Compensatory mechanisms governing the concentration of plasma low density lipoprotein

To evaluate factors regulating the concentrations of plasma low density lipoproteins (LDL), apolipoprotein B metabolism was studied in nine Pima Indians (25 +/- 2 yr, 191 +/- 20% ideal wt) with low LDL cholesterol (77 +/- 7 mg/dl) and apoB (60 +/- 4 mg/dl) and in eight age- and weight-matched Caucasians with similar very low density lipoprotein (VLDL) concentrations, but higher LDL (cholesterol = 104 +/- 18; apoB = 82 +/- 10; P less than 0.05). Subjects received autologous 131I-labeled VLDL and 125I-labeled LDL, and specific activities of VLDL-apoB, intermediate density lipoprotein (IDL)-apoB, and LDL-apoB were analyzed using a multicompartmental model. Synthesis of LDL-apoB was similar (1224 +/- 87 mg/d in Pimas vs 1218 +/- 118 mg/d in Caucasians) but in Pimas the fractional catabolic rate (FCR) for LDL-apoB was higher (0.48 +/- 0.02 vs 0.39 +/- 0.04 d-1, P less than 0.05). In the Pimas, a much higher proportion of VLDL-apoB was catabolized without conversion to LDL (47 +/- 3 vs 30 +/- 5%, P less than 0.01). When all subjects were considered together, LDL-apoB concentrations were negatively correlated with both FCR for LDL-apoB (r = -0.79, P less than 0.0001) and the non-LDL pathway (r = -0.43, P less than 0.05). Also, the direct removal (non-LDL) path was correlated with VLDL-apoB production (r = 0.49, P = 0.03), and the direct removal pathway and FCR for LDL-apoB were correlated (r = 0.49, P = 0.03). In conclusion, plasma LDL appear to be regulated by both the catabolism of LDL and the extent of metabolism of VLDL without conversion to LDL; both of these processes may be mediated by the apoB/E receptor, and appear to increase in response to increasing VLDL production.     

Glucagon chronically impairs hepatic and muscle glucose disposal

Defects in insulin secretion and/or action contribute to the hyperglycemia of stressed and diabetic patients, and we hypothesize that failure to suppress glucagon also plays a role. We examined the chronic impact of glucagon on glucose uptake in chronically catheterized conscious depancreatized dogs placed on 5 days of nutritional support (NS). For 3 days of NS, a variable intraportal infusion of insulin was given to maintain isoglycemia (approximately 120 mg/dl). On day 3 of NS, animals received a constant low infusion of insulin (0.4 mU.kg-1.min-1) and either no glucagon (CONT), basal glucagon (0.7 ng.kg-1.min-1; BasG), or elevated glucagon (2.4 ng.kg-1.min-1; HiG) for the remaining 2 days. Glucose in NS was varied to maintain isoglycemia. An additional group (HiG+I) received elevated insulin (1 mU.kg-1.min-1) to maintain glucose requirements in the presence of elevated glucagon. On day 5 of NS, hepatic substrate balance was assessed. Insulin and glucagon levels were 10+/-2, 9+/-1, 7+/-1, and 24+/-4 microU/ml, and 24+/-5, 39+/-3, 80+/-11, and 79+/-5 pg/ml, CONT, BasG, HiG, and HiG+I, respectively. Glucagon infusion decreased the glucose requirements (9.3+/-0.1, 4.6+/-1.2, 0.9+/-0.4, and 11.3+/-1.0 mg.kg-1.min-1). Glucose uptake by both hepatic (5.1+/-0.4, 1.7+/-0.9, -1.0+/-0.4, and 1.2+/-0.4 mg.kg-1.min-1) and nonhepatic (4.2+/-0.3, 2.9+/-0.7, 1.9+/-0.3, and 10.2+/-1.0 mg.kg-1.min-1) tissues decreased. Additional insulin augmented nonhepatic glucose uptake and only partially improved hepatic glucose uptake. Thus, glucagon impaired glucose uptake by hepatic and nonhepatic tissues. Compensatory hyperinsulinemia restored nonhepatic glucose uptake and partially corrected hepatic metabolism. Thus, persistent inappropriate secretion of glucagon likely contributes to the insulin resistance and glucose intolerance observed in obese and diabetic individuals.     

Acute effects of low density lipoprotein apheresis on metabolic parameters of apolipoprotein B

Apheresis is a treatment option for patients with severe hypercholesterolemia and coronary artery disease. It is unknown whether such therapy changes kinetic parameters of lipoprotein metabolism, such as apolipoprotein B (apoB) secretion rates, conversion rates, and fractional catabolic rates (FCR). We studied the acute effect of apheresis on metabolic parameters of apoB in five patients with drug-resistant hyperlipoproteinemia, using endogenous labeling with D(3)-leucine, mass spectrometry, and multicompartmental modeling. Patients were studied prior to and immediately after apheresis therapy. The two tracer studies were modeled simultaneously, taking into account the non-steady-state concentrations of apoB. The low density lipoprotein (LDL)-apoB concentration was 120+/-32 mg dl(-1) prior to and 52+/-18 mg dl(-1) immediately after apheresis therapy. The metabolic studies indicate that no change in apoB secretion (13.9+/- 4.9 mg kg(-1) day(-1)) is required to fit the tracer and apoB mass data obtained before and after apheresis and that in four of the five patients the LDL-apoB FCR (0.21+/-0.02 day(-1)) was not altered after apheresis. In one subject the LDL-apoB FCR temporarily increased from 0.22 day(-1) to 0.35 day(-1) after apheresis. The conversion rate of very low density lipoprotein (VLDL)-apoB to LDL-apoB is temporarily decreased from 76 to 51% after apheresis and thus less LDL-apoB is produced after apheresis. We conclude that an acute reduction of LDL-apoB concentration does not affect apoB secretion or LDL-apoB FCR, but that apoB conversion to LDL is temporarily decreased. Thus, in most patients the decreased rate of delivery of neutral lipids or apoB to the liver does not result in an upregulation of LDL receptors or in decreased apoB secretion.     

Characterization of hepatic and brain metabolism in young adults with glycogen storage disease type 1: a magnetic resonance spectroscopy study

In glycogen storage disease type 1 (GSD1), children present with severe hypoglycemia, whereas the propensity for hypoglycemia may decrease with age in these patients. It was the aim of this study to elucidate the mechanisms for milder hypoglycemia symptoms in young adult GSD1 patients. Four patients with GSD1 [body mass index (BMI) 23.2 +/- 6.3 kg/m, age 21.3 +/- 2.9 yr] and four healthy controls matched for BMI (23.1 +/- 3.0 kg/m) and age (24.0 +/- 3.1 yr) were studied. Combined (1)H/(31)P nuclear magnetic resonance spectroscopy (NMRS) was used to assess brain metabolism. Before and after administration of 1 mg glucagon, endogenous glucose production (EGP) was measured with d-[6,6-(2)H(2)]glucose and hepatic glucose metabolism was examined by (1)H/(13)C/(31)P NMRS. At baseline, GSD1 patients exhibited significantly lower rates of EGP (0.53 +/- 0.04 vs. 1.74 +/- 0.03 mg.kg(-1).min(-1); P < 0.01) but an increased intrahepatic glycogen (502 +/- 89 vs. 236 +/- 11 mmol/l; P = 0.05) and lipid content (16.3 +/- 1.1 vs. 1.4 +/- 0.4%; P < 0.001). After glucagon challenge, EGP did not change in GSD1 patients (0.53 +/- 0.04 vs. 0.59 +/- 0.24 mg.kg(-1).min(-1); P = not significant) but increased in healthy controls (1.74 +/- 0.03 vs. 3.95 +/- 1.34; P < 0.0001). In GSD1 patients, we found an exaggerated increase of intrahepatic phosphomonoesters (0.23 +/- 0.08 vs. 0.86 +/- 0.19 arbitrary units; P < 0.001), whereas inorganic phosphate decreased (0.36 +/- 0.08 vs. -0.43 +/- 0.17 arbitrary units; P < 0.01). Intracerebral ratios of glucose and lactate to creatine were higher in GSD1 patients (P < 0.05 vs. control). Therefore, hepatic defects of glucose metabolism persist in young adult GSD1 patients. Upregulation of the glucose and lactate transport at the blood-brain barrier could be responsible for the amelioration of hypoglycemic symptoms.     

Intramyocellular lipid accumulation and reduced whole body lipid oxidation in HIV lipodystrophy

Antiretroviral therapy in human immunodeficiency virus (HIV)-positive patients can induce a lipodystrophy syndrome of peripheral fat wasting and central adiposity, dyslipidemia, and insulin resistance. To test whether in this syndrome insulin resistance is associated with abnormal muscle handling of fatty acids, 12 HIV-1 patients (8 females/4 males, age = 26 +/- 2 yr, HIV duration = 8 +/- 1 yr, body mass index = 22.0 +/- 1.0 kg/m(2), on protease inhibitors and nucleoside analog RT inhibitors) and 12 healthy subjects were studied. HIV-1 patients had a total body fat content (assessed by dual-energy X-ray absorptiometry) similar to that of controls (22 +/- 1 vs. 23 +/- 2%; P = 0.56), with a topographic fat redistribution characterized by reduced fat content in the legs (18 +/- 2 vs. 32 +/- 3%; P < 0.01) and increased fat content in the trunk (25 +/- 2 vs. 19 +/- 2%; P = 0.03). In HIV-positive patients, insulin sensitivity (assessed by QUICKI) was markedly impaired (0.341 +/- 0.011 vs. 0.376 +/- 0.007; P = 0.012). HIV-positive patients also had increased total plasma cholesterol (216 +/- 20 vs. 174 +/- 9 mg/dl; P = 0.05) and triglyceride (298 +/- 96 vs. 87 +/- 11 mg/dl; P = 0.03) concentrations. Muscular triglyceride content assessed by means of (1)H NMR spectroscopy was higher in HIV patients in soleus [92 +/- 12 vs. 42 +/- 5 arbitrary units (AU); P < 0.01] and tibialis anterior (26 +/- 6 vs. 11 +/- 3 AU; P = 0.04) muscles; in a stepwise regression analysis, it was strongly associated with QUICKI (R(2) = 0.27; P < 0.0093). Even if the basal metabolic rate (assessed by indirect calorimetry) was comparable to that of normal subjects, postabsorptive lipid oxidation was significantly impaired (0.30 +/- 0.07 vs. 0.88 +/- 0.09 mg x kg(-1) x min(-1); P < 0.01). In conclusion, lipodystrophy in HIV-1 patients in antiretroviral treatment is associated with intramuscular fat accumulation, which may mediate the development of the insulin resistance syndrome.     

Determination of kinetic parameters of apolipoprotein B metabolism using amino acids labeled with stable isotopes.

The use of amino acids labeled with stable isotopes represents a relatively new approach for determining kinetic parameters of apolipoprotein metabolism; thus, several aspects of experimental protocols need to be defined. The aims of the present study were to determine whether a) different amino acid tracers or b) different methods of tracer administration affected apolipoprotein (apo) B kinetic parameters obtained by multicompartmental modeling, and c) to compare very low density lipoprotein (VLDL)-apoB metabolic parameters determined by multicompartmental modeling with those estimated by linear regression or by monoexponential analysis. [1-13C]leucine and [15N]glycine were given either as bolus injections or as primed constant infusions. A bolus of one amino acid was administered simultaneously with a primed constant infusion (8 h) of the other amino acid into four healthy normolipidemic subjects (age 23.0 +/- 1.4 yr; BMI 20.9 +/- 0.9 kg.m-2). VLDL-, intermediate density lipoprotein (IDL)-, and low density lipoprotein (LDL)-apoB enrichments were followed over 110 h. For subsequent analysis these values were converted to tracer/tracee ratios. Using the multicompartmental model, the fractional catabolic rate (FCR) for VLDL-apoB was estimated to be 0.36 +/- 0.09 h-1 after the administration of the tracer as a primed constant infusion and 0.35 +/- 0.07 h-1 when the tracer was administered as a bolus. The values for VLDL-apoB production were 14.6 +/- 6.5 mg.kg-1.d-1 and 14.1 +/- 5.4 mg.kg-1.d-1, respectively. The corresponding values for LDL-apoB were 0.027 +/- 0.016 h-1 (0.026 +/- 0.018 h-1) for the FCR and 10.5 +/- 3.7 mg.kg-1.d-1 (10.4 +/- 3.8 mg.kg-1.d-1) for the production following administration of the tracer as a primed constant infusion and a bolus, respectively. Approximately 47% of VLDL-apoB ultimately reached the LDL fraction via the VLDL-IDL-LDL pathway. Thirty-five percent of LDL-apoB did not originate from this cascade pathway, but was shunted from a rapidly turning over VLDL compartment directly into the LDL fraction. While there was some variation between individuals, VLDL-apoB and LDL-apoB parameters derived from the bolus and the primed constant infusions showed no significant differences and were closely correlated. Metabolic parameters were also independent of the two amino acids tested. Although values for FCRs of VLDL-apoB obtained from linear regression (0.36 +/- 0.19 h-1) or monoexponential analysis (0.50 +/- 0.36 h-1) did not differ significantly from those obtained by the multicompartmental model, there was considerable variation and no significant correlation in a given individual.(ABSTRACT TRUNCATED AT 400 WORDS)     

Glucose and lactate kinetics in the neonate.

To evaluate the ontogeny of neonatal glucose homeostasis, glucose production and lactate production have been measured in nine prematurely born appropriate for gestational age neonates [birth weight 1985 +/- 100 g, (SEM) gestational age 33.6 +/- 0.7 weeks] and five full term appropriate for gestational age neonates [birth weight 3254 +/- 111 g, gestational age 40.8 +/- 0.4 wks] and compared to six non pregnant, nondiabetic adults [weight of 57.7 +/- 2.2 kg, age 32 +/- 2 years]. Ra glucose (preterm) averaged 27.7 +/- 2.8 mumol.kg-1 min-1 (5.0 +/- 0.5 mg.kg-1 min-1) and Ra glucose (term) averaged 28.9 +/- 3.9 mumol.kg-1 min-1 (5.2 +/- 0.7 mg.kg-1 min-1); both were higher than the Ra glucose of the adult controls (16.1 +/- 2.8 mumol.kg-1 min-1 (2.9 +/- 0.5 mg.kg-1 min-1) (P less than 0.05 vs preterm and P less than 0.05 vs. term). Ra lactate (preterm) averaged 100 +/- 11.9 mumol.kg-1 min-1 (9.1 +/- 1.1 mg.kg-1 min-1) and Ra lactate (term) average 77.2 +/- 13.0 mumol.kg-1 min-1 (7.1 +/- 1.2 mg.kg-1 min-1); both were higher than the Ra lactate of the adult controls 35.9 +/- 6.5 mumol.kg-1 min-1 (3.3 +/- 0.6 mg.kg-1 min-1) (P less than 0.01 vs preterm and P less than 0.05 vs. term). The potential for gluconeogenesis from lactate was estimated by determining the ratio of [Ra Lactate/Ra Glucose]. The [Ra Lactate/Ra Glucose] (preterm) (187 +/- 12 (x10(-2)) was similar to that of the [Ra Lactate/Ra Glucose] (term) (136 +/- 16) (x10(-2)).(ABSTRACT TRUNCATED AT 250 WORDS)     

A comparison of the estimates of whole-body protein turnover in parenterally fed neonates obtained using three different end products

Protein turnover rates in neonates have been calculated largely by measuring urinary [15N]urea enrichment following administration of [15N]glycine. Although ammonia has been increasingly recognized as an end product of nitrogen metabolism, in neonates it yields a different estimate of protein turnover than does urea. Comparisons of ammonia and urea end products in parenterally fed neonates have not previously been reported. A third and independent way of estimating protein turnover, developed for adults, is to use breath 13CO2 as an end product following administration of [1-13C]leucine. We therefore carried out simultaneous measurements of protein turnover in 10 parenterally fed neonates, using the three end products. The infants were clinically stable, weighed 2.6 +/- 0.2 kg, and received 3.1 +/- 0.2 g.kg-1.d-1 of amino acid, 2.2 +/- 0.1 g.kg-1.d-1 of lipids, and an energy intake of 90 +/- 4 kcal.kg-1.d-1 (1 kcal = 4.186 kJ). The turnover estimates derived from the 13CO2 and [15N]urea end products were very similar. The [15N]ammonia end product produced values approximately 66% (p less than 0.01) of the other two. We conclude that the ammonia and urea end products probably originate in different precursor pools. The similarity of the urea and breath carbon dioxide results helps validate the use of the urea end product in studying the nitrogen metabolism of parenterally fed neonates. Ideally in future studies two or more end products should be used, since they provide information about different aspects of the neonates' protein metabolism.     

Plasma turnover of HDL apoC-I,apoC-III,and apoE in humans: in vivo evidence for a link between HDL apoC-III and apoA-I metabolism

Numerous factors are known to affect the plasma metabolism of HDL, including lipoprotein receptors, lipid transfer protein, lipolytic enzymes and HDL apolipoproteins. In order to better define the role of HDL apolipoproteins in determining plasma HDL concentrations, the aims of the present study were: a) to compare the in vivo rate of plasma turnover of HDL apolipoproteins [i.e., apolipoprotein A-I (apoA-I), apoC-I, apoC-III, and apoE], and b) to investigate to what extent these metabolic parameters are related to plasma HDL levels. We thus studied 16 individuals with HDL cholesterol levels ranging from 0.56-1.66 mmol/l and HDL apoA-I levels ranging from 89-149 mg/dl. Plasma kinetics of HDL apolipoproteins were investigated using a primed constant (12 h) infusion of deuterated leucine. Plasma HDL apolipoprotein levels were 41.8 +/- 1.5, 9.7 +/- 0.5, 4.9 +/- 0.5, and 0.7 +/- 0.1 micromol/l for apoA-I, apoC-I, apoC-III and apoE. Plasma transport rates (TRs) were 388.6 +/- 24.7, 131.5 +/- 12.5, 66.5 +/- 9.1, and 31.4 +/- 3.3 nmol.kg-1.day-1; and residence times (RTs) were 5.1 +/- 0.4, 3.7 +/- 0.3, 3.6 +/- 0.3, and 1.1 +/- 0.1 days, respectively. HDL cholesterol and apoA-I levels were significantly correlated with HDL apoA-I RT (r = 0.69 and r = 0.56), and were not significantly correlated with HDL apoA-I TR. In contrast, HDL apoC-I, apoC-III, and apoB levels were all positively related to their TRs and not their RTs. HDL apoC-III TR was positively correlated with levels of HDL apoC-III (r = 0.73, P < 0.01), and with those of HDL cholesterol and apoA-I (r = 0.54 and r = 0.53, P < 0.05, respectively). HDL apoC-III TR was in turn related to HDL apoA-I RT (r = 0.51, P < 0.05). Together, these results provide in vivo evidence for a link between the metabolism of HDL apoC-III and apoA-I, and suggest a role for apoC-III in the regulation of plasma HDL levels.     

Mevinolin and cholestyramine inhibit the direct synthesis of low density lipoprotein apolipoprotein B in miniature pigs

Previous studies established that following simultaneous injection of 125I-labeled homologous very low density lipoproteins (VLDL) and 131I-labeled homologous low density lipoproteins (LDL) into miniature pigs, a large proportion of LDL apolipoprotein B (apoB) was synthesized directly, independent of VLDL or intermediate density lipoprotein (IDL) apoB catabolism. The possibility that cholestyramine alone (a bile acid sequestrant) or in combination with mevinolin (a cholesterol synthesis inhibitor) could regulate the direct LDL apoB synthetic pathway was investigated. 125I-labeled VLDL and 131I-labeled LDL were injected into miniature pigs (n = 8) during a control period and following 18 days of cholestyramine treatment (1.0 g kg-1d-1) or following 18 days of treatment with cholestyramine and mevinolin (1.2 mg kg-1d-1). ApoB in each lipoprotein fraction was selectively precipitated using isopropanol in order to calculate specific activity. In control experiments, LDL apoB specific activity curves reached their peak values well before crossing the VLDL or IDL apoB curves. However, cholestyramine treatment resulted in LDL apoB curves reaching maximal values much closer to the point of intersection with the VLDL or IDL curves. Kinetic analyses demonstrated that cholestyramine reduced total LDL apoB flux by 33%, which was due entirely to inhibition of the LDL apoB direct synthesis pathway since VLDL-derived apoB was unaffected. In addition, the LDL apoB pool size was reduced by 30% and the fractional catabolic rate of LDL apoB was increased by 16% with cholestyramine treatment. The combination of mevinolin and cholestyramine resulted in an even more marked inhibition of the direct LDL apoB synthesis pathway (by 90%), and in two animals this pathway was completely abolished. This inhibition was selective as VLDL-derived LDL apoB synthesis was not significantly different. LDL apoB pool size was reduced by 60% due primarily to the reduced synthesis as well as a 40% greater fractional removal rate. These results are consistent with the idea that cholestyramine and mevinolin increase LDL catabolism by inducing hepatic apoB, E receptors. We have now shown that the direct synthesis of LDL apoB is selectively inhibited by these two drugs.     

Statin therapy restores sympathovagal balance in experimental heart failure.

Inhibitors of hydroxymethylglutaryl-CoA reductase or statins have been shown to alleviate endothelial dysfunction. Their effects on constitutive nitric oxide synthase in the central nervous system may hypothetically affect the autonomic balance in sympathoexcitatory states, such as chronic heart failure (CHF). To address this issue, simvastatin (SIM) (0.3, 1.5, or 3 mg. kg-1. day-1 po) was given to rabbits with pacing-induced CHF over a 3-wk period. Normal and CHF vehicle-treated rabbits served as controls. Autonomic balance was assessed by measuring heart rate variability, including power spectral analysis (PSA). In addition, changes in resting heart rate were assessed before and after vagal and sympathetic autonomic blockade by atropine and metoprolol, respectively. The SD for all intervals was 8.9 +/- 0.7 ms in normal, 4.9 +/- 0.6 ms in CHF (P < 0.01), 3.8 +/- 0.6 ms in CHF with 0.3 mg. kg-1. day-1 SIM (P < 0.001), 5.7 +/- 0.9 in CHF with 1.5 mg. kg-1. day-1 SIM (P < 0.05), and 7.2 +/- 0.5 in CHF with 3.0 mg. kg-1. day-1 SIM. Similarly, total power was 40.5 +/- 6.3 ms2 in normal, 10.1 +/- 3.0 ms2 in CHF (P < 0.01), 6.0 +/- 1.6 ms2 in CHF with 0.3 mg. kg-1. day-1 SIM (P < 0.01), 13.2 +/- 3.9 ms2 in CHF with 1.5 mg. kg-1. day-1 SIM (P < 0.05), and 22.0 +/- 3.0 ms2 in CHF with 3.0 mg. kg-1. day-1 SIM. Both PSA data for low (0.625-0.1875 Hz) and high frequencies (0.1875-0.5625 Hz) showed recovery in CHF animals on medium and high SIM doses without changes in the low-to-high-frequency ratio. SIM beneficially affects autonomic tone in CHF as seen by the reversal of depressed HRV and total power of PSA. These data have important implications for the treatment of patients with autonomic imbalance.     

Failure of hyperketonemia to alter basal and insulin-mediated glucose metabolism in man

The effect of physiologic elevations of plasma hydroxybutyrate induced by the infusion of sodium D,L-beta-hydroxybutyrate (15 mumol X kg-1 X min-1) on carbohydrate metabolism was examined with the euglycemic insulin clamp technique in nine healthy volunteers. Plasma insulin concentration was acutely raised and maintained at 126 +/- 6 microU/ml and plasma glucose was held constant at the fasting level by a variable glucose infusion. Glucose uptake of 6.53 +/- 0.80 mg X kg-1 X min-1 was unchanged by hyperketonemia when compared with an intraindividual control study using saline instead of beta-OH-butyrate infusion (6.26 +/- 0.59 mg X kg-1 X min-1). In studies, in which the degree of metabolic alkalosis accompanying butyrate infusion was mimicked by the continuous administration of bicarbonate, glucose uptake was also unaffected (6.25 +/- 0.45 mg X kg-1 X min-1). Furthermore, hyperketonemia had no effect on basal glucose production or the suppression of hepatic glucose production following hyperinsulinemia. It is concluded that moderate elevations in plasma beta-hydroxy-butyrate do not alter hepatic or peripheral glucose metabolism.     

Insulin effects on acetate metabolism

Acetate metabolism was studied in patients with insulin resistance. To evaluate the interaction between glucose and acetate metabolism, we measured acetate and glucose turnover with a hyperinsulinemic euglycemic clamp (hot clamp) in obese and diabetic patients with insulin resistance (n = 8) and in a control group with normal insulin sensitivity (n = 6). At baseline, acetate turnover and plasma concentrations were similar between the two groups (group means: 4.3 +/- 0.4 micromol x kg-1 x min-1 and 128.2 +/- 11.1 micromol/l). Acetate concentrations decreased in both groups with hyperinsulinemia but were significantly lower in the insulin-resistant group (20% vs. 12%, P < 0.05). After the hot clamp treatment, acetate turnover increased for the two groups and was higher in the group with normal insulin sensitivity: 8.1 +/- 0.7 vs. 5.5 +/- 0.5 micromol x kg-1 x min-1 (P < 0.001). No change related to insulin action was observed in either group in the percentage of acetate oxidation. This was approximately 70% of overall utilization at baseline and during the clamp. No correlation between glucose and acetate utilization was observed. Our results support the hypothesis that, like glucose metabolism, acetate metabolism is sensitive to insulin.     

Overexpression of apoC-III produces lesser hypertriglyceridemia in apoB-48-only gene-targeted mice than in apoB-100-only mice

The adaptive value of apolipoprotein B-48 (apoB-48), the truncated form of apoB produced by the intestine, in lipid metabolism remains unclear. We crossed human apoC-III transgenic mice with mice expressing either apoB-48 only (apoB48/48) or apoB-100 only (apoB100/100). Cholesterol levels were higher in apoB48/48 mice than in apoB100/100 mice but triglyceride levels were similar. Lipid levels were increased by the apoC-III transgene. However, triglyceride levels were significantly higher in apoB100/100C-III than in apoB48/48C-III mice (895 +/- 395 mg/dl vs. 690 +/- 252 mg/dl; P <0.01), whereas cholesterol levels were higher in the apoB48/48C-III mice than in apoB100/100C-III (144 +/- 35 mg/dl vs. 94 +/- 30 mg/dl; P <0.00001). Triglyceride clearance from VLDL was impaired to a greater extent in apoB100/100C-III vs. apoB100/100 mice than in apoB48/48C-III vs. apoB48/48 mice. Triglyceride secretion rates were no different in apoC-III transgenic mice than in their nontransgenic littermates. ApoB-48 triglyceride-rich lipoproteins were more resistant to the triglyceride-increasing effects of apoC-III but appeared more sensitive to the remnant clearance inhibition. Our findings support a coordinated role for apoB-48 in facilitating the delivery of dietary triglycerides to the periphery. Consistent with such a mechanism, glucose levels were significantly higher in apoB48/48 mice vs. apoB100/100 mice, perhaps on the basis of metabolic competition.     

Urinary 8-hydroxy-2'-deoxyguanosine,a metabolite of oxidized DNA,is not elevated in HIV patients on combination antiretroviral therapy

Mitochondrial toxicity of nucleoside analogues has been proposed to be the etiology of a range of side-effects from antiretroviral therapy of HIV infection. In this study, urinary 8-hydroxy-2'-deoxyguanosine (8OH2'dG), a metabolite of oxidized DNA, was measured to determine if antiretroviral therapy leads to oxidative damage to DNA. A cross-sectional study was carried out measuring urinary 8OH2'dG in three groups of HIV-infected patients: (1) antiretroviral medication na?ve, (2) patients on antiretroviral medications without lipodystrophy and (3) patients on antiretroviral medications with lipodystrophy. Twenty-five patients were enrolled in each group. The mean spot urinary 8OH2'dG measurements per mg creatinine for the three groups were: antiretroviral na?ve 4.27 +/- 0.61 (ng 8OH2'dG/mg creatinine +/- SEM), on antiretroviral medications without lipodystrophy 2.88 +/- 0.26, and on antiretroviral medications with lipodystrophy 3.27 +/- 0.30. The differences between the means of the three groups is not statistically significant (p = 0.055), and these results are not significantly different from reported values for healthy controls [A carbon column-based liquid chromatography electrochemical approach to routine 8-hydroxy-2-deoxyguanosine measurements in urine and other biologic matrices: a one-year evaluation of methods. Free Radical Biology and Medicine 27 (1999) 647-666].     

Beta-adrenergic blockade alters whole-body leucine metabolism in humans

This study examined the effects of a nonselective beta-blocking agent on whole-body leucine metabolism in humans. Five normal, healthy subjects (4 male, 1 female) underwent a 6-h primed, constant-rate infusion of L-[1-13C]leucine after 5 days of twice daily oral use of 80 mg propranolol and a placebo. Leucine turnover was determined by tracer dilution and leucine oxidation by 13C enrichment of the expired CO2. Propranolol decreased the total daily energy expenditure from 1,945 +/- 177.5 to 1,619 +/- 92.5 kcal/day (P less than 0.05). A fasting associated decrease in blood glucose and an attenuated rise in free fatty acids and ketones were observed during beta-blockade. Propranolol also increased plasma leucine concentrations (73.1 +/- 8.7 to 103.4 +/- 7.3 mumol/l; P less than 0.05) and leucine oxidation (13.2 +/- 1.2 to 17.1 +/- 1.3 mumol.kg-1.h-1; P less than 0.05), although leucine turnover was not significantly altered (100.5 +/- 7.3 vs. 126.0 +/- 12.3 mumol.kg-1.h-1). In addition, the urinary urea nitrogen-to-creatinine ratio was greater during propranolol administration (0.24 +/- 0.04 vs. 0.34 +/- 0.02 mol/g; P less than 0.05). These data suggest that the beta-adrenergic system plays a role in the modulation of whole-body leucine metabolism in humans. Whether these changes are the result of a direct effect on skeletal muscle or an indirect effect mediated by altering the fuel supply to skeletal muscle cannot be discriminated by the present study.     

Chenodeoxycholic acid normalizes elevated lipoprotein secretion and catabolism in cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is a rare inherited lipid storage disease caused by a defect in bile acid synthesis in which cholesterol and its product cholestanol are deposited in neurological and vascular tissue. Therapy with chenodeoxycholic acid but not with the 7 beta-epimeric ursodeoxycholic acid is usually successful. In an untreated patient, total and low density lipoprotein (LDL) cholesterol were found to be low (134 +/- 11 and 78 +/- 8 mg/dl, respectively). The production rate (PR) and fractional catabolic rate (FCR) of very low density (VLDL) apolipoprotein B (apoB) were, however, both markedly increased (34.7 mg/kg per day and 13.7 pools/day, respectively vs. 15.1 +/- 5.0 mg/kg per day and 6.2 +/- 3.8 pools/day in controls) while the PR and FCR of LDL apoB were moderately elevated (16.3 mg/kg per day and 0.65 pools/day, respectively vs. 12.9 +/- 1.2 mg/kg per day and 0.52 +/- 0.10 pools/day in controls). After 1 month of 750 mg/day of chenodeoxycholic acid, the FCR and PR of both VLDL and LDL apoB became normal while total plasma cholesterol increased significantly to 145 +/- 18 mg/dl. In a second patient who had been receiving 750 mg/day of chenodeoxycholic acid for 6 months lipoprotein kinetics were normal. These parameters did not change when the subject was switched to 750 mg/day ursodeoxycholic acid. We postulate that cholesterol biosynthesis in CTX is derepressed by a diminished hepatic pool of chenodeoxycholic acid and that the elevated secretion of apoB is a response to the increased rate of cholesterol production.     

Vildagliptin in drug-na?ve patients with type 2 diabetes: a 24-week, double-blind, randomized, placebo-controlled, multiple-dose study.

This 24-week double-blind, randomized, multicenter, placebo-controlled, parallel-group study was performed in 632 drug-na?ve patients with type 2 diabetes to assess efficacy and tolerability of vildagliptin (50 mg qd, 50 mg bid, or 100 mg qd). HbA1c decreased modestly in patients receiving placebo (Delta=-0.3+/-0.1%) and to a significantly greater extent in patients receiving vildagliptin 50 mg qd (Delta=-0.8+/-0 .1%), 50 mg bid (Delta=-0.8+/-0.1%), or 100 mg qd (Delta=-0.9+/-0.1%, p<0.01 for all groups VS. placebo) from an average baseline of 8.4%. In patients diagnosed >or=3 months before enrollment, HbA1c increased with placebo (Delta=+0.2+/-0.2%) and between-treatment differences (vildagliptin-placebo) were -0.8+/-0.2% (p<0.001), -0.7+/-0.2% (p=0.003), and -0.9+/-0.2% (p<0.001) with vildagliptin 50 mg qd, 50 mg bid, and 100 mg qd, respectively. There was no apparent dose-response in the overall population; however, in patients with high baseline HbA1c, there were greater reductions with either 100 mg dose regimen (Delta=-1.3+/-0.2% and -1.4+/-0.2%) compared to 50 mg qd (Delta=-0.8+/-0.1%). Body weight decreased modestly in all groups (by 0.3 to 1.8 kg). The incidence of adverse events was similar across all groups and 相似文献   

Decreased reliance on lactate during exercise after acclimatization to 4,300 m

We hypothesized that the increased exercise arterial lactate concentration on arrival at high altitude and the subsequent decrease with acclimatization were caused by changes in blood lactate flux. Seven healthy men [age 23 +/- 2 (SE) yr, wt 72.2 +/- 1.6 kg] on a controlled diet were studied in the postabsorptive condition at sea level, on acute exposure to 4,300 m, and after 3 wk of acclimatization to 4,300 m. Subjects received a primed-continuous infusion of [6,6-2D]glucose (Brooks et al. J. Appl. Physiol. 70:919-927, 1991) and [3-13C]lactate and rested for a minimum of 90 min followed immediately by 45 min of exercise at 101 +/- 3 W, which elicited 51.1 +/- 1% of the sea level peak O2 consumption (VO2peak; 65 +/- 2% of both acute altitude and acclimatization). During rest at sea level, lactate appearance rate (Ra) was 0.52 +/- 0.03 mg.kg-1.min-1; this increased sixfold during exercise to 3.24 +/- 0.19 mg.kg-1.min-1. On acute exposure, resting lactate Ra rose from sea level values to 2.2 +/- 0.2 mg.kg-1.min-1. During exercise on acute exposure, lactate Ra rose to 18.6 +/- 2.9 mg.kg-1.min-1. Resting lactate Ra after acclimatization (1.77 +/- 0.25 mg.kg-1.min-1) was intermediate between sea level and acute exposure values. During exercise after acclimatization, lactate Ra (9.2 +/- 0.7 mg.kg-1.min-1) rose from resting values but was intermediate between sea level and acute exposure values. The increased exercise arterial lactate concentration response on arrival at high altitude and subsequent decrease with acclimatization are due to changes in blood lactate appearance.(ABSTRACT TRUNCATED AT 250 WORDS)