Evidence for physiological importance of calcitonin in the regulation of plasma calcium in rats.

To determine the physiological importance of calcitonin in the regulation of plasma calcium, studies were carried out in fasting animals to (a) assess the acute effects of thyroparathyroidectomy (TPTX) and thyroidectomy (TX) on plasma and urinary calcium; (b) investigate whether the changes in plasma calcium produced by removal of the glands were dependent on the presence of the kidney; and (c) determine if the effect of TPTX on plasma calcium is affected by age. Except where otherwise indicated, all studies were carried out on fasting male Wistar rats weighing over 300 g. The following observations were made. (a) TPTX and TX caused an increase in plasma calcium in nephrectomized animals. (b) This increase was not dependent on nephrectomy since in intact animals bearing autoparathyroid transplants TX also caused a significant rise in the mean plasma calcium level (0.37 mg/100 ml at 1 1/2 h). (c) Urinary calcium increased twofold in the 3-h period immediately after TX. (d) In unnephrectomized immature (50-g) rats, TPTX caused a progressive decrease in plasma calcium in contrast to old (360-g) rats, where a significant fall observed at 6 h was preceded by an increase in plasma calcium (0.5 mg/100 ml at 1 1/2 h). From these observations we conclude that: (a) calcitonin must play an important physiological role in the regulation of plasma calcium since the termination of its basal secretion caused an immediate but transient increase in plasma calcium in old unfed rats; (b) the relative importance of calcitonin and parathyroid hormone in the acute regulation of plasma calcium is age-related; and (c) the action of parathyroid hormone on bone may be modified by changes in ambient calcitonin concentration.

The dawn phenomenon, an early morning glucose rise: implications for diabetic intraday blood glucose variation.

Eleven insulin-dependent (type I) diabetic subjects were studied during a 24-h period to assess intraday blood glucose (BG) variation and related free insulin (FI) levels. Ten patients exhibited the dawn phenomenon, a rise in early morning fasting blood glucose (123 +/- 81.1 m/dl; mean +/- SD). This increase was positively and significantly correlated with the morning postprandial BG peak (r = 0.723; P = 0.012). FI/BG ratios were highest during the night (0.717 and 0.666 at 2200 and 0400 h, respectively) and lowest during the early morning (0.294 at 0800 h) (P less than 0.01). Three of the four observed hypoglycemic episodes occurred during the period when free insulin levels were high relative to BG. We conclude that the dawn phenomenon contributed directly and significantly to the BG maximum and indirectly, in some cases, to nocturnal hypoglycemia. It thus played an important role in the intraday blood glucose variation of such patients.

Further studies on the hypercalcemic effect of acute calcitonin deficiency in rats.

Studies were carried out to determine the origin of the immediate increase in plasma calcium following acute calcitonin deficiency in mature rats. Animals were pre-labelled with 45calcium 24 hours and 4 weeks before thyroparathyroidectomy (TPTX) and 1 hour, 24 hours, 2 and 4 weeks before nephrectomy and TPTX and bled serially over the following 3 hours. In each study the final average weight of the rats was over 300 g. Plasma calcium increased after TPTX. In rats labelled with 45calcium 1 and 24 hours previously, the rise was to small to alter the specific activity of calcium although radiocalcium was unchanged. In contrast, in animals pre-labelled with 45calcium 2 and 4 weeks before TPTX, the increase in stable calcium was associated with a parallel increase in radiocalcium. Consequently, the specific activity of plasma calcium did not differ appreciably from that of controls. These findings confirm the theory that in mature unfed rats acute calcitonin deficiency results in an immediate rise in plasma calcium. Since this increase is due mainly to enhanced transport of calcium from deep bone, our observations are in accord with the view that calcitonin decreases plasma calcium primarily by inhibiting calcium transport from "stable" bone.

Short term improvement in glycemic control utilizing continuous subcutaneous insulin infusion: the effect on 24-hour integrated concentrations of counterregulatory hormones and plasma lipids in insulin-dependent diabetes mellitus.

Eight patients with established insulin-dependent diabetes mellitus were studied before and 2 weeks after the initiation of pumped continuous sc insulin infusion in order to investigate the effect of short term improvement of glycemic control on hormonal and lipid levels. Glycemic control was improved in all patients. Using a constant blood withdrawal pump, accurate 24-h average concentrations, denoted integrated concentrations, were obtained. The mean 24-h integrated concentrations of GH, cortisol, norepinephrine, and epinephrine did not change significantly. The mean fasting triglyceride concentration dropped from 119.1 to 83.4 mg/dl (P less than 0.05). The mean 24-h integrated concentration of plasma triglycerides fell from 132.1 to 101.5 mg/dl (P less than 0.02). Both mean fasting and mean 24-h integrated concentrations of plasma cholesterol were lower after improved control. Short term improvement in glycemic control was associated with a reduction in plasma lipid concentrations, but failed to alter mean 24-h integrated concentrations of the measured counterregulatory hormones.

Effect of calcium deprivation on parathyroid hormone-mediated bone and kidney contributions to the maintenance of plasma calcium in rats.

This study was designed to investigate the roles of bone and kidney in the acute regulation of plasma calcium by parathyroid hormone (PTH) during prolonged calcium deprivation. The effect of PTH was assessed by gland ablation. Animals were thyroparathyroidectomized or sham-operated and their urine was collected for 3 h. Subsequently they were anaesthetized and bled from the abdominal aorta. In rats fed on a low calcium diet, urinary hydroxyproline excretion was enhanced and, unlike animals fed on a normal diet, decreased 3 h after thyroparathyroidectomy (TPTX). In addition TPTX decreased plasma calcium by 0-45 mg/100 ml in normal rats compared with 1-94 mg/100 ml in animals fed on a calcium-deficient diet. Urinary calcium increased by 161 and 12 mug and accounted for 82 and 1-4 % of the fall in plasma calcium in normal and calcium-deprived animals respectively. The corresponding contributions of bone were 18 and 98-6%. These findings support the view that with prolonged calcium deprivation in adult rats, the relative contributions of bone and kidney to the acute regulation of the plasma calcium level by PTH are reversed. As a result, bone rather than kidney becomes the more important organ. At the same time non-PTH-mediated kidney reabsorption of calcium is increased.

Fasting hyperglycemia and associated free-insulin and cortisol changes in Somogyi-like patients.

Blood glucose levels were measured over a 24-h period in eight insulin-dependent diabetic subjects who were difficult to control and who presented with morning fasting hyperglycemia. At least seven exhibited clinical characteristics suggestive of the Somogyi phenomenon. A continuous glucose monitoring apparatus was used to relate the concentrations of glucose during the day to concomitant levels of free insulin and cortisol. In all patients a significant (P < 0.01) rise in fasting morning glucose started at about 0600 h, while they were still asleep. In six patients the morning elevation of blood glucose was preceded by stable, almost normal glucose levels during the night (117 ± 2.5 mg/dl); one of the two remaining patients (no. 7) exhibited high overnight glucose levels (268 ± 7 . 2 mg/dl), whereas the other (no. 8) had a mild hypoglycemic episode (45 mg/dl) 6 h before the hyperglycemic period.In all patients the fasting glucose rise was associated with the usual morning cortisol surge (P < 0.05)and with a significant decrease in the concentration of serum free insulin (P < 0.01). The free insulin levels in patient no. 8 were higher, while those of patient no. 7 were lower, than in the other six patients. We conclude that the diurnal morning rise in cortisol may cause hyperglycemia in insulin dependent diabetic patients if insufficient exogenous insulin remains and/or endogenous insulin is not secreted. In such patients the high levels of fasting glucose in the morning may misrepresent their overnight control of blood glucose and lead to an erroneous impression of the Somogyi phenomenon.