Abstract
BackgroundThere is an emerging theory suggesting that insulin, which is known to be the predominant postprandial anabolic hormone, is also a major regulator of mitochondrial oxidative phosphorylation in human skeletal muscle. However, little is known about its effects in the liver. Since there is a theoretical relationship between glycogen metabolism and energy status, a simultaneous and continuous investigation of hepatic ATP and glycogen content was performed in intact and isolated perfused liver by 31P and 13C nuclear magnetic resonance (NMR) The hepatic rates of ATP and glycogen changes were evaluated with different concentrations of insulin and glucose during continuous and short-term supply.ResultsLiver from rats fed ad libitum were perfused with Krebs-Henseleit Buffer (KHB)(controls) or KHB containing 6 mM glucose, 30 mM glucose, insulin alone, insulin + 6 mM glucose, insulin + 30 mM glucose. In the control, glycogenolysis occurred at a rate of -0.53 ± 0.021 %·min-1 and ATP content decreased at a rate of -0.28 ± 0.029 %·min-1. In the absence of insulin, there was a close proportional relationship between the glycogen flux and the glucose concentration, whereas ATP rates never varied. With insulin + glucose, both glycogen and ATP rates were strongly related to the glucose concentration; the magnitude of net glycogen flux was linearly correlated to the magnitude of net ATP flux: fluxglycogen = 72.543(fluxATP) + 172.08, R2 = 0.98.ConclusionOnly the co-infusion of 30 mM glucose and insulin led to (i) a net glycogen synthesis, (ii) the maintenance of the hepatic ATP content, and a strong positive correlation between their net fluxes. This has never previously been reported. The specific effect of insulin on ATP change is likely related to a rapid stimulation of the hepatic mitochondrial oxidative phosphorylation. We propose that variations in the correlation between rates of ATP and glycogen changes could be a probe for insulin resistance due to the action of substrates, drugs or pathologic situations. Consequently, any work evaluating insulin resistance on isolated organs or in vivo should determine both ATP and glycogen fluxes.
Highlights
There is an emerging theory suggesting that insulin, which is known to be the predominant postprandial anabolic hormone, is a major regulator of mitochondrial oxidative phosphorylation in human skeletal muscle
In the metformin treatment of insulin resistance-related complications, the mitochondrial effects of the drug are probably crucial in explaining its unique efficacy [1]
Mitochondrial dysfunctions have been reported in the muscle in type 2 diabetes [2] and in age-related insulin resistance [3], suggesting a link between insulin action and oxidative capacity in humans [4]
Summary
There is an emerging theory suggesting that insulin, which is known to be the predominant postprandial anabolic hormone, is a major regulator of mitochondrial oxidative phosphorylation in human skeletal muscle. Mitochondrial dysfunctions have been reported in the muscle in type 2 diabetes [2] and in age-related insulin resistance [3], suggesting a link between insulin action and oxidative capacity in humans [4]. One of its major functions is to store glucose as glycogen after meals (glycogen synthesis) and to release glucose from this glycogen (glycogenolysis) at the postabsorptive state, which accounts for most endogenous glucose production. Disturbance of this function is thought to play a major role in the hyperglycemia of type 2 diabetes and in other insulin-resistant states. Despite much work on the issue, the effect of insulin on hepatic glycogenosynthesis remains controversial: insulin is known to activate glycogen synthase in vitro [6], but hepatic glycogenesis in vivo seems to need an increase in both insulin and plasma glucose levels
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