Growth hormone signaling in pancreatic β-cells—Calcium handling regulated by growth hormone

Deficiency in insulin secretion is a fundamental part in the pathogenesis of all forms of diabetes, determined by impaired secretory function and inadequate β-cell mass. Growth hormone (GH) is a multifunctional hormone, involved in cellular metabolism, mitogenesis and differentiation. In pancreatic islets, GH is involved in maintaining β-cell mass, stimulating islet hormone production and insulin secretion, and, therefore, plays a role in maintaining normal insulin sensitivity and glucose homeostasis. The intracellular events that convey the GH signal into various cellular responses remain incompletely understood. In this review, we discuss GH signaling in the β-cells, with emphasis on Ca2+ handling and insulin secretion regulated by human GH (hGH). hGH-stimulated rise in [Ca2+]i is dependent on extracellular Ca2+ and is mediated by Ca2+-induced Ca2+ release (CICR) in the β-cell. This process is triggered by hGH-stimulated activation of the non-receptor tyrosine kinases JAK2 and c-Src, which causes tyrosine phosphorylation of RyRs, resulting in sensitization of CICR. The rise in [Ca2+]i elicited by hGH is associated with an enhanced insulin secretion, effects that are mediated mainly through the prolactin receptor. These mechanisms indicate that a rise in [Ca2+]i elicited by activation of PRLR is JAK2-dependent and is associated with enhanced insulin secretion. In contrast, GH receptor-mediated increase in [Ca2+]i is JAK2-independent and is dissociated from insulin secretion.