A radical explanation for glucose-induced β cell dysfunction
Michael Brownlee
Michael Brownlee
Published December 15, 2003
Citation Information: J Clin Invest. 2003;112(12):1788-1790. https://doi.org/10.1172/JCI20501.
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A radical explanation for glucose-induced β cell dysfunction

Abstract

The development of type 2 diabetes requires impaired β cell function. Hyperglycemia itself causes further decreases in glucose-stimulated insulin secretion. A new study demonstrates that hyperglycemia-induced mitochondrial superoxide production activates uncoupling protein 2, which decreases the ATP/ADP ratio and thus reduces the insulin-secretory response. These data suggest that pharmacologic inhibition of mitochondrial superoxide overproduction in β cells exposed to hyperglycemia could prevent a positive feed-forward loop of glucotoxicity that drives impaired glucose tolerance toward frank type 2 diabete

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Michael Brownlee

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Figure 1

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Model of glucose-stimulated insulin secretion in the pancreatic β cell. ...
Model of glucose-stimulated insulin secretion in the pancreatic β cell. Following phosphorylation by glucokinase (GK), glucose is converted to pyruvate by glycolysis. Pyruvate enters the mitochondria and fuels the TCA cycle, resulting in the transfer of reducing equivalents to the respiratory chain, hyperpolarization of the mitochondrial membrane, and ATP generation. Subsequent closure of KATP channels depolarizes the cell membrane, which opens voltage-gated calcium channels, increasing the concentration of cytosolic calcium ([Ca2+]c). This influx of calcium triggers insulin release from the cell. Figure modified with permission from Nature (17). Pyr, pyruvate; Δψm, mitochondrial membrane potential; Δψc, cell membrane potential.