SEARCH · PubMed Health

Results for “HOMEOSTASIS”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 451 records · Page 25Linked to original sources

PubMed1996

The effect of hydrocortisone and thyroxine on development of calcium homeostasis in embryonic intestinal epithelium.

Cytoplasmic Ca2+ concentration of epithelial cells from 14-day embryonic chick duodena decreased during 72 h of organ culture to a value 54% of that found at 17 days in vivo. The ability of cells to maintain a constant Ca2+ concentration when challenged with high extracellular calcium was also significantly reduced. Addition of 1 microM hydrocortisone during culture restored both parameters of Ca2+ homeostasis to that of 16-day uncultured duodena, and rise in cytoplasmic Ca2+ was significant within 4 h of hormone treatment. Thyroxine influenced epithelial Ca2+ similarly, but to a lesser degree and only after 48-72 h of culture. These data indicate that glucocorticoids, and possibly thyroid hormones, influence the development of calcium homeostasis in intestinal epithelium.

Animals↗

PubMed1997

Dynamics of cellular homeostasis: recovery time for a perturbation from equilibrium.

In the collecting duct in vivo, the principal cell encounters a wide range in luminal flow rate and luminal concentration of NaCl. As a consequence, there are substantial variations in the transcellular fluxes of Na+ and Cl-, conditions which would be expected to perturb cell volume and cytosolic concentrations. Several control mechanisms have been identified which can potentially blunt these perturbations, and these entail cellular regulation of the luminal membrane Na+ channel and peritubular membrane K+ and Cl- channels. To illustrate the impact of these regulated channels, a mathematical model of the principal cell of the rat cortical collecting duct has been developed, in which ion channel permeabilities are either constant or regulated. In comparison to the model with fixed permeabilities, the model with regulated channels demonstrates enhanced cellular homeostasis following steady-state variation in luminal NaCl. However, in the transient response to a cytosolic perturbation, the difference in recovery time between the models is small. An approximate analysis is presented which casts these models as dynamical systems with constant coefficients. Despite the presence of regulated ion channels, concordance of each model with its linear approximation is verified for experimentally meaningful perturbations from the reference condition. Solution of a Lyapunov equation for each linear system yields a matrix whose application to a perturbation permits explicit estimation of the time to recovery. Comparison of these solution matrices for regulated and non-regulated cells confirms the similarity of the dynamic response of the two models. These calculations suggest that enhanced homeostasis by regulated channels may be protective, without necessarily hastening recovery from cellular perturbations.

Animals↗

PubMed1989

Effect of L-lysine on cytosolic calcium homeostasis in cultured human normal fibroblasts.

L-lysine, a cationic essential amino acid, has been reported to affect calcium transport in both intestine and kidney. In order to investigate whether this effect is associated with changes in cytosolic calcium homeostasis, we studied the effect of L-lysine deprivation on intracellular calcium concentration ([Ca2+]i), as well as 45Ca efflux and accumulation in normal human fibroblasts. Steady state [Ca2+]i, measured using fura-2 fluorescence in cells cultured for 18 hours in a L-lysine-free medium, was significantly higher than in cells grown in the presence of as little as 4 microM L-lysine. L-lysine deprivation also led to a significant decrease of 45Ca fractional efflux compared with cells grown in complete medium. This effect was paralleled by a significant decrease in 45Ca accumulation. Lack of L-arginine from the growth medium for the same time period had no effect on either [Ca2+]i, 45Ca efflux, or 45Ca accumulation rate. Presumably, the lack of L-lysine for a significant amount of time impairs the active mechanisms of calcium extrusion, which is only partially compensated by a reduction of calcium accumulation rate. This leads to an increased steady state [Ca2+]i. It is concluded that L-lysine is an important modulator of cytosolic calcium homeostasis.

Calcium↗

PubMed1999

Effects of ethanol on calcium homeostasis in the nervous system: implications for astrocytes.

Ethanol is a major health concern, with neurotoxicity occurring after both in utero exposure and adult alcohol abuse. Despite a large amount of research, the mechanism(s) underlying the neurotoxicity of ethanol remain unknown. One of the cellular aspects that has been investigated in relationship to the neuroteratogenicity and neurotoxicity of ethanol is the maintenance of calcium homeostasis. Studies in neuronal cells and other cells have shown that ethanol can alter intracellular calcium levels and affect voltage and receptor-operated calcium channels, as well as G protein-mediated calcium responses. Despite increasing evidence of the important roles of glial cells in the nervous systems, few studies exist on the potential effects of ethanol on calcium homeostasis in these cells. This brief review discusses a number of reported effects of alcohol on calcium responses that may be relevant to astrocytes' functions.

Astrocytes↗

PubMed1998

Effects of low-molecular-weight aluminum complexes on brain tissue calcium homeostasis.

The in vitro effects of low-molecular-weight aluminum complexes (citrate, lactate, and ATP complex) on the Ca2+ uptake and aluminum-induced lipid peroxidation of brain tissue show that the modification of the calcium homeostasis is determined by the nature of the ligand and that there is no correlation between the aluminum-induced lipid peroxidation and the Ca2+ uptake. The same characteristics have been shown by a similar study performed with Ehrlich carcinoma cells. The electrophoretic analyses of the aluminum lactate-albumin and aluminum lactate-ATP interactions indicate an aluminum transfer from the lactate to the albumin and ATP ligands. The increased Ca2+ uptake when ATP is present in the incubation medium with aluminum citrate and aluminum lactate corroborates the suggested mediator role of ATP in cellular calcium homeostasis modification induced by iron.

Aluminum Compounds↗

PubMed1987

Acute calcium homeostasis in MHS swine.

To elucidate a pathogenesis for the reduction in bone calcium content observed in MHS individuals, we studied the acute calcium homeostasis of MHS swine. This was achieved by the serial measurement, with a calcium selective electrode, of calcium transients in Landrace MHS (five) and control Landrace/large white cross MH negative (five) swine following IV bolus injection of calcium gluconate 0.1 mmol X kg-1--a dose which induced an acute 45 per cent increase in plasma ionised calcium. Experimental animals were anaesthetised with ketamine 10 mg X kg-1 IM, thiopentone (intermittent divided doses) 15-25 mg X kg-1 (total) IV and N2O/O2 (FIO2 0.3) by IPPV to maintain a normal blood gas, acid/base state. The plasma ionised calcium decay curve observed in MHS swine did not differ from that of control normal swine. Further it was noted that the induced acute rise in plasma ionised calcium failed to trigger the MH syndrome in any MHS swine. It is concluded that the mechanisms of acute calcium homeostasis in MHS swine are normal. An explanation for the reduction in bone calcium content observed in MHS individuals must be sought, therefore, through study of the slow long-term component of the calcium regulatory process. In addition, the conventional strictures placed on the use, in MHS patients, of calcium gluconate are called in question.

Anesthesia, General↗

PubMed2002

Homeostasis in the small intestinal mucosa balanced between cell proliferation and apoptosis is regulated partly by the central nervous system.

The aim of this study was to investigate whether the central nervous system regulates mucosal cell growth and apoptosis in the rat small intestine. Ornithine decarboxylase is a key enzyme for polyamine synthesis, which plays an important role in intestinal mucosal growth. The increase in ornithine decarboxylase activity in the duodenum just before a dark period was abolished by truncal vagotomy. An infusion of 2-deoxy-D-glucose into the third cerebroventricle activated the enzyme activity in the small intestine. Epithelial homeostasis is balanced by the regulation of cell proliferation and cell death. Intestinal mucosal apoptosis decreased in rats with ventromedial hypothalamus lesions, which induced hyperphagia and obesity. In contrast, sustained anorexia induced by 1-deoxy-D-glucosamine increased intestinal apoptosis. These results indicate that the central nervous system, in addition to local factors, is related to the regulation of mucosal homeostasis in the intestinal mucosa.

Animals↗

PubMed1996

Thyroid hormones homeostasis in rats refed after short-term and prolonged fasting.

Effects of starvation on thyroid hormone homeostasis were usually determined after 2 or more days of fasting, however, both in man and in rodents, natural feeding cycles comprise far shorter fasting periods. Therefore serum levels of T4, FT4, T3, FT3 and rT3 were measured in rats refed chow diet for 1, 4, 8 or 24 hours after 14 or 48 hours of starvation. Both short-term (14 h) and long-term fasting (48 h) decreased body weight and serum glucose level. Short-term fast decreased serum FT3 and did not change serum levels of T4, FT4, T3 and rT3. Total T3 and reverse T3 increased after one and 4 hours, free T3 after 4 hours and total T4 after 4 and 8 hours of refeeding. Percent of FT3 did not change after short-term fast, declined after 1 and 4 hours of refeeding, and normalised thereafter. Prolonged starvation (48 h) decreased serum T4, T3, FT3 and % FT3 with no changes in FT4 and rT3. After 24 hours of refeeding only FT3 and % FT3 returned to control levels while total T4 and total T3 were still diminished, and reverse T3 levels did not change. The results suggest that the length of preceding fasting period may strongly influence thyroid hormone homeostasis during fasted-to-fed transition.

Animals↗

PubMed2006

Chronic gestational exposure to ethanol causes insulin and IGF resistance and impairs acetylcholine homeostasis in the brain.

In fetal alcohol syndrome (FAS), cerebellar hypoplasia is associated with impaired insulin-stimulated survival signaling. This study characterizes ethanol dose-effects on cerebellar development, expression of genes required for insulin and insulin-like growth factor (IGF) signaling, and the upstream mechanisms and downstream consequences of impaired signaling in relation to acetylcholine (ACh) homeostasis. Pregnant Long Evans rats were fed isocaloric liquid diets containing 0%, 2%, 4.5%, 6.5%, or 9.25% ethanol from gestation day 6. Ethanol caused dose-dependent increases in severity of cerebellar hypoplasia, neuronal loss, proliferation of astrocytes and microglia, and DNA damage. Ethanol also reduced insulin, IGF-I, and IGF-II receptor binding, insulin and IGF-I receptor tyrosine kinase activities, ATP, membrane cholesterol, and choline acetyltransferase (ChAT) expression. In vitro studies linked membrane cholesterol depletion to impaired insulin receptor binding and insulin-stimulated ChAT. In conclusion, cerebellar hypoplasia in FAS is mediated by insulin/IGF resistance with attendant impairments in energy production and ACh homeostasis.

Acetylcholine↗

PubMed2002

Orexins: from neuropeptides to energy homeostasis and sleep/wake regulation.

The neuropeptides orexin A and orexin B (also called hypocretin 1 and 2) were recently discovered by a "reverse pharmacology" approach as ligands for two previously orphan G protein coupled receptors: orexin receptors 1 and 2. Neurons producing orexins are located exclusively in the lateral hypothalamic area but project broadly to various parts of the brain, and they have been implicated in the control of energy homeostasis and arousal maintenance. The orexin receptors are also broadly expressed in the central nervous system. Murine and canine models suggest that defective signaling in the orexin system is responsible for the sleep/wake disorder narcolepsy. Although narcoleptic patients rarely have genetic defects in the orexin system, they lack these neuropeptides in the brain and cerebrospinal fluid, indicating that human narcolepsy is an orexin deficiency syndrome in the majority of cases. A connection between sleep/wake regulation and energy homeostasis is hypothesized with orexin neuropeptides as a molecular link.

Animals↗

PubMed2002

Diabetes-induced alterations in calcium homeostasis in sensory neurones of streptozotocin-diabetic rats are restricted to lumbar ganglia and are prevented by neurotrophin-3.

AIMS/HYPOTHESIS: In diabetic sensory polyneuropathy the earliest and most severe pathophysiology occurs in neurones with the longest axons. The aim of this study was to characterise a diabetes-induced neurodegenerative marker that was selective for sensory neurones with the longest axons. We studied alterations in calcium homeostasis since this occurs in other neurodegenerative diseases. METHODS: Sensory neurones were cultured from control and streptozotocin-diabetic rats, treated with or without human recombinant neurotrophin-3 (hrNT-3), and neurones from L4-L6 dorsal root ganglia (DRG) which exhibit the longest axons in vivo were compared with those from C5-L3 DRG. Fluorescent video-imaging was used to measure cytoplasmic calcium dynamics. RESULTS: Streptozotocin diabetes of 8 to 14 weeks, induced an increase in resting internal Ca(2+) concentration ([Ca(2+)](i)), from 67 +/- 7 nmol/l in small neurones and 79 +/- 9 nmol/l in big neurones obtained from control animals to 214 +/- 19 nmol/l in small neurones and 273 +/- 30 nmol/l in big neurones after 14 weeks of diabetes ( p < 0.05) in L4-L6 DRG cultures. Neurones from C5-L3 ganglia and non-neuronal cells were not affected. Treatment of 14-week streptozotocin-diabetic rats with subcutaneous injection of 5 mg/kg NT-3 normalised the increase in resting [Ca(2+)](i). The amplitudes induced by depolarisation, caffeine and ATP [Ca(2+)](i) responses were reduced in small ( < 30 microm diameter) but not big ( > 35 microm diameter) neurones of L4-L6 DRG from streptozotocin-diabetic animals; the C5-L3 DRG were not similarly affected and the changes in the L4-L6 DRG were corrected by NT-3 treatment. CONCLUSIONS/INTERPRETATION: Altered calcium homeostasis could be an early molecular marker linked to the onset of diabetic sensory neuropathy. This neurodegenerative index can be corrected by NT-3 therapy and should encourage further work aimed at understanding the mechanistic basis of these observations.

Adenosine Triphosphate↗

PubMed2006

Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver.

AIMS/HYPOTHESIS: We used oestrogen receptor-alpha (ERalpha) knockout (ERKO) and receptor-beta (ERbeta) knockout (BERKO) mice to investigate the mechanism(s) behind the effects of oestrogens on glucose homeostasis. METHODS: Endogenous glucose production (EGP) was measured in ERKO mice using a euglycaemic-hyperinsulinaemic clamp. Insulin secretion was determined from isolated islets. In isolated muscles, glucose uptake was assayed by using radiolabelled isotopes. Genome-wide expression profiles were analysed by high-density oligonucleotide microarray assay, and the expression of the genes encoding steroyl-CoA desaturase and the Leptin receptor (Scd1 and Lepr, respectively) was confirmed by RT-PCR. RESULTS: ERKO mice had higher fasting blood glucose, plasma insulin levels and IGT. The plasma leptin level was increased, while the adiponectin concentration was decreased in ERKO mice. Levels of both glucose- and arginine-induced insulin secretion from isolated islets were similar in ERKO and wild-type mice. The euglycaemic-hyperinsulinaemic clamp revealed that suppression of EGP by increased insulin levels was blunted in ERKO mice, which suggests a pronounced hepatic insulin resistance. Microarray analysis revealed that in ERKO mice, the genes involved in hepatic lipid biosynthesis were upregulated, while genes involved in lipid transport were downregulated. Notably, hepatic Lepr expression was decreased in ERKO mice. In vitro studies showed a modest decrease in insulin-mediated glucose uptake in soleus and extensor digitorum longus (EDL) muscles of ERKO mice. BERKO mice demonstrated normal glucose tolerance and insulin release. CONCLUSIONS/INTERPRETATION: We conclude that oestrogens, acting via ERalpha, regulate glucose homeostasis mainly by modulating hepatic insulin sensitivity, which can be due to the upregulation of lipogenic genes via the suppression of Lepr expression.

Adiponectin↗

PubMed2005

Dysregulation of energy homeostasis in mice overexpressing insulin-like growth factor-binding protein 6 in the brain.

AIMS/HYPOTHESIS: IGFs, IGF receptors and IGF binding proteins (IGFBPs) are widely expressed in the central nervous system. To investigate the physiological significance of IGFBP-6 in the brain we established two transgenic mouse lines overexpressing human (h)-IGFBP-6 under the control of glial fibrillary acidic protein promoter. Increasing evidence suggests that insulin/IGF signalling pathways could be implicated in the neuroendocrine regulation of energy homeostasis. We explored the impact of brain IGFBP-6 overexpression on the regulation of food intake and energy balance. METHODS: Transgenic mice were fed either a control diet or a high-fat diet for up to 3 months. Glucose and insulin tolerance tests were carried out before and after the diet period. Plasma parameters (insulin, leptin, glucose, NEFAs and triglycerides) were measured, and uncoupling protein 1 (UCP-1) expression was quantified in brown adipose tissue. Oxygen consumption was also measured in both groups. RESULTS: The transgenic mice fed a high-fat diet for 3 months developed obesity, showing increases in plasma leptin, glucose and insulin levels and mild insulin resistance. As compared with wild-type mice, no significant differences were found in the quantity of food intake. However, UCP-1 expression was down-regulated in the brown adipose tissue of the transgenic mice. CONCLUSIONS/INTERPRETATION: Our results show that brain IGFBP-6 has an impact on the regulation of energy homeostasis. These transgenic h-IGFBP-6 mice may be considered a new tool for studies of the involvement of the brain IGF system in metabolism control and obesity.

Adipose Tissue, Brown↗

PubMed2006

Oesophageal dysmotility, delayed gastric emptying and autonomic neuropathy correlate to disturbed glucose homeostasis.

AIMS/HYPOTHESIS: Among diabetic patients, glucose homeostasis may be affected by abnormal gastrointestinal motility and autonomic neuropathy. This study analysed whether oesophageal dysmotility, delayed gastric emptying or autonomic neuropathy affect glucose homeostasis. MATERIALS AND METHODS: Oesophageal manometry and gastric emptying scintigraphy were performed in 20 diabetic patients. Heart-rate variation during deep breathing (expiration/inspiration [E/I] ratio) and continuous subcutaneous glucose concentrations for a period of 72 h were also monitored in the same patients. RESULTS: Oesophageal dysmotility was found in eight of 14 patients. Eleven of 20 patients had delayed gastric emptying (abnormal gastric emptying half-time [T (50)]) and nine of 18 had an abnormal E/I ratio. Complaints of abdominal fullness were predictive of delayed gastric emptying. A low peristaltic speed of the oesophagus was associated with impaired T (50) (r ( s )=-0.67; p=0.02). One hour after breakfast, subcutaneous glucose levels decreased in patients with delayed gastric emptying but continued to rise in those with normal emptying. Consequently, the median glucose level 2.5 h after breakfast was lower in the former (9.1 [4.2-12.5] vs 14.3 [11.2-17.7] mmol/l; p<0.05). Glucose fluctuations during the 72 h were significantly higher in patients with an abnormal E/I ratio than in those with a normal E/I ratio (coefficient of variation: 41 [46-49] vs 28 [27-34]%; p=0.008). CONCLUSIONS/INTERPRETATION: Abdominal fullness predicted delayed gastric emptying that was associated with diminished glucose uptake after breakfast. Low oesophageal peristaltic speed was associated with slow gastric emptying whereas parasympathetic neuropathy was associated with increased glucose variations.

Autonomic Nervous System Diseases↗

PubMed1999

The effect of intense exercise on postprandial glucose homeostasis in type II diabetic patients.

AIMS/HYPOTHESIS: The influence of postprandial high intensity exercise on glycaemia was studied in patients with Type II diabetes mellitus. METHODS: Patients who were treated by diet only (n = 8) ate a standardised breakfast and 4 h later a standardised lunch. They were studied in the resting state (control day) and on another day (exercise day) when they did intermittent exercised at high intensity after breakfast) (4 bouts including 3 min at 56.5 +/- 3.9 % V.(O2) (max) (means +/- SEM), 4 min at 98.3 +/- 5.1 % V.(O2) (max) and 6 min of rest). Responses were calculated as areas under the plasma concentration curve (AUC) during 4 h after either breakfast or lunch. RESULTS: Breakfast-AUCs for glucose, insulin and C peptide were lower (p < 0.05) on the exercise day compared with the control day (glucose: 538 +/- 94 vs 733 +/- 64 mmol. l(-1). 240 min; insulin: 16 +/- 4 vs 22 +/- 3 pmol. ml(-1). 240 min; C peptide: 143 +/- 22 vs 203 +/- 29 pmol. ml(-1). 240 min). After breakfast glucose appearance was unaffected by exercise, whereas disappearance and clearance increased (p < 0.05). Muscle glycogen was diminished by exercise (p < 0.05). After lunch no differences were observed between experiments. Exercise-induced reductions in glucose, insulin and C peptide responses were similar (p > 0.05) in this study of intermittent, high intensity exercise and in a previous study of isocaloric but prolonged moderate (45 min at 53 +/- 2 % V.(O2) (max)) postprandial exercise. CONCLUSION/INTERPRETATION: Postprandial high intensity exercise does not deteriorate glucose homeostasis but reduces both glucose concentrations and insulin secretion. The effect of exercise is related to energy expenditure rather than to peak exercise intensity. Finally, postprandial exercise does not influence glucose homeostasis during a subsequent main meal. [Diabetologia (1999) 42: 1282-1292]

Blood Glucose↗

PubMed2006

Role of oxidative stress, mitochondrial membrane potential, and calcium homeostasis in human lymphocyte death induced by nickel carbonate hydroxide in vitro.

When isolated human lymphocytes were treated in vitro with various concentrations of soluble form of nickel carbonate hydroxide (NiCH) (0-1 mM), at 37 degrees C for 4 h, both concentration- and time-dependent effects of NiCH on lymphocyte death were observed. Increased generation of hydrogen peroxide (H(2)O(2)), superoxide anion (O(2)(-) ), depletion of both no protein (NP-) and protein (P-) sulfhydryl (SH) contents and lipid peroxidation (LPO) were induced by NiCH. Pretreatment of lymphocytes with either catalase (H(2)O(2) scavenger), or deferoxamine (DFO) (iron chelator), or excess glutathione (GSH) (an antioxidant) not only significantly reduced the NiCH-induced generation of H(2)O(2) and LPO, but also increased the NP-SH and P-SH contents initially reduced by NiCH. NiCH-induced generation of excess O(2)(-) but not excess LPO was significantly reduced by pretreatment with superoxide dismutase (SOD). NiCH-induced lymphocyte death was significantly prevented by pre-treatment with either catalase, or dimethylthiourea/mannitol (hydroxyl radical scavengers), or DFO, or excess GSH/N-acetylcysteine. NiCH-induced lymphocyte death was also significantly prevented by pretreatment with excess SOD. Thus, various types of oxidative stresses play an important role in NiCH-induced lymphocyte death. Cotreatment with cyclosporin A (a specific inhibitor of alteration in mitochondrial membrane potential (DeltaPsi(m)) not only inhibited NiCH-induced alteration in DeltaPsi(m), but also significantly prevented Ni-compound-induced lymphocyte death. Furthermore, NiCH-induced destabilization of cellular calcium homeostasis. As such, NiCH-induced lymphocyte death was significantly prevented by modulating intracellular calcium fluxes such as Ca(2+) channel blockers and intracellular Ca(2+) antagonist. Thus, the mechanism of NiCH (soluble form)-induced activation of lymphocyte death signalling pathways involves not only the excess generation of different types of oxidative stress, but also the induction of alteration in DeltaPsi(m) and destabilization of cellular calcium homeostasis as well.

Adult↗

PubMed1997

1alpha-hydroxyvitamin D2 partially dissociates between preservation of cancellous bone mass and effects on calcium homeostasis in ovariectomized rats.

Vitamin D metabolites can prevent estrogen depletion-induced bone loss in ovariectomized (OVX) rats. Our aim was to compare the bone-protective effects of 1alpha,25-dihydroxyvitamin D3 (1, 25(OH)2D3), 1alpha,25-dihydroxyvitamin D2 (1,25(OH)2D2), 1alpha-hydroxyvitamin D3 (1alpha(OH)D3), and 1alpha-hydroxyvitamin D2 (1alpha(OH)D2) in OVX rats. 1alpha(OH)D3 and 1alpha(OH)D2 are thought to be activated in the liver to form 1,25(OH)2D3 and 1, 25(OH)2D2, respectively. Forty-four 12-week-old female Fischer-344 rats were either OVX or sham-operated (SHAM). Groups of OVX rats (n = 7 each) received vehicle alone, 1,25(OH)2D3, 1,25(OH)2D2, 1alpha(OH)D3, or 1alpha(OH)D2, starting 2 weeks after surgery. All vitamin D metabolites were administered orally at a dose of 15 ng/day/rat. Urine and blood samples were collected 6, 9, 12, and 16 weeks after surgery. Serum samples were analyzed for total calcium and phosphate. Calcium, phosphate, creatinine, and free collagen cross-links (ELISA) were determined in urine. After tetracycline double labeling, the rats were sacrificed 16 weeks postsurgery, and the proximal tibiae and the first lumbar vertebrae were processed undecalcified for static and dynamic bone histomorphometry. 1,25(OH)2D3 and, to a slightly lesser extent, 1,25(OH)2D2 elevated vertebral cancellous bone mass in OVX rats to a level beyond that observed in SHAM animals, and both compounds increased serum calcium and urinary calcium excretion to similar extents. 1alpha(OH)D3 and 1alpha(OH)D2 resulted in a 64% and 84%, respectively, inhibition of ovariectomy-induced vertebral cancellous bone loss. In the proximal tibial metaphysis, all vitamin D metabolites tested could only partially prevent post-OVX trabecular bone loss, with a tendency for 1alpha(OH)D3 to be the least active compound. The effects of 1alpha(OH)D3 and 1alpha(OH)D2 on calcium homeostasis differed markedly, however. The mean increase in urinary calcium excretion over the whole experiment was fivefold for 1alpha(OH)D3, whereas the corresponding increase for 1alpha(OH)D2 was only twofold. We conclude that, compared with 1alpha(OH)D3, 1alpha(OH)D2 combined at least equal or higher bone-protective activity in OVX rats with distinctly less pronounced effects on calcium homeostasis. This effect was not due to a differential action of the corresponding main activation products, 1,25(OH)2D3 and 1,25(OH)2D2.

Animals↗

PubMed1998

Effects of candesartan cilexetil on glucose homeostasis. Multicenter Study Group.

In a multicenter, randomized, double-blind, placebo-controlled clinical trial the effects of candesartan cilexetil (cand.cil.), a novel angiotensin II antagonist selective for the AT1 receptor with long-lasting antihypertensive activity, on glucose homeostasis--and the serum lipid profile--were assessed in patients with mild hypertension and stable type II diabetes mellitus. A total of 161 men and women, 30-75 years old, with mild hypertension (sitting diastolic blood pressure 90-100 mmHg) and type II diabetes (HbA1c 5.5-9.0%), both measured after a 4-week placebo run-in period, were randomized to double-blind treatment with cand.cil. 8 mg o.i.d. (n = 83) or placebo (n = 78). Dose was increased to 16 mg o.i.d., if diastolic blood pressure remained > or = 90 mmHg. At randomization and after 12 weeks of treatment HbA1c (primary effect variable), blood glucose and the serum lipid profile (including total cholesterol, HDL and LDL cholesterol, triglycerides) were assessed. The statistical analysis of the differences between treatments was based on changes from randomization to the end of the study. Cand.cil. had no significant effect on HbA1c, blood glucose, and serum lipids compared to placebo. The median HbA1c both at baseline and after 12 weeks was 7.1% in patients on cand.cil., and 7.2% and 7.1% in patients on placebo. The 95% confidence interval for the median difference in change between the groups was narrow (-0.25; 0.16), including zero, which excluded any clinically important difference. The same held true for blood glucose (-1.10; 0.20), total cholesterol (-0.40; 0.20), and the other lipid parameters. More than 60% of the patients reached a diastolic blood pressure < 90 mmHg; adverse events and withdrawals were similar in both groups. Thus, in patients with mild hypertension and type II diabetes, cand.cil. 8 to 16 mg o.i.d. for 12 weeks does not affect glucose homeostasis respectively serum lipids. Blood pressure was controlled in most patients and cand.cil. was well tolerated.

Aged↗