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Biomedical subjects

E P Reaven

Publications and source records attributed to E P Reaven.

At least 19 recordsLinked to original sources
PubMed1987

Effect of age and sex on rat endocrine pancreas.

Maximal glucose-stimulated insulin secretion was quantified in perfused pancreases of 11-wk-old and 12-mo-old female and male rats. In addition, measurements were made of body weight, total pancreatic weight, and percentage of the pancreas occupied by islet tissue. Body weight (mean +/- SE) of male rats was greater than that of female rats at both 11 wk (319 +/- 3 vs. 237 +/- 13 g) and 12 mo (684 +/- 17 vs. 376 +/- 13 g) of age. Pancreatic weight and percentage of the pancreas occupied by islet tissue were also greater in male rats and increased in approximate proportion to the gain in weight. The first phase and the second phase of maximal glucose-stimulated insulin secretion were both qualitatively and quantitatively similar in all four groups of rats. However, because islet cell mass increased with age, maximal glucose-stimulated insulin secretion declined with age in rats of both sexes when expressed per unit islet tissue. Although the fall in insulin secretion (per islet cell mass) with age was observed in perfused pancreases from both male and female rats, the pancreases of female rats contained relatively less islet tissue and secreted more insulin per unit islet cell mass than pancreases of male rats at either age. Thus, there are sex differences in both islet cell structure and function, but the effect of age on endocrine pancreatic function seems to be independent of sex.

Aging↗
PubMed1986

The effect of exercise training on insulin resistance in sedentary year old rats.

The purpose of this study was to determine if exercise training of 12-month-old Sprague-Dawley rats could reverse the resistance to insulin-induced glucose uptake that has been shown to occur in these animals. Twelve-month-old rats were trained to run 1 1/2 miles/day in motorized exercise wheel cages, and the ability of insulin to stimulate glucose uptake in these rats was compared with values observed in two groups of similar aged sedentary rats--one fed rat chow ad libitum and the other a calorie-restricted diet for 4 months. Body weight increased and insulin-stimulated glucose uptake decreased as rats fed chow ad libitum grew from 12 to 16 months of age. In contrast, 4 months of either exercise training or calorie restriction prevented weight gain and loss of insulin-stimulated glucose uptake. Thus, the intensity of exercise training attained in this study did not result in an improvement in insulin action in older rats above and beyond that related to the reduction in rate of body weight gain.

Aging↗
PubMed1985

Glucose and fructose feeding lead to alterations in structure and function of very low density lipoproteins.

Young male rats were fed regular lab chow, or a diet containing 66% of total calories as either glucose or fructose. Both experimental diets led to hypertriglyceridemia, with fasting TG concentrations after one week of 195 +/- 20 and 296 +/- 44 mg/dl for rats fed glucose and fructose, respectively, compared to 94 +/- 10 mg/dl in the control rats. Moderate changes in VLDL composition were observed with both test diets, characterized by slight increases in TG: protein ratio, and increased total cholesterol and phospholipid content. In addition, VLDL isolated from rats fed high carbohydrate diets were increased in size, with a mean VLDL particle diameter of 666 A and 720 A in glucose-fed and fructose-fed rats, as compared to 536 A in control rats. The changes in lipid composition and size of VLDL particles isolated from glucose and fructose-fed donor rats were associated with an increase in their rate of removal from the circulation following their injection into normal recipient rats (half-life time 2.4 +/- 0.2 and 3.2 +/- 0.3 min respectively) as compared to VLDL-TG derived from chow fed donors (4.1 +/- 0.2 min). These data indicate that diets high in either glucose or fructose can lead to both structural and functional changes in VLDL, and provide additional evidence that the ability of fructose to induce profound hypertriglyceridemia is not secondary to a defect in VLDL-TG catabolism.

Animals↗
PubMed1983

Effect of antimicrotubule agents on terminal glycosyltransferases and other enzymes associated with rat liver subcellular fractions.

Previous studies have shown that anti microtubule agents disrupt Golgi complexes in hepatocytes and other cells, causing breakdown or vesiculation of Golgi cisternal membranes. Whether this change in the structure of the Golgi membranes is associated with changes in Golgi membrane function is not known. The present study was initiated to investigate this issue; i.e., to determine whether anti-microtubule agents that cause structural changes in Golgi membranes in vivo would, at the same time, affect characteristic enzyme functions of Golgi membranes. To this end, colchicine was given to young rats in vivo and various hepatic subcellular membranes were subsequently isolated and utilized for enzyme assays. Initially it was shown that colchicine (2.5 mg/kg body wt.) given for 5h significantly decreased the activities of the Golgi membrane associated enzymes galactosyl-, sialyl- and N-acetylglucosaminyl-transferases. More detailed experiments indicated that low doses of colchicine (0.8 mg/kg body wt.), although less effective than higher doses, decreased the activities of the terminal glycosylating enzymes maximally at 5h, with partial and complete recovery at 12 and 24h respectively. Treatment in vivo of rats with vinblastine (20 mg/kg body wt.) for 5h mimicked the action of colchicine. Two microsomal glycosylating enzymes (mannosyl and N acetylglucosaminyl transferases) were unaffected by the treatment with colchicine, as were various hepatic 'marker' enzymes such as 5' nucleotidase, glucose 6 phosphatase and succinate: 2-(p iodophenyl)-3-(p nitrophenyl)-5-phenyltetrazolium reductase (succinate dehydrogenase; EC 1.3.99.1), which were found to be enriched in plasma membrane, endoplasmic-reticulum and mitochondrial-membrane fractions respectively. These results show that anti-microtubule agents specifically suppress the activity of Golgi-associated glycosyltransferases in liver. Although it seems likely that these changes are related to the previously observed structural changes in hepatocyte Golgi complexes after colchicine treatment, to what extent the results are linked to the interaction of colchicine with microtubule protein remains to be clarified.

Animals↗
PubMed1983

Evidence of an age-related decline in mitochondrial glycerophosphate dehydrogenase activity of isolated rat islets.

The activities of three enzymes--two mitochondrial and one microsomal--were measured in isolated islets of Langerhans from 2-month-old and 12-month-old rats. Mitochondrial glycerophosphate dehydrogenase activity (expressed as nanomoles of iodonitrotetrazolium reduced per minute per milligram of protein), decreased (P less than 0.01) from a mean (+/- SEM) of 73.2 +/- 11.2 (2-month-old) to 34.7 +/- 5.9 (12-month-old). In contrast, activities of neither mitochondrial monoamine oxidase nor microsomal NADH cytochrome-c reductase changed with age. These results demonstrate that the activity of the glycerophosphate shuttle decreases as rats grow older, and it raises the possibility that the consequent difficulty in regenerating cytosolic NAD+ may play a role in the insulin secretory defect associated with aging.

Animals↗
PubMed1982

Does insulin removal rate from plasma decline with age?

The effect of age on the rate of insulin removal from plasma was studied in both rat and man. The experimental approach was based on measurement of the steady-state plasma insulin concentration achieved during a period in which endogenous insulin secretion was suppressed and exogenous insulin infused. Rats, 1 1/2 and 12 mo of age, were infused with 2.5, 5.0, and 10.0 mU/kg of insulin during a 180-min period in which endogenous insulin secretion was suppressed by epinephrine and propranolol. Steady-state plasma insulin concentrations were approximately twice as high in the older rats at every insulin infusion rate. Similar results were seen in man; significant correlations were observed between height of steady-state plasma insulin concentration and advancing age during infusion of exogenous insulin and suppression of endogenous insulin with either exogenous insulin (r = 0.66, P less than 0.001) or epinephrine and propranolol (r = 0.47, P less than 0.01). Since infusion rates of exogenous insulin were identical in all studies, these results suggest that there is an age-related decrease in insulin catabolism.

Adult↗
PubMed1981

Prevention of age-related hypertriglyceridemia by caloric restriction and exercise training in the rat.

Plasma triglyceride concentrations were determined in three experimental groups of rats as they grew from 1 1/2-12 mo of age. One group was kept sedentary and allowed food ad lib (control), the second group was allowed to eat and exercise in a running wheel ad lib, and the third calorically-restricted in order to maintain weight equal to that of the exercising rats. The exercise-trained and calorically-restricted rats gained less weight than did the control rats, and the age-related rise in plasma triglyceride concentration in control rats was totally abolished in the other two groups. In addition, exercise training and caloric restriction inhibited the increase in plasma insulin concentrations noted to occur with age in the control rats. These data indicate that there are two effective ways to prevent the development of hypertriglyceridemia that occurs with age in otherwise normal rats.

Aging↗
PubMed1981

Effect of variations in islet size and shape on glucose-stimulated insulin secretion.

The present study considers the effects of differences islet size and shape on in vitro glucose-stimulated insulin secretion. Islets were obtained from young rats and rapidly sorted into different size categories before incubation with 16.7 mM glucose. Subsequently, the diameters of each islet were measured and estimates of surface area and volume, assuming various spheroidal or ellipsoidal shapes, were obtained for each islet. These various figures were correlated with the amount of insulin secreted from the same islets and a regression curve was generated for each different islet shape. The results indicate that insulin secretion rates increased directly as a function of islet size (volume or surface area), regardless of islet shape (r = 0.78, p less than .01); thus, islet size is of major importance in predicting insulin secretion and studies utilizing isolated islets should be normalized for this factor. Measurements of islet diameter provide an easy solution to this problem.

Animals↗
PubMed1981

Structure and function changes in the endocrine pancreas of aging rats with reference to the modulating effects of exercise and caloric restriction.

The current study was conducted to determine if physical activity and/or weight control could influence the age-related decrease in beta cell insulin response noted in earlier studies. As such, virgin, male Sprague-Dawley rats were maintained in our facility for 1 yr on three differential experimental programs; in the first group, control rats lived under standard laboratory conditions; the second group of rats ran several miles a day in exercise wheels, and the third group was given a calorie-restricted diet designed to keep the rats weight-matched with the exercising rats. The results showed that the 12-mo-old sedentary control rats weighed an average of 800g. From the time these rats were 4 mo old, they were significantly hyperinsulinemic, with mean (+/- SEM) serum insulin levels of 55 +/- 6 microU/ml. Morphological studies on the pancreas of these rats at the end of the year revealed enlarged, multilobulated, fibrotic islets. After collagenase digestion, the most normal-appearing islets from the 12-mo-old controls were used for insulin secretion studies, these islets showed significantly reduced glucose-induced insulin release (0.83 microU insulin/min per volume islet) compared with islets from young rats (1.80 microU insulin/min per volume islet). In contrast, 12-mo-old exercised or calorie-restricted rats weighed approximately 500 g and did not show the changes in serum insulin levels or pancreas pathology exhibited by the sedentary control animals. However, islets from the calorie-restricted group functioned in vitro no better than islets from he sedentary control group. Islets from the exercised rats were somewhat improved in this regard. In summary, we believe exercise and weight control diminishes the animals' need for insulin-resulting in youthful-appearing islets after a year's time. However, these regimes do not appear able to correct the beta cell decline in function previously described.

Aging↗
PubMed1980

Effects of age on various aspects of glucose and insulin metabolism.

Age is known to be associated with the development of glucose intolerance. In this review an effort has been made to differentiate between the effects of age per se on glucose tolerance, as distinguished from those of such age-related variables as obesity, diet, development of frank diabetes, etc. At the same time, an attempt was made to evaluate the evidence implicating abnormalities of insulin secretion and/or insulin action in the development of glucose intolerance with age. It is concluded that the questions being asked are far from simple, and that available data do not provide unequivocal answers.

Adolescent↗
PubMed1980

Immunoperoxidase staining of glial fibrillary acidic (GFA) protein polymerized in vitro: an ultramicroscopic study.

The unlabeled antibody peroxidase-antiperoxidase (PAP) method of Sternberger et al. has been employed at the ultramicroscopic level to stain filaments polymerized in vitro from aqueous extracts of multiple sclerosis (MS) plaques. The filaments were heavily decorated with antiserum to the glial fibrillary acidic (GFA) protein but not stained with serum absorbed with GFA protein, preimmunization serum, or anti-rat brain tubulin but was not stained with antiserum to the GFA protein. The present study provides direct morphological evidence that filaments polymerized in vitro from extracts of MS plaques contain the GFA protein.

Animals↗
PubMed1980

Evidence that microtubules play a permissive role in hepatocyte very low density lipoprotein secretion.

To determine whether a minimum number of assembled microtubules is required for very low density lipoprotein (VLDL) triglyceride TG) secretion in hepatocytes, antimicrotubule drugs of different concentrations were given to rats. Hepatic VLDL-TG release was subsequently measured by a liver perfusion system, and hepatocyte ultrastructural changes were analyzed by quantitative ultrastructural methods. The results demonstrate a tight coupling between the reduction in hepatocyte microtubule content and the reduction in hepatic VLDL-TG secretion which is related to the dose of colchicine or vinblastine administered. The various estimates imply that a minimum number of microtubules is necessary for hepatic VLDL secretion to proceed normally and that hepatic VLDL secretion rates reach their nadir (10--30% of control) when microtubules comprise less than 0.005% of the cytoplasm (or less than 10% of control values) when microtubules comprise less than 0.005% of the cytoplasm (or less than 10% of control values). At this point, hepatocyte Golgi complexes are also greatly altered; Golgi complexes with recognizable dictyosomal membranes are reduced to 15% of control values and the region is filled with large numbers of electron-dense bodies which appear to be lysosomes in the process of digesting VLDL. There is a predilection for the remaining Golgi complexes to be associated with a few segments of microtubules, even when no microtubules can be measured in random samplings of hepatocytes. Clusters of vacuoles containing VLDL are also present throughout the cytoplasm; the limiting membranes of 25% of these vacuoles are studded with ribosomes. These findings demonstrate that the administration of antimicrotubule agents results in decreases in hepatic VLDL-TG secretion which are associated with loss of microtubules and alteration of existing Golgi complexes.

Animals↗
PubMed1979

Effect of age on glucose-stimulated insulin release by the beta-cell of the rat.

To assess the effect of age on beta-cell insulin release, collagenase-isolated islets of Langerhans were obtained from rats aged 2--18 mo and incubated with increasing concentrations of glucose. Similar islets were analyzed for insulin content or subjected to morphometric measurements to identify both the number of beta-cells and the volume of beta-granules per islet. In parallel studies, the islet content of intact pancreata was also determined. The results showed that beta-cell number increased from 2,300 t0 5,000 cells as rats aged from 2 to 18 mo and islet insulin content doubled. However, glucose-stimulated insulin release decreased progressively with age, and this was especially striking when considered in terms of the increase in number of beta-cells/islet; e.g., mean (+/- SEM) insulin secretion (nanounits per minute per beta-cell) of islets incubated with 450 mg/dl of glucose was 1.3 (+/- 0.02), 1.0 (+/- 0.1), 0.4 (+/- 0.05), and 0.3 (+/- 0.01), respectively for 2-, 6-, 12-, and 18-mo-old rats. Thus, insulin secretion per beta-cell was decreased, despite increased stores of insulin per cell. These findings demonstrate that the aging process leads to a profound defect in glucose-stimulated insulin release from the beta-cell. Whether this is a global secretory defect, or solely a failure of the beta-cell to respond to glucose, remains to be defined.

Aging↗
PubMed1979

Characterization of a model of dietary-induced hypertriglyceridemia in young, nonobese rats.

Healthy, nonobese, young rats developed hypertriglyceridemia (mean triglyceride levels of 250 mg/dl) following consumption of a sucrose-lard diet. The hypertriglyceridemia was apparent three days after start of the diet and persisted throughout the 4-week experimental period. Body weight, liver weight, and serum glucose levels were similar in animals eating either the sucrose-lard diet or standard rat chow. On the other hand, serum free fatty acid levels were slightly increased and serum insulin levels were substantially increased in animals eating the sucrose-lard diet. Determination of very low density lipoprotein turnover revealed that total triglyceride secretion in rats eating the sucrose-lard diet was significantly (P < 0.01) increased over that of rats eating standard chow. Direct measurement of hepatic and intestinal very low density lipoprotein secretion indicated that the observed rise in total triglyceride secretion was secondary to increased secretion of very low density lipoproteins by the liver. Finally, lipoprotein lipase activity of adipose tissue from rats eating the sucrose-lard diet was equal to, or greater than (depending upon sampling time), the activity of the enzyme from adipose tissue of rats eating the control diet. These data indicate that young, nonobese, rats develop hypertriglyceridemia when they ingest a sucrose-lard diet, and that the rise in plasma triglyceride levels results from an increase in hepatic very low density lipoprotein secretion. The dietary-induced hypertriglyceridemia is associated with elevated serum insulin levels, and, as such, may provide a useful animal model to use in studies aimed at defining the pathogenesis of endogenous hypertriglyceridemia in man.-Reaven, G. M., T. R. Risser, Y-D. I. Chen, and E. P. Reaven. Characterization of a model of dietary-induced hypertriglyceridemia in young, nonobese rats.

Animals↗
PubMed1978

Dissociation between rate of hepatic lipoprotein secretion and hepatocyte microtubule content.

The fact that colchicines inhibits hepatic secretion of very low density lipoprotein (VLDL) particles has been interpreted to mean that microtubules are involved in hepatic VLDL secretion. To further define this relationship, we have attempted to see if changes in hepatic VLDL secretion are associated with changes in hepatocyte microtubule or tubulin content. Accordingly, hepatic secretion of VLDL was increased in rats, and the hepatocyte content of both microtubules (using quantitative morphometric methods) and tubulin (using a time-decay colchicine binding assay) was determined. In acute experiments, VLDL secretion was increased by perfusion of isolated rat livers for 2 h with varying concentrations of free fatty acids (FFA). Results indicate that hepatic VLDL triglyceride (TG) secretion at perfusate FFA levels of 0.7 muEq/ml is threefold greater (P < 0.01) than when livers are perfused without added FFA. However, no differences are observed in the content of microtubules in these livers: specifically, microtubules occupy 0.029 percent of hepatocyte cytoplasm in livers perfused without FFA and 0.030 percent of cytoplasm in livers perfused with FFA. In chronic experiments, rats were fed for 1 wk with either standard rat chow or a hyperlipidemic (sucrose/lard) diet. With the experimental diet, plasma triglyceride levels increase threefold over controls, and liver VLDL-TG production, as determined by [(3)H]glycerol turnover studies, is 55 percent greater (P < 0.01) than controls. However, microtubules occupy 0.027 percent of the cytoplasm of hepatocyte cytoplasm whether rats are on standard or hyperlipidemic diets. Furthermore, the tubulin content of isolated hepatocytes does change, and represents 1 percent of hepatocyte soluble protein, irrespective of diet. These results suggest that increases in hepatic VLDL secretion can occur without any demonstrable change in hepatocyte assembled microtubule or tubulin content, and raise questions as to the role played by microtubules in hepatic VLDL secretion.

Animals↗
PubMed1978

Intestinal contribution to secretion of very low density lipoproteins into plasma.

To resolve the question of the magnitude of the intestine's contribution to circulating very low density lipoproteins (VLDL), measurements of intestinal, hepatic, and total VLDL--triglyceride were made on the same animals or on animals studied under comparable conditions. Animals were examined in the fasted state and during infusion of a fat-free meal. Intestinal VLDL secretion was determined through timed collections of lymph from the mesenteric lymph duct; hepatic and total VLDL secretion rates were estimated by the accumulation of plasma VLDL after injections of Triton WR 1339. Results indicate that the intestine contributes only a minor portion (11%) of the amount of triglyceride entering into the plasma compartment in the fasted state. Although intestinal triglyceride production is increased by 50% (p less than 0.01) in fed rats, the overall contribution of the intestine is not significantly altered in fed rats and represents only 14--17% of total body VLDL secretion. Thus, although intestinal VLDL secretion can be modified experimentally, its total impact on endogenous triglyceride production in normotriglyceridemic rats is small.

Animals↗