Biomedical subjects

G Reaven

Publications and source records attributed to G Reaven.

At least 37 records · Page 2Linked to original sources

PubMed1986

Comparison of glucose metabolism in adipocytes from Pima Indians and Caucasians.

The present study was designed to compare various aspects of glucose metabolism of adipocytes isolated from 10 obese Pima Indians and 10 Caucasians. All 20 subjects had normal glucose tolerance, and the two groups were matched for sex, age, degree of obesity, and fasting plasma glucose and insulin concentrations. The results indicated that adipocytes from the two groups were comparable in average cell size, basal and maximum insulin-stimulated glucose transport, glucose metabolism at 5.5 mmol/L glucose, ED50 of insulin for glucose transport and the inhibition of lipolysis, basal lipolysis rates, and insulin binding. The similarity between the metabolic behavior of adipocytes isolated from Pimas and Caucasians suggests that the study of adipocytes from Pima Indians yields information that is relevant to the understanding of obesity in other populations.

Adipose Tissue↗

PubMed1985

Relationship between degree of obesity and in vivo insulin action in man.

Previous studies have demonstrated reduced in vivo insulin action in obese subjects compared with lean controls. However, little data is available on the relationship between degree of obesity and insulin action, and this relationship has not been shown to be independent of individual differences in maximal aerobic capacity. We studied 55 male Pima Indians and 35 male Caucasians with normal glucose tolerance. In vivo insulin action was measured using the hyperinsulinemic, euglycemic clamp technique at a plasma insulin concentration of approximately 100 microU/ml. Body composition was determined by densitometry, and maximal aerobic capacity was estimated using a graded exercise test. The results showed that degree of obesity was nonlinearly related to in vivo insulin action. In both Indians and Caucasians there was a significant decline in insulin action with increasing obesity up to a percent body fat of approximately 28-30%. Further increases in obesity in the Indians were not associated with significant changes in insulin action. Maximal aerobic capacity was positively linearly correlated with insulin action over the entire range of insulin action in both racial groups. Degree of obesity and maximal aerobic capacity were each independently associated with insulin action although these independent relationships were of marginal significance in the Caucasians. Surprisingly, individual differences in obesity and maximal aerobic capacity accounted for only half the variability observed in insulin action in these glucose tolerant subjects.

Adult↗

PubMed1984

Sex difference in insulin-stimulated glucose transport in rat and human adipocytes.

In an effort to determine whether differences in basal and maximum insulin-stimulated glucose transport by isolated adipocytes are a function of donor sex, we measured glucose transport rates in the absence and presence of 8 nM insulin in adipocytes isolated from the abdominal subcutaneous fat tissue of nine male and ten female subjects with varying degrees of obesity and in adipocytes isolated from the abdominal subcutaneous and retroperitoneal fat tissue of (180-220 g) male and female rats. Because maximal insulin-stimulated glucose transport rate per cell of adipocytes isolated from subcutaneous abdominal tissue of male and female subjects was constant in each sex, the data have been normalized on the basis of transport per cell. The results demonstrated that basal and maximal insulin-stimulated glucose transport per cell was 53-75% higher per cell in the females versus males in adipocytes from human subcutaneous abdominal adipose tissue (P less than 0.01). A similar difference in glucose transport rate between males and females (P less than 0.001) was also found in rat abdominal subcutaneous adipose tissue. Adipocytes isolated from rat retroperitoneal adipose tissue had higher transport rates (approximately three-fold) and smaller sex differences (35% higher in females) than found in adipocytes from rat and human subcutaneous tissue. These results indicate that basal and maximum insulin-stimulated glucose transport is higher by adipocytes isolated from females and that this difference is independent of adipose cell size and species.

Adipose Tissue↗

PubMed1984

Glucose-induced insulin secretion by perfused pancreas of 2- and 12-mo-old Fischer 344 rats.

Previous studies have shown that cells from older Sprague-Dawley rats secrete insulin less efficiently in response to a maximal glucose challenge than do beta-cells from young animals. In the current study we have asked whether this change in beta-cell response occurs in another strain of rat, and, if so, whether the secretory defect occurs at submaximal as well as maximal glucose stimulatory levels. Pancreas perfusions were carried out on 2- and 12-mo-old Fischer 344 rats at perfusate glucose concentrations of 150 and 300 mg/dl. The secretory data for each pancreas was subsequently corrected for differences in islet cell mass and expressed as insulin secretion per unit islet cell. The results show that 12-mo-old Fischer rats release more insulin per total pancreas than do 2-mo-old animals at both glucose concentrations. However when corrected for islet cell mass, the amount of insulin secretion per islet cell is actually reduced in the older Fischer rat. These data are comparable to those seen previously in the 12-mo-old Sprague-Dawley rat and indicate that the insulin secretory defect seen as rats grow older is not species specific.

Aging↗

PubMed1984

Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects.

The relationships between insulin secretion, insulin action, and fasting plasma glucose concentration (FPG) were examined in 34 southwest American Indians (19 nondiabetics, 15 noninsulin-dependent diabetics) who had a broad range of FPG (88-310 mg/100 ml). Fasting, glucose-stimulated, and meal-stimulated plasma insulin concentrations were negatively correlated with FPG in diabetics but not in nondiabetics. In contrast, fasting and glucose-stimulated plasma C-peptide concentrations did not decrease with increasing FPG in either group and 24-h urinary C-peptide excretion during a diet of mixed composition was positively correlated with FPG for all subjects (r = 0.36, P less than 0.05). Fasting free fatty acid (FFA) was correlated with FPG in nondiabetics (r = 0.49, P less than 0.05) and diabetics (r = 0.77, P less than 0.001). Fasting FFA was also correlated with the isotopically determined endogenous glucose production rate in the diabetics (r = 0.54, P less than 0.05). Endogenous glucose production was strongly correlated with FPG in the diabetics (r = 0.90, P less than 0.0001), but not in the nondiabetics. Indirect calorimetry showed that FPG was also negatively correlated with basal glucose oxidation rates (r = -0.61, P less than 0.001), but positively with lipid oxidation (r = 0.74, P less than 0.001) in the diabetics. Insulin action was measured as total insulin-mediated glucose disposal, glucose oxidation, and storage rates, using the euglycemic clamp with simultaneous indirect calorimetry at plasma insulin concentrations of 135 +/- 5 and 1738 +/- 59 microU/ml. These parameters of insulin action were significantly, negatively correlated with FPG in the nondiabetics at both insulin concentrations, but not in the diabetics although all the diabetics had markedly decreased insulin action. We conclude that decreased insulin action is present in the noninsulin-dependent diabetics in this population and marked hyperglycemia occurs with the addition of decreased peripheral insulin availability. Decreased peripheral insulin availability leads to increased FFA concentrations and lipid oxidation rates (and probably also increased concentrations of gluconeogenic precursors) that together stimulate gluconeogenesis, hepatic glucose production, and progressive hyperglycemia.

Adolescent↗

PubMed1984

Inhibition of lipolysis by adenosine is potentiated with age.

The ability of a variety of hormones to activate cells declines with age. We have investigated the mechanism for the reduced ability of beta adrenergic stimulation to activate lipolysis in fat cells from older rats. Previously, we have found that these cells have an intact lipolytic response to a cAMP analogue but diminished cAMP accumulation after isoproterenol stimulation, suggesting that the blunted cAMP response is rate limiting. In the present study we have tested the hypothesis that enhanced inhibition of lipolysis by endogenously released adenosine accounts for the diminished lipolysis. Adenosine deaminase was added to media containing the adipocytes from older rats to remove endogenous adenosine. Under these conditions beta adrenergic stimulation of lipolysis is intact in fat cells from older rats. The adenosine analogue N6-phenylisopropyladenosine more effectively inhibited lipolysis in the older group (77 +/- 6%) than in the younger group (46 +/- 5%), suggesting that enhanced efficacy of endogenous adenosine may account for the reduced lipolytic response to catecholamines. When pertussis vaccine was used to functionally inactivate adenosine receptors in adipocytes from the younger and older rats, the ability of isoproterenol to activate lipolysis was restored in the older group. All the data are consistent with the hypothesis that enhanced inhibitory effects of adenosine explain the diminished ability of beta adrenergic agonists to activate lipolysis. It is possible that enhanced inhibitory pathways may be involved in blunting responses to stimulatory hormones in other tissues from older animals.

Adenosine↗

PubMed1984

The effect of sucrose content in high and low carbohydrate diets on plasma glucose, insulin, and lipid responses in hypertriglyceridemic humans.

To further understand the effect of high carbohydrate (CHO)-low fat diets and the role of variations in dietary sucrose on CHO and lipid metabolism, 10 patients with hypertriglyceridemia were fed 2 isocaloric, typical American diets, containing 40% and 60% CHO, for 15 days in random sequence. Each patient was their own control, and they were divided into 2 groups of 5 patients each. In one group, sucrose was held constant at 13% of total calories (40-13% and 60-13%), whereas the sucrose content was 9% of the total calories on a 40% CHO diet (40-9%), and 15% of total calories on a 60% CHO diet (60-15%) in the other group. Fasting and postprandial blood samples were analyzed for plasma glucose, insulin, cholesterol (Chol), and triglycerides (TG), as well as for Chol and TG in chylomicrons, very low density, low density, and high density lipoproteins (HDL). Fasting plasma TG levels were significantly increased in both groups on the 60% CHO diet, primarily due to increases in very low density-TG concentration. The magnitude of the elevation was attenuated when sucrose content was kept constant. Postprandial TG responses were qualitatively similar. There were no significant changes in plasma Chol concentrations, except for a modest fall in plasma HDL-Chol level after the 60-13% diet period (P less than 0.05). No significant differences were found in fasting plasma glucose or insulin concentration. However, postprandial glucose and insulin responses were increased on both high CHO diets. The results of these studies demonstrate that high CHO-low fat diets, in general, tend to elevate plasma glucose, insulin, and TG concentrations and reduce HDL-Chol concentration in patients with endogenous hypertriglyceridemia. In addition, these data illustrate the important role that small variations in dietary sucrose can play in modulation of CHO and lipid metabolism.

Blood Glucose↗

PubMed1983

Disparate effects of prazosin and propranolol on lipid metabolism in a rat model.

The effects of 14 days of daily intraperitoneal injections of prazosin hydrochloride (3.0 or 0.3 mg/kg) or propranolol (5 mg/kg) on various aspects of the lipid metabolism of normal rats was studied. The results indicate that plasma triglyceride and cholesterol concentrations were lower and the ratio of plasma HDL-cholesterol to total cholesterol concentration higher in prazosin-treated rats compared with propranolol-treated rats. The decline in plasma triglyceride levels in prazosin-treated rats was associated with a commensurate reduction in triglyceride secretion rates. Plasma free fatty acid levels were also lower in prazosin-treated rats, and this change may have contributed to the fall in triglyceride secretion rates. These data demonstrate that the disparate effects of alpha and beta receptor antagonists, previously shown to occur in hypertensive humans, can be duplicated in normal rats.

Animals↗

PubMed1983

Effect of age and environmental factors on insulin release from the perfused pancreas of the rat.

In this study we examined the effect of age and various age-related environmental factors on maximal glucose-stimulated insulin release by the intact perfused pancreas. Male Sprague-Dawley rats were maintained from 40 d to 12 mo of age on standard chow, or on a sucrose-rich or calorie-restricted diet. At 12 mo, studies were carried out on the isolated pancreas of each animal to determine maximal (300 mg/ml) glucose-stimulated insulin secretion. After these studies were completed, each pancreas was perfused with formalin fixative and processed for morphometric estimation of the mass of the endocrine pancreas. Data from these older animals were compared with data from 2-mo-old control rats. The results indicate that maximal glucose-stimulated insulin secretion per unit endocrine pancreas was markedly reduced in all three groups of 12-mo-old rats, and was only 25-33% of that of 2-mo-old rats. Thus, aging led to a decline in insulin secretion per beta cell that was not modifiable by environmental manipulation. On the other hand, environmental factors can influence the development of endocrine tissue within the pancreas, and in so doing, modify total pancreatic insulin secretion. The mass of the endocrine pancreas of 12-mo-old rats fed either sucrose or chow was between three and four times that of 2-mo-old control rats, and these older rats were able to maximally secrete as much insulin per total pancreas as the young rats. In contrast, the endocrine cell mass of the calorie-restricted rats had not enlarged to this extent, and the maximally stimulated perfused pancreas from these rats secreted less insulin. These data suggest that the aging animal, challenged in vivo to secrete insulin, can overcome the loss of the beta cell response by expanding its pancreatic pool of beta cells. Although this compensation is successful in the 12-mo-old, obese, middle-aged rat, it is not yet clear what effect further aging would have on these events.

Aging↗

PubMed1983

In vitro insulin resistance of human adipocytes isolated from subjects with noninsulin-dependent diabetes mellitus.

To assess possible cellular mechanisms of in vitro resistance in noninsulin-dependent diabetes mellitus (NIDDM), maximum insulin-stimulated glucose transport and utilization and insulin binding were measured in adipocytes isolated from weight-matched normal glycemic subjects and patients with NIDDM. Glucose transport rate was determined by measuring the amount of [U-14C]-D-glucose taken up by incubating adipocytes at trace concentrations of glucose (300 nM), and glucose metabolism by estimating the amount of lactate, CO2, triglyceride, and total glucose carbons retained in the cells following incubating at 5.5 mM glucose. Insulin binding was measured at 50, 100, and 200 pM [mono125I-tyrosinyl A14]insulin. Both maximum insulin-stimulated glucose transport and utilization in adipocytes from diabetic subjects were 40% (P less than 0.01) and 32% (P less than 0.05) lower, respectively, than values obtained for subjects with normal glucose tolerance. In addition, the maximum capacity of glucose transport was correlated with the maximum capacity of glucose utilization (r = 0.81, P less than 0.001). Furthermore, fasting plasma glucose concentrations of diabetic subjects were negatively correlated with both maximum insulin-stimulated glucose transport (r = -0.56, P less than 0.05) and glucose utilization (r = -0.67, P less than 0.05). Since basal glucose transport in adipocytes from diabetic subjects was also 33% lower than in adipocytes from normal subjects, there was no change in the relative ability of insulin to stimulate glucose transport. However, there was a 64% decrease in the sensitivity of the glucose transport system to insulin (P less than 0.05), unrelated to concomitant changes in insulin binding. These results demonstrate that both maximal insulin-stimulated glucose transport and utilization, and the sensitivity of the glucose transport system to insulin, was decreased in adipocytes isolated from subjects with NIDDM. These in vitro defects were associated with impaired glucose metabolism in vivo, consistent with the view that the metabolic alterations observed at the cellular level may contribute to the in vivo insulin resistance of NIDDM.

Adipose Tissue↗

PubMed1983

Improvement in in vitro insulin action after one month of insulin therapy in obese noninsulin-dependent diabetics. Measurements of glucose transport and metabolism, insulin binding, and lipolysis in isolated adipocytes.

It has been previously reported that maximum insulin-stimulated glucose transport and utilization were both decreased, while basal lipolysis was increased in adipocytes from obese subjects with noninsulin-dependent diabetes mellitus (NIDDM). To determine whether these values can be returned towards those obtained in equally obese subjects with normal glucose tolerance, these measures of adipocyte metabolism were quantified in 10 NIDDM subjects before and after control of hyperglycemia with insulin. The results demonstrate that maximum insulin-stimulated glucose transport (P less than 0.02) and glucose incorporation into triglyceride (P less than 0.01) and CO2 (P less than 0.05) (at 5.5 mM glucose) increased and basal lipolysis decreased (P less than 0.05) after 4 wk of insulin treatment. In contrast, glucose incorporation into lactate and other glycolytic metabolites (at 5.5 mM glucose), and sensitivity of glucose transport to insulin, did not improve with insulin therapy. The latter occurred despite an increase in insulin binding (P less than 0.01). Finally, the improvement in maximal insulin-stimulated glucose transport correlated with the fall in fasting hyperglycemia (r = 0.77, P less than 0.01). These findings demonstrate that several of the abnormalities of carbohydrate and lipid metabolism recently noted to be present in adipocytes from patients with NIDDM can be shown to significantly improve with insulin treatment.

Adipose Tissue↗

PubMed1983

Effect of exercise and diet on triglyceride metabolism in rats with moderate insulin deficiency.

The ability of exercise and diet to modify the effects of moderate streptozotocin-induced insulin deficiency on triglyceride metabolism has been studied in the rat. Insulin-deficient rats allowed to run spontaneously in exercise wheel cages had significantly lower (P less than 0.001) plasma glucose levels (187 +/- 19 mg/dl) than either sedentary (374 +/- 24 mg/dl) or sucrose-fed (450 +/- 13 mg/dl) diabetic rats, despite the fact that plasma insulin levels were comparable in all these groups. Plasma triglyceride (TG) levels in exercise-trained rats with diabetes (51 +/- 5 mg/dl) were actually lower than in control rats with normal glucose tolerance (90 +/- 14 mg/dl). In contrast, plasma TG levels were higher than control levels in diabetic sedentary rats (128 +/- 11 mg/dl), and severe hypertriglyceridemia developed in sucrose-fed diabetic rats (369 +/- 35 mg/dl). The ability of exercise training to attenuate diabetic hypertriglyceridemia, which was observed in both chow-fed and sucrose-fed rats, was secondary to a decrease in TG secretion, and appeared to be related to lower plasma FFA concentrations. In contrast, the accentuation of diabetic hypertriglyceridemia seen in sucrose-fed rats was related to a defect in TG catabolism. Adipose tissue lipoprotein lipase (LPL) activities were essentially identical in all diabetic rats, suggesting that the observed difference in TG kinetics could not be attributed to concomitant increases or decreases in adipose tissue LPL activity. These results emphasize the powerful impact of exercise and diet on TG metabolism in rats with moderate degrees of insulin deficiency.

Adipose Tissue↗

PubMed1982

Functional homogeneity of pancreatic islets of aging rats.

Islest from different regions of pancreases of aging rats were compared for size and variations of response to glucose stimulation. The results show that pancreatic islets from the ventral-duodenal and splenic regions of 12-mo-old retired breeder. Spraque dawley rats are comparable in all respects measured: thus, pancreatic regional differences cannot explain the age-associated reduction in beta cell secretory response noted in previous studies.

Aging↗

PubMed1982

Effect of age on plasma glucose and insulin responses to a test mixed meal.

Plasma glucose and insulin responses to an oral dextrose tolerance test and to a mixed-meal test were determined in fully ambulatory residents of a retirement community. The study population consisted of 127 women and 79 men, whose ages ranged from 47 to 90 years. Progressive hyperglycemia and hyperinsulinemia with age could be demonstrated in the women. These changes were observed with either type of tolerance test and could not be attributed to age-related differences in measurements of body mass index or estimates of physical activity. In contrast, no significant changes with age in either glucose or insulin responses were noted in men. The ability to document increases in the plasma glucose or insulin responses were noted in men. The ability to document increases in the plasma glucose and insulin responses to a mixed meal suggests that aging, at least in women, is associated with day-long elevations of both plasma glucose and insulin concentrations. The possible relationship of these metabolic changes to the development of atherosclerosis merits further consideration.

Adult↗

PubMed1982

Effect of variations in basal plasma glucose concentration on glucose utilization (M) and metabolic clearance (MCR) rates during insulin clamp studies in patients with non-insulin-dependent diabetes mellitus.

Two insulin clamp studies were performed at different steady-state plasma glucose concentrations in 13 patients with non-insulin-dependent diabetes mellitus (NIDDM). Steady-state plasma insulin concentrations were comparable, with mean +/- SEM levels of 94 +/- 3 and 95 +/- 4 muU/ml being achieved during the two studies. Glucose utilization rate (M) varied directly with plasma glucose concentration in each subject. Thus, the mean +/- SEM value of M was 4.92 +/- 0.73 mg/kg/min when patients were studied at a mean +/- SEM plasma glucose concentration of 226 +/- 15 mg/dl, and M was 2.71 mg/kg/min when the same subjects were studied at a glucose concentration of 118 +/- 6 mg/dl. In contrast, the values for glucose metabolic clearance rate (MCR), which were 2.35 +/- 0.50 and 2.49 +/- 0.47 ml/kg/min, respectively, during the two studies, did not vary significantly with plasma glucose concentration. These data indicate that the glucose metabolic clearance rate (MCR), but not glucose utilization rate (M), can be used to compare in vivo insulin action when insulin clamp studies are performed in subjects with different basal plasma glucose concentrations.

Blood Glucose↗

PubMed1981

Assessment of insulin resistance with the insulin suppression test and the euglycemic clamp.

Insulin resistance was quantified with two different methods in 30 subjects with varying degrees of glucose tolerance. One method, the insulin suppression test, is performed by continuously infusing epinephrine, propranolol, insulin, and glucose. Epinephrine and propranolol suppress endogenous insulin release, and steady-state plasma levels of exogenous insulin and glucose are reached in all individuals. Because the steady-state insulin level is the same in all subjects, the height of the steady-state plasma glucose level provides a direct estimate of insulin resistance. The other method, the euglycemic clamp technique, produces a steady-state level of exogenous hyperinsulinemia by means of a primed and continuous insulin infusion. Glucose is also infused at a rate sufficient to prevent an insulin-induced fall in glucose concentration, and the amount of glucose required to maintain the basal plasma glucose level provides the estimates of insulin resistance. The results indicated that estimates of insulin resistance generated by the two methods were highly correlated (r = 0.93). Furthermore, both methods of assessing insulin resistance indicated that the greater the degree of glucose intolerance, the more severe the insulin resistance. These results serve to further emphasize the importance of insulin resistance in the pathogenesis of hyperglycemia in type II diabetes.

Adult↗

PubMed1980

Effect of age on plasma triglyceride concentrations in man.

Plasma triglyceride (TG) concentrations increase with advancing age. To determine if this phenomenon is due to age per se or to age-related changes in other metabolic variables, determination of fasting plasma TG, glucose, insulin, and free fatty acid (FFA) concentrations, as well as body mass index (BMI), were made on 167 normal subjects from 18 to 77 yr of age. Significant simple correlation coefficients (r) were found between TG concentrations and age (0.47), BMI (0.39) and fasting plasma glucose (0.40), insulin (0.24), and FFA (0.20) concentrations. Multiple regression analysis was used to determine the total amount of variability in TG concentration that could be accounted for by the combination of the examined metabolic parameters. A highly significant (p < 0.0001) total correlation of 0.57 was obtained, indicating that these variables could account for approximately one-third of the total variances. Partial correlation analysis (fixing four of the five variables) yielded a correlation coefficient of 0.35 (p < 0.001) between age and fasting TG concentration. Hence, age per se, or an age-dependent phenomenon, appears to be an independent factor with a role in determining plasma TG concentrations.

Adolescent↗

PubMed1980

Effect of source of dietary carbohydrate on plasma glucose and insulin responses to test meals in normal subjects.

Plasma glucose and insulin responses were measured in 22 subjects after two meal tolerance tests that varied only in the food source of carbohydrate. Each meal contained 45% carbohydrate, 15% protein, and 40% fat and provided 40% of calculated daily caloric requirement. The meals elicited a similar glucose response; however, the insulin response was significantly lower when rice and corn supplied the carbohydrate as compared to potato and gelatin. The total insulin response, calculated as area under the response curve, was 60% (P less than 0.001) greater in the meal with potato and gelatin versus the rice and corn meal.

Adult↗