Similar Metabolic Effects Research Articles

Antidiabetic effects of sub-chronic administration of the cannabinoid receptor (CB 1) antagonist, AM251, in obese diabetic ( ob/ob) mice

Recent research suggests that cannabinoid CB 1 receptor antagonism reduces appetite and body weight gain. The present study was designed to assess the sub-chronic effects of the selective cannabinoid CB 1 receptor antagonist, AM251 ( N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3-carboxamide), in young ob/ob mice. Pair-fed animals were used as additional controls. Daily injection of AM251 (6 mg/kg body weight) for 18 days significantly ( P < 0.05) decreased daily and 18-day cumulative food intake. The corresponding body weight change did not achieve significance and values were not different from pair-fed mice. Non-fasting plasma glucose was decreased ( P < 0.05) from day 10 onwards by AM251 treatment. The glycaemic response to intraperitoneal glucose was correspondingly improved ( P < 0.05) in AM251 treated mice. In keeping with this, insulin sensitivity was enhanced ( P < 0.05) compared to controls. Furthermore, adipose mRNA levels of acetyl-CoA carboxylase 1 were significantly ( P < 0.05) reduced by 18 days AM251 treatment. There were no differences in either non-fasting or glucose-stimulated insulin release. Pair-feeding had broadly similar metabolic effects to AM251 treatment apart from increased ( P < 0.01) locomotor activity which was only observed in AM251 treated ob/ob mice. These data indicate that sub-chronic antagonism of the cannabinoid CB 1 receptor by daily treatment with AM251 counters aspects of the hyperphagia-related impairment of ob/ob mouse metabolism. Such effects seem predominantly mediated by restriction of energy intake.

Circulating adiponectin and adiponectin receptor expression in skeletal muscle: effects of exercise

Excess visceral fat can regulate insulin sensitivity and energy metabolism by releasing adipokines into the circulation which then bind with their cognate receptors in various tissues and alter glucose and lipid metabolism. Circulating levels of adiponectin, which promotes glucose uptake into skeletal muscle and increases fat oxidation rates, are decreased in obesity. Strategies to enhance the insulin-like and insulin-sensitizing actions of adiponectin have been shown to be effective in improving metabolic abnormalities associated with obesity and diabetes. Interestingly, the insulin-sensitizing effects of exercise have similar metabolic effects as adiponectin in that exercise also promotes glucose uptake into muscle and increases rates of fatty acid oxidation. Recent studies have begun to examine the potential role of adiponectin in mediating the insulin-sensitizing action of exercise by investigating changes in plasma adiponectin levels and tissue-specific adiponectin receptor (AdipoR) expression. In this review, we have summarized the key findings to date which suggest that changes in expression of AdipoR isoforms in skeletal muscle, rather than circulating total adiponectin levels, may be of physiological importance.

Insulin glulisine, insulin lispro and regular human insulin show comparable end‐organ metabolic effects: an exploratory study

To compare the end-organ metabolic effects of insulin glulisine (glulisine), insulin lispro (lispro) and regular human insulin (RHI) in patients with type 1 diabetes mellitus. Eighteen patients with type 1 diabetes mellitus (mean age 36.9 +/- 8.6 years, BMI 23.6 +/- 2.8 kg/m(2), haemoglobin A(1c) 7.4 +/- 0.9%) were randomized in this single-centre, double-blind, three-period cross-over, standard Latin-square, euglycaemic glucose clamp trial. Patients received sequential, primed stepwise intravenous infusions of glulisine, lispro or RHI (infusion rates were increased in a stepwise manner from an initial rate of 0.33 [180 min] to 0.66 [180 min] and 1.00 [180 min] mU/kg/min). The primary variables were the suppression of endogenous glucose production (S(EGP)) and glucose uptake (GU). Mean basal endogenous glucose production (EGP) was 1.88, 2.12 and 2.12 mg/kg/min for glulisine, lispro and RHI respectively. Mean (+/-s.e.) maximum absolute S(EGP) (adjusted for basal EGP) was -1.64 +/- 0.06, -1.72 +/- 0.05 and -1.56 +/- 0.05 mg/kg/min respectively. Mean (+/-s.e.) maximum absolute increase in GU (adjusted for basal GU) was 6.46 +/- 0.26, 6.23 +/- 0.24 and 6.72 +/- 0.24 mg/kg/min respectively. There were no clinically relevant differences between the three insulin treatments with respect to serum insulin, free fatty acid (FFA), glycerol or lactate levels. No serious adverse events and no episodes of severe hypoglycaemia were reported. This study shows that glulisine, lispro and RHI have similar effects on S(EGP), GU, FFA, glycerol and lactate levels, providing evidence for similar end-organ metabolic effects.

Expression profiling of insulin action in human myotubes: induction of inflammatory and pro-angiogenic pathways in relationship with glycogen synthesis and type 2 diabetes

Myotube cultures from patients with type 2 diabetes mellitus (T2DM) represent an experimental in vitro model of T2DM that offers a possibility to perform gene expression studies under standardized conditions. During a time-course of insulin stimulation (1μM) at 5.5mM glucose for 0 (no insulin), 0.5, 1, 2, 4, 8, and 24h, mRNA contents were analyzed in human myotubes for each time point using Affymetrix DNA chip technology. Insulin treatment induced an inflammatory and pro-angiogenic response in the myotubes, with expression of early response factors followed by inflammatory chemokines, metabolic enzymes, and finally cell cycle regulating genes. One-hundred-forty-four genes were differentially expressed in myotubes from donors with type 2 diabetes compared with control subjects, including HSP70, apolipoprotein D/E, tropomyosin, myosin, and actin previously reported from in vivo studies of diabetic skeletal muscle. We conclude, (i) that insulin induces a time-dependent inflammatory and pro-angiogenic transcriptional response in cultured human myotubes, (ii) that myotubes in vitro retain a gene expression pattern specific for type 2 diabetes and sharing five genes with that of type 2 diabetic skeletal muscle in vivo, and (iii) that insulin, despite similar metabolic effects of glucose uptake and glycogen synthesis, regulates different pools of genes in skeletal muscle during in vivo and in vitro conditions.

Viscous dietary fibre and metabolic effects

Fibre has recently been classified by the Dietary Reference Intake Committee of the Food and Nutrition Board of the Institute of Medicine of the National Academy of Sciences as total fibre, which is made up of dietary fibre and functional fibre. What was not defined as a separate entity was viscous fibre, yet it is this type of fibre, which has consistently been associated in short term and acute studies with serum cholesterol reduction and reduced postprandial glucose and insulin responses. Ironically, it is the insoluble cereal fibre, which is associated with protection from CHD and diabetes in cohort studies despite a relative absence of demonstrated metabolic effects. Viscous fibres appear to have their effect by reducing the rate of absorption from the small intestine. Similar metabolic effects have been seen with slowing the rate of absorption by other means such as sipping versus bolus ingestion of glucose, increasing meal frequency, or reducing the rate of glucose absorption by the use of low glycaemic index foods. However, in this last case, benefits have also been noted in cohort studies in terms of diabetes and CHD risk reduction. Furthermore benefits also appear in relation to the incidence of certain cancers. Viscous fibres therefore have good reasons to have a range of metabolic health benefits. Their potential uses, mechanisms of action and means of incorporation into diets require further exploration.

Leptin and its role in the central regulation of reproduction in cattle

Leptin, a 16 kDa product of the adipose obese ( ob) gene, has been shown to contribute to the regulation of energy metabolism, feeding behavior, and reproduction in several monogastric species, including humans. Recent reports have provided evidence that the leptin gene is functionally relevant in cattle and sheep, and may contribute to an array of important reproductive events, including puberty. Leptin gene expression and circulating leptin increase markedly during sexual maturation in heifers reaching puberty during late spring or early summer. In addition, serum leptin concentrations increased by over 30% from early winter to the summer solstice in mature cows, and also increased with significant changes in adiposity. However, only limited changes in circulating leptin have been observed during the estrous cycle. Short-term fasting of growing peripubertal heifers causes marked reductions in leptin gene expression and circulating leptin, concomitant with declines in LH pulse frequency, and serum concentrations of insulin and IGF-1. Although short-term fasting of mature cows in excellent body condition is without effects on LH pulse frequency, it has remarkably similar metabolic effects to those observed in heifers. Moreover, ICV administration of recombinant oleptin resulted in a marked hypersecretion of LH in fasted cows, and in vitro studies using both hypothalamic and anterior pituitary explants have provided evidence that this effect is at the pituitary level. Paradoxically, ICV administration of oleptin normalized circulating insulin in fasted cows but hleptin was without effect on insulin in estradiol-implanted wethers. Collectively, work in cattle and sheep indicates that leptin can modulate both the hypothalamic–pituitary axis and endocrine pancreas under defined nutritional conditions. Additional work to more fully characterize these roles is clearly warranted and could lead to the development of novel strategies for modifying reproductive potential in food-producing species.

In vivo response to alpha(1)-adrenoreceptor stimulation in human white adipose tissue.

Recent studies in rats suggest an important effect of alpha(1)-adrenoreceptor stimulation on glucose uptake in white adipocytes. It is not known if alpha(1)-adrenoreceptor stimulation elicits similar metabolic effects in humans. Three microdialysis catheters in abdominal subcutaneous adipose tissue were perfused with 0.00, 0.01, 0.10, 1.00, and 10.00 microM isoproterenol, phenylephrine, or phenylephrine plus 100 microM propranolol. Dialysate concentrations of ethanol, glycerol, glucose, and lactate were measured for estimating blood flow (ethanol-dilution technique), lipolysis, and glycolysis, respectively. Phenylephrine, with or without propranolol, did not elicit a change in ethanol ratio. In contrast, the ethanol ratio decreased markedly with isoproterenol. Dialysate glucose concentration decreased with phenylephrine with and without propranolol and increased with isoproterenol. Phenylephrine caused a dose-dependent increase in dialysate glycerol concentration, with a maximal effect similar to that of isoproterenol. The effect was attenuated with propranolol. Our findings suggest that alpha(1)-adrenoreceptor stimulation by phenylephrine increases glucose uptake and metabolism in human abdominal adipose tissue. Furthermore, phenylephrine elicits a marked increase in lipolytic activity in white adipose tissue through beta-adrenoreceptor activation.

Energy metabolism and metabolic rate of the alder leaf beetle Agelastica alni (L.) (Coleoptera, Chrysomelidae) under aerobic and anaerobic conditions: a microcalorimetric study

In early fall, adult alder leaf beetles (Agelastica alni L.) retreat, for overwintering, to the top layer of the soil near their forage trees where the ground gets easily waterlogged so that the beetles will be submerged and cut off from atmospheric oxygen. Hence, unlike most other adult insects, alder leaf beetles encounter hypoxia/anoxia in their natural habitat and this may occur at moderate temperature. Exposing beetles to pure nitrogen gas at 20°C had similar behavioral and metabolic effects as submerging them in water, causing rapid immobility and increasing the content of lactate about sevenfold to some 5μmolg−1 body weight during 10h anoxia. Recovery from 10 h hypoxia/anoxia in pure nitrogen was complete within about 90min.Hypoxia/anoxia triggered a marked decrease in metabolic activity in the beetles (microcalorimetry at 21.7°C) as indicated by a precipitous drop in their heat flow rate, from 1.39±0.27 to 0.08±0.04mWg−1 body weight, i.e. by about 94%, when the flow of gas through the calorimeter was switched from air to pure nitrogen. Post-anoxic recovery was accompanied by a peak in heat flow rate that exceeded the basal normoxic rate by about 50%. The homoeostasis of adenine nucleotides in Agelastica is lost when oxygen is wanting. Submergence at 15°C for three days caused a dramatic fall in ATP, to less than 2% of the normoxic value, and a marked increase in AMP, while the total contents of adenine nucleotides decreased by almost two-thirds. Reduced metabolic activity, combined with the capacity to regenerate ATP after readmission of air, is regarded as a key factor for surviving transient lack of oxygen in alder leaf beetles.

Fiber, Inulin and Oligofructose: Similarities and Differences

The biological, chemical and physical properties of dietary fibers are associated with physiologic actions in the small and large intestine that have important metabolic implications for health. These properties of fiber include dispersibility in water, bulk, viscosity, adsorption and binding of compounds and fermentability. Dietary fructans share some of the properties of dietary fiber and thus are likely to have similar metabolic effects. Within the small intestine, properties such as dispersibility in water, bulking and viscosity are associated with slowing the digestion and absorption of carbohydrate and lipid and promoting nutrient absorption along a greater length of the small intestine. Both of these actions are related to cholesterol reduction and blunting of alimentary gylcemia. Although fructans are dispersible in water and will provide some bulk because they are nondigestible in the small intestine, they do not appear to be associated with significant increases in viscosity. Thus one would predict that any immediate effects on alimentary glycemia or on cholesterol reduction are likely to be modest compared with more viscous polysaccharides. Fermentability and bulking capacity of nondigestible carbohydrates define an essential role of fiber in maintaining gastrointestinal health. Within the large intestine, carbohydrates that are not digested in the small intestine are available for fermentation by the microflora present. Carbohydrates that are dispersible in the aqueous phase are more readily digested by microbes. A large body of evidence indicates that dietary fructans are digested in the large intestine, resulting in an increase in microbial mass and production of short-chain fatty acids.

Functional brain imaging during anesthesia in humans: effects of halothane on global and regional cerebral glucose metabolism.

Propofol and isoflurane anesthesia were studied previously with functional brain imaging in humans to begin identifying key brain areas involved with mediating anesthetic-induced unconsciousness. The authors describe an additional positron emission tomography study of halothane's in vivo cerebral metabolic effects. Five male volunteers each underwent two positron emission tomography scans. One scan assessed awake-baseline metabolism, and the other scan assessed metabolism during halothane anesthesia titrated to the point of unresponsiveness (mean +/- SD, expired = 0.7+/-0.2%). Scans were obtained using a GE2048 scanner and the F-18 fluorodeoxyglucose technique. Regions of interest were analyzed for changes in both absolute and relative glucose metabolism. In addition, relative changes in metabolism were evaluated using statistical parametric mapping. Awake whole-brain metabolism averaged 6.3+/-1.2 mg x 100 g(-1) x min(-1) (mean +/- SD). Halothane reduced metabolism 40+/-9% to 3.7+/-0.6 mg x 100 g(-1) x min(-1) (P< or =0.005). Regional metabolism did not increase in any brain areas for any volunteer. The statistical parametric mapping analysis revealed significantly less relative metabolism in the basal forebrain, thalamus, limbic system, cerebellum, and occiput during halothane anesthesia. Halothane caused a global whole-brain metabolic reduction with significant shifts in regional metabolism. Comparisons with previous studies reveal similar absolute and relative metabolic effects for halothane and isoflurane. Propofol, however, was associated with larger absolute metabolic reductions, suppression of relative cortical metabolism more than either inhalational agent, and significantly less suppression of relative basal ganglia and midbrain metabolism.

Osteo-anabolic effects of human growth hormone with 22K- and 20K Daltons on human osteoblast-like cells.

Human growth hormone with 22,000 Dal (22K-hGH) stimulates proliferation and differentiation of osteoblasts as well as production of interleukin-6 in vitro and bone formation and remodeling in vivo. To investigate whether hGH isoform with 20Kd (20K-hGH), which accounts for 10% of circulating hGH, elicits similar metabolic effects on skeletal tissues, we studied the biological effects of 20K-hGH in cultured human osteoblast-like cells (HOB). HOB were obtained from trabecular bone explants and cultured in alpha-MEM supplemented with 10% FCS. In subconfluent cultures, 22K- and 20K-hGH stimulated [3H]thymidine incorporation by 62 +/- 27% and 63 +/- 23%, respectively (mean +/- SD, n=8, P>0.1). In confluent cultures, 22K- and 20K-hGH increased alkaline phosphatase activity by 38 +/- 23% and 41 +/- 23% (P>0.1), respectively, and increased the osteocalcin concentration in the presence of 10(-9) M 1,25-(OH)2D3 by 50% and 47% (P>0.1), respectively. Furthermore, both hGHs doubled the interleukin-6 (IL-6) concentration in the conditioned medium. RT-PCR analysis revealed that 22K- and 20K- hGH increased IL-6 gene expression 2.2 +/- 0.6 and 2.4 +/- 0.7 -fold, respectively. In summary, we have demonstrated that 20K-hGH elicits equipotent anabolic effects on HOB and stimulates to the same extent the production of IL-6, a cytokine which initiates osteoclastogenesis. These in vitro findings suggest that 22K- and 20K-hGH may equipotently stimulate bone remodeling and elicit anabolic effects on skeletal tissue when administered in vivo.

Relationship between decreased function and O2 consumption caused by cyclic GMP in cardiac myocytes and L-type calcium channels.

We tested the hypothesis that part of the decreased function and metabolism caused by cyclic guanosine monophosphate (GMP) in beating cardiac myocytes is related to inhibition of L-type calcium channels. The steady state oxygen consumption (VO2) of a suspension of ventricular myocytes isolated from hearts of New Zealand white rabbits was measured using oxygen electrodes. Cellular cyclic GMP levels were determined by radioimmunoassay. Cell shortening was measured with a video edge detector. The VO2 was obtained after: (1) adding sodium nitroprusside (NP 10(-8),(-6),(-4) M), (2) pretreatment by BAY K8644 10(-5) M (BAY, L-type calcium channel activator), nifedipine 10(-4) M (NF, L-type calcium channel blocker) or forskolin 10(-7) M (FK, adenylate cyclase activator), then adding NP 10(-8),(-6),(-4) M, (3) pretreatment with both FK 10(-7) M and NF 10(-4) M and subsequently adding NP 10(-8),(-6),(-4) M. NP 10(-4) M decreased VO2 from 707 +/- 34 to 410 +/- 13 (nl O2/min per 10(5) myocytes), decreased the percentage of shortening (Pcs) from 5.7 +/- 0.6 to 3.7 +/- 0.5 and the rate of shortening (Rs) from 65.5 +/- 4.5 (microns/s) to 46.2 +/- 5.5. NP 10(-4) M also increased cyclic GMP from 264 +/- 70 (fmol/10(5) myocytes) to 760 +/- 283. Both BAY and FK increased VO2, Pcs and Rs without changing cyclic GMP. NF decreased Pcs, Rs and VO2. Similar metabolic and functional effects of NP were observed with pretreatment with these agents separately, compared to NP alone, and the elevation of cyclic GMP level was not different from the control group. With FK alone, NP 10(-4) M decreased VO2 by 51%, Pcs by 44% and Rs by 39%. In the presence of both FK and NF, the negative effects of NP were diminished significantly. NP 10(-4) M decreased VO2 by 37%, Pcs by 25% and Rs 20%. Thus, in beating cardiac myocytes, the negative metabolic and functional effects of cyclic GMP were related to inhibition on L-type calcium channels only when adenylate cyclase was stimulated.

Effect of 2,4-dinitrophenol on the hypometabolic response to hypoxia of conscious adult rats.

During acute hypoxia, a hypometabolic response is commonly observed in many newborn and adult mammalian species. We hypothesized that, if hypoxic hypometabolism were entirely a regulated response with no limitation in O2 availability, pharmacological uncoupling of the oxidative phosphorylation should raise O2 consumption (VO2) by similar amounts in hypoxia and normoxia. Metabolic, ventilatory, and cardiovascular measurements were collected from conscious rats in air and in hypoxia, both before and after intravenous injection of the mitochondrial uncoupler 2,4-dinitrophenol (DNP). In hypoxia (10% O2 breathing, 60% arterial O2 saturation), VO2, as measured by an open-flow technique, was less than in normoxia (approximately 80%). Successive DNP injections (6 mg/kg, 4 times) progressively increased VO2 in both normoxia and hypoxia by similar amounts. Body temperature slightly increased in normoxia, whereas it did not change in hypoxia. The DNP-stimulated VO2 during hypoxia could even exceed the control normoxic value. A single DNP injection (17 mg/kg iv) had a similar metabolic effect; it also resulted in hypotension and a drop in systemic vascular resistance. We conclude that pharmacological stimulation of VO2 counteracts the VO2 drop determined by hypoxia and stimulates VO2 not dissimilarly from normoxia. Hypoxic hypometabolism is likely to reflect a regulated process of depression of thermogenesis, with no limitation in cellular O2 availability.

Amiodarone and Lipid Disorder

Pollak et al1described elevation of serum total cholesterol and triglyceride levels during amiodarone therapy. I observed a similar metabolic side effect in a patient treated with amiodarone. Report of a Case. A 41-year-old man had been taking amiodarone (400 mg/d) for more than 1 year to treat nonsustained ventricular tachyarrhythmias due to ischemic heart disease. He had been undergoing laboratory tests, including thyroid, renal, hepatic, and lipid profiles, and chest radiography every 6 months, and the results of both had been within normal ranges. The lipid profile had revealed a cholesterol level of 5.20 mmol/L (200 mg/dL), a triglyceride level of 2.82 mmol/L, and a high-density lipoprotein level of 1.00 mmol/L (40 mg/dL). A recent 6-month blood chemistry profile revealed a cholesterol level of 9.05 mmol/L (350 mg/dL), a triglyceride level of 7.24 mmol/L (280 mg/dL), a high-density lipoprotein level of 0.78 mmol/L (30 mg/dL), and a low-density

Continuous infusion versus daily injections of growth hormone (GH) for 4 weeks in GH-deficient patients.

Endogenous GH secretion is pulsatile. Animal studies indicate that GH administered in a pulsatile manner induces growth and insulin-like growth factor I (IGF-I) generation more effectively than continuous administration. Short term human studies, however, have reported similar metabolic effects with constant and pulsatile GH delivery. This study was carried out to compare the metabolic effects of longer term continuous infusion vs. daily injections of GH. Thirteen GH-deficient patients were studied in a cross-over design. The patients were randomized to receive GH as a continuous sc infusion by means of a portable pump for 1 month and as daily sc injections (at 1900 h) for another month. An average daily GH dosage (+/- SEM) of 3.15 +/- 0.27 IU was administered during both periods. Steady state 24-h profiles of GH, IGF-I, IGF-binding proteins (IGFBPs), insulin, glucose, lipid intermediates, and other metabolites were monitored after each treatment period. At the end of each study period (at 0800 h), an oral glucose tolerance test was performed. The mean (+/- SEM) integrated levels of serum GH (micrograms per L) were higher after GH injection [2.51 +/- 0.54 (injection) vs. 1.77 +/- 0.35 (infusion); P < 0.02]. Continuous infusion induced higher nighttime than daytime GH levels (P = 0.01), indicating a diurnal variation in the absorption or clearance of GH. Serum IGF-I levels (micrograms per L) were slightly higher (P < 0.05, by analysis of variance) after continuous GH infusion [312.5 +/- 50.2 (injection) and 334.6 +/- 46.6 (infusion)]. Similarly, constant GH delivery induced higher IGFBP-3 levels (P < 0.05, by analysis of variance). Serum IGFBP-1 levels were similar on the two occasions. Daily GH injections increased daytime insulin levels (P < 0.05), whereas 24-h levels were similar (P = 0.14). The trend toward increased insulin levels after GH injections was also found during the oral glucose tolerance test (P = 0.07). Blood glucose levels were identical on the two occasions. Nocturnal levels of nonesterified fatty acids were higher (P < 0.05) after GH injection. We conclude that continuous sc infusion of GH induced serum IGF-I and IGFBP-3 levels more effectively than daily sc injections. The constant appearance of GH in the circulation did not impair glucose tolerance, but resulted in a less physiological diurnal pattern of nonesterified fatty acids. Our data do not support the concept that a pulsatile GH pattern is of critical physiological significance.

The enhancement of ammonium assimilation in Rhizobium etli prevents nodulation of Phaseolus vulgaris.

The modification of the ammonium assimilation pathway of Rhizobium etli (GS-GOGAT) by adding an additional ammonium assimilation enzyme, GDH, strongly affects its symbiotic interaction with beans. The plasmid pAM1a, based in the stable vector pTR101 (M. Weinstein, R. C. Roberts, and D. R. Helsinki, J. Bacteriol. 174,7486-7489, 1992), containing the Escherichia coli gdhA gene flanked by two transcription-translation terminators was constructed. The expression of GDH in both, the wild type (CFN42/pAM1a) and a ntrC- mutant (CFN2012/pAM1a) R. etli strains, gave a similar metabolic effect, i.e., high GDH and reduced GOGAT activities, and an increased synthesis and excretion of several amino acids. The total inhibition of bean nodulation was observed when the minimum optimal inoculum of R. etli CFN42/pAM1a was used; however, an effective symbiosis occurred with the CFN2012/pAM1a mutant strain. While a total inhibition of the induction of the nodA gene by bean root exudate or by naringenin was observed in the CFN42/pAM1a strain, at 10 mM ammonium, the CFN2012/pAM1a showed an optimal nodA gene induction. A correlation between nodA gene induction, Nod factor production, and nodulation was observed. We conclude that in R. etli, there is a down-regulation of nod gene expression and nodulation when a high internal nitrogen content is built up by the presence of a functional GDH and that NtrC is involved in such regulation. An instability of the plasmid harboring the gdhA gene was observed during symbiosis, indicating a strong selection against cells containing this plasmid.

Insulin resistance and hypertension in the elderly. Optimal drug therapy.

Numerous trials have demonstrated the negative effects of some antihypertensive drugs upon glucose handling. Such findings seem particularly interesting in aged hypertensive patients who are also insulin resistant and affected by physiological changes in the renal and cardiovascular systems. It appears that calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors are the most appropriate drugs to lower blood pressure in aged insulin-resistant hypertensive patients. All calcium channel blockers studied have displayed similar metabolic effects, while among the ACE inhibitors studied, lisinopril was associated with the best metabolic responses. beta-Blockers and thiazide diuretics have strong negative effects on glucose handling. Further studies are needed in order to investigate the metabolic effects of alpha 1-antagonists in aged patients with insulin resistance and hypertension.

Changes in Serum Lipid and Lipoprotein Measures after Maximal Exercise in Men

Normolipidaemic, healthy male volunteers (age range 20-23 years) were studied after a session of three maximal exercises and serum lipid and lipoprotein concentrations were measured. The exercise programmes, one of which was performed each week, consisted of a triangular progressive test (TPT), a rectangular sustained test (RST) and an interval endurance test (IET). There was a significant (P less than 0.05) increase of 14% in serum total cholesterol concentrations after TPT, 9.6% after RST and 14% after IET. Serum triglyceride concentrations increased by 17% after TPT, 5.7% after RST and 8.2% after IET, but increases were not significant. High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), and apolipoprotein (A-I, A-II) concentrations rose significantly (P less than 0.05) after TPT. There were also insignificant increases in AI, AII and LDL-C after RST and IET, whereas HDL-C rose significantly (P less than 0.05) after IET. It is concluded that the three maximal exercises had similar metabolic effects which were independent of the exercise duration.

Pineal Hyperactivity in Spontaneously Hypertensive Rats: Muscarinic Regulation of Indole Metabolism

1. Choline acetyltransferase activity and [3H]quinuclidinyl benzylate-binding sites were detected in the pineal gland of normotensive Wistar-Kyoto rats and of spontaneously hypertensive rats. 2. In vitro, muscarinic activation by pilocarpine increased the pineal metabolic production of hydroxyindole derivatives up to 5-hydroxytryptamine and produced a less marked stimulation of melatonin biosynthesis. 3. Electrical field stimulation of pineal gland slices caused similar metabolic effects. 4. Muscarinic blockade with atropine inhibited the effects on hydroxyindole metabolism. 5. [3H]Quinuclidinyl benzylate-binding sites, indicative of muscarinic receptors, were more numerous, and basal 5-hydroxytryptamine and melatonin levels were higher, in the pineal gland of spontaneously hypertensive rats compared with Wistar-Kyoto rats. 6. The atropine-sensitive metabolic effects of pilocarpine and electrical field stimulation on the pineal gland were increased in spontaneously hypertensive rats compared with Wistar-Kyoto rats.

Ambulatory long-term subcutaneous salbutamol infusion in chronic severe asthma

Although most patients with asthma improve with currently available drugs, there appears to be a subset of patients with asthma resistant to intensive treatment, including large doses of systemic corticosteroids. In 10 patients with asthma difficult to treat, a double-blind, placebo-controlled, crossover study was performed to evaluate whether long-term, continuous subcutaneous infusion of large doses of salbutamol, in addition to steroids, could improve pulmonary function, compared with intermittent nebulization of salbutamol. Four weeks of administration of large doses (>14 mg/day) of β 2-agonists were well tolerated, elicited a significant decrease of corticosteroid consumption ( p < 0.01), and were associated with an improvement in pulmonary function ( p < 0.01), compared with run in or the placebo administration period. Mean morning and evening peak expiratory flow rates were similar during all periods, and the variability between morning and evening peak expiratory flow rates was only slightly and nonsignificantly reduced during the period when salbutamol was administered subcutaneously. Both nebulized and subcutaneous salbutamol elicited similar metabolic and muscular side effects, but these untoward reactions never caused any patient to stop the treatment. Local infection at the injection site was observed in two of 10 patients with continuous subcutaneous infusion. Tachyphylaxis to β 2-agonist, as measured by the reversibility of FEV 1 to inhaled salbutamol 12 hours after the end of each period, did not occur. In conclusion, large doses of β 2-agonist administered to patients with severe, chronic, and steroid-dependent asthma were able to improve respiratory function and to decrease corticosteroids requirements.