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Biomedical subjects

J Olefsky

Publications and source records attributed to J Olefsky.

18 recordsLinked to original sources
PubMed1991

Transdominant inhibition of tyrosine kinase activity in mutant insulin/insulin-like growth factor I hybrid receptors.

Classical insulin and insulin-like growth factor I (IGF-I) receptors exist as well defined alpha 2 beta 2 heterotetrameric complexes that are assembled from two identical alpha beta heterodimeric half-receptor precursors. Recent evidence suggests that insulin and IGF-I half-receptors can heterologously assemble to form alpha 2 beta 2 insulin/IGF-I hybrid receptor complexes in vivo and in vitro. We have utilized hybrid receptor complexes to examine ligand-stimulated transmembrane signaling of wild-type insulin (alpha beta INS.WT) or IGF-I (alpha beta IGF.WT) half-receptors assembled with a kinase-defective insulin half-receptor mutant (alpha beta INS.A/K). In vitro assembly of either (alpha beta)IGF.WT/(alpha beta)INS.A/K or (alpha beta)INS.WT/(alpha beta)INS.A/K hybrid receptors resulted in decreased substrate protein kinase activity. The degree of protein kinase inactivation directly correlated with the amount of immunologically cross-reactive hybrid receptors formed. In contrast to substrate kinase activity, insulin-stimulated autophosphorylation of the (alpha beta)INS.WT/(alpha beta)INS.A/K hybrid receptor complex was completely unaffected in comparison to the wild-type (alpha beta)INS.WT/(alpha beta)INS.WT receptor. To assess a molecular basis for this difference, autophosphorylation of a hybrid receptor composed of a truncated beta-subunit insulin half-receptor with the kinase-defective half-receptor, (alpha beta)INS. delta CT/(alpha beta)INS.A/K, demonstrated the exclusive autophosphorylation of the (alpha beta)INS.A/K half-receptor beta subunit. These results demonstrate that ligand-dependent substrate phosphorylation by insulin and IGF-I holoreceptors requires interactions between two functional beta subunits within the alpha 2 beta 2 heterotetrameric complex and occurs through an intramolecular trans-phosphorylation reaction.

Cell Membrane↗
PubMed1986

Effect of the alpha-glucosidase inhibitor Bay-O-1248 on the metabolic response of nondiabetic and diabetic rats to a high-carbohydrate diet.

The metabolic consequences of the addition of a new alpha-glucosidase inhibitor (BAY-O-1248) to a high carbohydrate diet (67% by calories) in which the carbohydrate comprised equal quantities (50% wt/wt) of wheat starch and sucrose (Diet A) or 100% glucose (Diet B) was studied in diabetic and nondiabetic rats. BAY-O-1248 led to a significant reduction in daily food intake and weight gain in rats fed Diet A but not Diet B. In diabetic rats fed Diet A with BAY-O-1248, daily urinary glucose was significantly diminished (6820 +/- 402 vs 3796 +/- 210 mg), while the postprandial plasma glucose excursions were similar. In nondiabetic rats, the addition of BAY-O-1248 decreased the postprandial plasma glucose level with no change in urine glucose. In summary, addition of an alpha-glucosidase inhibitor to a starch plus sucrose containing diet led to reductions in glycosuria (diabetic rats) and serum glucose levels (normal rats).

1-Deoxynojirimycin↗
PubMed1979

A structurally abnormal insulin causing human diabetes.

Insulin isolated from the pancreas of a diabetic patient with fasting hyperinsulinaemia showed decreased activity in binding to cell membrane insulin receptors and in stimulating cellular 2-deoxyglucose transport and glucose oxidation. Chemical studies suggest that the isolated hormone is a mixture of normal insulin and an abnormal variant which contains a leucine for phenylalanine substitution at position 24 or 25 of the insulin B-chain.

Amino Acid Sequence↗
PubMed1977

Postprandial plasma-glucose and -insulin responses to different complex carbohydrates.

We have studied the effects of dextrose, rice, potato, corn, and bread on postprandial plasma glucose and insulin responses in 16 subjects. All carbohydrate loads were calculated to contain 50 gm. of glucose. The data demonstrate (1) that dextrose and potato elicited similar plasma glucose responses whereas rice, corn, and bread elicited lower responses; (2) similarly, dextrose and potato elicited similar and greater plasma insulin responses than rice and corn, with the response to bread being intermediate; (3) when the study group was divided in half, on the basis of each subject's one-hour plasma glucose response to dextrose, the differences in the plasma glucose and insulin responses were greater in the subjects with the highest glucose response to dextrose than in the low responders. In conclusion, there is a range of plasma-glucose and insulin responses to different complex carbohydrates, with rice and corn producing the lowest response curves. Furthermore, these differences are accentuated in patients with reduced glucose tolerance.

Blood Glucose↗
PubMed1976

Insulin receptors of skeletal muscle: specific insulin binding sites and demonstration of decreased numbers of sites in obese rats.

A membrane preparation was obtained from rat striated muscle. The preparation used has been shown to contain plasma membranes by electron microscopy as well as by enrichment in specific activity of both a plasma membrane enzyme "marker" (5'-nucleotidase) and cell surface 125I-incorporated radioactivity. The characteristics of 125I-insulin binding to this striated muscle preparation were studied, and it was found that 125I-insulin readily and specifically binds to this membrane preparation. The binding reaction was time, pH, and temperature dependent with optimal steady-state binding conditions occurring at 20 degrees C and at pH 7.6. Under these conditions (20 degrees C, pH 7.6) skeletal muscle plasma membranes displayed little ability to degrade insulin. Binding of 125I-insulin was readily inhibited at physiologic concentrations of unlabeled insulin and the specificity of this receptor for insulin was demonstrated by finding that high concentrations of glucagon, b-LH, b-FSH, p-PRL, hCG, TSH, and HGH were without effect on 125I-insulin binding and that insulin analogues inhibited binding in proportion to their biologic activity. When membranes from older, fatter rats were compared to membranes from younger, lean animals, 5'-nucleotidase specific activity and insulin degrading activity were found to be comparable. On the other hand, insulin binding to membrane receptors was decreased 30%-40% in the older, fatter animals. Thus, these studies indicate that (1) specific insulin receptors exist in skeletal muscle plasma membranes, and (2) membranes from older, fatter rats have fewer receptors than those from younger, lean animals.

Age Factors↗
PubMed1976

Plasma glucose and insulin responses to orally administered simple and complex carbohydrates.

We have studied the effects of glucose, sucrose, and various starches on postprandial plasma glucose and insulin responses in 19 subjects. All carbohydrate loads were calculated to contain 50 gm. of glucose, and the response to each carbohydrate was tested twice: when given alone in a drink or when given in combination with other nutrients as a meal. The data demonstrate: (1) Glucose and sucrose elicited similar plasma glucose response curves, but sucrose elicited a somewhat greater (20 per cent) plasma insulin response. (2) Raw starch ingestion resulted in a 44 per cent lower glucose response and a 35-65 per cent lower insulin response than did either glucose or sucrose ingestion. (3) When carbohydrate was given as a meal the plasma glucose responses were 40-60 per cent lower than when the same carbohydrate was given as a drink, while the insulin responses were generally similar, and (4) when different cooked starches were compared, the plasma glucose and insulin responses to rice were significantly lower (50 per cent) than to potato. In conclusion, the size of the carbohydrate molecule appears to influence the postprandial glucose and insulin responses such that more complex carbohydrates (starches) elicit lower responses. This effect may be related to differences in digestion rather than to differences in absorption.

Adult↗
PubMed1975

Metabolic effects of increased caloric intake in man.

In order to determine if increased caloric intake could be responsible for the insulin resistance and elevated plasma glucose, insulin, and triglyceride levels commonly associated with obesity, hypercaloric diets were fed for 3 wk to eight normal subjects, and the metabolic consequences of this diet were assessed before significant weight gain had occurred. One wk of increased caloric intake led to statistically significant increases in fasting plasma insulin (22 per cent), glucose (5 per cent), and triglyceride (30 per cent) levels, as well as an increased insulin response (20 per cent) to oral glucose. Since the average weight gain during this period was only 1.6 kg, the observed changes appear to be secondary to increased caloric consumption, not obesity. Most of these changes returned toward baseline values during the succeeding 2 wk of increased caloric intake, but statistically significant elevations of fasting plasma glucose (10 per cent), insulin (8 per cent) and cholesterol (15 per cent) levels were still seen at the end of the hypercaloric dietary period. On the other hand, insulin resistance, as estimated by direct measurement of insulin responsiveness, did not change as a result of 3 wk of increased caloric intake. These results indicate that acute increases in caloric intake can lead to elevated plasma glucose, insulin, cholesterol, and triglyceride levels. These changes occurred before significant weight gain had taken place, and raised the possibility that at least some of the abnormalities of carbohydrate and lipid metabolism attributed to obesity may be due to increased caloric intake. However, this conclusion would not seem to apply to the insulin resistance associated with obesity, as 3 wk of increased caloric intake did not produce any change in the responsiveness of these subjects to insulin's action.

Adult↗
PubMed1975

Quantification of plasma cholesterol and triglyceride levels in hypercholesterolemic subjects receiving ascorbic acid supplements.

In order to assess the possible effects of ascorbic acid on plasma cholesterol and triglyceride levels and plasma lipoprotein composition, nine hypercholesterolemic subjects were treated with oral ascorbic acid (4 g/day) for 2 months. The data demonstrate: 1) no significant change in plasma cholesterol or triglyceride levels; 2) no significant change in the cholesterol or triglyceride concentrations of the major lipoprotein classes; and 3) the unexpected appearance of extra pre-beta bands on lipoprotein electrophoresis by the end of the ascorbic acid treatment period.

Adult↗
PubMed1975

Comparison of 125-I-insulin binding and degradation to isolated rat hepatocytes and liver membranes.

UNLABELLED: We have compared the ability of rat liver plasma membranes and isolated hepatocytes to bind and degrade insulin. Isolated cells were prepared in two different ways: by mechanical separation of cells and by collagenase digestion of extracellular matric. In all studies the binding and degradative characteristics of both types of hepatocyte preparations were identical. Furthermore, with one exception, the binding characteristics of membranes and cells were also quite similar. The only exception concerned the amount of insulin bound by hepatocytes as compared to liver membranes. Thus, at concentrations of cells (1.2 times 10(6) cells per milliliter) and membranes (150 mug. protein per milliliter) that gave equal binding at insulin concentrations less than 100 ng./ml., the amount of insulin specifically bound at insulin concentrations greater than 100 ng./ml. was greater with use of hepatocytes. Additional studies indicated that, in contrast to membranes, at the higher insulin concentration only 75 per cent of the previously bound insulin could be recovered from hepatocytes. Thus, a nondissociable component exists; which probably represents intracellular radioactivity and appears to account for the higher specific insulin binding by cells at higher insulin concentrations. When insulin degradation was studied at the above hepatocyte and plasma membrane concentrations, cells degraded 30 per cent more insulin than did membranes. Kinetic analysis of these data revealed that the Km for insulin degradation (5 times 10(-7) M at 37 degrees) was the same for both systems wereas the Vmax was greater with use of hepatocytes. IN CONCLUSION: (1) Preparation of hepatocytes by collagenase digestion does not appear to alter insulin binding or degradation; (2) studies of liver membranes and isolated hepatocytes obtained from normal rats should yield similar information about insulin-receptor interaction as long as insulin concentrations less than 100 ng./ml. are used; (3) at very high insulin concentrations, some of the radioactivity appears to enter the cells; (4) the kinetics of insulin degradation by hepatocytes and liver membranes are similar; and (5) insulin degradation appears to be primarily a membrane phenomenon.

Animals↗
PubMed1974

Effects of weight reduction on obesity. Studies of lipid and carbohydrate metabolism in normal and hyperlipoproteinemic subjects.

Considerable controversy exists over the purported role of obesity in causing hyperglycemia, hyperlipemia, hyperinsulinemia, and insulin resistance; and the potential beneficial effects of weight reduction remain incompletely defined. Hypertriglyceridemia is one of the metabolic abnormalities proposed to accompany obesity, and in order to help explain the mechanisms leading to this abnormality we have proposed the following sequential hypothesis: insulin resistance --> hyperinsulinemia --> accelerated hepatic triglyceride(TG) production --> elevated plasma TG concentrations. To test this hypothesis and to gain insight into both the possible role of obesity in causing the above metabolic abnormalities and the potential benefit of weight reduction we studied the effects of weight loss on various aspects of carbohydrate and lipid metabolism in a group of 36 normal and hyperlipoproteinemic subjects. Only weak to absent correlations (r = 0.03 - 0.46) were noted between obesity and the metabolic variables measured. This points out that in our study group obesity cannot be the sole, or even the major, cause of these abnormalities in the first place. Further, we have observed marked decreases after weight reduction in fasting plasma TG (mean value: pre-weight reduction, 319 mg/100 ml; post-weight reduction, 180 mg/100 ml) and cholesterol (mean values: pre-weight reduction, 282 mg/100 ml; post-weight reduction, 223 mg/100 ml) levels, with a direct relationship between the magnitude of the fall in plasma lipid values and the height of the initial plasma TG level. We have also noted significant decreases after weight reduction in the insulin and glucose responses during the oral glucose tolerance test (37% decrease and 12% decrease, respectively). Insulin and glucose responses to liquid food before and after weight reduction were also measured and the overall post-weight reduction decrease in insulin response was 48% while the glucose response was relatively unchanged. In a subgroup of patients we studied both the degree of cellular insulin resistance and the rate of hepatic very low density (VLDL) TG production before and after weight reduction. These subjects demonstrated significant decreases after weight reduction in both degree of insulin resistance (33% decrease) and VLDL-TG production rates (40% decrease). Thus, weight reduction has lowered each of the antecedent variables (insulin resistance, hyperinsulinemia, and VLDL-TG production) that according to the above hypothesis lead to hypertriglyceridemia, and we believe the overall scheme is greatly strengthened. Furthermore, the consistent decreases in plasma TG and cholesterol levels seen in all subjects lead us to conclude that weight reduction is an important therapeutic modality for patients with endogenous hypertriglyceridemia.

Adult↗