Hypocalcemia in magnesium-depleted dogs: evidence for reduced responsiveness to parathyroid hormone and relative failure of parathyroid gland function

The effect of magnesium depletion on serum calcium and magnesium and on the response to the infusion of parathyroid extract (PTE) was evaluated in nine adult mongrel dogs during a control period, magnesium depletion, and following magnesium repletion. Magnesium depletion was associated with a fall in serum magnesium and calcium, and both returned to normal with magnesium repletion. There was a significant direct correlation between the serum concentration of calcium and magnesium in the magnesium-deficient state. During magnesium depletion, there were significant calcemic and phosphaturic responses to PTE, but these effects were reduced; the impaired responsiveness of the skeleton and the kidney to PTE returned to normal after magnesium repletion. Serum levels of immunoreactive parathyroid hormone, measured in two animals during the control and magnesium depletion state, remained stable during magnesium depletion, despite the hypocalcemia present. These results indicate that both impaired responsiveness of the skeleton to parathyroid hormone and reduced secretion of the hormone in response to hypocalcemia exist in dogs with magnesium depletion. Each of these factors probably contributes to a reduced level of serum calcium in magnesium depletion, and they may compound each other and hence aggravate the degree of hypocalcemia.     

Skeletal responsiveness to parathyroid hormone in pseudohypoparathyroidism

BACKGROUND: Although there have been some case reports suggesting that bone in patients with pseudohypoparathyroidism (PHP) might respond to parathyroid hormone (PTH), no information is available as to whether serum PTH concentration is related to bone metabolic markers or to bone mineral density (BMD) in PHP. OBJECTIVE: To address these relationships, by comparing intact serum PTH, bone metabolic markers and BMD in patients with PHP with those in patients with idiopathic hypoparathyroidism (IHP) and postoperative hypoparathyroidism (OHP). METHODS: Intact serum PTH, bone metabolic markers (osteocalcin, tartrate-resistant acid phosphatase, pyridinoline, deoxypyridinoline) and BMD by dual-energy X-ray absorptiometry or single-photon absorptiometry were measured in patients with PHP Ia (n=2) and PHP Ib (n=8). The results were compared with those in patients with IHP (n=5) and OHP (n=14). RESULTS: All bone metabolic markers measured were present in significantly greater amounts in patients with PHP Ib than in those with IHP+OHP. The Z score (standard deviation of average BMD at each age) of the BMD of femoral neck was significantly lower in patients with PHP Ib than in those with IHP+OHP. The Z scores of BMD of lumbar spine and radius were also lower in patients with PHP Ib than in those with IHP+OHP, but the difference was not significant. Moreover, the intact serum PTH concentrations were significantly and positively related to bone metabolic marker levels in all patients, and the intact serum PTH concentrations were significantly and negatively related to BMD of lumbar spine in PHP patients. CONCLUSIONS: These results suggest that PTH stimulates bone turnover in PHP Ib patients, resulting in a relatively lower BMD in PHP Ib patients than in IHP+OHP patients. The present study indicates that bones of most cases of PHP could respond to PTH.     

Skeletal responsiveness to endogenous parathyroid hormone in postmenopausal osteoporosis.

To test the hypothesis that increased sensitivity of bone to PTH may be a major cause of bone loss in postmenopausal osteoporosis, we induced acute calcium deprivation and measured bone responsiveness to endogenous PTH under physiological conditions. Eighteen osteoporotic and 17 normal postmenopausal women with similar dietary calcium intakes were studied before and after 4 days of calcium deprivation (dietary calcium 230 mg/day and treatment with a calcium-binding agent). Despite decreased serum PTH values, the baseline indices of bone turnover (serum osteocalcin level and 24-h urinary excretions of total deoxypyridinoline/creatinine and pyridinoline/creatinine corrected for total body bone mineral content), were higher in the osteoporotic women. During calcium deprivation, the changes in bone markers from baseline were similar in both groups, except for serum osteocalcin and serum type I procollagen carboxy-terminal propeptide. Changes in the normal and the osteoporotic women were, respectively: serum ionized calcium concentration decreased 3.3% and 2.1%; serum intact PTH increased 65% and 56%; plasma 1,25-dihydroxyvitamin D3 increased 29% and 39%; pyridinoline/creatinine increased 12% and 11%; and deoxypyridinoline/creatinine increased 27% and 12%. Serum osteocalcin increased 2.3% and serum procollagen carboxy-terminal propeptide decreased 9.4% in the normal women but did not change in the osteoporotic women. We conclude that women with postmenopausal osteoporosis do not have increased skeletal responsiveness to PTH compared with age-comparable normal postmenopausal women. Therefore, the higher bone turnover in postmenopausal osteoporosis, despite lower serum intact PTH concentration, must be due to other factors. Assessment of acute changes in bone turnover during physiological alterations in endogenous PTH secretion is a useful test in metabolic bone diseases.     

葡萄糖钳夹技术在糖尿病研究中的应用

本文介绍葡萄糖钳夹技术在糖尿病研究中的应用。通过葡萄糖钳夹技术可研究在正常或高血糖情况下机体的胰岛素敏感性，胰岛素分泌和葡萄糖，脂类和蛋白质代谢等变化。     

Maternal and fetal parathyroid hormone responsiveness in pregnant primates

Maternal and fetal parathyroidd hormone (PTH) responsiveness to hypocalcemia induced by EDTA infusion (50 mg/kg over 2 h) was studied in rhesus monkeys in late pregnancy. Although baseline serum total calcium (Ca) levels in the fetus exceeded those in the mother (4.83 +/- 0.13 vs. 4.28 +/- 0.15 meq/liter; P < 0.001), PTH values were not significantly different (5.62 +/- 0.37 vs. 6.18 +/- 0.33 muleq/ml; P > 0.05). EDTA infusion directly to five fetuses produced significant hypocalcemia (maximal decline averaging 19 +/- 2%) and PTH response (maximal increase averaging 46 +/- 5%). In contrast, in four control studies involving fetal saline infusion, there were no significant changes in fetal Ca or PTH levels. Four maternal control infusions produced no significant changes in either Ca or PTH levels. A comparison of maternal and fetal PTH responses indicated considerable similarity, although fetal PTH levels tended to return to baseline somewhat more gradually after cessation of the hypocalcemic stimulus than did maternal levels. These studies indicate that fetal PTH secretion, both baseline and in response to hypocalcemia, is quantitatively similar to that of the adult, and thus, the fetal parathyroid does not appear to be suppressed by the relative hypercalcemia of late fetal life.     

Growth hormone neuroregulation in diabetes mellitus.

GH secretion is markedly altered in diabetic rats and humans. Diabetes in the rat, whether occurring spontaneously or after streptozotocin administration, results in depressed GH secretion. This defect is likely caused by an increase in hypothalamic somatostatin tone and decreased pituitary GH. The effects of diabetes in humans depend upon the etiology of the disease. In type-1 diabetes, GH secretion is increased and in type 2 it is decreased. Again, these changes are hypothesized to be due to opposite alterations in hypothalamic somatostatin. Current evidence suggests that GH hypersecretion in human type-1 diabetes may be relevant to important metabolic and angiopathic complications of the disease.     

Ia-Type alloantigens and humoral autoimmune responsiveness in insulin-dependent diabetes mellitus.

In the search for markers either closely linked to or identical with the hypothetical "diabetogenic major histocompatibility gene," immune region-associated alloantigens were defined in 80 patients with insulin-dependent diabetes and in 107 controls. A close association between the Ia-type alloantigen DRw3 and DRw4 and insulin-dependent diabetes was obtained. DRw3 was found in 36% and DRw4 in 32% of the patients compared to 11% and 16%, respectively, of the controls. In addition, a significant influence of DRw3 and humoral anti-islet-cell autoimmunity could be observed, which was found to be due to a high incidence of DRw3 in those patients with islet cell antibody persistence. Islet-cell antibodies (ICA) were observed in 60% of the DRw3-positive patients compared to only 9% of the DRw3-negatives with longstanding disease (greater than 5 yr). These data show a significant association between insulin-dependent diabetes and the Ia-type alloantigens DRw3 (p uncorr. less than 0.0005) and DRw4 (p uncorr. less than 0.025). Furthermore, they provide direct evidence of an association between an Ia-type alloantigen and persisting humoral autoimmune responsiveness in man.     

Osteoblastic cells mediate osteoclastic responsiveness to parathyroid hormone

Indirect evidence suggests that cells of the osteoblastic lineage may mediate augmented osteoclastic bone resorption induced by PTH. To test this suggestion, osteoclasts were disaggregated from neonatal rat long bones and incubated on slices of human femoral cortical bone. Resorption was measured by computer-assisted morphometric and stereophotogram-metric quantification of osteoclastic excavations, identified in the scanning electron microscope after culture. We compared the effect of PTH on bone resorption by osteoclasts incubated alone with the effect of the hormone on resorption by osteoclasts cocultured with osteoblastic cells. PTH had no effect on bone resorption by osteoclasts alone, but in the presence of any of three osteoblast-containing cell populations, or in the presence of cloned, hormone-responsive osteosarcoma cells, PTH caused a 2- to 4-fold increase in osteoclastic resorption. Significant stimulation was observed at 10(-4) IU/ml PTH. None of the osteoblastic cell populations caused morphologically detectable bone resorption in the absence of osteoclasts. These results indicate that PTH acts primarily on osteoblasts, which are induced by the presence of the hormone to stimulate osteoclastic bone resorption.     

Vertebral hyperostosis and diabetes mellitus: a case-control study.

OBJECTIVE--To compare glucose metabolism in patients with vertebral hyperostosis (VH), with that in control patients. METHODS--We studied 50 patients aged 60 years or more who had VH according to Resnick's criteria, and 50 control patients without VH, matched for sex, age, weight and height. Plasma glucose was evaluated before and 120 minutes after ingestion of 75 g glucose. World Health Organisation criteria for diabetes mellitus (DM) were used. Radiographs of the pelvis and thoracic and lumbar spine were performed and read blind by two physicians. RESULTS--Statistical analysis showed no difference between cases and control patients for prevalence of DM, and plasma glucose at 0 and 120 minutes. CONCLUSION--These data suggest that glucoregulation in patients with VH does not differ from that in matched controls.     

Bone responsiveness to parathyroid hormone in normal and osteoporotic postmenopausal women

Increased bone loss in estrogen-deficient normal and osteoporotic postmenopausal women may be due mainly to increased sensitivity of bone-resorbing cells to circulating PTH, but this is supported only by indirect data. Therefore, we tested the responsiveness of bone to PTH directly by using a 3-day iv infusion of bovine PTH-(1-34) at 400 U/day in 9 normal premenopausal women, 10 normal postmenopausal women, and 12 osteoporotic postmenopausal women. Serum calcium and urinary hydroxyproline concentrations increased (P less than 0.001) over baseline values during infusion, but the mean increases in both variables did not differ among groups. The data do not support the hypothesis that estrogen deficiency increases the sensitivity of bone to PTH or that the sensitivity in osteoporotic women is greater than that in normal postmenopausal women. Within the constraints imposed by the method of testing, we conclude that the additional bone resorption induced by menopause and by osteoporosis may be due to mechanisms that are not due to enhanced responsiveness of bone to PTH.     

Ophthalmoplegia in diabetes mellitus: a retrospective study

Ophthalmoplegia, despite being a rare entity in diabetes mellitus, is associated with great anxiety for the patients and often appears to be a serious problem from a diagnostic and therapeutic point of view. There have been few studies primarily concerned with the relative frequencies and clinical characteristics of oculomotor neuropathies in diabetic subjects. Those published have emanated largely from neurological and/or ophthalmological referral centres rather than metabolic departments. Objective of this study was to determine the incidence, the clinical characteristics and risk factors for developing ophthalmoplegia among persons with diabetes mellitus. We have performed a retrospective study of all diabetic patients with ophthalmoplegia who were seen in the Metabolic Division at “S. Biagio” Hospital, Marsala, over the 10 year period from 1998 to 2007. A detailed history and blood laboratory profile were obtained for each patient. During the period of the survey a total of 6,765 diabetic subjects were hospitalised and ophthalmoplegia was identified in 27 patients (0.40%). Isolated III nerve palsies accounted for the majority of patients (59.3%), with VI nerve palsies (29.6%) occurring more frequently than multiple palsies (11.1%). These patients had a marked comorbidity and were found to have a poorly controlled diabetes. The patients with VI nerve palsies showed a tendency toward a higher coexistence of diabetic retinopathy and cardiovascular risk factors than those with III cranial nerve palsies. Ophthalmoplegia is a serious and not common problem among patients with diabetes mellitus; the oculomotor nerve was most frequently affected in our case-report. The fact that the coexistence of diabetic complications and cardiovascular risk factors was slightly higher in patients with VI nerve palsy is compatible with the hypothesis that this ischemic event might be more closely related to diabetes and metabolic syndrome in its pathogenesis.     

Cardiovascular responsiveness to parathyroid hormone (PTH) and PTH-related protein in genetic hypertension.

Hypertension is often accompanied by abnormalities of calcium homeostasis, including hyperparathyroidism with reduced target organ responses to PTH in kidney and bone. Due to this association between PTH and hypertension and since PTH and the paracrine factor PTH-related protein (PTHrp) have both been shown to exert marked changes in cardiovascular activity, these actions of PTH and PTHrp were examined in spontaneously hypertensive rats (SHR) and in control normotensive Wistar-Kyoto rats (WKY). Fourteen-week-old SHR [systolic blood pressure (SBP), 201 +/- 4.4 mm Hg] and WKY (SBP, 141 +/- 2.5 mm Hg) were studied. Renal cortical membranes were prepared and assayed for radioligand binding with [125I]PTH-(1-34) and [125I]PTHrp-(1-34). There was no apparent alteration in the affinity of the binding sites to either peptide in the SHR, but specific binding in SHR renal tissue was only 60% of that observed in WKY tissue for both peptides. Serum immunoreactive PTH levels were 4-fold higher in SHR than WKY, while serum total calcium and 1,25-dihydroxyvitamin D3 levels were not different. The iv administration of both PTH and PTHrp produced dose-dependent reductions in SBP and increases in heart rate in conscious unrestrained SHR and WKY. Both peptides caused greater absolute reductions in blood pressure in SHR than in WKY. However, when the hypotensive response was normalized for the higher baseline pressure in the SHR, the blood pressure reductions caused by PTH and PTHrp were not different in SHR and WKY. Conversely, the chronotropic responses to PTH and PTHrp were lower in SHR compared to WKY. These findings indicate that the SHR exhibits elevated PTH levels, with a reduced number of renal PTH/PTHrp receptors and a depressed chronotropic response to either PTH or PTHrp. In contrast, the hypotensive response to PTH or PTHrp was not altered, indicating possible tissue-specific receptor subclasses or tissue-specific regulation of PTH and PTHrp receptors.     

Hypomagnesemia with increased metabolism of parathyroid hormone and reduced responsiveness to calcitropic hormones.

A patient with severe hypomagnesemia due to chronic alcoholism is presented who repeatedly exhibited marked hypocalcemia with a dissociation between radioimmunoassay findings for mid region of parathyroid hormone (PTH-M) and immunoradiometric assay findings of serum intact PTH (PTH-intact). Serum PTH-M was moderately elevated whereas serum PTH-intact was in a low normal range every time when her serum magnesium (Mg) concentration was markedly reduced. There was also a marked reduction in serum osteocalcin concentration. Supplementation of Mg resulted in a sharp increase in serum PTH level with a rapid disappearance of the dissociation between the two immunoassays of PTH. Shortly after serum PTH and 1,25(OH)2D levels reached their peak, serum osteocalcin started to increase, and was elevated into a supranormal level with normalization of serum Ca concentration. Mg is thought to act as a mimic/antagonist of calcium (Ca), and high extracellular Ca is shown to cause an inhibition of secretion with a stimulation of degradation of PTH. Thus, these observations are consistent with the hypothesis that Mg deficiency causes an increase in the metabolism of PTH and a reduction in the secretion of bioactive intact PTH by increasing the sensitivity of parathyroid cells to Ca. In addition, the fact that hypocalcemia disappeared concomitant with a marked increase of serum osteocalcin from undetectable levels suggest that refractoriness of bone to calcitropic hormones is present which plays a significant role in the development of hypocalcemia under hypomagnesemia, and that serum osteocalcin can be a good marker for the assessment of the responsiveness of bone to calcitropic hormones in these patients.     

Skeletal responsiveness to parathyroid hormone in healthy females: relationship to menopause and oestrogen replacement

In order to directly evaluate the role of parathyroid hormone (PTH) and its interaction with oestrogens for postmenopausal bone loss, studies were performed where synthetic human (1-38) PTH was infused s.c. over 24 h in 15 healthy females. Measurements were made of serum electrolytes, PTH and biochemical indices of bone turnover: serum osteocalcin and alkaline phosphatase and fasting urinary hydroxyproline and calcium. During the infusion of PTH there were significant increases of serum calcium (15%), fasting urinary calcium (55%) and hydroxyproline (80%) but a reduction of the serum osteocalcin concentrations (15%). There were significant relations between the calcaemic response and the increases of urinary calcium and hydroxyproline and the two latter were also closely related. There was, however, no correlation between the responses to PTH for the formative vs the resorptive indices. Postmenopausal women displayed greater increases of serum calcium and fasting urinary hydroxyproline indicating greater skeletal sensitivity to exogenous PTH. Following treatment with oestrogens the indices of skeletal responsiveness were reversed towards the premenopausal values. The findings demonstrate that during short-term infusion of PTH there is a dissociation between bone resorption and formation and, furthermore, that the menopause is associated with an enhanced skeletal sensitivity for PTH.     

Exaggerated pressor responsiveness to norepinephrine in nonazotemic diabetes mellitus

Pressor responses to norepinephrine (NE) or angiotensin II (All) were studied in 27 diabetic patients without heart or renal failure and in 27 normal subjects. Mean plasma or 24-hour urinary sodium, blood volume and preinfusion plasma NE levels were similar in diabetic and normal subjects; exchangeable sodium was higher (p < 0.02) and preinfusion plasma renin activity (PRA) was slightly lower in diabetic patients. The NE pressor and threshold doses were lower in diabetic patients than in normal subjects (76 versus 141 and 16 versus 41 ng/kg/min, respectively; p < 0.05). The All pressor dose also tended to be lower in diabetic patients (7.2 versus 11.9 ng/ kg/min; p < 0.05), but the All threshold dose did not differ between the two groups (1.1 versus 1.6 ng/kg/min). These findings were similar in the diabetic subgroup without or with retinopathy (N = 13 and 14, respectively) and in those with normal or high blood pressure (N = 17 and 10, respectively). These observations suggest that in nonazotemic diabetes mellitus increases in All pressor responsiveness are associated with a concomitant reduction in PRA. However, cardiovascular pressor responsiveness to NE tends to be exaggerated despite normal plasma NE levels and this alteration may occur already in the normotensive stage of diabetes mellitus. Cardiovascular hyperresponsiveness in diabetic subjects may be related to excess body sodium or structural alterations in the vasculature, or both.     

Effect of age on renal responsiveness to parathyroid hormone and calcitonin in rats

The purpose of these studies was to determine whether the responsiveness of the kidney to parathyroid hormone (PTH) and calcitonin changed with age. Experiments were performed in young (3 months old), adult (12-14 months old) and old (22-24 months old) male Fischer 344 rats fed normal diets and thyroparathyroidectomized. Parathyroid hormone was administered i.p. at 24, 12 and 2 h before death and calcitonin was given i.p. at 12 and 2 h before death. Parathyroid hormone significantly increased the conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) by renal slices from young but not adult or old animals. A similar age-related decline in the capacity of PTH to raise serum 1,25-dihydroxyvitamin D (1,25-(OH)2D) levels was also seen. Parathyroid hormone significantly decreased tubular reabsorption of phosphorus, increased concentrations of urinary cyclic AMP (cAMP) and increased serum concentrations of calcium in all age groups. In contrast, calcitonin significantly increased 1,25-(OH)2D3 production by renal slices from both young and adult animals. Calcitonin decreased serum concentrations of calcium in young but not in adult rats. These results suggest that there are maturational changes in the PTH- and cAMP-dependent pathways in the kidney but not in the calcitonin- and cAMP-independent pathways. The changes in the PTH- and cAMP-dependent pathways affect the stimulation of 1,25-(OH)2D production but not the inhibition of phosphate transport.