Biomedical subjects

J M Miles

Publications and source records attributed to J M Miles.

At least 19 recordsLinked to original sources

PubMed1992

Neuropathologic findings in multi-infarct dementia associated with anticardiolipin antibody. Evidence for endothelial injury as the primary event.

OBJECTIVE: There are few reports describing histopathologic changes associated with the antiphospholipid antibody syndrome. We describe a patient with multi-infarct dementia and antiphospholipid antibody syndrome, in whom a brain biopsy was performed. METHODS: Biopsy material from the left frontal cortex, including meninges, cortex, and underlying subcortical white matter, was investigated. Microscopic examination and special staining were performed. RESULTS: Microscopic examination showed lumenal occlusion by thrombi, and marked endothelial hyperplasia of small meningeal and cortical arterioles. CONCLUSION: These findings suggest that the pathogenesis of this cerebral vasculopathy is noninflammatory and is associated with reactive endothelial hyperplasia and thrombosis of small arterioles.

Antibodies, Anticardiolipin↗

PubMed1992

Systemic and regional acetate kinetics in dogs.

Little is known about the sites of production and uptake of acetate in nonruminants. We placed blood sampling catheters in the femoral artery and in the femoral, portal, hepatic, and renal veins of mongrel dogs (n = 11). The animals were studied in the conscious state 2 wk later during a primed continuous infusion of [1-14C]acetate. Systemic acetate turnover, oxidation, and clearance were determined, as well as regional uptake and release, by measuring 14CO2 excretion as well as plasma concentration and specific activity at the five sampling sites. Results showed systemic acetate turnover was 8.8 +/- 1.9 mumol.kg-1.min-1, approximating 5% of energy expenditure in dogs. Simultaneous uptake and release of acetate was demonstrated in intestine, liver, kidney, and hindlimb. The intestine was the greatest contributor to acetate production, whereas the liver was the most important site of uptake. Plasma acetate oxidation was 77 +/- 4% of turnover. Both systemic clearance (129 +/- 22 ml.kg-1.min-1) and tissue fractional extraction (68-85%) were many times greater than values reported for glucose, free fatty acids, lactate, or amino acids. In conclusion, most tissues simultaneously take up and release acetate in dogs. This may represent a mechanism for interorgan transport of energy, especially under conditions of caloric deprivation.

Acetates↗

PubMed1991

Effects of intravenous methyl palmoxirate on the turnover and oxidation of fatty acids in conscious dogs.

Methyl palmoxirate (MP) is a member of a class of hypoglycemic agents that inhibit fatty acid oxidation in vitro. The studies presented here were undertaken to determine the effects of intravenous (IV) MP on tracer-determined rates of fatty acid oxidation and systemic adipose tissue lipolysis in dogs. MP (40 mg/kg) was administered IV to five mongrel dogs using a primed continuous infusion of [1-14C]palmitate to determine palmitate kinetics. Palmitate concentration and rate of appearance decreased rapidly (from 155 +/- 25 to 47 +/- 6 mumol/L and 2.9 +/- 0.5 to 0.9 +/- 0.2 mumol.kg-1.min-1, respectively, at 15 minutes, both P less than .05). Palmitate oxidation also decreased, from 1.5 +/- 0.4 to 0.3 +/- 0.1 mumol.kg-1.min-1, P less than .05. Oxidative clearance decreased by approximately 50% 90 minutes after MP administration (P less than .05). Fractional oxidation of palmitate also decreased by approximately 40% (P less than .05). Plasma insulin increased from 45 +/- 6 to 240 +/- 93 pmol/L at 15 minutes (P less than .05). Plasma glucose decreased over the course of study by approximately 20% (P less than .05). In summary, MP has a specific inhibitory effect on plasma free fatty acid (FFA) oxidation in dogs, confirming previous in vitro observations in an in vivo model. In addition, it has a potent antilipolytic effect when administered IV, an effect likely mediated by stimulation of insulin secretion. The observation that systemic FFA oxidation was only partially suppressed at this relatively high dose of MP is consistent with previous studies suggesting that MP may exert its major effect in the liver, and may be less potent in extrahepatic tissues.

Animals↗

PubMed1991

How valid are isotopic measurements of fatty acid oxidation?

These studies were performed 1) to compare two isotopic methods (3H2O and 14CO2 production) of measuring free fatty acid (FFA) oxidation; 2) to determine whether isotopic estimates of fatty acid oxidation during hypoinsulinemia are plausible when compared with those obtained using indirect calorimetry; and 3) to examine whether the delay between the exit of [14C]FFA from plasma and the appearance of 14CO2 in breath is accounted for solely by bicarbonate kinetics. Studies in 11 healthy volunteers revealed that [14C]- and [3H]FFA tracers provide similar estimates of FFA turnover and oxidation. Isotopic estimates of fatty acid oxidation were less than those of indirect calorimetry under basal conditions but equaled or exceeded indirect calorimetry estimates after 3 h of acute hypoinsulinemia (somatostatin induced). After stopping tracer infusions, the half-life of plasma [14C]FFA was 3.7 +/- 0.1 min. The half-life of 14CO2 decay from [14C]bicarbonate was 37 +/- 1 min, and the half-life of 14CO2 decay after discontinuation of [14C]FFA infusion was 141 +/- 10 min. Intracellular preoxidative fatty acid pools (possibly triglycerides) most probably account for the marked delay between the exit of FFA tracers from plasma and the appearance of isotopic markers of oxidation in measurable spaces. This delay can result in erroneous estimates of "FFA oxidation." We conclude that tracer measurements of FFA oxidation are invalid under most circumstances.

Adult↗

PubMed1991

Growth hormone and lipids.

It has been known for more than 30 years that growth hormone has a lipolytic properties and growth hormone excess (acromegaly) and growth hormone deficiency have been reported to be associated with abnormalities in serum lipoprotein concentrations. Due to the lipolytic effect of growth hormone, its administration in man has been reported to increase plasma nonesterified fatty acid (NEFA) concentrations. Ketone body production increases during acute growth hormone excess as a result of increased NEFA concentrations; similarly, the increase in serum triglycerides may be explained by an increase in substrate (NEFA) supply to the liver for VLDL production. The effect may be enhanced by a simultaneous decrease of serum lipoprotein lipase activity. The cholesterol-lowering effect of growth hormone administration has not been investigated in detail, specifically, the effect of growth hormone on LDL kinetics is unknown. Growth hormone-excess and growth hormone deficiency have been reported to be associated with increased risk for atherosclerosis; an association with serum lipoprotein changes is likely but evidence for a causal link is yet lacking.

Diabetes Mellitus↗

PubMed1991

Effects of glucagon on free fatty acid metabolism in humans.

To determine whether physiological changes in plasma glucagon concentrations are important in regulating basal adipose tissue lipolysis, FFA flux ([1-14C]palmitate) was measured in response to increases and decreases in plasma glucagon. Eight volunteers with insulin-dependent diabetes mellitus (IDDM) and nine healthy nondiabetic volunteers were studied using the pancreatic clamp technique to control plasma insulin, GH, and glucagon concentrations at desired levels. Palmitate flux at the chosen euglucagonemic hormone infusion rates was similar to baseline values (1.73 +/- 0.12 vs. 1.75 +/- 0.23 and 1.35 +/- 0.18 vs. 1.35 +/- 0.16 mumol/kg.min, respectively, in IDDM and nondiabetic subjects). No significant changes in palmitate flux occurred in response to glucagon withdrawal or mild (nondiabetic volunteers) or high physiological (IDDM volunteers) hyperglucagonemia. Thus, under conditions of normal FFA availability, changes in plasma glucagon concentrations within the physiological range have little or no effect on adipose tissue lipolysis.

Adipose Tissue↗

PubMed1991

Stimulation of lipolysis in humans by physiological hypercortisolemia.

The effect of glucocorticoids on adipose tissue lipolysis in animals and humans is controversial. To determine whether a physiological increase in plasma cortisol, similar to that observed in diabetic ketoacidosis and other stress conditions, stimulates lipolysis, palmitate kinetics were measured in seven nondiabetic volunteers on two occasions with [1-14C]palmitate as a tracer. Subjects received a 6-h infusion of either 2 micrograms.kg-1.min-1 hydrocortisone or saline in random order. On both occasions, a pancreatic clamp (0.12 micrograms.kg-1.min-1 somatostatin, 0.05 mU.kg-1.min-1 insulin, and 3 ng.kg-1.min-1 growth hormone) was used to maintain plasma hormone concentrations at desired levels. Plasma cortisol concentrations increased to approximately 970 nM during cortisol infusion. Palmitate rate of appearance (Ra) and concentration increased by approximately 60% during cortisol infusion but did not change during saline infusion. Increments in palmitate Ra and concentration over the 6-h study were significantly greater during cortisol than saline infusion when compared by area-under-the-curve analysis (152 +/- 52 vs. -48 +/- 23 mumol.kg-1 and 12.2 +/- 4.1 vs. -4.9 +/- 4.1 mmol.min-1.L-1, respectively; P less than 0.02). Plasma glucose concentrations did not change significantly during cortisol (5.0 +/- 0.3 vs. 6.1 +/- 0.6 mM, NS) or saline (4.9 +/- 0.2 vs. 4.9 +/- 0.1 mM, NS) infusion. In nondiabetic volunteers, a 6-h cortisol infusion was associated with a 60% increase in palmitate Ra that did not occur with saline infusion. Thus, physiological hypercortisolemia may contribute to the increased rates of lipolysis observed in humans during stress.

Adult↗

PubMed1990

Metabolism of ketone bodies by skeletal muscle in starvation and uncontrolled diabetes.

Previous studies have suggested that skeletal muscle may be responsible for as much as 25% of ketone body (KB) production in poorly controlled diabetes. In the present studies, acetoacetate (AcAc) and beta-hydroxybutyrate production was quantitated in the canine hindlimb from surgically placed arterial and venous catheters in conscious insulin-withdrawn diabetic (n = 5) and 4-day fasted (n = 7) dogs. A two-pool modeling technique, using simultaneous infusions of 13C acetoacetate and 14C beta-hydroxybutyrate (beta OHB) was employed to quantitate total body and hindlimb KB kinetics. Total KB production was 9.4 and 39.3 mumol.kg-1.min-1 in the fasted and diabetic animals, respectively. Hindlimb KB production was negligible in both groups. The two-pool model estimates of hindlimb KB utilization were similar to the values obtained by an arterial-venous difference calculation. In conclusion, the hindlimb does not contribute to de novo synthesis of KBs in either fasted or diabetic dogs. Since species differences in KB metabolism occur, it is possible that muscle may be a site for KB production in humans.

Animals↗

PubMed1990

Measurement of non-steady-state free fatty acid turnover.

The accuracy of non-steady-state equations for measuring changes in free fatty acid rate of appearance (Ra) is unknown. In the present study, endogenous lipolysis (traced with [14C]-linoleate) was pharmacologically suppressed in six conscious mongrel dogs. A computer-responsive infusion pump was then used to deliver an intravenous oleic acid emulsion in both constant and linear gradient infusion modes. Both non-steady-state equations with various effective volumes of distribution (V) and steady-state equations were used to measure oleate Ra [( 14C]oleate). Endogenous lipolysis did not change during the experiment. When oleate Ra increased in a linear gradient fashion, only non-steady-state equations with a large (150 ml/kg) V resulted in erroneous values (9% overestimate, P less than 0.05). In contrast, when oleate Ra decreased in a similar fashion, steady-state and standard non-steady-state equations (V = plasma volume = 50 ml/kg) overestimated total oleate Ra (18 and 7%, P less than 0.001 and P less than 0.05, respectively). Overall, non-steady-state equations with an effective V of 90 ml/kg (1.8 x plasma volume) allowed the most accurate estimates of oleate Ra.

Animals↗

PubMed1990

Validation of two-pool model for in vivo ketone body kinetics.

Previous studies have indicated that simultaneous infusions of two ketone body tracers ([13C]acetoacetate and [14C]beta-hydroxybutyrate) provide accurate estimates of exogenous ketone body inflow when an open two-pool model is employed. In the present studies, net hepatic ketone body production was determined from surgically placed arterial, portal venous, and hepatic venous catheters in conscious diabetic (n = 6) and 4-day fasted (n = 7) dogs. [13C]acetoacetate and [14C]beta-hydroxybutyrate were infused simultaneously, and ketone body production was calculated from either acetoacetate (AcAc) single-isotope data, beta-hydroxybutyrate (beta-OHB) single-isotope data, the sum of individual fluxes, or the two-pool model. In fasted animals, both the AcAc single-isotope calculation and the sum of individual fluxes overestimated net hepatic production by approximately 50% (P less than 0.05), whereas the beta-OHB single-isotope calculation and the two-pool model gave accurate estimates. In the diabetic animals, the beta-OHB single-isotope calculation underestimated net hepatic production by approximately 30% (P less than 0.05). The sum of individual fluxes overestimated net hepatic production by approximately 46% (P less than 0.05), whereas both the AcAc single-isotope calculation and the two-pool model gave accurate estimates. In conclusion, single-isotope methods give erroneous estimates of net hepatic production of ketone bodies. In contrast, a two-pool model provided an accurate estimate of net hepatic production and thus appears to be suitable for determination of ketone body kinetics in humans.

3-Hydroxybutyric Acid↗

PubMed1990

Lack of effect of hyperglycemia on lipolysis in humans.

Controversy exists regarding whether plasma glucose concentrations are independently involved in the regulation of adipose tissue lipolysis. In the present study, six subjects with insulin-dependent diabetes and six nondiabetic volunteers were studied during infusion of somatostatin, growth hormone, and insulin at rates designed to maintain basal rates of lipolysis, which was traced using a constant infusion of [1-14C]palmitate. A euglycemic (approximately 5 mmol/l) clamp was performed for 3 h, followed by 3 h of hyperglycemia (approximately 9 and approximately 11 mmol/l in nondiabetic and diabetic subjects, respectively). Ten nondiabetic subjects were studied during 6 h of euglycemia to exclude time-dependent changes in lipolysis. The results showed that palmitate concentrations did not change between euglycemia and hyperglycemia in either group [118 +/- 10 vs. 132 +/- 14 mumol/l and 145 +/- 21 vs. 134 +/- 15 mumol/l in nondiabetic and diabetic subjects, respectively; both P = not significant (NS)]. Similarly, palmitate rate of appearance (Ra) did not change during hyperglycemia (1.0 +/- 0.1 and 1.7 +/- 0.4 mumol.kg-1.min-1 in nondiabetic and diabetic subjects, respectively) compared with euglycemia (1.0 +/- 0.1 and 1.6 +/- 0.4 mumol.kg-1.min-1 in nondiabetic and diabetic subjects, respectively; P = NS). Palmitate concentrations and Ra did not change during 6 h of euglycemia in nondiabetic volunteers. Thus hyperglycemia per se has no effect on free fatty acid turnover. Changes in lipolysis that occur coincident with hyperglycemia are probably due to changes in other circulating substrates or hormones known to affect lipolysis.

Adult↗

PubMed1990

Differences between prebreakfast and late afternoon glycemic responses to exercise in IDDM patients.

Little information is available regarding the optimal timing of exercise in insulin-dependent diabetes mellitus (IDDM) patients. In this study, six IDDM patients receiving ultralente-based intensive insulin therapy were studied during 30 min of exercise (approximately 60% VO2max), before breakfast, and at 1600. On two other occasions, they were studied at rest. Plasma glucose increased from 6.7 +/- 0.4 to 9.1 +/- 0.4 mM during morning exercise (P less than 0.01). In contrast, mean plasma glucose did not change during afternoon exercise (delta = 0.3 +/- 0.5 mM, NS); however, there was a 0.3- to 1.0-mM decrease in three subjects. The observed difference in the glycemic response to exercise could not be explained on the basis of changes in plasma glucagon, growth hormone, norepinephrine, or epinephrine. Plasma cortisol was higher (P less than 0.02) in the morning than in the afternoon, and plasma free-insulin concentrations were lower (P less than 0.05). These data indicate that the risk of exercise-induced hypoglycemia is lowest before breakfast. The reason for the divergent glycemic responses to exercise is not entirely clear but may be related to the observed differences in free-insulin concentrations. Because of the lower risk of hypoglycemia, our results suggest prebreakfast exercise may be preferable for some IDDM patients receiving intensive insulin therapy. Whether these findings are relevant to patients receiving other types of insulin therapy will require further investigation.

Adult↗

PubMed1989

Calcium, magnesium, and phosphorus metabolism in dogs given intravenous triacetin.

Previous studies suggested that acetate in parenteral solutions may adversely affect mineral metabolism by causing sequestration of inorganic phosphate and calcium in the liver. In this study, triacetin, a short-chain triglyceride of acetate and a potential parenteral nutrient, was infused for 3 h at an isocaloric rate in mongrel dogs (n = 6) to test its effects on serum phosphorus, calcium, and magnesium metabolism. There was no change in serum P or Ca. The serum Mg concentration decreased from 0.7 +/- 0.03 to 0.57 +/- 0.03 mmol/L (p less than 0.001) by 90 min and remained at this level for the remainder of the study. The triacetin infusion did not influence fractional urinary Mg excretion; thus, the decrease in serum Mg was likely because of an increase in cellular transport of this cation. A short-chain triglyceride administered to dogs at a rate approximating resting energy expenditure has no demonstrable adverse effects on mineral metabolism.

Acetates↗

PubMed1989

L-carnitine: effect of intravenous administration on fuel homeostasis in normal subjects and home-parenteral-nutrition patients with low plasma carnitine concentrations.

We studied the effects of intravenous L-carnitine on the metabolism of fatty acids, ketone bodies, glucose, and branched-chain amino acids in four normal volunteers and four patients on long-term home parenteral nutrition (HPN) with low plasma carnitine concentrations. Substrate kinetics were determined by use of [1-14C]palmitate, [3,4-13C2]-acetoacetate, [6,6-2H2]glucose, and [5,5,5-2H3]leucine before and during a 3-h intravenous infusion of L-carnitine. HPN patients were restudied after 1 mo of nightly intravenous carnitine administration. HPN patients tolerated the short-term fast well, exhibiting neither hypoglycemia nor hypoketonemia. Intravenous carnitine had no effect on rates of fatty acid oxidation, ketone body production, glucose production, or leucine kinetics in either group. Routine addition of carnitine to the HPN regimen does not appear to be necessary. The failure of L-carnitine administration to have discernable effects on intermediary metabolism in normal volunteers casts doubt on its role in the treatment of a variety of medical conditions.

Acetoacetates↗

PubMed1989

Influence of body fat distribution on free fatty acid metabolism in obesity.

UNLABELLED: In order to determine whether differences in body fat distribution result in specific abnormalities of free fatty acid (FFA) metabolism, palmitate turnover, a measure of systemic adipose tissue lipolysis, was measured in 10 women with upper body obesity, 9 women with lower body obesity, and 8 nonobese women under overnight postabsorptive (basal), epinephrine stimulated and insulin suppressed conditions. RESULTS: Upper body obese women had greater (P less than 0.005) basal palmitate turnover than lower body obese or nonobese women (2.8 +/- 0.2 vs. 2.1 +/- 0.2 vs. 1.8 +/- 0.2 mumol.kg lean body mass (LBM)-1.min-1, respectively), but a reduced (P less than 0.05) net lipolytic response to epinephrine (59 +/- 7 vs. 79 +/- 5 vs. 81 +/- 7 mumol palmitate/kg LBM, respectively). Both types of obesity were associated with impaired suppression of FFA turnover in response to euglycemic hyperinsulinemia compared to nonobese women (P less than 0.005). These specific differences in FFA metabolism may reflect adipocyte heterogeneity, which may in turn affect the metabolic aberrations associated with different types of obesity. These findings emphasize the need to characterize obese subjects before studies.

Adipose Tissue↗

PubMed1989

Insulin regulation of lipolysis in nondiabetic and IDDM subjects.

To determine whether insulin regulation of lipolysis is abnormal in subjects with poorly controlled insulin-dependent diabetes mellitus (IDDM), free-fatty acid flux ([1-14C]palmitate) was measured under conditions ranging from complete insulin withdrawal to hyperinsulinemia. Seven nondiabetic and seven IDDM subjects were studied with the pancreatic clamp technique to control plasma insulin, growth hormone, and glucagon concentrations at the desired levels. Preliminary studies were performed to validate the experimental design. The palmitate flux response to insulin withdrawal (2.5 +/- 0.2 vs. 2.5 +/- 0.2 mumol.kg-1.min-1) and maximally antilipolytic insulin concentrations (0.17 +/- 0.02 vs. 0.23 +/- 0.03 mumol.kg-1.min-1) were not different in nondiabetic and IDDM subjects, respectively. In contrast, IDDM subjects required significantly greater plasma free-insulin concentrations to result in equivalent suppression of palmitate flux compared with nondiabetic subjects. Lipolysis was found to be very sensitive to insulin in nondiabetic humans, with half-maximal suppression occurring at plasma free-insulin concentrations of approximately 12 pM (less than 2 microU/ml). We conclude that adipose tissue lipolysis is normally exquisitely sensitive to insulin and that sensitivity, but not responsiveness to insulin, is impaired in poorly controlled IDDM.

Adult↗

PubMed1989

Effects of acute metabolic acidosis and alkalosis on leucine metabolism in conscious dogs.

To determine the effects of acute metabolic acidosis and alkalosis on leucine metabolism in vivo, mongrel dogs were infused with [1-14C]leucine for 8 h, along with NaCl, HCI, or NaHCO3 over the last 4 h. Arterial pH did not change from the basal value during NaCl infusion but decreased (P less than .01) and increased (P less than .01) during HCl and NaHCO3 infusions, respectively. Total leucine carbon entry did not change from the basal value during saline infusion but increased (P less than .01) with acidosis and decreased (P less than .05) with alkalosis. Compared with saline controls, acidosis increased (P less than .01) leucine oxidation. During alkalosis decreased (P less than .01) leucine oxidation. During acidosis, total plasma essential and nonessential amino acid concentrations increased (P less than .05), whereas during alkalosis, total plasma essential and nonessential amino acid concentrations decreased (P less than .05). These studies suggest that acute alterations in arterial pH may affect the regulation of protein metabolism in vivo and must be considered in the interpretation of results from experiments in which alterations of acid-base homeostasis may have occurred.

3-Hydroxybutyric Acid↗

PubMed1988

L-carnitine therapy in home parenteral nutrition patients with abnormal liver tests and low plasma carnitine concentrations.

Persistent abnormalities of liver function tests occur in approximately 15% of home parenteral nutrition (HPN) patients and are associated with steatosis, steatohepatitis, and, rarely, fibrosis or cirrhosis. Approximately one-third of patients with gut failure on long-term HPN have low total and free plasma carnitine concentrations, and it has been suggested that a deficiency of L-carnitine may be responsible for the steatosis and steatohepatitis in HPN patients. To determine whether administration of L-carnitine is capable of reversing steatosis in HPN patients, 4 adult women on HPN for a mean of 53 mo (range 21-80 mo) were studied before and after 1 mo of intravenous L-carnitine supplementation (1 g/day). All patients had abnormalities in standard liver function tests and low total and free plasma carnitine values. The mean total and free plasma carnitine concentrations and the mean total hepatic carnitine concentration were reduced before supplementation and rose to normal values after treatment (27.4 +/- 2.3 to 35.5 +/- 3.1 nmol/ml, 19.4 +/- 2.8 to 25.7 +/- 2.5 nmol/ml, and 3.5 +/- 0.65 to 6.5 +/- 1.2 nmol/mg of noncollagen protein, respectively). However, there were no significant changes in mean serum aspartate aminotransferase and alkaline phosphatase levels (65 +/- 21 vs. 54 +/- 12 IU and 429 +/- 220 vs. 472 +/- 224 IU, respectively), plasma free fatty acids, plasma triglycerides, hepatic free fatty acid and triglyceride concentrations, or the grade of hepatic steatosis on light microscopy. These results suggest that carnitine deficiency is not a major cause of steatosis and steatohepatitis in patients receiving HPN.

Adult↗