Exp Clin Endocrinol Diabetes 2014; 122 - OP4_13
DOI: 10.1055/s-0034-1371988

The hepatokine fetuin-A associates with insulin resistance and induces inflammation but selectively improves cAMP-dependent insulin secretion of human islets

G Kaiser 1, 2, F Gerst 1, 2, N Stefan 1, 2, S Ullrich 1, 2, HU Haering 1, 2
  • 1University of Tuebingen, Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Tuebingen, Germany
  • 2Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tuebingen (IDM), Partner in the German Center for Diabetes Research (DZD), Tuebingen, Germany

Nonalcoholic fatty liver disease leads to an altered secretion of proteins, so called hepatokines. Previously, we found that increased plasma levels of the hepatokine fetuin-A strongly predicts the incidence of type-2 diabetes in humans. Fetuin-A inhibits insulin receptor signaling and augments inflammation. Interestingly, fatty acid-induced activation of TLR4 has been found to depend on fetuin-A. In humans with impaired glucose tolerance, plasma fetuin-A levels negatively correlate with insulin secretion. The present study aims to examine effects of fetuin-A in human islets.

Isolated islets from mouse and human donors received from the European Centers of Islet Transplantation (ECIT) were cultured in CMRL-1066 medium supplemented either with 0.6 mg/ml human fetuin-A or serum albumin as control for 48h. Changes in gene expression were analyzed by microarray and real-time PCR. Apoptotic cell death was estimated by TUNEL staining of isolated islets cells. Insulin secretion was evaluated by radioimmunoassay after static incubation of batches of 10 islets/0.5 ml modified Krebs-Ringer-bicarbonate buffer in the presence of test substances.

Fetuin-A increased 2-fold the production of interleukins, IL33, IL1b, IL24 and IL17RB, in human islets, and decreased the mRNA of CXCL10 and CXCL9 by 74% and 48%, respectively. Fetuin-A did not increase cell death under control culture conditions but reduced palmitic acid-induced apoptosis. Furthermore, glucose-induced insulin secretion and the augmentation by palmitate were not affected by fetuin-A. Most surprisingly, cAMP-induced potentiation of insulin secretion by 10µM forskolin was 4-fold higher in fetuin-A treated than in control islets.

These results suggest that fetuin-A affects the production of interleukins and cytokines in human islets but this effect does not contribute to palmitate-induced beta-cell death. In contrast, fetuin-A improved cAMP-dependent amplification of insulin secretion.