In vivo JNK activation in pancreatic β-cells leads to glucose intolerance caused by insulin resistance in pancreas.

Abstract

Insulin resistance is a key condition in the development of type 2 diabetes. It is well established that exacerbated Jun NH2-terminal kinase (JNK) activity is involved in promoting insulin resistance in peripheral insulin-target tissues; however, this involvement is less documented in pancreatic β-cells. Using a transgenic mouse model, here we show that JNK activation in β-cells led to glucose intolerance as a result of impaired capacity to increase insulinemia in response to hyperglycemia. Pancreatic islets from these mice showed no obvious morphostructural abnormalities or decreased insulin content. In contrast, these islets failed to secrete insulin in response to glucose or insulin but were competent in succinate-, ketoisocaproate-, 3-isobutyl-1-methylxanthine (IBMX-), KCl-, and tolbutamide-induced insulin secretion. At the molecular level, JNK activation in β-cells inhibited insulin-induced Akt phosphorylation, pancreatic and duodenal homeobox 1 nucleocytoplasmic shuttling, and transcription of insulin-target genes. Remarkably, rosiglitazone restored insulin secretion in response to hyperglycemia in mice and insulin-induced insulin secretion and signaling in isolated islets. In conclusion, the mere activation of JNK suffices to induce insulin resistance in pancreatic β-cells by inhibition of insulin signaling in these cells, but it is not sufficient to elicit β-cell death. In addition, we provide the first evidence that thiazolidinediones exert insulin-sensitizing action directly on pancreatic β-cells.

• Authors: Jordi Lanuza-Masdeu, M Isabel Arévalo, Cristina Vila, Albert Barberà, Ramon Gomis, Carme Caelles
• Journal: Diabetes (Diabetes) Vol. 62 Issue 7 Pg. 2308-17 (Jul 2013) ISSN: 1939-327X [Electronic] United States
• PMID: 23349497 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Thiazolidinediones
• Rosiglitazone
• MAP Kinase Kinase 7

Topics

• Animals
• Glucose Intolerance (metabolism)
• Insulin Resistance (physiology)
• Insulin-Secreting Cells (drug effects, metabolism)
• MAP Kinase Kinase 7 (metabolism)
• MAP Kinase Signaling System (drug effects, physiology)
• Mice
• Mice, Transgenic
• Pancreas (drug effects, metabolism)
• Rosiglitazone
• Thiazolidinediones (pharmacology)