A research group including Professor Yusaku Iwasaki and Researcher Kento Ohbayashi of the Graduate School of Life and Environmental Sciences at Kyoto Prefectural University, along with the Center for Integrative Physiology at the Kansai Electric Power Medical Research Institute, has discovered that D-allulose, a type of rare sugar, enhances insulin sensitivity, thereby effectively improving high blood glucose with a smaller amount of insulin. This discovery raises expectations for the development of novel technologies to improve insulin resistance. The findings were published in Diabetes on May 1.
Provided by Kyoto Prefectural University
One of the primary causes of type 2 diabetes is insulin resistance, a condition where the efficacy of insulin declines. Previously, the research group had demonstrated that D-allulose promotes the secretion of glucagon-like peptide-1 (GLP-1), a gut hormone, thereby improving glucose tolerance. However, the exact mechanism by which it improved glucose tolerance remained unknown.
Therefore, in this study, the group aimed to clarify this mechanism through experiments using mice. First, when D-allulose was orally administered to type 2 diabetes model mice exhibiting hyperglycemia, GLP-1 was secreted from the gut, temporarily increasing insulin sensitivity and improving high blood glucose. Conversely, the administration had no effect on blood glucose levels in mice with normal blood glucose levels.
Next, it was shown that GLP-1 secreted from the gut collaborates with insulin secreted from the pancreas during hyperglycemia to strongly activate the vagal afferent neurons, which are visceral sensory neurons that connect the gut and the brain, thereby enhancing whole-body insulin sensitivity.
The vagal afferent neurons serve as a neural pathway that transmits visceral information to the brain. Many gastrointestinal and pancreatic hormones, whose secretion fluctuates after meals, act on the vagus neuron that innervates the digestive system.
This stimulation is converted into electrical signals and transmitted to the brain. When the functions of the vagal afferent neurons were suppressed using multiple methods, the insulin sensitivity-enhancing effect of D-allulose disappeared regardless of the method used.
In particular, the disappearance of this effect was remarkable when suppressing the function of GLP-1 receptor/IRS2-expressing neurons on the left side of the vagal afferent neurons.
It became clear that the vagal afferent neurons innervating the liver and the area around the hepatic portal vein are crucial for this insulin sensitivity-enhancing effect, and that signal transduction via the GLP-1 receptor and insulin receptor substrate 2 (IRS2) expressed in these regions is indispensable.
To verify the efficacy of D-allulose, a single dose was administered to severe type 2 diabetes model mice. It powerfully improved high blood glucose without causing excessive insulin secretion.
In contrast, a single dose of exendin-4 (generic name: exenatide), an existing GLP-1 receptor agonist used for treating type 2 diabetes, showed limited efficacy. Two types of hormones secreted after meals, GLP-1 and insulin, collaborate to act on the nervous system.
While existing drugs lower blood glucose levels by promoting insulin secretion, the study revealed that D-allulose improves high blood glucose by enhancing insulin sensitivity without excessively increasing insulin secretion. This could lead to new prevention and treatment strategies for diabetes that reduce the strain on the pancreas.
Iwasaki stated: "Enhancing insulin sensitivity and improving insulin resistance is one of the crucial challenges in diabetes treatment. We felt great surprise and anticipation when we found that a rare sugar, which is a dietary component, induces this effect and demonstrated efficacy outperforming an existing diabetes drug in mouse studies. Furthermore, we learned that the regulation of the autonomic nervous system is involved in this effect. Future research is expected to lead to the development of new prevention and improvement methods for type 2 diabetes utilizing dietary approaches."
Journal Information
Publication: Diabetes
Title: Gut-Derived GLP-1 Released by Rare Sugar d-Allulose Cooperates With Insulin to Activate Left-Sided Vagal Afferents and Enhance Insulin Sensitivity
DOI: 10.2337/db25-1134
This article has been translated by JST with permission from The Science News Ltd. (https://sci-news.co.jp/). Unauthorized reproduction of the article and photographs is prohibited.