title: 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.
authors.affiliation: University of Virginia, Department of Medicine, Charlottesville, Virginia 22908, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: O'Neill
authors.forename: Christine
authors.initials: C
authors.lastname: Lu
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Corbin
authors.forename: Poonam R
authors.initials: PR
authors.lastname: Sharma
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Dula
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Carter
authors.forename: James W
authors.initials: JW
authors.lastname: Ramadan
authors.forename: Wenjun
authors.initials: W
authors.lastname: Xin
authors.forename: Jae K
authors.initials: JK
authors.lastname: Lee
authors.forename: Craig S
authors.initials: CS
authors.lastname: Nunemaker
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D017209:Apoptosis / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D004343:Drug Implants; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D055104:Infusions, Subcutaneous; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood*; D015850:Interleukin-6 / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood*; D007515:Islets of Langerhans / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D011236:Prediabetic State / Q000097:blood* / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D013047:Specific Pathogen-Free Organisms; D046509:Tissue Culture Techniques
chemical_list: D004343:Drug Implants; D007328:Insulin; D053583:Interleukin-1beta; D015850:Interleukin-6; D011994:Recombinant Proteins; D005947:Glucose