The aim of the present experiments is to validate, in conscious dogs, the tracer infusion methods of measuring nonsteady turnover rates. This was done in nine experiments performed in four normal dogs by infusing isotopically labeled glucose (2-3H, 6-3H, 1-14C) and monitoring the concentrations of both the labeled and unlabeled substances. The validation is based on the observation that a high exogenous infusion of glucose will suppress endogenous glucose production and become the sole source of glucose in the body. By infusing glucose at a high, time-varying rate, calculating its rate of appearance, (Ra) and comparing it to the infused rate, the method can be verified. The calculations were based on: a) a single-compartment model with a modified volume of distribution; b) a two-compartment model; and c) a generalized dispersion model. The absolute values of the areas of the deviations of the calculated from the infused curves were found to be, respectively, 9.5, 8.4, and 7.8 percent of the total area under the infused curve. It was concluded that the tracer infusion method can reliably measure Ra of glucose when it is changing rapidly, and the system is out of steady state.

Hepatic glycogen is replenished during the absorptive period postprandially. This repletion is prompted partly by an increased hepatic uptake of glucose by the liver, partly by metabolite and hormonal signals in the portal vein, and partly by an increased gluconeogenic flux to glycogen (glyconeogenesis). There is some evidence that the direct formation of glycogen from glucose and that formed by gluconeogenic pathways is linked. This includes: (i) the inhibition of all glycogen synthesis, in vivo, when gluconeogenic flux is blocked by inhibitors; (ii) a dual relationship between glucose concentrations, lactate uptake by the liver and glycogen synthesis (by both pathways) which indicates that glucose sets the maximal rates of glycogen synthesis while lactate uptake determines the actual flux rate to glycogen; (iii) the decrease of both gluconeogenesis and glycogen synthesis by the biguanide, metformin; and (iv) correlations between increased gluconeogenesis and liver glycogen in obese patients and animal models. The degree to which the liver extracts portal glucose is not entirely agreed upon although a preponderance of evidence points to about a 5% extraction rate, following meals, which is dependent on a stimulation of glucokinase. This enzyme may be linked to the expression of other enzymes in the gluconeogenic pathway. Perivenous cells in the liver may induce additional gluconeogenesis in the periportal cells by increasing glycolytically produced lactate. A number of potential mechanisms therefore exist which could link glycogen synthesis from glucose and gluconeogenic substrate.

Insulin is the principal hormone of metabolic regulation. Reduced responses to insulin constitute an underlying feature of type 2 diabetes. It is, therefore, incumbent on those who work in this area (as well as many others) to characterize this response, in as simple and consistent a way as possible, so that this measure can be used both in the investigational and clinical setting. This type of approach, although eminently useful, is necessarily an oversimplification. Not only does insulin sensitivity change in pathological situations, but also in normal physiology. Tissue-specific, metabolite-specific, as well as process-specific responses may be expected to occur. Variations also occur in time-depending on the physiological state of the individual (e.g. pregnancy, aging) or following diurnal rhythms. It is perhaps remarkable that any consistent assessment of overall insulin sensitivity can be made. The observation that this can often be achieved has led to hypotheses suggesting that sensitivity to insulin is primarily determined at a single site (tissue, metabolite). At the same time, there are many discussions about the inconsistencies inherent in different approaches to the measurement of this parameter, suggesting that some of these variants, metabolic or otherwise, could lead to the low correlation between methods sometimes seen. Nevertheless, most methods used in the assessment of insulin sensitivity examine the response to insulin of a single metabolite, glucose, primarily in the muscle and liver, and under fasting conditions and should, therefore, demonstrate insulin sensitivity that is comparable among methods.

No abstract