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A research group led by Dr. Kimitaka Shibue (diabetic endocrinologist) at the Medical Research Institute Kitano Hospital (located at 2-4-20 Ogimachi, Kita-ku, Osaka; President: Nobuya Inagaki), a public interest incorporated foundation, in collaboration with the Joslin Diabetes Center (affiliated with Harvard Medical School) in the United States, has for the first time elucidated the function of Sec31A, a molecule that protects alpha cells, another key factor in diabetes. This result deepens our understanding of how to treat diabetes more safely while preventing hypoglycemia, and brings a new perspective to diabetes research.
The results of this research were published in the international academic journal Nature Communications on October 15, 2025.
The main cause of diabetes is well known to be the decline in function and death of beta cells*2, which secrete the hormone "insulin"*1, which lowers blood sugar. However, pancreatic islets*3 also contain alpha cells*5, which secrete the hormone "glucagon*4," which raises blood sugar, and these cells play an important role in stabilizing blood sugar levels.
Glucagon is a hormone that acts on the liver during hypoglycemia to stimulate glucose production and restore blood glucose levels. If this regulation does not work properly, severe hypoglycemia accompanied by loss of consciousness and convulsions can occur, which can be life-threatening. Therefore, maintaining alpha cell function is another important pillar for diabetic patients to continue safe treatment.
In diabetes, pancreatic islet cells are exposed to various cellular stresses, such as endoplasmic reticulum stress (ER stress)*6 and oxidative stress*7, due to stimuli such as chronic hyperglycemia and inflammation. If these stresses continue for a long time, beta cells undergo cell death and insulin secretion declines. On the other hand, alpha cells within the same pancreatic islets are known to survive relatively well even in these diverse stress environments. Why are only alpha cells able to withstand the same stressful environment? The mechanism behind this has not been clear until now.
Through treating patients with diabetes and those who have undergone pancreatectomy*8, we have seen many cases in which severe hypoglycemia significantly restricts daily life and makes it difficult to continue treatment. This clinical reality led us to want to clarify how alpha cells maintain their function even in harsh environments - this was the starting point for this research.
To elucidate this mechanism, our research group conducted genome-wide CRISPR screening*9 using mouse-derived alpha cells (αTC6 cells). Furthermore, we performed in vivo verification using nematodes (C. elegans), and analysis using human type 1 diabetes pancreatic islets and human alpha cell pseudoislets*10, using a consistent approach from animals to humans to analyze the stress response of alpha cells.
As a result, we discovered that Sec31A*11, a known molecule involved in intracellular transport, controls the stress resistance of α cells.
Furthermore, RNA analysis using human pseudo-islets revealed that the molecules and pathways activated downstream of Sec31A differ between α and β cells, indicating that Sec31A forms distinct networks depending on the cell type, even within the same islet, supporting different survival strategies.
In the treatment of diabetes, it is just as important to prevent hypoglycemia as it is to treat hyperglycemia. This research is the first in the world to reveal the molecular basis of the survival ability of alpha cells, and it may lead to new ideas for preventing severe hypoglycemia and maintaining pancreatic islet function in clinical settings.
In the future, we will analyze the regulatory mechanism of Sec31A in detail and aim to apply it to drug control and cell protection.
This research was initiated as an international collaborative study with the Joslin Diabetes Center (affiliated with Harvard Medical School) in the United States while Researcher Shibue was studying abroad. After returning to Japan, it was continued and completed with the support of the research system at the Kitano Hospital Medical Research Institute and the Kitano Cadet*12 research grant.
*1 Insulin: A hormone secreted from beta cells that lowers blood sugar. Diabetes is a disease in which this secretion or action is impaired.
*2 β (beta) cells: Cells in the pancreatic islets that secrete insulin. They play a role in lowering blood sugar, and their number decreases in diabetes.
Or function may be impaired.
*3 Pancreatic islets: A collection of hormone-secreting cells scattered throughout the pancreas. These cells include insulin-producing beta cells and glucagon-producing cells.
These cells contain alpha cells that secrete α-glucan, and play a central role in maintaining a constant blood sugar level.
*4 Glucagon: A hormone secreted from alpha cells that acts on the liver to raise blood sugar. It has the opposite effect to insulin.
Prevents hypoglycemia.
*5 α (alpha) cells: Cells present in the pancreatic islets that secrete the hormone glucagon, which increases blood sugar.
It has a restorative effect.
*6 Endoplasmic reticulum stress (ER stress): A stress placed on the endoplasmic reticulum, which produces proteins within cells, preventing proteins from being produced correctly.
This condition can lead to cell death in diabetes and aging.
*7 Oxidative stress: A condition in which active oxygen increases in the body, damaging cells and tissues. This can cause problems such as diabetes and lifestyle-related diseases.
*8 Post-pancreatectomy diabetes: Diabetes that occurs after partial or total removal of the pancreas. Because both insulin (which lowers blood sugar) and glucagon (which raises blood sugar) are reduced, blood sugar levels fluctuate widely and hypoglycemia is likely to occur. It requires management that is different from regular diabetes.
*9 CRISPR screening: Destroying many genes in a cell one by one, and then applying conditions such as drugs to identify which genes are affected.
Comprehensive genetic analysis technology to determine whether the offspring are affected by the condition. This allows for unbiased discovery of important genes.
do.
*10 Pseudo-islet: A pancreatic islet structure artificially formed by collecting human alpha cells and beta cells in a test tube. It resembles a human pancreatic islet.
An experimental model that can reproduce various reactions.
*11 Sec31A: A molecule that transports proteins inside cells by packaging them in vesicles. It has previously been known to be involved in intracellular transport.
However, this study demonstrates a novel role for regulating stress resistance in α cells.
*12 Kitano Cadet: This is the organization's program for fostering young medical researchers. Young doctors and researchers with a strong desire to pursue research are selected as "Kitano Cadets" and are given opportunities to work in both clinical and research fields. The program aims to discover and develop the next generation of medical talent and contribute to the development of society through the advancement of medical research.
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