Inhibition of lipolysis reduces beta1-adrenoceptor-mediated thermogenesis in man

The purpose of the study was to investigate whether the increase in energy expenditure and lipid oxidation during beta1-adrenergic stimulation is caused by the concomitant increase in lipolysis. Twelve healthy male subjects participated in three trials: no-LIP/-, inhibition of lipolysis by pretreatment with acipimox followed by saline infusion; -/BETA, no pretreatment, with dobutamine infusion to stimulate beta1-adrenoceptors; and no-LIP/BETA, pretreatment with acipimox followed by dobutamine infusion. Inhibition of lipolysis did not affect baseline energy expenditure, but decreased lipid oxidation and increased carbohydrate oxidation. Energy expenditure and lipid oxidation increased significantly during beta1-adrenergic stimulation, but this increase was significantly smaller when lipolysis was inhibited ([baseline v infusion period] energy expenditure: -/BETA, 5.15 +/- 0.16 v 6.11 +/- 0.26 kJ/min, P < .001; no-LIP/BETA, 5.28 +/- 0.17 v 5.71 +/- 0.19 kJ/min, P < .01; lipid oxidation: -/BETA, 0.059 +/- 0.004 v 0.073 +/- 0.006 g/min, P < .01; no-LIP/BETA, 0.034 +/- 0.005 v 0.039 +/- 0.006 g/min, P < .05). Baseline plasma glycerol and nonesterified fatty acid (NEFA) concentrations decreased after inhibition of lipolysis. Glycerol and NEFA increased significantly during beta1-adrenergic stimulation alone (glycerol, 65.0 +/- 5.3 v 117.0 +/- 10.9 micromol/L; NEFA, 362 +/- 24 v 954 /- 89 micromol/L; both P < .001). Concomitant administration of acipimox prevented a substantial part of the increase in lipolysis during beta1-adrenergic stimulation, but the increase in plasma glycerol and NEFA remained significant (glycerol, 40.4 +/- 2.2 v 44.8 +/- 2.2 micromol/L; NEFA, 118 +/- 18 v 160 +/- 19 micromol/L; both P < .05). In conclusion, a reduced availability of plasma NEFA was associated with a reduced increase in energy expenditure and lipid oxidation during beta1-adrenergic stimulation in man.     

Evidence for an inhibitory effect of physiological levels of insulin on the growth hormone (GH) response to GH-releasing hormone in healthy subjects

It has been previously reported that in healthy subjects, the acute reduction of free fatty acids (FFA) levels by acipimox enhances the GH response to GHRH. In the present study, the GH response to GHRH was evaluated during acute blockade of lipolysis obtained either by acipimox or by insulin at different infusion rates. Six healthy subjects (four men and two women, 25.8 +/- 1.9 yrs old, mean +/- SE) underwent three GHRH tests (50 micrograms iv, at 1300 h) during: 1) iv 0.9% NaCl infusion (1200-1500 h) after oral acipimox administration (250 mg) at 0700 h and at 1100 h; 2) 0.1 mU.kg-1.min-1 euglycemic insulin clamp (1200-1500 h) after oral acipimox administration (250 mg at 0700 h and at 1100 h); 3) 0.4 mU.kg-1.min-1 euglycemic insulin clamp (1200-1500 h) after oral placebo administration (at 0700 and 1100 h). Serum insulin (immunoreactive insulin) levels were significantly different in the three tests (12 +/- 2, 100 +/- 10, 194 +/- 19 pmol/L, P < 0.06), plasma FFA were low and similar (0.04 +/- 0.003, 0.02 +/- 0.005, 0.02 +/- 0.003, not significant), and the GH response to GHRH was progressively lower (4871 +/- 1286, 2414 +/- 626, 1076 +/- 207 micrograms/L 120 min), although only test 3 was significantly different from test 1 (P < 0.05). Pooling the three tests together, a significant negative regression was observed between mean serum immunoreactive insulin levels and the GH response to GHRH (r = -0.629, P < 0.01). Our results indicate that in healthy subjects, acipimox and hyperinsulinemia produce a similar decrease in FFA levels and that at similar low FFA, the GH response to GHRH is lower during insulin infusion than after acipimox. These data suggest that insulin exerts a negative effect on GH release. Because the insulin levels able to reduce the GH response to GHRH are commonly observed during the day, for instance during the postprandial period, we conclude that the insulin negative effect on GH release may have physiological relevance.     

Hyperkalemia in hospitalized patients treated with trimethoprim-sulfamethoxazole

OBJECTIVE: To determine the effect of standard-dose trimethoprim-sulfamethoxazole on serum potassium concentration in hospitalized patients. DESIGN: Prospective chart review. SETTING: Community-based teaching hospital. PATIENTS: 105 patients with various infections were hospitalized and treated. Eighty patients treated with standard-dose trimethoprim-sulfamethoxazole (trimethoprim, < or = 320 mg/d; sulfamethoxazole, < or = 1600 mg/d) composed the treatment group; 25 patients treated with other antibiotic agents served as the control group. MEASUREMENTS: Serum sodium, potassium, and chloride concentrations; serum carbon dioxide content; anion gap; blood urea nitrogen level; and serum creatinine level. RESULTS: The serum potassium concentration in the treatment group (mean +/- SD) was 3.89 +/- 0.46 mmol/L (95% CI, 3.79 to 3.99 mmol/L), and it increased by 1.21 mmol/L (CI, 1.09 to 1.32 mmol/L) 4.6 +/- 2.2 days after trimethoprim-sulfamethoxazole therapy was initiated. Blood urea nitrogen levels increased from 7.92 +/- 5.7 mmol/L (CI, 6.67 to 9.16 mmol/L) to 9.2 +/- 5.8 mmol/L (CI, 7.9 to 10.5 mmol/L), and serum creatinine levels increased from 102.5 +/- 49.5 mumol/L (CI, 91.4 to 113.6 mumol/L) to 126.1 +/- 70.7 mumol/L (CI, 110.3 to 141.9 mumol/L). Patients with a serum creatinine level of 106 mumol/L (1.2 mg/dL) or more developed a higher peak potassium concentration (5.37 +/- 0.59 mmol/L [CI, 5.15 to 5.59 mmol/L]) than patients with a serum creatinine level of less than 106 mumol/L (4.95 +/- 0.48 mmol/L [CI, 4.80 to 5.08 mmol/L]). Patients with diabetes had a slightly higher peak potassium concentration (5.14 +/- 0.45 mmol/L [CI, 4.93 to 5.39 mmol/L]) than did patients without diabetes (5.08 +/- 0.59 mmol/L [CI, 4.93 to 5.23 mmol/L]), but the difference was not statistically significant. The serum potassium concentration in the control group was 4.33 +/- 0.45 mmol/L (CI, 4.15 to 4.51 mmol/L), and it decreased nonsignificantly over 5 days of therapy. CONCLUSIONS: Standard-dose trimethoprim-sulfamethoxazole therapy used to treat various infections leads to an increase in serum potassium concentration. A peak serum potassium concentration greater than 5.0 mmol/L developed in 62.5% of patients; severe hyperkalemia (peak serum potassium concentration > or = 5.5 mmol/L) occurred in 21.2% of patients. Patients treated with standard-dose trimethoprim-sulfamethoxazole should be monitored closely for the development of hyperkalemia, especially if they have concurrent renal insufficiency (serum creatinine level > or = 106 mumol/L).     

Acarbose in NIDDM patients with poor control on conventional oral agents. A 24-week placebo-controlled study

OBJECTIVE: To determine the efficacy of acarbose, compared with placebo, on the metabolic control of NIDDM patients inadequately controlled on maximal doses of conventional oral agents. RESEARCH DESIGN AND METHODS: In this three-center double-blind study, 90 Chinese NIDDM patients with persistent poor glycemic control despite maximal doses of sulfonylurea and metformin were randomly assigned to receive additional treatment with acarbose 100 mg thrice daily or placebo for 24 weeks, after 6 weeks of dietary reinforcement. Efficacy was assessed by changes in HbA1c, fasting and 1-h postprandial plasma glucose and insulin levels, and fasting lipid levels. RESULTS: Acarbose treatment was associated with significantly greater reductions in HbA1c (-0.5 +/- 0.2% vs. placebo 0.1 +/- 0.2% [means +/- SEM], P = 0.038), 1-h postprandial glucose (-2.3 +/- 0.4 mmol/l vs. placebo 0.7 +/- 0.4 mmol/l, P < 0.001) and body weight (-0.54 +/- 0.32 kg vs. placebo 0.42 +/- 0.29 kg, P < 0.05). There was no significant difference between the two groups regarding changes in fasting plasma glucose and lipids or fasting and postprandial insulin levels. Flatulence was the most common side effect (acarbose vs. placebo: 28/45 vs. 11/44, P < 0.05). One patient on acarbose had asymptomatic elevations in serum transaminases that normalized in 4 weeks after acarbose withdrawal. Another patient on acarbose developed severe hypoglycemia; glycemic control was subsequently maintained on half the baseline dosage of sulfonylurea. CONCLUSIONS: In NIDDM patients inadequately controlled on conventional oral agents, acarbose in moderate doses resulted in beneficial effects on glycemic control, especially postprandial glycemia, and mean body weight. Additional use of acarbose can be considered as a useful alternative in such patients if they are reluctant to accept insulin therapy.     

Predictable value of fasting blood glucose level for the incidence of non-insulin-dependent diabetes mellitus]

In order to investigate the predictable value of fasting blood glucose (FBG) level for the incidence of non-insulin-dependent diabetes mellitus (NIDDM), 638 nondiabetic subjects who were investigated in 1986 (including 341 subjects with normal glucose tolerance and 297 subjects with impaired glucose tolerance) were reexamined in 1992. The results showed that the 6-year-incidence of NIDDM was significantly increased with rising of baseline FBG level. After adjusting for age, sex and body mass index (BMI), proportional hazard regression analysis showed that FBG level in impaired glucose tolerance group was positively associated with the development of NIDDM (P = 0.0001). Subjects with mean FBG level of 5.19 mmol/L had a higher risk of developing NIDDM than subjects with mean FBG level of 4.61 mmol/L (RR 2.1, 95% CI 1.19-3.74, P = 0.01). The risk ratio of NIDDM was further increased in the group with mean FBG level of 6.l5 mmol/L (RR = 2.9, 95% CI 1.79-4.59, P = 0.0001). The result indicates that FBG level is an independent risk factor for the development of NIDDM.     

Myocardial glucose uptake in patients with NIDDM and stable coronary artery disease

Whole body insulin resistance characterizes patients with NIDDM, but it is not known whether insulin also has impaired ability to stimulate myocardial glucose uptake (MGU) in these patients. This study was designed to evaluate MGU as measured by 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET) in patients with NIDDM and stable coronary artery disease (CAD) under standardized metabolic conditions. Eight patients with NIDDM, 11 nondiabetic patients with CAD, and 9 healthy control subjects were enrolled in the study. MGU was quantitated in the normal myocardial regions with [18F]FDG and PET and the whole body glucose disposal by glucose-insulin clamp technique (serum insulin, -430 pmol/l). Plasma glucose and serum insulin concentrations were comparable in all groups during PET studies. The whole body glucose uptake was 45% lower in NIDDM patients (22 +/- 9 micromol x min(-1) X kg(-1) body wt [mean +/- SD]), compared with healthy control subjects (40 +/- 17 micromol x min(-1) x kg(-1) body wt, P < 0.05). In CAD patients, whole body glucose uptake was 30 +/- 9 micromol x min(-1) x kg(-1) body wt (NS between the other groups). MGU was similar in the normal segments in all three groups (69 +/- 28 micromol x min(-1) x 100 g(-1) in NIDDM patients, 72 +/- 17 micromol x min(-1) x 100 g(-1) in CAD patients, and 76 +/- 10 micromol x min(-1) x 100 g(-1) in healthy control subjects, NS). No correlation was found between whole body glucose uptake and MGU. As studied by [18F]FDG PET under stable normoglycemic hyperinsulinemic conditions, MGU is not reduced in patients with NIDDM and CAD in spite of peripheral insulin resistance. These findings suggest that there is no significant defect in MGU in patients with NIDDM.     

Effect of acute pharmacological reduction of plasma free fatty acids on growth hormone (GH) releasing hormone-induced GH secretion in obese adults with and without hypopituitarism

In obesity, there is a markedly decreased GH secretion. The diagnosis of GH deficiency (GHD) in adults is based on peak GH responses to stimulation tests. In the severely obese, peak GH levels after pharmacological stimulation are often in the range that is observed in hypopituitary patients. To distinguish obese subjects from GHD patients, it will be necessary to demonstrate that reduced GH responsiveness to a given test is reversible in the former, but not in the latter, group. Recent studies have shown that reduction of plasma free fatty acids (FFA) with acipimox in obese patients restores their somatotrope responsiveness. There are no data evaluating GH responsiveness to acipimox plus GHRH in obese adults with hypopituitarism. The aim of the present study was to evaluate the effect of acute pharmacological reduction of plasma FFA on GHRH-mediated GH secretion in obese normal subjects and obese adults with hypopituitarism. Eight obese patients with a body mass index of 34.2+/-1.2; eight obese adults with hypopituitarism, with a body mass index of 35.5+/-1.9; and six control subjects were studied. All the patients showed an impaired response to an insulin-tolerance test (0.15 U/kg, i.v.), with a peak GH secretion of less than 3 microg/L. Two tests were carried out. On one day, they were given GHRH (100 microg, i.v., 0 min), preceded by placebo; and blood samples were taken every 15 min for 60 min. On the second day, they were given GHRH (100 microg, i.v., 0 min), preceded by acipimox (250 mg, orally, at -270 min and -60 min); and blood samples were taken every 15 min for 60 min. The administration of acipimox induced a FFA reduction during the entire test. Normal control subjects had a mean peak (microg/L) of 23.8+/-4.8 after GHRH-induced GH secretion; previous acipimox administration increased GHRH-induced GH secretion, with a mean peak of 54.7+/-14.5. In obese patients, GHRH-induced GH secretion was markedly reduced, with a mean peak (microg/L) of 3.9+/-1; previous administration of acipimox markedly increased GHRH-mediated GH secretion, with a mean peak of 16.0+/-3.2 (P < 0.05). In obese adults with hypopituitarism, GHRH-induced GH secretion was markedly reduced, with a mean peak (microg/L) of 2+/-0.7; previous acipimox administration did not significantly modify GHRH-mediated GH secretion, with a mean peak of 3.3+/-1.1 (P < 0.05). The GH response of obese patients and obese adults with hypopituitarism was similar after GHRH alone. In contrast, the GH response after GHRH plus acipimox, was markedly decreased in obese adults with hypopituitarism (mean peak, 3.3+/-1.1), compared with obese patients (mean peak, 16.0+/-3.2) (P < 0.05) and control subjects (mean peak, 54.7+/-14.5) (P < 0.01). In conclusion, GH secretion, after GHRH-plus-acipimox administration, is reduced in obese adults with hypopituitarism patients, when compared with obese normal patients. Testing with GHRH plus acipimox is safe and is free from side effects and could be used for the diagnosis of GHD in adults.     

Purification of the renaturable protein kinase PK55 by preparative isoelectric focusing and high performance electrophoretic chromatography and the generation of PK55 monoclonal antibodies by in vitro B cell stimulation

The possible association between lipoprotein(a) [Lp(a)] and albumin excretion rate (AER) is a topic that generates conflicting views. In addition, Lp(a) phenotypes have not previously been considered as factors influencing AER. In order to clarify this issue, we studied 70 non-insulin-dependent diabetes mellitus (NIDDM) patients without clinically detectable macroangiopathy, 27 with microalbuminuria and 43 without it. Both groups were matched for the known variables that could influence AER and serum Lp(a) levels. Lp(a) was determined by enzyme-linked immunosorbent assay (ELISA), and Lp(a) phenotypes were assessed by electrophoresis followed by immunoblotting. Lp(a) phenotypes were grouped as follows: 'small' (F, S1 and S2), 'big' (S3 and S4) and 'null'. The NIDDM patients with microalbuminuria presented higher serum Lp(a) concentrations than the patients without it [15.7 mg dL-1 (95% CI 0.5-36.5) vs. 4.5 mg dL-1 (95% CI 0.1-18.5); P < 0.001] and a direct correlation between Lp(a) and AER was observed (r = 0.34; P < 0.01). AER was significantly different when Lp(a) phenotypes were considered ['small': median 19 micrograms min-1 (range 1-195); 'big': median 9.5 micrograms min-1 (range 1-186); 'null': 4 micrograms min-1 (range 1-9); P = 0.04]. None of the NIDDM patients with a 'null' phenotype showed an AER of > 10 micrograms min-1. In conclusion, this case-control study provides evidence that microalbuminuria is associated with high serum Lp(a) in NIDDM without clinically detectable macroangiopathy. Furthermore, NIDDM patients with a 'null' phenotype could be considered at low risk for the development of microalbuminuria.     

Effect of caffeine on the recognition of and responses to hypoglycemia in humans

OBJECTIVE: To determine whether two effects of acute caffeine ingestion--decrease in cerebral blood flow and increase in brain glucose use--alter the recognition of and physiologic responses to hypoglycemia. DESIGN: On two occasions, a hyperinsulinemic glucose clamp technique (2 mU/kg body weight per minute) was used to maintain plasma glucose at 5 mmol/L for 90 minutes, followed by 60 minutes at 3.8 mmol/L, and then 2.8 mmol/L. After 30 minutes at 5 mmol/L, participants consumed, using a randomized, double-blind design, caffeine-free cola with or without caffeine (400 mg) added. SETTING: Yale Clinical Research Center. PARTICIPANTS: Eight healthy, nonobese volunteers (5 men; age range, 20 to 33 years). MEASUREMENTS: Middle cerebral artery velocity (V MCA), counter-regulatory hormone levels, hypoglycemic symptoms, and cognitive function (P300 evoked potentials). RESULTS: Caffeine caused an immediate and sustained 23% decrease in VMCA from 64 to 49 cm/s (point estimate of difference, +15 cm/s [95% CI, 10 to 21 cm/s], P < 0.001). At a glucose level of 3.8 mmol/L, only the participants given caffeine had warning symptoms and "felt hypoglycemic." Moreover, the level of epinephrine was 118% ([CI of point difference, 76% to 158%] [CI, P < 0.001]) higher after caffeine consumption compared with placebo. Similarly, levels of norepinephrine (41% [CI, 26% to 60%], P < 0.002), cortisol (65% [CI, 26% to 78%], P < 0.008), and growth hormone (60% [CI, 16% to 143%], P < 0.05) were higher after caffeine consumption compared with placebo. At 2.8 mmol/L, epinephrine (40% [point estimate of the percentage difference], P < 0.05), norepinephrine (27%, P < 0.05), and cortisol (24%, P < 0.05) levels were higher, participants were more aware (P < 0.02) of hypoglycemia, and P300 latency was prolonged in the group that consumed caffeine (7.2%, P < 0.05). CONCLUSIONS: Acute ingestion of caffeine is associated with sympathoadrenal activation and awareness of hypoglycemia at a glucose level not usually considered hypoglycemic. Our data suggest that individuals who ingest moderate amounts of caffeine may develop hypoglycemic symptoms if plasma glucose levels fall into the "low-normal" range, as might occur in the late postprandial period after ingestion of a large carbohydrate load.     

Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study

CONTEXT: Although cholesterol-reducing treatment has been shown to reduce fatal and nonfatal coronary disease in patients with coronary heart disease (CHD), it is unknown whether benefit from the reduction of low-density lipoprotein cholesterol (LDL-C) in patients without CHD extends to individuals with average serum cholesterol levels, women, and older persons. OBJECTIVE: To compare lovastatin with placebo for prevention of the first acute major coronary event in men and women without clinically evident atherosclerotic cardiovascular disease with average total cholesterol (TC) and LDL-C levels and below-average high-density lipoprotein cholesterol (HDL-C) levels. DESIGN: A randomized, double-blind, placebo-controlled trial. SETTING: Outpatient clinics in Texas. PARTICIPANTS: A total of 5608 men and 997 women with average TC and LDL-C and below-average HDL-C (as characterized by lipid percentiles for an age- and sex-matched cohort without cardiovascular disease from the National Health and Nutrition Examination Survey [NHANES] III). Mean (SD) TC level was 5.71 (0.54) mmol/L (221 [21] mg/dL) (51 st percentile), mean (SD) LDL-C level was 3.89 (0.43) mmol/L (150 [17] mg/dL) (60th percentile), mean (SD) HDL-C level was 0.94 (0.14) mmol/L (36 [5] mg/dL) for men and 1.03 (0.14) mmol/L (40 [5] mg/dL) for women (25th and 16th percentiles, respectively), and median (SD) triglyceride levels were 1.78 (0.86) mmol/L (158 [76] mg/dL) (63rd percentile). INTERVENTION: Lovastatin (20-40 mg daily) or placebo in addition to a low-saturated fat, low-cholesterol diet. MAIN OUTCOME MEASURES: First acute major coronary event defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. RESULTS: After an average follow-up of 5.2 years, lovastatin reduced the incidence of first acute major coronary events (1 83 vs 116 first events; relative risk [RR], 0.63; 95% confidence interval [CI], 0.50-0.79; P<.001), myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% CI, 0.43-0.83; P=.002), unstable angina (87 vs 60 first unstable angina events; RR, 0.68; 95% CI, 0.49-0.95; P=.02), coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95% CI, 0.52-0.85; P=.001), coronary events (215 vs 163 coronary events; RR, 0.75; 95% CI, 0.61-0.92; P =.006), and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95% CI, 0.62-0.91; P = .003). Lovastatin (20-40 mg daily) reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6% to 1.02 mmol/L (39 mg/dL). There were no clinically relevant differences in safety parameters between treatment groups. CONCLUSIONS: Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL-C levels. These findings support the inclusion of HDL-C in risk-factor assessment, confirm the benefit of LDL-C reduction to a target goal, and suggest the need for reassessment of the National Cholesterol Education Program guidelines regarding pharmacological intervention.     

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.     

A preliminary placebo-controlled crossover trial of fludrocortisone for chronic fatigue syndrome

To investigate the time course of the hepatic glucose metabolism in non-insulin-dependent diabetes (NIDDM), we measured hepatic glucose production (HGP) and first-pass uptake of portal glucose infusion by the liver (HGU) using dual-tracer methods in a NIDDM model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats, and in normal controls, Long-Evans Tokushima Otsuka (LETO) rats, at 8, 14, and 28 weeks of age (n = 5, respectively). The fasting plasma glucose level in OLETF rats was significantly higher than in LETO rats at 28 weeks of age (8.9 +/- 1.7 v 6.3 +/- 0.4 mmol/L, P < .01), while there was no significant difference at 8 and 14 weeks. Hyperinsulinemia in OLETF rats appeared at > or = 8 weeks of age. Basal HGP was significantly higher in OLETF than in LETO rats at 8 and 28 weeks (8 weeks, 12.7 +/- 1.7 v 9.4 +/- 1.8 mg x kg(-1) x min(-1), P < .05; 28 weeks, 10.9 +/- 1.6 v 7.1 +/- 1.3 mg x kg(-1) x min(-1), P < .01). At 14 weeks, basal HGP was not significantly different between OLETF and LETO rats. However, at all study points, HGU during a portal glucose infusion was significantly lower in OLETF than in LETO rats (8 weeks, 0.9 +/- 0.2 v 2.3 +/- 0.5, P < .01; 14 weeks, 0.8 +/- 0.3 v 1.4 +/- 0.3, P < .05; 28 weeks, 0.7 +/- 0.2 v 1.4 +/- 0.3 mg x kg(-1) x min(-1), P < .01). Fasting plasma free fatty acid (FFA) levels were not significantly different between OLETF and LETO, except at 8 weeks. Suppression of plasma FFA levels by endogenous insulin during a portal glucose infusion was impaired in OLETF rats compared with LETO rats. In summary, this study demonstrates that derangement of hepatic glucose handling, such as increased basal HGP and decreased HGU, is observed in obese NIDDM model OLETF rats at the prediabetic phase when hyperglycemia is still not apparent. Furthermore, these derangements may be accompanied by impaired lipid metabolism.     

Suppression of plasma cholesteryl ester transfer protein activity in acute hyperinsulinemia and effect of plasma nonesterified fatty acid

Cholesteryl ester transfer protein (CETP) is a major determinant of the plasma high-density lipoprotein cholesterol (HDL-C) level and plays an important role in the reverse cholesterol transport system. The purpose of this study was to determine the effect of acute hyperinsulinemia on plasma CETP activity in normal subjects and patients with non-insulin-dependent diabetes mellitus (NIDDM). Hyperinsulinemia was achieved using the hyperinsulinemic-euglycemic clamp. CETP activity was determined as the transfer of radiolabeled cholesterol in HDL3 to acceptor lipoprotein. Mean plasma CETP activity during an insulin infusion in both subject groups was significantly decreased compared with the mean basal activity. Suppression of plasma CETP activity in the NIDDM patients was significantly less than in the normal subjects (-4.2% +/- 7.9% v -9.6% +/- 6.4%, P < .02). Regression analysis showed that this suppression was correlated with plasma nonesterified fatty acid (NEFA) levels after the clamp and with the magnitude of the NEFA decrease (r = .318, P < .02 and r = .292, P < .05, respectively). The data suggest that acute hyperinsulinemia reduces plasma CETP activity through a decrease in plasma NEFA.     

Prolactin and beta-endorphin responses to hypoglycemia are reduced in well-controlled insulin-dependent diabetes mellitus

Several pituitary hormones, including corticotropin (ACTH), growth hormone (GH), prolactin, and beta-endorphin (but not thyrotropin, follicle-stimulating hormone, or luteinizing hormone), are released in response to hypoglycemia in normal subjects. In patients with insulin-dependent diabetes mellitus (IDDM), the degree of glycemic control is known to alter ACTH and GH responses to hypoglycemia. The current study was performed to examine the effect of glycemic control on prolactin and beta-endorphin responses to hypoglycemia in subjects with IDDM. We performed 3-hour stopped hypoglycemic-hyperinsulinemic clamp studies (12 pmol/kg/min) during which plasma glucose was decreased from 5.0 mmol/L to 2.2 mmol/L in steps of 0.6 mmol/L every 30 minutes in 20 subjects with uncomplicated IDDM (12 males and eight females; age, 26 +/- 2 years; IDDM duration, 10 +/- 1 years; body mass index, 23.6 +/- 0.6 kg/m2) and 10 healthy subjects (five males and five females aged 30 +/- 1 years). The 10 diabetic subjects in good glycemic control (mean hemoglobin A1 [HbA1], 7.5% +/- 0.3%; normal range, 5.4% to 7.4%) were compared with the 10 poorly controlled patients (mean HbA1, 12.6% +/- 0.5%; P < .001 v well-controlled diabetic group). During hypoglycemia, prolactin levels in the well-controlled diabetic group did not change (7 +/- 1 microgram/L at plasma glucose 5.0 mmol/L to 9 +/- 2 micrograms/L at plasma glucose 2.2 mmol/L), whereas prolactin levels increased markedly in the poorly controlled diabetic group (7 +/- 2 micrograms/L to 44 +/- 17 micrograms/L) and healthy volunteers (12 +/- 2 micrograms/L to 60 +/- 19 micrograms/L, P < .05 between IDDM groups). The plasma glucose threshold required for stimulation of prolactin secretion was 2.2 +/- 0.1 mmol/L in well-controlled IDDM, 3.0 +/- 0.4 mmol/L in poorly controlled IDDM, and 2.4 +/- 0.1 mmol/L in healthy subjects (P < .05 between IDDM groups). Responses in males and females were similar. The increase in beta-endorphin levels was also attenuated in well-controlled IDDM patients (4 +/- 1 pmol/L at plasma glucose 5.0 mmol/L to 11 +/- 4 pmol/L at plasma glucose 2.2 mmol/L) versus poorly controlled IDDM patients (5 +/- 1 pmol/L to 26 +/- 7 pmol/L) and healthy subjects (8 +/- 1 pmol/L to 56 +/- 13 pmol/L). The plasma glucose threshold required for stimulation of beta-endorphin release was again lower in well-controlled IDDM versus poorly controlled IDDM patients (2.2 +/- 0.1 v 3.0 +/- 0.3 mmol/L) and healthy subjects (2.5 +/- 0.4 mmol/L, P < .05 between IDDM groups). In conclusion, prolactin and beta-endorphin responses to a standardized hypoglycemic stimulus (plasma glucose, 2.2 mmol/L) are reduced and plasma glucose levels required to stimulate release of prolactin and beta-endorphin are lower in well-controlled IDDM compared with poorly controlled IDDM and healthy subjects. Thus, stress hormones not previously considered to have a primary role in plasma glucose recovery from hypoglycemia are affected by glycemic control, suggesting a more generalized alteration of hypothalamic-pituitary responses to hypoglycemia in IDDM patients with strict glycemic control.     

Risk factors for chronic graft-versus-host disease after bone marrow transplantation: a retrospective single centre analysis

We retrospectively compared the changes in serum albumin concentration and colloid osmotic pressure between survivors and nonsurvivors of prolonged (> or = 7 days) critical illness over a 2-year period from 1 July 1995. All patients had serum albumin measured daily, and colloid osmotic pressure measured 5 days a week, throughout their ICU admission. They received crystalloid and colloid infusions as well as parenteral or enteral feeding. Infusions of albumin were not used to treat hypoalbuminaemia. One hundred and forty-five patients were included, 66 nonsurvivors and 79 survivors. Nonsurvivors were significantly older than survivors [mean (95% CI): 58 (3.8) and 49 (4.1) years, respectively] and had a greater risk of death [mean (95% CI): 0.44 (0.06) and 0.28 (0.05); p < 0.05]. There was no significant difference in gender, APACHE II score [mean (95% CI): 22 (2.7) (nonsurvivors); 18 (2.3) (survivors)] or length of stay [median (interquartile range): 14 (9-27) days (nonsurvivors); 15 (9-26) days (survivors)]. There was no difference between the two groups in the absolute minimum serum albumin concentrations reached, the time to reach that minimum or the minimum in the first 7 days. However, nonsurvivors had a significantly lower mean serum albumin concentration: [mean (95% CI): 15.7 (5.1) g.l-1 compared with 18.3 (4.6) g.l-1 in survivors; p < 0.05]. They also had a lower recovery mean (the weighted mean after the minimum value): [mean (95% CI): 13.3 (5.1) g.l-1 (nonsurvivors) and 18.6 (5.3) g.l-1 (survivors); p < 0.01]. Analysis of colloid osmotic pressure results showed no difference between the groups in mean, minimum or recovery mean. Regression analysis of mean colloid osmotic pressure and albumin revealed that albumin only contributed 17% of the colloid osmotic pressure in these patients. The similar decrease in albumin in nonsurvivors and survivors may reflect the acute inflammatory response and/or haemodilution. However, survivors showed an ability to increase serum albumin concentrations, possibly owing to resumption of synthesis. The colloid osmotic pressure varied little between or within either group of patients, possibly because of the use of artificial colloids. There was no relationship between death and colloid osmotic pressure.     

Measurement of platelet aggregation peptide inhibitors by ultrasonic interferometry

In healthy subjects, basal hepatic glucose production is (partly) regulated by paracrine intrahepatic factors. It is unknown if these paracrine factors also influence basal glucose production in infectious diseases with increased glucose production. We compared the effects of 150 mg indomethacin (n = 9), a nonendocrine stimulator of glucose production in healthy adults, and placebo (n = 7) on hepatic glucose production in Vietnamese adults with uncomplicated falciparum malaria. Glucose production was measured by primed, continuous infusion of [6,6-2H2]glucose. After indomethacin, the plasma glucose concentration and glucose production increased in all subjects from 5.3 +/- 0.1 mmol/L to a maximum of 7.1 +/- 0.3 mmol/L (P < .05) and from 17.6 +/- 0.8 micromol x kg(-1) x min(-1) to a maximum of 26.2 +/- 2.5 micromol x kg(-1) x min(-1) (P < .05), respectively. In the control group, the plasma glucose concentration and glucose production declined gradually during 4 hours from 5.4 +/- 0.2 mmol/L to 5.1 +/- 0.1 mmol/L (P < .05) and from 17.1 +/- 0.8 micromol x kg(-1) x min(-1) to 15.1 +/- 1.0 micromol x kg(-1) x min(-1) (P < .05), respectively. There were no differences in plasma concentrations of insulin, counterregulatory hormones, or cytokines between the groups. We conclude that indomethacin administration results in a transient increase in glucose production in patients with uncomplicated falciparum malaria in the absence of changes in plasma concentrations of glucoregulatory hormones or cytokines. Thus, this study indicates that in uncomplicated falciparum malaria, the rate of basal hepatic glucose production is also regulated by paracrine intrahepatic factors.     

Influence of intravenous L-carnitine administration in sheep preceding an oral urea drench

Two experiments were conducted to investigate the effect of i.v. administration of L-carnitine on selected metabolites in sheep and to determine the feasibility of using L-carnitine to ameliorate the deleterious effects of hyperammonemia in sheep. In Exp. 1, i.v. L-carnitine solutions were administered at three levels in a replicated Latin square: 0 (CONT), 6.36 (CAR 1), and 12.72 (CAR 2) mmol L-carnitine/kg x (75) BW using Suffolk ewes (n = 6; average BW 75+/-3 kg). Plasma L-carnitine concentration was increased (P<.05) by treatment (51.9 vs 102.3, and 96.4 micromol/L in CONT, CAR 1, and CAR 2, respectively). Plasma glucose concentration was elevated (P<.05) in CAR 2 and CAR 1. Plasma NEFA concentration was highest (P<.05) in CAR 2. Area under the response curve for glucose was greater (P<.02) in CAR 2. In Exp. 2, Suffolk ewes (n = 16; average BW 48+/-2 kg) were used in a randomized complete block design with a 2x2 factorial treatment arrangement to determine the effects of i.v. L-carnitine administration during an oral urea load test (OULT). L-Carnitine (0 and 6.36 mmol/kg x (75) BW) was administered i.v. at 30 min, and an oral urea drench (50% wt/vol; 0 and 300 mg/kg BW) was administered at 60 min. Plasma L-carnitine was increased (P<.0001) by i.v. L-carnitine. Plasma ammonia N was highest (P<.0001) in the UREA treatment compared with the CONT, CARN, and CARN + UREA treatments (148 vs 95, 101, and 108 micromol/L, respectively). Intravenous L-carnitine administration influenced plasma glucose and NEFA concentrations in sheep and, when administered 30 min preceding an OULT, prevented the development of subclinical hyperammonemia in sheep.     

Relationships between infant temperament, demographic variables, and family dynamics of childrearing families

The prothrombinase complex (factor [F]Xa, FVa, calcium ions, and lipid membrane) converts prothrombin to thrombin (FIIa). To determine whether plasma lipoproteins could provide a physiologically relevant surface, we determined the rates of FIIa production by using purified human coagulation factors, and isolated fasting plasma lipoproteins from healthy donors. In the presence of 5 nmol/L FVa, 5 nmol/L FXa, and 1.4 micromol/L prothrombin, physiological levels of very low density lipoprotein (VLDL) (0.45 to 0.9 mmol/L triglyceride, or 100 to 200 micromol/L phospholipid) yielded rates of 2 to 8 nmol Flla x L(-1) x s(-1) in a donor-dependent manner. Low density lipoprotein (LDL) and high density lipoprotein (HDL) also supported prothrombinase but at much lower rates (< or =1.0 nmol FIIa x L(-1) x s[-1]). For comparison, VLDL at 2 mmol/L triglyceride yielded approximately 50% the activity of 2X10(8) thrombin-activated platelets per milliliter. Although the FIIa production rate was slower on VLDL than on synthetic phosphatidylcholine/phosphatidylsenne vesicles (approximately 50 nmol FIIa x L(-1) x s[-1]), the prothrombin Km values were similar, 0.8 and 0.5 micromol/L, respectively. Extracted VLDL lipids supported rates approaching those of phosphatidylcholine/phosphatidylserine vesicles, indicating the importance of the intact VLDL conformation. However, the presence of VLDL-associated, factor-specific inhibitors was ruled out by titration experiments, suggesting a key role for lipid organization. VLDL also supported FIIa generation in an assay system comprising 0.1 nmol/L FVIIa; 0.55 nmol/L tissue factor; physiological levels of FV, FVIII, FIX, and FX; and prothrombin (3 nmol/L FIIa x L(-1) x s[-1]). These results indicate that isolated human VLDL can support all the components of the extrinsic coagulation pathway, yielding physiologically relevant rates of thrombin generation in a donor-dependent manner. This support is dependent on the intact lipoprotein structure and does not appear to be regulated by specific VLDL-associated inhibitors. Further studies are needed to determine the extent of this activity in vivo.     

Effects of concentrated electrolytes administered via a paste on fluid, electrolyte, and acid base balance in horses

OBJECTIVES: To test effectiveness of an electrolyte paste in correcting fluid, electrolyte and acid base alterations in response to furosemide administration. ANIMALS: 6 Standardbreds. PROCEDURES: Horses received electrolyte paste or water only (control). The paste was given orally 3 hours after furosemide administration (1 mg/kg of body weight, IM). Water was given ad libitum soon after the paste and 3 hours after furosemide administration to treated and control groups, respectively. Paste Na+, K+, and Cl- composition was approximately 2,220, 620, and 2,840 mmol, respectively. The PCV and plasma concentrations of total protein ([TP]), [Na+], [K+], [Cl-]), and bicarbonate ([HCO3-]) were determined, and urinary fluid and electrolyte excretion, fecal water, and body weight changes were measured. RESULTS: At the end of a 6-hour period, the paste-treated group had higher water consumption, which resulted in lower plasma [TP]; net electrolyte losses also were substantially less. With paste administration, [Na+] was approximately 2 mmol/L above a prefurosemide value of 137.3 mmol/L; control horses had values similar to the prefurosemide value. Plasma [Cl-] remained at the prefurosemide value, but values in control horses decreased by 7 mmol/L with water consumption. Plasma [K+] remained approximately 0.8 mmol/L below prefurosemide values in both groups. Venous [HCO3-] returned to prefurosemide values after paste administration, but alkalosis persisted in control horses after consumption of water only. Body weight loss was less after paste administration. CONCLUSIONS: Administration of electrolyte paste is advantageous over water alone in restoring fluid, electrolyte, and acid base balance after fluid and electrolyte loss attributable to furosemide administration.     

Forearm nitric oxide balance, vascular relaxation, and glucose metabolism in NIDDM patients

Endothelium-dependent and -independent vascular responses were assessed in 10 NIDDM patients and 6 normal subjects with no evidence of atherosclerotic disease. Changes in forearm blood flow and arteriovenous (AV) serum nitrite/nitrate (NO2-/NO3-) concentrations were measured in response to intra-arterial infusion of acetylcholine (ACh) (7.5, 15, 30 microg/min, endothelium-dependent response) and sodium nitroprusside (SNP) (0.3, 3, 10 microg/min, endothelium-independent response). Insulin sensitivity (determined by minimal model intravenous glucose tolerance test) was lower in NIDDM patients (0.82 +/- 0.20 vs. 2.97 +/- 0.29 10(4) min x microU(-1) x ml(-1); P < 0.01). Baseline forearm blood flow (4.8 +/- 0.3 vs. 4.4 +/- 0.3 ml x 100 ml(-1) tissue x min(-1); NS), mean blood pressure (100 +/- 4 vs. 92 +/- 4 mmHg; NS), and vascular resistance (21 +/- 1 vs. 21 +/- 1 units; NS), as well as their increments during ACh and SNP, infusion were similar in both groups. No difference existed in baseline NO2-/NO3- concentrations (4.09 +/- 0.33 [NIDDM patients] vs. 5.00 +/- 0.48 micromol/l [control subjects]; NS), their forearm net balance (0.31 +/- 0.08 [NIDDM patients] vs. 0.26 +/- 0.08 micromol/l x 100 ml(-1) tissue x min(-1); NS), and baseline forearm glucose uptake. During ACh infusion, both NO2- and NO3- concentrations and net balance significantly increased in both groups, whereas glucose uptake increased only in control subjects. When data from NIDDM and control groups were pooled together, a correlation was found between the forearm AV NO2- and NO3- differences and blood flow (r = 0.494, P = 0.024). On the contrary, no correlation was evident between NO2- and NO3- concentrations or net balance and insulin sensitivity. In summary, 1) no difference existed in basal and ACh-stimulated NO generation and endothelium-dependent relaxation between uncomplicated NIDDM patients and control subjects; 2) in both NIDDM and control groups, forearm NO2- and NO3- net balance following ACh stimulation was related to changes in the forearm blood flow; and 3) ACh-induced increase in forearm blood flow was associated with an increase in glucose uptake only in control subjects but not in NIDDM patients. In conclusion, our results argue against a role of impaired NO generation and blood flow regulation in determining the insulin resistance of uncomplicated NIDDM patients; rather, it supports an independent insulin regulation of hemodynamic and metabolic effects.