Hypocalcaemia is a well-recognized manifestation of magnesium deficiency. We have studied seventeen patients with this syndrome in an attempt to determine the pathogenesis of the hypocalcaemia. Mean initial serum calcium concentration was 5-6 mg/dl and mean initial serum magnesium concentration was 0-75 mg/dl. Serum immunoreactive parathyroid hormone (IPTH) was measured in sixteen patients in the untreated state. Despite severe hypocalcaemia, serum IPTH was either undetectable (less than 150 pg/ml) or normal (less than 550 pg/ml) in all but two patients. Serial measurements made during the initial 4 days of magnesium therapy in four patients showed an increase in serum IPTH within 24h, but a delayed increase in serum calcium, which required approximately 4 days to reach normal values. The effect of the rapid normalization of serum magnesium on serum IPTH and serum calcium concentration was studied in three patients. Within 1 min after 144-300 mg of elemental magnesium was administered i.v., serum IPTH had risen from undetectable to 3600 pg/ml and 1725 pg/ml in two patients and from 425 pg/ml to 937 pg/ml in the third. Serum calcium concentrations were unchanged after 30-60 min. These data provide evidence for impaired parathyroid gland function in most of the magnesium deficient patients. The rapidity with which serum IPTH rose in response to magnesium therapy indicates that this may reflect a defect in parathyroid hormone (PTH) secretion rather than its biosynthesis. The failure of serum calcium concentration to increase during the initial days of magnesium repletion, at a time when serum IPTH concentrations were normal or elevated, suggests end-organ resistance to PTH in these patients. The renal response to PTH was examined in two magnesium deficient patients by measurement of urinary cyclic AMP excretion following administration of parathyroid extract. In both patients there was a minimal increase in urinary cyclic AMP concentrations. In contrast, when the hepatic response to glucagon was tested on the same patients by measurement of plasma cyclic AMP concentrations following administration of glucagon, normal increases were observed. These results suggest that adenylate cyclase systems of various organs may be affected differentially by a state of magnesium deficiency. It is suggested that magnesium deficiency may result in defective cyclic AMP generation in the parathyroid glands and in the PTH target organs. This could be the principal mechanism operative in both impaired PTH secretion and end-organ resistance to PTH which together contribute to the development of hypocalcaemia.

The effect of an acute elevation of the serum magnesium concentration on the concentrations of serum immunoreactive parathyroid hormone (IPTH) were studied in hypocalcemic hypomagnesemic patients, hyperparathyroid patients, and normal individuals. Basal serum IPTH concentrations in the hypomagnesemic patients ranged from undetectable to 3 times the upper limit of normal. All hypomagnesemic patients were observed to have an immediate rise in the serum IPTH concentration after magnesium administration regardless of the basal IPTH concentration. In contrast, normal individuals and patients with primary and secondary hyperparathyroidism responded to magnesium administration with either a decrease or little change in the serum IPTH concentration. These date indicate that an acute stimulation of PTH secretion induced by magnesium is characteristic of the magnesium-deficient state. The consistency of this response suggests that impaired PTH secretion is a significant factor contributing to the hypocalcemia of magnesium deficiency.

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The influence of forskolin and 3-iso-butyl-1-methylxanthine (IBMX) on mouse pancreatic beta-cell electrical activity, whole islet cAMP content, and insulin release were investigated. The two drugs potentiated to a similar extent both glucose-stimulated electrical activity and insulin release. In terms of the electrical response, both drugs potentiated the silent depolarization of the membrane in response to low (substimulatory) glucose concentrations, whereas at higher (stimulatory) glucose concentrations they caused an increase in the plateau fraction, with a response similar to the effect of increasing the glucose concentration. Both phases of insulin release were increased by each of the drugs. Ten micromolar forskolin and 100 microM IBMX caused an increase in intraislet adenosine 3',5'-cyclic monophosphate (cAMP) in the presence of 11.1 mM glucose, the former a 17-fold and the latter a 2-fold increase over the cAMP concentration in the presence of glucose alone. Because the two drugs lead to an increase in islet cAMP content, it is proposed that protein phosphorylation resulting from an activation of beta-cell cAMP-dependent protein kinases is responsible for the potentiation of the glucose-induced insulin release and beta-cell electrical activity. The observed effects on electrical activity are compatible with the hypothesis that cAMP-dependent phosphorylation induces alteration of the kinetics of the calcium-sensitive potassium permeability of the beta-cell plasma membrane. The increase in calcium entry into the beta-cell that would result from these alterations may be responsible for the cAMP-dependent potentiation of insulin release.

Abstract. We have produced an antiserum to porcine parathyroid hormone (PTH) which distinguishes between the PTH in human hyperparathyroid serum and that in extracts of parathyroid adenomata. The PTH secreted into the medium by parathyroid adenoma slices in culture reacts with this antiserum in the same way as the PTH in human hyperparathyroid serum, but extraction of the same serum by a conventional procedure used for the extraction of glandular tissue converts the serum hormone to a species which reacts more like hormone extracted from adenomata. The results suggest that we have immunologically identified a native molecular species of PTH, that the antiserum used recognizes primarily this species in human hyperparathyroid serum, and that the PTH extracted from parathyroid adenomata is immunochemically altered.It is likely that the naturally occurring form of a secreted polypeptide hormone is the ideal molecular species to use as a standard preparation in immunoassays of the hormone in serum. It often has been assumed that polypeptide hormones extracted and isolated from glandular tissue are true representatives of the native secreted species, but there is little evidence that, in specific instances, this is true.Most studies of the biologic and immunologic activities1'-0 as well as the covalent sequence8' 10 and specific molecular configuration5 8'11 of parathyroid hormone (PTH) have been made with a molecular species extracted and isolated from bovine glandular tissue by procedures' 8'12 which have the potential for altering the native structure of the molecule. We have now produced an antiserum to PTH which distinguishes between the PTH in extracts of human parathyroid adenomata and the PTH in hyperparathyroid serum. In our immune system, serum PTH cannot be distinguished from the PTH in parathyroid tumor culture medium, but extraction of the serum by the procedures used in the isolation of bovine PTH from glands" 8'12 converts the serum PTH to a species which reacts immunologically in a manner similar to PTH extracted from adenomata. The results of these experiments suggest that we have immunologically identified a native molecular species of human PTH, that the antiserum used recognizes primarily the native hormone in serum, and that the hormone extracted from parathyroid adenomata is immunochemically altered.