Role of Phosphatidylinositol 3-Kinaseγ in the β-Cell: Interactions with Glucagon-Like Peptide-1

Abstract

Glucagon-like peptide-1 (GLP-1) increases beta-cell function and growth through protein kinase A- and phosphatidylinositol-3-kinase (PI3-K)/protein kinase B, respectively. GLP-1 acts via a G protein-coupled receptor, and PI3-Kgamma is known to be activated by G(betagamma.) Therefore, the role of PI3-Kgamma in the chronic effects of GLP-1 on the beta-cell was investigated using PI3-Kgamma knockout (KO) mice treated with the GLP-1 receptor agonist, exendin-4 (Ex4; 1 nmol/kg sc every 24 h for 14 d). In vivo, glucose and insulin responses were similar in PBS- and Ex4-treated KO and wild-type (WT) mice. However, glucose-stimulated insulin secretion was markedly impaired in islets from PBS-KO mice (P < 0.05), and this was partially normalized by chronic Ex4 treatment (P < 0.05). In contrast, insulin content was increased in PBS-KO islets, and this was paradoxically decreased by Ex4 treatment, compared with the stimulatory effect of Ex4 on WT islets (P < 0.05-0.01). Transfection of INS-1E beta-cells with small interfering RNA for PI3-Kgamma similarly decreased glucose-stimulated insulin secretion (P < 0.01) and increased insulin content. Basal values for beta-cell mass, islet number and proliferation, glucose transporter 2, glucokinase, and insulin receptor substrate-2 were increased in PBS-KO mice (P < 0.05-0.001) and, although they were increased by Ex4 treatment of WT animals (P < 0.05), they were decreased in Ex4-KO mice (P < 0.05-0.01). These findings indicate that PI3-Kgamma deficiency impairs insulin secretion, resulting in compensatory islet growth to maintain normoglycemia. Chronic Ex4 treatment normalizes the secretory defect, thereby relieving the pressure for expansion of beta-cell mass. These studies reveal a new role for PI3-Kgamma as a positive regulator of insulin secretion, and reinforce the importance of GLP-1 for the maintenance of normal beta-cell function.

Glucagon-like Peptide-1 Activation of TCF7L2-dependent Wnt Signaling Enhances Pancreatic Beta Cell Proliferation

“…However, another report indicates that PI3K is questionably required for the activation of Akt (57). Furthermore, in mice deficient in PI3K␥, no growth impairment of beta cells was observed (58). Although in most cell systems the actions of Akt in the activation of Wnt signaling are downstream of PI3K (56,59), there are exceptions; Akt may be activated by PI3K-independent mechanisms.…”

R-spondin1 deficiency in mice improves glycaemic control in association with increased beta cell mass

“…However, such discrepancies in null animal models are not without precedence. For example, although we have previously reported that the incretin hormone glucagonlike peptide-1 enhances beta cell mass in vivo in normal mice and induces beta cell proliferation in vitro, administration of GLP-1 to animals lacking Pi3kγ (also known as Pik3cg) causes a paradoxical reduction in both variables [25]. Similarly, despite the known effect of insulin-like growth factor-1 to enhance beta cell proliferation in vitro, beta cell-specific knockout of the insulin-like growth factor-1 receptor does not alter beta cell mass in vivo [30].…”

“…In vitro secretion assays Secretion studies using isolated mouse islets were performed as previously described by Li et al [25]. Briefly, islets were cultured overnight in 20 mmol/l glucose RPMI1640 (Gibco/Invitrogen, Burlington, ON, Canada) with 10% FBS and penicillin/streptomycin.…”

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

“…However there are at least two instances in which GLP-1R stimulation alleviated diabetes in rodent models in which there was a decrease in β cell mass. This can be attributed to the improvement in β cell function (Li et al, 2006) and/or a decrease in insulin resistance (Gedulin et al, 2005) therefore less β cell mass is required. Here we review in chronological order the studies in rodents where pancreatic endocrine mass has been modulated by treatment with GLP-1R agonists and studies in cell lines and isolated β cells that outline the mechanism by which this may occur (Fig.…”