Evidence that low-grade systemic inflammation can induce islet dysfunction as measured by impaired calcium handling.
In obesity and the early stages of type 2 diabetes (T2D), proinflammatory cytokines are mildly elevated in the systemic circulation. This low-grade systemic inflammation exposes pancreatic islets to these circulating cytokines at much lower levels than seen within the islet during insulitis. These low-dose effects have not been well described. We examined mouse islets treated overnight with a low-dose cytokine combination commonly associated with inflammation (TNF-alpha, IL-1 beta, and IFN-gamma). We then examined islet function primarily using intracellular calcium ([Ca(2+)](i)), a key component of insulin secretion and cytokine signaling. Cytokine-treated islets demonstrated several features that suggested dysfunction including excess [Ca(2+)](i) in low physiological glucose (3mM), reduced responses to glucose stimulation, and disrupted [Ca(2+)](i) oscillations. Interestingly, islets taken from young db/db mice showed similar disruptions in [Ca(2+)](i) dynamics as cytokine-treated islets. Additional studies of control islets showed that the cytokine-induced elevation in basal [Ca(2+)](i) was due to both greater calcium influx through L-type-calcium-channels and reduced endoplasmic reticulum (ER) calcium storage. Many of these cytokine-induced disruptions could be reproduced by SERCA blockade. Our data suggest that chronic low-grade inflammation produces circulating cytokine levels that are sufficient to induce beta-cell dysfunction and may play a contributing role in beta-cell failure in early T2D.
Dula
Stacey B
SB
Department of Medicine, University of Virginia, Charlottesville, 22908, United States.
Jecmenica
Mladen
M
Wu
Runpei
R
Jahanshahi
Pooya
P
Verrilli
Gretchen M
GM
Carter
Jeffrey D
JD
Brayman
Kenneth L
KL
Nunemaker
Craig S
CS
D000138:Acidosis / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism / Q000633:toxicity; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology*; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D018836:Inflammation Mediators / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism
C506944:Atp2a1 protein, mouse; D020746:Calcium Channels, L-Type; D016207:Cytokines; D018836:Inflammation Mediators; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D005947:Glucose; D002118:Calcium
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