Abstract
We have investigated the effects of prolonged exposure (24 h) to pro-inflammatory cytokines on beta-cell metabolism and insulin secretion using clonal BRIN-BD11 beta cells. Addition of IL-1beta, tumour necrosis factor-alpha and IFN-gamma (at concentrations that did not induce apoptosis) inhibited chronic (24 h) and acute stimulated levels of insulin release (by 59 and 93% respectively), increased cellular glucose and alanine consumption, and also elevated lactate and glutamate release. However, ATP levels and cellular triacylglycerol were decreased while glutathione was increased. We conclude that sub-lethal concentrations of pro-inflammatory cytokines appear to shift beta-cell metabolism away from a key role in energy generation and stimulus-secretion coupling and towards a catabolic state which may be related to cell defence.
Highlights
Nutrient metabolism is tightly coupled to insulin secretion in the pancreatic b cell (McClenaghan 2007)
Some cells were further incubated for 40 min in the presence of 1.1 mmol/l glucose followed by 20 min in the presence of 16.7 mM glucose www.endocrinology-journals.org and 10 mM alanine, when an aliquot of the incubation medium was removed, centrifuged at 200 g for 5 min and analysed for insulin using the Mercodia Ultrasenstive Rat Insulin ELISA kit
Previous studies have reported that exposure of rat or mouse pancreatic islets to relatively high concentrations of the proinflammatory cytokines IL-1b or tumour necrosis factor-a (TNF-a) or a mixture of IL-1b, TNF-a and IFN-g resulted in decreased glucose oxidation, decreased activity of glycolytic enzymes and inhibition of insulin secretion (Eizirik et al 1988, Park et al 1999, Wallstrom et al 2003)
Summary
Nutrient metabolism is tightly coupled to insulin secretion in the pancreatic b cell (McClenaghan 2007). Mitochondrial metabolism is crucial for the coupling of glucose and amino acid recognition to exocytosis of insulin granules. This is illustrated by in vitro and in vivo observations that mitochondrial dysfunction severely impairs insulin secretion. Numerous studies have sought to identify the factors that mediate the key amplifying pathway over the Ca2C signal in nutrient-stimulated insulin secretion. These factors are nucleotides (ATP, GTP, cAMP and NADPH), metabolites have been proposed, such as long-chain acyl-CoA derivatives and glutamate (Maechler & Wollheim 1999). Glucose has been reported to protect b cells from apoptosis (Hoorens et al 1996), while glutamine has been reported to afford protection from apoptosis in a wide variety of cells (Curi et al 2005)
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