A new study has revealed a significant reason why individuals with type 1 diabetes (T1D) have impaired glucagon production. The research, which utilized both non-obese diabetic (NOD) mice and human islet cells, provides insight into the biological mechanisms that hinder glucagon secretion and proposes a potential new therapeutic approach.
In this study, researchers explored why glucagon secretion is impaired in T1D. They discovered that while the ability of the pancreas to produce glucagon in NOD mice remains intact, the secretion of the hormone in response to low blood sugar is significantly disrupted. The cause of this disruption was traced to elevated levels of somatostatin, a hormone that suppresses glucagon release.
Somatostatin, produced by pancreatic delta cells, acts as a brake on glucagon secretion. The researchers found that in T1D, somatostatin levels are abnormally high due to a breakdown in communication between insulin-producing beta cells and delta cells. The destruction of beta cells, a hallmark of T1D, leads to unchecked somatostatin release because the normal signalling pathway that limits somatostatin secretion during low glucose is disrupted. By blocking somatostatin receptors in diabetic NOD mice, the researchers were able to restore normal glucagon secretion. This finding suggests that targeting somatostatin signalling could be a promising new approach to managing hypoglycaemia in T1D.
The researchers also tested their findings in human islet cells from T1D patients and observed similar results, indicating that the phenomenon is not limited to mice but may also apply to humans. This discovery bridges a significant gap in understanding why glucagon secretion is impaired in T1D patients, a question that has puzzled scientists for years.
One of the key insights from the study is that the destruction of beta cells not only leads to insulin deficiency but also disrupts the electrical communication between beta cells and delta cells, which is crucial for regulating somatostatin release. In healthy individuals, when blood sugar drops, beta cells send signals that suppress somatostatin release, allowing glucagon to be secreted. In T1D, however, this ‘electric brake’ on somatostatin is lost due to beta cell destruction, leading to excessive somatostatin release and impaired glucagon secretion.
Advanced techniques such as live-cell imaging, optogenetics, and gene expression analysis allowed the researchers to precisely map out how this process unfolds in real time. Their work provides new insights into the cellular mechanisms behind glucagon dysregulation in T1D. The implications of this research are significant. Hypoglycemia is one of the most dangerous complications of T1D, accounting for up to 10% of the mortality in patients with the disease. Current treatments focus on managing insulin levels, but the new findings suggest that targeting somatostatin could offer a novel therapeutic strategy to prevent hypoglycemia by restoring glucagon secretion.
Although more research is required to turn these findings into clinical treatments, the study presents promising new avenues for enhancing the management of T1D. By targeting somatostatin signaling, researchers could potentially develop therapies that not only tackle insulin deficiency but also correct glucagon dysregulation, providing improved protection against hypoglycemia for individuals with T1D.
References
- Hill TG, Gao R, Benrick A, Kothegala L, Rorsman N, Santos C, et al. Loss of electrical β-cell to δ-cell coupling underlies impaired hypoglycaemia-induced glucagon secretion in type-1 diabetes. Nat Metab. 2024 Sep 23;
- Gubitosi-Klug RA, Braffett BH, Hitt S, Arends V, Uschner D, Jones K, et al. Residual β cell function in long-term type 1 diabetes associates with reduced incidence of hypoglycemia. The Journal of Clinical Investigation [Internet]. 2021 Feb 2 [cited 2024 Oct 14];131(3). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843223/