inhibiting glucagon secretion. Additionally, studies suggest it may function as an enterogastrone and is a component of the “ileal brake” mechanism, potentially suppressing gastrointestinal motility and secretion. Appetite and food intake seem to be physiologically regulated by GLP-1 as well.

These effects have prompted the investigation of GLP-1 and GLP-1 receptor agonists as potential research candidates in the context of type 2 diabetes. Research suggests that the development of obesity may be influenced by decreased secretion of GLP-1, whereas postprandial reactive hypoglycemia might be caused by oversecretion.

“Incretin mimetics” are a class of substances that have recently been added to the arsenal of antidiabetics researched in correlation to type 2 diabetes mellitus (T2DM). These substances block glucagon secretion and increase insulin release from pancreatic β-cells in a glucose-dependent manner, which appears to be more effective in hyperglycemic conditions.

Hypoglycemia was thought to be less common with this family of compounds compared to insulin secretagogues like sulphonylureas. Hypoglycemia in functional normoglycemic research models has been suggested to be an effect of GLP-1 receptor agonists, suggesting that their activity is not as glucose-dependent as previously believed. The risk depends on other individual characteristics, and other studies purported that they may not cause hypoglycemia.

This review summarizes the research on the hypoglycemic potential of GLP-1 receptor agonists.

GLP-1 Peptide and Hypoglycemia

Solid research data does not yet support the likelihood of hypoglycemia caused by a single GLP-1 agonist. For type 2 diabetic research models, GLP-1 receptor agonists have suggested promising results in glucose control. Neither the potential for weight gain nor the danger of hypoglycemia has been speculated about GLP-1 receptor agonists.

Hypoglycemia, according to reviews, is impossible in type 2 diabetic research models due to insulin resistance and reduced insulin responsiveness. On the other hand, 30% of models examined also indicated hypoglycemia.

However, type 2 diabetic models may not experience hypoglycemia as a result of their impaired insulin sensitivity and resistance, as was the case in the other studies that suggested hypoglycemic phenotype in conjunction with GLP-1 agonists and other substances like sulphonylureas.

Because of their potential impact on glycemic control—which may be difficult to attain at times—GLP-1 receptor agonists have been regarded as a viable choice since their discovery.

GLP-1 Peptide and Insulin

The 2014 Lancet study evaluated the potential and effectiveness of IdegLira, a fixed-ratio mix of insulin degludec and liraglutide, compared to each substance given alone. Research models of type 2 diabetes were randomly allocated to receive daily concentrations of IDegLira, insulin degludec, or liraglutide in the 26-week randomized experiment. It was predicted that a combination of insulin plus a GLP-1 receptor agonist would increase the risk of hypoglycemia; this was supported by the report that IDegLira had 1.8 confirmed hypoglycemic incidents per subject-year, liraglutide had 0.2, and insulin degludec had 2.6.17 The LixiLan-L study looked at 736 research models whose type 2 diabetes mellitus did not appear to be well managed by basal insulin or any combination of 1 or 2 substances that reduce blood sugar. More reductions in HbA1c and no significant variations in the incidence of hypoglycemia were suggested in research models presented with iGlarLixi (insulin glargine/lixisenatide titratable fixed-ratio combination) compared to those presented with insulin glargine.

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References

[i] Labarre J. Sur Les Possibilites d’un Traitement Du Diabete par I’incretine. 1932.

[ii] Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741-744.

[iii] Näslund E, Bogefors J, Skogar S, et al. GLP-1 slows solid gastric emptying and inhibits insulin, glucagon, and PYY release in humans. Am J Physiol. 1999;277:R910-R916.

[iv] Shah M, Vella A. Effects of GLP-1 on appetite and weight. Rev Endocr Metab Disord. 2014;15:181-187.

[v] Davies MJ, D’Alessio DA, Fradkin J, et al. Correction to: management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the american Diabetes association (ADA) and the european association for the study of Diabetes (EASD). Diabetologia. 2019;62:873-2498.