Quantitation of basal endogenous glucose production in Type II diabetes: importance of the volume of distribution

Abstract

The rate of endogenous glucose production (EGP) is important in understanding the pathophysiology of Type II (non-insulin-dependent) diabetes mellitus, the aetiology of its complications, and the identification of potential therapeutic targets. A great deal of effort has therefore been expended in its evaluation. Most measurements in humans have been made using tracers, or labelled analogues of glucose. Experimental strategies have included the injection and the infusion of such tracers which were often primed to achieve constant concentrations of the label more quickly. Primers have either been fixed or adjusted to the ambient glycaemia in each diabetic subject. Analyses were carried out using steady-state or non-steady-state calculations, the latter based on a one-compartment model or higher order systems. The principal finding of this review is that all approaches yield the same EGP when an appropriate model of the system is used. Under basal conditions, a single compartment model is sufficient to evaluate EGP, but the estimation of the volume of distribution, V, from individual data is critical in obtaining consistent results. Other sources of variation arose from the length of the fasting period and the patient population being studied. Overall, in Type II diabetes, EGP is frequently high in the morning and decreases gradually to rates comparable to healthy control subjects. This can be a very delayed response to a preceding meal, but more likely corresponds to an accentuated circadian rhythm in glucose production. Metabolic clearance of glucose, on the other hand, is decreased in diabetes, and remains so during the course of the day.

SIRT4 Coordinates the Balance between Lipid Synthesis and Catabolism by Repressing Malonyl CoA Decarboxylase

“…Deuterium atoms exchange with hydrogen atoms on different carbon positions of glucose metabolites as they go through the glycolytic/gluconeogenic pathways and the TCA cycle (Radziuk and Pye, 2002), and the accumulation of these deuterated metabolites can contribute to deuterium labeling of fatty acids during de novo lipogenesis. The extent of labeled palmitate, representing de novo lipid synthesis, can be measured by GC-MS. We observed a 50% reduction in the percentage of newly synthesized lipids in SIRT4 KO WAT compared to WT tissue, highlighting the importance of SIRT4 to de novo lipogenesis in vivo (Figure 5H).…”

Quantifying rates of glucose production in vivo following an intraperitoneal tracer bolus

“…Those studies assumed a volume of distribution that was equivalent to~20% of body mass. Provided that pool sizes do not dramatically change over the course of an experiment, it is not surprising that one would obtain some agreement between the different approaches for administering the glucose tracers (27,28).…”

“…type 2 diabetes; insulin resistance; stable isotopes; tracer kinetics; animal models TYPE 2 DIABETES IS TYPICALLY CHARACTERIZED by the presence of fasting hyperglycemia, which largely results from a disruption in the control of basal glucose production (9,10). Numerous investigators have aimed to quantify glucose production using isotopic tracers to better understand the pathophysiology surrounding type 2 diabetes and states of insulin resistance (27,28,38). In that regard, emphasis has been placed on coupling tracer kinetics with the use of a "glucose-insulin clamp" to address questions regarding the insulin sensitivity of endogenous glucose production (10,16,38).…”

“…As our understanding of physiology has advanced, in part due to the application of mathematical models, it became clear that one could use different approaches for administering a tracer. For example, one could dose a tracer via a single intravenous injection, a continuous infusion, or a primed infusion (27,28,41). Glucose flux rates are then determined by measuring the dilution of the isotope and estimating the pool size (e.g., when using the intravenous bolus approach) or by simply measuring the rate of tracer dilution (e.g., when using either a constant infusion and/or a primed infusion) (28,38).…”

Characteristics of Glucose Metabolism in Nordic and South Asian Subjects with Type 2 Diabetes

“…Both were steady state for plasma glucose, with only relatively small changes in glucose concentration and tracer enrichment over time. Thus, steady state equations, where rate of appearance equals rate of disappearance, have been applied for the calculation of both EGP and total glucose disposal (TGD) [8], [9]. The EGP in the basal state was calculated as follows: EGP basal  = I((E i /E p(basal) ) –1), where I is the rate of [6,6- 2 H 2 ]-glucose infusion (µmol/m 2 ⋅min), E i is the enrichment of the tracer infusion in moles percent excess (mpe) and E p(basal) is the mean [6,6- 2 H 2 ]-glucose enrichment in plasma (mpe) at the end of the basal stabilisation period.…”