Why hypoglycemia-induced glucagon secretion becomes impaired in diabetes

By Dr. Chinta SidharthanReviewed by Danielle Ellis, B.Sc.Sep 27 2024

New findings raise the possibility of promising therapeutic strategies for the management of hypoglycemia in type 1 diabetes patients. 

In a recent study published in Nature Metabolism, a team of European researchers used polygenic mouse models of human type 1 diabetes to determine the underlying mechanisms of impaired hypoglycemia-induced glucagon secretion.

Background

Type 1 diabetes is an autoimmune disorder in which the body's immune cells attack the β-cells that produce insulin. Insulin regulates blood sugar levels by allowing cells to absorb glucose from the bloodstream. However, type 1 diabetes also involves the dysregulation of the hormone glucagon, which is secreted in the pancreas in response to hypoglycemia and stimulates the liver to release stored glucose into the bloodstream.

The disruption of the glucagon response in individuals with type 1 diabetes leads to dangerously low levels of blood sugar, contributing to close to 10% of the mortality among type 1 diabetes patients. In mouse models of type 1 diabetes, the secretion of glucagon for the counter-regulation of blood sugar levels is restored when treated with somatostatin receptor antagonists. However, the underlying mechanisms of this restored glucagon secretion and whether the same mechanism is effective in humans remains unclear.

About the study

The present study used a widely recognized type 1 diabetes mouse model, the non-obese diabetic or NOD mice, to understand the impaired hypoglycemia-induced secretion of glucagon in type 1 diabetes. The researchers compared the biological mechanisms associated with glucagon secretion in NOD mice with those in non-diabetic mice.

The mice's blood glucose levels were monitored regularly, and they were studied at different ages and compared in various experimental settings. Additionally, other genetically modified mouse models were used to investigate specific cellular activities.

The study also used human islet cells obtained from donors with and without type 1 diabetes, which were cultured for two days before the hormone secretion patterns were studied. The islet cells from the pancreas of the NOD and non-diabetic mice were also isolated and cultured for further analysis.

The researchers performed live-cell calcium imaging on the islet cells, where the cells were immobilized in custom chambers. They also conducted time-lapse imaging using a confocal microscope. The data obtained from this was analyzed to normalize fluorescence signals and calculate the calcium ion oscillation frequency.

The islet cells were also fixed in paraformaldehyde, permeabilized, and then incubated with primary and secondary antibodies to stain for glucagon, insulin, and somatostatin. A glucometer and enzyme-linked immunosorbent assay (ELISA) was used to measure the plasma levels of glucose and glucagon, respectively, before and after insulin injections. In some of the experiments, somatostatin receptor antagonists were also administered.

Furthermore, electrophysiological recordings were conducted for the δ-cells, the endocrine cells in the pancreatic islets that produce somatostatin, which regulates the secretion of insulin and glucagon. Additionally, optogenetic analyses, where light-sensitive proteins are introduced into cells to enable light-based control of cellular activity, were conducted on both β- and δ-cells of the islets.

Molecular methods such as ribonucleic acid (RNA) extraction, copy deoxyribonucleic acid (cDNA) synthesis, and quantitative polymerase chain reaction (qPCR) were conducted to measure gene expression and for glycogen measurements in liver tissue.

Results

The study reported a 97% reduction in the insulin content in the pancreas and a significant decrease in the islet area with no change in the glucagon content. In non-diabetic mice, low blood sugar resulted in strong stimulation of glucagon secretion, but in the NOD mice, the response to hypoglycemia was substantially weaker. However, the capacity to produce and secrete glucagon remained unaffected in the NOD mice, indicating that the problem lay not in the production of the hormone but in the regulation.

The study further found that the NOD mice showed a marked increase in the secretion of somatostatin, which inhibits the release of glucagon, explaining why somatostatin receptor antagonists were effective in mouse models of type 1 diabetes. These findings highlighted the role of excessive somatostatin secretion in the impaired glucagon function in type 1 diabetes.

The study also revealed that the electrical coupling between the β-cells and the somatostatin-producing δ-cells was disrupted in type 1 diabetes. Normally, the activity of the δ-cells would be suppressed by the β-cells in hypoglycemic conditions, preventing the release of somatostatin, which would result in the secretion of glucagon. However, the destruction of β-cells in type 1 diabetes results in the unchecked secretion of somatostatin, inhibiting glucagon release.

Similar disruptions were observed in the human islet cells, with elevated levels of somatostatin and low glucagon secretion even under hypoglycemic conditions. These results suggested that the inhibition of somatostatin could restore the secretion of glucagon, providing a potential therapeutic strategy for the management of hypoglycemia in type 1 diabetes patients.

Conclusions

Overall, the study found that the impaired secretion of glucagon in type 1 diabetes is due to the excessive secretion of somatostatin due to disrupted regulation of δ-cells by the β-cells. Blocking the somatostatin receptors could potentially restore the secretion of glucagon, providing a promising therapeutic strategy for the management of hypoglycemia in type 1 diabetes patients.