Glycogenesis and glucose oxidation during an intravenous glucose tolerance test in man

Abstract

The quantity of deuterated glucose customarily given in labelled IVGTTs (intravenous glucose tolerance tests) changes the isotopic composition of the subject's body water enough to be detected by mass spectrometric techniques. Glucose undergoing direct glycogenesis does not contribute label to the body water pool, and isotope incorporated into it must have come from glucose that has either been oxidized or undergone indirect glycogenesis. By subtracting the amount of label found in body water from the total amount of glucose utilized, as calculated from the minimal model of glucose disappearance, it should be possible to study the partitioning of the dose given between direct glycogenesis in skeletal muscle and other metabolic pathways. To establish these principles, we used isotope ratio MS to determine body water composition in groups of healthy ( n =7; mean weight, 76 kg; fasting plasma glucose and insulin, 5.1 mmol and 40 pmol respectively) and Type II diabetic ( n =5; mean weight, 84 kg; fasting plasma glucose and insulin, 6.2 mmol and 75 pmol respectively) subjects undergoing IVGTTs. It was found that, for healthy subjects, 31% of the dose given was utilized in direct glycogenesis and this was decreased to 15% in diabetes. Defects in muscle glycogen synthesis in diabetes of the same order are well known from magnetic resonance studies. We conclude that measurement of label incorporation into body water is potentially useful for investigation of the metabolism of a glucose load in vivo during an IVGTT.

13C- and 2H-labelled glucose compared for minimal model estimates of glucose metabolism in man

“…Appropriate values for each of our four subject categories are not known, but this study is concerned with investigating the equivalence of the behaviour of two different tracers and detection techniques. We have, however, included correction for urinary losses which are significant for DM subjects but not healthy individuals [15].…”

“…However, validation over a wide range of insulin sensitivities is needed since, although the deuterium label at the 6-position of the glucose molecule is either directly incorporated into glycogen or lost in glycolysis [14] (this has been used to determine the relative contributions of these processes to glucose disposal [15]), skeletal carbon is retained during the course of glycolysis and is available for gluconeogenesis (Cori cycle). Thus label recycling in the course of an IVGTT could perturb parameter estimates.…”

Failure of hyperglycemia and hyperinsulinemia to compensate for impaired metabolic response to an oral glucose load

“…The differences between results from our studies and these data likely reflect important differences in the populations studied, with our studies evaluating a broader range of metabolic dysfunction. This interpretation is bolstered by prior observations using a water labeling method that showed significantly lower net glucose oxidation in type 2 diabetes (31), and a continuous relationship between the rate of appearance of tracer in body water and clamp-measured insulin resistance (32). Methodologic differences may also contribute to the contrasting observations; for example, 13 C-labeled intermediates can be redirected to metabolic fates other than immediate mitochondrial uptake and oxidation.…”

Measures of Insulin Sensitivity

“…Several investigators have described the use of deuterated glucose in further analysis of the disposition of parenteral glucose using the minimal model [72,73]. This is now being studied as a potential commercial product by KineMed, Inc., with oral administration of 2 H-glucose followed after several hours by measurement of plasma 2 H 2 O, allowing a measure of glucose metabolism comparable to that from the euglycemic hyperinsulinemic clamp study [74].…”