Krishan L. Raheja

Lack of relationship between plasma insulin and glucagon levels and angiographically-documented coronary atherosclerosis☆

In 120 consecutive patients undergoing diagnostic coronary arteriography, fasting blood glucose, plasma insulin, glucagon, serum cholesterol and triglyceride concentrations were measured. The insulin-glucose ratio and insulin-glucagon ratio were calculated. Forty-five patients had normal coronary arteries, 19 had single vessel coronary artery disease and 56 patients had multiple vessel disease. Fasting blood glucose was greater than 120 mg/100 ml in 37 patients (group A) and included 9 of the 10 known diabetics, 3 of whom were being treated with insulin. Seventy-seven patients included in group B had fasting blood glucose concentration less than 120 mg/100 ml. Patients with multiple vessel coronary disease in either group had higher blood glucose and cholesterol concentrations than those with normal coronary arteries or the ones with single vessel disease, but they did not have higher plasma insulin or glucagon levels nor increased insulin-glucose or insulin-glucagon ratios. With comparable extent of coronary artery disease patients in group A had higher plasma insulin levels and insulin-glucagon ratios than those in group B, but no correlation exists between the presence or extent of coronary atherosclerosis and these variables in either group. Thus, neither fasting plasma insulin level nor insulin-glucagon ratio predicts the status of underlying coronary atherosclerosis in either diabetics or nondiabetics.

Comparative Effects of Soy and Casein Protein on Plasma Cholesterol Concentrations

The effects of soy and casein protein on cholesterol metabolism were determined under normocholesterolemic and hypercholesterolemic conditions in male Wistar rats and in Swiss White mice. Hypercholesterolemia was induced by feeding cholesterol and cholic acid in the diet for a period of 2 weeks. Our results demonstrate that there are significant species differences. The hypercholesterolemic effect of exogenous cholesterol was more pronounced in the mouse than in the rat. The rats fed the basal (no cholesterol, no cholic acid) semisynthetic diet containing either soy or casein had plasma cholesterol concentrations similar to those observed in chow-fed controls. However, plasma cholesterol concentrations in the mice fed the basal semisynthetic diet containing either of the two proteins were significantly elevated compared to the control mice fed commercial chow. Rat data demonstrate that the hypercholesterolemia induced by exogenous cholesterol administration is of a lesser magnitude in the presence of soy compared to casein as a dietary protein source. The mice data show that the concentrations of hepatic and biliary cholesterol and plasma triglycerides and in response to exogenous cholesterol are significantly lower in the soy protein diet compared to the casein protein diet.

Failure of exogenous prostaglandin to afford complete protection against acetaminophen‐induced hepatotoxicity in the rat

The protective effect of 16, 16-dimethylprostaglandin E2 (dm-PGE2) against acetaminophen-induced hepatotoxicity was determined in the rat. The dm-PGE2 was administered at two dose levels both before and after acetaminophen administration. The hepatotoxicity was evaluated by a rise in serum transaminases 24 h after acetaminophen administration and by histological examination of liver preparations. The urinary acetaminophen and its metabolites were determined by high-pressure liquid chromatography. The results suggest that exogenous dm-PGE2 administration had a modest protection against acetaminophen-induced hepatotoxicity, in contrast to its well established cytoprotective effect against many noxious agents in the gastrointestinal tract. Prostaglandin treatment had little effect on acetaminophen metabolites excretion in the urine, suggesting that it did not affect the cytochrome P-450-dependent mixed-function oxidase drug-metabolizing enzyme system. The livers from dm-PGE2-acetaminophen-treated rats showed less advanced necrosis compared to those from saline-acetaminophen-treated rats. Whereas only 2 of 13 rats died in the prostaglandin-treated group, 4 of 13 rats died in the saline-treated group.

Inhibitory effect of propylthiouracil-induced hypothyroidism in rat on oxidative drug metabolism

The effect of propylthiouracil (PTU) pretreatment on in vivo and in vitro oxidative drug metabolism was determined in the rat. Whereas pentobarbital sleeping time (PBST) and zoxazolamine paralysis time (ZZPT) were used as indices of in vivo drug metabolizing activity, biotransformation of aminopyrine and aniline by hepatic microsomal preparations were used as indices of in vitro drug metabolizing enzymes activities. PTU pretreatment significantly prolonged both PBST and ZZPT. Whereas PTU did not affect microsomal protein concentration or cytochrome P-450 content, it significantly decreased microsomal cytochrome c reductase and aniline hydroxylase activities. These changes in enzymatic activities were observed in microsomal preparations from either non-fasted or 24-hr fasted rats. Our results suggest that PTU-induced hypothyroidism modifies the metabolism and effectiveness or toxicity of concomitantly administered drugs.

Effect of dietary composition on liver glycogen accumulation and lipid metabolism in the hypothyroid chick (Gallus domesticus)

Abstract 1. 1. Since propylthiouracil-induced hypothyroidism in the mash (commercial high carbohydrate diet) fed chick results in liver enlargement with excessive accumulation of glycogen, these studies were conducted to determine the effect of diet composition on carbohydrate and lipid metabolism in the hypothyroid chick. 2. 2. PTU (0.1%) was fed for 2 weeks in mash, high carbohydrate (HC), high fat (HF), or in high protein (HP) diets. 3. 3. Thyroid glands were significantly enlarged in all PTU treated chicks independent of the nature of dietary composition. 4. 4. Liver weight increased and glycogen accumulated in all hypothyroid chicks, the maximum in HC diet and minimum in HF diet fed group. 5. 5. Plasma glucose levels did not correlate with liver glycogen concentrations. 6. 6. Hypothyroidism significantly increased plasma triglycerides in HC and mash fed, cholesterol in mash fed and phospholipids in HC and HF diets fed groups. HP diet had a hypocholesterolemic effect. 7. 7. PTU significantly decreased bile phospholipids. Bile cholesterol was also decreased except in HF diet fed group. 8. 8. The results demonstrate profound changes in carbohydrate and lipid metabolism in hypothyroid chicks. These changes are modulated by dietary composition and liver glycogen accumulation probably is dependent on dietary carbohydrate supply.

Effects of somatostatin on gastric acid secretion and on lipid and carbohydrate metabolism in the rat.

1 Studies were conducted to examine the effects of somatostatin on pentagastrin‐induced gastric acid secretion, and on bile, plasma and liver lipid composition in the rat. 2 In addition, liver glycogen and plasma glucose concentrations were measured. 3 Somatostatin was administered intravenously as a bolus (100 ug) at the start of the experiment followed by a continuous infusion (50 ug/h) for 2 h. 4 Controls were infused with isotonic saline (1 ml/h) throughout the experiment. Gastric secretions and bile were collected during the infusions. 5 Somatostatin significantly decreased the volume of gastric secretion as well as total gastric acid output but it had no effect on bile flow or bile lipid composition. 6 Plasma and liver lipids were not affected. Plasma glucose concentrations were significantly elevated but liver glycogen was not changed. 7 Our results suggest that somatostatin probably decreases glucose uptake by peripheral tissue. The effect of somatostatin on bile composition and glucose levels in the rat is different from observations reported in other species.

Prevention of acetaminophen hepatotoxicity by propylthiouracil in the glutathione depleted rat

This study was designed to investigate the protective effect of PTU pretreatment against acetaminophen hepatotoxicity in rats whose hepatic GSH had been depleted by prior diethylmaleate (DEM) administration. A single injection of DEM depleted hepatic GSH showing lowest level after 90 min in both control and PTU pretreated rats. Triple injection schedule kept the hepatic GSH concentrations consistently very low up to 6 hr. Whereas a toxic dose of acetaminophen administration did not effect SGOT and SGPT levels after 30 hr in PTU pretreated rats given either a single or multiple injections of DEM, the same dose of acetaminophen in the control rats raised these transaminases to a very high level. High activity of transaminases was associated with significant histological hepatic damage. Our results suggest that PTU pretreatment affords significant protection against acetaminophen hepatotoxicity even under conditions when hepatic GSH concentrations have been significantly depleted prior to acetaminophen administration.

Lipid and carbohydrate metabolism in euthyroid and hypothyroid chick embryo (Gallus domesticus).

1. The effect of propylthiouracil (PTU)-induced hypothyroidism on carbohydrate and lipid metabolism was studied in the chick embryo. 2. A single dose of PTU (250 micrograms/embryo) was administered on day 11 and embryos sacrificed on day 20 of incubation. 3. Thyroid glands were significantly enlarged (6 fold) by PTU administration. 4. Increased thyroid weight was associated with growth retardation and decreased plasma thyroxine levels. 5. Plasma glucose level was lower and phospholipids were significantly higher in the hypothyroid embryo. 6. Liver lipid concentrations in the control and hypothyroid embryos were not different but were significantly higher in both groups when compared to previously reported values in the young chick. 7. In contrast to PTU treatment after hatching, liver glycogen levels were not increased in the hypothyroid chick embryo. This was attributed to the high lipid nutrient condition of the chick embryo since a high lipid diet in the young chick decreased hepatic glycogen accumulation significantly.

Effects of chronic β-glycerophosphate administration on growth rate and on serum, liver and bile lipid composition in the squirrel monkey — a toxicity study***

Oral administration of beta-glycerophosphate lowers the lithogenic index in patients with cholesterol gallstones and is considered to have potential for dissolving them. A high dose of beta-glycerphosphate was fed to primates (Squirrel monkeys) for a period of 15 months. There were no adverse effects on body weight, hematological or liver function tests. Serum, liver and bile lipids concentrations were not significantly changed, although serum and hepatic bile phospholipids were increased. Organ weights expressed as percent of body weight were not changed except for a slight increase in kidney weight. Histological examination of liver and kidneys did not reveal any pathological findings. Slight renal hypertrophy was attributed to the sodium content of beta-glycerophosphate.

Propylthiouracil-induced hypothyroid hyperlipidemic chick: A model for clofibrate-induced toxicity

An animal model for clinically observed clofibrate (p-chlorophenoxy isobutyrate, CPIB)-induced toxicity has been tested. It is demonstrated that propylthiouracil-induced hypothyroid-hyperlipidemic chick develops severe toxic manifestations following clofibrate administration. Toxic symptoms are characterized by listlessness, drowziness, and extreme muscular weakness. This is associated with elevation of blood urea nitrogen, creatine phosphokinase, uric acid and glutamic oxaloacetic transaminase. Histological examination of muscle specimen from chicks exhibiting toxic syndrome showed degeneration and vacuolization of muscle fibers. The biochemical and histological changes observed are quite similar to those reported in clinical practice in some patients given clofibrate. It is suggested that this chick model could be used to investigate the biochemical basis of clofibrate toxicity.