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ABSTRACT
Severe dietary calcium (Ca) or phosphorus (P) deficiency leads to a similar degree of stimulation of (1) plasma and intestinal 1,25-dihydroxycholecalciferol (calcitriol) levels and (2) intestinal Ca absorption. In contrast, P depletion causes a much smaller increase in the renal 25-hydroxycholecalciferol-1-hydroxylase enzyme activity than does Ca depletion. To test the hypothesis that a reduced metabolic clearance rate (MCR) during P depletion might, in part, account for the observed increase in calcitriol levels, we have developed a simple primed-infusion technique to determine the MCR and production rate (PR) of calcitriol, in vivo, in pigs fed low Ca and low P diets. The MCR of calcitriol was unchanged (0·92 ml/min per kg metabolic body size (MBS)) when low P diets were fed, but showed a significant 15% increase (1·06 ml/min per kg MBS) during the feeding of low Ca diets. The PR of calcitriol increased by 2·3-fold when low P diets were fed and by fourfold during Ca depletion. Thus the increase in plasma calcitriol levels during P depletion of pigs is caused by an increase in production rather than a decrease in clearance. In contrast, Ca depletion is associated with a slightly higher PR than indicated by measurement of plasma calcitriol levels because of the increased MCR.
J. Endocr. (1985) 105, 169–173
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SUMMARY
Sera from inbred rabbit strains have been studied to determine radio-thyroxine distribution after electrophoresis, to measure protein binding capacity for thyroxine (T4) and to examine possible interrelationships of binding capacity and serum protein-bound iodine (PBI). In electrophoretic studies at pH 7·4, serum albumin and prealbumin, the latter a previously unrecognized carrier of T4 in the rabbit, are the principal transport proteins. At pH 9·0, prealbumin is the major carrier (61% of tracer). Prealbumin also binds significant quantities of tri-iodothyronine. The mean binding capacity of serum prealbumin for T4 in 12 rabbit strains was 500 μg/100 ml.
Protein-bound iodine levels are known to be strain-dependent in the rabbit. In the current studies, however, there was no strain-specificity of prealbumin binding capacity, and no correlation between PBI and binding capacity of prealbumin, the principal T4-specific transport protein. These observations suggest that factors other than the capacity of binding proteins for T4 may be primary determinants of hormone levels (PBI) in blood in the rabbit.
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SUMMARY
The phenomenon of adaptation of intestinal calcium absorption to changes in dietary calcium has been studied in conscious pigs with Thiry–Vella jejunal loops. The result of decreasing the calcium content of the diet from 1·2 to 0·1% was an increase in the efficiency of the net absorption of calcium from the fluid used to perfuse the jejunal loop; this increase took place 4–6 days after the change in diet. A similar effect was noted in four pigs which had previously been parathyroidectomized and in two thyroparathyroidectomized pigs with thyroxine replacement therapy. The effect seen in the parathyroidectomized animals was not attributable to an increase in the concentration gradient of calcium ions between the jejunal lumen and the blood after the change to the low calcium diet. There was a marked increase in the amount of calcium-binding protein in the mucosa taken from the distal three-quarters of the small intestine of intact pigs fed a low calcium diet. However, after parathyroidectomy, the level of calcium in the diet had no significant effect on the amount of calcium-binding protein in the small intestine.
It is concluded that, in pigs, neither parathyroid hormone nor calcitonin is necessary for intestinal adaptation to a low calcium diet and that, although this adaptation may be mediated by 1,25-dihydroxycholecalciferol, a significant increase in the level of calcium-binding protein in the intestine is only seen when the parathyroid glands are intact.
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SUMMARY
Human granulosa cells from Graafian follicles aspirated 3–4 h before the expected time of ovulation were incubated with various steroid substrates, including pregnenolone, androstenedione, testosterone and dehydroepiandrosterone (DHA). Steroid production after 3 and 10 h of incubation was determined by radioimmunoassay.
Progesterone and 17α-hydroxyprogesterone were the major products of granulosa cells in control short-term cultures with endogenous substrates. The addition of pregnenolone increased the synthesis of progesterone and 17α-hydroxyprogesterone compared with the controls, although the response varied considerably between paired short-term cultures. Little or no oestradiol-17β was produced from endogenous precursors or short-term cultures to which pregnenolone had been added; one follicle, however, produced similar amounts of oestradiol-17β in the control cultures and after incubation with pregnenolone.
When granulosa cells were cultured with various amounts of androstenedione, DHA or testosterone, large amounts of oestradiol-17β were produced, especially in short-term cultures in which larger amounts of substrate were added. Progesterone production continued and progesterone was synthesized more rapidly or in greater amounts in some short-term test cultures than in the controls.
The results indicate that human granulosa cells are one source of oestradiol-17β during the preovulatory phase. The data support the two-cell theory for oestradiol synthesis, for granulosa cells do not appear to undertake steroid conversion via the 5-unsaturated pathway, but aromatize androgens known to be produced by thecal cells. It is also suggested that either androgens or oestradiol-17β stimulate progesterone production by granulosa cells, at least in vitro.
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Although the inhibitory effect of glucocorticoids on the intestinal absorption of calcium is well recognized, their effect on the absorption of phosphate is less well documented. We studied the effect of the oral administration of betamethasone (BM; 25 μg/kg per day) on the duodenal absorption of phosphate in chicks fed normal calcium, normal phosphorus (NCaNP), normal calcium, low phosphorus (NCaLP) or low calcium, normal phosphorus (LCaNP) diets using the ligated loop technique in vivo. The daily oral administration of BM for 8 days significantly reduced the absorption of phosphate in chicks fed the NCaNP diet (21% decrease) but had less effect in chicks fed the NCaLP (14% decrease) or LCaNP (9% decrease) diets in which birds the absorption of phosphate was significantly raised (49 and 87% respectively). In one group of chicks, BM was administered for 9 days before the birds were transferred to the NCaLP or LCaNP diets. Adaptation was again unaffected by the treatment. Thirty-four per cent of the absorbed phosphate was retained in the duodenal tissue. Treatment with BM reduced the amount retained but this may have been caused by the lower weight of the duodenal segment in these chicks as BM administration markedly reduced growth rate. We have concluded that the duodenal absorption of phosphate in the chick can be inhibited by treatment with BM, although this may be secondary to the reduced rate of growth, but the increase in the absorption of phosphate caused by feeding NCaLP or LCaNP diets was unaffected by the steroid.
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Department of Biological Engineering, Division of Comparative Medicine
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Genetic mutations resulting in obesity and type 2 diabetes mellitus (T2D) are described for both inbred and outbred mice. However, no known mouse model completely recapitulates human T2D and its comorbidities. We identified a cohort of obese, male, outbred Swiss-Webster (SW) mice as polyuric, polydipsic, glucosuric, and hyperglycemic. Prevalence of glucosuria in the SW colony reached 60% (n=70) in males 8 weeks to 6 months of age. Despite severe obesity in some females, no females were diabetic. Pathologic findings in affected males included cachexia, dilated gastrointestinal tracts with poor muscular tone, pancreatic islet degeneration and atrophy with compensatory metaplasia and/or neogenesis, bacterial pyelonephritis, membranous glomerulopathy, and late-onset hepatic tumors with macrosteatosis, microsteatosis, and hydropic change in aged males. Serum insulin correlated with blood glucose in a nonlinear pattern, suggestive of islet exhaustion. Circulating leptin levels showed a weak inverse correlation with glucose. Diabetic males were bred with obese colony females to produce 20 male and 20 female offspring. Prevalence of diabetes in male offspring was 80% (16/20) with a median age of onset of 18 weeks. By contrast, no diabetic females were identified, despite being significantly more obese than males. Male predominance is likewise a feature of T2D in humans. To our knowledge, this is the first documentation of hepatocellular carcinoma and islet metaplasia and/or neogenesis in a spontaneous outbred mouse model of T2D. The SW availability and histopathologic features represent a promising new model for the study of T2D.
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Intraperitoneal transplantation of collagenase-digested, isogeneic, neonatal rat pancreatic tissue successfully reversed streptozotocin-induced diabetes in 77% of recipients. The low serum immunoreactive insulin, hyperglycaemia, glycosuria and weight loss, characteristic of the diabetic animal, were corrected and the reduced activities of hepatic glucokinase and pyruvate kinase, and the low glycogen concentration of the liver of diabetic rats were restored to normal. Forty-three per cent of the successfully transplanted rats became normoglycaemic within 1 month of transplantation whereas 57% took from 1 to 6 months to achieve normoglycaemia and displayed a mild glucose intolerance when subjected to a glucose load. The rats which had not become normoglycaemic 6 months after transplantation showed some amelioration of the diabetic state, as shown by increased serum immunoreactive insulin and hepatic glycogen concentration and a slow weight gain compared with diabetic controls.
