Abstract
To understand the role of mitochondrial uncoupling protein (UCP) in regulating insulin signaling and glucose homeostasis, we created transgenicDrosophila lines with targeted UCP expression in insulin producing cells (IPCs). Increased UCP activity in IPCs results in decreased steady state Ca(2+) levels in IPCs as well as decreased PI3K activity and increased FoxO nuclear localization in periphery. This reduced systemic insulin signaling is accompanied by a mild hyperglycemia and extended life span. To test the hypothesis that ATP-sensitive potassium (K(ATP)) channels may link changes in metabolic activity (e.g., glucose mediated ATP production or UCP-mediated ATP reduction) with insulin secretion, we characterized the effects of glucose and a specific K(ATP) channel blocker, glibenclamide on membrane potential in adult IPCs. Exposure to glucose depolarizes membrane potential of IPCs and this effect is mimicked with glibenclamide, suggesting that K(ATP) channels contribute to the mechanism whereby IPCs sense changes in circulating sugar. Further, as demonstrated in mammalian beta-pancreatic cells, high glucose initiates a robust Ca(2+) influx in adult IPCs. The presence of functional K(ATP) channels in adult IPCs is further substantiated by in situ hybridization detecting the transcript for the sulfonylurea receptor (Sur) subunit of the K(ATP) channel in those cells. Quantitative expression analysis demon-strates a reduction in transcripts for both Sur and the inward rectifying potassium channel (Kir) subunits when IPCs are partially ablated. In summary, we have demonstrated a role for UCP in adult Drosophila IPCs in influencing systemic insulin signaling and longevity by a mechanism that may involve K(ATP) channels.
Highlights
Mammalian mitochondrial uncoupling proteins (UCPs) have been shown to be involved in energy metabolism, β-pancreatic cell function, and aging [1,2,3,4,5,6]
We have demonstrated that increased UCP activity in adult fly insulin producing cells (IPCs) modulates systemic insulin signaling as measured by both molecular events in the insulin signaling pathway and glucose homeostasis at the organismal level
As expected, attenuated insulin signaling measured in dilp2Gal4/UAS-mucp1 and dilp2-Gal4/UAS-hucp2 flies is associated with a significant life span extension in females and a moderate increase in males [24]
Summary
Mammalian mitochondrial uncoupling proteins (UCPs) have been shown to be involved in energy metabolism, β-pancreatic cell function, and aging [1,2,3,4,5,6]. Insulin secretion depends upon detection of changes in the ATP levels generated by mitochondrial oxidative phosphorylation [7, 8]. No. cause an increase in the ATP/ADP ratio, leading to closure of the ATP-dependent potassium (KATP) channel, plasma membrane depolarization, opening of the voltage-gated calcium channel, calcium influx, and insulin secretion. Consistent with this paradigm, elevated UCP2 activity in β-pancreatic cells that should lead to a decrease in the ATP/ADP ratio has been shown to have a negative effect on glucose-stimulated insulin secretion [2, 4, 9]. Additional studies including the finding that UCP2 activity is stimulated by glucotoxicity and lipotoxicity in diabetic animal models have established a crucial role for UCP2 in the regulation of insulin secretion and β-cell function [10]
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