The delta cells in the pancreatic islets are like sensors or switches that activate the other cells in the islets, either in contexts of low sugar (alpha cells) or high sugar (beta cells). The three types of cells function in a circuit and need an electrical balance to remain healthy. Illustration by Rita Félix

Read the full story here (in Portuguese) — exclusive edition of Público newspaper

The pancreas regulates numerous metabolic functions and its malfunctioning is behind diseases that are highly prevalent today, such as diabetes. To better understand this complex organ, scientist Quan Zhang is building a laboratory at the Center for Neuroscience and Cell Biology at the University of Coimbra (CNC-UC, part of the Center for Innovative Biomedicine and Biotechnology — CiBB) dedicated to studying the physiology of pancreatic islets, small endocrine organs that play a central role in metabolism. The lab will use electrophysiology and live-cell imaging, an approach currently unique in the country.

Although pancreatic islets (or Langerhans islets) have been known for over a century, exactly how they work remains not completely understood. They are found throughout the pancreas and contain mainly alpha, beta, and delta cells, which secrete glucagon (that raises glucose), insulin (that inhibits glucose), and somatostatin, a powerful inhibitor of glucagon and insulin. The balance of pancreatic islets depends on the proper regulation between these cells and how effectively they communicate with one another.

“We are interested in understanding how islet cells respond to fluctuations in nutrient levels and circulating factors, including hormones and other signaling molecules. We study not only beta cells, that secrete insulin, but also alpha cells, which protect us from hypoglycaemia [low glucose levels], and delta cells, that are master regulators of islet function, as well as their dynamic communication with each other. It may explain how these interactions change in diabetes and how we can repair them”, explains Quan Zhang.

In a 2024 study published in Nature Metabolism, Zhang and his team found that abnormalities in electrical communications between beta and delta cells underlie the dysregulation of insulin and somatostatin secretion in type 1 diabetes, in which most beta cells are destroyed by the immune system. Their most recent article, also published in Nature Metabolism in January this year, takes a step further on the study of electrical dysfunctions in pancreatic islets.

In this study, Zhang discovered that delta cells have a highly sensitive system that detects the activity and secretion of alpha cells. In healthy organisms, this allows delta cells to precisely adjust somatostatin release, targeting only overactive alpha cells while sparing normal ones, keeping glucagon secretion within an optimal range.

“Using electrophysiology and live-cell imaging, together with transgenic models and human islets, we discovered that delta cells are central coordinators of islet function: they continuously monitor the activity of neighboring alpha and beta cells, integrate this information, and fine-tune insulin and glucagon secretion accordingly. Delta cells are like ‘motion-detection’ switches: their sensing of the activity of neighbouring alpha and beta cells must be very fast and precise”, says Quan Zhang.

Scientist Quan Zhang in the laboratory he is establishing at CNC-UC

However, these mechanisms deteriorate in type 1 diabetes, and “miscommunication” between alpha and delta cells makes it more difficult for the body to recover from low glucose levels. The study sheds light on the long-standing clinical observation that “hypoglycaemia begets hypoglycaemia”. By increasing negative feedback of delta cells, an episode of hypoglycaemia impairs the future glucagon response of alpha cells. With each episode, recovery is more difficult for the cells of a diabetic pancreas, which can create a dangerous and recurring cycle of hypoglycaemia. Patients who have experienced it are more prone to future hypoglycaemic attacks and to iatrogenic hypoglycaemia (a sharp drop in glucose caused by insulin administration).

The scientist also discovered that a single episode of hypoglycaemia can “sensitize” delta cells: if it lasts longer than one hour, hypoglycaemia can change delta cell function, suppressing the glucagon response if another low glucose event occurs within the following three days. This makes recovery from dangerous hypoglycaemia much more difficult. “It seems that the islets can remember experienced hypoglycaemia, so we decided to call this phenomenon a ‘metabolic memory’—which can lead to longer and more severe hypoglycaemic episodes, further weakening the body’s defence against recurrent hypoglycaemia, creating a dangerous vicious cycle”, remarks Zhang.

The discovery that this metabolic memory in delta cells can be prevented by a fast-acting glucagon receptor blocker suggests a potential therapeutic strategy for preventing recurrent hypoglycaemia. Future studies will explore drugs that modulate intra-islet signaling as a new approach for treating diabetes.

The study published in 2024 indicated that the loss of electrical connection in diabetes between beta (insulin) and delta (somatostatin) cells is at the root of the inhibition of glucagon secretion. “In healthy people, when glucose levels are high, this electrical connection contributes to the counterregulation of insulin secretion; at low glucose levels, it should act as an ‘electrical brake’ to prevent the release of somatostatin—which, if it does not happen, suppresses the release of glucagon and leads to hypoglycemia”, explains the scientist.

Zhang has been studying the islets of Langerhans using electrophysiology, a technique that measures the electrical activity of cells. He is reviving a field that had been largely absent Portugal, but in which the CNC-UC was an international reference since the 1980s, through the work of a pioneer lab of islet electrophysiology. For Quan, it is urgent to continue this work, especially in Portugal, where 14 percent of the population is diabetic, the second-highest diabetes prevalence rate in Europe.

Sugar (glucose) is the essential fuel for normal body function, but its level in the blood must be kept within the right range. Diabetes is a disease of uncontrolled blood sugar, and either too low or too high can cause severe damage to the body. It affects around 10 percent of worldwide population and is very difficult to reverse, causing severe long-term issues. Some therapies, such as insulin replacement, often cause too low blood glucose, a dangerous condition called hypoglycaemia.

The articles Antecedent hypoglycaemia impairs glucagon secretion by enhancing somatostatin-mediated negative feedback control (January 13, 2026) and Loss of electrical β-cell to δ-cell coupling underlies impaired hypoglycaemia-induced glucagon secretion in type-1 diabetes (September 23, 2024), are both published in the journal Nature Metabolism.

Inês Amado da Silva with CNC-UC