Hormonal control of substrate cycling in humans.

Abstract

Recent studies have established the existence of substrate cycles in humans, but factors regulating the rate of cycling have not been identified. We have therefore investigated the acute response of glucose/glucose-6P-glucose (glucose) and triglyceride/fatty acid (TG/FA) substrate cycling to the infusion of epinephrine (0.03 gg/kg min) and glucagon. The response to a high dose glucagon infusion (2 gg/kg -min) was tested, as well as the response to a low dose infusion (5 ng/kg. min), with and without the simultaneous infusion of somatostatin (0.1 gg/kg min) and insulin (0.1 mU/kg min).Additionally, the response to chronic prednisone (50 mg/d) was evaluated, both alone and during glucagon (low dose) and epinephrine infusion. Finally, the response to hyperglycemia, with insulin and glucagon held constant by somatostatin infusion and constant replacement of glucagon and insulin at basal rates, was investigated. Glucose cycling was calculated as the difference between the rate of appearance (R.) of glucose as determined using 24k-and 6,642-glucose as tracers. TG/FA cycling was calculated by first determining the R. glycerol with d5-glycerol and the R. FFA with 11-'3Cqpalmitate, then subtracting R. FFA from three times R. glycerol.The results indicate that glucagon stimulates glucose cycling, and this stimulatory effect is augmented when the insulin response to glucagon infusion is blocked. Glucagon had minimal effect on TG/FA cycling. In contrast, epinephrine stimulated TG/FA cycling, but affected glucose cycling minimally. Prednisone had no direct effect on either glucose or TG/FA cycling, but blunted the stimulatory effect of glucagon on glucose cycling. Hyperglycemia, per se, had no direct effect on glucose or TG/FA cycling. Calculations revealed that stimulation of TG/FA cycling theoretically amplified the sensitivity of control of fatty acid flux, but no such amplification was evident as a result of the stimulation of glucose cycling by glucagon.

Comparison of [3,4‐13C2]glucose to [6,6‐2H2]glucose as a tracer for glucose turnover by nuclear magnetic resonance

“…[2-2 H]Glucose is thought to overestimate glucose turnover because the deuterium can be lost by exchange between glucose-6-phosphate and fructose-6-phosphate which results in appearance of unlabeled plasma glucose. In fact, glucose turnover measured by [2-2 H]glucose (or the radioactive counterpart) has been compared to other measures of glucose turnover to specifically assess futile cycling between extracellular glucose and the glucose-6-phosphate pool (12,13). In contrast, the deuterium labels of [6,6-2 H 2 ]glucose are not lost during futile cycling, and for this reason [6,6-2 H 2 ]glucose is considered to report the true value of hepatic GP (14,15).…”

“…A basic assumption in measurement of glucose turnover is that a tracer molecule is not released from liver as the result of glycogenolysis or gluconeogenesis. A number of biochemical pathways could be followed by [3,[4][5][6][7][8][9][10][11][12][13] (Fig. 3).…”

“…Unlike [1,[6][7][8][9][10][11][12][13] C 2 ]MAG, [3,[4][5][6][7][8][9][10][11][12][13] C 2 ]MAG yields a characteristic pair of doublets in a 13 C NMR spectrum due to spin-spin coupling, which is easily observed. Most importantly, detection with NMR has the considerable advantage that the presence of 13 C does not interfere with measurement of 2 H enrichment by 2 H NMR at typical levels of enrichment.The goal of this study was to compare GP measured by a standard tracer, [6,6-2 H 2 ]glucose, to GP measured by NMR detection of [3,[4][5][6][7][8][9][10][11][12][13] C 2 ]glucose. Also, a convenient method to quantify 2 H enrichment in plasma glucose is introduced using an internal reference, deuterated dimethylformamide (DMF-d 7 ).…”

“…A simple derivative, monoacetone glucose (1,2-diisopropylidene glucofuranose, also termed MAG), offers well-resolved 2 H and 13 C NMR spectra while preserving the informative 2 H and 13 C distribution. Unlike [1,[6][7][8][9][10][11][12][13] C 2 ]MAG, [3,[4][5][6][7][8][9][10][11][12][13] C 2 ]MAG yields a characteristic pair of doublets in a 13 C NMR spectrum due to spin-spin coupling, which is easily observed. Most importantly, detection with NMR has the considerable advantage that the presence of 13 C does not interfere with measurement of 2 H enrichment by 2 H NMR at typical levels of enrichment.…”

“…The goal of this study was to compare GP measured by a standard tracer, [6,6-2 H 2 ]glucose, to GP measured by NMR detection of [3,[4][5][6][7][8][9][10][11][12][13] C 2 ]glucose. Also, a convenient method to quantify 2 H enrichment in plasma glucose is introduced using an internal reference, deuterated dimethylformamide (DMF-d 7 ).…”