Counter Regulation Research Articles

Homeostatic response of Zn metabolism to dietary Zn supplements from sulfate, gluconate, orotate, aspartate or histidine in 65Zn labeled non-growing rats as a model to adult individuals

The objective of the study was the long-term reaction of Zn homeostasis on dietary Zn supplies from gluconate, orotate, aspartate and histidine under condition of a sufficient Zn supply. Method: Thirty female rats were homogenously labeled with 65 Zn according to the alimentary technique with a semisynthetic diet containing Na phytate (8 g/kg) and 50 ppm Zn from ZnSO 4 . At a mean body weight of 224 g the animals were allotted to 6 groups (n = 5) and were fed restrictively (7.9 g/d) for 14 days 6 diets with either unchanged composition (control) or with an extra addition of 50 ppm Zn from sulfate, gluconate, orotate, aspartate or histidine. Results: The extra additions of dietary Zn were completely compensated by increased fecal Zn excretions irrespective of the Zn source, while urinary Zn and retention of Zn remained constant among all animal groups. Absorption of dietary Zn and fecal excretion of endogenous Zn was increased in all extra Zn groups without being altered by the type of Zn source. Concentrations and amounts of Zn in various organs, tissues and whole body were affected neither by quantity nor by type of dietary Zn. The rate of Zn exchange in tissues and whole body increased due to extra Zn additions irrespective of the type of Zn source. Conclusions: Dietary Zn from sulfate, gluconate, orotate, aspartate and histidine is physiologically equivalent as soon as the metabolic requirement of Zn is met. Possible differences in bioavailability are covered completely by counter regulation of Zn homeostasis.

Gender differences in counter regulation to hypoglycaemia in type 2 diabetes mellitus

Gender differences in counter regulation to hypoglycaemia in type 2 diabetes mellitus

Cytokine expression in three mouse models of experimental hepatitis.

The activation of T-cells and macrophages and subsequent induction of cytokines are critical factors in the development of hepatitis. Up-regulation of pro-inflammatory cytokines, e.g. TNF has been shown to induce liver injury while counter regulation by anti-inflammatory cytokines, e.g. IL-10 is protective. We compared the induction of liver injury and the expression pattern of a variety of cytokines in T-cell- versus non-T-cell-dependent mouse models of liver injury. TNF, IFNgamma, IL-2, IL-4, IL-6, IL-10 and IL-12 were measured in plasma and liver tissue after either Concanavalin A (Con A), D-galactosamine/lipopolysaccharide (GalN/LPS) or high dose LPS induced liver injury. Additionally, the intra-hepatic expression of the putative pathogenicity factor high mobility group 1 protein (HMG-1) was compared in all three models.

Glucocorticoid counter regulation: macrophage migration inhibitory factor as a target for drug discovery.

Over the past year, human studies have confirmed and expanded the involvement of macrophage migration inhibitory factor (MIF) in a number of diseases that had originally been studied in animals. In addition to sepsis, rheumatoid arthritis, glomerulonephritis and inflammatory lung disease, elevated MIF levels have been described in patients suffering from ulcerative colitis, inflammatory neurological diseases and cancer. Cellular studies indicate that in addition to macrophages, MIF affects the activities of CD4+ and CD8+ T cells, natural killer cells, fibroblasts and endothelial cells, actions that may explain the contribution of MIF to inflammatory diseases and cancer. Molecular studies have identified direct interactions between MIF and several intracellular regulatory proteins (Jab1, PAG and p53) that control cellular growth and proliferation; however, how interactions with these proteins fit into a general scheme to explain MIF's biological activity has not been elucidated. The three-dimensional structure of MIF has offered some surprising clues and if the potential enzymatic sites identified are involved with MIF-associated diseases, they may provide good targets for therapeutic intervention.

Chronic Colitis in IL-10-/- Mice: Insufficient Counter Regulation of a Th1 Response

IL-10-deficient (IL-10-/-) mice, generated by a gene-targeted mutation, develop abnormal immune responses as a result of uncontrolled interactions between antigen presenting cells and lymphocytes. The studies reviewed herein have focused on the enterocolitis that spontaneously develops in IL-10-/- mice. Not unexpectedly, heightened production of proinflammatory mediators accompanied pathologic changes in the gastrointestinal tract of young mutants. In a series of studies, the proinflammatory mediators responsible for initiating the pathogenic response were distinguished from those that were elicited as a consequence of persistent inflammation. We have also investigated the possibility that different mediators are involved in the inductive versus the maintenance phase of disease. The findings of these mechanistic studies as they relate to our understanding of progressive inflammatory disease and the role of IL-10 in controlling the acute and chronic stages are discussed.

Neonatal hypoglycaemia in Nepal 2. Availability of alternative fuels

AIMSTo study early neonatal metabolic adaptation in a hospital population of neonates in Nepal.METHODSA cross sectional study was made of 578 neonates, 0 to 48 hours after birth, in the...

Biobehavioral correlates in migraine: the role of hypersensitivity and information-processing dysfunction.

In this paper we address the role of specific abnormal behavioral patterns (such as perfectionism or hypersensitivity) which have been described as psychological characteristics in migraine patients. We propose that behavioral abnormalities may be the result of a determined cortical hypersensitivity and an associated social learning process. New neuro(psycho)physiological data support the concept that migraine is a brainstem-related information-processing dysfunction that is characterized by cortical hypersensitivity and reduced habituation to stimuli. The cortical activity reflects a (time) periodicity and may be due to endogenous or exogenous factors. Based on the current understanding of behavioral and neurophysiological aspects of migraine, we postulate a two-process model of migraine aetiology: (i) a genetically determined hyperactivity of the central monoaminergic (catecholaminergic) system, which could be possibly modulated by learning processes and (ii) a homeostatic (counter) regulation and mobilization of reduced (mitochondrial) energy reserve.

Major Histocompatibility Class II HLA-DRα Gene Expression in Thyrocytes: Counter Regulation by the Class II Transactivator and the Thyroid Y Box Protein

Aberrant expression of major histocompatibility complex (MHC) class II proteins on thyrocytes, which is associated with autoimmune thyroid disease, is mimicked by gamma-interferon (gamma-IFN). To define elements and factors that regulate class II gene expression in thyrocytes and that might be involved in aberrant expression, we have studied gamma-IFN-induced HLA-DR alpha gene expression in rat FRTL-5 thyroid cells. The present report shows that class II expression in FRTL-5 thyrocytes is positively regulated by the class II transactivator (CIITA), and that CIITA mimics the action of gamma-IFN. Thus, as is the case for gamma-IFN, several distinct and highly conserved elements on the 5'-flanking region of the HLA-DR alpha gene, the S, X1, X2, and Y boxes between -137 to -65 bp, are required for class II gene expression induced by pCIITA transfection in FRTL-5 thyroid cells. CIITA and gamma-IFN do not cause additive increases in HLA-DR alpha gene expression in FRTL-5 cells, consistent with the possibility that CIITA is an intermediate factor in the gamma-IFN pathway to increased class II gene expression. Additionally, gamma-IFN treatment of FRTL-5 cells induces an endogenous CIITA transcript; pCIITA transfection mimics the ability of gamma-IFN treatment of FRTL-5 thyroid cells to increase the formation of a specific and novel protein/DNA complex containing CBP, a coactivator of CRE binding proteins important for cAMP-induced gene expression; and the action of both gamma-IFN and CIITA to increase class II gene expression and increase complex formation is reduced by cotransfection of a thyroid Y box protein, which suppresses MHC class I gene expression in FRTL-5 thyroid cells and is a homolog of human YB-1, which suppresses MHC class II expression in human glioma cells. We conclude that CIITA and TSH receptor suppressor element binding protein-1 are components of the gamma-IFN-regulated transduction system which, respectively, increase or decrease class II gene expression in thyrocytes and may, therefore, be involved in aberrant class II expression associated with autoimmune thyroid disease.

Major Histocompatibility Class II HLA-DR Gene Expression in Thyrocytes: Counter Regulation by the Class II Transactivator and the Thyroid Y Box Protein

Major Histocompatibility Class II HLA-DR Gene Expression in Thyrocytes: Counter Regulation by the Class II Transactivator and the Thyroid Y Box Protein

Interleukin (IL) 1beta, IL-1 receptor antagonist, IL-10, and IL-13 gene expression in the central nervous system and anterior pituitary during systemic inflammation: pathophysiological implications.

The pathophysiology of systemic inflammation and sepsis involves peripheral organs, causing gastrointestinal, renal, and cardiovascular alterations, as well as the central nervous system (CNS), affecting sleep, temperature regulation, behavior, and neuroendocrine function. The molecular basis of the CNS effects of systemic inflammation are not fully elucidated. Here we show that the CNS responds to systemic inflammation with pronounced IL-1beta gene expression and limited IL-1 receptor antagonist (IL-1ra), IL-10, and IL-13 gene expression. This pattern occurs throughout the CNS, including areas such as the subfornical organ, pineal gland, neurohypophysis, and hypothalamus. In contrast, in the anterior pituitary, we found limited IL-1beta gene expression but marked induction of the mRNA encoding for the secreted isoform of IL-1ra, secreted IL-1ra. We conclude that the central manifestations of peripheral inflammation are mediated by endogenous brain IL-1beta synthesized during systemic inflammation in the context of limited central cytokine counter regulation of IL-1. As IL-1beta is a potent stimulus for inducible nitric oxide synthase expression and activity, these findings explain our previous observation that systemic inflammation promotes inducible nitric oxide synthase gene expression in the brain and the spillover of NO metabolites into cerebrospinal fluid. The CNS transcription of the HIV-1 replication factor IL-1beta in the context of limited transcription of the IL-1 replication inhibitors IL-1ra, IL-10, and IL-13 might help explain the negative impact of systemic inflammation on the clinical course of AIDS. In addition, we propose that IL-1ra may be secreted by the anterior pituitary as a systemic anti-inflammatory hormone that is released in response to IL-1beta originated from multiple sources.

The Expression of and Insulin Binding to Cellular Thyroid Hormone Binding Protein, but Not Insulin Degrading Enzyme, Is Increased during 3T3-L1 Adipocytes Differentiation

Specific insulin binding to several proteins (cytosolic insulin binding proteins; CIBPs) in the isolated cytoplasm of numerous cell types has been demonstrated. CIBPs include insulin degrading enzyme (IDE), CIBP p55 (identified as cellular thyroid hormone binding protein (CTHBP), which is also known as protein disulfide isomerase, or glutathione insulin transhydrogenase). To assess the possible role of CIBP p55\\CTHBP in insulin action, we compared125I-insulin binding to CIBP in cytosol isolated from 3T3-L1 cells at various time points during differentiation of the adipocytes. Insulin did not bind to CTHBP in fibroblasts, but the labeling was markedly increased during adipocyte differentiation. In contrast, insulin binding to IDE did not change during differentiation. Protein expression level of CTHBP in the cytosol fraction increased gradually during the differentiation of adipocytes, whereas that of IDE did not change throughout the period. These data indicate that CTHBP, but not IDE, was up-regulated during differentiation of the adipocytes, suggesting that CIBP p55\\CTHBP may play a role in regulating some insulin action, especially the counter regulation between insulin and other hormones during adipocyte differentiation.

Heparin Selectively Inhibits Gene Expression of Matrix Metalloproteinase Transin in Cultured Mesangial Cells

The aim of this study is to examine the transcriptional regulation of matrix metalloproteinase transin in glomerular mesangial cells responding to inflammatory cytokines and heparin. Northern blot analysis revealed that IL-1β preferentially induced transin mRNA. The stimulatory effect was not specific to transin, and upregulation of procollagen α1(IV), laminin B2 and tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNAs was also observed. After IL-1 stimulation, expression of the transin transcript increased progressively for up to 48 hours, differing from the limited induction of procollagen α1(IV) or TIMP-1. When mesangial cells were stimulated by IL-1β in the presence of heparin, transin expression was markedly suppressed in a dose-dependent manner. The inhibitory effect of heparin was specific to transin, and induction of procollagen α1(IV), laminin B2 or TIMP-1 by IL-1β was not affected. These findings revealed the selective counter regulation by IL-1β and heparin of the transin expression in mesangial cells.

Study of the rate of early glucose disappearance following insulin injection: insulin sensitivity index

The euglycaemic hyperinsulinaemic glucose clamp is usually considered as the reference technique to evaluate insulin sensitivity. As it is an-expensive and time-consuming tool, we therefore tried to validate a simple insulin tolerance test (ITT) (IV bolus of 0.1 IU/kg of regular insulin, with glucose sampling at −5, 0, 3, 5, 7, 10 and 15 min) and to demonstrate its usefulness. Insulin sensitivity was measured by DG G0 ratio (G0 = initial glycaemia, DG is the variation between G0 and the glycaemia obtained at 15 min by the calculation of the regression plot). We confirmed the existence of a correlation between the glucose uptake (mg/kg per min) evaluated by glucose clamp and the DG G0 index ( r = 0.9, P < 0.01). There was no stimulation of hormonal counter regulation during the test. The ITT was significantly correlated both with fasting insulin ( r = −0.43, P < 0.01), and post-glucose load insulin concentration ( r = −0.67, P < 0.01); each measurement expressing insulin sensitivity. Four groups of patients with different insulin sensitivity; controls, NIDDM, gynoid and android obese subjects, were clearly separated by ITT. We showed that fasting glycaemia and DG G0 were correlated ( y = 2.63 x − 0.093 ; r = 0.82, P < 0.01). These results suggest that ITT could be an easy, quick and low cost method to evaluate insulin resistance in clinical practice and epidemiological studies.

Antitumor effect of a specific aromatase inhibitor, 1 -methyl-androsta-1,4-diene-3,17-dione (Atamestane), in female rats bearing DMBA-induced mammary tumors

Atamestane is a potent competitive inhibitor of estrogen biosynthesis (aromatase) in several species, in vitro and in vivo, and has no endocrine side effects. In this study, the efficacy of atamestane in suppressing tumor growth was evaluated in comparing with that of a non-steroidal aromatase inhibitor (CGS 16949A, Ciba-Geigy) and ovariectomy. Female Sprague-Dawley rats bearing DMBA-tumors were treated s.c. once daily either with 30 or 150 mg/kg atamestane or with 0.1 or 0.5 mg/kg CGS 16949A for 4 weeks. At these biologically equivalent doses both aromatase inhibitors effectively inhibited tumor growth: at the end of treatment they caused a marked reduction in tumor size (up to 70%), while ovariectomy led to a complete remission of tumor growth. The histo-morphological pictures of the mammary tumors from treated animals were qualitatively almost similar to those of the control. In hosts, neither compound exerted any influence on the weight of genital organs (ovary, uterus and vagina), although the peripheral LH levels were significantly elevated by the higher dose of the aromatase inhibitors. This effect on LH levels is probably due to the elimination of the negative feed-back effect of estrogens on gonadotropin secretion (counter regulation). The serum prolactin levels were decreased by the aromatase inhibitors, indicating a diminution of estrogen levels in the treated animals. The present results clearly demonstrate that, in spite of the counter regulation, a pure aromatase inhibitor such as atamestane in sufficiently high doses is able to inhibit the growth of DMBA-induced mammary tumors in intact female rats.

Sympatho-adrenal response to hypoglycaemia in infants.

The response of the sympathoadrenal system to hypoglycaemia of different etiology was studied in seven infants, aged 10-189 days. Five infants had hyperinsulinism secondary to nesidioblastosis or to a beta-cell adenoma of the pancreas, one infant had neonatal sepsis due to staphylococcal infection and one infant congenital growth hormone (HGH) and adrenocorticotropic hormone (ACTH) deficiency. In babies with hyperinsulinism, plasma noradrenaline increased from 0.29 +/- 0.03 to 0.61 +/- 0.09 ng/ml (P less than 0.01), whereas adrenaline increased only in three, but did not change in two babies. Increases in heart rate and blood pressure paralleled these changes. In hypoglycaemia due to congenital sepsis, noradrenaline increased from 0.39 to 1.64 ng/ml and adrenaline from 0.05 to 0.86 ng/ml. This was associated with marked haemodynamic changes. In congenital HGH and ACTH deficiency, the low basal plasma levels of noradrenaline (0.12 ng/ml) and adrenaline (0.01 ng/ml) remained unchanged in response to hypoglycaemia. Heart rate and blood pressure were unaffected. The sympathoadrenal system was activated by hypoglycaemia in all infants except in congenital HGH and ACTH deficiency. In contrast to adults, noradrenaline was the preferentially released catecholamine, suggesting an involvement of noradrenaline in glucose counter regulation in infancy.

Impaired Counter Regulation of Hypoglycemia in a Group of Insulin‐dependent Diabetics with Recurrent Episodes of Severe Hypoglycemia

The counterregulatory response to insulin-induced hypoglycemia was investigated in 22 insulin-dependent diabetics (IDD) with recurrent hypoglycemia and in 6 healthy volunteers. Hypoglycemia was induced by a constant rate infusion of insulin (2.4 U/h) up to four hours. Conventional insulin therapy was changed to an i.v. infusion of regular insulin 24 hours prior to the experiment. The presence of diabetic autonomic neuropathy was evaluated by respiratory sinus arrhythmia and Valsalva maneuver. In healthy subjects, blood glucose was decreased to 2.5 mmol, here reaching steady state level and giving rise to marked glucagon and growth hormone (GH) responses. The majority of IDD (group A) reached a slightly lower steady state glucose level and exhibited similar glucagon and GH responses while the epinephrine response was augmented. Six IDD (group B) showed a continuous decrease in blood glucose to 1.2 +/- 0.1 mmol/l at which level the infusion of insulin was discontinued due to neuroglucopenic symptoms. These subjects had no glucagon and epinephrine responses while their GH and cortisol responses were normal. A comparison of the diabetic groups revealed a longer duration of diabetes and a more impaired autonomic nervous function in group B while glycosylated hemoglobin was similar. It is concluded that most IDD have normal hormonal responses (epinephrine, glucagon, GH, cortisol) and normal counterregulartory capacity to hypoglycemia induced by a prolonged infusion of a moderate dose of insulin. Some patients with long-term diabetes and impaired capacity to counteract hypoglycemia exhibit deficient glucagon and epinephrine responses to hypoglycemia.

Counter regulation of basal insulin secretion during alcohol hypoglycemia in hypercalcemic and normocalcemic man.

In seven normocalcemic subjects, fasted for 48 hours, alcohol hypoglycemia has been accompanied by a significant decline in basal insulin secretion. In another six healthy subjects, fasted for two days, infusion of calcium also induced a significant fall in basal secretion of insulin. However, when six healthy volunteers, fasted for two days, were infused with calcium and given alcohol simultaneously, no significant fall in insulin was recorded, even though the hypoglycemia, following this combined load, was of the same magnitude as in the subjects given alcohol alone. The implications of these findings are discussed.

Disturbances of the hypothalamo-hypophysial-adrenocortical system in the alloxan diabetic rat.

In insulin-treated alloxan diabetic rats some parameters of the hypothalamo-hypophysial-adrenocortical (HHA) system are normal: half-life and circadian rhythm of plasma corticosterone, maximal and submaxirnal stimulation of the adrenal cortex by exogenous and endogenous ACTH, dex-amethasone suppression of stress stimuli of different strengths. If insulin treatment is withheld, 40 hr after the last insulin injection morning levels of plasma corticosterone are elevated, adrenocortical response to exogenous ACTH is increased, the onset of dexamethasone inhibition of weak stress signals is delayed, different stress stimuli overcome the dexamethasone blockade. These disturbances of the regulation of the HHA-system could be interpreted as counter regulation in insulin-deficient alloxan diabetic rats. (Endocrinology 95: 760, 1974)

Relation between plasma glucose levels of mother and fetus during maternal hyperglycemia, hypoglycemia, and fasting in the rat.

Extract: The relation between the concentration of glucose in maternal and fetal plasma was examined in pregnant rats during the last three days of gestation. Rats were studied after being fasted for 16 hours following two hours of infusion of physiologic saline or insulin (1,000 μU/minute) in either 30% glucose or saline. After a constant concentration of glucose in maternal plasma had been achieved, the rats were sacrificed rapidly and fetal blood was obtained. In fasting animals, before day 20, the concentration of glucose in fetal plasma was low, and a gradient of 2.0 or greater prevailed between maternal and fetal plasma glucose. This gradient fell rapidly during days 20 and 21 to average 1.0 for the last 24–48 hours before term. In the fetus, the rise in the level of glucose paralleled that of hepatic glycogen. When maternal hyperglycemia was induced by infusion of glucose, the gradient in the younger fetuses was poorly maintained and fetal hyperglycemia occurred at all ages. When maternal hypoglycemia was induced by infusion of insulin, the younger fetuses displayed proportional hypoglycemia; however, after day 20, the level of plasma glucose in the fetus exceeded the maternal level, and the placental gradient for glucose was reversed. It is concluded that during maternal hypoglycemia, the near-term fetus is capable of independently regulating the level of glucose in blood for at least two hours. During maternal hyperglycemia, the normal placental gradient for glucose characteristic of the younger fetus fails to prevent completely fetal hyperglycemia, and near-term, maternal hyperglycemia is transmitted to the fetus without evident fetal counter regulation. Speculation: This study provides additional evidence for the thesis that the near-term fetus develops independent mechanisms for production and regulation of glucose during periods of glucose deprivation. The development and use of such mechanisms in utero during maternal fasting may represent an important preparation for extrauterine existence. It remains to be determined whether the prevailing hyperglycemia of diabetes during gestation might delay development of the pathways involved.

Experimental studies concerning regulation of the peripheral vessels. III. On the question of humeral counter regulation: Hoff, H., and Pichler, E.: Klin. Wchnschr. 15: 1599, 1936

Experimental studies concerning regulation of the peripheral vessels. III. On the question of humeral counter regulation: Hoff, H., and Pichler, E.: Klin. Wchnschr. 15: 1599, 1936