Ingested interferon alpha suppresses type I diabetes in non-obese diabetic mice

Glutamine is an important gluconeogenic amino acid in postabsorptive humans. To assess the effect of glucagon on renal and hepatic glutamine gluconeogenesis, we infused six normal healthy postabsorptive subjects with glucagon at a rate chosen to produce circulating glucagon concentrations found during hypoglycemia and, using a combination of isotopic and net balance techniques, determined the systemic, renal, and hepatic glucose release and renal and hepatic production of glucose from glutamine. Infusion of glucagon increased systemic and hepatic glucose release (both P < .02), but had no effect on renal glucose release (P = .26). Systemic and hepatic glutamine gluconeogenesis increased from 0.45 +/- 0.3 and 0.11 +/- 0.02 micromol x kg(-1) x min(-1), respectively, to 0.61 +/- 0.04 (P = .002) and 0.31 +/- 0.03 micromol x kg(-1) x min(-1) (P = .001), respectively, whereas renal glutamine gluconeogenesis was unchanged (from 0.33 +/- 0.03 to 0.30 +/- 0.04 micromol x kg(-1) x min(-1), P = .20). The hepatic contribution to systemic glutamine gluconeogenesis increased from 25.2% +/- 6.2% to 51.6% +/- 5.5% (P = .002), while that of the kidney decreased from 74.8% +/- 6.2% to 48.4% +/- 5.5% (P = .003). Glucagon had no effect on the renal net balance, fractional extraction, or uptake and release of either glucose or glutamine. We thus conclude that glucagon stimulates glutamine gluconeogenesis in normal postabsorptive humans, predominantly due to an increase in hepatic glutamine conversion to glucose. Thus, under certain conditions such as counterregulation of hypoglycemia, the liver may be an important site of glutamine gluconeogenesis.     

Influence of circulating epinephrine and norepinephrine on insulin-like growth factor binding protein-1 in humans

The aim of the present study was to investigate the influence of circulating epinephrine (Epi) and norepinephrine (Norepi) on serum insulin-like growth factor binding protein-1 (IGFBP-1) concentrations. Healthy men received 0.3 nmol.kg.min Epi iv (n = 6), 0.5 nmol.kg.min Norepi iv (n = 7), or saline (n = 5) during 30 min. Arterial blood samples were obtained before, during, and 120 min after infusion. During the catecholamine infusion arterial Epi and Norepi plasma concentrations reached 6.35 +/- 0.53 and 15.65 +/- 2.71 nmol/L, respectively, which resulted in significant increases in glucose concentrations. When Epi was infused, IGFBP-1 increased from 45 +/- 6 micrograms/L to 76 +/- 10 micrograms/L (P < 0.05) 60 min after the infusion. Epi was also followed by increases in insulin, C-peptide, and glucagon. Norepi resulted in a slight increase in circulating IGFBP-1 (43 +/- 6 to 54 +/- 8 nmol/L, NS). The findings suggest that Epi, at plasma concentrations similar to those reached during physical stress, stimulates the production of IGFBP-1 in humans.     

3-Hydroxybutyrate inhibits noradrenaline-induced thermogenesis in lean but not in obese Zucker rats

OBJECTIVE: To determine the effect of 3-hydroxybutyrate (3OHB) on the thermogenic response to noradrenaline (NA) in lean and genetically obese Zucker fa/fa rats. DESIGN: Rats were infused with 18.7 nmol x kg(-1) x min(-1) of NA, supplemented, for 15 min, with 66.7 micromol x kg(-1) x min(-1) of R-3-hydroxybutyrate (3OHB). SUBJECTS: Pentobarbital-anaesthetized lean and obese Zucker rats. MEASUREMENTS: Aortic and interscapular brown adipose tissue (BAT) temperature; plasma NA, 3OHB, glucose and insulin levels during infusion. RESULTS: The NA-induced increase in aortic and BAT temperature was more marked in lean than in obese rats. In lean rats, the rise was arrested by 3OHB; but in obese rats 3OHB had no effect. Infusion of saline, glucose or 3OHB in the absence of NA did not induce changes in either temperature. NA infusion resulted in a rapid increase in plasma NA to 45-50 nM in both groups; this plateau was maintained for up to 60 min. The presence of 3OHB decreased the plasma NA of lean rats, but did not affect the plasma NA of the obese rats. Blood 3OHB rose to 1.2 mM during 3OHB infusion in both groups, and decreased on cessation of infusion. Blood glucose levels increased with NA infusion in both groups; the presence of high 3OHB levels decreased glucose levels only in lean rats. CONCLUSION: The changes in NA levels induced by 3OHB may help explain the effects observed on temperature and glucose. The defective thermogenic system of obese rats cannot be modulated by 3OHB, unlike thermogenesis in lean rats, on which 3OHB has a marked effect.     

Intravenous cocaine induces platelet activation in the conscious dog

BACKGROUND: Cocaine consumption has been associated with thrombosis of coronary and peripheral arteries. Since cocaine has been found to induce platelet activation in vitro, we sought to establish whether cocaine induced platelet activation in vivo. METHODS AND RESULTS: Chronically instrumented, conscious dogs were infused with cocaine (1 mg/kg), norepinephrine (0.2 to 0.4 mg/kg), or saline intravenously over 1 minute. Activated canine platelets were identified in whole blood collected from an indwelling aortic catheter by flow cytometric detection of the binding of a monoclonal antibody directed against the activation-dependent antigen P-selectin. Infusion of cocaine resulted in an elevation of mean arterial pressure (91 +/- 3 to 128 +/- 7 mm Hg [P < .01]) and heart rate (87 +/- 9 to 125 +/- 11 beats per minute [P < .01]). A similar change (P = NS) in mean arterial pressure followed norepinephrine infusion (100 +/- 5 to 137 +/- 13 mm Hg [P < .04]), whereas saline infusion had no effect. Cocaine resulted in a substantial but delayed increase in platelet P-selectin expression (14 +/- 7% [P < .08], 31 +/- 12% [P < .04], and 55 +/- 22% [P < .04] at 17, 22, and 27 minutes after drug infusion, respectively). The magnitude of this increase was similar to that found in blood treated ex vivo with the agonists ADP or PAF (23 +/- 7% and 53 +/- 15%, respectively). No significant increase in P-selectin expression was detected in the blood of animals that received norepinephrine or saline. Serum cocaine concentrations were highest immediately after infusion (538 +/- 55 ng/mL at 2 minutes) but declined rapidly (185 +/- 22 and 110 +/- 25 ng/mL at 17 and 32 minutes after infusion); in contrast, the increase in benzoylecgonine concentrations was delayed (from < 25 ng/mL in all but one animal [34 ng/mL] at 2 minutes to 46 +/- 4 and 71 +/- 11 ng/mL at 17 and 32 minutes, respectively, after infusion). CONCLUSIONS: Intravenous cocaine induces activation of individual circulating platelets; this effect is not reproduced by infusion of norepinephrine at doses sufficient to exert similar hemodynamic effects. The delay in detection of activated platelets after treatment with cocaine may result from the adhesion and subsequent detachment of activated platelets; alternatively, cocaine metabolites, rather than the drug itself, may induce platelet activation.     

Influence of reduced glutathione infusion on glucose metabolism in patients with non-insulin-dependent diabetes mellitus

To evaluate the relationship between oxidative stress and glucose metabolism, insulin sensitivity and intraerythrocytic reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio were measured in 10 non-insulin-dependent diabetes mellitus (NIDDM) patients and 10 healthy subjects before and after the intravenous administration of GSH. In particular, after baseline insulin sensitivity was assessed by a 2-hour euglycemic hyperinsulinemic clamp, either glutathione (1.35 g x m2 x min(-1)) or placebo (saline) were infused over a period of 1 hour. The same protocol was repeated at a 1-week interval, in cross-over, according to a randomized, single-blind design. In healthy subjects, baseline intraerythrocytic GSH/GSSG ratio (P < .0005) and total glucose uptake (P < .005) were significantly higher than in NIDDM patients. In the same subjects, GSH infusion significantly increased total glucose uptake (from 37.1 +/- 6.7 micromol kg(-1) x min(-1) to 39.5 +/- 7.7 micromol x kg(-1) x min(-1), P < .05), whereas saline infusion was completely ineffective. In addition, the mean intraerythrocytic GSH/GSSG ratio significantly increased after GSH infusion (from 21.0 +/- 0.9 to 24.7 +/- 1.3, P < .05). Similar findings were found in diabetic patients, in whom GSH infusion significantly increased both total glucose uptake (from 25.3 +/- 9.0 micromol x kg(-1) x min(-1) to 31.4 +/- 10.0 micromol x kg(-1) x min(-1), P < .001) and intraerythrocytic GSH/GSSG ratio (from 14.8 +/- 4.1 to 21.7 +/- 6.7, P < .01). Pooling diabetic patients and controls, significant correlations were found between intraerythrocytic GSH/GSSG ratio and total glucose uptake (r = .425, P < .05), as well as between increments of the same variables after GSH infusion (r = .518, P < .05). In conclusion, our data support the hypothesis that abnormal intracellular GSH redox status plays an important role in reducing insulin sensitivity in NIDDM patients. Accordingly, intravenous GSH infusion significantly increased both intraerythrocytic GSH/GSSG ratio and total glucose uptake in the same patients.     

Interaction of intrathecally infused morphine and lidocaine in rats (part II): effects on the development of tolerance to morphine

BACKGROUND: There has been little information regarding the effects of local anesthetics on tolerance to opioids, although chronic use of combination of opioids and local anesthetics is popular for pain control. This study was designed to examine the effects of lidocaine on morphine tolerance to somatic and visceral antinociception. METHODS: Rats received a continuous intrathecal infusion of morphine (0.3-10 microg x kg(-1) x h(-1)), lidocaine (30-1000 microg x kg(-1). h(-1)), a combination of those, or saline. After 6- day infusion, intrathecal morphine challenge test (5 microg/10 microl) was performed, and time-response curve was constructed to assess the magnitude of tolerance. The tail flick (TF) test and colorectal distension (CD) test were used to measure somatic and visceral antinociceptive effects, respectively. RESULTS: Antinociceptive effects in the TF and CD tests caused by morphine challenge were reduced (P < 0.01) in the morphine infused groups. The magnitude of the tolerance was inversely associated with the amount of morphine infused. Lidocaine infusion induced no different change in the morphine challenge test from that seen in the saline infusion group. Development of tolerance was greater in morphine 3 microg x kg(-1) h(-1) than in morphine 0.75 microg x kg(-1) x h(-1) + lidocaine 150 microg x kg(-1) x h(-1) despite their similar antinociceptive effects during intrathecal infusion. The infusion of a low dose of morphine (0.3 microg kg(-1) x h(-1)) did not reduce the antinociceptive effects in the challenge test. CONCLUSION: Lidocaine in combination with morphine does not reduce tolerance to morphine nor develop cross-tolerance. The intrathecal infusion of morphine induced tolerance to somatic and visceral antinociception in a dose-dependent fashion.     

In pubertal girls, naloxone fails to reverse the suppression of luteinizing hormone secretion by estradiol

Estradiol (E2) negative feedback on LH secretion was examined in 10 pubertal girls, testing the hypothesis that E2 suppresses LH pulse frequency and amplitude through opioid pathways. At 1000 h, a 32-h saline infusion was given, followed 1 week later by an E2 infusion at 13.8 nmol/m2 x h. During both infusions, four iv boluses of saline were given hourly beginning at 1200 h, and four naloxone iv boluses (0.1 mg/kg each) were given hourly beginning at 1200 h on the following day. Blood was obtained every 15 min for LH determination and every 60 min for E2 determination from 1200 h to the end of the infusion. E2 infusion increased the mean serum E2 concentration from 44+/-17 to 112+/-26 pmol/L (P < 0.01). The mean LH concentration between 2200-1200 h decreased from 3.19+/-0.89 to 1.99+/-0.65 IU/L (P = 0.014), and LH pulse amplitude decreased from 3.4+/-0.6 to 2.6+/-0.5 IU/L (P = 0.0076). Although there were 1.2 fewer pulses during E2 infusion compared to saline infusion, differences did not reach significance (P = 0.1; 95% confidence interval for the difference, -3.5, 1.1). Pituitary responsiveness to GnRH, assessed at the end of the infusion by administering 250 ng/kg GnRH iv, did not change during E2 infusion. The effect of naloxone blockade of opioid activity on LH secretion was determined by assessing the area under the curve (AUC) from 1200-1600 h. During saline infusion, the LH AUC was 1122+/-375 IU/L during saline boluses and 1575+/-403 IU/L during naloxone boluses (P = 0.39). When E2 was infused, the LH AUCs during saline and naloxone boluses were 865+/-249 and 866+/-250 IU/L, respectively. Thus, in pubertal girls: 1) E2 decreases the LH concentration and LH pulse amplitude; 2) the main site of negative feedback effect of E2 appears to be at the level of the hypothalamus; 3) an increase in LH secretion after naloxone administration could not be demonstrated in these girls and may depend on the maturity of the hypothalamic-pituitary-gonadal axis; and 4) opioid receptor blockade does not reverse the E2 inhibition of LH secretion even in the most mature girls. Thus, E2 suppression of LH secretion in pubertal girls appears to be mediated by a decrease in hypothalamic GnRH secretion that is independent of opioid pathways.     

Basal and stimulated sympathetic responses after epinephrine: no evidence of augmented responses

Delayed facilitation of norepinephrine release through the action of epinephrine (NE) at presynaptic beta-adrenoceptors has been postulated to account for the delayed hemodynamic effects of epinephrine and to be a mechanism causally related to the development of hypertension. To determine whether a short-term increase in epinephrine concentrations resulted in subsequent facilitation of sympathetic responses, 9 healthy subjects (age, 21+/-0.9 years) were studied at rest and during physiological stress on 2 occasions when they received an infusion of either saline or epinephrine (20 ng/kg per minute) in random order. Heart rate, blood pressure, forearm blood flow, epinephrine concentrations, and NE spillover were measured at rest, during mental stress (Stroop test), and during a cold pressor test. Measurements were performed before, during the 1-hour infusion of epinephrine or placebo, and 1 hour after the infusion. A radioisotope dilution method was used to measure NE spillover. Hemodynamic measurements and NE spillover were increased during the infusion of epinephrine, but 1 hour after discontinuation of epinephrine there was no significant augmentation of hemodynamic or sympathetic responses. NE spillover 1 hour after saline or epinephrine infusion was similar (0.85+/-0.2 versus 0. 87+/-0.2 microg/min; P=0.92). In addition, there was no delayed facilitation of stress-induced hemodynamic or NE responses after epinephrine. These findings do not support the hypothesis that epinephrine results in delayed facilitation of NE release.     

Continuous i.v. administration of the angiotensin-converting enzyme inhibitor enalaprilat in the critically ill: effects on regulators of circulatory homeostasis

Several components are responsible for circulatory control at the central, regional, and microcirculatory level. Angiotensin-converting enzyme (ACE) inhibitors are known to act beneficially on circulation by various mechanisms. The influence of continuous i.v. administration of the ACE inhibitor enalaprilat on regulators of circulation was studied in 45 critically ill patients. According to a prospective randomized sequence, either 0.25 mg/h (group 1, n = 15) or 0.5 mg/h (group 2, n = 15) of enalaprilat or saline solution as placebo (control group, n = 15) were continuously given. Infusion was started on the day of admission to the intensive care unit (ICU) and continued for the next 5 days. From arterial blood samples, plasma levels of endothelin-1 (ET), atrial natriuretic peptide (ANP), renin, vasopressin, angiotensin-II, and catecholamines (epinephrine, norepinephrine) were measured. All measurements were carried out before infusion (= baseline values) and during the next 5 days. In both enalaprilat groups, mean arterial blood pressure (MAP) decreased similarly; heart rate (HR) and central venous pressure (CVP) did not change, and were without differences in comparison to the untreated control. Except for ET, plasma levels of all vasoactive substances exceeded normal range at baseline. Angiotensin-II plasma concentrations significantly decreased during enalaprilat infusion (0.25 mg/h: from 53.1 +/- 11.3 to 22.1 +/- 9.3 pg/ml; 0.50 mg/h: 62.1 +/- 14.4 to 17.9 +/- 7.9 pg/ml), but they remained significantly elevated in the untreated control patients. Vasopressin plasma level increased only in the control group (p < 0.01) and decreased in the patients in whom 0.50 mg/h of enalaprilat was infused.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of the stable prostacyclin analogue iloprost on mesenteric blood flow in porcine endotoxic shock

OBJECTIVE: To determine the effects of the stable prostacyclin analog, iloprost, in a porcine model of endotoxin-induced mesenteric ischemia. DESIGN: Prospective, experimental, randomized, controlled study. SETTING: Animal research laboratory at a university medical center. INTERVENTIONS: Pigs were randomized to receive a constant infusion of iloprost (0.18 microg/kg/min) or an equivalent amount of carrier solution (normal saline) 30 mins before being infused with endotoxin (100 microg/kg over 1 hr). The infusion with iloprost or carrier solution was continued for the duration of the experiment. MEASUREMENTS AND MAIN RESULTS: Twelve pigs (six per group), weighing between 20 and 22 kg, underwent laparotomy during which a magnetic flowprobe was placed around the superior mesenteric artery and an ileal tonometer was inserted. Thirty minutes before they were infused with endotoxin, the animals were randomized to receive intravenous iloprost or normal saline. Endotoxin was infused centrally over a 60-min period. Animals received normal saline at a rate of 1.2 mL/kg/min which was begun at the start of the endotoxin infusion. Data were measured at the end of the endotoxin infusion (E60) and 1 hr later (E120). Mean arterial pressure was not affected by the dosage of iloprost used in this experiment. After resuscitation, the cardiac output returned to baseline in the iloprost-treated group but remained decreased in the control group (2.6 +/- 0.5 vs. 1.6 +/- 0.4 L/min). Superior mesenteric blood flow increased 34% above baseline levels in animals pretreated with iloprost (from 363 +/- 85 to 485 +/- 81 mL/min). The superior mesenteric PCO2 was significantly higher (53 +/- 9 vs. 40 +/- 5 torr; 7.1 +/- 1.2 vs. 5.3 +/- 0.7 kPa) and the ileal intramucosal pH was significantly lower (7.07 +/- .28 vs. 7.44 +/- .23) in the control group than in the iloprost-treated group. CONCLUSIONS: Pretreatment with intravenous iloprost effectively increased intestinal blood flow in this model of endotoxin-induced mesenteric ischemia. This action of the drug resulted in an attenuation of ileal intracellular acidosis. Since low-dose iloprost had no effect on mean arterial pressure, it may be a useful adjunct in the treatment of sepsis and septic shock.     

Effect of continuous subcutaneous insulin infusion with lispro on hepatic responsiveness to glucagon in type 1 diabetes

OBJECTIVE: People with type 1 diabetes frequently develop a blunted counterregulatory hormone response to hypoglycemia coupled with a decreased hepatic response to glucagon, and consequently, they have an increased risk of severe hypoglycemia. We have evaluated the effect of insulin lispro (Humalog) versus regular human insulin (Humulin R) on the hepatic glucose production (HGP) response to glucagon in type 1 diabetic patients on intensive insulin therapy with continuous subcutaneous insulin infusion (CSII). RESEARCH DESIGN AND METHODS: Ten subjects on CSII were treated for 3 months with lispro and 3 months with regular insulin in a double-blind randomized crossover study After 3 months of treatment with each insulin, hepatic sensitivity to glucagon was measured in each subject. The test consisted of a 4-h simultaneous infusion of somatostatin (450 microg/h) to suppress endogenous glucagon, regular insulin (0.15 mU x kg(-1) x min(-1)), glucose at a variable rate to maintain plasma glucose near 5 mmol/l, and D-[6,6-2H2]glucose to measure HGP During the last 2 h, glucagon was infused at 1.5 ng x kg(-1) x min(-1). Eight nondiabetic people served as control subjects. RESULTS: During the glucagon infusion period, free plasma insulin levels in the diabetic subjects were 71.7+/-1.6 vs. 74.8+/-0.5 pmol/l after lispro and regular insulin treatment, with plasma glucagon levels of 88.3+/-1.8 and 83.7+/-1.5 ng/l for insulin:glucagon ratios of 2.8 and 3.0. respectively (NS). However, plasma glucose increased to 9.2+/-1.1 mmo/l after lispro insulin compared with 7.1+/-0.9 mmol/l after regular insulin (P < 0.01), and the rise in HGP was 5.7 +/-2.8 micromol x kg(-1) x min(-1) after lispro insulin versus 3.1+/-2.9 micromol x kg(-1) x min(-1) after regular insulin treatment (P=0.02). In the control subjects, HGP increased by 10.7+/-4.2 micromol x kg(-1) x min(-1) under glucagon infusion. CONCLUSIONS: Insulin lispro treatment by CSII was associated with a heightened response in HGP to glucagon compared with regular human insulin. This suggests that insulin lispro increases the sensitivity of the liver to glucagon and could potentially decrease the risk of severe hypoglycemia.     

Buspirone: future directions

Glucagon-like peptide 1(7-36) amide (GLP-1) is postulated to be the major physiological incretin in humans, but evidence is indirect. We report the first studies examining the physiological role of GLP-1 in the postprandial state in humans using the GLP-1 antagonist exendin 9-39. Exendin 9-39 completely blocked GLP-1-induced glucose-stimulated insulin release from perifused human islets of Langerhans. In healthy fasted volunteers, intravenous infusion of exendin 9-39 at 500 pmol x kg(-1) x min(-1) in the hyperglycemic state abolished the insulinotropic effect of a physiological dose of GLP-1 and fully reversed the glucose-lowering effect of GLP-1. Nine healthy subjects consumed a 150-g oral glucose tolerance test and were infused with 500 pmol x kg(-1) x min(-1) exendin 9-39 or saline. Exendin 9-39 increased the peak postprandial glucose level (exendin 9-39, 8.67 +/- 0.35 vs. saline, 7.67 +/- 0.35 mmol/l, P < or = 0.005) and increased postprandial plasma glucose incremental area under the curve by 35% (exendin 9-39, 152 +/- 19 vs. saline, 113 +/- 16 mmol x min x l(-1), P < or = 0.05). This could be explained as partly secondary to the blockade of glucose-induced suppression of glucagon and maybe also to an increased rate of gastric emptying. Thus, in humans exendin 9-39 acts as an antagonist of GLP-1 both in vitro and in vivo. When infused alone, exendin 9-39 causes a deterioration in postprandial glycemic control, suggesting that GLP-1 may be important for maintenance of normal postprandial glucose homeostasis in humans.     

Glucagon-like peptide 1 improves the ability of the beta-cell to sense and respond to glucose in subjects with impaired glucose tolerance

Impaired glucose tolerance (IGT) and NIDDM are both associated with an impaired ability of the beta-cell to sense and respond to small changes in plasma glucose concentrations. The aim of this study was to establish if glucagon-like peptide 1 (GLP-1), a natural enteric peptide and potent insulin secretagogue, improves this defect. Two weight-matched groups, one with eight subjects having IGT (2-h glucose, 10.1 +/- 0.3 mmol/l) and another with seven subjects with diet-treated NIDDM (2-h glucose, 14.5 +/- 0.9 mmol/l), were studied on two occasions during a 12-h oscillatory glucose infusion, a sensitive test of the ability of the beta-cell to sense and respond to glucose. Glucose was infused with a mean rate of 4 mg x kg(-1) x min(-1), amplitude 33% above and below the mean rate, and periodicity of 144 min, with infusion of saline or GLP-1 at 0.4 pmol x kg(-1) x min(-1) for 12 h. Mean glucose levels were significantly lower in both groups during the GLP-1 infusion compared with during saline infusion: 9.2 +/- 0.4 vs. 6.4 +/- 0.1 mmol/l in the IGT subjects (P < 0.0004) and 14.6 +/- 1.0 vs. 9.3 +/- 0.7 mmol/l in NIDDM subjects (P < 0.0002). Despite this significant reduction in plasma glucose concentration, insulin secretion rates (ISRs) increased significantly in IGT subjects (513.3 +/- 77.6 vs. 583.1 +/- 100.7 pmol/min; P < 0.03), with a trend toward increasing in NIDDM subjects (561.7 +/- 122.16 vs. 642.8 +/- 128 pmol/min; P = 0.1). These results were compatible with enhanced insulin secretion in the presence of GLP-1. Spectral power was used as a measure of the ability of the beta-cell to secrete insulin in response to small changes in the plasma glucose concentration during the oscillatory infusion. Spectral power for ISR increased from 2.1 +/- 0.9 during saline infusion to 7.4 +/- 1.3 during GLP-1 infusion in IGT subjects (P < 0.004), but was unchanged in NIDDM subjects (1.0 +/- 0.4 to 1.5 +/- 0.6; P = 0.3). We concluded that low dosage GLP-1 improves the ability of the beta-cell to secrete insulin in both IGT and NIDDM subjects, but that the ability to sense and respond to subtle changes in plasma glucose is improved in IGT subjects, with only a variable response in NIDDM subjects. Beta-cell dysfunction was improved by GLP-1 infusion, suggesting that early GLP-1 therapy may preserve beta-cell function in subjects with IGT or mild NIDDM.     

Effects of oral clonidine premedication on plasma glucose and lipid homeostasis associated with exogenous glucose infusion in children

BACKGROUND: Oral clonidine may influence plasma glucose and lipid homeostasis by modulating endocrinologic responses to surgical stress. The effect of oral clonidine premedication on plasma glucose and lipid homeostasis associated with exogenous glucose infusion were investigated in children undergoing minor surgery. METHODS: Otherwise healthy children (n, 120; aged 3-13 yr) were assigned randomly to six groups according to the glucose concentration of the intravenous solution (0%, 2%, or 5%, at a rate of 6 ml kg(-1) x h(-1)) and the preoperative medications (4 microg/kg clonidine or placebo given 100 min before anesthesia) they were to receive. The plasma concentrations of glucose, nonesterified fatty acid, ketone bodies, epinephrine, norepinephrine, and cortisol were determined. RESULTS: Infusion of 5% glucose caused hyperglycemia (mean glucose concentration >200 mg/dl) in six children receiving placebo and two receiving clonidine. Although the mean plasma glucose concentration increased in three placebo groups, it was unchanged and the plasma concentrations of total ketone bodies and nonesterified fatty acid were increased in children receiving clonidine and glucose-free solution. The plasma epinephrine, norepinephrine, and cortisol levels in children receiving placebo increased in response to surgery. Clonidine attenuated the increase in catecholamines and cortisol. CONCLUSIONS: Oral clonidine premedication attenuated the hyperglycemic response, probably by inhibiting the surgical stress-induced release of catecholamines and cortisol. Infusion of 2% of glucose maintained plasma glucose concentrations within physiologic ranges in children receiving clonidine.     

Epinephrine inhibits tumor necrosis factor-alpha and potentiates interleukin 10 production during human endotoxemia

Short-term preexposure of mononuclear cells to epinephrine inhibits LPS-induced production of TNF, whereas preexposure for 24 h results in increased TNF production. To assess the effects of epinephrine infusions of varying duration on in vivo responses to LPS, the following experiments were performed: (a) Blood obtained from eight subjects at 4-24 h after the start of a 24-h infusion of epinephrine (30 ng/kg per min) produced less TNF after ex vivo stimulation with LPS compared with blood drawn before the start of the infusion, and (b) 17 healthy men who were receiving a continuous infusion of epinephrine (30 ng/kg per min) started either 3 h (EPI-3; n = 5) or 24 h (EPI-24; n = 6) were studied after intravenous injection of LPS (2 ng/kg, lot EC-5). EPI-3 inhibited LPS-induced in vivo TNF appearance and also increased IL-10 release (both P < 0.005 versus LPS), whereas EPI-24 only attenuated TNF secretion (P = 0.05). In separate in vitro experiments in whole blood, epinephrine increased LPS-induced IL-10 release by a combined effect on alpha and beta adrenergic receptors. Further, in LPS-stimulated blood, the increase on IL-10 levels caused by epinephrine only marginally contributed to concurrent inhibition of TNF production. Epinephrine, either endogenously produced or administered as a component of sepsis treatment, may have a net antiinflammatory effect on the cytokine network early in the course of systemic infection.     

Renal lactate metabolism and gluconeogenesis during insulin-induced hypoglycemia

The contribution of gluconeogenic precursors to renal glucose production (RGP) during insulin-induced hypoglycemia was assessed in conscious dogs. Ten days after surgical placement of sampling catheters in the right and left renal veins and femoral artery and an infusion catheter in the left renal artery, systemic and renal glucose and glycerol kinetics were measured with peripheral infusions of [6-3H]glucose and [2-13C]glycerol. Renal blood flow was determined with a flowprobe, and the renal balance of lactate, alanine, and glycerol was calculated by arteriovenous difference. After baseline, six dogs received 2-h simultaneous infusions of peripheral insulin (4 mU x kg(-1) x min(-1)) and left intrarenal [6,6-2H]dextrose (14 micromol x kg(-1) x min(-1)) to achieve and maintain left renal normoglycemia during systemic hypoglycemia. Arterial glucose decreased from 5.3 +/- 0.1 to 2.2 +/- 0.1 mmol/l; insulin increased from 46 +/- 5 to 1,050 +/- 50 pmol/l; epinephrine, from 130 +/- 8 to 1,825 +/- 50 pg/ml; norepinephrine, from 129 +/- 6 to 387 +/- 15 pg/ml; and glucagon, from 52 +/- 2 to 156 +/- 12 pg/ml (all P < 0.01). RGP increased from 1.7 +/- 0.4 to 3.0 +/- 0.5 (left) and from 0.6 +/- 0.2 to 3.2 +/- 0.2 (right) micromol x kg(-1) x min(-1) (P < 0.01). Whole-body glycerol appearance increased from 6.0 +/- 0.5 to 7.7 +/- 0.7 micromol x kg(-1) x min(-1)(P < 0.01); renal conversion of glycerol to glucose increased from 0.13 +/- 0.04 to 0.30 +/- 0.10 (left) and from 0.11 +/- 0.03 to 0.25 +/- 0.05 (right) micromol x kg(-1) x min(-1), (P < 0.05). Net renal gluconeogenic precursor uptake increased from 1.5 +/- 0.4 to 5.0 +/- 0.4 (left) and from 0.9 +/- 0.2 to 3.8 +/- 0.4 (right) micromol x kg(-1) x min(-1) (P < 0.01). Renal lactate uptake could account for approximately 40% of postabsorptive RGP and for 60% of RGP during hypoglycemia. These results indicate that gluconeogenic precursor extraction by the kidney, particularly lactate, is stimulated by counterregulatory hormones and accounts for a significant fraction of the enhanced gluconeogenesis induced by hypoglycemia.     

Liquefied aftercataract: a complication of continuous curvilinear capsulorhexis and intraocular lens implantation in the lens capsule

OBJECTIVE: To compare effects of N(G)-monomethyl-L-arginine (L-NMMA; a NO synthase inhibitor) and L-arginine (a NO synthase substrate) on haemodynamics in healthy men at rest and during exercise. METHODS: We infused L-NMMA and saline placebo intravenously in two groups of eight healthy men. Each group underwent a two-phase, randomized, single-blind crossover study. Men in one group received 3 mg/kg L-NMMA and men in the other group received 6 mg/kg L-NMMA. Haemodynamic measurements were performed before, during and after a 12 min stepped exercise protocol starting 6 min after the intravenous infusion. A further six men received, according to the same study design, 30 g L-arginine over 30 min and saline placebo before exercise. Blood pressure was measured by sphygmomanometry and cardiac output by bioimpedance, allowing computation of total systemic vascular resistance index (SVRI). RESULTS: Infusion of 6 mg/kg L-NMMA into men at rest produced modest increases (compared with effect of saline placebo) in systolic and diastolic blood pressures of 4.1 +/- 1.1 and 12.6 +/- 3.5%, respectively (means +/- SEM, P < 0.01 for both comparisons) and a marked increase in SVRI of 39.2 +/- 5.2% (P < 0.01). Cardiac index and heart rate were 22.0 +/- 3.3 and 17.0 +/- 4.4% lower after administration of L-NMMA (P < 0.01 for each comparison) than after infusion of saline placebo. During exercise there was no significant difference between total SVRI after infusions of L-NMMA and saline (difference not significant, diminished with increasing exercise). Six minutes into recovery the difference between total SVRI after infusions of L-NMMA and saline reappeared with SVRI 25 +/- 6.9% higher after infusion of L-NMMA than after infusion of saline (P < 0.01). Administration of L-arginine had no significant effect on haemodynamics in men at rest, during exercise and during recovery. CONCLUSIONS: Effects of L-NMMA on total systemic vascular resistance during exercise are less marked than are those on subjects at rest, probably because vasodilatation of resistance vessels of skeletal muscle during exercise is mediated mainly by factors other than NO. Our results also suggest that NO synthesis in healthy men is not substrate limited either at rest or during exercise.     

Counterregulation by epinephrine and glucagon during insulin-induced hypoglycemia in the conscious dog

We assessed the combined role of epinephrine and glucagon in regulating gluconeogenic precursor metabolism during insulin-induced hypoglycemia in the overnight-fasted, adrenalectomized, conscious dog. In paired studies (n = 5), insulin was infused intraportally at 5 mU.kg-1.min-1 for 3 h. Epinephrine was infused at a basal rate (B-EPI) or variable rate to simulate the normal epinephrine response to hypoglycemia (H-EPI), whereas in both groups the hypoglycemia-induced rise in cortisol was simulated by cortisol infusion. Plasma glucose fell to approximately 42 mg/dl in both groups. Glucagon failed to rise in B-EPI, but increased normally in H-EPI. Hepatic glucose release fell in B-EPI but increased in H-EPI. In B-EPI, the normal rise in lactate levels and net hepatic lactate uptake was prevented. Alanine and glycerol metabolism were similar in both groups. Since glucagon plays little role in regulating gluconeogenic precursor metabolism during 3 h of insulin-induced hypoglycemia, epinephrine must be responsible for increasing lactate release from muscle, but is minimally involved in the lipolytic response. In conclusion, a normal rise in epinephrine appears to be required to elicit an increase in glucagon during insulin-induced hypoglycemia in the dog. During insulin-induced hypoglycemia, epinephrine plays a major role in maintaining an elevated rate of glucose production, probably via muscle lactate release and hepatic lactate uptake.     

Renovascular interaction of epinephrine, dopamine, and intraperitoneal sepsis

OBJECTIVE: To determine the effect of intraperitoneal sepsis on the systemic and renal actions of the continous infusion of epinephrine or dopamine, and during the concurrent administration of both drugs. DESIGN: Prospective, randomized study. SETTING: Laboratory at a university hospital. SUBJECTS: Seven conscious, chronically catheterized, adult merino sheep. INTERVENTIONS: Epinephrine at 40 micrograms/min or dopamine at 2 micrograms/kg/min, or both drugs concurrently were infused for 4 hrs on separate study days in healthy sheep. This protocol was then repeated following the induction of sepsis after the intraperitoneal injection of 10(11) Escherichia coli, 10(12) Bacteroides fragilis, and bran. MEASUREMENTS AND MAIN RESULTS: Systemic oxygen delivery (DO2) and consumption were measured using thermodilution cardiac output and measured oxygen content. Renal blood flow was measured using an electromagnetic flow transducer, and creatinine clearance was calculated as the quotient of renal blood flow and the renal extraction ratio of creatinine. Infusion of epinephrine augmented systemic DO2 and mean arterial pressure (MAP) during both healthy and septic studies. Systemic oxygen consumption was only increased during epinephrine infusion in the septic study. During the healthy animal study, renal blood flow was initially decreased during epinephrine infusion, but increased to 36% above baseline (p = .003). However, creatinine clearance remained unchanged. During the experimental sepsis study, the infusion of epinephrine had less marked effects on renal blood flow (unchanged from baseline), while an initial reduction (15 mins) in creatinine clearance (p = .04) was not sustained and had returned to baseline by 3 hrs. Dopamine alone produced no change in systemic oxygen variables or MAP during the studies on healthy or septic animals. Although dopamine produced renal vasodilation and an increase in renal blood flow in the healthy state, these results were not found during the septic state. In addition, concurrent infusion of dopamine with epinephrine did not alter the systemic or renal effects of epinephrine during the healthy or septic states. CONCLUSIONS: These results do not support the routine use of low-dose dopamine, and demonstrate a change in renovascular responses to catecholamines during intraperitoneal sepsis. The infusion of epinephrine at 40 micrograms/min had few deleterious effects on the kidney, and augmented both MAP and systemic DO2. Its role as a catecholamine in the management of sepsis may need to be reconsidered.     

Terazosin in the treatment of hypertension and symptomatic benign prostatic hyperplasia: a primary care trial

In vitro experimental data show that magnesium increases beta-receptor affinity to agonists. We studied the effect of a mild increase in serum magnesium level on the bronchial dose-response curve to salbutamol in six patients with asthma (age 54 +/- 3.6 years, FEV1 49.2 +/- 4.9 per cent of predicted), with a normal serum magnesium level, in a double blind placebo-controlled design. The salbutamol dose-response curve was obtained on two separate days, starting 30 min after an intravenous infusion of saline or MgSO4 (20 mg/kg over 10 min, followed by 10 mg/kg/h). The baseline FEV1 values and the values after 30 min infusion on the two test days were not significantly different. During MgSO4 infusion, the serum magnesium level increased significantly from 0.86 +/- 0.01 to 1.31 +/- 0.19 mmol/litre after 30 min and 1.29 +/- 0.17 mmol/litre at the end of the study. FEV1 values after salbutamol were significantly higher during MgSO4 than during saline infusion at the low doses of salbutamol: 1480 +/- 253 vs. 1368 +/- 212 ml, P < 0.05, after 5 micrograms, and 1596 +/- 585 vs. 1378 +/- 532 ml, P < 0.01, after 10 micrograms of salbutamol. The maximum increase in FEV1 obtained after the maximum dose of salbutamol (400 micrograms) was not significantly different during saline and MgSO4 infusion. In conclusion, a mild sustained increase in serum magnesium level increases the bronchodilating effect of low doses of salbutamol, possibly through an increased beta-receptor affinity. There was no effect on the maximum bronchodilating effect of salbutamol.