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Updated: Feb 23, 2026
Fat-Covered Islet Transplantation Using Epididymal White Adipose Tissue
Published on: May 25, 2021
Inhibition of Y1 receptor signaling improves islet transplant outcome
Kim Loh1,2, Yan-Chuan Shi1,3, Stacey Walters4
1Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, 2010, Australia.
Abstract:
Failure to secrete sufficient quantities of insulin is a pathological feature of type-1 and type-2 diabetes, and also reduces the success of islet cell transplantation. Here we demonstrate that Y1 receptor signaling inhibits insulin release in β-cells, and show that this can be pharmacologically exploited to boost insulin secretion. Transplanting islets with Y1 receptor deficiency accelerates the normalization of hyperglycemia in chemically induced diabetic recipient mice, which can also be achieved by short-term pharmacological blockade of Y1 receptors in transplanted mouse and human islets. Furthermore, treatment of non-obese diabetic mice with a Y1 receptor antagonist delays the onset of diabetes. Mechanistically, Y1 receptor signaling inhibits the production of cAMP in islets, which via CREB mediated pathways results in the down-regulation of several key enzymes in glycolysis and ATP production. Thus, manipulating Y1 receptor signaling in β-cells offers a unique therapeutic opportunity for correcting insulin deficiency as it occurs in the pathological state of type-1 diabetes as well as during islet transplantation.Islet transplantation is considered one of the potential treatments for T1DM but limited islet survival and their impaired function pose limitations to this approach. Here Loh et al. show that the Y1 receptor is expressed in β- cells and inhibition of its signalling, both genetic and pharmacological, improves mouse and human islet function.
Insights
Blocking Y1 receptor signaling in pancreatic beta cells enhances insulin secretion, offering a new therapeutic strategy for type-1 diabetes and improving islet transplantation success by boosting insulin production.
Area of Science:
- Endocrinology
- Molecular Biology
- Diabetes Research
Background:
- Insulin deficiency is central to type-1 and type-2 diabetes.
- Impaired islet cell function limits the success of islet transplantation therapies.
Purpose of the Study:
- To investigate the role of Y1 receptor signaling in pancreatic beta cells.
- To explore the therapeutic potential of modulating Y1 receptor activity for diabetes treatment and islet transplantation.
Main Methods:
- Examined Y1 receptor expression and signaling in mouse and human islets.
- Utilized genetic Y1 receptor deficiency and pharmacological Y1 receptor antagonists.
- Assessed effects on insulin secretion, hyperglycemia, and diabetes onset in mouse models.
- Investigated downstream molecular mechanisms involving cAMP and CREB pathways.
Main Results:
- Y1 receptor signaling was found to inhibit insulin release from beta cells.
- Genetic deletion or pharmacological blockade of Y1 receptors improved insulin secretion.
- Transplantation of Y1 receptor-deficient islets accelerated glycemic control in diabetic mice.
- Y1 receptor antagonist treatment delayed diabetes onset in non-obese diabetic mice.
- Y1 receptor signaling suppresses cAMP production, down-regulating glycolysis and ATP synthesis.
Conclusions:
- Inhibition of Y1 receptor signaling in beta cells enhances insulin secretion.
- Targeting Y1 receptors presents a promising therapeutic avenue for type-1 diabetes and islet transplantation.
- Modulating Y1 receptor activity can improve beta cell function and potentially correct insulin deficiency.
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