Effect of Chronic Vitamin D Infusion Upon In Vivo Glucose Disposal

We have previously demonstrated that parathyroid hormone (PTH) infusion decreases glucose disappearance rate (K_g) 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, K_g (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 K_g. 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 μg/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 (K_g) 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. Received: 24 March 1998 / Accepted: 29 June 1998     

Metabolic effects of erythropoietin in patients on peritoneal dialysis

Insulin and lipid metabolism were studied in seven patients (19±1 years) with end-stage renal disease on continuous cycling peritoneal dialsysis (CCPD) before and after 6 months of therapy with human recombinant erythropoietin (EPO) to correct anemia. Hematocrit increased from 22.2±1.8% to 34.8±1.8% (P<0.001) following EPO treatment. Serum ferritin (P<0.05) and serum iron (P<0.01) decreased significantly after anemia correction. There were no significant differences in the height, weight, anthropometric measures, or intakes of protein and total calories in the patients before and after the 6 months of EPO therapy. There were no differences in serum biochemical parameters, including 1,25-dihydroxyvitamin D₃ and parathyroid hormone in these patients before and after 6 months of EPO therapy. Residual renal function and Kt/V_urea were also not different before and after 6 months of EPO therapy. The hyperinsulinemic euglycemic clamp technique was used to measure insulin sensitivity. Before EPO, insulin sensitivity was low in patients on CCPD (238±19 mg/m² per min) compared with controls (320±30; P<0.01). After 6 months of EPO therapy, insulin sensitivity increased by 28% (305±26, P<0.01 vs. pre-EPO values), so that these values were no longer different from control values. The hyperglycemic clamp technique was used to measure insulin secretion. Before EPO, both early- and late-phase insulin secretion were elevated in patients on CCPD compared with controls (P<0.01 in both cases). These indices of insulin secretion decreased significantly (P<0.01) following 6 months of EPO. Before EPO, plasma triglycerides, total cholesterol, low-density lipoprotein, cholesterol, and apolipoprotein B were elevated in patients compared with controls. These lipid concentrations decreased significantly following 6 months of EPO. Thus, treatment of anemia by EPO is associated with improvements in insulin and lipid abnormalities in uremic patients on CCPD. Received September 23, 1997; received in revised form January 20, 1998; accepted January 22, 1998     

Control of plasma 1,25-(OH)2-vitamin D concentrations by calcium and phosphorus in the rat: Effects of hypophysectomy

Summary The mechanism by which dietary phosphate deprivation elevates plasma 1,25-(OH)₂-D levels is not known. To evaluate the role of the pituitary in regulating plasma 1,25-(OH)₂-D concentrations, the responses of plasma 1,25-(OH)₂-D to dietary phosphate deprivation and, separately, to dietary calcium deprivation were evaluated in intact and hypophysectomized male rats. Among intact and hypophysectomized rats eating normal diets, plasma 1,25-(OH)₂-D levels averaged 228±76 and 148±62 pmol/1, respectively (P<0.01). During dietary phosphate deprivation, plasma 1,25-(OH)₂-D levels rose to 1160±260 in intact rats and fell to 90±26 pmol/l in hypophysectomized rats (P<0.001). By contrast, during dietary calcium deprivation, plasma 1,25-(OH)₂-D levels rose in both intact and hypophysectomized animals to 856±107 and 742±279 pmol/l, respectively (NS). In response to dietary phosphate deprivation, serum calcium concentrations rose as 1,25-(OH)₂-D concentrations rose in intact rats but remained at control levels in hypophysectomized rats. These results support the hypothesis that a pituitary hormone acting either directly or indirectly on the kidney mediates the increase in plasma 1,25-(OH)₂-D during dietary phosphate deprivation. The hypercalcemia that occurs in rats during dietary phosphate deprivation appears to depend on the elevation of plasma 1,25-(OH)₂-D.     

Tumoral calcinosis: Evidence for concurrent defects in renal tubular phosphorus transport and in 1α,25-dihydroxycholecalciferol synthesis

Summary A 50-year-old Latin American man with tumoral calcinosis presented with hyperphosphatemia (6.62±1.04 SD mg/dl), elevated renal threshold phosphorus concentration (TmP) (7.3 mg/GFR), and 1,25-dihydroxyvitamin D [1,25-(OH)₂D] (69 pg/ml) hypercalciuria (239 mg/day), and a high fractional intestinal calcium (Ca) absorption (0.74). Sodium cellulose phosphate therapy (20 g/day) lowered urinary Ca, and partially reduced serum phosphorus (P) and TmP to 5.91±0.63 mg/dl and 6.2 mg/GFR, respectively. Serum 1,25-(OH)120D remained elevated at 58–64 pg/ml. Amphojel therapy (4 oz/day) decreased urinary P to 23±21 mg/day and lowered serum P to 5.75±0.36 mg/dl (P<0.05). TmP increased to a value of 8.0 mg/GFR while serum 1,25-(OH)₂D continued to remain elevated at 53 pg/ml. This case illustrates the probable operation of dual abnormalities in tumoral calcinosis represented by augmented renal conservation of P and an elevation in the circulating concentration of 1,25-(OH)₂D.     

The Effect of Recombinant PTH(1–34) and PTH(1–84) on Serum Ionized Calcium, 1,25-Dihydroxyvitamin D,and Urinary Calcium Excretion: A Pilot Study

We investigated the frequency of hypercalcemia and/or hypercalciuria following parathyroid hormone (PTH) 1–34 and 1–84 administration in a crossover trial. Ten postmenopausal osteoporotic women previously treated with bisphosphonates were subdivided into two groups of five patients each. A 24-h urine collection to determine baseline calcium (Ca) and creatinine (Cr) the day before administration of PTH was followed by determination of serum ionized Ca (Ca²⁺), Cr, 25(OH)D, and 1,25(OH)₂D at baseline. Thereafter, 100 mcg of PTH(1–84) or 20 mcg of PTH(1–34) was administered. A 24-h urinary collection and blood samples 2, 4, and 24-h after each PTH administration were again taken. One week after the first PTH administration patients were rechallenged with the second PTH. The PTH peptides did not differ with respect to changes in Ca²⁺ at 2, 4, and 24 h postinjection; at the last time point the values were virtually identical to the initial values. There was no difference in urinary Ca on the day following PTH injection compared to baseline, in terms both of Ca/Cr and of Ca excretion. The two PTH peptides did not differ with respect to changes in 1,25(OH)₂D at 2, 4, and 24 h considering both the absolute values and the percent changes with respect to baseline (24-h 1–84 = 125.6 ± 58.6 pg/ml, 153% increase; 1–34 = 124.1 ± 64.7, 130%). Our results indicate no difference in postinjection serum Ca²⁺, 1,25(OH)₂D, or urinary Ca excretion after a single dose of either PTH(1–84) or PTH(1–34) in patients previously treated with bisphosphonates.     

The Effect of Acute Exercise on Undercarboxylated Osteocalcin and Insulin Sensitivity in Obese Men

Acute exercise improves insulin sensitivity for hours after the exercise is ceased. The skeleton contributes to glucose metabolism and insulin sensitivity via osteocalcin (OC) in its undercarboxylated (ucOC) form in mice. We tested the hypothesis that insulin sensitivity over the hours after exercise is associated with circulating levels of ucOC. Eleven middle‐aged (58.1 ± 2.2 years mean ± SEM), obese (body mass index [BMI] = 33.1 ± 1.4 kg/m²) nondiabetic men completed a euglycemic‐hyperinsulinemic clamp at rest (rest‐control) and at 60 minutes after exercise (4 × 4 minutes of cycling at 95% of HR_peak). Insulin sensitivity was determined by glucose infusion rate relative to body mass (GIR, mL/kg/min) as well as GIR per unit of insulin (M‐value). Blood samples and five muscle biopsies were obtained; two at the resting‐control session, one before and one after clamping, and three in the exercise session, at rest, 60 minutes after exercise, and after the clamp. Exercise increased serum ucOC (6.4 ± 2.1%, p = 0.013) but not total OC (p > 0.05). Blood glucose was ～6% lower and insulin sensitivity was ～35% higher after exercise compared with control (both p < 0.05). Phosphorylated (P)‐AKT (Ak thymoma) was higher after exercise and insulin compared with exercise alone (no insulin) and insulin alone (no exercise, all p < 0.05). In a multiple‐linear regression including BMI, age, and aerobic fitness, ucOC was associated with whole‐body insulin sensitivity at rest (β = 0.59, p = 0.023) and after exercise (β = 0.66, p = 0.005). Insulin sensitivity, after acute exercise, is associated with circulating levels of ucOC in obese men. Whether ucOC has a direct effect on skeletal muscle insulin sensitivity after exercise is yet to be determined. © 2014 American Society for Bone and Mineral Research.     

Adaptation of Insulin Clearance to Metabolic Demand Is a Key Determinant of Glucose Tolerance

With the development of insulin resistance (IR), there is a compensatory increase in the plasma insulin response to offset the defect in insulin action to maintain normal glucose tolerance. The insulin response is the result of two factors: insulin secretion and metabolic clearance rate of insulin (MCR_I). Subjects (104 with normal glucose tolerance [NGT], 57 with impaired glucose tolerance [IGT], and 207 with type 2 diabetes mellitus [T2DM]), divided in nonobese and obese groups, received a euglycemic insulin-clamp (40 mU/m² ⋅ min) and an oral glucose tolerance test (OGTT) (75 g) on separate days. MCR_I was calculated during the insulin-clamp performed with [3-³H]glucose and the OGTT and related to IR: peripheral (glucose uptake during the insulin clamp), hepatic (basal endogenous glucose production × fasting plasma insulin [FPI]), and adipocyte (fasting free fatty acid × FPI). MCR_I during the insulin clamp was reduced in obese versus nonobese NGT (0.60 ± 0.03 vs. 0.73 ± 0.02 L/min ⋅ m², P < 0.001), in nonobese IGT (0.62 ± 0.02, P < 0.004), and in nonobese T2DM (0.68 ± 0.02, P < 0.03). The MCR_I during the insulin clamp was strongly and inversely correlated with IR (r = −0.52, P < 0.0001). During the OGTT, the MCR_I was suppressed within 15–30 min in NGT and IGT subjects and remained suppressed. In contrast, suppression was minimal in T2DM. In conclusion, the development of IR in obese subjects is associated with a decline in MCR_I that represents a compensatory response to maintain normal glucose tolerance but is impaired in individuals with T2DM.     

Bone metabolism during antler growth in female reindeer

Summary Two female reindeer (Rangifer tarandus) were investigated for alterations in skeletal metabolism during the annual antler growth cycle. During July and January, rib samples were obtained by biopsy after double tetracycline labeling for gravimetric, chemical, and histomorphometric analyses. Though antler length increased from 8 to 55 cm between April and September, body weight increased from only 56 to 77 kg. Rib bone density (g/cm³) increased from 1.39±0.01 (mean±SEM) in July to 1.53±0.01 in January, and Ca content (mg/cm³) increased from 213±8 to 300±14, respectively. Histomorphometric data indicated that rib bones were more porous and active in July and had a higher turnover rate than did January samples. Plasma 1,25(OH)₂D, parathyroid hormone (PTH), and osteocalcin levels were significantly lower and estradiol levels were significantly higher in the January as opposed to the July samples. The data indicate that during antler growth, female reindeer undergo bone loss that corresponds to the changes in plasma calcemic hormones and estradiol levels. This bone loss is eventually repaired when antler growth stops.     

Glucose-dependent hepatic membrane transport in nonbacteremic and bacteremic thermally injured patients

Hepatic clearance of indocyanine green was measured in 106 studies in 25 thermally injured patients with an average total body surface burn of 59% and a mean age of 35 years. Seventeen patients subsequently developed positive blood cultures and were restudied. Fourteen serial measurements of dye concentration taken over a 70-min period were computer fitted to describe each disappearance curve, and the two rate constants, k₁ and k₂ were determined (all r² > 0.94).ICG plasma disappearance was unimpaired in nonbacteremic patients when glucose or glucose plus amino acids were part of the parenteral regimen (?k₁ = 0.241 ± 0.023 and 0.255 ± 0.009 min^?1) but significantly decreased when near isocaloric amounts of glucose-free amino acid solutions were administered (?k₁ = 0.150 ± 0.016 min^?1, P < 0.001). Bacteremic patients had markedly impaired ICG hepatic clearance irrespective of the hypocaloric dietary regimen. Both exclusion of glucose from the nutrient infusates in nonbacteremic patients and bacteremia result in a marked reduction in the maximal velocity of the ICG dye transport reaction.Septic patients infused with glucose and insulin improved their clearance of the dye (from k₁ = 0.169 ± 0.029 to 0.183 ± 0.028 min^?1, P < 0.01). These alterations could not be related to changes in circulation or perfusion. Urea production varied inversely and endogenous insulin levels directly with the k₁ suggesting that membrane transport is related to the ornithine cycle and/or is influenced by insulin.Optimal metabolic integrity of the hepatocyte is substrate specific and dependent upon the provision of exogenous energy. Hepatic transport function is limited in bacteremic patients as well as burn patients who are deprived of glucose. Restoration of hepatic transport processes may be achieved by providing sufficient energy in the form of glucose.     

Effects of age and sex on the regulation of plasma 1,25-(OH)2-D by phosphorus in the rat

Summary Dietary phosphate deprivation in women, but not men, is accompanied by a fall in plasma PO₄ and a rise in plasma 1,25-(OH)₂-vitamin D concentrations. In contrast, young male rats exhibit a fall in plasma PO₄ and a rise in plasma 1,25-(OH)₂-D concentrations in response to PO₄ deprivation. To evaluate whether age and sex influence basal plasma 1,25-(OH)₂-D levels and their regulation by PO₄ deprivation, plasma 1,25-(OH)₂-D, PO₄, and Ca levels were measured in male and female rats ranging in age from 6 weeks to 6 months while they were eating normal or low PO₄ diets for 1 to 16 days. Similar observations were also made in 6-week-old castrated male and female rats, males replaced with testosterone, and females replaced with estradiol. Basal plasma 1,25-(OH)₂-D levels were higher in 6-week-old males (228±76 pmol/l) than in 6-week-old females (148±62 pmol/l;P<0.01) and declined by age 11 weeks to stable levels averaging about 100 pmol/l without sex difference. Dietary PO₄ deprivation resulted in a three-to fourfold increase in plasma 1,25-(OH)₂-D concentrations regardless of age and sex, accompanied by a correlated rise in serum Ca concentrations. Castration of 6-week-old males and females eliminated the sex difference in basal plasma 1,25-(OH)₂-D levels and appeared to enhance the elevation of plasma 1,25-(OH)₂-D concentrations in response to PO₄ deprivation in females. Although gonadal hormones may modify basal plasma 1,25-(OH)₂-D levels, they are not required for the augmentation of plasma 1,25-(OH)₂-D levels in response to PO₄ deprivation.     

Adrenocorticotrophic hormone,cortisol and catecholamine concentrations during insulin hypoglycaemia in dogs anaesthetized with thiopentone

Glucose homeostasis is maintained by complex neuroendocrine control mechanisms. Increases in plasma concentrations of various glucose-raising hormones such as glucagon, catecholamines, adrenocorticotrophic hormone (ACTH), and cortisol are observed under certain conditions associated with stress (haemorrhage and hypoglycaemia). The purpose of this study was to determine the effect of thiopentone anaesthesia on the cathecholamine, ACTH and cortisol response to insulin hypoglycaemia in dogs. Blood sugar (BS), plasma cathecholamine, and ACTH, and serum cortisol concentrations were measured during the course of (1) an intravenous insulin test (ITT) and (2) an ACTH test in conscious and in anaesthetized fasted dogs. During the ITT, the anaesthetized dogs showed a moderate resistance, compared with conscious dogs, to the hypoglycaemic action induced by insulin (blood sugar concentration 30 min after insulin injection: 2.91 ± 0.25 vs 1.93 ± 0.12 mM · L^?1; P < 0.01). In addition, decreased epinephrine (220 ± 27 vs 332 ± 32 pg · ml^?1 ACTH (65 ± 6 vs 90 ± 5 pg · ml^?1) and cortisol (4.48 ± 0.3 vs 6.25 ± 0.5 μg · ml^?1) concentrations were detected 60 min after insulin injection (P < 0.01). The norepinephrine response to hypoglycaemia was not altered by anaesthesia (273 ± 33 vs 325 ± 25 pg · ml^?1). Anaesthetized dogs showed a decreased cortisol response to ACTH at 45 min (5.68 ± 0.54 vs 8.87 ± 0.47 μg · ml^?1) when compared with control dogs (P < 0.001). Haemodynamic variables during anaesthesia showed little changes (P < NS); while respiratory rate was altered (P < 0.01 between 60 and 105 min). Arterial pH was decreased (7.29 ± 0.03 vs 7.36 ± 0.04; P < 0.05) and PaCO₂ was increased (6.8 ± 0.3 vs 5.2 ± 0.3; P < 0.01) at 30 min from induction of anaesthesia but little change was seen after the beginning of the ITT and ACTH tests. We conclude that thiopentone anaesthesia provokes a moderate resistance to the hypoglycaemic action of insulin. This does not appear to be related to increases in plasma concentrations of cathecholamines, cortisol or ACTH. Since the hyperglycaemic effects of cathecholamines and glucagon are synergistic it is possible that glucagon plays an important role in the altered blood sugar response to insulin administration.     

Effect of maternal insulin deficiency on vitamin D metabolite concentrations in normoglycemic pregnant rats and their fetuses

Summary The effects on vitamin D metabolite concentrations of insulin deficiency, not accompanied by hyperglycemia, were investigated in pregnant rats and in their fetuses injected with 75 mg/kg BW streptozotocin (SZ). These concentrations were measured in maternal plasma and whole fetal body. In the insulinopenic mothers, the 25OHD concentration was found to rise compared with that of control pregnant rats (7.00±1.66 ng/ml, n=16, versus control 4.50±1.60, n=10, 0.001<P<0.01). The concentration of 1,25 (OH)₂D, which was previously found to decrease in pregnant rats that were both hypoinsulinic and hyperglycemic, was not different in our control and insulinopenic rats (107.36±38.25 pg/ml, n=11, versus control 122.90±18.20, n=8). In fetuses from our SZ-injected rats, the 24,25 (OH)₂D level diminished compared with the control level (2.12±0.70 ng/g, n=11, versus control 5.23±0.95 ng/g, n=13,P<0.001). The Ca/P ratio in fetal body also decreased (0.68 versus control 1.12). It is suggested that the placental metabolism is an important determinant of normal fetal growth.     

Response of plasma 1,25-dihydroxyvitamin D in the human PTH(1–34) infusion test: An improved index for the diagnosis of idiopathic hypoparathyroidism and pseudohypoparathyroidism

Summary Synthetic human parathyroid hormone (1–34) (hPTH(1–34) infusion test has been utilized in the differential diagnosis of hypoparathyroidism by examining the incremental response of urinary phosphate and cyclic adenosine monophosphate (AMP). The response of plasma levels of 1,25-dihydroxyvitamin D (1,25(OH)₂D) in parathyroid hormone (PTH) infusion test was studied as a new criterion for the differential diagnosis of idiopathic hypoparathyroidism (IHP) and pseudohypoparathyroidism (PHP). Fourteen patients with IHP, 4 patients with PHP, and five control subjects were studied. All subjects received an intravenous infusion of 30 μg hPTH(1–34) over 5 minutes. The basal levels of plasma 1,25(OH)₂D in patients with IHP and PHP were significantly lower than those in control subjects, but there was no significant difference between the levels in patients with IHP and in patients with PHP. The plasma levels of 1,25(OH)₂D increased after the infusion of hPTH(1–34) and reached a peak 6 to 24 hours afterward. The 1,25(OH)₂D increase at 24 hours after the infusion (Δ1,25(OH)₂D) in control subjects and in patients with IHP were 18.1±3.91 (mean±SEM) and 24.1±2.80 pg/ml, respectively. There was no significant increase in patients with PHP (Δ1,25(OH)₂D=4.9±1.97 pg/ml). From these results, the measurement of Δ1,25(OH)₂D in hPTH(1–34) infusion test is useful as a criterion for the differential diagnosis of hypoparathyroidism.     

Poor Glycemic Control Impairs the Response of Biochemical Parameters of Bone Formation and Resorption to Exogenous 1,25-Dihydroxyvitamin D3 in Patients with Type 2 Diabetes

Osteoblast deficit plays a principal role in the development of diabetic osteopenia. We have previously reported that high glucose conditions impair the function of osteoblast-like MG-63 cells. This study was performed to assess the sensitivity of osteoblasts to 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) in patients with type 2 diabetes without insulin deficiency or overt diabetic complications. During stimulation with 1,25(OH)₂D₃ at 2.0 mg/day for 6 consecutive days in 9 type 2 diabetic patients, serum levels of bone alkaline phosphatase (BALP), osteocalcin (OC) and the carboxyterminal propeptide of type 1 procollagen, and the urinary excretion of pyridinoline and deoxypyridinoline (DPYR), were monitored. As parameters of glycemic control, the mean level of fasting plasma glucose (mFPG) throughout the 1,25(OH)₂D₃ stimulation test and the level of HbA_1C were used. 1,25(OH)₂D₃ increased serum 1,25(OH)₂D significantly by day 2, which was followed by a significant reduction in the serum level of intact parathyroid hormone. The maximal increment of serum OC adjusted for that of 1,25(OH)₂D was negatively correlated with both mFPG and HbA_1C levels (p50.05). Furthermore, the magnitude of 1,25(OH)₂D₃-induced bone resorption, as reflected by the maximal increase in urinary DPYR excretion, was negatively correlated with the mFPG level (p50.05). Basal BALP tended to be negatively correlated with HbA_1C, although not to a significant extent. In conclusion, our findings would indicate that poor glycemic control impairs the responses of osteoblasts and osteoclasts to 1,25(OH)₂D₃ in normo-insulinemic type 2 diabetic patients. Received: 9 February 1998 / Accepted: 10 November 1998     

Growth hormone and triiodothyronine permit an increase in plasma 1,25(OH)2D concentrations in response to dietary phosphate deprivation in hypophysectomized rats

Summary Hypophysectomy abolishes the four- to fivefold increase in plasma 1,25(OH)₂D levels that normally accompanies dietary phosphate deprivation in rats despite a smaller but significant decrease in plasma phosphate in these animals. This effect appears within 1 week of hypophysectomy and may be the result of a lack of GH, T₃, or some other pituitary hormone. In hypothyroid rats (2 weeks after TPTX) not given replacement T₃, plasma 1,25(OH)₂D levels rose threefold from 148±57 pmol/l to 402±96 pmol/l (mean±SD) after 4 days of dietary phosphate deprivation. However, in hypophysectomized animals given replacement T₃ alone, plasma 1,25(OH)₂D levels rose fourfold from 82±13 to 333±230 pmol/l after 4 days of phosphate deprivation. In addition, in hypophysectomized animals replaced with GH alone, plasma 1,25(OH)₂D levels rose from 243±86 to 525±85 pmol/l during phosphate deprivation. These results would suggest that both GH and T₃ must be absent to prevent enhanced renal 1,25(OH)₂D synthesis during phosphate deprivation. GH and T₃ appear to play a permissive role since plasma levels of these hormones do not increase when intact rats are deprived of phosphate. Furthermore, bioassayable somatomedin levels are also not increased in intact rats during phosphate deprivation as well as plasma levels of prolactin. As observed previously, plasma 1,25(OH)₂D levels were inversely correlated to plasma phosphate concentrations (r=0.46,P<0.025), despite the inclusion of data points for unreplaced hypophysectomized animals who were hypophosphatemic but showed no increase in plasma 1,25(OH)₂D. Thus the possibility remains that GH and T₃ may exert their effect by permitting the renal 25OHD-1α-hydroxylase to respond to a change in phosphate concentrations during dietary phosphate deprivation, that, in turn, may ultimately increase renal 1,25(OH)₂D synthesis and plasma levels of this hormone.     

Effects of experimental diabetes on the vitamin D metabolism of pregnant rats and their fetuses

Summary The effects of streptozotocin-induced diabetes on the vitamin D metabolism of pregnant rats were investigated in mothers and their fetuses, 11 and 14 days after streptozotocin (SZ) injection, i.e., on days 18 and 21 of gestation. In the mothers' plasma, the levels of 25-hydroxycholecalciferol (25OHD) and 1,25-dihydroxycholecalciferol (1,25(OH)₂ D) were not different from control levels on day 18, but on day 21, 25OHD had increased, 1,25 (OH)₂ D had diminished, and significant hypercalcemia was noted (10.1±0.27 mg/dl vs. 9.47±0.19 mg/dl, mean ±SD). In hyperglycemic fetuses from the diabetic mothers, plasma insulin levels were reduced at day 18 but enhanced at day 21. 25OHD levels were not different from those of the controls at day 18, but were lower at day 21 (2.12±0.70 ng/g BW, n=13, vs. 3.75±1.40 ng/g BW n=29 controls, means ±SD). Fetal body levels of 1,25 (OH)₂ D were lower than that in the controls at day 18 (16.6±2.9 pg/g BW, n=9×2, vs. 28.7±6.3 pg/g BW, n=7×2, mean ±SDP <0.001), but identical to control levels on day 21. The role of fetal or placental enzymes in the regulation of vitamin D metabolism in fetuses is discussed.     

Extrarenal metabolism of 25-hydroxycholecalciferol in the rat: Regulation by 1,25-dihydroxycholecalciferol

Summary To determine the role of the kidney in regulation of 25-hydroxycholecalciferol (25OHD₃, metabolism, the effects of 1,25-dihydroxycholecalciferol [1,25(OH)₂D₃] on³H-25OHD₃ were compared in intact and nephrectomized vitamin D-deficient rats. Sixteen hours after the intravenous administration of³H-25OHD₃, extracts of serum and pooled small intestinal mucosa were fractionated by Sephadex LH-20 column chromatography followed by high performance liquid chromatography. In intact rats, 1,25(OH)₂D₃ (50 ng/day i.p. for 7 days) increased mean serum³H-24,25-dihydroxycholecalciferol [³H-24,25(OH)₂D₃] from 2±2–210±80 fmol/ml (mean±1 SD), increased mean serum³H-25,26-dihydroxycholecalciferol [³H-25,26(OH)₂D₃] from 2±2–12±6 fmol/ml and lowered mean serum³H-1,25(OH)₂D₃ from 210±40–4±4 fmol/ml. Similarly, in nephrectomized animals, 1,25(OH)₂D₃ increased mean serum³H-24,25-(OH)₂D₃ from 6±11–115±30 fmol/ml and increased mean serum³H-25,26(OH)₂D₃ from 3±3–26 ± 10 fmol/ml. Nephrectomy increased serum³H-25(OH)D₃ in untreated (from 1450±225–2675±225 fmol/ml serum) and 1,25(OH)₂D₃ treated rats (from 1600±175–3075±100 fmol/ml).³H-1,25(OH)₂D₃ averaged 74±16% of total radioactivity in intestinal mucosa of untreated intact rats and was not detected in either the serum or intestinal mucosa of nephrectomized animals. The results suggest that in intact animals, extrarenal synthesis can account for substantial 24,25(OH)₂D₃ production and for most 25,26(OH)₂D₃ production. Further, the observed stimulation of production of 24,25(OH)₂D₃ and 25,26(OH)₂D₃ by 1,25(OH)₂D₃ in anephric — D rats providesin vivo evidence for regulation of extrarenal 25OHD₃: 24- and 26-hydroxylases.     

Intestinal Calcium Absorption Decreases Dramatically After Gastric Bypass Surgery Despite Optimization of Vitamin D Status

Roux‐en‐Y gastric bypass (RYGB) surgery has negative effects on bone, mediated in part by effects on nutrient absorption. Not only can RYGB result in vitamin D malabsorption, but the bypassed duodenum and proximal jejunum are also the predominant sites of active, transcellular, 1,25(OH)₂D‐mediated calcium (Ca) uptake. However, Ca absorption occurs throughout the intestine, and those who undergo RYGB might maintain sufficient Ca absorption, particularly if vitamin D status and Ca intake are robust. We determined the effects of RYGB on intestinal fractional Ca absorption (FCA) while maintaining ample 25OHD levels (goal ≥30 ng/mL) and Ca intake (1200 mg daily) in a prospective cohort of 33 obese adults (BMI 44.7 ± 7.4 kg/m²). FCA was measured preoperatively and 6 months postoperatively with a dual stable isotope method. Other measures included calciotropic hormones, bone turnover markers, and BMD by DXA and QCT. Mean 6‐month weight loss was 32.5 ± 8.4 kg (25.8% ± 5.2% of preoperative weight). FCA decreased from 32.7% ± 14.0% preoperatively to 6.9% ± 3.8% postoperatively (p < 0.0001), despite median (interquartile range) 25OHD levels of 41.0 (33.1 to 48.5) and 36.5 (28.8 to 40.4) ng/mL, respectively. Consistent with the FCA decline, 24‐hour urinary Ca decreased, PTH increased, and 1,25(OH)₂D increased (p ≤ 0.02). Bone turnover markers increased markedly, areal BMD decreased at the proximal femur, and volumetric BMD decreased at the spine (p < 0.001). Those with lower postoperative FCA had greater increases in serum CTx (ρ = ?0.43, p = 0.01). Declines in FCA and BMD were not correlated over the 6 months. In conclusion, FCA decreased dramatically after RYGB, even with most 25OHD levels ≥30 ng/mL and with recommended Ca intake. RYGB patients may need high Ca intake to prevent perturbations in Ca homeostasis, although the approach to Ca supplementation needs further study. Decline in FCA could contribute to the decline in BMD after RYGB, and strategies to avoid long‐term skeletal consequences should be investigated. © 2015 American Society for Bone and Mineral Research.     

Increased Serum 1,25-Dihydroxyvitamin D after Growth Hormone Administration is not Parathyroid Hormone-Mediated

To assess the effects of growth hormone (GH) on serum 1,25-dihydroxyvitamin D [1,25(OH)₂D], we performed the following prospective crossover study in six healthy, young, adult, white men. During each of two admissions for 2? days to a general clinical research center, subjects were placed on a daily dietary calcium intake of 400 mg. Serum calcium, phosphorus, 1,25(OH)₂D, immunoreactive intact parathyroid hormone (PTH), insulin-like growth factor I (IGF-I), IGF binding protein 3 (IGFBP3), tubular reabsorption of phosphate (TRP), and maximum tubular reabsorption of phosphate (TMP/GFR) were measured. Recombinant human GH (rhGH, Humatrope) (25 μg/kg/day subcutaneously for 1 week) was administered prior to and during one of the admissions. Results are expressed as mean ± SEM. Whereas serum 1,25(OH)₂D (58.9 ± 7.7 versus 51.6 ± 7.4 pg/ml, P < 0.01), serum phosphorus (4.5 ± 0.1 versus 3.7 ± 0.1 mg/dl, P < 0.01), TRP (92.0 ± 0.5 versus 87.8 ± 0.7 mg/dl, P < 0.005), TMP/GFR (4.6 ± 0.1 versus 3.5 ± 0.2, P < 0.005), and urinary calcium (602 ± 49 versus 346 ± 25 mg/day, P < 0.001) increased significantly, serum PTH decreased significantly (19.9 ± 1.9 versus 26.8 ± 4.0 pg/ml, P < 0.05) and serum calcium did not change when subjects received rhGH. These findings indicate that in humans, GH affects serum 1,25(OH)₂D independently of circulating PTH and that this effect is mediated by IGF-I. We propose, therefore, that one potential mechanism by which GH stimulates increases in bone mass is via modest increases in serum 1,25(OH)₂D. Received: 2 May 1996 / Accepted: 18 October 1996     

Different effects of glyburide and glipizide on insulin secretion and hepatic glucose production in normal and NIDDM subjects

Glyburide (GB) and glipizide (GZ) differ in their pharmacokinetics, but it is not known whether they also differ in mode of action. To examine this question, 10 young healthy subjects and 6 non-insulin-dependent diabetic (NIDDM) patients participated in each of three studies: 1) infusion of saline for 120 min followed by a 100-min hyperglycemic (125 mg/dl) clamp; 2) 120-min primed continuous infusion of GZ followed by a 100-min hyperglycemic clamp; and 3) 120-min primed continuous infusion of GB followed by a 100-min hyperglycemic clamp. The GB and GZ infusions were continued throughout the hyperglycemic clamp. Similar plasma concentrations of GB and GZ were obtained in both groups. All studies were performed with [3-3H]glucose to allow quantification of hepatic glucose production. When administered under basal conditions of glycemia, the acute phase (0-10 min) of plasma insulin and C-peptide increase in both control and NIDDM subjects was twice as great with GZ compared with GB (P less than .01). During the hyperglycemic-clamp studies performed in normal subjects, both GB and GZ increased the first- (1.6-fold) and second- (2.2-fold) phase plasma insulin responses more than hyperglycemia alone. During the hyperglycemic clamp in NIDDM subjects, the first-phase plasma insulin response was absent, and the second-phase insulin response was markedly impaired. Neither GB nor GZ improved first-phase insulin secretion in the NIDDM patients. In both NIDDM and control subjects, the effects of hyperglycemia and sulfonylurea drugs (both GB and GZ) on the first- and second-phase plasma insulin responses were simply additive.(ABSTRACT TRUNCATED AT 250 WORDS)