Opposite effects of glucose on plasma membrane Ca2+-ATPase and Na/Ca exchanger transcription, expression, and activity in rat pancreatic beta-cells.
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When stimulated by glucose the pancreatic beta-cell displays large oscillations of the intracellular free Ca2+concentration, resulting from intermittent Ca2+ entry from the outside and outflow from the inside, the latter process being mediated by the plasma membrane Ca2+-ATPase (PMCA) and the Na+/Ca2+ exchanger (NCX). To understand the respective role of these two mechanisms, we studied the effect of glucose on PMCA and NCX transcription, expression, and activity in rat pancreatic islet cells. Glucose (11.1 and 22.2 mm) induced a parallel decrease in PMCA transcription, expression, and activity. In contrast the sugar induced a parallel increase in NCX transcription, expression, and activity. The effects of the sugar were mimicked by the metabolizable insulin secretagogue alpha-ketoisocaproate and persisted in the presence of the Ca2+-channel blocker nifedipine. The above results are compatible with the view that, when stimulated, the beta-cell switches from a low efficiency Ca2+-extruding mechanism, the PMCA, to a high capacity system, the Na/Ca exchanger, to better face the increase in Ca2+ inflow. These effects of glucose do not result from a direct effect of the sugar itself and are not mediated by the increase in intracellular free Ca2+ concentration induced by the sugar. (+info)
Effects of fatty acids on hepatic amino acid catabolism and fibrinogen synthesis in young healthy volunteers.
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Increased synthesis rate of fibrinogen, an independent risk factor for cardiovascular disease, was recently reported in obese insulin-resistant female adolescents with chronic elevated nonesterified fatty acids (NEFA). It is unknown whether a short-term change of NEFA concentrations controls hepatic fibrinogen synthesis. Therefore, 10 healthy male volunteers (24.5 +/- 3.3 yr, body mass index 23.5 +/- 2.9 kg/m2) were investigated in random order under basal and elevated NEFA for 8 h. Leucine metabolism, the fractional synthesis rates (FSR) of plasma fibrinogen, and endogenous urea production rates were measured during primed, continuous infusion of [1-13C]leucine and [15N2]urea, respectively. Plasma alpha-[13C]ketoisocaproic acid and [15N2]urea enrichment values were measured with GC-MS. Plasma fibrinogen was isolated with the beta-alanine method, and fibrinogen-related [13C]leucine enrichment was analyzed by GC-CIRMS. Lipofundin infusion and subcutaneous heparin tripled NEFA and triglycerides in the tests. Plasma glucose, circulating insulin, human C-peptide, and plasma glucagon were not changed by the study procedure. Fibrinogen FSR were significantly lower in tests with NEFA elevation (18.44 +/- 4.67%) than in control tests (21.48 +/- 4.32%; P < 0.05). Plasma fibrinogen concentrations measured were not significantly different (NEFA test subjects: 1.85 +/- 0.33, controls: 1.97 +/- 0.54 g/l). Parameters of leucine metabolism, such as leucine rate of appearance, leucine oxidation, and nonoxidative leucine disposal, were not influenced by NEFA elevation, and endogenous urea production remained unchanged. NEFA contributes to short-term regulation of fibrinogen FSR in healthy volunteers under unchanged hormonal status, leucine metabolism, and overall amino acid catabolism. Its contribution might be of relevance at least after fat-rich meals, counteracting by reduction of FSR the blood viscosity increase implied by hyperlipidemia. (+info)
Gender differences in the regulation of amino acid metabolism.
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Exercising men, compared with women, have a greater increase in leucine oxidation but not lysine rate of appearance. The cause for this sexual dimorphism is unknown; however, an inhibition of beta-adrenoreceptor activity has previously been shown to mediate amino acid metabolism (Lamont LS, McCullough AJ, and Kalhan SC. Am J Physiol Endocrinol Metab 268: E910-E916, 1995; Lamont LS, Patel DG, and Kalhan SC. J Appl Physiol 67: 221-225, 1989). This study was a gender comparison of leucine and lysine kinetics during a beta-adrenoreceptor blockade (beta1,beta2-blockade) and a placebo control by using a double-blind crossover protocol. Subjects exercised at 50% of their trial-specific maximal O2 consumption (1 h) after 7 days of dietary control. During exercise with beta-blockade, men had an increased nonprotein respiratory exchange ratio (P < 0.001), whereas women had an increased circulation of free fatty acids (P < 0.001). The genders also displayed distinct differences in exercise amino acid kinetics. The men, but not the women, increased leucine oxidation (P < 0.005) and lysine rate of appearance (P < 0.009) when exercising during beta-adrenergic blockade. This study indicates that during beta-blockade, exercising men increase their need for amino acids (and carbohydrate) to fuel energy needs, whereas women increase their mobilization of fat, thereby requiring less alternative fuels such as carbohydrate and amino acids. Gender-specific fuel preferences during exercise are regulated by beta-adrenergic-receptor activity. Substrate availability during exercise appears to modulate the amino acid oxidation differences between genders. (+info)
Allosteric activators of glucokinase: potential role in diabetes therapy.
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Glucokinase (GK) plays a key role in whole-body glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic beta cells and hepatocytes. We describe a class of antidiabetic agents that act as nonessential, mixed-type GK activators (GKAs) that increase the glucose affinity and maximum velocity (Vmax) of GK. GKAs augment both hepatic glucose metabolism and glucose-induced insulin secretion from isolated rodent pancreatic islets, consistent with the expression and function of GK in both cell types. In several rodent models of type 2 diabetes mellitus, GKAs lowered blood glucose levels, improved the results of glucose tolerance tests, and increased hepatic glucose uptake. These findings may lead to the development of new drug therapies for diabetes. (+info)
Shift in metabolic substrate uptake by the heart during development of alloxan-induced diabetes.
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Inhibition of endothelial nitric oxide (NO) synthase (eNOS) is associated with an increase in glucose uptake by the heart. We have already shown that Type I diabetes also causes a decrease in eNOS protein expression and altered NO control of both coronary vascular resistance and oxygen consumption. Therefore, we predict that the increase in plasma glucose and the reduction in eNOS during diabetes together would result in a large increase in cardiac glucose uptake. Arterial (A) and coronary sinus (C) plasma levels of glucose, free fatty acid (FFA), beta-hydroxybutyric acid (beta-HBA), and lactate were measured, and myocardial uptake was calculated before and at week 1, 2, 3, and 4 of alloxan-induced diabetes. The heart of healthy dogs consumed FFA (19.2 +/- 2.6 microeq/min) and lactate (19.7 +/- 3.4 micromol/min). Dogs in the late stage of diabetes (at week 4) had elevated arterial beta-HBA concentrations (1.6 +/- 0.7 micromol/l) that were accompanied by an increased beta-HBA uptake (0.3 +/- 0.2 micromol/min). In contrast, myocardial lactate (-4.8 +/- 3.0 micromol/min) and FFA uptake (2.5 +/- 1.9 microeq/min) were significantly reduced in diabetic animals. Despite a marked hyperglycemia (449 +/- 25 mg/dl), the heart did not take up glucose (-7.9 +/- 4.1 mg/dl). Our results indicate significant changes in the myocardial substrate utilization in dogs only in the late stage of diabetes, at a time when myocardial NO production is already decreased. (+info)
BIOCHEMICAL CHANGES OCCURRING DURING SPORULATION OF BACILLUS CEREUS T. II. EFFECT OF ESTERS OF ORGANIC ACIDS ON SPORULATION.
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Gollakota, K. G. (University of Illinois, Urbana) and H. Orin Halvorson. Biochemical changes occurring during sporulation of Bacillus cereus T. II. Effect of esters of organic acids on sporulation. J. Bacteriol. 85:1386-1393. 1963.-Sporulation of Bacillus cereus T in yeast extract-glucose-minerals medium was specifically inhibited by alpha-picolinic acid (APA), if the acid was added before the pH of the culture began to rise. The effects of APA could be reversed by aspartic acid or asparagine, among the amino acids, and by intermediates of the tricarboxylic acid cycle, with the exception of alpha-ketoglutarate and fumarate. Formate, malonate, and certain other organic acids also possessed this ability. Succinate was the best reversing agent. Fluoroacetic acid (FAA) also inhibited sporulation, but had no effect on vegetative growth or germination of spores of B. cereus T. Unlike APA, FAA inhibited sporulation even when added after the pH of the culture had started to rise. Bisulfite was similar to FAA in its effects on sporulation. With the exception of pyruvate, acetate, aspartate, and malate, most of the compounds reversing the effects of APA also overcame the effects of FAA or bisulfite on sporulation. Esters of some of the acids reversing the effects of the above inhibitors were studied for their action on germination, growth, and sporulation. Ethyl pyruvate prevented germination of the spores, slowed down growth, and inhibited sporulation. Ethyl malonate and ethyl succinate inhibited only sporulation. All the above inhibitors prevented the synthesis of dipicolinic acid (DPA) also. When B. cereus T was grown in the absence of glucose (in extracted yeast extract-minerals medium), the above inhibitors had no effect on sporulation. Ethyl oxamate permitted sporulation, but the spores produced were heat-sensitive. Ethyl pimelate caused lysis when added before the pH of the culture began to rise. When added after the pH of the culture began to rise, it also permitted sporulation, and the spores were sensitive to heat. (These heat-sensitive spores were refractile and dormant, and did not stain with crystal violet. However, they germinated normally, losing refractibility and became stainable.) The effect of ethyl oxamate and ethyl pimelate could be overcome by DPA. APA, FAA, ethyl malonate, and ethyl succinate also inhibit the sporulation of a number of other bacilli. (+info)
PREPARATION OF OPTICALLY ACTIVE GAMMA- AND DELTA-LACTONES BY MICROBIOLOGICAL REDUCTION OF THE CORRESPONDING KETO ACIDS.
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It was found, by means of simple screening methods, that several yeasts (Saccharomyces and Candida), molds (Cladosporium), and bacteria (Sarcina) are able to reduce keto acids to hydroxy acids, which are easily converted into lactones. Chemical analysis showed that some of the microorganisms (Saccharomyces and Candida) produce dextrorotatory lactones and others (Cladosporium and Sarcina) produce levorotatory lactones. High yields of dextrorotatory (both gamma- and delta-lactones) were obtained by using Saccharomyces cerevisiae. The physical properties of the carefully distilled lactones obtained indicated high purity and high optical purity. (+info)
SOME FACTORS INFLUENCING ACID PRODUCTION BY AN OXYTETRACYCLINE-RESISTANT STRAIN OF STREPTOCOCCUS LACTIS.
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Induction of oxytetracycline resistance in a strain of Streptococcus lactis caused this organism to display reduced acid production, salt tolerance, pyruvate synthesis, growth at alkaline pH, and a loss in ability to produce ammonia from arginine. alpha-Ketoglutaric and oxaloacetic acids were found to accumulate in the growth medium of resistant cells, in contrast to none in the medium of susceptible cells. No free arginine could be detected in the intracellular fraction of resistant cells, but arginine was present in the intracellular fraction of susceptible cells and decreased in concentration upon the addition of oxytetracycline to the growth medium. Depressed acid production in milk by the oxytetracycline resistant strain is evidently a consequence of the inability of this organism to metabolize arginine effectively. (+info)