The following is a summary of “Mathematical Models of the Effect of Glucagon on Glycemia in Individuals With Type 2 Diabetes Treated With Dapagliflozin,” published in the June 2024 issue of Endocrinology by Yamada, et al.

For a study, researchers sought to shed light on the intricate hormonal and metabolic dynamics underlying the glucose-lowering effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors. These drugs have been shown to reduce blood glucose levels by enhancing urinary glucose excretion, yet their broader impact on hormonal regulation and metabolic status remains unclear.

To address this gap, they conducted hyperinsulinemic-euglycemic clamp and oral glucose tolerance tests in individuals with type 2 diabetes treated with the SGLT2 inhibitor dapagliflozin. Additionally, they analyzed data from similar tests performed on individuals with varying glucose tolerance levels who were not receiving SGLT2 inhibitor treatment, serving as a control group.

The analysis involved developing mathematical models to elucidate the feedback loops involving glucose and insulin (GI model) or glucose, insulin, and glucagon (GIG model). This approach allowed them to explore the intricate interactions between these key hormonal regulators and their impact on glycemia.

The results revealed notable differences in the hormonal regulation of glycemia between individuals treated with dapagliflozin and those not receiving SGLT2 inhibitor therapy. Specifically, the traditional metric of insulin sensitivity and secretion, known as the disposition index_/clearance, was found to be correlated with glycemia only in subjects not taking SGLT2 inhibitors. Conversely, in individuals treated with dapagliflozin, a metric representing glucagon sensitivity, secretion, and clearance (production index_/clearance) emerged as significantly correlated with blood glucose levels.

In conclusion, the findings highlighted the distinct alterations in hormonal regulation induced by SGLT2 inhibitor treatment, suggesting that the effect of insulin on blood glucose concentration may be modified, while glucagon may play a more prominent role in determining glycemia in individuals receiving these drugs. These insights contributed to a deeper understanding of the mechanisms underlying the therapeutic effects of SGLT2 inhibitors and may inform future approaches to optimize diabetes management.

Reference: academic.oup.com/jes/article/8/6/bvae067/7641923