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Biomedical subjects

J M Miles

Publications and source records attributed to J M Miles.

At least 37 records · Page 2Linked to original sources
PubMed1996

Effects of pulsatile delivery of basal growth hormone on lipolysis in humans.

Growth hormone (GH) excess stimulates lipolysis, but its role in the hierarchy of lipolysis regulation is not clear. We studied whether pulsatile GH delivery is required for its lipolytic effect. With use of the pancreatic clamp, eight subjects were randomized to three protocols: protocol A, GH deficiency; protocol B, constant GH infusion; protocol C, pulsatile GH delivery (same total GH as protocol B). Pulsatile GH was given in four consecutive bursts, with symmetric peak width (60 min), amplitude of 10.7 (men) and 15 (women) ng.kg-1.min-1, and peak width at half-height of 15 min. Palmitate flux (PF) was measured at baseline and in the last hour of each study with [3H]palmitate. GH (ng/ml) decreased from approximately 3.5 to 2.0 in protocol A (P < 0.05), it remained between 3.2 and 4.0 in protocol B (P < 0.05), but in protocol C it fluctuated between approximately 2.7 and approximately 5.0 (P < 0.05). Palmitate concentration (in mumol/l) was approximately 150 at baseline; it did not change in protocols A and B (137 +/- 17 and 136 +/- 12, respectively) but increased to 198 +/- 16 (P < 0.05) in protocol C. PF (mumol.kg-1.min-1) was approximately 2.7 at baseline and did not change in protocol B (2.4 +/- 0.2); it decreased to 2.2 +/- 0.1 in protocol A (P < 0.05); it increased to 3.1 +/- 0.3 (P < 0.05) in protocol C. These experiments provide evidence that pulsatile secretion of GH is required for its lipolytic effect.

Adult↗
PubMed1994

Suramin-induced weakness from hypophosphatemia and mitochondrial myopathy. Association of suramin with mitochondrial toxicity in humans.

BACKGROUND: Suramin is an antiparasitic drug being evaluated as an antitumor compound. Suramin therapy commonly causes weakness and is known to cause neuropathy. Two potential causes of suramin-induced muscular weakness are described. METHODS: Suramin was administered to 15 patients with advanced cancer as part of a Phase I study. Weekly dosing was adjusted to achieve mean plasma concentrations of 210 micrograms/ml. RESULTS: Serum phosphate levels fell significantly (P < 0.0001) in all 15 patients on the 42nd day of treatment from a pretreatment average of 4.0 mg/dl (standard deviation [SD] +/- 0.37) to 3.0 mg/dl (SD +/- 0.20). Absolute hypophosphatemia developed in two patients with more prolonged suramin treatment due to Fanconi's syndrome. The patient who received the largest amount of suramin (19.2 g over 14 weeks) had severe proximal muscle weakness despite 6 weeks of effective phosphate repletion. A muscle biopsy was performed, which demonstrated markedly decreased cytochrome c oxidase activity by muscle histochemistry and biochemistry. Electron microscopy revealed subsarcolemmal collections of abnormal mitochondria. This mitochondrial myopathy resolved clinically 7 weeks after discontinuing suramin. CONCLUSIONS: This report indicates that suramin is associated with hypophosphatemia of Fanconi's syndrome and a mitochondrial myopathy. The clinical combination of mitochondrial myopathy and Fanconi's syndrome is similar to descriptions of congenital mitochondrial cytochrome c oxidase deficiency of de Toni-Fanconi-Debré syndrome. These findings in humans correlate with the authors' in vitro observations that suramin causes toxic mitochondrial changes, indicating a mechanism of suramin's toxicity and possibly its antitumor effect.

Electron Transport Complex IV↗
PubMed1994

Insulin regulation of renal glucose metabolism in conscious dogs.

Previous studies indicating that postabsorptive renal glucose production is negligible used the net balance technique, which cannot partition simultaneous renal glucose production and glucose uptake. 10 d after surgical placement of sampling catheters in the left renal vein and femoral artery and a nonobstructive infusion catheter in the left renal artery of dogs, systemic and renal glucose and glycerol kinetics were measured with peripheral infusions of [3-3H]glucose and [2-14C]glycerol. After baseline measurements, animals received a 2-h intrarenal infusion of either insulin (n = 6) or saline (n = 6). Left renal vein insulin concentration increased from 41 +/- 8 to 92 +/- 23 pmol/l (P < 0.05) in the insulin group, but there was no change in either arterial insulin, (approximately 50 pmol/l), glucose concentrations (approximately 5.4 mmol/l), or glucose appearance (approximately 18 mumol.kg-1.min-1). Left renal glucose uptake increased from 3.1 +/- 0.4 to 5.4 +/- 1.4 mumol.kg-1.min-1 (P < 0.01) while left renal glucose production decreased from 2.6 +/- 0.9 to 0.7 +/- 0.5 mumol.kg-1.min-1 (P < 0.01) during insulin infusion. Renal gluconeogenesis from glycerol decreased from 0.23 +/- 0.06 to 0.17 +/- 0.04 mumol.kg-1.min-1 (P < 0.05) during insulin infusion. These results indicate that renal glucose production and utilization account for approximately 30% of glucose turnover in postabsorptive dogs. Physiological hyperinsulinemia suppresses renal glucose production and stimulates renal glucose uptake by approximately 75%. We conclude that the kidney makes a major contribution to systemic glucose metabolism in the postabsorptive state.

Animals↗
PubMed1994

Glucose content of tracheal aspirates: implications for the detection of tube feeding aspiration.

OBJECTIVE: To determine, using a sensitive glucose assay, whether monitoring of tracheal aspirate glucose concentration could serve as a marker of aspiration of enteral feedings. DESIGN: Prospective, controlled trial. SETTING: Intensive care units of a tertiary care hospital. PATIENTS: Fifteen enterally fed and 15 nonenterally fed, tracheally intubated patients who had normal lung fields on a routine chest radiograph. INTERVENTIONS: Patients with endotracheal tubes undergoing routine tracheal suctioning had tracheal secretions collected three times per day with a minimum of 4 hrs between samples for up to 5 days. Daily chest radiographs were reviewed for evidence of the development of pneumonitis using defined criteria. MEASUREMENTS AND MAIN RESULTS: Glucose concentrations in five commonly used commercial feeding formulas, as well as in the medications patients were receiving enterally or as an oral wash, were measured. Tracheal secretion glucose concentrations were 66 +/- 54 (SD) mg/dL (3.7 +/- 3.0 mmol/L) and 105 +/- 70 mg/dL (5.8 +/- 3.9 mmol/L) in the enterally fed and nonenterally fed patients, respectively (p = NS). Of the medications administered, the majority contained negligible glucose, but ten had > 3 mg/dose of glucose. However, there was no correlation between administration of these medications and the tracheal glucose concentrations. Tracheal glucose concentrations were similar in patients who received medications containing glucose and patients who received either no medications or medications with negligible glucose content. A small but significant correlation between blood glucose and tracheal secretion glucose concentrations (r2 = .15, p < .05) was observed. None of the patients developed aspiration pneumonitis. Glucose concentrations in widely used commercial formulas (44 to 202 mg/dL; 2.4 to 11.2 mmol/L) overlapped considerably with glucose concentrations in tracheal secretions in the absence of aspiration and were for the most part within 2 SD of mean values in tracheal secretions. CONCLUSIONS: Tracheal secretions contain high glucose concentrations, both in enterally fed patients without evidence of aspiration pneumonitis and in nonenterally fed patients. The concentration of glucose in tracheal secretions appears to be determined, in part, by ambient extracellular glucose concentrations. We conclude that measurement of glucose in tracheal secretions is unlikely to be useful in monitoring for tube feeding aspiration in tracheally intubated, enterally fed patients.

Aged↗
PubMed1994

In vivo regulation of lipolysis in humans.

Fatty acids are important oxidative fuel for liver, kidney, skeletal muscle, and myocardium. There has been much interest in the role of fatty acids in the pathogenesis of non-insulin-dependent diabetes because they compete with glucose for oxygen and inhibit whole body glucose disposal via the 'Randle cycle,' Control of lipolysis in adipose tissue determines systemic fatty acid supply. A wide range of hormones and other substances have been recognized as regulators of lipolysis, but insulin and catecholamines appear to be the most important. The regulation of lipolysis, in most circumstances, provides a supply of lipid fuel exceeding the rate of lipid oxidation, requiring reesterification to triglyceride of surplus circulating free fatty acids. Thus, free fatty acid supply is usually not matched to the demand for lipid oxidation, and there is no known mechanism for accurately sensing such demand. This lax regulation may be disadvantageous in conditions such as aging, stress, obesity, and diabetes, where the antilipolytic effect of insulin is impaired and lipolysis is therefore increased. In these conditions, the surfeit of fatty acid may impair glucoregulation. In addition, the excess lipolysis may induce hypertriglyceridemia (via increased very low density lipoprotein production) and thus contribute to atherogenesis. Considerable additional research is needed in order to fully understand both normal lipolytic regulation and the abnormalities of lipolysis which accompany pathological conditions.

Adipose Tissue↗
PubMed1993

Metabolism of triacetin-derived acetate in dogs.

Triacetin is a water-soluble triglyceride that may have a role as a parenteral nutrient. In the present study triacetin was administered intravenously to mongrel dogs (n = 10) 2 wk after surgical placement of blood-sampling catheters in the aorta and in the portal, hepatic, renal, and femoral veins. [1-14C]Acetate was infused to allow quantification of organ uptake of acetate as well as systemic turnover and oxidation. Systemic acetate turnover accounted for approximately 70% of triacetin-derived acetate, assuming complete hydrolysis of the triglyceride. Approximately 80% of systemic acetate uptake was rapidly oxidized. Significant acetate uptake was demonstrated in all tissues (liver, 559 +/- 68; intestine, 342 +/- 23; hindlimb, 89 +/- 7; and kidney, 330 +/- 37 mumol/min). In conclusion, during intravenous administration in dogs, the majority of infused triacetin undergoes intravascular hydrolysis, and the majority of the resulting acetate is oxidized. Thus, energy in the form of short-chain fatty acids can be delivered to a resting gut via intravenous infusion of a short-chain triglyceride.

Acetates↗
PubMed1993

Effect of parenteral administration of short-chain triglycerides on leucine metabolism.

The present studies investigated the effects of intravenous administration of the short-chain triglyceride triacetin on leucine metabolism in dogs. Animals received infusions of triacetin at 1.0 x estimated resting energy expenditure (REE), hyperenergetic triacetin at 1.5 x REE, glycerol, or saline during infusion of [1-14C]leucine. During both triacetin infusions, plasma alpha-ketoisocaproate concentrations increased (P < 0.05). During triacetin infusion at 1.5 REE, the plasma leucine concentration decreased (P < 0.05) and leucine rate of appearance decreased by approximately 19% (P < 0.05); this was significantly greater than the changes that occurred during triacetin at 1.0 x REE and glycerol (P < 0.05). There was no difference in leucine oxidation between the dogs given triacetin at 1.0 x REE and control groups, whereas leucine oxidation decreased by 53% during triacetin infusion at 1.5 x REE (P < 0.05). Nonoxidative leucine disappearance, an indicator of protein synthesis, did not change in any of the studies. These results indicate that triacetin has effects on leucine metabolism similar to those previously reported with long-chain triglyceride emulsions. Because of its water solubility, lack of toxicity, and favorable effects on protein metabolism, further studies are warranted regarding the use of triacetin as a parenteral nutrient.

Analysis of Variance↗
PubMed1993

Effects of recombinant human IGF-I on glucose and leucine kinetics in men.

To examine the effects of recombinant human (rh) insulin-like growth factor I (IGF-I), insulin, and saline on metabolic parameters, we studied 20 young nonobese healthy men. Euglycemic clamps with 240-min IGF-I infusions at two doses (49 and 33 pmol.kg-1 x min-1, n = 8 and 12 subjects) were performed and compared with hyperinsulinemic-euglycemic clamps (2.25 pmol.kg-1 x min-1, n = 9). Leucine and glucose kinetics were examined with L-[1-13C]leucine and [3-3H]glucose. Glucose rate of appearance (Ra) declined equivalently in the 49 pmol.kg-1.min-1 IGF-I and insulin clamps but remained at basal levels during the 33 pmol.kg-1 x min-1 IGF-I infusions. In contrast, Rd of glucose was increased by 176% in the 49 pmol.kg-1 x min-1 IGF-I and 78% in the 33 pmol.kg-1 x min-1 IGF-I infusions. Furthermore, to prevent hypoglycemia after the termination of both rhIGF-I infusions, it was necessary to infuse glucose for an additional 2-20 h. Ra of leucine was suppressed significantly by both IGF-I and insulin, whereas leucine oxidation was not affected by either hormone. Therefore, the rate of disappearance of leucine expressed as the difference between Ra and oxidation rates was significantly reduced in all clamps. In addition, IGF-I significantly suppressed beta-cell secretion without affecting the other glucoregulatory hormones. In contrast to insulin, IGF-I had no apparent effect on lipolysis, as measured by changes in nonesterified fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Lipid fuel metabolism in health and disease.

Rates of adipose tissue lipolysis are increased in critically ill patients, thus increasing the systemic supply of free fatty acids. This increase in the availability of free fatty acids is probably mediated by various factors including increases in counterregulatory hormones and tumor necrosis factor alpha. The cytokines tumor necrosis factor and interleukin-1 also promote de novo lipogenesis in the liver and may be responsible for impaired triglyceride removal in peripheral tissues; these effects together contribute to the hypertriglyceridemia often seen in septic states. This hypertriglyceridemia may have a teleologic basis, because triglyceride-rich lipoproteins have been shown to bind and inactivate endotoxin. When present in excess, free fatty acids may be responsible for tissue injury in the cold-stored liver allograft, in ischemic-reperfusion cardiac injury, and in ischemic brain injury. Hypoketonemia commonly occurs in septic states and may be due to the combination of a defect in hepatic ketogenesis and accelerated ketone body uptake by peripheral tissues. Both tumor necrosis factor and interleukin-1 have a hypoketonemic effect in animals. Whether ketone bodies have significant protein-sparing properties remains controversial.

Adipose Tissue↗
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↗