Growth Hormone-Releasing Hormone in Diabetes

Abstract

Growth hormone-releasing hormone (GHRH) is produced by the hypothalamus and stimulates growth hormone synthesis and release in the anterior pituitary gland. In addition, GHRH is an important regulator of cellular functions in many cells and organs. Expression of GHRH G-Protein Coupled Receptor (GHRHR) has been demonstrated in different peripheral tissues and cell types, including pancreatic islets. Among the peripheral activities, recent studies demonstrate a novel ability of GHRH analogs to increase and preserve insulin secretion by beta-cells in isolated pancreatic islets, which makes them potentially useful for diabetes treatment. This review considers the role of GHRHR in the beta-cell and addresses the unique engineered GHRH agonists and antagonists for treatment of type 2 diabetes mellitus. We discuss the similarity of signaling pathways activated by GHRHR in pituitary somatotrophs and in pancreatic beta-cells and possible ways as to how the GHRHR pathway can interact with glucose and other secretagogues to stimulate insulin secretion. We also consider the hypothesis that novel GHRHR agonists can improve glucose metabolism in Type 2 diabetes by preserving the function and survival of pancreatic beta-cells. Wound healing and cardioprotective action with new GHRH agonists suggest that they may prove useful in ameliorating certain diabetic complications. These findings highlight the future potential therapeutic effectiveness of modulators of GHRHR activity for the development of new therapeutic approaches in diabetes and its complications.

Keywords: GLP-1; diabetic complications; insulin; islet; pancreatic beta-cell.

Figure 1

Mechanism of the action of GHRH on Ca²⁺ and K⁺ channels: coupling with protein kinase A (PKA) and protein kinase C (PKC) systems. This diagram illustrates the coupling of the Ca²⁺ and K⁺ channels with GHRH receptors. cAMP–PKA system mediates the action of GHRH on voltage-gated Ca²⁺ currents, and the PKC system is essential for the action of GHRH on voltage-gated K⁺ currents in somatotropes. AC, adenylyl cyclase; PLC, phospholipase C. Reprinted by permission from Macmillian Publishers Ltd., from Ref (23), Figure 11.

Figure 2

Schematic of the beta-cell signaling pathways and hypothetical role of GHRHR. Arrows indicate activation or an increase in concentration. The line ending with a bar indicates inhibition or closure. Glucose metabolism increases the ATP/ADP ratio, leading to the closure of K_ATP channels, reduction of K⁺ efflux, membrane depolarization, increase of intracellular Ca²⁺, and insulin secretion. Glucose also leads to insulin secretion through amplifying pathways that are independent of K_ATP channels. Carbachol stimulation enhanced insulin secretion via the acetylcholine (muscarinic) receptor and phospholipase C pathways. IP₃ is inositol 1,4,5-trisphosphate, DAG is diacylglycerol. As depicted, GLP-1 and GHRH both enhance insulin secretion via the cAMP pathway.