Gluconeogenesis in non-obese diabetic (NOD) mice: in vivo effects of vandadate treatment on hepatic glucose-6-phoshatase and phosphoenolpyruvate carboxykinase.

The contribution of gluconeogenesis to hyperglycemia in non-obese diabetic (NOD) mice has been investigated using oral vanadate administration. Vanadate compounds have been shown to mimic many actions of insulin; however, the exact mechanism is poorly understood. The aims of the present study were (1) to elucidate vanadate's action in vivo, and to assess the possibility that its glucose-reducing effect is dependent on the presence of a minimal concentration of insulin; and (2) to evaluate the effects of vanadate administration on the key hepatic gluconeogenesis enzymes, glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK), as well as glucose-6-phosphate dehydrogenase (G-6-PDH). Vanadate caused a significant reduction in blood glucose but failed to normalize it, despite effective serum vanadate concentrations (26.2 +/- 1.6 micromol/L). Two weeks after initiation of treatment, blood glucose levels were 26.0 +/- 1.8, 21.7 +/- 3.0, 16.0 +/- 1.6, and 14.3 +/- 2.3 mmol/L in the control (C), insulin (I), vanadate (V), and combined vanadate and insulin (V + I) groups, respectively (P < .001). G-6-Pase activity was significantly reduced by vanadate (622 +/- 134 v365 +/- 83 nmol/min/mg protein in C vV, P < .05). PEPCK activity was also significantly reduced (844 +/- 370, 623 +/- 36, 337 +/- 43, and 317 +/- 75 nmol/min/mg in the C, I, V, and V + I groups, respectively, P < .001). No significant differences in the hepatic glycogen stores and G-6-PDH activity were noted between treatment groups. Our study suggests that the inhibition of hepatic G-6-Pase and PEPCK activity by vanadate plays an important role in reducing blood glucose levels in NOD mice.

Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiving long-term furosemide therapy.

PURPOSE: We have previously found thiamine (vitamin B1) deficiency in patients with congestive heart failure (CHF) who had received long-term furosemide therapy. In the present study, we assessed the effect of thiamine repletion on thiamine status, functional capacity, and left ventricular ejection fraction (LVEF) in patients with moderate to severe CHF who had received furosemide in doses of 80 mg/d or more for at least 3 months. PATIENTS AND METHODS: Thirty patients were randomized to 1 week of double-blind inpatient therapy with either i.v. thiamine 200 mg/d or placebo (n = 15 each). All previous drugs were continued. Following discharge, all 30 patients received oral thiamine 200 mg/d as outpatients for 6 weeks. Thiamine status was determined by the erythrocyte thiamine-pyrophosphate effect (TPPE). LVEF was determined by echocardiography. RESULTS: TPPE, diuresis, and LVEF were unchanged with i.v. placebo. After i.v. thiamine, TPPE decreased (11.7% +/- 6.5% to 5.4% +/- 3.2%; P < 0.01). LVEF increased (0.28 +/- 0.11 to 0.32 +/- 0.09; P < 0.05), as did diuresis (1,731 +/- 800 mL/d to 2,389 +/- 752 mL/d; P < 0.02), and sodium excretion (84 +/- 52 mEq/d to 116 +/- 83 mEq/d, P < 0.05). In the 27 patients completing the full 7-week intervention, LVEF rose by 22% (0.27 +/- 0.10 to 0.33 +/- 0.11, P < 0.01). CONCLUSIONS: Thiamine repletion can improve left ventricular function and biochemical evidence of thiamine deficiency in some patients with moderate-to-severe CHF who are receiving longterm furosemide therapy.

Differentiation between organophosphate and carbamate poisoning.

We propose a novel and simple assay for the real-time differentiation between carbamate and organophosphate inhibition of cholinesterase, based on our observations of the kinetic behavior of inhibited enzyme. The assay of carbamylated cholinesterase activity over time follows a non-linear kinetic pattern, whereas that of phosphorylated enzyme activity is linear. This feature can be exploited to differentiate between carbamate and organophosphate cholinesterase inhibition. The non-linear pattern characteristic of carbamates is easily discernible at degrees of inhibition of 40% or more. In this setting, cholinesterase activity ought to be measured continuously for about 1 h to obtain the kinetic pattern of enzyme activity. The initial activity, measured during the first 5 min of assay, represents the activity of enzyme in vivo. In vitro reactivation of inhibited cholinesterase allows the estimation of full potential activity of enzyme prior to poisoning, so that percentage of inhibition can be calculated. Reactivation of carbamylated cholinesterase is obtained by the incubation of diluted enzyme at 37 degrees C for 2.5 h prior to assay, whereas phosphorylated (non-aged) enzyme is reactivated by a 30 min incubation with oximes. In cases of mild exposure to cholinesterase inhibitors (< 40% inhibition), the response of enzyme to in vitro reactivation serves as a complementary test for exposure and for the nature of the inhibitor. All the results presented in this work refer to plasma cholinesterase. Erythrocyte cholinesterase was found to behave very similarly to plasma enzyme and its results have not been reported here.

Mononuclear cell magnesium content remains unchanged in various hypertensive disorders of pregnancy.

Serum magnesium levels, as well as magnesium content of red blood cells and peripheral mononuclear cells, were examined in 31 pregnant women in their third trimester. Ten were preeclamptic; chronic hypertension was found in 10, and 11 were normotensive. Magnesium serum levels were 1.2 +/- 0.1, 1.2 +/- 0.1 and 1.3 +/- 0.1 mEq/l in the normotensives, chronic hypertensives and preeclamptics, respectively. Red blood cell magnesium concentration was 3.4 +/- 0.4, 3.7 +/- 0.7 and 3.5 +/- 0.5 mEq/l, and mononuclear magnesium content was 37.9 +/- 30.6, 27.6 +/- 15.9 and 30.2 +/- 25.7 fg/cell in the same groups, respectively. These changes were not statistically significant. The results do not support the hypothesis that magnesium deficiency is involved in the pathophysiology of preeclampsia.

Acute pyridostigmine overdose: a report of nine cases.

Pyridostigmine is known as a pre-treatment drug against intoxication with organophosphorus nerve agents. During the Persian Gulf war, we encountered a cluster of nine cases of pyridostigmine self-poisoning, of which three presented with mixed drug poisoning. The clinical and laboratory features of pyridostigmine toxicity are presented. Doses ranged between 390 and 900 mg. Pyridostigmine ingestion resulted in mild to moderate cholinergic symptoms such as abdominal cramps, diarrhea, emesis, nausea, hypersalivation, urinary incontinence, fasciculations, muscle weakness and blurred vision. No central nervous system manifestations were evident. The symptoms developed within several minutes and lasted up to 24 h. All patients underwent gastric emptying followed by administration of activated charcoal. Atropine (1-8 mg) was required in only three patients. Measurement of serum cholinesterase inhibition was found to be a reliable and sensitive diagnostic tool in pyridostigmine poisoning. No clear correlation was found between the extent of cholinesterase inhibition and the incidence or severity of the cholinergic signs. The clinical recovery was faster than the spontaneous recovery of the enzyme. Pyridostigmine intoxication is self-limited and well tolerated by young healthy adults.

Longitudinal study of magnesium status of Israeli military recruits.

The following study was conducted to assess the biochemical and nutritional status of new military recruits during 12 weeks of strenuous physical activity. Calorie and magnesium (Mg) intake, energy expenditure, and serum, red blood cell (RBC) and mononuclear cell (MNC) Mg were assessed at the start, after 6 weeks and after 12 weeks of training. The results provide evidence that MNC Mg content decreases, whereas serum Mg increases, under prolonged, strenuous training conditions in previously unconditioned military recruits. Mg dietary intake alone could not account for these changes. It is postulated that this decrease in MNC Mg (from 64.76 +/- 34.99 to 23.81 +/- 15.55 fg/cell), unparalleled by similar changes in serum Mg or RBC Mg, reflects a reduction in exchangeable Mg body stores, and the onset of a Mg deficiency state.

On the solubility of calcium deoxycholate: kinetics of precipitation and the effect of conjugated bile salts and lecithin.

In view of the low solubility of calcium deoxycholate and the possible induction of cholesterol precipitation in the gallbladder by calcium insoluble salts, we find it of interest to study the precipitation of calcium deoxycholate and its dependence on other bile components. The findings of these studies were as follows: (i) Precipitation of calcium deoxycholate from mixtures of calcium chloride and monomeric deoxycholate (at concentrations below the critical micelle concentration (CMC] is very slow even at relatively high CaCl2 concentrations (more than 20 days at 50 mM CaCl2). (ii) At higher deoxycholic acid (DOC) concentrations, precipitation of micellar DOC is faster and requires much lower calcium chloride concentrations. For any given calcium concentration, the rate of precipitation is maximal at an optimal DOC concentration. In solutions containing 150 mM NaCl, the maximal rate of precipitation occurs at about 10 mM DOC, almost independent of Ca2+ concentration. At lower ionic strength (10 mM NaCl), the optimal DOC concentration is 30 mM. These observations suggest that the most important factors in determining the rate of Ca(DOC)2 precipitation are (a) the ratio between calcium ions bound to the surface of a DOC micelle, and the [DOC] (the Ca2+/DOC binding ratio) and (b) the concentration of DOC micelles. (iii) In the presence of conjugated deoxycholates, the crystallization of calcium deoxycholate is inhibited. Phosphatidylcholine has a similar, although smaller, inhibitory effect. Upon precipitation of calcium deoxycholate from a mixed micellar system containing sodium deoxycholate, phosphatidylcholine and cholesterol, the latter two components spontaneously form vesicles. The anti-nucleating effect of PC and conjugated bile salts is explained in terms of "poisoning" of the crystallization process. In view of the latter results we conclude that under normal conditions calcium deoxycholate is not likely to precipitate in the gallbladder.

Altered erythrocyte and plasma sodium and potassium in hypertension, a facet of hyperinsulinemia.

Red blood cell sodium and potassium, plasma potassium, glucose and insulin responses to oral glucose load, serum urate, and plasma triglycerides were determined in a stratified subsample (n = 89) of a representative population sample (n = 1211), comprising 30 nonobese normotensive subjects with normal glucose tolerance (reference group) and 59 subjects representing each of the seven possible combinations of abnormal glucose tolerance, obesity, and hypertension. Rate of cation imbalance (red blood cell sodium greater than or equal to 7.0 mEq/L, potassium less than 92.5 mEq/L, or plasma potassium greater than or equal to 4.5 mEq/L) was 88.1% in subjects with abnormal tolerance, obesity, or hypertension, as compared with 40.0% in the reference group (p less than 0.001). These subjects were also characterized by significantly greater rates of insulin response: 60- and 120-minute postload levels of 100 mU/L or more (88.1 vs 46.7%), plasma triglycerides of 80 mg/dl or more (89.8 vs 53.3%) and serum uric acid of 5.5 mg/dl or more (61.0 vs 26.7%; p less than 0.001 for all). The rate of cation imbalance was significantly associated with each of these three biochemical correlates: insulin response (p less than 0.01), triglycerides (p less than 0.001), and urate (p less than 0.001). In the total population sample, the rate of untreated hypertension increased from 18% to 35% to 55.3% (p less than 0.001), with an increase in the number of biochemical correlates of cation imbalance in combination with glucose intolerance and obesity.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperinsulinemia--a link between glucose intolerance, obesity, hypertension, dyslipoproteinemia, elevated serum uric acid and internal cation imbalance.

A representative sample (n = 1211) of the Jewish population in Israel age 40-70 (excluding known diabetics), underwent a glucose tolerance test. Insulin response was found to be independently and positively associated with the GOH conditions--glucose intolerance (p less than 0.001), obesity (p less than 0.001), and hypertension (p less than 0.01) and with elevated serum uric acid (p less than 0.001) after accounting for the effects of sex, age, serum creatinine and use of antihypertensive medications. In a representative subgroup of 542 individuals, total VLDL and LDL fractions were estimated by standardized values (based on the reference group--individuals free of the GOH conditions), of their cholesterol and triglyceride components. Hyperinsulinemia was characterized by jointly elevated VLDL and LDL with reduced HDL. The risk ratio for this pattern (adjusted for the effects of age, sex, smoking and presence of any of the GOH conditions) was 3.4 (p less than 0.001). There was no further association of this disturbed lipoprotein profile with the GOH conditions. Cation concentrations were determined in a stratified subsample (n = 89) of the study group. The subsample comprised 30 individuals in the reference group, and 59 representing each of the seven possible combinations of abnormal glucose tolerance, obesity and hypertension (GOH group). Rate of cation imbalance defined as presence of at least one of three cation concentration--red blood cell sodium greater than or equal to 7.0 mEq/l, red blood cell potassium less than 92.5 mEd/l or plasma potassium greater than or equal to 4.5 mEq/l was 88.1% in the GOH, compared to 40.0% in the reference group (p greater than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Serum theophylline concentrations are not affected by coadministration of doxycycline.

Doxycycline (D) is often administered during respiratory infections to asthmatic patients, many of them treated by theophylline (T) as well. We therefore investigated a possible interaction between D and T. Steady-state basal T levels were measured on two successive days before and after three and four days of D administration in ten stable asthmatic patients. Mean T levels before D were 9.9 +/- 3.1 micrograms/mL and after D 10.1 +/- 2.9 micrograms/mL, which are not significantly different. But T levels in four patients increased and in two patients, T levels decreased. We conclude that in some patients, T concentrations may be affected by D. This may require determination of T blood levels and T dose adjustment in some patients treated by T and D.

Hyperinsulinemia. A link between hypertension obesity and glucose intolerance.

Hypertension and glucose intolerance, determined in a random population sample (n = 2,475), showed a highly significant (P less than 0.001) association from the mildest levels of both conditions, independent of the confounding effects of age, sex, obesity, and antihypertensive medications. Summary rate ratios for hypertension were 1.48 (1.18-1.87) in abnormal tolerance and 2.26 (1.69-2.84) in diabetes compared with normal tolerance. Altogether, 83.4% of the hypertensives were either glucose-intolerant or obese--both established insulin-resistant conditions. Fasting and post-load insulin levels in a representative subgroup (n = 1,241) were significantly elevated in hypertension independent of obesity, glucose intolerance, age, and antihypertensive medications. The mean increment in summed 1- and 2-h insulin levels (milliunits per liter) compared with nonobese normotensives with normal tolerance was 12 for hypertension alone, 47 for obesity alone, 52 for abnormal tolerance alone, and 124 when all three conditions were present. The prevalence of concentrations (milliequivalents per liter) of erythrocyte Na+ greater than or equal to 7.0, K+ less than 92.5, and plasma K+ greater than or equal to 4.5 in a subsample of 59 individuals with all combinations of abnormal tolerance obesity and hypertension was compared with those in 30 individuals free of these conditions. Altogether, 88.1% of the former vs. 40.0% of the latter group presented at least one of these three markers of internal cation imbalance (P less than 0.001). We conclude that insulin resistance and/or hyperinsulinemia (a) are present in the majority of hypertensives, (b) constitute a common pathophysiologic feature of obesity, glucose intolerance, and hypertension, possibly explaining their ubiquitous association, and (c) may be linked to the increased peripheral vascular resistance of hypertension, which is putatively related to elevated intracellular sodium concentration.