This section addresses the relation of coenzyme Q or ubiquinone to diabetes. Obviously, CoQ is a fundamental life molecule without which all electron transport and energy production would cease. Hence, it seems a bit odd to these authors that more attention has not been directed to CoQ and its biosynthesis, as related to diabetes.
CoQ is fat soluble and localizes to hydrophobic regions within mitochondrial membranes wherein it is mobile and functions as an electron carrier. About one half of total body CoQ is synthesized endogenously, whereas the remainder derives from the diet (113
). CoQ side-chain synthesis is dependent on 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and proceeds through steps common to cholesterol biosynthesis to the intermediate compound farnesyl pyrophosphate which then diverges either to cholesterol, cis
-prenylation to dolichol, or trans
-prenylation to the side chain of ubiquinone. Synthesis of the benzoquinone ring of CoQ and the long side-chain converge when the two are linked by the COQ2
gene product. At that point CoQ synthesis proceeds within or adjacent to the mitochondrial inner membrane, where at least 10 different gene products are involved in the final generation of CoQ.
Ubiquinone, in final form, consists of a 50-carbon side chain attached to the quinone moiety. The carbon chain consists of ten 5-carbon prenyl units; hence the name CoQ10. In rats and mice, unlike humans, the predominant form contains nine 5-carbon units and is designated CoQ9 (2
). The completed CoQ with its long carbon side chain is very mobile within lipid membranes and, thus, able to serve its essential role as an electron carrier. In addition to mitochondrial membranes, CoQ also is present in Golgi vesicles and lysosomes and is present in other membrane structures as well (315
The antioxidant properties of CoQ are not due to direct scavenging of superoxide but appear to be mediated through regeneration of active ascorbic acid and tocopherol, the reduced from of vitamin E (66
). Moreover, CoQ in the semiquinone form also acts as a chain-breaking agent, thereby protecting against lipid peroxidation (147
). Although often thought of (and marketed as) an antioxidant, it is important to point out that CoQ also has prooxidant properties. As depicted in and , the semiquinone form of CoQ leaks electrons to form superoxide during electron transport through the Q-cycle in complex III. Moreover, at least suggestive evidence exists for involvement of the semiquinone form of CoQ in electron transport at complex I (40
). In this regard, CoQ may actually be needed for superoxide formation, because the radical may have important signaling properties, for example, to induce UCP activity, as discussed earlier, or to enhance the expression/activity of regulatory proteins like AMPK (60
). Moreover, it is worth noting that superoxide may not be harmful if followed by detoxification to H2
by SOD and breakdown of H2
Coenzyme Q concentrations appear to be reduced in diabetic states. An early study of liver mitochondria, which used cytochrome c
oxidation to measure CoQ, reported increased concentrations in mitochondria of pancreatectomized diabetic rats (37
). However, later studies with HPLC reported a reduction in liver (180
) and kidney (180
) mitochondrial CoQ content and an ~75% reduction in heart mitochondria of 8-week STZ-diabetic rats (180
). Unpublished studies in our laboratory show a substantial depletion of skeletal muscle mitochondrial CoQ in insulin-deficient diabetic rats. Evidence also exists for reduced CoQ in plasma of humans with diabetes (113
It is possible that coenzyme Q may be particularly important when diabetes patients are treated with HMG-CoA reductase inhibitors (commonly referred to as “statins”), widely used in patients with diabetes to reduce cholesterol. HMG-CoA blockade is more potent at inhibiting cholesterol biosynthesis than CoQ biosynthesis because of differing Km
values for trans
-prenyltransferase (leads to CoQ) and squalene synthetase (leads to cholesterol) at the farnesyl-PP branch point (315
). Conversely, it is possible that CoQ depletion in diabetes might engender more sensitivity to adverse effects of these drugs, in particular, myopathy. We believe this issue needs further study directed at mechanisms underlying the reductions in CoQ seen in diabetes. Severe myopathy is rare, but milder muscle pain remains a major reason that some patients do not tolerate statins. Moreover, in diabetes, this is of particular importance, given the need to control concomitant cholesterol elevation.
To summarize, CoQ is related to diabetes through its fundamental action on electron transport, direct involvement in both the generation of ROS and antioxidant protection, and as an important regulator of mitochondrial uncoupling. Important therapeutic implications exist, as discussed in the next section.