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Biomedical subjects

D H Lockwood

Publications and source records attributed to D H Lockwood.

At least 73 records · Page 4Linked to original sources
PubMed1978

Loss of insulin response to ingested amino acids after jejunoileal bypass surgery for morbid obesity.

Amino acid tolerance tests were performed before and after jejunoileal bypass surgery for morbid obesity to determine whether an enteric factor(s) originating in the bypassed jejunum and/or ileum potentiates the insulin response to oral nitrogen loading. Preoperatively a 30-gm. mixture of amino acids given orally evoked a larger peak insulin than an intravenous load yielding comparable plasma amino acid elevations (82 +/- 17 muU./ml versus 38 +/- 8 muU./ml., p less than 0.05). Four months after operation, basal insulin concentrations were 46 per cent (p less than 0.001) of preoperative values. After surgery the response to intravenous amino acids was preserved when expressed as percentage increase above basal. In contrast, the peak increment and the percentage increase in insulin secretion after 30-gm. oral amino acid loading was significantly blunted (p less than 0.005). A smaller amino acid load (16.5 gm.) was given preoperatively to duplicate the plasma amino acid elevations seen postoperatively with the 30-gm. mixture given by mouth. The insulin response postoperatively was still significantly lower (167 +/- 33 per cent versus 98 +/- 16 per cent, p less than 0.05). After various explanations for the diminished postoperative insulin release following oral amino acid ingestion are considered, the results are best explained by the loss of an enteric insulinotrophic factor(s) normally released by the bypassed portions of jejunum or ileum in response to ingested protein.

Amino Acids↗
PubMed1978

[14C]palmitate uptake in isolated rat liver mitochondria: effects of fasting, diabetes mellitus, and inhibitors of carnitine acyltransferase.

The rapid association of Na-[16-(14)C]palmitate with isolated rat liver mitochondria was measured by an oil separation method. This association was time and temperature-dependent and was absolutely dependent on the presence of exogenous ATP and CoASH and partially dependent on exogenous carnitine. Carnitine dependence was enhanced at lower concentrations of [(14)C]palmitate. At 6.5 micro M [(14)C]palmitate (molar ratio of palmitate to albumin equal to 0.54), the rate of association was linear for 20 sec and was increased more than 100% in the presence of carnitine. Carnitine-dependent association was inhibited by 2-bromopalmitate, an inhibitor of carnitine acyltransferase I, but not by (+)-octanoylcarnitine, a presumed inhibitor of carnitine acyltransferase II. The association of [(14)C]palmitate with mitochondria was enhanced from 190 to 330% in mitochondria isolated from fasted animals and from 160 to 230% in mitochondria isolated from diabetic, ketotic animals as compared to control animals. The enhanced association with mitochondria from fasted animals was inhibited by 2-bromopalmitate. These studies demonstrate a method of evaluating fatty acid association with mitochondria which, because of its dependence on carnitine and carnitine acyltransferase I activity, most likely represents true uptake into mitochondria. Furthermore, these studies indicate that the carnitine-dependent uptake of fatty acids into mitochondria is enhanced in the two ketotic states evaluated and that the carnitine acyltransferase system may be a regulatory site in ketone body production.

Acyltransferases↗
PubMed1977

Insulin-like effects of polyamines in fat cells. Mediation by H2O2 formation.

Significant amounts of H2O2 were produced when the polyamines, spermine, or spermidine were incubated with a Krebs-Ringer phosphate buffer that contained bovine serum albumin (Fraction V). This effect was specific for certain amines and could be prevented by treatment of the albumin fraction with isoniazid or aminoguanidine. These features suggest that H2O2 is formed during oxidative deamination of the polyamines catalized by spermine oxidase, a known contaminant of Fraction V bovine serum albumin. The insulin-like effects elicited by polyamines in fat cells (e.g. enhancement of glucose transport and inhibition of cAMP-mediated lipolysis) were dependent on H2O2 production. Incubation of cells with catalase or treatment of the albumin fraction with isoniazid abolished the stimulation of glucose uptake by polyamines but did not alter the stimulatory effects of insulin or vitamin K5. The H2O2 generating activity was partially separated from the albumin by gel filtration; only those fractions which formed H2O2 provided support for the activation of glucose transport by polyamines. Also, the time needed to activate glucose uptake was markedly shortened by incubation of the albumin buffer with the polyamines before addition of the cells. These findings indicate that the polyamines do not themselves mimic the actions of insulin but that the insulin-like effects result from the formation of H2O2 which has been shown to stimulate glucose transport.

Adipose Tissue↗
PubMed1977

Effect of oral amino acid supplementation on liver disease after jejunoileal bypass for morbid obesity.

Previous work in our laboratory and others suggests that protein malnutrition plays an important role in the pathogenesis of hepatic steatosis and dysfunction which characteristically appears after jejunoileal bypass for morbid obesity. Postoperative protein-calorie malnutrition is at least in part a consequence of diminished intestinal absorption of free amino acids. In an attempt to prevent liver disease, six morbidly obese patients were orally supplemented with essential amino acids for 4 months after surgery. Oral amino acid supplementation only partially influenced protein malnutrition and had no effect on deterioration of hepatic morphology and dysfunction. Although this mode of therapy appears to be ineffective in preventing postoperative liver abnormalities, other studies suggest that oral oligopeptide supplementation and parenteral administration of amino acids are beneficial. In addition to protein deificiency, other factors which may contribute to the development of liver disease are reviewed.

Amino Acids↗
PubMed1976

Insulin resistance in obesity.

The insulin resistance seen in obesity, which is characterized by elevated basal levels of insulin and an exaggerated insulin response to such stimuli as glucose ingestion, was thought to be related to another common characteristic of obesity--enlargement of the fat cell. Now, recent studies suggest that the enlarged fat cell is not the major source of insulin insensitivity in obesity and may, in fact, be the victim of the insulin-resistant state.

Adipose Tissue↗
PubMed1975

Effect of glucocorticoids on the glucose transport system of isolated fat cells.

Glucocorticoids inhibit glucose utilization by fat cells. The possibility that this effect results from altered glucose transport was investigated using an oil-centrifugation technique which allows a rapid (within 45 s) estimation of glucose or 3-O-methylglucose uptake by isolated fat cells. At high concentration (greater than 25 muM), dexamethasone inhibited glucose uptake within 1 min of its addition to fat cells. Efflux of 3-O-methylglucose was also impaired by 0.1 mM dexamethasone. However, diminished glucose uptake was not a specific effect of glucocorticoids; high concentrations (0.1 mM) of 17beta-estradiol, progesterone, and deoxycorticosterone produced a similar response in adipocytes. At a more physiologic steroid concentration (0.1 muM), glucocorticoids inhibited glucose uptake in a time-dependent manner (maximum effect in 1 to 2 hours). This effect was specific for glucocorticoids since, under these conditions, glucose uptake was not changed by the non-glucocorticoid steroids. Lineweaver-Burk analysis showed that 0.1 muM dexamethasone treatment produced a decrease in Vmax for glucose uptake but did not change the Ku. Hexokinase activity and ATP levels were not altered by this treatment, suggesting that processes involved in glucose phosphorylation were not affected. Dexamethasone treatment also caused a reduction in uptake of 3-O-methylglucose when assayed using a low sugar concentration (0.1 mM). At a high concentration (10 mM), uptake of the methyl sugar was only slightly less than normal in treated cells. Stimulation by insulin markedly enhanced uptake of glucose and 3-O-methylglucose by both treated and untreated cells. At a low hexose concentration (0.1 mM) and in the presence of insulin, sugar uptake by dexamethasone-treated cells was slightly less than control cells. Stimulation by insulin did however completely overcome the alteration in hexose uptake when larger concentrations of sugars (greater than 5 mM) were used. There was no detectable change in total protein synthesis during incubation of fat cells with dexamethasone. However, actinomycin C blocked the inhibitory effect of dexamethasone on glucose uptake. Cycloheximide, which caused a small inhibition in glucose uptake, prevented the full expression of the inhibitory effect of dexamethasone on glucose transport. These results indicate that dexamethasone alters the facilitated transport of glucose and, secondly, suggest that synthesis of RNA and protein is needed for glucocorticoid action.

Adipose Tissue↗
PubMed1975

Insulin receptor: role in the resistance of human obesity to insulin.

Large adipocytes from obese subjects have similar receptor numbers and affinities for insulin as small adipocytes from subjects of normal weight. These results indicate that the insulin insensitivity of large fat cells from obese humans occurs after the insulin-receptor interaction and might be explained by either a dilution of receptors over the cell surface or by alterations in intracellular metabolism.

Adipose Tissue↗
PubMed1975

Relation of insulin receptors to insulin resistance.

The status of insulin-receptor interactions in a variety of insulin-resistant states is reviewed. Utilizing large adipocytes from adult rats and small fat cells from young rats, we have conducted a series of in vitro experiments in an attempt to determine the cellular alteration(s) responsible for the insulin resistance associated with obesity. Stimulation of glucose oxidation by insulin is reduced in large cells. Studies using a mimicker of insulin action, spermine, as well as measurements of 125I-insulin binding to large and small cells indicate that receptor number and affinity are not responsible for hormone resistance. Furthermore, when rapid and direct measurements of sugar uptake were made, insulin stimulation was virtually identical in both cell types. These findings indicate that large adipocytes have an efficient insulin-responsive D-glucose transport system and suggest that the apparent hormone resistance may be due to alterations in intracellular glucose metabolism. It has been proposed that altered insulin-receptor interaction underlies the insulin resistance of human obesity. We have investigated this particular aspect of insulin action by 125I-insulin binding studies. Similar numbers of insulin receptors per cell and affinity for insulin were observed in adipocytes obtained from normal weight subjects and morbidly obese patients. Thus, the initial step in insulin action is unaltered in human obesity.

Adipose Tissue↗
PubMed1974

Studies of glucagon resistance in large rat adipocytes: 125I-labeled glucagon binding and lipolytic capacity.

This study is concerned with potential modifications of large fat cells from adult rats (400-450 g) that make them resistant to stimulation by glucagon. The lipolytic capacity and (125)I-labeled glucagon-binding capability of these cells were compared with these properties of small glucagon-sensitive cells from young rats (130-160 g). As determined by maximal stimulation with theophylline, dibutyryl cAMP, or epinephrine, the lipolytic capacity of large cells was not markedly different from small cells, which suggests that an alteration contributing to glucagon insensitivity is not present in the enzymes involved with hormone-mediated lipolysis. Glucagon-binding studies did indicate a difference between the two cell types. Both large cells and particulate fractions from large cells bound less (125)I-labeled glucagon than small cells or small-cell particles. That diminished binding is not a consequence of glucagon degradation is indicated by the similar amounts of (125)I-labeled glucagon degraded by both cell types. The decrease in (125)I-labeled glucagon binding was not as marked as the decrease in lipolytic response to glucagon stimulation. This lack of correlation and the relationship between elevated phosphodiesterase levels and glucagon insensitivity described in the accompanying report suggest that diminished binding explains only in part the marked resistance to glucagon found in large cells.

Adipose Tissue↗
PubMed1974

Role of phosphodiesterase in glucagon resistance of large adipocytes.

The role of phosphodiesterase in glucagon resistance of large adipocytes was investigated. A comparison was made of phosphodiesterase activities of homogenates prepared from isolated small (mean diameter approximately 45 micro m) and large (mean diameter approximately 78 micro m) adipocytes, using various concentrations (5 x 10(-4) to 1 x 10(-7) M) of 3',5'-cAMP. Kinetic analyses revealed two distinct catalytic activities (high and low affinities) in both cell types; however, the activities of both high- and low-affinity enzymes were significantly elevated in large adipocytes. Lipolysis was measured in isolated adipocytes in the presence of different concentrations (0.1-0.6 mM) of the phosphodiesterase inhibitor aminophylline. Large adipocytes were less responsive to low levels of methylxanthine, suggesting that greater amounts of phosphodiesterase must be inhibited before lipolysis can be stimulated. To evaluate the influence of phosphodiesterase during glucagon-stimulated lipolysis, small and large adipocytes were incubated with a maximally effective concentration of glucagon (1.5 x 10(-6) M) in combination with various concentrations (0.1-0.6 mM) of aminophylline. Although the glucagon effect was potentiated in both cell types, the maximum lipolytic response of large adipocytes (at 0.4 mM aminophylline) was approximately 36% lower than that observed in small adipocytes (at 0.2 mM aminophylline). This reduction correlates closely with the decreased glucagon binding present in large cells; therefore, it appears that the glucagon-resistant state is adequately explained by elevations in phosphodiesterase levels and diminished glucagon-cell association.

Adipose Tissue↗
PubMed1972

Insulin insensitivity of large fat cells.

Large insulin-insensitive adipocytes from adult rats have normal binding capacities and affinities for insulin. Diminished insulin-like responses to spermine and reduced rates of glucose oxidation are also evident in these cells. The results indicate that the defect responsible for this insulin-resistant state exists in a step subsequent to insulin binding, possibly in transmission of the insulin-receptor "signal" since insensitivity occurs under conditions where glucose transport and oxidative processes are not apparently impaired.

Adipose Tissue↗