Incorporation of orally administered glucose-U-14C and fructose-U-14C into the triglyceride of liver, plasma, and adipose tissue of rats

Male rats, fasted for 5–6 hr, were given glucose-U-¹⁴C or fructose-U-¹⁴C, with their respective carrier, by intragastric instillation. Sequential radioactivity in plasma carbohydrates and in the triglyceride of the liver, plasma, and adipose tissue and plasma immunoreactive insulin and free fatty acids were measured. The validity of taking the triglyceride labeling rate as the triglyceride synthesis rate was tested by measuring the metabolic activity of endogenous glucose. Two or three times greater radioactivity was found in the liver and plasma triglycerides after fructose than after glucose while the reverse was true for adipose tissue. The greater radioactivity in triglyceride of the liver and plasma after fructose was mainly due to triglyceride-glycerol radioactivity. The greater radioactivity in adipose tissue triglyceride was due to the radioactivity of both triglyceride-fatty acids and triglyceride-glycerol. Three hours after glucose, 92% of the total radioactivity in triglyceride was in adipose tissue and 8% was in the liver. However, 3 hr after fructose, 57% of the radioactivity was in adipose tissue and 42% was in the liver. Daily repetition of such a pattern of fructose handling may lead to abnormal metabolism of endogenous triglyceride.     

Urinary excretion of carnitine in patients with hyperthyroidism and hypothyroidism: Augmentation by thyroid hormone

Urinary excretion of carnitine and serum concentrations of carnitine, triglyceride, and free fatty acids were measured in 54 hyperthyroid and 13 hypothyroid patients, and the results were compared with those of normal subjects. In hyperthyroid patients urinary excretion of carnitine was highly increased above that of the control subjects. On adequate treatment with antithyroid drug, carnitine excretion was reduced to the normal range, and serum lipids changed in parallel. In contrast, carnitine excretion was markedly reduced in hypothyroid patients. After substitution therapy with thyroid hormones the excretion increased in these patients. This change was associated with a marked reduction of serum triglyceride. There was an inverse correlation between urinary excretion of carnitine and serum triglyceride concentration. Carnitine excretion was significantly correlated with serum thyroxine concentration in hyper- and hypothyroid patients. The results suggest that thyroid hormones play an important role in carnitine metabolism, which in turn influences serum triglyceride metabolism.     

Urinary excretion of carnitine and serum concentrations of carnitine and lipids in patients with hypofunctional endocrine diseases: involvement of adrenocorticoid and thyroid hormones in ACTH-induced augmentation of carnitine and lipids metabolism.

The promoting effect of ACTH on carnitine and lipid metabolism was studied in patients with various endocrine hypofunctions. The results were compared with those of normal subjects. In adrenocortical insufficiency, hypothyroidism and hypopituitarism urinary excretion of carnitine was significantly lower than in normal subjects. On intramuscular injection of synthetic beta1-24 ACTH-Z urninary excretion of carnitine in normal subjects increased sixfold on the day of the injection and returned to the pretreatment level on the third day. Serum concentrations of carnitine and FFA increase in parallel with carnitine excretion, while serum triglyceride was lowered in response to ACTH administration. These responses were totally lacking or substantially suppressed in patients with the above endocrine insufficiencies. In hypothyroid and hypopituitary patients substitution therapy restored the responses to ACTH in the same fashion as those in normal subjects. These findings suggest that the promoting effect of ACTH on carnitine and lipid metabolism requires the presence of intact adrenocortical and thyroid functions.     

Amino acid metabolism in parenteral nutrition: With special reference to the calorie: Nitrogen ratio and the blood urea nitrogen level

A clinical and experimental study was made on amino acid metabolism during parenteral nutrition with glucose and a synthetic amino acid solution. Good correlation was noted between the calorie: nitrogen ratio of the infusate and the blood urea nitrogen level, as well as between the calorie: nitrogen ratio and the amount of urinary excretion of urea nitrogen, nonprotein nitrogen, and amino nitrogen. Final results revealed that the extent to which amino acid is utilized for protein synthesis is directly proportional to the caloric supply, and for complete utilization of 1 g of nitrogen the required caloric intake is in the neighborhood of 450 total calories or 425 nonprotein calories. Blood urea nitrogen level can be used as a parameter of amino acid utilization during parenteral nutrition. Its level is influenced not only by renal function but also by calorie: nitrogen ratio of infusate.     

Amino acid modulation of glucose-induced insulin and glucagon release in diabetic patients

In order to determine whether amino acids have a beneficial effect on glucose tolerance in diabetes, the effect of intravenous infusion of mixed amino acids on plasma insulin, glucagon, and blood glucose responses to oral glucose loading was studied in patients with mild to moderate diabetes. Intravenous infusion of mixed amino acids over a period of 30 min which was started 30 min or immediately before oral glucose loading significantly augmented the insulin response but did not improve the blood glucose curve, probably due to excessive glucagon response. However, amino acid infusion over a period of 60 min started immediately before oral glucose loading evoked a sustained rise of plasma insulin associated with a lesser degree of glucagon secretion, thus causing significant improvement of the blood glucose curve.     

Circulating renin in essential hypertension: an evaluation of its significance in the Japanese population

Plasma renin activity (PRA) was measured in 139 healthy subjects and 200 patients with essential hypertension. There was an obvious relationship between the PRA levels and aging. Elevated PRA values were obtained only in younger subjects under 20 years of age, while the PRA levels were very low only in advanced ages over 60 years.In essential hypertensive subjects, subnormal resting PRA was found in 23.5 per cent, normal PRA in 64.5 per cent, and high PRA in 12 per cent. A marked impairment of renal function and severe retinal changes were observed in the patient with high resting PRA values. On the contrary, hypertensive complications of the kidney and ocular fundi were mild in the patients with low resting PRA values.A reaction of renin secretion was studied in 161 patients with essential hypertension. There were no apparent relationships between the responsiveness of the renin system to intravenous furosemide following upright posture and hypertensive vascular injury.     

Thyroid peroxidase activity in euthyroid and mild hypothyroid patients with Hashimoto's thyroiditis

Thyroid peroxidase (TPO) activity was measured spectrophotometrically according to Hosoya's guaiacol method. The mean TPO activity in ten patients with Hashimoto's thyroiditis was 19.8 +/- 7.6 (mean +/- SE) in an arbitrary unit, which was not significantly different from the normal value in seven normal thyroid tissues (33.7 +/- 5.4). The ten patients were divided into two groups, euthyroid and mild hypothyroid, on the basis of their basal serum TSH. In the euthyroid group, TPO activity (8.17 +/- 1.3) was significantly less than the normal tissue (p less than 0.01). In the hypothyroid group, TPO activity (27.64 +/- 13.8) was almost similar to the normal tissue. A positive correlation was obtained between TPO activity and serum TSH in ten patients with Hashimoto's thyroiditis (r = 0.85, p less than 0.01). It was concluded that TPO activity is significantly decreased in Hashimoto's thyroiditis even when the thyroid function was still within normal range, but the activity might be restored to normal in hypothyroid patients by the stimulation of elevated TSH.     

Effect of clofibrate on postheparin plasma triglyceride lipase activities in patients with hypertriglyceridemia

The lipoprotein lipase (LPL) and hepatic triglyceride lipase (HL) activities of post-heparin plasma were determined by a specific immunochemical method in 17 patients with primary hyperlipoproteinemia before and during treatment with clofibrate. The drug caused a significant reduction of serum cholesterol (11%) and triglyceride (45%) levels. Postheparin plasma LPL activity rose in all subjects, the average change being 46% (P < 0.001). The increase of LPL was positively correlated to the pretreatment LPL activity. There was no correlation between the serum triglyceride concentration and post-heparin LPL activity either before or during clofibrate administration. On the other hand, in the clofibrate responders there was a weak correlation between the relative changes of triglyceride concentration and LPL activity (r = 0.43, p < 0.05). During clofibrate treatment the LPL activity of the hypertriglyceridemic patients was significantly higher than the corresponding value of untreated healthy normoglyceridemic subjects of similar age. The post-heparin plasma HL activity was not influenced by clofibrate.     

Glucagon secretion in primary endogenous hypertriglyceridemia before and after clofibrate treatment.

Arginine-induced insulin and glucagon secretion preceding and following clofibrate treatment was studied in 13 patients with endogenous hypertriglyceridemia. A positive correlation was demonstrated between fasting insulin and triglyceride levels and between the fasting insulin/glucagon molar ratio and triglyceride levels. In patients with endogenous hypertriglyceridemia, anginine infusion induced a significantly increased glucagon response with respect to that found in controls. No correlation was found to exist between glucagon and free fatty acids (FFA) or between glucagon and triglyceride levels. The same lack of correlation was found in normal subjects rendered hypertriglyceridemic by means of Intralipid infusion, which did not modify the fasting glucagon-like immunoreactivity (GLI) or the GLI response to arginine. Clofibrate treatment induces a triglyceride reduction (incrementTG) which is correlated with the reduction in the insulin/glucagon molar ration (incrementI/G). After clofibrate treatment there is also a significant reduction in fasting GLI levels and in the insulin response to arginine, and an increase in the glucagon response. Clofibrate could exercise its hypolipidemic effect by modifying the relationship between insulin and glucagon levels.     

Norepinephrine levels in the coronary sinus in patients with cardiovascular diseases at rest and during isometric handgrip exercise

In order to evaluate cardiac sympathetic nerve activity, plasma norepinephrine levels in the coronary sinus (NE_CS) and in the artery (NE_A) were determined in 24 subjects with cardiovascular diseases and in six with functional murmur. The resting NE_CS was greater than NE_A in 14 subjects with normal left ventricular end-diastolic pressure (LVEDP) (p < 0.01) and/or in 22 with normal cardiac index (p < 0.05), whereas NE_CS was not significantly different from NE_A in the remaining patients with elevated LVEDP and/or with reduced cardiac index. Isometric handgrip exercise increased both NE_CS and NE_A (p < 0.001). When subjects were divided into two groups according to the slope of the ventricular function curve (Δ stroke work index/ΔLVEDP), NE_CS during exercise was greater than NE_A in the group having slopes of 1.0 or more (p < 0.01), but neither values significantly differed in the group with slopes of less than 1.0. In the latter group, cardiac NE overflow rate calculated from the difference between NE_CS and NE_A multiplied by coronary sinus plasma flow, was significantly less than that of the former group before and during handgrip (p < 0.05 and p < 0.01, respectively). These results suggest that cardiac norepinephrine release into the coronary sinus is reduced in patients with impaired cardiac function.     

Doxazosin: A newly developed,selective α1-inhibitor in the management of patients with pheochromocytoma

Although surgical removal is the therapy of choice in patients with pheochromocytoma, medical management is necessary in the preoperative preparation of these patients and in inoperable cases. An α-adrenoceptor-blocking agent is routinely used as initial therapy to control hypertension, with a β-blocker used as a second-step agent to control tachycardia when indicated. Doxazosin, a selective α₁-inhibitor used as an antihypertensive agent for the reduction of coronary heart disease risk in hypertensive patients, appears to be a good agent to control blood pressure with minimal changes in heart rate. The aim of this study was to assess the antihypertensive efficacy and safety of doxazosin when used alone or in conjunction with a β-blocker in 24 patients with pheochromocytoma. Overall excellent or good antihypertensive efficacy was assessed by physicians in 19 of 24 patients (79.2%) enrolled in the study. Doxazosin monotherapy was effective in eight of 12 patients (66.7%), and combined therapy with a β-blocker was effective in 11 of 12 patients (91.7%). The mean pulse rate remained constant throughout therapy. Adverse reactions were minor and transient and occurred in only three patients. Urinary and plasma catecholamine levels tended to decrease or remained unchanged during doxazosin therapy. There were no clinically hazardous abnormalities or problems in hematologic and biochemical laboratory data. Overall, doxazosin was considered very useful or useful in 83.3% of patients. In conclusion, doxazosin appears to be an excellent agent for the management of hypertension assoclated with pheochromocytoma.     

Effect of glycerol on triglyceride metabolism in the rat

Lipid metabolic studies were carried out on the male Wistar rats fed on glycerol-rich diet in order to elucidate the mechanism of glycerol-induced hypertriglyceridemia. No difference was found between the glycerol fed rats and the control rats in the rate of triglyceride secretion from the liver measured by the Triton WR-1339 method as well as in the rate of incorporation of labeled glycerol into liver triglyceride. The facts that the half-life of the intravenously injected intralipid^® in the blood was significantly delayed in the glycerol fed rats and that the lipoprotein lipase activity released from epididymal adipose tissue of the glycerol fed rats was markedly decreased to 19% of that of the control rats seem to account for the serum triglyceride elevation induced by the glycerol feeding.     

Differential tissue sensitivity to elevated endogenous insulin levels during experimental peritonitis in rats

Disturbances of glucose metabolism consequent to experimental peritonitis in rats were studied by measurement of insulin-related metabolism of isolated tissues in correlation with blood insulin and substrate levels. Blood insulin concentrations were threefold higher in infected fasting rats than in normal fasting controls, despite approximately equal blood glucose concentrations, suggesting resistance to the hypoglycemic action of insulin. The increased circulating insulin was associated with a threefold elevation of the insulin-sensitive adipose tissue pyruvate dehydrogenase enzyme complex, and a threefold increase in the rate of conversion of glucose to CO₂ by fragments of epididymal fat pads. Fasting infected animals also had reduced circulating nonesterified fatty acids and relatively less depletion of epididymal adipose tissue, when compared to fasted controls presumably due to the potent action of insulin in opposing lipid mobilization. In contrast, diaphragm pyruvate dehydrogenase was not elevated, nor was diaphragm glucose conversion to CO₂ stimulated in response to the elevated circulating insulin. It is proposed that reduced fat mobilization without concomitantly accelerated glucose oxidation by muscle may result in insufficient metabolic fuel for muscle and this may, in turn, promote amino acid combustion by muscle to meet cellular energy requirements. This suggested mechanism may provide a hypothetical biochemical explanation for the excessive protein catabolism associated with severe infection.     

Human placental thyroxine inner ring monodeiodinase in complicated pregnancy

Production of rT3 from T4 in the placenta were measured in four patients with induced abortion, in three patients with spontaneous abortion, in 19 patients with various complications of pregnancy including Graves' disease, and in 18 normal pregnancies. The placentas, obtained at delivery, were homogenized and centrifuged at 800 X g. Supernatants (1 mg protein) were incubated with 1 microgram of stable T4 and 50 mmol/L dithiothreitol at 37 degrees C for 60 minutes. The generated rT3 was measured by radioimmunoassay (RIA). In patients who delivered at 38 to 41 weeks with complicated pregnancy, the net placental rT3 production from T4 was 7.3 +/- 2.5 ng/tube, which was not significantly different from that obtained in normal pregnancy (8.5 +/- 2.4) at an equivalent gestational age. In patients with abortions, the net placental rT3 generation from T4 was very high, and there was a significant negative correlation between the net placental rT3 production from T4 and gestational age. These results indicate that the net placental rT3 production from T4 is not affected by complications of pregnancy, but shows a significant change with the progress of gestation.     

Myocardial infarction in the familial forms of hypertriglyceridemia.

Among 74 hypertriglyceridemic patients who were referred for study because of hypertriglyceridemia, family investigations detected 19 with familial hypertriglyceridemia and 24 with familial combined hyperlipidemia. The frequency of myocardial infarction among adult living hyperlipidemic relatives of patients with familial combined hyperlipidemia was 17.5% (10/57). Five of these relatives had their infarct between the ages of 40 and 50 yr of age, and five before the age of 40 yr. The frequency of myocardial infarction in living hyperlipedemic relatives with familial hypertriglyceridemia was 4.7% (2/43) and was similar to the frequency of myocardial infarction among normolipidemic relatives (4.5%) or among spouse controls (5.2%). Mortality data due to myocardial infarction among relatives of index patients failed to contribute meaningful information.     

Effect of vasoactive intestinal polypeptide infused intrapancreatically on glucagon and insulin secretion

Synthetic vasoactive intestinal polypeptide (VIP) was infused at a dose of 50 ng/kg/min for 10 min into the cranial pancreaticoduodenal artery in anesthetized dogs. Both mean blood flow and plasma glucagon concentration in the cranial pancreaticoduodenal vein were significantly enhanced during the infusion, indicating a great augmentation in glucagon output. The pancreatic venous plasma concentration of insulin was not significantly raised, but its output increased during the infusion, again due to the increase in plasma flow. Plasma concentration of glucagon in the femoral artery was not significantly augmented, whereas that of insulin was enhanced during VIP infusion. Mean arterial plasma glucose levels rose gradually during the infusion. Intrapancreatic pretreatment with propranolol failed to exert any significant inhibiting effect upon the VIP-induced enhancement in plasma glucose, pancreatic venous blood flow, or bihormonal output. These results suggest that the vasoactive polypeptide of intestinal origin may regulate the function of the endocrine pancreas and that this effect may not be mediated mainly via the β-adrenergic receptor system.     

Relationship between plasma and erythrocyte magnesium and potassium concentrations in fasting obese subjects

During 18-day fasts undertaken by 19 obese patients, plasma magnesium concentrations decreased in those given no mineral supplements or given calcium or sodium supplements, but did not decrease in those given magnesium supplements. The extent of the decreases ranged from 9% in the nonsupplemented group to 25% in the sodium-supplemented group. Plasma potassium concentrations decreased more gradually in all patients, irrespective of magnesium supplementation. Erythrocyte magnesium concentrations remained unchanged in all patients. Erythrocyte potassium concentrations decreased by between 5% and 9% in those patients who had a decreased plasma magnesium concentration, but did not change in the patients who were given magnesium supplements. These findings indicate a possible effect of extracellular magnesium concentration, or of some other correlate of magnesium supplementation, on potassium distribution and transport between extra- and intracellular compartments.     

Altered insulin and glucagon secretion in treated genetic hyperlipemia: A mechanism of therapy?

The influence of Halofenate therapy on insulin and glucagon secretion was examined in the Zucker rat with genetic endogenous hyperlipemia. Coincident with the lipid lowering effects of Halofenate, the net change in the basal bihormonal axis favored glucagon, with the I/G molar ratio (Insulin/Glucagon) decreasing from 2.72 +/- 0.53 to 0.96 +/- 0.20 during treatment with this drug. Following arginine stimulation the I/G ratio remained reduced at 0.87 +/- 0.13 in Halofenate treated animals, contrasting with the statistically greater ratio of 2.5 +/- 0.55 in control animals. The Halofenate induced state of reduced insulin:glucagon was associated with hypolipemia, postarginine hyperglycemia, and hyperketonemia,-three metabolic parameters characteristic of glucagon excess relative to insulin. It is suggested that the lipid-lowering action of Halofenate in genetic hyperlipemia may reflect the altered bihormonal axis induced by the drug.     

Effects of ethanol ingestion on glucose tolerance and insulin secretion in normal and diabetic subjects

To investigate the effect of ethanol on carbohydrate homeostasis in circumstances in which food and ethanol are usually ingested, ethanol was administered hourly in the afternoon prior to the ingestion of a glucose load at 5:00 p.m. in a group of normal subjects and in mild diabetics. In both groups the blood glucose levels following the glucose load were $\text{30–80 mg}\text{100 ml}$ lower and the early insulin secretory response (15–45 min) was 35%–40% higher after ethanol ingestion. In contrast, ethanol intake had no effect on the glucagon response to glucose ingestion. These data suggest that ethanol enhances glucose-stimulated insulin secretion. The dampened blood glucose rise observed with ethanol may be related to the augmented insulin response or to decreased gastrointestinal absorption of glucose. In mild diabetic patients, moderate intake of ethanol is without acute deleterious effects on carbohydrate homeostasis and may in some instances improve the blood glucose response to ingested carbohydrate.     

Permissive role of thyrotropin on thyroid radioiodine uptake during the recovery phase of subacute thyroiditis

Serial measurements of serum triiodothyronine (T₃), thyroxine (T₄), thyrotropin (TSH), and 4-hr thyroidal ¹³¹I uptake were carried out in nine patients with subacute thyroiditis. In the acute phase, suppressed TSH and ¹³¹I uptake were observed simultaneously with the elevations of T₃ and T₄. Thyrotropin-releasing hormone (TRH) failed to increase TSH in all patients studied. The mean value of an increment in serum TSH was only 1.8 μU/ml during the recovery phase when ¹³¹I uptake was normal or hyper-normal. In addition, and elevated ¹³¹I uptake was not necessarily associated with an immediate increase in the serum T₃ and T₄. These observations suggest that the resumption of the iodide pump may be more important than an increment in TSH in producing normal or hypernormal ¹³¹I uptake during the recovery phase. There appears to be a dissociation between the reestablishment of ¹³¹I uptake and the resumption of the mechanism of hormonal synthesis and secretion in the thyroid.