The insulin that is released by the beta cells of the pancreas is the main regulator of blood sugar. Previous and current studies by a research group at the University of Lund in Sweden have identified about one hundred different receptors on the surface of beta cells, with a different functional impact on them. A few years ago, researchers from Lund University in collaboration with Sharjah University in the United Arab Emirates found that one of these receptors plays a key role in insulin release. The receptor is activated when it binds to a specific metabolite, derived from the metabolism of cholesterol in the liver. The results show that this oxidized cholesterol metabolite has the ability to increase insulin secretion by activating one of these identified surface receptors. Research has also indicated that the cholesterol metabolite also protects beta cells from cellular stress induced by chronic hyperglycemia, which is known to cause dysfunctional insulin secretion. In previous studies, this research team mapped more than 130 receptors found on the beta cell surface.
Over time, researchers have continued to study the function of some of them. For example, one of these is called GPRC5 and is a previously orphaned G protein receptor (ie with no known ligand) that could bind the active metabolite of vitamin A, retinoic acid. This receptor, however, has two subtypes, 5B and 5C, which bind to two completely different compounds. GPRC5B is the one that binds to glutamate, the amino acid neurotransmitter used in the brain and in many other body tissues; the 5C receptor, on the other hand, is the one that binds to retinoic acid. Importantly, the 5B receptor was able to explain the effect of glutamate on insulin production, an effect that until then was believed to depend only on glutamate metabolism. These receptors were able to protect beta cells from toxic insults, programmed cell death, and improve insulin secretion in response to blood sugar. Then they turned onto the GPR183 receptor (orphan 183 protein G receptor).
GPR183 has been shown to have a greater effect on insulin release in human rat and donor cells when activated. Furthermore, the pancreatic islets of diabetic subjects have it in greater quantities than normal pancreases. And it appears exclusive to β cells while missing on α cells in human islets. The GPR183 agonist (the metabolite called 7,25-dioxy-cholesterol or 7α-25-DHC) enhanced insulin secretion and protected beta cells in human islets from oxidative damage triggered by excessive glucose concentrations. Silencing of GPR183 in INS-1 cells reduced the expression of the transcription factor genes Pdx1 and Maf-A (which regulate insulin synthesis), with concomitant reduced production of cyclic AMP, a second messenger that regulates secretion of insulin. Scholars believe the finding may be significant in another respect: people with high cholesterol are often overweight or obese. This could mean that their state is capable of producing more cholesterol metabolites capable of affecting this receptor.
The same (or almost) sequence of facts was recorded for the GPR142 receptor, the next one on which the research team has focused its interest. This receptor also appears to be distributed uniquely on both human and mouse beta cells and potentiates oral glucose loading-induced insulin release. When pancreatic islets are made genetically absent for this receptor, there is an increased local production of inflammatory factors such as interferon gamma, TNF-alpha and MCP-1, together with immune tolerance receptors TLR5 and TLR7. The first is a bacterial flagellin sensor and appears to be involved in chronic inflammatory bowel disease (IBD). From this, scientists think that the dysregulation of this receptor can act as a bridge between innate immunity and the onset of diabetes and conditions such as ulcerative colitis. TLR7, on the other hand, recognizes both cellular and viral RNA strands. In both cases, the bacterial and viral factor has been recognized to underlie the predisposition of the appearance of some forms of diabetes (post-rotavirus or post-enterovirus) and intestinal inflammation or autoimmunity.
Last year the research team published data concerning the P2Y14 receptor, a member of the G protein receptors that are activated by nucleotides and their analogues (P2X and P2Y). The P2Y14 receptor is selectively activated by a cellular metabolite known as UDP-glucose, a component of the glycosylation reactions that occur intracellularly in many types of cells, especially in hepatocytes, in the process of glycogen metabolism. UDP-glucose is also released in physiological and pathological conditions; among the latter, it has also been seen to be released from brain tumors, although the significance of this is not known. However, unlike GPR142, which enhances the glucose-induced release of insulin, the activation of P2Y14 by UDP-glucose has just the opposite effect. Instead of being protective, in case of excess glucose the activated P2Y14 receptor enhances cell death triggered by glucotoxic stress. UDP-glucose itself is able to modulate the ability of beta cells to replicate and regenerate.
All these data indicate that nature is not redundant. Assuming that half of the beta cell receptors have a positive effect on insulin and the other half a negative effect, they cannot all be activated by the same stimulus. The fact that each of them can be activated or blocked with a molecule, a metabolite or a drug, indicates that they exist for the purpose of responding to a wide spectrum of external stimuli which have the ultimate goal of maintaining the functioning of the pancreas and protecting it (or damage it) depending on the physiological or clinical context. A wonderful little molecular cross-section of Einstein’s famous saying “God doesn’t play dice”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Parandeh F et al. J Biol Chem 2020; 295(45) 15245–252.
Taneera J et al. Mol Cell Endocrinol. 2020; 499:110592.
Al-Amily IM et al. Pflugers Archives 2019; 471(4):633-645.
Amisten S et al. J Diabetes Complic. 2018; 32(9):813-818.
Amisten S et al., Salehi A. Endocr J. 2017; 64(3):325-338.