The neuropeptide Y system consists of neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP), which are a group of short (36 amino acid) peptides that play a key role in the regulation of energy homeostasis. The NPY system is widely expressed in the central nervous system as well as in peripheral tissues. The growth, survival, and general secretory function of insulin-producing cells have all been shown to benefit from persistent activation of pancreatic beta-cell neuropeptide Y1 receptors (NPY1R’s). In this context, it has been demonstrated that enzymatically stable PYY(1-36) peptides from phylogenetically old fish operate as long-acting, powerful, and precise NPY1R agonists. The fact that abnormal beta- and alpha-cell secretory activity characterizes diabetes as a metabolic illness suggests that NPY1R regulation may have highly plausible anti-diabetic potential. Alpha and beta cells have a similar transcriptome despite playing opposing roles in blood glucose regulation, and it is conceivable that SL-PYY(1- 36) may impact transdifferentiation of both cell types to contribute to the observed NPY1R-mediated changes in pancreatic islet shape.
In a recent study published in Frontiers in Endocrinology, British researchers Dr. Ryan Lafferty, Dr. Neil Tanday, Dr. Charlotte Moffett, Professor Peter Flatt and Professor Nigel Irwin from the Ulster University together with Professor Professor Frank Reimann and Professor Fiona Gribble at University of Cambridge used transgenic mice and traced alpha- and beta-cell lineages to investigate the role of transdifferentiation of alpha- and beta-cells in the improvements of pancreatic islet architecture brought on by the administration of SL-PYY(1-36) peptide in diabetes. The new study specifically investigated the effects of prolonged NPYR1 activation on islet cell composition and alpha- and beta-cell lineage transitions using streptozotocin (STZ) diabetic transgenic GluCreERT2;ROSA26-eYFP and Ins1Cre/+;Rosa26-eYFP mouse models.
In their studies the research team turn to an ancient species of fish called sea lamprey in a bid to find a better way to treat diabetes. Sea lampreys are native to the Atlantic Ocean, are found along the North American coast from Newfoundland and Labrador to Florida, and also inhabit the eastern North Atlantic and the Baltic, Adriatic, and Mediterranean seas. Sea lampreys live in marine environments but spawn in freshwater rivers and streams. These strange-looking fish are rendered particularly uncanny by their boneless, tooth-lined mouth. They are also parasitic, feeding on the blood of other fish. The researchers previously found that these aquatic-dwellers may provide a better type of neuropeptide Y (1-36) that has improved biological effects on pancreatic cells. They created an enzymatically stable, long-acting PYY (1–36) peptides of the native sea lamprey neuropeptide Y to improve the therapeutic benefits of sustained activation of NPYR1’s in diabetes. They tried in the new study to explain what makes neuropeptide Y1 receptor (NPYR1) agonists, sea lamprey PYY(1-36) (SL-PYY(1-36)), interesting is their ability to improve glucose regulation in diabetes by targeting pancreatic islets.
Both GluCreERT2; Rosa26-eYFP and Ins1Cre/+;Rosa26-eYFP STZ-diabetic transgenic mice experienced typical pancreatic islet beta-cell death, acute insulin insufficiency, and increases in blood glucose as a result of repeated low dosage STZ administration. A more severe diabetic phenotype was seen in Ins1Cre/+;Rosa26-eYFP mice, which is interesting because there were noticeable differences between these transgenic mice in terms of STZ susceptibility and effects on body weight, food and fluid intake, as well as alpha-cell derived circulating glucagon and degree of hyperglycemia. In the present scenario, elevations in alpha- and beta-cell areas led to increases in islet area following 11-day SL-PYY (1-36) therapy in both diabetic transgenic mice. Intriguingly, STZ administration in GluCreERT2;Rosa26-eYFP animals reduced an apparent high intrinsic transition of glucagon positive alpha-cells to insulin positive beta-cells.
The authors findings showed that transdifferentiation of beta cells into alpha cells and maybe a lack of alpha cell dedifferentiation are plausible sources of the extra positively labeled glucagon cells in both STZ-diabetic models studied, that impairs glucose homeostasis. Most notably, STZ-induced deleterious islet cell transdifferentiation events appeared to be totally or partially reverted by SLPYY(1-36) therapy. Intriguingly, SL-PYY (1-36) therapy in both mice models lowered pancreatic glucagon content despite an increase in the alpha cell area. This could indicate that a sizable portion of alpha-cells are currently transitioning, perhaps toward a more beta-cell-like phenotype, and as a result have a lower glucagon concentration. SLPYY(1-36) had no influence on the alpha-cell secretion of circulating glucagon, but it is thought that any effect on glucagon would be more pronounced under fasting conditions, which were not examined in the current work. The GluCreERT2;Rosa26-eYFP transgenic model demonstrated a nearly full restoration of normoglycaemia, in contrast to Ins1Cre/+;Rosa26-eYFP mice, showing that exogenous peptide delivery can directly impact islet cell transdifferentiation.
In conclusion, the current work shows that SL-PYY(1-36)-mediated sustained NPYR1 activation dramatically improved overall metabolic control by preventing beta-cell loss and enhancing beta-cell function in chemically induced insulin-deficient diabetes. The transitioning of both islet alpha- and beta-cells appeared to be positively influenced by SL-PYY(1-36), in addition to enhanced beta-cell proliferation as well as apoptosis reduction. The potential for stable, long-acting NPYR1 agonists to induce persistent, disease-modifying advantages in diabetes, connected to a potential change of alpha cell activity and transdifferentiation of alpha to beta cells, is highlighted by this recently identified, positive islet cell lineage effect. The new study by the scientists from Ulster University and University of Cambridge is one step forward for the realisation of the full antidiabetic potential of this new drug candidate and its future translational benefits.
In a statement to Medicine Innovates Professor Nigel Irwin said: “We are really excited about the ability of our neuropeptide Y receptor modulating peptides from fish to reverse the primary underlying pathophysiological issue in all forms of diabetes, namely loss on insulin secreting beta cell mass. Our new therapy has translatable disease modifying benefits that are not seen with any of the current treatment options for diabetes – we are leading the way in unlocking a novel and exciting innovative approach for diabetes therapy”.
Lafferty RA, Tanday N, Moffett RC, Reimann F, Gribble FM, Flatt PR, Irwin N. Positive effects of NPY1 receptor activation on islet structure are driven by pancreatic alpha-and beta-cell transdifferentiation in diabetic mice. Frontiers in Endocrinology. 2021 ;12:633625.