The endocrine control of growth in children with chronic renal failure.
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Adolescent↗
Biomedical subjects
D H Lockwood
Publications and source records attributed to D H Lockwood.
Prophase chromosome unique band sequences: definition and utilization.
Extensive experience with the analysis of human prophase chromosomes and studies into the complexity of prophase banding patterns have suggested that at least some prophase chromosomal segments can be accurately identified and characterized independently of the morphology of the chromosome as a whole. The feasibility of identifying and analyzing specified prophase chromosome segments was thus investigated as an alternative approach to prophase chromosome analysis based on whole-chromosome recognition. Through the use of prophase idiograms at the 850-band stage (Francke, 1981) and a systematic comparison system, we have demonstrated that it is possible to divide the 24 human prophase idiograms into a set of 94 unique band sequences, each of which has a banding pattern that is recognizable and distinct from any other nonhomologous chromosome portion. The use of a unique band sequence approach in prophase chromosome analysis is expected to increase efficiency and sensitivity through more effective use of available banding information.
Chromosome Banding↗
Insulin resistance: receptor and post-binding defects in human obesity and non-insulin-dependent diabetes mellitus.
Insulin resistance is a prominent feature of three clinical conditions: obesity, impaired glucose tolerance, and non-insulin-dependent (type II) diabetes mellitus. Numerous studies over the past 15 years have provided a better understanding, from both a clinical and cellular standpoint, of the pathophysiology of these insulin-resistant states as well as of insulin action. In addition, it has recently been recognized that correction of glucose intolerance leads to an improvement in insulin secretion and a reduction in insulin resistance. Examination of the most recent data suggests that the basis for insulin resistance in these common clinical disorders is often multifactorial. In uncomplicated obesity, the cellular alterations responsible for insulin resistance appear to be at the level of the hepatic insulin receptor and in post-binding processes in peripheral target tissues. In type II diabetes, a post-binding defect(s) in peripheral tissues appears to be the primary lesion. In humans, many of the factors that mediate the changes leading to insulin resistance are still unknown and are the object of current investigations.
Adipose Tissue↗
Cellular mechanisms in selected states of insulin resistance: human obesity, glucocorticoid excess, and chronic renal failure.
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Animals↗
Characterization and partial purification of a factor from uremic human serum that induces insulin resistance.
We have previously shown that the incubation of normal rat adipose tissue with sera from nondialyzed, nondiabetic uremic patients reduces the transport and metabolism of glucose, in the absence and presence of insulin. In this study insulin-stimulated glucose metabolism by normal rat adipocytes was used as a bioassay to identify the resistance activity, assess the effect of chemical modification on it, and the clinical states associated with its production. The resistance activity was trypsin-labile and had an apparent isoelectric point between 6 and 7, but was not retained by either protein A or concanavalin A columns. The insulin resistance activity was decreased by coincubation with the protein synthesis inhibitor, cycloheximide. Purification to greater than 200,000-fold was attained by heating (100 degrees C) uremic serum, subjecting the supernatant to Sephadex G-25 chromatography and subsequent adsorption to DEAE at pH 7.8 and elution at pH 6.5. The partially purified resistance activity was retained within dialysis tubing of 1,000-mol wt cutoff but not within 2,000-mol wt cutoff. Hemodialysis of patients over 1 wk to 18 mo reduced significantly the amount of resistance activity in their sera. The resistance activity, present in most uremic patients, was not found in the sera of individuals with normal renal function but who were either obese, fasted, elderly or had type II diabetes mellitus. Thus, a circulating small molecular weight peptide, unique to uremia, induced insulin resistance by a protein synthesis-dependent mechanism.
Adipose Tissue↗
Insulin resistance in chronic renal failure.
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Adipose Tissue↗
Effects of sulfonylureas on the actions of insulin and insulin-mimickers: potentiation of stimulated hexose transport in adipocytes.
The sulfonylurea glyburide, a 'second-generation' oral hypoglycemic compound, was studied in vitro in order to determine its cellular mechanism of action in adipocytes prepared from cultured rat epididymal fat tissue. Glyburide treatment (1 microgram/ml) for 20 h did not alter insulin receptor number or affinity, or down-regulation by insulin. Biologic responses of these cells were measured in the presence of insulin or the oxidants Vitamin K5 and H2O2, which have insulin-like activity, but do not act through the binding portion of the receptor. 2-Deoxyglucose uptake was not significantly changed by exposure to glyburide alone. However, the sulfonylurea increased the insulin-stimulated or insulin-mimicker-activated uptake by approximately 30%. Insulin-stimulated glucose oxidation was also potentiated when glucose transport was rate limiting for metabolism. These findings extend our earlier observation that in adipose tissue the primary cellular mechanism of action of sulfonylureas is to potentiate insulin-stimulated hexose transport, and that this process may account for their hypoglycemic activity.
Adipose Tissue↗
X-linked, polymorphic genetic variation of thyroxin-binding globulin (TBG) in baboons and screening of additional primates.
X-linked polymorphic variation of thyroxin-binding globulin (TBG) is observed in several human groups. Isoelectric focusing of plasma samples labeled in vitro with [125I]thyroxin, followed by autoradiography, also reveals genetically determined polymorphic electrophoretic variation in baboon TBG. The protein detected by this method in baboon plasma is immunologically similar to human TBG and is distinct from the other thyroxin-binding proteins, albumin and prealbumin. The isoelectric patterns of human and baboon TBG are very similar and both have an isoelectric range of pH 4.1 to 4.5. The baboon TBG polymorphism is inherited in a two-allele X-linked fashion, with a frequency of 72% for the "common" allele and 28% for the "slow" allele. A survey of seven other primate species including African green monkey, bonnet macaque, chimpanzee, crab-eating macaque, gorilla, rhesus monkey, and spider monkey revealed no polymorphic variation in TBG, although isoelectric patterns were similar to the human and baboon patterns. In addition, samples from pregnant chimpanzees demonstrate a pronounced quantitative anodal shift in relative band densities, a shift also observed in pregnant humans. This shift was not observed in samples from pregnant baboons. TBG should prove to be a useful X-linked genetic marker in baboons and provides a model of serum protein changes in pregnancy, at least in humans and chimpanzees.
Animals↗
Induction of insulin resistance in normal adipose tissue by uremic human serum.
An incubation of uremic human serum with normal rat adipose tissue will make the subsequently isolated adipocytes less responsive to insulin. To examine the extent of insulin resistance, we obtained sera from nondiabetic, uremic patients, who had not undergone dialysis therapy. The sera were then dialyzed (3500 molecular-weight cutoff) for 18 hr against a defined culture medium to eliminate possible in vitro effects of altered levels of end-product metabolites, electrolytes, and metabolic substrates. After an incubation of epididymal fat tissue from normal rats, for 3 hr with the dialyzed sera (50% vol/vol), cells were isolated and washed. The insulin stimulation of 14C-glucose (0.2 mM) incorporation to 14CO2 and total lipids was significantly reduced in the adipocytes pretreated with sera from 19 of the 29 uremic patients. Although elevated in the uremic patients, the sera levels of insulin, and parathyroid and growth hormones were not correlated to insulin resistant activity. Furthermore, incubation of adipose tissue for 3 hr with insulin, glucagon, or PTH did not produce resistance. The uremic sera reduced glucose utilization equally at 0.2 and 50 mM glucose, suggesting that the insulin resistance was induced additionally at a site distal to the glucose transport system. However, the concentration of insulin (22 microunits/ml) required for half-maximal stimulation of glucose metabolism was not altered by pretreatment with uremic serum. Also, neither the isoproterenol-stimulated lipolysis nor the inhibition of this cellular event was influenced by pretreatment with uremic sera.(ABSTRACT TRUNCATED AT 250 WORDS)
Adipose Tissue↗
Very low calorie diets in the management of obesity.
Very low calorie diets (VLCD) consisting of 300-500 kcal are known to be an effective means of weight reduction. Several years ago the most popular VLCD were found to be associated with cardiac arrhythmias and, in some cases, unexpected death. Although the cause(s) of cardiac irritability has never been determined, this problem appears to be markedly diminished by vigorous supplementation of the diets with essential elements, micronutrients, vitamins. Based on current knowledge, recommendations for VLCD usage are provided.
Arrhythmias, Cardiac↗
Resting metabolic rates of obese women after rapid weight loss.
Reduced energy expenditure associated with reduced energy intake has been used as an explanation for resistance to weight loss in obese patients. Decreases in serum T3 concentrations and body cell mass induced by restriction of energy intake may contribute to the reduced energy needs. In the present study, mean resting metabolic rate (RMR) was reduced by 9.4% after 5 weeks of a very low energy diet (472 Cal/day) in six obese women, and the mean serum T3 concentration decreased 46%. However, the lowest RMR values measured were similar in these subjects (mean, 1328 Cal/day; range, 1110-1578 Cal/day) to RMR values of lean women (n = 19; mean, 1241 Cal/day; range, 938-1450 Cal/day) and moderately overweight women ingesting ad libitum diets (n = 8; mean, 1335 Cal/day; range, 1064-1533). Decreases in total body potassium (10%) and 24-h urinary creatinine excretion (23%) suggested that there was a substantial loss of body cell mass during weight loss, whereas nitrogen balance suggested that changes in body cell mass were slight. These data and those of previous studies indicate that even after rapid weight loss, the resting energy requirements of obese or previously obese subjects are not abnormally low relative to those of nonobese subjects, even though the concentrations of T3, a major thermogenic hormone, are substantially reduced. The hypometabolic response to weight loss cannot explain the failure of obese subjects to lose weight on weight-reducing regimens.
Adult↗
A double-blind clinical trial in weight control. Use of fenfluramine and phentermine alone and in combination.
We performed a double-blind, controlled clinical trial comparing phentermine resin (30 mg in the morning), fenfluramine hydrochloride (20 mg three times a day), and a combination of phentermine resin (15 mg in the morning) and fenfluramine hydrochloride (30 mg before the evening meal), and placebo. We combined low doses of the two drugs to maintain efficacy while diminishing adverse effects. Eighty-one people with simple obesity (130% to 180% of ideal body weight) participated. Individualized diets were prescribed and discussed again during the 24-week study period. Weight loss in those receiving the combination (8.4 +/- 1.1 kg; mean +/- SEM) was significantly greater than in those receiving placebo (4.4 +/- 0.9 kg; Scheff é's test) and equivalent to that of those receiving fenfluramine (7.5 +/- 1.2 kg) or phentermine (10.0 +/- 1.2 kg) alone. Adverse effects were less frequent with the combination regimen than with other active treatments. Thirty-seven participants dropped out of the study, 18 for reasons related to drug treatment. Combining fenfluramine and phentermine capitalized on their pharmacodynamic differences, resulting in equivalent weight loss, fewer adverse effects, and better appetite control.
Adolescent↗
Cellular alterations responsible for insulin resistance in obesity and type II diabetes mellitus.
Numerous studies in animals and man have demonstrated that insulin resistance is a prominent feature in both obesity and type II diabetes mellitus. Considerable work over the past decade has provided us with a clearer understanding of the pathophysiology of these insulin resistant states. Although some alterations responsible for insulin resistance have been identified, the factors that mediate these undesirable changes are still unknown. Recent evidence demonstrates that improving blood sugar levels by conventional means at least partially corrects both the insulin resistance and relative insulin deficiency of type II diabetes mellitus. Thus, future efforts should be directed towards a clearer understanding of pathophysiology and more efficacious methods of achieving metabolic control.
Animals↗
Extrapancreatic effects of sulfonylureas. Potentiation of insulin action through post-binding mechanisms.
Pieces of rat epididymal fat tissue were maintained in a biochemically defined medium for 20 to 44 hours in either the absence or presence of a sulfonylurea at levels known to be effective in humans. Prolonged exposure of adipocytes to sulfonylureas did not influence the number of insulin receptors or their affinity to insulin or the ability of insulin to induce receptor loss (down-regulation). Also, the sulfonylureas did not influence the basal uptake of the D-glucose analogs 2-deoxyglucose and 3-O-methylglucose. However, exposure to these drugs resulted in a potentiation of the stimulatory effects of insulin on hexose transport at submaximal and maximally effective concentrations of insulin. The average potentiation was approximately 30%. In addition, sulfonylureas enhanced stimulation of hexose uptake by the insulin mimickers, hydrogen peroxide and vitamin K5. These oxidants are known to manifest insulin-like actions subsequent to insulin binding. Under conditions in which glucose transport was rate limiting, the conversion of glucose to carbon dioxide and the total lipids mirrored the findings of hexose uptake. However, at a glucose concentration of 50 mM, at which hexose transport is no longer rate limiting, sulfonylureas did not potentiate metabolism in th absence or presence of insulin. These results may help to explain the hypoglycemic action of the drug in view of the recent finding that a postreceptor deficit is present in noninsulin-dependent diabetes mellitus.
Adipose Tissue↗
Vigorous supplementation of a hypocaloric diet prevents cardiac arrhythmias and mineral depletion.
We have previously demonstrated that a hypocaloric, nutritionally deficient, liquid protein diet is associated with potentially life-threatening cardiac arrhythmias, which increased in frequency and complexity over the duration of the study. The present investigation was designed to evaluate the metabolic and cardiac changes associated with a hypocaloric, but otherwise nutritionally complete, diet. Six healthy, obese females from 154 to 182 percent of ideal body weight were evaluated in a metabolic ward for 48 days. The subjects ingested a weight maintenance diet during an eight-day period, which was followed by 40 days of an experimental diet containing 472 kcal of a mixture of protein (60 percent of calories), carbohydrate (25 percent), and fat (15 percent). This diet equaled or exceeded the recommended daily allowances for minerals, trace elements, vitamins, and essential fatty acids. The subjects were monitored for balances of nitrogen and minerals, as well as for the appearance of cardiac arrhythmias by 24-hour electrocardiographic recordings. Nitrogen balance was positive, and the previously demonstrated negative balances for potassium, sodium, calcium, magnesium, and phosphorus were either reversed or markedly decreased. In contrast to our previous study, no arrhythmias were observed in subjects ingesting the present experimental diet, and no significant change in cardiac rhythm was found in 13 obese, but otherwise healthy, outpatients. The data, based on a limited number of subjects, suggest that a hypocaloric diet vigorously supplemented with essential elements, micronutrients, and vitamins appears to be safer than the once popular, incomplete liquid protein preparation.
Adult↗
Extrapancreatic action of sulfonylureas: hypoglycemic effects are not dependent on altered insulin binding or inhibition of transglutaminase.
It has been proposed by others that sulfonylureas exert their extrapancreatic hypoglycemic effects by increasing insulin binding through inhibition of receptor-mediated hormone internalization. In this study, we examined the possibility that the drugs act by inhibiting transglutaminase, an enzyme thought important in the internalization process. For ten days, male rats were fed pulverized chow containing either no drug, glipizide (5 mg/kg initial body wt/d), or tolazamide (75 mg/kg initial body wt/d). Prior to sacrifice, the six-hour fasting level of serum glucose was significantly reduced from 96 mg/100 ml in the control rats to 81 and 42 mg/100 ml in the glipizide- and tolazamide-treated rats, respectively. In contrast, the serum level of insulin was similar for all groups. The activity of transglutaminase in the postnuclear fraction of liver homogenate also was the same for all experimental groups. The specific binding of labeled insulin to purified liver plasma membranes was examined over a broad range of insulin concentrations; once again, there was no difference between experimental groups. Thus, the hypoglycemia caused by sulfonylurea administration could not be attributed to increases in insulin binding, inhibition of transglutaminase activity, or enhanced insulin levels. These data support our previous suggestion, based on in vitro studies, that sulfonylureas act predominately on processes beyond the binding portion of the insulin receptor.
Acyltransferases↗
Effects of carbohydrate-containing and carbohydrate-restricted hypocaloric and eucaloric diets on serum concentrations of retinol-binding protein, thyroxine-binding prealbumin and transferrin.
The effects of diet on the serum concentrations of albumin, transferrin, thyroxine-binding prealbumin (TBPA) and retinol-binding protein (RBP) were studied in 3 groups of obese subjects (Groups I-III) and 1 group of normal weight subjects (Group IV). Group I subjects ate either a 830 kcal carbohydrate-containing diet (CCD) or carbohydrate-restricted diet (CRD), Group II and III subjects ate a hypocaloric CRD. Subjects in Group IV ate a eucaloric CRD. Serum albumin concentrations did not change in any of the 4 groups. Only the subjects in Group II had a statistically significant decrease in serum transferrin concentration 6 wk after starting the hypocaloric, CRD. Group I individuals eating the CRD and the subjects in Groups II, III and IV had significant decreases in the serum concentrations of TBPA and RBP after 1 wk which persisted without further change during the remaining 3-5 wk of the diets. Group I subjects eating the CCD had a significant decrease in TBPA concentration at 1 and 6 wk. The RBP serum concentration was significantly decreased after 1 wk on the diet, but was not significantly different from the control diet period at 6 wk. The magnitude of the decreases in serum concentrations of TBPA and RBP in the Group I subjects eating the CRD were significantly greater than in the Group I subjects eating the CCD. Thus, ingestion of a hypocaloric, CRD by obese individuals results in decreased serum concentrations of TBPA and RBP. Isocaloric substitution of carbohydrate for fat reduces this effect. Dietary carbohydrate apparently modulates the serum concentrations of TBPA and RBP, independently of caloric intake, since ingestion of a eucaloric CRD by normal weight individuals also decreased the serum concentration of the two visceral proteins.
Adult↗
Cellular basis of insulin resistance in chronic uremia.
To define the cellular alterations responsible for insulin resistance during uremia, we studied insulin action in adipocytes isolated from rats 2 wk after 75% partial nephrectomy. Insulin binding to fat cells and purified liver plasma membranes prepared from uremic rats was unaltered. In contrast, hexose transport was significantly decreased, with and without insulin, in the fat cells from the uremic animals. The concentration of insulin that elicited half-maximal response was not altered. Glucose utilization was reduced in the absence or presence of insulin by partial nephrectomy. The stimulation of hexose transport and glucose metabolism by the insulin mimickers, hydrogen peroxide and vitamin K5, were also inhibited. Hexose transport activity in adipocytes obtained from uremic rats was no longer decreased when pieces of fat tissue were cultured for 20 h. Finally, hexose transport was reduced in the cells isolated from normal adipose tissue that was preincubated for 3 h with uremic serum, but insulin binding was not different than control. Thus, insulin resistance associated with uremia may be primarily accounted for by altered postreceptor events that appear to result from a circulating factor(s).
Adipose Tissue↗