Estimation of the initial distribution volume of glucose by an incremental plasma glucose level at 3 min after i.v. glucose in humans

AIMS: The initial distribution volume of glucose (IDVG) could be a clinically useful indicator of the central extracellular fluid (ECF) space volume, namely the interstitial fluid volume status of highly perfused organs. In this study, we determined the formula of IDVG using incremental plasma glucose levels after i.v. glucose. METHODS: One hundred and fifty patients admitted to the general intensive care unit of the University of Hirosaki hospital were entered into this prospective study which was conducted in two stages. In the first stage 300 data points from 100 patients were used to measure the IDVG (3 determinations for each patients). This utilized a one compartment model to describe the incremental plasma glucose decay curve following an intravenous bolus injection of glucose which, in turn, was used to derive the parameters of an equation for IDVG prediction following a single plasma sample. The second stage was a validation of the equation using a separate data set (150 points) from a further 50 patients. RESULTS: A one phase exponential decay model was well-fitted for the IDVG-postadministration glucose level curve, and indicated that the incremental glucose level at 3 min after i.v. glucose was best-correlated to the IDVG compared with those at 1, 2, 4, 5 and 7 min postadministration. The formula of the IDVG was obtained from the curve: IDVG=24.44xe-0.0298xDeltaGL+2.70, where DeltaGL=incremental glucose level at 3 min after i.v. glucose. Another 150 samples showed that the measured-IDVG from a one compartment model and predicted-IDVG from the formula were 7.24+/-1. 63 and 7.27+/-1.52 l, respectively, and that there was a significant correlation between the two IDVGs (r=0.966, P<0.0001). CONCLUSIONS: Using an incremental glucose level at 3 min after i.v. glucose, we have established the reliable formula for determination of the IDVG which could be a clinically useful indicator of the central ECF volume.     

Modulation of glucose homeostasis by doxepin.

Blood glucose level (BGL) was estimated up to 4 h (3 h in case of GTT) in 18-h fasted albino rabbits following acute and chronic (one month) feeding of doxepin and thereafter for another 8 days together with either insulin or glibenclamide or adrenaline. A single dose of doxepin produced significant hypoglycemia which peaked at 4 h and lasted up to 10 h. On chronic doxepin feeding there was complete attenuation of initial hypoglycemia on the 7th and 14th days, culminating into frank hyperglycemia on the 21st day. However, there was complete recovery on the 29th day exhibiting tolerance to initial hypo-as well as delayed hyperglycemia. Similarly, glucose intolerance was accentuated on the 8th day followed by a gradual recovery on the 15th and 22nd days, culminating in disappearance of glucose intolerance on the 30th day. The hypoglycemic effect of insulin was markedly potentiated in chronically doxepin fed animals which was further enhanced on continuing administration of both agents. Profound hypoglycemia was observed during GTT in such animals. The hyperglycemic effect of adrenaline was enhanced in chronically doxepin fed animals, which may be due to TCA induced enhancement of the response of exogenous adrenaline. Suppression of this hyperglycemia with continued administration of both drugs seems to be due to subsensitivity of alpha 2-adrenoceptors. Additive hyperglycemia was observed during GTT in such animals.     

Pharmacodynamics of glucose regulation by methylprednisolone. II. normal rats

A physiologic pharmacodynamic model was developed to jointly describe the effects of methylprednisolone (MPL) on adrenal suppression and glycemic control in normal rats. Six groups of animals were given MPL intravenously at 0, 10 and 50 mg/kg, or by subcutaneous 7 day infusion at rates of 0, 0.1 and 0.3 mg/kg/h. Plasma concentrations of MPL, corticosterone (CST), glucose and insulin were determined at various times up to 72 h after injection and 336 h after infusion. The pharmacokinetics of MPL was described by a two‐compartment model. A circadian rhythm for CST was found in untreated rats with a stress‐altered baseline caused by handling, which was captured by a circadian harmonic secretion rate with an increasing mesor. All drug treatments caused CST suppression. Injection of MPL caused temporary increases in glucose over 4 h. Insulin secretion was thereby stimulated yielding a later peak around 6 h. In turn, insulin can normalize glucose. However, long‐term dosing caused continuous hyperglycemia during and after infusion. Hyperinsulinemia was achieved during infusion, but diminished immediately after dosing despite the high glucose concentration. The effects of CST and MPL on glucose production were described with a competitive stimulation function. A disease progression model incorporating reduced endogenous glucose uptake/utilization was used to describe glucose metabolism under different treatments. The results exemplify the roles of endogenous and exogenous hormones in mediating glucose dynamics. The pharmacokinetic/pharmacodynamic model is valuable for quantitating diabetogenic effects of corticosteroid treatments and provides mechanistic insights into the hormonal control of the metabolic system. Copyright © 2009 John Wiley & Sons, Ltd.     

Pharmacodynamics of glucose regulation by methylprednisolone. I. Adrenalectomized rats

Mechanisms related to the adverse effects of corticosteroids on glucose homeostasis were studied. Five groups of adrenalectomized (ADX) rats were given methylprednisolone (MPL) intravenously at 10 and 50 mg/kg, or a continuous 7 day infusion at rates of 0, 0.1, 0.3 mg/kg/h via subcutaneously implanted Alzet mini‐pumps. Plasma concentrations of MPL, glucose and insulin were determined at various time points up to 72 h after injection or 336 h after infusion. The pharmacokinetics of MPL was captured with a two‐compartment model. The Adapt II software was used in modeling. Injection of MPL caused a temporary glucose increase over 6 h by stimulating gluconeogenesis. The glucose changes stimulated pancreatic β‐cell secretion yielding a later insulin peak at around 10 h. In turn, insulin can stimulate glucose disposition. However, long‐term MPL treatment caused continuous hyperglycemia during and after infusion. Insulin was increased during infusion, and immediately returned to baseline after the infusion was terminated, despite the almost doubled glucose concentration. A disease progression model incorporating the reduced endogenous glucose disposition was included to capture glucose homeostasis under different treatments. The results exemplify the importance of the steroid dosing regimen in mediating pharmacological and adverse metabolic effects. This mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model quantitatively describes the induction of hyperglycemia and provides additional insights into metabolic disorders such as diabetes. Copyright © 2009 John Wiley & Sons, Ltd.     

Frontal glucose hypometabolism in abstinent methamphetamine users.

Changes in relative regional cerebral glucose metabolism (rCMRglc) and their potential gender differences in abstinent methamphetamine (MA) users were explored. Relative rCMRglc, as measured by (18)F-fluorodeoxyglucose positron emission tomography, and frontal executive functions, as assessed by Wisconsin card sorting test (WCST), were compared between 35 abstinent MA users and 21 healthy comparison subjects. In addition, male and female MA users and their gender-matched comparison subjects were compared to investigate potential gender differences. MA users had lower rCMRglc levels in the right superior frontal white matter and more perseveration and nonperseveration errors in the WCST, relative to healthy comparison subjects. Relative rCMRglc in the frontal white matter correlated with number of errors in the WCST in MA users. In the subanalysis for gender differences, lower rCMRglc in the frontal white matter and more errors in the WCST were found only in male MA users, not in female MA users, relative to their gender-matched comparison subjects. The current findings suggest that MA use causes persistent hypometabolism in the frontal white matter and impairment in frontal executive function. Our findings also suggest that the neurotoxic effect of MA on frontal lobes of the brain might be more prominent in men than in women.     

Letter: Pyridoxine and oestrogen-induced glucose intolerance.

Clinical examination of the possibility that xanthurenic acid is the cause of oral contraceptive (OC) induced glucose tolerance and gestational diabetes has been carried out. The reduction by pyridoxine of excessive xanthurenic acid excretion following a tryptophan load has been associated with an improvement in glucose tolerance, yet it is not believed that the 2 are causally related. Instead, the beneficial effects of pyridoxine are possibly because of normalization of other tryptophan metabolites. Some women suffer from estrogen-induced glucose intolerance independent of any abnormalities in xanthurenic acid excretion. It has been found that the administration of xanthurenic acid 120 mg/kg intraperitoneally in ammoniated saline failed to alter blood glucose in male Sprague Dawley or Wistar rats. The experiments were repeated using the special high fat diet which had been used in the original studies on the diabetogenic effects of xanthurenic acid, and xanthurenic acid was found to be inactive. Xanthurenic acid did not impair glucose tolerance when given 1 hour before an oral glucose load in further experiments. The failure to demonstrate any diabetogenic effect of xanthurenic acid could not be because of contamination with the 8-methyl ether of xanthurenic acid, which has been reported to be antidiabetogenic, since the sample of xanthurenic acid used was found to be free from this contaminant.     

Acute effect of benfluorex on glucose metabolism.

The antihyperlipidaemic agent benfluorex [1-(3-trifluoromethylphenyl)-2-(2-benzoyl-oxyethyl)-aminopropane] and its metabolite S422 [1-(3-trifluoromethylphenyl)-2-(2-hydroxyethyl)-aminopropane] were examined for an acute (after 1-2 hr) effect on glucose metabolism in normal rats. Enteral administration of benfluorex (25 mg/kg) did not affect basal plasma glucose and insulin concentrations. However, enteral and intravenous glucose tolerance were modestly improved without enhancing the insulin response to glucose. Hepatic gluconeogenesis from lactate was not acutely altered by benfluorex (25 mg/kg) in vivo or by S422 (1 mM) in vitro, but S422 (1 mM) slightly reduced (by 11%) hepatic glycogen mobilization in vitro after 2 hr. S422 (1 mM) increased (by 47%) glucose oxidation by diaphragm muscle in vitro. The effect was additive to that of insulin. Anaerobic glucose metabolism and glycogenesis of diaphragm muscle were not affected by S422. The results suggest that benfluorex can acutely improve glucose tolerance associated with increased glucose oxidation by muscle.     

不同标准空腹血糖受损人群葡萄糖负荷后血糖代谢特征

目的：分析两种标准空腹血糖受损人群葡萄糖负荷后血糖代谢特点。方法：对3828名40岁以上居民进行流行病学调查,对空腹血糖≥5.6mmol/L者行75g葡萄糖负荷试验,据不同空腹血糖受损诊断标准分析负荷后2h血糖代谢情况。结果：在以空腹血糖为6.1mmol/L为切点诊断的245例空腹血糖受损（IFG）人群中,糖耐量减低（IGT）的患病率为41.22%,女性（25.71%）高于男性（15.51%）;2型糖尿病（T2DM）患病率为20.82%,女性（11.84%）高于男性（8.98%）。在以空腹血糖为5.6mmol/L为切点诊断的627例空腹血糖受损人群中,糖耐量减低的患病率为37.00%,女性（23.76%）高于男性（13.23%）;2型糖尿病患病率为13.88%,女性（9.52%）高于男性（4.63%）。结论：以空腹血糖为5.6mmol/L和6.1mmol/L为切点诊断的空腹血糖受损人群葡萄糖负荷后2h血糖代谢异常率分别为50.88%和62.04%,患病率女性均高于男性。     

Influence of diftalone on tolbutamide test and i.v. glucose tolerance test.

In 16 healthy volunteers tolbutamide tests or i.v. glucose tolerance tests were performed with and without previous oral administration of 1000 mg diftalone. Blood sugar and serum insulin were assayed in regular intervals. Both with and without previous administration of diftalone blood glucose after tolbutamide did not show any difference. IRI response to tolbutamide, measured by planimetrical integration showed a statistically significant augmentation (0.05 greater than p greater than 0.01) after diftalone. Glucose assimilation (K-value) after diftalone was decreased (0.05 greater than p greater than 0.01) yet within normal range. For the accompanying insulin levels however no statistically significant difference was observed. In addition a normalisation of pathological tolbutamide test after diftalone could be noted in five patients with subclinical diabetes. Our results indicate that diftalone seems to have the following three actions: 1. Enhancement of the tolbutamide action. 2. direct augmentation of IRI secretion, 3. a peripheral action on glucose metabolism.     

维格列汀与西格列汀降糖疗效对比

目的:比较维格列汀和西格列汀的降糖效果。方法:受试者随机分配维格列汀组,或者西格列汀组。先后分服两药,使用动态血糖监测(CGM)测定24h的平均血糖、平均血糖波动幅度(MAGE)、空腹血糖、餐后血糖、HbA1c、GA、1,5AG、IRI、CPR、BNP、PAI-1以及尿C肽。结果:维格列汀组的24h平均血糖低于西格列汀组(142.1±35.5vs.153.2±37.0mg/dL;P=0.012)。与西格列汀相比,服用维格列汀的患者,MAGE下降(110.5±33.5vs.129.4±45.1mg/dL;P=0.040),晚餐后血糖峰值也下降(206.1±40.2vs.223.2±43.5mg/dL;P=0.015),早餐后3h内AUC≥180mg/dL也下降(484.3vs.897.9mg/min/dL;P=0.025),尿CPR显著上升(97.0±41.6vs.85.2±39.9μg/day;P=0.008)。两组间HbA1c,GA,1,5AG,IRI,CPR,BNP,或PAI-1均无意义。结论:与西格列汀比较,维格列汀的降糖效果更好,副作用更小,对心血管的保护作用更佳,值得临床推广应用。     

Role of intestinal glucose absorption in glucose tolerance

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Metal-induced hormesis requires cPKC-dependent glucose transport and lowered respiration.

Previously, cytotoxicity studies using an 3-(4,5 dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT)-based in vitro toxicity assay found that low concentrations of mercuric, cadmium and cupric chloride (0.7, 1 and 3 pM, respectively) induced hormesis in McCoy cells after 24 h exposure. An investigation of the biochemical events required for the induction of this phenomenon revealed that hormesis was dependent on two simultaneous but independent events, namely, an 11-15% conventional protein kinase C (cPKC)-dependent increase in glucose uptake and a protein synthesis-dependent 19-23% drop in mitochondrial respiration. The inhibition of either event was sufficient to abolish hormesis for all three metal toxicants. Furthermore, an investigation of the energy status of cells prior to and during hormesis revealed an oscillating level of ATP production found to be in phase with mitochondrial respiration, independent of cPKC-activated glucose transport and found to coincide with a 16-20% drop in AMP-activated protein kinase activity. These findings suggest that hormesis is not a form of energy compensation but is most likely a reductive burst where an increase in glucose uptake together with a simultaneous reduction in oxygen consumption results in a significant increase in reduction equivalents, which may then be utilized by cells to counteract the effects of oxidative stress induced by heavy metal toxicants.     

Oral verapamil does not affect glucose tolerance in non-diabetics.

Verapamil, a calcium antagonist used to treat angina pectoris, inhibits insulin release in vitro and, when administered intravenously to humans, decreases glucose tolerance. Oral verapamil, 120 mg/day for 1 week increasing thereafter to 240 mg/day in divided doses, was given to nine non-diabetic patients with angina pectoris for 4 weeks. The glucose and insulin responses to a standard glucose load showed no significant difference before and after verapamil. Oral verapamil in the doses used in this study had no significant effect on glucose tolerance in non-diabetics.