Incomplete suppression of hepatic glucose production in non-insulin dependent diabetes mellitus measured with [6,6-2H2]glucose enriched glucose infusion during hyperinsulinaemic euglycaemic clamps (original) (raw)
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European Journal of Clinical Investigation, 1992
We have minimized methodological errors in the isotope dilution technique by using stable isotope, [6,6-'H2]glucose, thus avoiding the problem of contamination of tritiated glucose tracers and, by maintaining a constant plasma tracer enrichment have reduced error due to mixing transients. Using these modifications we have calculated hepatic glucose production in 20 patients with non-insulin-dependent diabetes mellitus during low (1 mU kg-' min-') and high (8 mU kg-' min-') dose insulin infusions. Mean fasting hepatic glucose production was 14.2 f 0.8 pmol kg-' min-'. This suppressed by only 68% to 4.6k0.8 pmol kg-I min-' during the low-dose insulin infusion (plasma insulin 0.85k0.05 nmol I-') and did not suppress further during the high-dose insulin infusion (plasma insulin I435 f0.83 nmol I-'). Hepatic glucose production was significantly higher than zero throughout the study.
Diabetes, 1989
Recent studies indicate that hydrogen-labeled glucose tracers underestimate glucose turnover in humans under conditions of high flux. The cause of this underestimation is unknown. To determine whether the error is time-, pool-, model-, or insulin-dependent, glucose turnover was measured simultaneously with [6-3 H]-, [6,6-2 H 2 ]-, and [6-14 C]glucose during a 7-h infusion of either insulin (1 mU • kg~1 • min~1) or saline. During the insulin infusion, steady-state glucose turnover measured with both [6-3 H]glucose (8.0 ± 0.5 mg k g 1 mirr 1) and [6,6-2 H 2 ]glucose (7.6 ± 0.5 mg kg-1 min~1) was lower (P < .01) than either the glucose infusion rate required to maintain euglycemia (9.8 ± 0.6 mg k g 1 min~1) or glucose turnover determined with [6-14 C]glucose and corrected for Cori cycle activity (9.8 ± 0.7 mg k g 1 min 1). Consequently "negative" glucose production rates (P < .01) were obtained with either [6-3 H]-or [6,6-2 HJbut not [6-14 C]glucose. The difference between turnover estimated with [6-3 H]glucose and actual glucose disposal (or 14 C glucose flux) did not decrease with time and was not dependent on duration of isotope infusion. During saline infusion, estimates of glucose turnover were similar regardless of the glucose tracer used. High-performance liquid chromatography of the radioactive glucose tracer and plasma revealed the presence of a tritiated nonglucose contaminant. Although the contaminant represented only 1.5% of the radioactivity in the [6-3 H]glucose infusate, its clearance was 10-fold less (P < .001) than that of [6-3 H]glucose. This resulted in accumulation in plasma, with the contaminant accounting for 16.6 ± 2.09 and 10.8 ± 0.9% of what customarily is assumed Glucose 1 mM = 18 mg/dl Insulin 1 pM = 0.139
American Journal of Physiology-Endocrinology and Metabolism, 1998
The rates (and extent) of appearance of glucose in arterialized plasma from an oral glucose load and from liver (RaO, RaH) can be estimated in humans using radioisotopes, but estimates vary among laboratories. We investigated the use of stable isotopes and undertook 22 primed intravenous infusions ofd-[6,6-2H2]glucose with an oral load includingd-[13C6]glucose in healthy humans. The effective glucose pool volume (VS) had a lower limit of 230 ml/kg body weight (cf. 130 ml/kg commonly assumed). This VSin Steele’s one-compartment model of glucose kinetics gave a systemic appearance from a 50-g oral glucose load per 70 kg body weight of 96 ± 3% of that ingested, which compared with a theoretical value of ∼95%. Mari’s two-compartment model gave 100 ± 3%. The two models gave practically identical RaOand RaHat each point in time and a plateau in the cumulative RaOwhen absorption was complete. Less than 3% of13C was recycled to [13C3]glucose, suggesting that recycling errors were practicall...
Diabetes, 2002
The purposes of this study were to quantify the impact of the duration of infusion and choice of stable isotope of glucose on measures of glucose rate of appearance (glucose R a) and to determine whether the differences observed were due to tracer recycling via the glycogen pool (direct pathway) or gluconeogenesis (indirect pathway). Six healthy adult volunteers were studied on four occasions in the postabsorptive state during infusions of [1-13 C]glucose and [6,6-2 H 2 ]glucose: 2.5-h infusion of both (A), and 2.5-h infusion of one (B) and 14.5-h infusion of the other isotope (C), and 5-h infusion of [6,6-2 H 2 ]glucose and 2.5-h infusion of [1-13 C]glucose (D). Infusion of both isotopes for 2.5 h resulted in similar glucose R a values. When compared with a 14.5-h infusion, the 2.5-h glucose tracer infusion overestimated glucose R a by 26-35%. Glucose 13 C recycled via the Cori cycle, resulting in slower decay from the plasma pool and longer half-life of [1-13 C]glucose compared with [6,6-2 H 2 ]glucose. There was no detectable release of [ 13 C]glucose or [ 2 H 2 ]glucose tracer into the plasma pool after administration of glucagon. These data demonstrate that glucose R a varies not as a result of isotope cycling but as a result of differences in duration of isotope infusion regardless of the isotope used. This is most likely due to incomplete isotope and substrate equilibration with the 2.5-h infusion. The potential error was reduced by nearly 80% using a 5-h infusion of [6,6-2 H 2 ]glucose. These studies demonstrate that the duration of isotope infusion has significantly greater impact on quantitation of glucose R a than does the selection of isotope.
Diabetologia, 1993
Intraperitoneal infusion of insulin should be more physiological than intravenous insulin since part of the insulin is directed toward the portal vein, which allows the liver to retain its major role in glucose homeostasis. The regulation of hepatic glucose production during the intraperitoneal and intravenous infusions of insulin were compared in eight Type 1 (insulin-dependent), C-peptide-deficient diabetic patients. Primed, continuous infusions of [6,6-aH] glucose were given in the postabsorptive state and during continuous infusion of unlabelled glucose at 1.5 and 4 mg/kg, min, while normoglycaemia was maintained by closed-loop intraperitoneal and intravenous insulin delivery. During all three periods, plasma glucose concentrations remained near normal (variations 3.8-6.1%). The insulin infusion rates required for normal plasma glucose concentrations were essentially the same for the intravenous and intraperitoneal routes in all cases, although the variations were greater with intraperitoneal insulin. Plasma flee-insulin levels were only slightly, non-significantly lower with intraperitoneal infusion than with intravenous infusion. Hepatic glucose production was significantly lower with intraperitoneal insulin during all three conditions: basal: 1.71 + 0.14, i.p. vs 2.37 + 0.26 mg/kg, rain, i.v.; 1.5mg/kg.min glucose infusion: 0.49+0.23, i.p. vs 0.88 + 0.18 mg/kg, min, i.v.; 4 mg/kg, min glucose infusion: 0.31 + 0.10, i.p. vs 0.56 +0.12 mg/kg, rain, i.v.. These results, obtained with steady-state conditions for plasma glucose, isotopic plasma glucose enrichments and unlabelled glucose infusion rates, suggest that better control of hepatic glucose production leading to normoglycaemia was achieved with the intraperitoneal infusion.
Diabetes, 2001
Based on our earlier work, a 2.5-fold increase in insulin secretion should completely inhibit hepatic glucose production through the hormone's direct effect on hepatic glycogen metabolism. The aim of the present study was to test the accuracy of this prediction and to confirm that gluconeogenic flux, as measured by three independent techniques, was unaffected by the increase in insulin. A 40-min basal period was followed by a 180-min experimental period in which an increase in insulin was induced, with euglycemia maintained by peripheral glucose infusion. Arterial and hepatic sinusoidal insulin levels increased from 10 ؎ 2 to 19 ؎ 3 and 20 ؎ 4 to 45 ؎ 5 U/ml, respectively. Net hepatic glucose output decreased rapidly from 1.90 ؎ 0.13 to 0.23 ؎ 0.16 mg ⅐ kg ؊1 ⅐ min ؊1 . Three methods of measuring gluconeogenesis and glycogenolysis were used: 1) the hepatic arteriovenous difference technique (n ؍ 8), 2) the [ 14 C] phosphoenolpyruvate technique (n ؍ 4), and 3) the 2 H 2 O technique (n ؍ 4). The net hepatic glycogenolytic rate decreased from 1.72 ؎ 0.20 to ؊0.28 ؎ 0.15 mg ⅐ kg ؊1 ⅐ min ؊1 (P < 0.05), whereas none of the above methods showed a significant change in hepatic gluconeogenic flux (rate of conversion of phosphoenolpyruvate to glucose-6-phosphate). These results indicate that liver glycogenolysis is acutely sensitive to small changes in plasma insulin, whereas gluconeogenic flux is not. Diabetes 50:1872-1882, 2001 RESEARCH DESIGN AND METHODS Animal care and surgical procedures. Experiments were conducted on eight conscious mongrel dogs (23-29 kg) of either sex that had been fed a once-daily meat and chow diet (34% protein, 46% carbohydrate, 14.5% fat, and From the
A modelling approach to hepatic glucose production estimation
PLOS ONE
Stable isotopes are currently used to measure glucose fluxes responsible for observed glucose concentrations, providing information on hepatic and peripheral insulin sensitivity. The determination of glucose turnover, along with fasting and postprandial glucose concentrations, is relevant for inferring insulin sensitivity levels. At equilibrium (e.g. during the fasting state) the rate of glucose entering the circulation equals its rate of disappearance from the circulation. If under these conditions tracer is infused at a constant rate and Specific Activity (SA) or Tracer to Tracee (TTR) ratio is computed, the Rate of Appearance (RA) equals the Rate of Disappearance (RD) and equals the ratio between infusion rate and TTR or SA. In the post-prandial situation or during perturbation studies, however, estimation of RA and RD becomes more complex because they are not necessarily equal and, furthermore, may vary over time due to gastric emptying, glucose absorption, appearance of ingeste...
AJP: Endocrinology and Metabolism, 2009
To determine the effect of an acute increase in hepatic glycogen on net hepatic glucose uptake (NHGU) and disposition in response to insulin in vivo, studies were performed on two groups of dogs fasted 18 h. During the first 4 h of the study, somatostatin was infused peripherally, while insulin and glucagon were replaced intraportally in basal amounts. Hyperglycemia was brought about by glucose infusion, and either saline ( n = 7) or fructose ( n = 7; to stimulate NHGU and glycogen deposition) was infused intraportally. A 2-h control period then followed, during which the portal fructose and saline infusions were stopped, allowing NHGU and glycogen deposition in the fructose-infused animals to return to rates similar to those of the animals that received the saline infusion. This was followed by a 2-h experimental period, during which hyperglycemia was continued but insulin infusion was increased fourfold in both groups. During the initial 4-h glycogen loading period, NHGU averaged ...
Diabetic Medicine, 2003
Multiple defects in the regulation of glucose metabolism are believed to play a role in the pathophysiology of Type 2 diabetes mellitus . Thus, basal rates of glucose production are often elevated , and suppression of glucose production (GP) as well as stimulation of glucose disappearance ( R d) by insulin, is impaired in Type 2 diabetes . In the study of this issue, the primed-constant tracer infusion method plays a major role. This method is combined with the euglycaemic hyperinsulinaemic clamp technique to assess the effects of insulin on glucose metabolism, independent of the effects of hyperglycaemia per se .