Glucagon-Like Peptide-1 Protects Human Islets against Cytokine-Mediated β-Cell Dysfunction and Death: A Proteomic Study of the Pathways Involved

Abstract

Glucagon-like peptide-1 (GLP-1) has been shown to protect pancreatic β-cells against cytokine-induced dysfunction and destruction. The mechanisms through which GLP-1 exerts its effects are complex and still poorly understood. The aim of this study was to analyze the protein expression profiles of human islets of Langerhans treated with cytokines (IL-1β and IFN-γ) in the presence or absence of GLP-1 by 2D difference gel electrophoresis and subsequent protein interaction network analysis to understand the molecular pathways involved in GLP-1-mediated β-cell protection. Co-incubation of cytokine-treated human islets with GLP-1 resulted in a marked protection of β-cells against cytokine-induced apoptosis and significantly attenuated cytokine-mediated inhibition of glucose-stimulated insulin secretion. The cytoprotective effects of GLP-1 coincided with substantial alterations in the protein expression profile of cytokine-treated human islets, illustrating a counteracting effect on proteins from different functional classes such as actin cytoskeleton, chaperones, metabolic proteins, and islet regenerating proteins. In summary, GLP-1 alters in an integrated manner protein networks in cytokine-exposed human islets while protecting them against cytokine-mediated cell death and dysfunction. These data illustrate the beneficial effects of GLP-1 on human islets under immune attack, leading to a better understanding of the underlying mechanisms involved, a prerequisite for improving therapies for diabetic patients.

Absence of Glucagon and Insulin Action Reveals a Role for the GLP-1 Receptor in Endogenous Glucose Production

“…As a result, plasma concentrations of a-cell-derived glucagon and GLP-1 rise dramatically (Table 1) (17,26). Because GLP-1R activation helps regulate glucose homeostasis (26)(27)(28)(29), we investigated whether GLP-1R expression plays a role in maintaining euglycemia in insulin-deficient Gcgr 2/2 mice. For these studies, Glp-1r 2/2 mice were crossed with Gcgr +/2 mice to produce double heterozygous breeders that enabled the generation of animals lacking both genes.…”

The skeleton in the closet: actin cytoskeletal remodeling in β-cell function

“…We have observed glucose-stimulated morphological changes at the ␤-cell surface that are reminiscent of actin and FA remodeling in cell migration (103,104), and adhesion to a biologically compatible ECM enhances both GSIS and ␤-cell survival (16,42). Glucose-stimulated spreading of ␤-cells coincides with reorganization of actin stress fibers into thick networks and the phosphorylation of the two main FA proteins FAK and paxillin (Fig.…”

“…Pathological modification of the ECM in type 2 diabetes, for example by high-fat diet, hyperglycemia-induced advanced glycation end-products (AGEs), or inflammatory cytokine-induced fibrosis, has thus been shown to participate in the insulin resistance state of insulin-targeted tissues (muscle, adipose tissue, and liver) and could impair ␤-cell function in a similar fashion (4,50,59,107,138,146,147). Deleterious cytokines that are elevated in the circulation of individuals with type 2 diabetes directly affect the expression of proteins of different functional classes including the actin cytoskeleton in ␤-cells (103); perhaps this may also occur in target cells to modulate their insulin sensitivity.…”

Brusatol inhibits the response of cultured beta-cells to pro-inflammatory cytokines in vitro

“…Thus, in RAW 264.7 cells IFNg-dependent iNOS induction is inhibited by the immunosuppressive cytokine TGF-b1 through enhanced protein degradation [16]. Similarly, the metabolic hormone GLP-1 (glucagon-like peptide-1) stimulates iNOS protein degradation and attenuates iNOS protein induction in RINm5F beta-cells challenged with IL-1b [17,18]. Both signaling factors, TGFb1 and GLP-1, inhibit iNOS protein expression without any effect on iNOS gene transcription induced by pro-inflammatory cytokines [16,17].…”