When blood sugar levels fall too low, the body normally mounts a rapid hormonal defence to restore them. But in people who experience repeated episodes of low blood sugar, this protective response often weakens or fails altogether. A new study now sheds light on why.
Researchers in RDM’s Oxford Centre for Diabetes, Endocrinology and Metabolism have discovered that previous episodes of hypoglycaemia alter how cells within the pancreas communicate, reducing the release of glucagon - the hormone responsible for raising blood glucose levels when they fall dangerously low.
The study, published in Nature Metabolism, shows that after hypoglycaemia, pancreatic delta cells produce too much inhibitory hormone somatostatin, preventing sufficient glucagon release. This heightened suppression persists even when glucose levels drop again, effectively dampening the body’s natural counter-regulatory response. As a consequence, the body remains in a low-glucose state for longer, increasing discomfort and potential danger.
‘Glucagon is one of the body’s most important defences against hypoglycaemia,’ said Quan Zhang, Associate Professor of Endocrine Cell Physiology and lead author of the paper.
‘Our findings show that prior low-glucose episodes change the balance of signals inside the pancreas, making it harder for this defence to be activated when it is needed most.’
A cellular explanation for a clinical problem
Clinicians have long observed that hypoglycaemia increases the risk of further hypoglycaemic episodes. Until now, the biological mechanisms behind this effect have remained poorly understood.
Using a combination of mouse models and isolated human pancreatic tissue, the researchers found that earlier hypoglycaemia enhances inhibitory signalling from neighbouring pancreatic cells, suppressing glucagon release.
Crucially, the effect was not due to damage or loss of glucagon-producing cells, but to changes in how pancreatic cells communicate.
Implications for diabetes research
The findings help explain why people with diabetes, particularly those treated with insulin, can lose their ability to sense and respond to falling blood sugar levels over time. This impaired counter-regulatory response increases the risk of severe hypoglycaemia, which can be dangerous and life-threatening.
The research identifies a specific signalling pathway that could be explored in future studies aimed at improving the body’s natural protection against hypoglycaemia.