Glucose-dependent insulinotropic polypeptide signaling in pancreatic β-cells and adipocytes

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin to be identified. In addition to stimulating insulin secretion, GIP plays regulatory roles in the maintenance, growth and survival of pancreatic islets, as well as impacting on adipocyte function. The current review focuses on the intracellular signaling pathways by which GIP contributes to the regulation of β-cell secretion and survival, and adipocyte differentiation and lipogenesis. Studies on signaling underlying the insulinotropic actions of the incretin hormones have largely been carried out with glucagon-like peptide-1. They have provided evidence for contributions by both protein kinase A (PKA) and exchange protein directly activated by cyclic adenosine monophosphate (EPAC2), and their probable role in GIP signaling is discussed. Recent studies have shown that inhibition of the kinase apoptosis signal-regulating kinase 1 (ASK1) by GIP plays a key role in reducing mitochondria-induced apoptosis in β-cells through protein kinase B (PKB)-mediated pathways, and that GIP-induced post-translational modification of voltage- dependent K(+) (Kv) channels also contributes to its prosurvival role. Through regulation of gene expression, GIP tips the balance between pro- and anti-apoptotic members of the B-cell lymphoma-2 (Bcl-2) protein family towards β-cell survival. GIP also plays important roles in the differentiation of pre-adipocytes to adipocytes, and in the regulation of lipoprotein lipase expression and lipogenesis. These events involve interactions between GIP, insulin and resistin signaling pathways. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00196.x, 2012).

Keywords: Apoptosis; Glucose‐dependent insulinotropic polypeptide; Incretin.

Figure 1

Signaling pathways proposed to be involved in proximal events in glucose‐dependent insulinotropic polypeptide (GIP)‐mediated potentiation of glucose‐induced insulin secretion. (a) Evidence has been presented supporting roles for both protein kinase A (PKA) and cyclic adenosine monophosphate (cAMP)‐activated guanine nucleotide exchange factor (cAMP‐GEF)/exchange protein directly activated by cAMP (Epac) in the modulation of adenosine triphosphate (ATP)‐sensitive K⁺ (K_ATP) channels. Dissociation of cAMP‐Epac2 from sulfonulurea receptor 1 (SUR1) binding has been proposed to activate phospholipase C‐ε (PLCε) through Ras‐related protein 1 (Rap1), resulting in phosphatidylinositol 4,5 bisphosphate (PIP₂) metabolism and inhibition of adenosine triphosphate‐sensitive channel subunit, Kir6.2, membrane depolarization and activation of voltage‐dependent Ca²⁺ channels (VDCC). (b) Diacylglycerol‐activated PKCε potentiates calcium‐induced calcium release through ryanodine receptors and phosphatidylinositol trisphosphate (IP₃) stimulates Ca²⁺ release from IP₃ sensitive endoplasmic reticulum (ER) Ca²⁺ stores. PKA might act to sensitize the Ca²⁺ release channels (based on references 15, 20, 31, 36). AC, adenylyl cyclase; CAM, calmodulin; Gαs, stimulatory G protein α‐subunit, IP₃R, inositol trisphosphate receptor; P, phosphate; RyR, ryanodine receptor; SERCA, sarco(endo)plasmic reticulum Ca²⁺‐ATPase.

Figure 2

Proposed signaling pathways by which glucose‐dependent insulinotropic polypeptide (GIP) regulates endocytosis of voltage‐dependent K⁺ (Kv)2.1. Binding of GIP to its receptor (GIPR) activates protein kinase A (PKA) and, potentially, mitogen‐ and stress‐activated kinase‐1 (MSK‐1), resulting in phosphorylation of Kv2.1. Through an unknown mechanism, cyclic adenosine monophosphate‐response element binding protein binding protein (CBP) is translocated from the nucleus to the plasma membrane, where it acetylates Kv2.1. Potentiation of Kv2.1 internalization results in reduced K⁺ fluxes and reduced β‐cell apoptosis. AC, adenylyl cyclase; Ac, acetylated; CREB, cAMP‐response element binding protein; Gαs, stimulatory G protein α‐subunit; P, phosphorylated; TORC2, transducer of regulated cyclic adenosine monophosphate response element binding protein activity.

Figure 3

Glucose‐dependent insulinotropic polypeptide receptor (GIPR) and peroxisome proliferator‐activated receptor (PPAR)γ protein expression levels in adipose tissue depots from lean and obese Vancouver Diabetic Fatty (VDF) Zucker rats. Tissue was collected from 18‐week‐old rats and western blot analyses were carried out, with quantification by densitometry (n = 4–6 rats). Significance was tested using analysis of variance (anova) with Newman–Keuls post‐hoc test. **P < 0.05 vs lean control group. IBAT, interscapular brown adipose tissue.