G protein-coupled receptors (GPCRs) are the most abundant receptor family encoded by the human genome and are the targets of a high percentage of drugs currently in use or in clinical trials for the treatment of diseases such as diabetes and its associated complications. Thus orphan GPCRs, for which the ligand is unknown, represent an important untapped source of therapeutic potential for the treatment of many diseases. We have identified the previously orphan GPCR, GPR146, as the putative receptor of proinsulin C-peptide, which may prove to be an effective treatment for diabetes-associated complications. For example, we have found a potential role of C-peptide and GPR146 in regulating the function of the retinal pigment epithelium, a monolayer of cells in the retina that serves as part of the blood–retinal barrier and is disrupted in diabetic macular edema. However, C-peptide signaling in this cell type appears to depend at least in part on extracellular glucose concentration and its interaction with insulin. In this review, we discuss the therapeutic potential of orphan GPCRs with a special focus on C-peptide and GPR146, including past and current strategies used to ‘deorphanize’ this diverse family of receptors, past successes, and the inherent difficulties of this process.
Hepatic glucose production (HGP) and output are regulated by a complex system of hormones, receptors, signaling mechanisms, glycolytic and gluconeogenic enzymes, and many overlapping transcription factors. The proteins involved in HGP are attractive targets for antidiabetic therapy, yet better pharmacological interventions are still needed for treatment. Therefore, it is critical to identify and characterize new targets within HGP regulation. We identified a novel peptide, neuronostatin, encoded in the somatostatin prohormone that exerts effects in the central nervous system, the heart, and the pancreas. Neuronostatin is produced in the delta cells of the pancreatic islets and plays an important role in maintaining glucose homeostasis through enhancing glucagon secretion from the α cell and reducing insulin release from the β cell. In male rats, a bolus injection of neuronostatin significantly increased blood glucose over 30 minutes after administration. Likewise, the peptide delayed glucose clearance and diminished the insulin response to hyperglycemia in a glucose tolerance test. Our group also identified the orphan GPCR, GPR107, as a cognate receptor for the peptide. GPR107 is expressed in numerous tissues, including the liver. In searching for the role of neuronostatin in hepatic physiology, we observed that hepatocellular carcinoma cell line HEPG2 expressed GPR107. Thus, we hypothesized that neuronostatin would elicit a biologic effect on the liver using HEPG2 cell line as in‐vitro model. We found that treatment of HEPG2 cells with neuronostatin significantly elevated cFos mRNA expression, indicating that HEPG2 cells respond to the peptide. In addition, neuronostatin induced expression of gluconeogenic enzymes, such as phosphoenolpyruvate carboxykinase and glucose‐6‐phosphatase. These results indicate potential effects of neuronostatin on HGP, so we sought to determine if the effects of neuronostatin on blood glucose were due to increased glucagon secretion or due to a direct effect in the liver. In rats treated with a glucagon receptor antagonist, neuronostatin increased blood glucose, supporting a glucagon‐independent action on HGP. Thus, our results suggest that neuronostatin could play a physiologically relevant role in the liver and that GPR107 may be a new target in hepatic glucose production. Support or Funding Information National Institute of Health
The tight regulation of blood glucose with insulin and antidiabetic agents greatly increases the risk and dangers of hypoglycemia in patients with Type 1 and Type 2 Diabetes. In addition, repeated bouts of hypoglycemia diminish the sympathetic arms of the counterregulatory response and blunt awareness of symptoms, creating a vicious cycle of unawareness and increasingly severe hypoglycemia. The only option in preventing or reversing hypoglycemia unawareness is careful avoidance of hypoglycemia through close monitoring– an often unobtainable goal. There is great need for other therapies and better understanding of diabetic hypoglycemia. We recently identified a novel peptide, neuronostatin (NST), encoded in the somatostatin preprohormone and found in all somatostatin‐positive tissues and cells. However, the activity of NST is functionally distinct from other preprosomatostatin products. Furthermore, it appears the physiologic stimuli of the peptides are different and that the peptides are sequestered in separate secretory vesicles. Our group identified the orphan GPCR, GPR107, as a cognate receptor of NST. Through an interaction with GPR107, NST enhanced proglucagon mRNA expression and glucagon release from isolated islets and immortalized alpha cells. NST also reduced beta cell release of insulin in response to high glucose conditions in isolated islets. Based off our findings, we hypothesized that NST is a pancreatic component of the counterregulatory response to hypoglycemia. In support of our hypothesis, an infusion of NST substantially increased plasma glucose levels over a 30‐minute time period in male rats. Additionally, NST delayed glucose clearance and diminished the insulin response to hyperglycemia in a glucose tolerance test. Fasting blood glucose raised plasma NST levels in rats, and exposure to low glucose stimulated NST release from human islets. Further experiments will confirm the role of NST in preventing or reversing hypoglycemia and determine how NST plays a role in the complex relationships of islet regulation and signaling. We propose that NST could represent a novel therapeutic target for the treatment and prevention of hypoglycemia in diabetes.Support or Funding InformationThis work was completed with funding support from the NIH and NIDDK, and the Helmsley Charitable Trust.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Regulation of blood glucose is a tightly controlled system with numerous players, woven by both hyperglycemic and hypoglycemic agents that interact in secretion and signaling mechanisms. However, this complex system is deranged in both Type 1 and Type 2 Diabetes, in the response to hyperglycemia (insulin) and hypoglycemia (counterregulatory factors such as glucagon). In treating diabetes with insulin and antidiabetic agents, there is significant risk of hypoglycemia due to improper dosing or inadequate food intake. In addition, repeated bouts of hypoglycemia diminish the counterregulatory response and blunt awareness of symptoms, creating a vicious cycle of unawareness and increasingly severe hypoglycemia. There is great need for better understanding of the players and mechanisms in blood glucose maintenance, and specifically in diabetic hypoglycemia. We recently identified a novel peptide, neuronostatin (NST), encoded in the somatostatin prohormone and found in all somatostatin‐positive tissues. However, the activity of NST is functionally distinct from other prosomatostatin products. Furthermore, it appears the physiologic stimuli of the peptides are different and that the peptides are sequestered in separate secretory vesicles. Our group identified the orphan GPCR, GPR107, as a cognate receptor of NST. Through an interaction with GPR107, NST enhanced glucagon release from isolated islets and immortalized alpha cells. NST also reduced release of insulin in response to high glucose conditions in isolated islets. Based off our findings, we hypothesized that NST is a component of the pancreatic arm of the counterregulatory response. In support of our hypothesis, an infusion of NST substantially increased plasma glucose levels over 30 minutes in male rats, and diminished the insulin response to hyperglycemia in a glucose tolerance test. Additionally, antagonism of the glucagon receptor did not prevent the hyperglycemic effects of NST, suggesting the peptide can act independent of glucagon to increase blood glucose. In insulin‐induced hypoglycemia, NST blunts the drop in blood glucose, further reinforcing the role of NST in counterregulation. The secretion of NST release also appears tied to glucose levels. Fasting blood glucose raised plasma NST levels in rats and humans, and exposure to low glucose stimulated NST release from human islets. Further experiments will confirm the regulatory mechanisms involved in the release of NST, and the importance of its receptor, GPR107. We propose that NST could represent a novel therapeutic target for the treatment and prevention of hypoglycemia in diabetes. Support or Funding Information This work was funded by the NIDDK and the Helmsley Charitable Trust.
Neuronostatin (NST) is a 13-amino acid hormone derived from the somatostatin (SST) preprohormone that exerts metabolic and cardiovascular actions in many tissue types. In transformed alpha cell lines and isolated rat islets neuronostatin enhanced low glucose-stimulated proglucagon transcription and glucagon secretion1. Additionally, neuronostatin inhibited high glucose-stimulated insulin secretion from isolated rat islets, which was mirrored in vivo in rats subjected to an intra-arterial glucose tolerance test. Rats that received a bolus injection of neuronostatin followed by infusion glucose exhibited delayed glucose disposal and impaired insulin release, causing an increased peak blood glucose1. We, therefore hypothesized the ability of neuronostatin to act as a counterregularoty factor to protect against hypoglycemia. We found that Neuronostatin administered prior to an insulin tolerance test significantly reduced hypoglycemia compared to the saline control. In addition, we found that administration of exogenous Insulin significantly reduced Neuronostatin plasma levels. These data suggest Neuronostatin may act as a counterregulatory factor in adult, male rats to prevent hypoglycemia. However, after menopause or OVX, a precipitous decline in insulin sensitivity parallels an increase in fat mass, suggesting estrogens at physiological concentrations may maintain insulin action and glucose tolerance. We therefore investigated the neuronostatin-induced blood glucose changes in conscious, cycling females. We found blood glucose levels following neuronostatin administration decreased on diestrus, when both estrogen and progesterone levels are low, but not on proestrus or estrus. From these data we conclude that the metabolic actions of Neuronostatin are modulated by sex hormone status. Further studies are required to determine the contributions of chromosomal sex and individual sex hormones to these metabolic effects of Neuronostatin.1. Salvatori AS, Elrick MM, Samson WK, Corbett JA, Yosten GL. Neuronostatin inhibits glucose-stimulated insulin secretion via direct action on the pancreatic alpha-cell. Am J Physiol Endocrinol Metab. 2014;306:E1257–E1263. Saint Louis University Internal Funds This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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