Circulating Levels of IL-1B+IL-6 Cause ER Stress and Dysfunction in Islets From Prediabetic Male Mice

Abstract

Elevated levels of circulating proinflammatory cytokines are associated with obesity and increased risk of type 2 diabetes, but the mechanism is unknown. We tested whether proinflammatory cytokines IL-1B+IL-6 at low picogram per milliliter concentrations (consistent with serum levels) could directly trigger pancreatic islet dysfunction. Overnight exposure to IL-1B+IL-6 in islets isolated from normal mice and humans disrupted glucose-stimulated intracellular calcium responses; cytokine-induced effects were more severe among islets from prediabetic db/db mice that otherwise showed no signs of dysfunction. IL-1B+IL-6 exposure reduced endoplasmic reticulum (ER) calcium storage, activated ER stress responses (Nos2, Bip, Atf4, and Ddit3 [CHOP]), impaired glucose-stimulated insulin secretion, and increased cell death only in islets from prediabetic db/db mice. Furthermore, we found increased serum levels of IL-1B and IL-6 in diabetes-prone mice at an age before hyperglycemia was exhibited, suggesting that low-grade systemic inflammation develops early in the disease process. In addition, we implanted normal outbred and inbred mice with subcutaneous osmotic mini-pumps containing IL-1B+IL-6 to mimic the serum increases found in prediabetic db/db mice. Both IL-1B and IL-6 were elevated in serum from cytokine-pump mice, but glucose tolerance and blood glucose levels did not differ from controls. However, when compared with controls, isolated islets from cytokine-pump mice showed deficiencies in calcium handling and insulin secretion that were similar to observations with islets exposed to cytokines in vitro. These findings provide proof of principle that low-grade systemic inflammation is present early in the development of type 2 diabetes and can trigger ER stress-mediated islet dysfunction that can lead to islet failure.

IL-1β reciprocally regulates chemokine and insulin secretion in pancreatic β-cells via NF-κB

“…6). Thus, nitric oxide accumulation most likely prevents the release of calcium from internal storage depots, which is consistent with reduced insulin release observed in our studies and complementary to findings from previous studies (38). Collectively, we interpret these data to indicate that the mitochondria are responsive to both nitric oxide and metabolic signals and that an initial increase in intracellular nitric oxide production acts as a rheostat to rapidly and reversibly diminish insulin secretion in response to a specific inflammatory signal (e.g., IL-1␤) via multiple mechanisms.…”

MiR-301a Mediates the Effect of IL-6 on the AKT/GSK Pathway and Hepatic Glycogenesis by Regulating PTEN Expression

“…Mixture of IL-6 and IL-1B, not only IL-6, was used in their experiments. They found that low-grade inflammation could trigger β-cell decline early in the development of type 2 diabetes, and suggested that IL-1B and IL-6 might have a synergistic effect on β-cell function [27]. In the present study, 16μg/ml IL-6 was used in vivo , as previously described in Reference 6 in which mice chronically treated for 5 days with hIL-6 (16μg/ml) with Azlet pumps.…”

Endothelial PPAR-γ provides vascular protection from IL-1β-induced oxidative stress

“…Concentrations of 500 pg/ml IL-1␤ are also commonly seen in a systemic inflammatory response syndrome, which is associated with endothelial dysfunction in the rat aorta (28). Serum levels of 30 pg/ml IL-1␤ have also been observed in young db/db mice compared with control mice, a threefold increase compared with control mice (32). Thus, the concentrations of IL-1␤ (5-500 pg/ml) used in the present study have pathobiological relevance.…”