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Abstract
Pro-inflammatory cytokines cause pancreatic beta cell failure during the development of type 2 diabetes. This beta cell failure associates with mitochondrial dysfunction, but the precise effects of cytokines on mitochondrial respiration remain unclear. To test the hypothesis that pro-inflammatory cytokines impair glucose-stimulated insulin secretion (GSIS) by inhibiting oxidative ATP synthesis, we probed insulin release and real-time mitochondrial respiration in rat INS-1E insulinoma cells that were exposed to a combination of 2 ng/mL interleukin-1-beta and 50 ng/mL interferon-gamma. We show that 24-h exposure to these cytokines dampens both glucose- and pyruvate-stimulated insulin secretion (P < 0.0001 and P < 0.05, respectively), but does not affect KCl-induced insulin release. Mirroring secretory defects, glucose- and pyruvate-stimulated mitochondrial respiration are lowered after cytokine exposure (P < 0.01). Further analysis confirms that cytokine-induced mitochondrial respiratory defects occur irrespective of whether fuel oxidation is coupled to, or uncoupled from, ATP synthesis. These observations demonstrate that pro-inflammatory cytokines attenuate GSIS by restricting mitochondrial pyruvate oxidation capacity. Interleukin-1-beta and interferon-gamma also increase mitochondrial superoxide levels (P < 0.05), which may reinforce the inhibition of pyruvate oxidation, and cause a modest (20%) but significant (P < 0.01) loss of INS-1E cells. Cytokine-induced INS-1E cell failure is insensitive to palmitoleate and linoleate, which is at odds with the cytoprotection offered by unsaturated fatty acids against harm caused by nutrient excess. Our data disclose a mitochondrial mechanism for cytokine-impaired GSIS in INS-1E cells, and suggest that inflammatory and nutrient-related beta cell failure emerge, at least partly, through distinct paths.
Highlights
Impaired glucose-stimulated insulin secretion (GSIS) by pancreatic beta cells (β-cells) contributes to the hyperglycemic state that characterizes type 2 diabetes [1]
INS-1E cells increased their insulin secretion rate 2.7-fold in response to 20 mM glucose, a stimulation that lowered to 1.4-fold when cells had been exposed to a mixture of IL-1β (2 ng/mL) and IFN-γ (50 ng/mL) for 24 h (Fig 1A)
Cytokine attenuation of GSIS is owing to decreased insulin release at a stimulatory glucose level since basal insulin release was unaffected (Fig 1A), which is consistent with the deleterious effects of pro-inflammatory cytokines on insulin secretion reported by others [21,41,42]
Summary
Impaired glucose-stimulated insulin secretion (GSIS) by pancreatic beta cells (β-cells) contributes to the hyperglycemic state that characterizes type 2 diabetes [1]. The cause of β-cell inflammation in type 2 diabetes is debated, but likely relates to obesity as it is widely accepted that elevated nutrient levels stimulate the expression of interleukin-1β (IL1β) in human pancreatic islets, via activation of the NLRP3 inflammasome [8,9,10] or the NFκB pathway [11], which causes a pro-inflammatory state [12]. Chronic upregulation of pro-inflammatory cytokines is regarded a hallmark for impaired insulin secretion [5] and increased β-cell apoptosis [5] in the pathophysiology of type 2 diabetes
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