Effect of clofibrate on arginine-stimulated glucagon and insulin secretion in man

Insulin and glucagon have been reported to have opposing effects upon the mechanisms regulating serum triglyceride concentration. Glucagon in excess of insulin will lower serum lipids in man. In the present studies, we have examined the possibility that a change in glucagon and insulin regulation might contribute to the hypolipemic action of the drug clofibrate. Control insulin and glucagon secretion were evaluated in 24 normal subjects by intravenous arginine infusion, which resulted in a prompt rise in both serum immunoreactive insulin and glucagon concentration. During the maximum rise in concentration of these hormones, plasma triglyceride concentration was acutely reduced from basal levels of $\text{104 ± 6}\text{mg}\text{100}\text{ml}$ to $\text{75 ± 5}\text{mg}\text{100}\text{ml}$ (p ≤ 0.001). Following 7 days of clofibrate therapy, basal plasma triglyceride concentration attained a new mean level of $\text{78 ± 5}\text{mg}\text{100}\text{ml}$, while basal insulin and glucagon concentrations remained unchanged. However, arginine infusion now resulted in a reduction of the insulin secretory response to 56% of the preclofibrate studies with an associated normal glucagon secretory response. Serum triglyceride concentration was further reduced during arginine infusion to $\text{46 ± 3}\text{mg}\text{100}\text{ml}$, demonstrating this minimum level as maximum plasma glucagon levels were attained, representing an excess of this hormone relative to the reduced insulin concentration. These observations are consistent with an effect of clofibrate on the hormonal regulation of triglyceride physiology in man. Glucose tolerance was unimpaired by clofibrate therapy in these normal subjects, in spite of an apparent reduction in glucose-stimulated insulin secretion.     

Effect of acute uremia on triglyceride kinetics in the rat

Plasma triglyceride (TG) levesl were elevated 24 hr after the production of acute uremia in rats. The effect of acute uremia on TG production rate was estimated by determining the rate of TG accumulation following Triton WR 1339 inhibition of lipoprotein removal, by measuring hepatic TG secretion rate during in situ liver perfusion, and by quantifying hepatocyte very low density lipoprotein content with the electron microscope. The results of all three of these approaches indicated that TG synthesis and secretion were decreased in acute uremia, suggesting that the associated increase in plasma TG levels had to result from a removal defect. This hypothesis was tested directly by injecting pre-labeled very low density lipoprotein TG into acutely uremic and control rats, and measuring its rate of disappearance from plasma. The t1/2 of removal in acutely uremic rats was found to be approximately twice that of control, confirming the hypothesis that the rise in plasma TG levels in acute uremia is due to a defect in removal of TG from plasma.     

The effects of hypothyroidism,age, and nutrition on LDL catabolism in the rat

To determine the effects of thyroid deficiency on LDL metabolism and degradation, the plasma clearance of ¹²⁵I-LDL was determined in normal rats and rats fed chow containing propylthiouracil (PTU) 0.1% w/w and KI $\text{0.16 gm}\text{1}$ in the drinking water. After two weeks, T₄ levels were significantly lower in the PTU groups compared to controls and plasma LDL cholesterol increased from $\text{17.5 ± 1.2}{}^1\text{1}\text{Results given as mean ± SEM.}\text{mg}\text{100 ml}$ in controls to $\text{32.5 ± 3.0 mg}\text{100 ml}$ in the hypothyroid animals. Human ¹²⁵I-LDL (d 1.019–1.045) was injected intravenously under light anesthesia and tail tip blood was sampled repeatedly over 33–100 hr periods. In a semi-log plot the curve of ¹²⁵I-LDL clearance described a log-linear profile suggesting a two-pool model. Compartmental analysis according to Matthews revealed two exponential curves, an initial rapid phase representing equilibration with an extravascular compartment (exponential 2), and a later slow phase of irreversible degradation (exponential 1). There was a marked delay in clearance of ¹²⁵I-LDL in the hypothyroid rats as the slope of exponential 1 was 0.043 ± 0.001 ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{= 16.2 hr}$) versus 0.065 ± 0.002 ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{= 10.7 hr}$) in controls (P < 0.01). Additionally, the fractional catabolic rate of LDL was reduced (P < 0.01) from 0.079 ± 0.003 in normals to 0.054 ± 0.002 (pools/hr) in hypothyroid rats. The delay in LDL clearance which occurred in hypothyroidism occurred in both growing and mature rats. Pair-feeding excluded any artifact due to the weight loss commonly seen in hypothyroid rats. LDL clearance was age-dependent as the slope of exponential 1 was significantly lower in mature (521 ± 3 gms) as compared to growing (256 ± 12 gm) rats. Experiments performed after a 24 hr fast showed that acute starvation did not affect LDL clearance. The data suggest that the hypercholesterolemia of hypothyroidism is at least partly secondary to an acquired catabolic defect of LDL, and implies that the LDL catabolic pathway(s) is influenced by thyroid hormones.     

Age-related changes in very low density lipoprotein metabolism in normal rats

Plasma triglyceride (TG) concentrations rise with age, and we have carried out studies of very low density lipoprotein (VLDL) kinetics in the rat in an effort to define the cause of this phenomenon. Efficiency of VLDL-TG secretion by perfused rat liver decreases as rats age from $\text{1}\text{1}\text{2}\text{–12}\text{mo}$. However, this is compensated for by an increase in liver weight, and VLDL-TG secretion per perfused liver does not change with age. In contrast, total VLDL-TG secretion by the intact rat increases significantly as rats grow from $\text{1}\text{1}\text{2}\text{–12}\text{mo}$ of age, and this increase is proportionate to the age-related increase in liver weight. The ability of the older rat to maintain VLDL-TG secretion proportionate to liver weight is most likely due to the concomitant rise in plasma free fatty acid concentration that occurs with age. However, the efficiency with which VLDL-TG is removed from plasma is not maintained as rats age. Consequently, the age-related rise in plasma TG concentration is due to an increase in VLDL-TG secretion proportionate to secretory mass, accompanied by a relative decline in efficiency of VLDL-TG removal from plasma.     

Effect of single large doses of oral calcium on serum calcium levels in the young and the elderly

Single large oral doses of calcium carbonate containing 4 g elementary calcium caused a mean peak rise in serum Ca of $\text{1.47}\text{mg}\text{100}\text{ml}$ at 2 hr in six young volunteers (mean age, 28 yr) in the fasting state. A 4-g load taken with breakfast produced a higher mean peak value ($\text{11.77}\text{mg}\text{100}\text{ml}$), with hypercalcemia sustained for 2 hr. In six healthy elderly subjects (mean age, 81 yr) the mean rise in serum calcium after 4 g of oral calcium was $\text{1.26}\text{mg}\text{100}\text{ml}$. One week after pretreatment with an injection of 400,000 U of calciferol the fasting level was $\text{1}\text{mg}\text{100}\text{ml}$ higher and the mean rise after loading was $\text{1.7}\text{mg}\text{100}\text{ml}$, with hypercalcemia sustained for 3 hr. In another group of five elderly subjects a 4-g calcium load produced a rise in serum calcium of only $\text{0.69}\text{mg}\text{100}\text{ml}$, but after 1 wk of pretreatment with 5000 units calciferol daily, the same load led to a rise of $\text{1.39}\text{mg}\text{100}\text{ml}$. We hope that orally induced hypercalcemia in conjunction with physiologic calciferol supplementation may be of benefit in the treatment of osteoporosis comparable to that obtained by calcium infusions. We also suggest that some elderly people even in sunny climates may suffer from subclinical vitamin D deficiency. These postulates need further investigation.     

Alcoholic cardiomyopathy. II. The inhibition of cardiac microsomal protein synthesis by acetaldehyde

Previous studies in this laboratory had shown that while ethanol at levels of $\text{200 to 300 mg}\text{100 ml}$ had no effect on cardiac protein synthesis, acetaldehyde ($\text{3.5 mg}\text{100 ml}$ or 0.8 mm) markedly inhibited cardiac protein synthesis in the intact heart in vitro. In order to localize further the action of acetaldehyde and to separate the protein synthetic effects from contractile function, studies on cell free systems with cardiac muscle microsomes were carried out at concentrations of acetaldehyde seen in humans after moderate ethanol ingestion.There was a significant reduction of microsomal protein synthesis even at these levels of acetaldehyde. Thus, with an acetaldehyde concentration of $\text{0.53 mg}\text{100 ml}$ (0.12 mm) the protein synthesis was reduced to 52 ± 5.3% of the control microsomes. With acetaldehyde concentrations of 0.13 to $\text{0.26 mg}\text{100 ml}$ (0.03 to 0.06 mm), the microsomal protein synthesis was 65 ± 8.6% of the controls. The differences from the controls were statistically significant. These data show that at concentrations seen in humans following ethanol ingestion, acetaldehyde interferes with normal cardiac protein synthesis independent of contractile action and thus may play a role in the ultimate development of ethanolic cardiomyopathy.     

Aspects of glucose homeostasis in uremia as assessed by the hyperinsulinemic euglycemic clamp technique

A three-step hyperinsulinemic euglycemic clamp was performed in 14 nondialyzed uremic and ten age-matched healthy subjects. Nine of the uremics were restudied for a mean of 42 days (range, 21 to 88 days) after initiation of dialysis therapy. Insulin was infused at the following three rates: 0.5 mU·kg^?1·min^?1, 2.0 mU·kg^?1·min^?1, and 4.0 mU·kg^?1·min^?1. Each dose was given for 120 minutes. Glucose uptake during the last 30 minutes of each clamp were consistently lower in uremic patients pre-dialysis than in controls (2.3 ± 0.3 v 6.6 ± 0.8 mg·kg^?1·min, 7.8 ± 0.6 v 13.2 ± 1.1mg·kg^?1·min^?1 and 9.6 ± 0.7 v 15.5 ± 1.0 mg·kg^?1·min^?1, all P < 0.001). Serum insulin levels wre similar in the two groups, and blood glucose values during steady state were maintained at 79 ± 2, 77 ± 2, and $\text{77 ± 2 mg}\text{100 mL}$ in uremic subjects and at 72 ± 3, 73 ± 2, and $\text{75 ± 2 mg}\text{100 mL}$ in healthy subjects. The insulin levels required to elicit half-maximal biological response in uremics (82 ± 5 μU/mL) were markedly higher than in controls (54 ± 8 μU/mL, P < 0.01). Dialysis therapy enhanced maximal glucose disposal (8.7 ± 0.9 v 11.4 ± 0.8 mg·kg^?1·min^?1, P < 0.01), while insulin concentrations required to achieve half-maximal glucose metabolism were virtually identical in the two situations (86 ± 7 μU/mL and 85 ± 11 μU/mL). No difference in I¹²⁵ insulin binding to monocytes was observed in the uremic patients and a separate control group. In contrast to the impaired glucose uptake in uremia the insulin effect on lipolysis and ketogenesis was normal as estimated by measurement of serum NEFA, blood glycerol and 3-hydroxybutyrate. The response of the gluconeogenic precursors, lactate and alanine, was also similar in the uremic and control subjects. The impaired peripheral glucose uptake in nondialysed uremics could not be ascribed to different levels of cortisol, catecholamines, or NEFA, although a possible participation of growth hormone could not be ruled out. In conclusion, severely impaired peripheral glucose uptake is present in nondialysed uremic subjects. Short-term dialysis therapy (hemodialysis or continuous ambulatory peritoneal dialysis; CAPD) tends to abolish this defect. Since an apparently normal first step in insulin action, namely binding to receptors, was found, the uremic insulin resistance is a result of depressed insulin action at postbinding sites. However, it cannot be excluded that a superimposed intrinsic defect glucose transport system eg an impaired insulin-independent glucose uptake may contribute. In contrast to the abnormal glucose uptake, the responses of key intermediary metabolites were normal in uremia indicating normal insulin action on lipolysis, ketogenesis, and gluconeogenesis.     

Effect of intravenous glucose on serum glucose determinations

Hyperglycemia is frequently seen in hospitalized nondiabetic patients receiving intravenous glucose solutions. As no standard method of interpreting the serum glucose value has been defined in patients receiving intravenous glucose, we have attempted to determine if any correlation can be made. It was found that with a 5% dextrose in water infusion at 100 ml/hr, the mean change in serum glucose was $\text{9}\text{mg}\text{100}\text{ml}$ above the fasting serum glucose; with a 5% dextrose in water at 200 ml/hr, the mean serum glucose rose $\text{24}\text{mg}\text{100}\text{ml}$ above the fasting serum glucose obtained in the arm opposite the intravenous infusion. It was thus determined that a serum glucose level greater than $\text{20}\text{mg}\text{100}\text{ml}$ above the fasting serum glucose level in an individual with a 5% glucose in water infusion at 100 ml/hr, or $\text{42}\text{mg}\text{100}\text{ml}$ above the fasting serum glucose in an individual with a 5% glucose in water infusion at 200 ml/hr, which are 3 SD above the mean glucose, should be early evidence for mild subclinical glucose intolerance.     

HDL-cholesterol and other plasma lipid and lipoprotein concentrations in middle-aged male and female tennis players

Fasting plasma lipid and lipoprotein concentrations were determined in 25 men and 25 women (mean ages 42 and 39 yr respectively) whose exclusive mode of regular exercise was tennis play. When compared to a sedentary group matched for age, sex, and education, the tennis players exhibited similar plasma total cholesterol and LDL-cholesterol concentrations and significantly lower triglyceride and VLDL-cholesterol concentrations. Plasma HDL-cholesterol was significantly higher in the tennis players($\text{57.8 ± 13.9}\text{versus}\text{46.2 ± 12.0}\text{mg}\text{100}\text{ml}$ in the men and $\text{73.9 ± 12.3}\text{versus}\text{61.7 ± 13.3}\text{mg}\text{100}\text{ml}$ in the women). When we simultaneously controlled for age, relative weight, cigarette smoking, alcohol intake, and oral contraceptive use (in females), the significance of the difference in plasma HDL-cholesterol as well as triglyceride and VLDL-cholesterol concentrations was unaffected in the males but substantially reduced in the females. It is concluded that frequent tennis playing is associated with increased plasma HDL-cholesterol concentrations and that this relationship is independent of other factors known to alter plasma HDL-cholesterol concentration.     

Regulation of gonadal function in uremia

Gonadal function and its neuroendocrine control were studied in seven uremic men on chronic hemodialysis. Testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured in plasma or serum by established radioimmunoassay techniques. The metabolic clearance rate (MCR) of testosterone was also determined by constant infusion of ³H testosterone, and blood production rates were then estimated from the AM plasma level and the metabolic clearance rates. Predialysis, plasma testosterone in these uremic men were subnormal, measuring only $\text{289 ng}\text{100 ml ± 60 SE}$ (normal male values are 660 ± 70). The blood production rate of testosterone was also subnormal, averaging 2.7 mg/day in the two individuals studied, since the metabolic clearance rates were normal. However, after dialysis testosterone levels rose to $\text{408 ± 49 ng}\text{100 ml}$ (p < 0.01), the MCR to 1570 liters/day, and the calculated mean production rate increased to a normal level of 6.9 mg/day. Base-line serum LH was increased in the uremic state to 22.7 ± 1.8 mlU/ml (normal 5.9 ± 2), while FSH levels were normal at 7.7 mlU/ml ± 1.2 SE. Dialysis did not significantly alter serum immunoassayable gonadotropin levels. Gonadal stimulation by chorionic gonadotropin (4000 IU/day) initially did not increase testosterone levels, but continued stimulation-caused a two- to threefold rise by the fourth day. Clomiphene citrate (200 mg daily for 7 days) produced variable changes in testosterone and LH; two subjects did not respond, while two had a rise in both testosterone and gonadotropin. Luteinizing releasing hormone (LRH-Guillemin 150 μg intravenously) caused a two- to threefold rise in serum LH in both subjects studied. This work indicates that uremic men have subnormal testosterone production which is rapidly reversible with hemodialysis. The subnormal testosterone production appears to be primarily that of Leydig cell dysfunction, since there is elevated serum immunoassayable LH and a blunted initial response to exogenous gonadotropin.     

Hyperosmolar nonketotic diabetic coma: a complication of propranolol therapy

A 46-yr-old hypertensive man treated for 1 yr with apresoline 200 mg and propranolol 240 mg daily, was admitted in deep coma, severely dehydrated, serum glucose $\text{1130}\text{mg}\text{100}\text{ml}$ without ketonemia, normal serum CO₂, blood pH 7.52, serum osmolarity 357 mOsm/kg, fever of 105.6°F, and central venous pressure of less than 1 cm. The plasma free fatty acid was 270 μeg/liter, insulin 16 μU/ml and growth hormone 2.5 ng/ml. He responded excellently to 100 units regular insulin and 8 liters of hypotonic infusions. Seven months later he had a similar episode despite addition of 1 g tolbutamide daily in the interim. When studied without any medication he had fasting hyperglycemia of $\text{175–200}\text{mg}\text{100}\text{ml}$. An intravenous tolbutamide test was diabetic. When repeated following intravenous propranolol, 10 mg, the insulin response to tolbutamide was diminished. Without propranolol or hypoglycemic therapy, fasting hyperglycemia increased over 5–6 wk to $\text{630}\text{mg}\text{100}\text{ml}$, with traces of ketonemia, FFA level of 1350 μeq/liter and serum osmolarity of 305 mOsm/kg. The study was later repeated with the addition of oral propranolol 240 mg daily. Uncontrolled diabetes was again clinically manifest, although glucose levels rose more slowly. Despite fasting glucose levels reaching $\text{930}\text{mg}\text{100}\text{ml}$, no sign of ketosis occurred when the patient was taking propranolol. FFA level at this time was only 640 μeq/liter and serum osmolarity had risen to 335 mOsm/kg. His diabetes is now satisfactorily treated with insulin injections, to avoid the disturbances of carbohydrate metabolism caused by propranolol. These studies indicate that large amounts of propranolol may precipitate hyperosmolar nonketotic coma in an untreated diabetic by a blockade of lipolysis and/or impairment of insulin response.     

Relationship of serum gastrin to parathyroid hormone secretion in sheep

The influence of hypergastrinemia on secretion of parathyroid hormone (PTH) was studied in sheep. Synthetic human gastrin I, 4–9 μg/kg/hr, was infused for 1 hr into fasted, unanesthetized sheep. Blood was obtained at 15-min intervals before, during, and after infusion of gastrin from an indwelling arterial catheter. Blood pH, serum total calcium and circulating gastrin and PTH (radioimmunoassay) were determined. Despite the fact that gastrin infusion resulted in marked hypergastrinemia and in a small but statistically significant decrease in total serum calcium concentration (mean change in serum calcium $\text{0.28}\text{mg}\text{100}\text{ml}$), P < 0.005), PTH concentrations after gastrin infusions (34 ± 5 μl-eq/ml) did not change from basal (35 ± 6 μl-eq/ml). These studies do not substantiate the suggestion that acute hypergastrinemia, directly or indirectly, results in the release of PTH.     

Regulation of rat liver glycogen synthesis and activities of glycogen cycle enzymes by glucose and galactose

Direct regulation of rat liver glycogen metabolism by glucose and galactose was studied using an isolated liver perfusion system. Activation of glycogen synthase and net glycogen synthesis increased linearly when perfusate glucose concentration was increased from $\text{125 to 500 mg}\text{100 ml}$. Galactose, rapidly taken up by isolated rat liver regardless of circulating glucose concentration, increased these responses to glucose. In the presence of galactose ($\text{≥ 75 mg}\text{100 ml}$), activation of synthase and glycogen synthesis were 1.5-fold higher at any given glucose concentration. The addition of insulin did not appreciably alter synthase activation by glucose and galactose. Phosphorylase activity, low at circulating glucose levels above $\text{125 mg}\text{100 ml}$, was further decreased as glucose was increased or when galactose was added to the perfusate. Release of glucose into the perfusate in response to aglycemia was increased in the presence of galactose.     

Elevation of serum lipid levels during diuretic therapy of hypertension

In a study attempting to improve coronary risk status, serum cholesterol and triglyceride levels were measured before and during treatment of 74 patients with mild primary hypertension. In 35 patients there was a satisfactory reduction in elevated blood pressure levels with diet therapy alone. In the remaining 39 patients a diuretic drug was required in addition to the diet. Diet therapy alone was followed by a decrease of $\text{11 mg}\text{100 ml}$ in mean serum cholesterol (p < 0.01 versus pretreatment value) and no change in serum triglyceride. The use of diuretics was accompanied by an average increase of $\text{11 mg}\text{100 ml}$ in serum cholesterol and of $\text{34 mg}\text{100 ml}$ in serum triglyceride (p < 0.01 versus pretreatment level for both). In a subgroup of 21 patients with greatest elevations in lipid levels during the administration of diuretics, little improvement in coronary risk status occurred because the increase in serum cholesterol balanced the decrease in systolic blood pressure, according to Framingham risk tables. If the level of serum lipids is a factor in the pathogenesis of coronary atherosclerosis, then the observed effect of diuretic drugs to elevate serum cholesterol and triglyceride levels may explain, in part, the continuing high rate of occurrence of myocardial infarction during the treatment of hypertension.     

Evidence for a physiologic role of pancreatic glucagon in human glucose homeostasis: Studies with somatostatin

To study the role of glucagon in human glucose homeostasis, experimental glucagon deficiency was produced by infusing somatostatin (i.v. 250 μg bolus, followed by infusion of 500 μg/hr) in six normal subjects and in two hypophysectomized patients—an insulin-dependent diabetic and a nondiabetic. In normal subjects, somatostatin lowered plasma glucagon from a mean (± SE) basal level of 85 ± 15 to 33 ± 10 pg/ml, p < 0.001. Concurrently, plasma glucose fell from $\text{90 ± 2 to 73 ± 3 mg}\text{100 ml}$, p < 0.001. Serum insulin and growth hormone fell slightly during somatostatin infusion, while plasma free fatty acids rose. In both hypophysectomized patients, somatostatin lowered plasma glucagon and glucose levels. In all subjects, after stopping somatostatin infusions, plasma glucagon and glucose returned promptly to control values, while serum growth hormone did not change. In additional in vitro studies, somatostatin (1 μg/ml) had no effect on muscle glucose uptake. Since it is known that somatostatin has no direct effect on hepatic glucose production, these results suggest that the fall in plasma glucose during somatostatin infusion resulted from inhibition of glucagon secretion, thus providing evidence that this hormone plays a physiologic role in the maintenance of fasting euglycemia in man.     

Effect of intravenously administered glucose on glucagon and insulin secretion during fat absorption

The intravenous infusion of glucose was found to alter profoundly the response of insulin and glucagon to an intraduodenally administered fat meal in conscious dogs from that of dogs given only intravenous saline as a control. In the latter, insulin rose only 4 μU/ml and glucagon rose from 142 SEM ± 8 to a peak of 221 pg/ml SEM ± 50. When glucose was infused, raising plasma glucose above $\text{170 mg}\text{100 ml}$, the administration of fat was associated with a rise in mean insulin to 344 μU/ml, and glucagon remained suppressed by hyperglycemia to below baseline levels, despite the fat meal. The peak insulin response to a fat meal plus glucose infusion was more than three times the peak level observed when glucose was infused alone without a meal or with a nonabsorbable intraduodenal volume load in the form of mineral oil. This suggests that the absorption of fat elicits an entero-insular signal that is greatly potentiated by exogenous glucose. These glucose-induced changes in the hormonal response to a fat meal may mediate certain of the metabolic effects of carbohydrates.     

Triglyceride removal efficiency and lipoprotein lipases: effects of Oxandrolone

Very low density lipoprotein triglyceride turnover rate, fractional turnover rate, and half-life were studied using Glycerol ^?3H to label VLD-TG in 16 patients with familial Type IV hyperlipoproteinemia. The patients were maintained on an isocaloric diet with determination of triglyceride turnover after 2 wk of placebo, and a second determination after 2 wk of Oxandrolone (an anabolic-androgenic synthetic steroid). On placebo, mean very low density lipoprotein triglyceride (VLD-TG) was 539, falling on Oxandrolone to $\text{254 mg}\text{100 ml}$ (p < 0.05). Mean half-life ($\text{T}\text{1}\text{2}$) was 10.3 hr on placebo and was shortened to 5.2 hr on drug (p < 0.05). The fractional turnover rate (FTR) on placebo was 0.104 ± 0.016 hour^?1, and rose to 0.166 ± 0.016 on drug (p < 0.05). Mean turnover rate (TR) rose slightly from 17.6 mg/kg/hr on placebo to 19.04 mg/kg/hr on Oxandrolone. Both postheparin lipolytic activity (PHLA) and postheparin triglyceride lipase (TGL) were appreciably increased on drug, rising respectively from 0.297 μeq FFA/ml/min and 11.7 mμeq FFA/ml/hr (on placebo) to 0.396 and 23.7 (on drug). The changes (Δ) in VLD-TG on Oxandrolone correlated with $\text{Δ T}\text{1}\text{2}$ (R = 0.761) and with Δ FTR (R = ?0.532). Oxandrolone may lower very low density lipoprotein triglyc eride by substantially increasing fractional turnover rate and shortening half-life while slightly augmenting turnover rate and improving efficiency of VLD-TG removal.     

Postheparin plasma triglyceride lipases in chronic hemodialysis: evidence for a role for hepatic lipase in lipoprotein metabolism.

Elevated plasma triglyceride levels frequently occur in patients with chronic renal failure receiving longterm hemodialysis. Postheparin plasma lipolytic activity, an indirect measure of triglyceride removal, is low in hemodialysis patients, but this activity measures both hepatic triglyceride lipase (HTGL) and lipoprotein lipase (LPL). To determine if HTGL and/or LPL are low in hemodialysis patients and related to lipoprotein lipid levels, both activities were measured by a selective antibody-inhibition technique in postheparin plasma from 20 hemodialysis patients with a wide range of plasma triglyceride levels ($\text{104–676}\text{mg}\text{100}\text{ml}$), and the relationships between the enzyme activities and lipoprotein lipid levels were examined. To more accurately compare subjects, the heparin doses were adjusted for the differences in plasma volumes between the hemodialysis patients and the nonuremic control subjects. Hemodialysis patients with elevated plasma triglyceride levels (↑TG) had HTGL levels (148 ± 67 nmole/min/ml, n=10) which were similar to the dialysis patients with normal triglyceride levels (nlTG) (134 ± 64 nmole/min/ml, n=10) and both groups were significantly lower (p<0.05, p<0.02, respectively) than the levels of the control subjects (208 ± 61 nmole/min/ml, n=11). The HTGL levels of the hemodialysis patients with ↑TG correlated inversely with plasma total cholesterol (r_s=−0.833, p<0.01) and the d>1.006 fraction cholesterol (low + high density lipoproteins, r_s=−0.863,p<0.01), but not triglyceride. The activity of HTGL of the entire group of hemodialysis patients correlated with the plasma total cholesterol (r_s=−0.615, p<0.01), d>1.006 fraction cholesterol (r_s=−0.731, p<0.01) and low density lipoprotein cholesterol (r_s=−0.659, p<0.01). The LPL levels of the hemodialysis patients with the ↑TG (52 ± 24 nmole/min/ml) were lower than those with nlTG (70 ± 25 nmole/min/ml) and the levels of both hemodialysis groups were significantly lower (p<0.01, p<0.02, respectively) than the LPL levels in the control subjects (110 ± 43 nmole/min/ml). The ratio of LPL to total postheparin plasma lipolytic activity was lower in the hemodialysis patients with ↑TG (0.32 ± 0.15), than in the hemodialysis patients with nlTG (0.47 ± 0.18, p<0.06) or the control subjects (0.45 ± 0.09, p<0.05). Unlike HTGL, the levels of LPL did not correlate with lipid levels in the hemodialysis patients. Thus, both postheparin plasma HTGL and LPL are low in hemodialysis patients. The relationship between HTGL and low density lipoprotein cholesterol levels suggests a possible role for HTGL in low density lipoprotein catabolism.     

Plasma levels of colchicine after oral administration of a single dose

Plasma colchicine levels have been measured serially after the oral administration of 1.0 mg of the drug to ten volunteer subjects. Peak colchicine concentrations averaged $\text{0.323 ± 0.173 μ}\text{g}\text{100}\text{ml}$. Two populations were evident within the group, one with highest concentrations $\text{1}\text{2}\text{hr}$ after administration, and a second with highest concentrations 2 hr after administration of colchicine by mouth.