Showing papers in "Metabolism-clinical and Experimental in 1978"
TL;DR: With more precise use of these terms and a more complete understanding of insulin action, it will be possible to begin to segregate the roles of the various prereceptor, receptor and postreceptor factors that are involved in producing the differing patterns of metabolism observed in disease.
Abstract: Insulin resistance may be said to exist whenever normal concentrations of insulin produce a less than normal biologic response. Hormone resistant states may be divided into those due to decreased sensitivity to a hormone (i.e., a shift in the dose-response curve to the right), those due to a decrease in the maximal response to the hormone, and those that are combinations of decreased sensitivity and decreased responsiveness. This distinction is important, since the molecular mechanisms that produce these various forms of insulin resistance may be different. Disorders associated with alterations prior to the interaction of insulin with its receptor are more likely to produce states of decreased sensitivity, where disorders associated with alterations at the intracellular steps in insulin action are more likely to produce decreased responsiveness. Alterations in the insulin receptor itself may produce either, although most frequently changes in receptor affinity as well as in receptor number will be manifest as changes in sensitivity. This is a result of the large number of "spare" receptors for most insulin effects. In many studies, the differential diagnosis between states of altered sensitivity and altered responsiveness is difficult due to the complicated and interrelated nature of the metabolic pathways of insulin action. This is frequently further complicated by incomplete data (usually the result of studying response to only one hormone concentration rather than a full dose-response) and change in rates of basal metabolism in different diseases. The latter is a particularly difficult problem, but it is clear that use of "fold-" or "percent-" stimulation may further obscure the nature of the change when complete data are not provided. With more precise use of these terms and a more complete understanding of insulin action, it will be possible to begin to segregate the roles of the various prereceptor, receptor and postreceptor factors that are involved in producing the differing patterns of metabolism observed in disease.
797 citations
TL;DR: It is concluded that endurance training is associated with an adaptive increase of LPL activity not only in skeletal muscle but also in adipose tissue, and the high HDL-cholesterol levels of physically well-trained people are probably accounted for by the increased LPLactivity and the concomitant rapid turnover or triglyceride-rich lipoproteins.
Abstract: Physically well-trained people generally have lower VLDL-triglyceride and higher HDL-cholesterol levels than sedentary subjects. To examine the underlying mechanisms of this lipoprotein pattern, we measured the lipoprotein lipase (LPL) activity in needle biopsy specimens of adipose tissue and skeletal muscle of competitive runners and of body weight-matched, physically less-active controls. The active sportsmen were either sprinters, whose training program consisted mainly of athletics of short duration or long distance runners undergoing a strenuous endurance exercise program. In sprinters (all males) the serum lipid and lipoprotein concentrations did not differ significantly from those of controls and the mean LPL activities in muscle and adipose tissue were also similar in these two groups. The long distance runners (both sexes), on the other hand, had higher means levels of HDL-cholesterol than the respective controls. The LPL-activity of both adipose tissue (p less than 0.05) and skeletal muscle (p less than 0.01) was significantly higher in male long distance runners than in control males. Female runners had higher muscle LPL activity than controls (p less than 0.01) but in adipose tissue the difference in LPL activity was not significant. Rough estimates calculated for LPL activity present in whole body adipose tissue and skeletal muscle indicated that total LPL activity was 2.3 times higher in male long distance runners and 1.5 times higher in female long distance runners than in the respective controls. In combined groups of male runners and controls, there was a highly significant positive correlation between the serum HDL-cholesterol level and the LPL activity of adipose tissue expressed per tissue weight (r = +0.72, p less than 0.001) or per whole body fat (r = +0.62, p less than 0.001). The group means of HDL-cholesterol and adipose tissue LPL activity in the five cohorts studied (male sprinters, distance runners and controls and female distance runners and controls) were also positively correlated (r = +0.94). It is concluded that endurance training is associated with an adaptive increase of LPL activity not only in skeletal muscle but also in adipose tissue. These changes are not observed in sprinters who are trained by exercises of shorter duration. The high HDL-cholesterol levels of physically well-trained people are probably accounted for, at least partly, by the increased LPL activity and the concomitant rapid turnover or triglyceride-rich lipoproteins.
325 citations
TL;DR: It is apparent that normal human serum contains 4–6 times more IGF II than IGF I, which points to the liver as one site of production of IGFs, and IGF I may be the more important growth factor, and the two seem to be regulated differently.
Abstract: It is now known that nonsuppressible insulin-like activity extracted from human serum (NSILA-S) consists of at least two chemically and biologically closely related polypeptides with a molecular weight of 7500. Their primary and tertiary structures strikingly resemble that of human proinsulin and suggest a common phylogenetic ancestor. Beyond their acute insulin-like actions on insulin target tissues the two polypeptides exert pronounced effects on growth of cultured cells and on sulfation, RNA and protein synthesis of cartillage. For these reasons they have been termed insulin—like growth factors (IGF I and II). In adipose tissue, their biologic potency is ∼60 times lower than that of insulin and corresponds to their weak affinity for the insulin receptor rather than to their high affinity for a specific IGF-receptor whose functional role is still unclear. By contrast, their biologic potency in heart and skeletal muscle is close to that of insulin ( 1 2 – 1 5 ) although their affinity for the insulin receptor is ∼100 times lower than that of insulin. Therefore, the insulin-like actions of IGFs on muscle appear to be mediated by the IGF-receptor. In fibroblasts and chondrocytes, binding of IGFs to specific high affinity IGF-receptors correlates closely with their effects on growth indices and sulfation. The latter effects occur at ∼50 times lower concentrations than with insulin. In native blood, IGFs are tightly associated with a specific carrier protein and the free forms are barely detectable. Binding to the carrier blocks their action on insulin target tissues, which explains the absence of acute insulin-like effects of endogenous IGF in vivo. In contrast, tissues concerned with growth may possess mechanisms to “extract” IGFs from the carrier complex. IGFs are under the control of growth hormone: total IGF levels are increased in acromegalics and decreased in hypopituitary and Laron dwarfs. This characteristic and their distinct biologic properties coin IGFs as members of the somatomedin family. The close relationship is further underlined by the pronounced cross-reactivity with somatomedins in radioreceptor and radioimmunoassays. Low serum IGF values are also found in patients with liver cirrhosis. Among other evidence, this points to the liver as one site of production of IGFs. Total IGF levels were not found to be elevated in 15 patients with hypoglycemia caused by extrahepatic tumors. Antibodies that allow to discriminate between the two species of IGF have recently been raised in rabbits. From the results of the radioimmunoassays, it becomes apparent that normal human serum contains 4–6 times more IGF II than IGF I. In acromegalic patients, only IGF I is elevated, whereas IGF II lies within the normal range. In hypopituitary and in Laron dwarfs, but also in patients with liver cirrhosis, IGF I is more drastically reduced than IGF II. Thus, IGF I may be the more important growth factor, and the two seem to be regulated differently. Besides carrier-bound IGFs, another large molecular weight peptide with nonsuppressible insulin-like activity is present in human serum. It is not interconvertible to small molecular weight IGF and it is not active on sulfation of cartilage. Therefore, it represents an entity different from IGFs. Thus, bioassays carried out in whole serum detect different insulin-like activities: Since carrier-bound IGF is inactive on adipose tissue the fat pad assay measures large molecular weight NSILA rather than IGF, whereas the sulfation assay reflects the serum level of carrier-bound IGFs and other somatomedins.
237 citations
TL;DR: Man might, thus, be uniquely limited in the capacity to dispose of extra carbohydrate in the sedentary state, which might speculatively be thought to be an explanation for a carbohydrate excess syndrome in thesedentary state that may well increase the risk for obesity, hyperinsulinemia, and diabetes mellitus.
Abstract: Recent information indicates that the capacity of man to store carbohydrate energy by transformation into fatty acids synthetized de novo is very limited in adipose tissue as well as in liver and intestine. This seems to be in contrast to other species such as the rat where de novo fatty acid synthesis can be induced to a high capacity of glucose removal. This leaves man with a limited capacity to store excess carbohydrate. The remaining possibilities are both the main glycogen stores in liver and in muscle. The latter is by far the largest. The capacity of muscle to assimilate glucose is dependent on its glycogen content that in turn is dependent on previous glycogen depletion to supply energy for muscle contraction. Man might, thus, be uniquely limited in the capacity to dispose of extra carbohydrate in the sedentary state. This might speculatively be thought to be an explanation for a carbohydrate excess syndrome in the sedentary state that may well increase the risk for obesity, hyperinsulinemia, and diabetes mellitus. The logical treatment for such a syndrome then is either a decreased intake of energy as carbohydrate or an increased disposal of carbohydrate energy by exercise. Exercise has, indeed, been shown to have such effects both after physical training programs and, perhaps more pertinent to the question, during a few days after a single exercise bout that has consumed a large amount of muscle glycogen.
227 citations
TL;DR: It is concluded that although insulin lowers glucagon levels, restoration to normal of the A-cell dysfunction of diabetes requires that plasma insulin levels vary appropriately with glycemic change and that glucagon suppression could be a potentially useful adjunct to conventional antihyperglycemic treatment of diabetics.
Abstract: The current controversy concerning the role of glucagon in the pathogenesis of diabetes is reviewed. The traditional "unihormonal abnormality concept," namely, that all of the metabolic derangements of diabetes are the direct consequence of deficient insulin secretion or activity, and the newer so-called bihormonal abnormality hypothesis, proposing that the fullblown diabetic syndrome requires, in addition to the insulin abnormality, a relative glucagon excess, are scrutinized. The relationship of insulin deficiency to the A-cell malfunction of diabetes, the conflicting evidence concerning the essential role of glucagon in mediating the marked overproduction of glucose and ketones in severe insulin deficiency and the contribution of glucagon to the endogenous hyperglycemia of diabetics without insulin deficiency are examined. Finally, the possibility that therapeutic suppression of diabetic hyperglucagonemia may make possible better control of hyperglycemia than is presently attainable by conventional therapeutic methods is considered. It is concluded that (1) although insulin lowers glucagon levels, restoration to normal of the A-cell dysfunction of diabetes requires that plasma insulin levels vary appropriately with glycemic change; (2) that glucagon mediates the severe endogenous hyperglycemia and hyperketonemia observed in the absence of insulin; (3) that in diabetics in whom insulin is present but relatively fixed an increase in glucagon causes hyperglycemia and glycosuria; and (4) that glucagon suppression could be a potentially useful adjunct to conventional antihyperglycemic treatment of diabetics.
217 citations
TL;DR: In normal man approximately 90% of an ingested glucose load is absorbed and passes through the liver to appear in the systemic pool, and estimates of initial splanchnic uptake of ingested glucose and the concomitant suppression of endogenous glucose production were obtained by validated tracer techniques for non--steady-state turnover measurement.
Abstract: Estimates of initial splanchnic uptake of ingested glucose and the concomitant suppression of endogenous glucose production were obtained in man by validated tracer techniques for non-steady-state turnover measurement. Nine normal volunteers (18–44 yr old) fasted overnight received intravenous infusions of tracer (3-3H-glucose or 1-14C-glucose) and a low (45 ± 1 g) or high (96 ± 5 g) oral load of glucose labeled with an alternative tracer (1-14C-glucose or 2-3H-glucose). A two-compartment model was used to derive rates of peripheral appearance (Ra) of glucose from all sources (total) and the Ra of ingested glucose. Ra (total glucose) and Ra (ingested glucose) were integrated from the first appearance of ingested glucose until the basal Ra (total glucose) of 116 ± 6 (SEM) mg/min was reattained. The total amount of glucose reaching the systemic pool in this time was 95 ± 4 g and 46 ± 3 g with high and low doses, respectively. Of these quantities 86 ± 4 g and 40 ± 3 g originated in the oral glucose, representing 90% ± 4% of the administered glucose. The remainder (11% ± 2% of the total) represented endogenous production, suppressed by 66% ± 6% relative to basal. Sequestration of ingested glucose and subsequent release did not take place during the study since identical results were obtained with ingested 1-14C-glucose or 2-3H-glucose. The latter label would have been lost if the glucose had entered the hexose-phosphate pool. Thus, in normal man approximately 90% of an ingested glucose load is absorbed and passes through the liver to appear in the systemic pool.
216 citations
TL;DR: A method of high pressure liquid chromatography (HPLC) is described which enables the isolation of Hb Alc in 27 min using only 12 microgram of HB (100 microliter of blood) and a second method for the isolated of total fast Hb components (also elevated in diabetes) in 11 min.
Abstract: Hemoglobin (Hb) AIc is a minor component of Hb found in normal individuals but elevated two or threefold in patients with diabetes mellitus. Limited studies have suggested that the level of Hb AIc is proportional to the integrated concentration of glucose over time. Thus it could serve as an index of hyperglycemia. Its measurement may enable a more objective approach to assessing whether or not the control of hyperglycemia can be correlated with the severity of complications of diabetes. Large scale clinical studies of Hb AIc have not been undertaken for lack of a rapid assay system. This article describes a method of high pressure liquid chromatography (HPLC) which enables the isolation of Hb AIc in 27 min using only 12 μg of Hb (100 μl of blood) and a second method for the isolation of total fast Hb components (also elevated in diabetes) in 11 min. Using the first method, a total of 36 assays were performed on the blood of a single normal volunteer over a one month period. The mean level of Hb AIc was 4.95 ± 0.12% (SD) ± 0.02% (SEM), while the coefficient of variation (C.V.) was 2.4%. The mean Hb AIab p
206 citations
TL;DR: Somatostatin analogs are now available that are more potent, longer-acting, and possess a different spectrum of biologic activities, including those that have already been applied to several physiologic and clinical studies.
Abstract: With the realization of the numerous powerful effects of somatostatin (SS) on the adenohypophysis, pancreas, gastrointestinal tract, and central nervous system,1,2 it was considered that analogs of this peptide might provide important investigational and, perhaps, therapeutic tools. Since the characterization of SS 5 yr ago, hundreds of analogs have been synthesized and biologically tested. These analogs have provided an appreciation of the structural requirements for somatostatin's multiple biologic activities. It must be recognized, however, that the interpretation of structure/activity data is complicated by several factors; the biologic activity of an analog relative to SS can reflect variations in distribution and rates of metabolism, receptor affinity, or intrinsic activity (ability of the SS receptor complex to induce the appropriate intracellular mediatory signals). Furthermore, the observed biologic activities of an analog could reflect either an involvement of the altered regions in SS in the metabolism or action of the peptide, or might be secondary to changes in intramolecular associations and conformation. Somatostatin analogs are now available that are more potent, longer-acting, and possess a different spectrum of biologic activities. As will be described, such peptides have already been applied to several physiologic and clinical studies. Other SS analogs have been tailor-made for a variety of purposes, including their use as immunogens and receptor-binding assays.
175 citations
TL;DR: In the absence of a change in the pancreatic hormonal milieu, elevations in the normal fasting plasma glucose level have little effect on glucose clearance, and the previously established responsiveness of M to hormones can be considered to represent a useful index of hormone action on glucose uptake in vivo.
Abstract: In the absence of a change in the pancreatic hormonal milieu, elevations in the normal fasting plasma glucose level have little effect on glucose clearance. In view of these data, and the previously established responsiveness of M to hormones, glucose clearance can be considered to represent a useful index of hormone action on glucose uptake in vivo. Care should be taken, however, when interpreting clearance data obtained under hypoglycemic conditions, since there is a possibility that clearance may spontaneously increase at very low plasma glucose levels.
157 citations
156 citations
TL;DR: Dietary carbohydrate is an important factor in reversing the fall in serum T 3 caused by fasting, and men show more significant changes in serum thyroid hormone concentrations during fasting than women do, and absorption of T 3 is not altered during fasting.
Abstract: To assess the effect of starvation and refeeding on serum thyroid hormones and thyrotropin (TSH) concentrations, 45 obese subjects were studied after 4 days of fasting and after refeeding with diets of varying composition. All subjects showed an increase in both serum total and free thyroxine (T 4 ), and a decrease in serum total and free triiodothyronine (T 3 ) following fasting. These changes were more striking in men then in women. The serum T 3 declined during fasting even when the subjects were given oral L-T 4 , but not when given oral L-T 3 . After fasting, the serum reverse T 3 (rT 3 ) rose, the serum TSH declined, and the TSH response to thyrotropin-releasing hormone (TRH) was blunted. Refeeding with either a mixed diet ( n = 22) or a carbohydrate diet ( n = 8) caused the fasting-induced changes in serum T 3 , T 4 , rT 3 , and TSH to return to control values. In contrast, refeeding with protein ( n = 6) did not cause an increase in serum T 3 or in serum TSH of fasted subjects, while it did cause a decline in serum rT 3 toward basal value. The present data suggest that: (1) dietary carbohydrate is an important factor in reversing the fall in serum T 3 caused by fasting; (2) production of rT 3 is not as dependent on carbohydrate as that of T 3 ; (3) men show more significant changes in serum thyroid hormone concentrations during fasting than women do, and (4) absorption of T 3 is not altered during fasting.
TL;DR: The results show that a lack of insulin response can occur as a consequence of adaption to physical training, but a reduced insulin response does not necessarily indicate a diabetic or prediabetic state.
Abstract: Insulin secretion and glucose tolerance were examined in 6 highly conditioned athletes in comparison with a control group of 115 normal healthy persons. During glucose infusion the athletes showed low insulin secretion although there was no difference in the levels of blood glucose compared to the control group. It is concluded that under physiologic conditions the extent of insulin secretion is not dependent only upon the blood glucose levels. The results show that a lack of insulin response can occur as a consequence of adaption to physical training. A reduced insulin response, therefore, does not necessarily indicate a diabetic or prediabetic state.
TL;DR: Low-fat, low-cholesterol, high-P:S-ratio diets greatly affect plasma lipid levels and it is important to have information on the latter to understand diet-induced changes in the metabolism of lipoproteins.
Abstract: Low-fat, low-cholesterol, high-P:S-ratio diets greatly affect plasma lipid levels There is no information as to whether such diets affect only lipoprotein levels or also levels of apoproteins and lipoprotein compositions It is important to have information on the latter to understand diet-induced changes in the metabolism of lipoproteins Since vegetarians regularly eat an extremely low-cholesterol, low-fat, and-high-P:S ratio diet, they represent an ideal group to study Fifty-eight vegetarians who eat no animal products and live on a farm commune were examined Venous bloods were drawn after 12–14 hr fasts and analyzed for lipoprotein-lipids by Lipid Research Clinic procedures and for apoA-I and apoB by radioimmunoassay Their normal dietary intake was evaluated with 24-hr food diaries They averaged 2200 kcal/day with 17% protein, 32% fat, and 51% carbohydrate Negligible amounts of cholesterol (
TL;DR: Assessment of the major apolipoproteins of HDL, A-I and A-II, in addition to HDL cholesterol in 90 male myocardial infarction survivors and their lipid-matched male controls found that the MI survivors had significantly lower HDL cholesterol.
Abstract: Subjects with existing coronary heart disease and those with many of the conditions associated with increased risk of coronary disease have reduced levels of high-density lipoprotein (HDL) cholesterol. Since HDL cholesterol is only one index of HDL composition, a reduction of HDL cholesterol could reflect a change in HDL composition and/or a decrease in all HDL constituents. Therefore the present studies assessed the major apolipoproteins of HDL, A-I and A-II, in addition to HDL cholesterol in 90 male myocardial infarction (MI) survivors and their lipid-matched male controls. The MI survivors had significantly lower (p
TL;DR: The use of ER assays in the primary breast tumor specimen to predict for early recurrence and ultimate survival is a new finding, however, and will probably be employed in future trials of adjuvant therapy.
Abstract: The role of cytoplasmic estrogen receptor (ER) assays in determining therapeutic strategies for advanced breast cancer is certainly well established. The use of ER assays in the primary breast tumor specimen to predict for early recurrence and ultimate survival is a new finding, however, and will probably be employed in future trials of adjuvant therapy. The prevalence and significance of nuclear-bound ER still requires additional clarification. Our previous suggestion that progesterone receptor measurements might be a useful marker for hormone dependence in advanced breast cancer is gaining support and may soon have a place in routine therapeutic decision-making. The emphasis on early adjuvant therapy has hastened the search for a safe endocrine therapy that would have good patient compliance and achieve remission rates comparable to previous agents and procedures. Antiestrogens show promise of meeting these requirements. We are now beginning an era in which primary and secondary systemic therapies for breast cancer can be based on sound biologic principles. The empirical approach is out-dated.
TL;DR: The data suggest that early increments in LPL activity in adipose tissue of the "pre-obese" rat may significantly contribute to the early fat cell hypertrophy seen during the development of this genetic obesity.
Abstract: Lipoprotein lipase (LPL) enzyme activity in epididymal adipose tissue from obese and lean Zucker rats was measured. At 5, 10, 13, and 20 wk of age obese rats have heavier fat pads, larger fat cells, and more LPL per epididymal fat pad and per fat cell than do their lean littermate controls. Although LPL per fat cell increased as fat cell size increased in lean rats, the increased LPL activity in the obese could not be attributed solely to increased fat cell size. When obese and lean rats had similar cell sizes, LPL per fat cell was still significantly increased in the obese compared to lean. Furthermore LPL activity was increased in "preobese" (fa/fa) rats compared to either lean genotype (Fa/fa or Fa/Fa) during the second postnatal week. The data suggest that early increments in LPL activity in adipose tissue of the "pre-obese" rat may significantly contribute to the early fat cell hypertrophy seen during the development of this genetic obesity. Furthermore, early increased LPL activity may prove useful as a predictor of the onset of obesity.
TL;DR: A major part of acetate released from the splanchnic region is taken up by the muscles, leg glucose uptake is decreased by a reduction of the same magnitude as the actate uptake, and leg blood flow is reduced, probably owing to a constriction of muscle vessels.
Abstract: Splanchnic and leg exchange of ethanol, acetate, glucose, lactate, pyruvate, glycerol, and free fatty acids was studied in five healthy volunteers before and after a 60-min infusion of ethanol. Leg and splanchnic blood flows were determined simultaneously using a modified indicator dilution technique. The blood alcohol concentration obtained was 1.88 mmoles/liter and splanchnic uptake of ethanol was calculated to be 1.18 mmoles/min. All subjects showed an acetate uptake over the legs with a mean of 0.25 mmole/min. Splanchnic glucose production was attenuated in four of five subjects after ethanol treatment, and glucose uptake by the legs was significantly reduced. The normal splanchnic uptake of lactate was changed by ethanol to a release, and the arterial concentration was nearly doubled. Net leg release of lactate decreased significantly. Splanchnic blood flow and oxygen uptake were uninfluenced by ethanol, whereas leg blood flow decreased from a mean of 0.77 to 0.65 liter/min. It is concluded that, following ethanol treatment, (1) a major part of acetate released from the splanchnic region is taken up by the muscles, (2) leg glucose uptake is decreased by a reduction of the same magnitude as the actate uptake, and (3) leg blood flow is reduced, probably owing to a constriction of muscle vessels.
TL;DR: It is suggested that CHO and P, but not L, are important modulators of hepatic outer ring thyronine deiodination in the rat, perhaps due to increased intracellular glucose.
Abstract: To evaluate the effect of starvation, oral and i.v. nutriments, and hypothyroidism on the peripheral conversion of thyroxine (T4) to 3,3', 5-triiodothyronine (T3) in the rat and mouse, an in vitro system for assessing T4 conversion to T3 by fresh liver homogenates was used. A 2-day starvation in the rat reduced hepatic T3 generation from T4 by 47% +/- 3.5% (mean +/- SE) in six separate experiments and also impaired the metabolism of 125I-r-T3. Administration of carbohydrate (CHO) and amino acids (P), but not lipid (L), significantly increased T3 generation above values observed in the starved rat. The mean serum glucose concentration was similar in all nutriment-infused groups, but serum insulin was significantly greater in the CHO- and P-infused as compared to the L-infused rats. These findings suggest that CHO and P, but not L, are important modulators of hepatic outer ring thyronine deiodination in the rat, perhaps due to increased intracellular glucose. Hypothyroidism in the rat induced by thyroidectomy and congenital secondary hypothyroidism in the dwarf mouse resulted in a striking decrease in hepatic conversion of T4 to T3. This decrease was restored to normal by the daily s.c. administration of physiologic doses of T4 (1.5 microgram/100 g) or T3 (0.5 microgram/100 g) for 14 days, and was increased above normal following treatment of normal rate with greater than physiologic doses of T4 (3microgram/100 g) or T3 (1 microgram/100g). In vitro hepatic conversion of T4 to T3 is, therefore, dependent upon thyroid function. Since 2-days starvation in the rat was associated with decreased serum concentrations of T4, T3, and TSH, and hypothyroidism resulted in decreased conversion of T4 to T3, the effect of a constant 2-day infusion of physiologic doses of T4 or T3 in the starved rat on the in vitro deiodination of T4 was assessed. Thyroid hormone replacement did not enhance the conversion of T4 to T3 in the starved rat. These observations suggest that the starvation-induced decrease in hepatic generation of T3 from T4 is not due to hypothyroidism and that the mechanism(s) of the decreased T3 production observed in starvation and hypothyroidism is different.
TL;DR: Serum and urine levels of free carnitine and its renal clearance decreased during the fast, however, the serum concentration and urinary excretion of acylcarnitines increased during the same interval, and a significant negative correlation was found between serum levels offree L-carn itine and beta-hydroxybutyrate and free fatty acids during thefast.
Abstract: Serum levels of free L-carnitine, acylcarnitines, creatinine, beta-hydroxybutyrate, free fatty acids, cholesterol, triglycerides, and glucose were determined in healthy volunteers during a 24-36-hr fast. The effect of oral administration of free L-carnitine (1 g/person) on these parameters was studied. Urinary excretion of carnitine and creatinine was monitored throughout. Serum and urine levels of free carnitine and its renal clearance decreased during the fast. However, the serum concentration and urinary excretion of acylcarnitines increased during the same interval. Following the ingestion of free L-carnitine, both serum and urinary levels of free L-carnitine rose. Within 6 hr of ingestion, 10% of the administered dose could be accounted for by urinary excretion. No significant effect on the other serum constituents under study was seen following the oral L-carnitine dose. A significant negative correlation was found between serum levels of free L-carnitine and beta-hydroxybutyrate and free fatty acids (r equal -0.567, p less than 0.001 and r equal -0.607, p less than 0.001, respectively) during the fast.
TL;DR: Dietary changes had less effect on blood pressure in normotensive rats of the same strain (Wistar-Kyoto--WKY), consistent with the hypothesis that caloric restriction lowers sympathetic activity.
Abstract: In the spontaneously hypertensive rat (SHR), caloric restriction without sodium restriction is associated with reduced blood pressure Four days of fasting lowered blood pressure 19% while 4 days of eating 50% of ad lib intake reduced blood pressure 10% Similar dietary changes had less effect on blood pressure in normotensive rats of the same strain (Wistar-Kyoto--WKY) These data are consistent with the hypothesis that caloric restriction lowers sympathetic activity
TL;DR: This review attempts to describe the major findings related to hormone desensitization or resistance of these hormones that have plasma-membrane-bound receptors.
Abstract: Hormone receptors are those components of target-cells that specifically bind hormones and convey the hormonal message to the intracellular machinery. Such receptors can be localized inside the cell, such as the nuclear receptors of thyroid hormones and the nuclear and cytoplasmic receptors of steroid hormones, or on the outer surface of the plasma membrane, such as the membrane-bound receptors of polypeptide hormones and neurotransmitters. Extensive studies during recent years have shown that the interaction between hormone and membrane-bound receptor can affect the receptor characteristics in at least two ways. Firstly, receptor occupancy can modify, by way of cooperativity, the affinity of homologue receptors for the given hormone 1–7 . Secondly, the binding capacity of a target cell appears to vary a function of the preexposure of the cell to the hormone. The latter phenomenon has been related to the so-called states of subsensitivity, desensitization, or refractoriness, and might be responsible for the physiologic regulation of the target cell sensitivity and for the hormone resistance which accompanies various metabolic disorders. 8–11 In this review we attempt to describe the major findings related to hormone desensitization or resistance for these hormones that have plasma-membrane-bound receptors. Data from the literature are presented independently for each hormone and when applicable, conflicting results are discussed in each section. The various theories which might explain hormone desensitization are outlined in the last section of this paper.
TL;DR: The data suggest that marathon running may be associated with prevention of the changes that occur in body composition with aging and raise the possibility that exercise may prevent the involutional loss of skeletal and lean body mass.
Abstract: Skeletal and lean body mass was measured in 30 male marathon runners and in 16 subjects of comparable ages who were relatively sedentary. Skeletal mass was measured by total body neutron activation analysis (total body calcium—TBCa) and photon absorptiometry of the distal radius (bone mineral content—BMC). Lean body mass was estimated by the measurement of 40K in a whole body counter (total body K—TBK). The marathon runners were slightly taller and lighter than the contrast group; the bone width of the radius was essentially the same for both groups. When the values for TBK and TBCa were corrected for age and body size, the marathon runners were found to have values that were 7% (p < .002) and 11% (p < .001) higher, respectively. The values of BMC were somewhat elevated in the marathon runners but this increase in regional bone mass was not statistically significant. These data suggest that marathon running may be associated with prevention of the changes that occur in body composition with aging and raise the possibility that exercise may prevent the involutional loss of skeletal and lean body mass.
TL;DR: In this paper, total starvation in the rat for 2 days did not alter the hypothalamic content of thyrotropin-releasing hormone (TRH), but did decrease both pituitary TSH content and serum TSH concentration.
Abstract: Total starvation in the rat for 2 days did not alter the hypothalamic content of thyrotropin-releasing hormone (TRH), but did decrease both pituitary TSH content and serum TSH concentration. Five days starvation resulted in a significant decrease in serum TSH and a slightly enhanced serum TSH response to exogenous TRH, suggesting that the pituitary retains its sensitivity to TRH. Fasting for 5 days resulted in a decreased 1 and 4th, but an increased 24th thyroid 131I uptake. Other starvation-induced abnormalities of intrathyroid 131I metabolism were a consistent increase in the percent of organified 131I present as MIT and DIT and a decreased percent 131I labeled T4 AND T3. These alterations in the intrathyroid metabolism of 131I in the starved rat probably reflect both a decrease in serum TSH concentration and a decrease in urinary and fecal loss of administered 131I. The serum total and free T4 and total and free T3 concentrations were decreased following 2 and 5 days of starvation.
TL;DR: The fact that in insulin-dependent diabetics somatostatin did not improve the intravenous glucose tolerance but only the peroral one suggests that the different effects of som atostatin in the gut may be partly the result of inhibition of various duodenal hormones.
Abstract: Using "the artificial beta cell," previous studies have demonstrated that in insulin-dependent diabetics somatostatin reduces insulin requirements up to 70% and causes a marked flattening of the blood glucose curve after food intake. 1 Furthermore, in insulin-dependent diabetics somatostatin diminishes by 75%–100% rises in blood glucose after oral glucose, but did not influence glucose levels following intravenous glucose. 2 Since during the somatostatin infusion, a 30% reduction in splanchnic blood flow was observed, 2 the diminution of postprandial hypoglycemia following somatostatin seemed attributable primarily to a circulation-dependent delay in carbohydrate absorption. The fact that radioimmunoassayable somatostatin has been found not only in the stomach of the rat but also in the upper intestine, 3 in amounts comparable to those found in the hypothalamus, allow the assumption that somatostatin is a hormone in the gastrointestinal tract, coordinating the secretion of the other hormones. Recently, somatostatin-positive cells were shown to be present in the bottom of the intestinal crypt by immunohistochemical methods; 18 these cells were distinguished from those in other organs by the presence of a cytoplasmic process reaching the gut lumen (external environment). The assumed physiological importance of somatostatin or a somatostatin-like substance in the alimentary tract is emphasized by the fact that recently 4 a somatostatin-like immunoreactive peptide was isolated from the porcine duodenum. It has been known for many years that various gastrointestinal hormones exert an influence on the blood flow of the gastrointestinal tract. 5,6 It is unclear whether the effect of somatostatin on the splanchnic blood flow can be explained by the inhibition of various gastrointestinal hormones. The fact that in insulin-dependent diabetics somatostatin did not improve the intravenous glucose tolerance but only the peroral one suggests that the different effects of somatostatin in the gut may be partly the result of inhibition of various duodenal hormones. The present studies were undertaken to characterize the influence of somatostatin on the release and the biological activities of the two classic intestinal hormones, secretin and pancreozymin.
TL;DR: Choline administration increases blood Choline, brain choline, and brain acetylcholine levels in rats and appears to be a useful treatment for some patients with tardive dyskinesia, a brain disease probably associated with deficient cholinergic tone.
Abstract: Choline administration increases blood choline, brain choline, and brain acetylcholine levels in rats. It also increases blood choline levels in humans and appears to be a useful treatment for some patients with tardive dyskinesia, a brain disease probably associated with deficient cholinergic tone. In order to characterize other possible metabolic and hormonal effects of choline-containing compounds, we measured changes in serum choline, glucose, insulin, cortisol, prolactin, cholesterol, and triglyceride levels resulting from ingestion of low- or high-choline meals in 16 normal human subjects. After the consumption of a single meal containing 3 g choline chloride, serum choline rose by 86% ( p p p
TL;DR: Serum Tg may remain elevated long after clinical and other biochemical mainfestations of this disease have disappeared, suggesting that the disruption in thyroid function in patients with subacute thyroiditis may persist in a subclinical form for longer periods than previously suspected.
Abstract: Serum thyroglobulin (Tg), triiodothyronine (T3), and thyroxine (T4) concentrations were measured in sera from selected patients with hyperthyroidism due to Graves' disease and with subacute thyroiditis. In agreement with previous reports, the concentration of serum Tg was elevated in untreated hyperthyroidism due to Graves' disease, being 132 +/- 124 ng/ml (mean +/- SD) as opposed to 11 +/- 6.4 ng/ml in normal subjects. During treatment of hyperthyroidism with antithyroid drugs with or without iodide, reductions in thyroid hormone concentrations were not associated with a change in serum Tg. On the other hand, marked elevations in serum Tg to concentrations as high as 7000 ng/ml were observed within 24-48 hr after subtotal thyroidectomy or 131I treatment of patients with Graves' disease. These abrupt 10-50-fold increases in serum Tg were not associated with changes in serum T3 and T4. As previously demonstrated, patients with subacute thyroiditis may have elevated serum Tg concentrations that are not associated with elevations in serum T3 and T4. Serum Tg may remain elevated long after clinical and other biochemical mainfestations of this disease have disappeared. These data suggest that the disruption in thyroid function in patients with subacute thyroiditis may persist in a subclinical form for longer periods than previously suspected. Serum Tg appears to be a sensitive indicator of acute thyroidal damage due to surgical, radiation, or inflammatory trauma. The absence of parallel changes in serum Tg, T3, and T4 indicates that release of these thyroidal components can occur by different mechanisms and that nonthyroid tissues cannot efficiently generate T3 and T4 from circulating Tg. Accordingly, local or systemic stimulation of thyroidal Tg hydrolysis may be involved in the generation of hyperthyroidism sometimes seen in patients with subacute thyroiditis.
TL;DR: Samples of psoas muscle from nine infants and of several skeletal muscles from seven adult males were analyzed for content of protein-bound Ntau-methylhistidine (3- methylhistidine; 3-Mehis), compared with reported values and with published estimates of the rate of muscle protein breakdown in human subjects.
Abstract: Samples of psoas muscle from nine infants (aged 1 day to 14 mo) and of several skeletal muscles from seven adult males (age 19-74 yr) were analyzed for content of protein-bound Ntau-methylhistidine (3-methylhistidine; 3-Mehis). The mean content of 3-Mehis (expressed as mumoles/g mixed protein) was 3.2 (range 2.4-3.7) in infants and 4.2 (range 3.7-4.6) in adults. The daily urinary excretion of 3-Mehis was measured in four young adult males receiving an egg-protein, flesh-free diet. Mean excretion of 3-Mehis was 211 (range 167-252) mumoles/day. From these two sets of data the mean rate of muscle protein breakdown in adult males was estimated to be 50 g/day, or 0.7 +/- 0.1 g/kg body weight/day. These results are compared with reported values for the 3-Mehis content of mixed proteins in muscle of various species, and with published estimates, computed by other techniques, of the rate of muscle protein breakdown in human subjects.
TL;DR: The data suggest that attainment of a critical adipocyte size accompanied by maximum levels of plasma IRI may act in concert to potentiate fat cell hyperplasia in Zucker obese rats.
Abstract: Obese female Zucker rats show persistent increases in fat cell number compared to lean female Zucker rats from 5 to 52 wk of age. The hyperplastic obesity of the Zucker rat is also accompanied by fat cell hypertrophy and elevated plasma immunoreactive insulin (IRI). Average adipocyte size reaches a peak value at 14 wk of age in the subcutaneous, retroperitoneal and parametrial depots of the female obese rat. Plasma IRI also shows a peak at 14 wk of age. In addition, at this age thymidine kinase activity, a measure of proliferative capacity in tissue, is elevated in obese compared to lean rats, and at 151/2 wk of age a bimodal distribution of adipocytes is present in obese rat adipose tissue. The data suggest that attainment of a critical adipocyte size accompanied by maximum levels of plasma IRI may act in concert to potentiate fat cell hyperplasia in Zucker obese rats.
TL;DR: Gl glucose intolerance is universally present in uremic subjects and results primarily from peripheral tissue insensitivity to insulin, which is probably the result of a defect in intracellular metabolism or in the glucose transport system.
Abstract: The pathogenesis of glucose intolerance in uremia was examined with the glucose clamp technique. Hyperglycemic clamp ( n = 8): The plasma glucose concentration is acutely raised and maintained at 125 mg/dl above basal levels. Under these steady state conditions the glucose infusion rate, M , equals the amount of glucose metabolized: Predialysis M averaged 4.23 ± 0.36 mg/kg/min and increased to 7.71 ± 0.43 postdialysis ( p M/l ratio, a measure of tissue sensitivity to insulin, increased by 80% ± 25% ( p p n = 10): The plasma insulin concentration is acutely raised by 100 μU/ml and the plasma glucose concentration is held constant at the basal level. Predialysis both M (3.37 ± 0.36 mg/kg/min) and M/1 (3.56 ± 0.33 mg/kg/min per μU/ml X 100) were significantly less than controls ( p M and M/1 increased significantly ( p n = 6), 2.15 ± 0.09 mg/kg/min, was similar to controls and fell (87% ± 4%) normally during the insulin clamp. In five uremic subjects in whom insulin binding to monocytes was measured, there was no correlation with tissue sensitivity to insulin ( M/1 ). Significant abnormalities in both growth hormone and glucagon physiology were present in uremic individuals, but no correlation with either the presence or degree of glucose intolerance was demonstrable. In conclusion, glucose intolerance is universally present in uremic subjects and results primarily from peripheral tissue insensitivity to insulin. Insulin secretion is usually enhanced in an attempt to compensate for this insulin resistance but in occasional subjects uremia also inhibits beta cell sensitivity to glucose. Hepatic glucose production is unaffected by uremia. The lack of correlation between insulin binding and tissue sensitivity to insulin suggests that the cellular mechanism accounting for the insulin resistance is probably the result of a defect in intracellular metabolism or in the glucose transport system.
TL;DR: This report shall attempt to summarize the work from several laboratories, including the authors' own, on the distribution of cellular elements containing SRIF immunoreactivity in the gastroenteropancreatic endocrine system.
Abstract: The notion of a hypothalamic factor capable of inhibiting the release of growth hormone was suggested by the work of Krulich and collaborators.1 This activity can now be largely attributed to the tetradecapeptide somatostatin (SRIF), which was purified, sequenced, synthesized, and characterized in terms of biological activity by Brazeau et al.2 This remarkable work has enabled numerous laboratories to uncover the widespread distribution and range of activity of SRIF. In this report, we shall attempt to summarize the work from several laboratories, including our own, on the distribution of cellular elements containing SRIF immunoreactivity. Additional information is found in the work of Sofroniew and Wiendl elsewhere in these Proceedings. A more detailed description of SRIF immunoreactivity in the gastroenteropancreatic endocrine system are found in the reports of Falkmer et al., Forssmann et al., and Heitz et al elsewhere in these Proceedings.