A radical explanation for glucose-induced beta cell dysfunction

Abstract

The development of type 2 diabetes requires impaired beta 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 beta cells exposed to hyperglycemia could prevent a positive feed-forward loop of glucotoxicity that drives impaired glucose tolerance toward frank type 2 diabetes.

Figure 1

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.

Figure 2

Effect of hyperglycemia on mitochondrial electron-transport chain function in the pancreatic β cell. Hyperglycemia increases production of electron donors from the tricarboxylic acid (TCA) cycle (NADH and FADH₂). This increases the membrane potential (Δμ_H⁺), because protons are pumped across the mitochondrial inner membrane in proportion to electron flux through the electron-transport chain. Inhibition of electron transport at Complex III by increased Δμ_H⁺ increases the half-life of free radical intermediates of coenzyme Q, which reduce O₂ to superoxide. Krauss and colleagues (13) have demonstrated that hyperglycemia-induced mitochondrial superoxide activates UCP2-mediated proton leak, thus lowering ATP levels and impairing glucose-stimulated insulin secretion. Figure modified with permission from Nature (15). P_i, inorganic phosphorus.