Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The calcitonin gene peptide superfamily consists of calcitonin (CT), calcitonin gene-related peptide (CGRP), and amylin. CT and CGRP derive from the CT/CGRP gene, which is encoded on chromosome 11. Alternative splicing of the primary RNA transcript leads to the translation of CGRP and CT peptides in a tissue-specific manner. CGRP (a 37-amino-acid neuropeptide) and its receptors are widely distributed in the body, and it is the most potent endogenous vasodilatory peptide discovered so far. CT (a 32-amino-acid peptide) is, however, a hormone primarily involved in protecting the skeleton during periods of "calcium stress" such as growth, pregnancy, and lactation. CT derives from the C cells of the thyroid gland and is the most potent peptide inhibitor of osteoclast-mediated bone resorption. Therefore, treatment with CT is highly effective for conditions associated with increased bone turnover such as Paget's disease, osteoporosis, Sudeck's atrophy, and hypercalcemia. Amylin (a 37-amino-acid peptide) is generated from a gene located on chromosome 12 (thought to be an evolutionary duplication of chromosome 11) and shares 46% amino acid sequence homology with CGRP and 20% with human CT. Amylin is predominantly located in the beta cells of the islets of the pancreas and may be involved in the pathogenesis of type II diabetes by deposition as amyloid within the pancreas, leading to beta cell destruction. Adrenomedullin, a recently discovered 52-amino-acid vasoactive peptide from adrenal tissue, shares 24% homology with CGRP and is also a member of this superfamily of peptides. A portion of the B-chain of insulin is strongly homologous to these four peptides. Not only does adrenomedullin (13-52) show 24% amino acid homology with CGRP, it also has a biological activity profile similar to that of CGRP.CGRP, CT, and amylin are related to the insulin gene superfamily of peptides, which may all have diverged from a common ancestral gene during evolution. When the crystallographic- and nuclear magnetic resonance-based molecular modeling of the three-dimensional structure of CGRP, CT, amylin, and adrenomedullin peptides and their receptors is available, it will lead to a greater understanding of the involvement of this family of peptides in pathophysiology. Together, CGRP, CT, amylin and adrenomedullin have overlapping biological effects owing to their structures and cross-reactivity between receptors. I propose that CT, CGRP, adrenomedullin, and amylin belong to a family of G-protein-coupled receptors (an "insulin superfamily" of peptides) and therefore share some of the characteristics of insulin, such as growth factor-like effects, and possible interaction at insulin receptor sites as an antagonist.
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PMID:Amylin, calcitonin gene-related peptide, calcitonin, and adrenomedullin: a peptide superfamily. 920 29

Revascularization of a limb after a severe and prolonged period of ischemia may be associated with high rates of mortality and amputation, because of the development of a postrevascularization syndrome, regardless the cause of occlusion (ischemia, trauma, iatrogenic) or the methods used to achieve reperfusion (fibrinolysis, surgery, resuscitative therapy). This "revascularization" syndrome includes several complications, both local (explosive swelling of the limb, compartment syndrome and skeletal muscle infarction (rhabdomyolysis) and general (acidosis, hypercalcemia, hypovolaemic shock, renal, hepatointestinal and pulmonary failures, arrhythmias and cardiac arrest (multiple organ dysfunction). Current therapies are directed against complications after they occurred, once revascularization is completed: fasciotomy, mannitol and diuretics administration for forced diuresis, fluid administration to correct hypovolaemia, use of resins, insulin and glucose or haemodialysis to deal with hypercalcemia, administration of buffers (THAM, bicarbonate) to correct acidosis, control of hypercalcaemia with orthophosphates and calcitonin.... Nevertheless, a substantial percentage of the injury is generated upon reperfusion and the muscle may remain viable after prolonged period of ischemia. Intra and extraacellular swelling, tissue acidosis, free radical mediated damage, loss of adenine nucleotide precursors, and intracellular calcium overload have been suggested to be the mechanisms responsible for reperfusion injury. Careful control of both the composition and the physical conditions of the initial reperfusion (controlled reperfusion) may result, in selected cases, in improvements in the metabolism, structure and function of the limb after reperfusion.
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PMID:Local and systemic consequences of severe ischemia and reperfusion of the skeletal muscle. Physiopathology and prevention. 977 43

We have previously demonstrated that parathyroid hormone (PTH) infusion decreases glucose disappearance rate (Kg) in vivo. Because in the rodent model used it was not possible to determine whether the PTH itself, the induced hypercalcemia, or both contributed to the glucose intolerance, we examined the effect of vitamin D infusion on insulin-mediated glucose disposal. In this model also hypercalcemia is induced but PTH levels are suppressed. Thirty male Sprague Dawley rats were continuously infused with vit D for 5 days using an Alzet miniosmotic pump, at a rate of 9.7 pmol/hour. Thirty controls were infused with the vehicle alone. On the 5th day, glucose 700 mg/kg and insulin 0.35 U/kg were given as a bolus through the left femoral vein and blood samples were obtained from the right femoral vein just prior to and at 2, 5, 10, and 20 minutes post-glucose/insulin infusion. At the end of 5 days, plasma calcium levels were higher in the vit D-infused rats than in the control rats (12.8 +/- 0.1 versus 10.0 +/- 0.1 mg/dL, P < 0.01) and rat PTH levels were suppressed (2.1 +/- 0.1 versus 62 +/- 12 pg/ml, P < 0. 01). Glucose levels were higher in the vit D animals only at 5 minutes following glucose/insulin bolus (375 +/- 7 versus 350 +/- 6 mg/dL, P < 0.01) but at no other time. There were no differences between serum insulin levels at any time. Unlike previous findings in PTH-infused rats, Kg (measured from 2 to 20 minutes following glucose/insulin bolus) was not different between groups (4.5 +/- 0.3 versus 4.7 +/- 0.2, P = 0.92.) A positive correlation between serum calcium and serum glucose was found only at 5 minutes (r = 0.55, P < 0.01) and only in the vit D animals. The areas under the glucose curves approached statistically significant differences (vit D-infused 5258 +/- 142 mg/dL/18 minutes versus control 4947 +/- 127, P = 0.06.) Analysis of serum glucose data by two-factor analysis of variance (ANOVA) suggests that the two groups differ slightly in glucose values (P = 0.03) but have parallel Kg. In order to define whether different effects of PTH (1-34) and vit D on intracellular calcium [Ca2+]i levels could partly explain the different effects of PTH and vit D infusion on glucose disposal, we investigated the effect of PTH and vit D infusions on basal and concanavalin A (con A)-stimulated changes in mononuclear [Ca+2]i levels. Following 5 days of PTH, vit D, or control infusion, peripheral mononuclear cells were incubated with 50 microgram/ml con A. Changes in [Ca+2]i over 5 minutes were calculated by flow cytometric measurement of the calcium sensitive fluo-3 AM dye. Despite achieving significant and comparable degrees of hypercalcemia in the PTH and vit D infused animals, there were no differences in basal or con A-stimulated [Ca+2]i levels from control. Consequently, we conclude that vit D-induced hypercalcemia associated with suppressed PTH levels has mild affects on glucose homeostasis but does not affect glucose disappearance rate in vivo (Kg) as does hypercalcemia induced by PTH infusion, and that neither chronic PTH infusion nor chronic vit D infusion are associated with long-standing changes in [Ca2+]i levels.
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PMID:Effect of chronic vitamin D infusion upon in vivo glucose disposal. 1002 84

Disturbances of glucose metabolism with hyperinsulinism and peripheral insulin resistance are frequently observed in patients with hyperparathyroidism. The mechanism of how hyperparathyroidism affects glucose metabolism is not known. Hypercalcemia, hypophosphatemia and the parathyroid hormone itself seem to be involved. However, parathyroidectomy exerted rather variable effects on glucose metabolism: In patients with fully developed diabetes mellitus both, a complete normalisation of glucose tolerance as well as no change in the metabolic situation have been observed. We report a 64-year old female patient with primary hyperparathyroidism and diabetes mellitus. The patient had severe insulin resistance with insulin requirements of 200 IU/day. Fasting insulin and C-peptide levels were elevated. After successful operation of a parathyroid adenoma there was a marked improvement in diabetes, and the patient's insulin requirement decreased to one third of the preoperative dose. This case further illustrates the association between primary hyperparathyroidism and diabetes mellitus and the potential improvement of the metabolic situation after parathyroidectomy.
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PMID:[Improvement of diabetes mellitus after excision of a parathyroid adenoma]. 1002 37

1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) concentrations have been found to be decreased in diabetic humans and rats. To investigate further the regulation of plasma Ca in diabetes, first we measured Ca(2+), P, Mg, parathyroid hormone(1-34) (PTH), and total and free 1,25(OH)(2)D(3) in male spontaneously diabetic rats 7 and 28 days after the onset of glycosuria. Secondly, we studied changes in the levels of PTH and 1,25(OH)(2)D(3) in response to hypocalcaemia induced by an i.v. infusion of EGTA (2.5%, wt/vol.) for 24 h, and changes in the levels of 1,25(OH)(2)D(3) in response to an i.v. infusion of rat PTH (10 microgram over 24 h) without or with concomitant EGTA infusion (producing hypercalcaemia or normo/hypocalcaemia respectively), in diabetic and control rats. Ca(2+), P, Mg and PTH concentrations remained within the control ranges after 7 and 28 days of glycosuria; 1,25(OH)(2)D(3) concentrations were decreased after 7, but not after 28, days of glycosuria. PTH concentrations showed a similar rise during EGTA-induced hypocalcaemia in control and diabetic rats compared with saline-infused rats, whereas 1,25(OH)(2)D(3) concentrations were unchanged in both groups. Total and free 1,25(OH)(2)D(3) levels were comparably (about 3-fold) increased during PTH, but not during combined PTH and EGTA infusion in control and diabetic rats. Total 1, 25(OH)(2)D(3) concentrations were lower in the diabetic groups infused with saline or PTH than in their respective controls, and there was a similar trend in the PTH+EGTA-infused group; free 1, 25(OH)(2)D(3) levels, however, were normal or increased in the diabetic groups, confirming our previous data. The novel finding of this study is that, despite severe insulin deficiency and altered 1, 25(OH)(2)D(3) levels, the in vivo response of PTH levels to hypocalcaemia and the in vivo response of 1,25(OH)(2)D(3) levels to PTH in diabetic rats are comparable with those found in nondiabetic rats.
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PMID:Calciotrophic hormones during experimental hypocalcaemia and hypercalcaemia in spontaneously diabetic rats. 1042 63

The calcium-sensing receptor gene was recently shown to be expressed in rat pancreatic islets and purified islet B-cells. In this study, we investigated the possible role of this receptor in the regulation of insulin release from isolated rat pancreatic islets. Poly-L-arginine (0.2-0.3 microM) and poly-L-lysine (0.03-0.1 microM) increased insulin output evoked by D-glucose (8.3 mM). This positive effect faded out at higher concentrations of the basic peptides. Likewise, the release of insulin evoked by 8.3 mM D-glucose was significantly lower at high (1.0 mM) than low (0.05-0.1 mM) concentrations of neomycin. The insulinotropic action of Ba2+ in Ca2+-deprived islets was potentiated in rats pretreated with pertussis toxin. However, Gd3+ inhibited insulin release evoked by D-glucose in islets prepared from normal rats or animals pretreated with pertussis toxin and incubated in the absence or presence of either theophylline or forskolin. Gd3+ (0.3 mM) failed to affect effluent radioactivity from islets prelabeled with myo-[2-3H]inositol and cyclic AMP net production in islets incubated in the absence or presence of forskolin. Gd3+ decreased, however, 45Ca efflux from prelabeled islets perifused in the absence or presence of extracellular Ca2+. It is speculated that a negative insulinotropic action mediated by the calcium-sensing receptor, and possibly attributable to a fall in cytosolic Ca2+ concentration, may prevent excessive insulin secretion in pathological situations of hypercalcemia.
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PMID:Possible participation of an islet B-cell calcium-sensing receptor in insulin release. 1078 26

We studied two patients (a 54-year-old woman and her 16-year-old son) with familial benign hypocalciuric hypercalcaemia (FBHH) associated with severe insulin resistant diabetes in the context of a partial lipodystrophic syndrome. Sequencing of the entire coding sequence of the calcium-sensing receptor (CaR) gene revealed a novel heterozygous mutation at codon 395, leading to the substitution of a cysteine by an arginine residue (Cys395Arg) in the extracellular ligand-binding domain. This mutation was absent in two normocalcaemic relatives and in 54 control subjects. It was recently shown, in transfection studies, that the substitution of this amino acid results in incomplete receptor processing, a severe decrease in cell surface expression and altered signal transduction (Fan et al., 1998). This mutation is therefore likely to be responsible of the FBHH phenotype. A pathophysiological link between this mutation and insulin resistance remains unclear.
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PMID:A new missense mutation in the calcium-sensing receptor in familial benign hypercalcaemia associated with partial lipoatrophy and insulin resistant diabetes. 1097 59

Primary hyperparathyroidism (PHPT) is associated with increased cardiovascular risk, although the mechanisms involved remain unclear. Recent evidence has shown increased pulse pressure to be a powerful predictor of cardiovascular events. As increases in pulse pressure are due largely to arterial stiffening, we measured arterial stiffness in 21 subjects with PHPT (18 women and 3 men; 46-71 yr old) and 21 age- and sex-matched healthy controls using pulse wave analysis, a technique that measures peripheral arterial pressure waveforms and generates corresponding central aortic waveforms. This allows determination of the augmentation of central pressure resulting from wave reflection and augmentation index, a measure of vessel stiffness. Metabolic parameters were also measured. The serum calcium level among PHPT subjects was (mean +/- SD) 2.74+/-0.14 mmol/L. pulse wave analysis showed that both augmentation and the augmentation index were significantly higher in the PHPT group vs. controls [16+/-5 vs. 10+/-4 mm Hg (P < 0.001) and 36+/-9% vs. 25+/-6% (P < 0.001)] despite comparable brachial systolic pressures between groups (136+/-13 vs. 134+/-18 mm Hg). Patients with PHPT had higher fasting serum insulin levels [median (range), 15.8 (7.4-39.4) vs. 11.6 (5.1-23) mU/L; P < 0.05] and triglyceride (1.6+/-0.6 vs. 1.2+/-0.4 mmol/L; P < 0.05), but lower high density lipoprotein cholesterol (1.4+/-0.4 vs. 1.6+/-0.3 mmol/L; P < 0.05). These data indicate that subjects with mild PHPT (calcium, <3.0 mmol/L) have increased arterial stiffness, as evidenced by higher augmentation of central aortic pressures. Enhanced vessel stiffness may arise from a combination of structural and functional vascular changes due to hypercalcemia and/or metabolic abnormalities. Increased vascular stiffness in subjects with PHPT may account in part for the increased cardiovascular risk in this group.
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PMID:Augmentation of central arterial pressure in mild primary hyperparathyroidism. 1106 92

The endocrine adaptations to critical illness are varied. In the diabetic patient, counterregulatory hormones predispose to insulin resistance and hyperglycemia, a derangement accentuated by the use of glucocorticoids and enteral or parenteral nutrition. Thyroid abnormalities include the euthyroid sick syndrome, which may manifest as a low T3, low T4, low TSH, or all three. Illness in patients with pre-existing hypothyroidism or hyperthyroidism may precipitate myxedema coma or thyroid storm, respectively. The most important issue related to calcium is that of acute hypercalcemia, which, in the intensive care unit, usually is caused by malignancy and dehydration. Hyponatremia, a frequently encountered electrolyte disturbance, is evaluated best and treated according to volume status.
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PMID:Endocrine problems in the chronically critically ill patient. 1131 56

The propensity for breast cancer cells to metastasize to bone and to induce osteolysis has long been recognized. Characteristics of both the tumor cells and the bone microenvironment contribute to this phenomenon. The presence of tumor in bone is associated with activation of osteoclasts, resulting in excessive bone resorption and subsequent osteolysis. Breast cancer cells and other tumor types influence osteoclastic bone resorption by increasing the number of osteoclasts and enhancing their resorptive activity. Parathyroid hormone-related peptide, in addition to its role in humorally mediated hypercalcemia, is secreted by metastatic breast cancer cells in bone in which it acts as a paracrine factor to stimulate osteoclasts. As bone matrix is broken down by activated osteoclasts, a rich supply of mitogenic factors is released, including insulin-like growth factors, bone morphogenetic proteins, and fibroblast growth factors. Transforming growth factor (TGF)-beta, one of the most abundant of the bone-derived factors, promotes increased production of parathyroid hormone-related peptide by tumor cells, establishing a "vicious cycle" leading to progressive tumor growth and bone destruction. Bisphosphonates interrupt this cycle by inhibiting osteoclasts, in part by inducing osteoclast apoptosis. In several animal models of breast cancer metastasis to bone, bisphosphonates decrease the number of new bone metastases and inhibit progression of existing lesions. A single 3 microg intravenous injection of zoledronic acid (Zometa; Novartis Pharmaceuticals Corp, East Hanover, NJ), a new highly potent bisphosphonate, prevented destruction of trabecular bone in an orthotopic mouse mammary tumor model. Tumor volume in bone was decreased by zoledronic acid in a dose-dependent manner in the same model, and tumor cell apoptosis was increased by zoledronic acid in bone metastases in the 4T1 murine model of mammary carcinoma metastasis. Zoledronic acid at a dose of 1.0 microg/d for 10 days also reduced bone lesion area in a nude mouse model with existing bone metastases. Although bisphosphonates, including zoledronic acid, are able to induce apoptosis in tumor cells in vitro, studies in animal models to date have generally not shown a reduction in nonosseous tumor. Therefore, bisphosphonate-associated tumor reduction in bone is most likely mediated by osteoclast inhibition or is related to high local concentrations of bisphosphonates in the bone compartment.
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PMID:Preclinical studies with zoledronic acid and other bisphosphonates: impact on the bone microenvironment. 1134 63


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