Attenuation of insulin secretion by insulin-like growth factor 1 is mediated through activation of phosphodiesterase 3B

Abstract

Both insulin and insulin-like growth factor 1 (IGF-1) are known to reduce glucose-dependent insulin secretion from the ␤ cells of pancreatic islets. In this paper we show that the mechanism by which IGF-1 mediates this effect is in large part through activation of a specific cyclic nucleotide phosphodiesterase, phosphodiesterase 3B (PDE3B). More specifically, in both isolated pancreatic islets and insulin-secreting HIT-T15 cells, IGF-1 inhibits insulin secretion that has been increased by glucose and glucagonlike peptide 1 (GLP-1). Moreover, IGF-1 decreases cAMP levels in parallel to the reduction of insulin secretion. Insulin secretion stimulated by cAMP analogs that activate protein kinase A and also are substrates for PDE3B is also inhibited by IGF-1. However, IGF-1 does not inhibit insulin secretion stimulated by nonhydrolyzable cAMP analogs. In addition, selective inhibitors of PDE3B completely block the ability of IGF-1 to inhibit insulin secretion. Finally, PDE3B activity measured in vitro after immunoprecipitation from cells treated with IGF-1 is higher than the activity from control cells. Taken together with the fact that pancreatic ␤ cells express little or no insulin receptor but large amounts of IGF-1 receptor, these data strongly suggest a new regulatory feedback loop model for the control of insulin secretion. In this model, increased insulin secretion in vivo will stimulate IGF-1 synthesis by the liver, and the secreted IGF-1 in turn feedback inhibits insulin secretion from the ␤ cells through an IGF-1 receptormediated pathway. This pathway is likely to be particularly important when levels of both glucose and secretagogues such as GLP-1 are elevated.

Mechanisms of action of glucagon-like peptide 1 in the pancreas

“…Insulin and IGF-1 increase levels of PDE3B in β cells. Treatment of HIT-T15 cells (a hamster clonal β cell line) with IGF-1 (50 nM) roughly halved the insulin secreted in response to GLP-1 (10 nM) in the presence of high levels (12 mM) of glucose (Zhao et al, 1997). This directly correlated to an equivalent reduction in cAMP levels.…”

Cyclic Nucleotide Phosphodiesterase 3B Is a Downstream Target of Protein Kinase B and May Be Involved in Regulation of Effects of Protein Kinase B on Thymidine Incorporation in FDCP2 Cells

“…Insulin, IGF-1, or IL-4, each of which utilizes IRS proteins to initiate at least some of its receptor signaling cascades, activates PDE3 in adipocytes (16,17,21), FDCP2 cells, pancreatic ␤ cells (77), hepatocytes (78), and Xenopus oocytes (8,79,80). In these cells, some effects of the polypeptides are counterregulatory to those of cAMP, which increases lipolysis (19,20,81), inhibits cell proliferation/survival (41-55), stimulates insulin secretion (77) and glycogenolysis (82), and blocks meiosis (8), respectively.…”

Phosphorylation and activation of phosphodiesterase type 3B (PDE3B) in adipocytes in response to serine/threonine phosphatase inhibitors: deactivation of PDE3B in vitro by protein phosphatase type 2A

“…Since it has recently been shown that PDE3B is controlled by a variety of hormones in addition to insulin and catecholamines, such as leptin [12,13] Manganiello, unpublished work), IL-4 [11] and growth hormone [15], it is possible that the new phosphopeptides identified in this work contain sites phosphorylated by kinases activated by these signalling molecules. The identities of the kinases involved and the physiological significance of these phosphorylations are presently being investigated.…”

“…Pierce, T. Rahn Landstro$ m, M. Quon, E. Degerman and V. Manganiello, unpublished work). PDE3B has also been shown to be activated in FDCP2 cells in response to interleukin 4 (IL-4) [11], in pancreatic β-cells in response to IGF-I [12], leptin [13] and glucagon-like peptide 1 [13], in autoreactive CD4 + T cell clones specific for myelin basic protein in response to antigen stimulation [14] and has also been shown to be involved in Abbreviations used : PP, protein phosphatase ; PP1c, PP2Ac, catalytic subunits of PP1 and PP2A respectively ; IGF-I, insulin-like growth factor I ; PDE, phosphodiesterase ; C 13 E 12 , a non-ionic alkyl poly(oxyethylene glycol) detergent ; IL-4, interleukin 4. 1 To whom correspondence should be addressed (e-mail svante.resjo!medkem.lu.se).…”

“…The effects of insulin, growth hormone, IGF-I and IL-4 on PDE3B have been suggested to be important in antagonizing biological responses induced by cAMP, such as lipolysis in adipocytes [6,15,16], glycogenolysis in the liver [17], insulin secretion in β-cells [12,13] and inhibition of proliferation in FDCP2 cells. The cAMPmediated activation of PDE3B, presumably catalysed by protein kinase A, has been suggested to be important in feedback regulation of cAMP [18].…”