Altered white matter integrity in adults with autism spectrum disorder and an IQ >100: a diffusion tensor imaging study.

OBJECTIVE: White matter (WM) alterations have been reported in children and adults with autism spectrum disorder (ASD). In particular, impaired connectivity of limbic structures may be related to social deficits. Heterogeneous findings could be explained in terms of differences in sample characteristics and methodology. In this context, non-syndromic forms might differ substantially in WM structure from secondary ASD forms. METHOD: In an attempt to recruit a homogeneous study sample, we included adults with high-functioning ASD and an IQ > 100 to decrease the influence of syndromic forms being often associated with cognitive deficits. Diffusion tensor imaging (DTI) was performed in 30 participants with ASD and 30 pairwise-matched controls. Fractional anisotropy (FA) and mean diffusivity (MD) as surrogate imaging markers for WM integrity were calculated. RESULTS: We found a significant FA decrease in the ASD group in the genu and body of the corpus callosum (CC). Increased MD was detected in the subgenual anterior cingulate cortex (sACC). CONCLUSION: The finding of decreased WM integrity in the genu of the CC is in line with earlier studies reporting a decreased number of interhemispheric fibers in the frontal lobe of ASD. Alterations in the sACC might be associated with 'Theory of mind' deficits.

Disturbed cingulate glutamate metabolism in adults with high-functioning autism spectrum disorder: evidence in support of the excitatory/inhibitory imbalance hypothesis.

Over the last few years, awareness of autism spectrum disorder (ASD) in adults has increased. The precise etiology of ASD is still unresolved. Animal research, genetic and postmortem studies suggest that the glutamate (Glu) system has an important role, possibly related to a cybernetic imbalance between neuronal excitation and inhibition. To clarify the possible disruption of Glu metabolism in adults with high-functioning autism, we performed a magnetic resonance spectroscopy (MRS) study investigating the anterior cingulate cortex (ACC) and the cerebellum in adults with high-functioning ASD. Twenty-nine adult patients with high-functioning ASD and 29 carefully matched healthy volunteers underwent MRS scanning of the pregenual ACC and the left cerebellar hemisphere. Metabolic data were compared between groups and were correlated with psychometric measures of autistic features. We found a significant decrease in the cingulate N-acetyl-aspartate (NAA) and the combined Glu and glutamine (Glx) signals in adults with ASD, whereas we did not find other metabolic abnormalities in the ACC or the cerebellum. The Glx signal correlated significantly with psychometric measures of autism, particularly with communication deficits. Our data support the hypothesis that there is a link between disturbances of the cingulate NAA and Glx metabolism, and autism. The findings are discussed in the context of the hypothesis of excitatory/inhibitory imbalance in autism. Further research should clarify the specificity and dynamics of these findings regarding other neuropsychiatric disorders and other brain areas.

Aluminum-associated bone disease in chronic renal failure: high prevalence in a long-term dialysis population.

Twenty-seven asymptomatic patients treated with hemodialysis longer than 8 years (mean 12.9 +/- 3.1 years) underwent bone biopsy to determine the prevalence of aluminum-associated bone disease. None had excess aluminum exposure from the dialysate. Ten patients (37%) had aluminum-associated bone disease as defined by a bone formation rate (BFR) below normal in the presence of stainable bone aluminum that covered more than 25% of the trabecular surface. The predominant type of bone histology in this group was the aplastic lesion characterized by low bone turnover, a decreased number of osteoblasts, and lack of excess unmineralized osteoid. Osteoblastic osteoid was highly correlated with stainable surface bone aluminum (r = -.82, p less than .001). Among the dynamic bone parameters, the double-tetracycline labeled surface was a more sensitive indicator of impaired bone function than was the bone apposition rate (BAR), since half of the patients with aluminum-associated bone disease had a normal BAR. In all of the biopsies the extent of double-labeled surfaces was inversely proportional to the amount of stainable aluminum on the bone surface (r = -.71, p less than .001), whereas stainable bone aluminum did not correlate with BAR. In seven of the patients with aluminum-associated bone disease, amino-terminal PTH levels were in the normal range while only one patient had a normal plasma mid-region PTH. PTH correlated directly with osteoblastic osteoid, BFR, and double-labeled surfaces. These results indicate that long-term oral aluminum intake in hemodialysis patients results in a high prevalence of aluminum-associated bone disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone histomorphometry of renal osteodystrophy in diabetic patients.

Bone biopsies and plasma parathyroid hormone (PTH) from 27 diabetic dialysis patients were compared to biopsies and PTH levels from matched patients without diabetes to determine if PTH has a role in preserving bone mass in diabetic renal osteodystrophy. Significantly lower values were present in the diabetic group for mineralized bone area (p less than 0.003), osteoblastic osteoid (p less than 0.01), resorptive surface (p less than 0.001), fibrosis (p less than 0.005), bone apposition rate (p less than 0.01), bone formation rate (BMU level) (p less than 0.04), and plasma PTH (p less than 0.05). Bone-surface aluminum was higher in the diabetic group (44 +/- 5% vs. 20 +/- 5%, p less than 0.005). Linear regression analysis revealed significant positive correlations of mineralized bone area with time on dialysis, bone formation rate, bone resorption, and PTH only in the group without diabetes. While both groups had significant positive correlations of PTH with osteoblastic osteoid and bone resorption, only in the nondiabetic group was there a positive correlation of PTH with bone apposition and bone formation rate (BMU level), observations suggesting that the lower bone formation in the diabetic patients may have arisen in part from a failure of PTH to promote bone mineralization. We conclude that relatively low PTH levels and high bone aluminum in diabetic patients with chronic renal failure may be responsible in part for low bone mass when compared to uremic patients without diabetes.

Effect of long-distance running on bone mass in women.

The effect of long-distance running on bone mass was assessed in 10 premenopausal and 9 estrogen-deprived postmenopausal women and compared to that in closely matched sedentary control women. Vertebral trabecular bone density (VBD) was determined by computed tomography and radial cortical bone density (CBD) by single-photon absorptiometry. Physical fitness was assessed by determining maximal oxygen consumption (VO2max) on a treadmill run to exhaustion. VBD was 183 +/- 7 mg/cm3 and VO2max was 48 +/- 1 ml/kg per minute in young women runners and 163 +/- 8 mg/cm3 and 32 +/- 2 ml/kg per minute in sedentary young women. A positive correlation was noted between VBD and VO2max in these groups (r = 0.509, p less than 0.03). Despite a significantly higher VO2max in postmenopausal women runners compared with sedentary controls (37 +/- 2 versus 24 +/- 2 ml/kg per minute), VBD was identical (112 +/- 5 versus 111 +/- 5 mg/cm3) and no correlation was seen between VBD and VO2max (r = 0.187, p = 0.457). Radial cortical bone density was not different between the runners or sedentary groups in young women (0.738 +/- 0.01 versus 0.732 +/- 0.1 g/cm2) or postmenopausal women (0.617 +/- 0.3 versus 0.665 +/- 0.4 g/cm2). These results suggest that although physical fitness enhances vertebral bone density in premenopausal women, it does not appear to prevent age- and/or sex steroid deficiency-induced bone loss in postmenopausal women.

1,25-Dihydroxyvitamin D maintains bone cell activity, and parathyroid hormone modulates bone cell number in dogs.

The singular and combined effects of 1,25-dihydroxyvitamin D [1,25-(OH)2D] and PTH on bone were evaluated in a long term in vivo study in dogs. Dogs were rendered deficient in 1,25-(OH)2D and PTH by five sixths nephrectomy and parathyroidectomy. A control group was sham operated. Various combinations in status of 1,25-(OH)2D and PTH were produced by daily sc injections of 1,25-(OH)2D (1.25) and/or continuous infusion of 1-34 bovine PTH. These were 1.25+/PTH+, 1.25-/PTH-, 1.25+/PTH-, 1.25-/PTH+. Serum calcium levels were kept in the normal range by the administration of one or two of the hormones or by oral supplementation of calcium lactate. Histomorphometric evaluation of static and dynamic parameters of bone after 8 months of experimental observation revealed that deficiency in 1,25-(OH)2D and PTH resulted in decreased number and activity of bone-forming and resorbing cells. Administration of 1,25-(OH)2D increased the activity but not the number of bone cells. In contrast, administration of PTH increased the number but not the activity of bone cells. Tissue level activity was decreased when one or both hormones were deficient, and normal tissue level activity was found only when both hormones were given. These data are relevant for understanding and management of diseases with perturbations in vitamin D and/or PTH.

Influence of continuous infusion of citrate on responses of immunoreactive parathyroid hormone, calcium and magnesium components, and other electrolytes in normal adults during plateletapheresis.

To study the relationships between changes in concentrations of different forms of calcium and the responses of immunoreactive PTH in humans during citrate-induced hypocalcemia, we studied 12 healthy donors undergoing continuous flow plateletapheresis. Concentrations of intact, amino-terminal, and midregion PTH; ionized, ultrafiltrable, and total calcium; total and ultrafiltrable magnesium; protein; albumin; pH; phosphate; and citrate were measured in sera collected during the first 95 min of apheresis. Although ionized calcium decreased steadily in every donor, both intact and amino-terminal PTH rose quickly in most donors to a peak level 5-15 min after starting the infusion of citrate and then declined during the remainder of apheresis. Midregion PTH also rose quickly by 5-remainder of apheresis. Midregion PTH also rose quickly by 5-15 min, but levelled off at 30-90 min. Total calcium inversely correlated with both intact PTH (r = -0.76) and amino-terminal PTH (r = -0.81) better than did ionized calcium (r = -0.47 and -0.46, respectively). The rapid rise and then gradual fall of PTH may be due to glandular depletion of stored PTH, increased peripheral metabolism of PTH, or PTH initiation of other hormonal actions that compensate for hypocalcemia. Protein-bound calcium measured, and this change probably reflected dissociation of calcium from its albumin-binding sites to minimize the changes in ionized calcium concentrations.

Effect of experimental human magnesium depletion on parathyroid hormone secretion and 1,25-dihydroxyvitamin D metabolism.

Magnesium (Mg) deficiency in man may result in hypocalcemia, impaired PTH secretion, and low serum concentrations of 1,25-dihydroxyvitamin D [1,25-(OH)2D]. To determine whether these changes are due to selective Mg depletion, we studied 26 normal subjects before and after a 3-week low Mg (less than 1 meq/day) diet. This diet induced Mg deficiency, as demonstrated by a fall in pre- to postdiet serum Mg levels from 0.80 +/- 0.01 to 0.61 +/- 0.02 mmol/L (P less than 0.001), an increase in Mg retention from 11 +/- 4% to 62 +/- 4% (P less than 0.001), and a fall in red blood cell free Mg2+ from 205 +/- 10 to 162 +/- 7 microM (P less than 0.001). Serum calcium (Ca) fell significantly from 2.36 +/- 0.02 to 2.31 +/- 0.03 mmol/L (P less than 0.05), and serum 1,25-(OH)2D fell from 55 +/- 4 to 43 +/- 3 pmol/L (P less than 0.05). PTH secretion was impaired, as demonstrated by a fall or no change in serum PTH in 20 of 26 subjects despite a fall in the serum Ca and Mg. In addition, an iv injection of Mg in eight subjects after the diet resulted in a significant rise in PTH from 15 +/- 2 to 19 +/- 2 ng/L (P less than 0.01), whereas a similar injection given to six of the subjects before the diet resulted in a significant fall from 28 +/- 5 to 13 +/- 3 ng/L (P less than 0.001). The fall in serum 1,25-(OH)2D may be due to both the decrease in PTH secretion and a renal resistance to PTH. PTH resistance was suggested, as no increase in serum 1,25-(OH)2D was observed in the six subjects in which the PTH concentration rose by mean of 68% after the diet. Also, the rise in serum 1,25-(OH)2D after a 6-h human PTH-(1-34) infusion was significantly less after Mg deprivation. The results demonstrate that mild Mg depletion can impair mineral homeostasis and may be implicated as risk factor for osteoporosis in disorders such as chronic alcoholism and diabetes mellitus, in which Mg deficiency and osteoporosis are both common.

Serum vitamin D2 and vitamin D3 metabolite concentrations and absorption of vitamin D2 in elderly subjects.

The serum vitamin D2 and vitamin D3 metabolite concentrations and intestinal absorption of vitamin D2 were determined in healthy ambulatory and chronically institutionalized elderly subjects with normal renal function. The 25-hydroxyvitamin D (25OHD) concentrations were normal in all subjects (range, 8-43 ng/ml), although institutionalized subjects had a significantly lower mean value [19.2 +/- 2 (+/- SEM) ng/ml; P less than 0.01] compared with ambulatory subjects (25.3 +/- 2 ng/ml). All but one ambulatory subject had 25OHD3 as the major circulating form, whereas 25OHD2 was the major circulating metabolite in one third of the institutionalized subjects. The mean 1,25-dihydroxyvitamin D [1,25-(OH)2D] concentration in both groups was normal, but nine subjects had levels at or below the lower limit of normal despite normal 25OHD concentrations. Separate assay of 1,25-(OH)2D2 and 1,25(OH)2D3 revealed proportional distributions similar to those for 25OHD2 and 25OHD3. To study the effect of age on the intestinal absorption of vitamin D, we compared serum vitamin D2 concentrations after oral administration of 50,000 IU vitamin D2 in both healthy vitamin D-sufficient elderly subjects and young adults. We found no evidence of malabsorption of vitamin D in the elderly subjects. In summary, elderly subjects in New York, whether institutionalized or not, have normal serum 25OHD concentrations. However, while most elderly subjects have normal serum 1,25-(OH)2D levels, a significant proportion fail to produce normal concentrations of 1,25-(OH)2D, possibly due to age-related disturbances in renal synthesis of the hormone.

Age-related changes in serum immunoreactive parathyroid hormone and its biological action in healthy men and women.

Circulating levels of PTH and related parameters of calcium and phosphate metabolism were measured in healthy free-living elderly and young subjects residing in the Southwest to determine if parathyroid function changes with aging. Serum immunoreactive PTH (iPTH) was measured with two well characterized antisera; an amino (N)-terminal antiserum which cross-reacts with the biologically active domain (1-34) and recognizes intact hormone, and a midregion (44-68) antiserum which cross-reacts with intact hormone and biologically inactive midregion/C-terminal fragments. Serum iPTH in both RIAs was significantly increased in the elderly population. An age-related increase was also found for total urinary cAMP and serum alkaline phosphatase, whereas the tubular reabsorptive maximum for phosphate (TmP/GFR) decreased with age. No difference was found between men and women of the same age group for serum iPTH, urinary cAMP, or serum alkaline phosphatase. TmP/GFR declined with age in men, but not women. Correspondingly, serum phosphate was significantly lower in elderly men than in elderly women. Urinary calcium excretion was higher in elderly women than in men of the same age group. Neither serum total or ionized calcium decreased with age. In conclusion, the age-related increase in N-terminal PTH and alterations in associated parameters of phosphate and calcium metabolism are consistent with increased parathyroid function as men and women age. Factors other than PTH are responsible for the sex-related differences observed in TmP/GFR, calcium excretion, and serum phosphate. The cause of the increased circulating levels of apparently biologically active PTH is unclear, but extends beyond the age-related decrease in renal function.

Biochemical assessment of bone formation and resorption in acromegaly.

The effects of chronic GH and insulin-like growth factor-I (IGF-I) excess on bone metabolism were examined by measuring serum markers of bone formation and urine markers of bone resorption as well as vertebral bone densities in patients with active acromegaly. Fasting serum GH levels were elevated in all 27 patients (31 +/- 11 micrograms/L). Serum calcium levels were within the normal range, except in 3 of 27 (10%) patients with mild hypercalcemia. Urinary calcium excretion, however, was increased in 6 (22%) patients despite mainly normal serum PTH and 1,25-dihydroxyvitamin D levels, suggesting a direct renal GH and/or IGF-I-mediated calciuric effect. Urinary hydroxyproline/creatinine excretion was increased in all except 1 patient and correlated with plasma IGF-I levels (r = 0.49; P < 0.02; n = 22). A more specific indicator of bone collagen turnover, urinary type I collagen cross-linked N-telopeptide, was elevated in all except 1 patient and correlated with serum GH (r = 0.47; P < 0.02), IGF-I (r = 0.60; P < 0.005), and urinary hydroxyproline/creatinine excretion (r = 0.62; P < 0.001). Serum bone Gla protein (osteocalcin), a specific marker of osteoblastic activity, was also increased in 50% of the patients and correlated with urinary N-telopeptide (r = 0.47; P < 0.02), but not with serum GH or IGF-I concentrations. Trabecular bone density, as determined by quantitative computerized tomography of the lumbar spine, was increased in only 1 patient; 13 others had subnormal bone density. The results suggest that in long-standing acromegaly, osteoblastic and osteoclastic activities are increased. Vertebral trabecular bone mass is usually reduced. Urinary collagen cross-links may serve as a more specific marker of bone resorption in acromegaly.

Ketoconazole decreases the serum 1,25-dihydroxyvitamin D and calcium concentration in sarcoidosis-associated hypercalcemia.

Ketoconazole is an antifungal agent capable of inhibiting human steroid hormone synthesis, including renal 1,25-dihydroxyvitamin D [1,25-(OH)2D] synthesis. The ability of this drug to inhibit the extrarenal production of 1,25-(OH)2D, as occurs in human granuloma-forming disease states, including sarcoidosis, has not been evaluated. We examined the effect of ketoconazole on the 1,25-(OH)2D-calcium homeostatic mechanism in a hypercalcemic patient with sarcoidosis and on the synthesis of 1,25-(OH)2D3 in vitro by cultured pulmonary alveolar macrophages (PAM) from this and another host. Oral ketoconazole therapy (800 mg/day) decreased the serum 1,25-(OH)2D concentration 73% within 4 days; this was associated with a 15% decrease in the serum calcium concentration and a 57% decrease in the fractional urinary calcium excretion rate. In vitro, ketoconazole had a rapid onset, concentration-dependent inhibitory effect on sarcoid PAM 1,25-(OH)2D3 synthesis (ED50 = 0.1 mumol/L) that was not reversible by exposure to leukotriene C4, a potent stimulator of PAM 1,25-(OH)2D3 synthesis. Kinetic analysis of ketoconazole's action on the macrophage 1 alpha-hydroxylation reaction was examined at concentrations achieved in vivo when the drug is given orally. The velocity of the 1 alpha-hydroxylation reaction at ketoconazole concentrations of 0.01-1.0 mumol/L increased as the concentration of substrate 25-hydroxyvitamin D3 increased from 12-2000 nmol/L.

Osteomalacia and aplastic bone disease in aluminum-related osteodystrophy.

The bone histology in patients with chronic renal failure and aluminum-related bone disease does not always show the excess accumulation of unmineralized osteoid (matrix) characteristic of osteomalacia. Frequently, bone aluminum accumulation is associated with normal or reduced amounts of unmineralized osteoid and low bone formation and is referred to as aplastic bone disease. In this study, we compared static and dynamic bone histomorphometric parameters and plasma PTH and aluminum levels in 12 patients with osteomalacia and 18 patients with aplastic bone disease who had been receiving dialysis for the same duration to determine if the difference in osteoid accumulation in these 2 lesions might be explained by differences in aluminum accumulation or PTH levels. The stainable bone surface aluminum level was significantly higher in the patients with osteomalacia compared to that in the group with aplastic bone [61 +/- 5% (+/- SEM) vs. 43 +/- 4%; P less than 0.02]. The rates of bone apposition and bone formation were lower in the group with osteomalacia (P less than 0.01). Plasma amino-terminal PTH was not significantly different in the 2 groups. The increment in plasma aluminum levels after a single infusion of deferoxamine was higher in the osteomalacic group than in the aplastic group, suggesting that the patients with osteomalacia accumulated more total body chelatable aluminum than did those with aplastic bone disease during a comparable length of time on dialysis. We conclude that the excess unmineralized osteoid in aluminum-related osteomalacia results from the high rate of total body aluminum accumulation, which directly causes uncoupling of matrix mineralization and matrix production, independent of PTH levels. Patients with aplastic bone disease who have accumulated lesser amounts of total body aluminum fail to develop excess unmineralized osteoid because production and mineralization of matrix are more closely coupled than in the osteomalacic lesion, despite a decline in osteoblast numbers.

Comparison of parathyroid hormone assays with bone histomorphometry in renal osteodystrophy.

Bone biopsies were studied in 67 dialysis patients to determine if a PTH RIA specific for intact plasma PTH is a better predictor of osteitis fibrosa than a RIA that measures inactive carboxy-terminal/midregion plasma PTH fragments. An amino-terminal-specific antiserum that cross-reacts with intact PTH, but not midregion or carboxy-terminal fragments, and an antiserum that cross-reacts with the 44-68 region of the PTH molecule and measures both intact and midregion/carboxy-terminal PTH fragments were used in the comparisons. Plasma PTH concentrations measured by both assays correlated positively with bone formation rate, bone apposition rate, osteoblastic osteoid, osteoclast number, and marrow fibrosis. The optimum predictive value of the amino-terminal PTH assay for osteitis fibrosa was 88%, compared to 74% for the midregion PTH assay. This difference in predictive value could be attributed to the highly significant correlation of marrow fibrosis with plasma amino-terminal PTH. In conclusion, these data suggest that a PTH RIA that uses an amino-terminal-specific antiserum may be a better predictor of osteitis fibrosa in patients undergoing maintenance hemodialysis.

Low serum concentrations of 1,25-dihydroxyvitamin D in human magnesium deficiency.

The effect of magnesium deficiency on vitamin D metabolism was assessed in 23 hypocalcemic magnesium-deficient patients by measuring the serum concentrations of 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D [1,25-(OH)2D] before, during, and after 5-13 days of parenteral magnesium therapy. Magnesium therapy raised mean basal serum magnesium [1.0 +/- 0.1 (mean +/- SEM) mg/dl] and calcium levels (7.2 +/- 0.2 mg/dl) into the normal range (2.2 +/- 0.1 and 9.3 +/- 0.1 mg/dl, respectively; P less than 0.001). The mean serum 25OHD concentration was in the low normal range (13.2 +/- 1.5 ng/ml) before magnesium administration and did not significantly change after this therapy (14.8 +/- 1.5 ng/ml). Sixteen of the 23 patients had low serum 1,25-(OH)2D levels (less than 30 pg/ml). After magnesium therapy, only 5 of the patients had a rise in the serum 1,25-(OH)2D concentration into or above the normal range despite elevated levels of serum immunoreactive PTH. An additional normocalcemic hypomagnesemic patient had low 1,25-(OH)2D levels which did not rise after 5 days of magnesium therapy. The serum vitamin D-binding protein concentration, assessed in 11 patients, was low (273 +/- 86 micrograms/ml) before magnesium therapy, but normalized (346 +/- 86 micrograms/ml) after magnesium repletion. No correlation with serum 1,25-(OH)2D levels was found. The functional capacity of vitamin D-binding protein to bind hormone, assessed by the internalization of [3H]1,25-(OH)2D3 by intestinal epithelial cells in the presence of serum was not significantly different from normal (11.42 +/- 1.45 vs. 10.27 +/- 1.27 fmol/2 X 10(6) cells, respectively). These data show that serum 1,25-(OH)2D concentrations are frequently low in patients with magnesium deficiency and may remain low even after 5-13 days of parenteral magnesium administration. The data also suggest that a normal 1,25-(OH)2D level is not required for the PTH-mediated calcemic response to magnesium administration. We conclude that magnesium depletion may impair vitamin D metabolism.

Inhibition of insulin release by cyclosporine and production of peripheral insulin resistance in the dog.

Cyclosporine has been shown to cause glucose intolerance in both humans and animals. This can result from alterations in insulin release, insulin metabolism, the sensitivity of peripheral or hepatic tissues to insulin, or a combination of these factors. The present study was designed to simultaneously evaluate the effect of CsA on these variables. A group of chronically catheterized dogs were administered oral CsA (20 mg/kg/day) for a period of 10 weeks. The glucagon stimulation test (GST) and the euglycemic glucose clamp technique, using a primed continuous infusion of 3H-3-glucose and a continuous insulin infusion (0.8 mU/kg/min), were employed to evaluate pancreatic insulin release, peripheral glucose disposal rate (Rd), hepatic glucose output (HGO), and metabolic clearance rate (MCR) of insulin. The dogs were tested before and after 2, 6, and 10 weeks of CsA administration. Serum CsA levels were 358 +/- 85, 244 +/- 48, and 355 +/- 81 ng/ml at 2, 6, and 10 weeks, respectively (P = NS). Elevated fasting glucose and an abnormal glucose response to an i.v. bolus of glucagon (0.25 U) were noted after 2, 6, and 10 weeks of CsA administration. The areas under the glucose curve (AUCG) for 0-60 min were 9605 +/- 773, 11634 +/- 1226, 12380 +/- 719, and 12626 +/- 1560 mg/min/dl at 0, 2, 6, and 10 weeks, P(F3, 15 = 5.1) = 0.012, demonstrating a CsA-induced disturbance of glucose homeostasis. The areas under the insulin curve (AUCI) for 0-20 min of the insulin response curve were 2033 +/- 203, 1089 +/- 187, 1038 +/- 179, and 972 +/- 161 uU/min/dl at 0, 2, 6, and 10 weeks, P(F3, 15 = 13.1) less than 0.001, indicating a 50% reduction during CsA treatment. CsA did not affect basal Rd, but peripheral insulin resistance was noted in the insulin-stimulated state. Rd during the third hour of the insulin infusion decreased from 6.72 +/- 0.69 to 4.42 +/- 0.44, 5.02 +/- 0.64, 4.47 +/- 0.52 mg/kg/min at 0, 2, 6, and 10 weeks, respectively, P(F3, 15 = 6.94) less than 0.004. HGO suppression by insulin and MCR of insulin were not altered by CsA. Similarly, glucagon secretion did not appear to be influenced by CsA. In conclusion, this study has simultaneously evaluated the effect of CsA on several aspects of glucose and insulin metabolism in the dog. CsA administration produces abnormal glucose homeostasis by reducing pancreatic insulin release, in addition to inducing peripheral insulin resistance.(ABSTRACT TRUNCATED AT 400 WORDS)

Recovery and hypersecretion of insulin and reversal of insulin resistance after withdrawal of short-term cyclosporine treatment.

We have previously demonstrated decreased insulin release and insulin resistance in dogs treated with cyclosporine (20 mg/kg/day). In this study we examine the changes caused by a lower CsA dose and evaluate the reversal of these changes. Six animals were treated for 2 weeks with oral CsA (15 mg/kg/day), after which CsA was discontinued. Glucagon stimulation tests (GST) and euglycemic clamp studies (ECS) were used to evaluate changes in insulin release and insulin resistance. GST were performed before CsA, after 2 weeks of CsA, and 3, 9, and 15 days after discontinuing CsA. ECS were performed before CsA, after 2 weeks of CsA, and 2, 4, 8, and 14 days after discontinuing CsA. The mean serum CsA level after 2 weeks of treatment was 188 +/- 28 ng/ml. GST demonstrated decreased insulin release during CsA with recovery and hypersecretion after CsA withdrawal. ECS showed peripheral insulin resistance during CsA with a rapid recovery and a temporary increase in insulin sensitivity after CsA withdrawal. Comparisons were made with our previous study group given 20 mg/kg/day of CsA. In summary, CsA induces a dose-dependent impairment of glucose homeostasis due to inhibition of insulin release and development of peripheral insulin resistance. Withdrawal of short-term CsA at commonly used therapeutic doses results in reversal of and temporary overcompensation for these changes. CsA withdrawal after long-term treatment results in a slower normalization of the insulin response as compared with after short-term treatment. The hypersecretory reaction of the beta cell may be of help in further investigations of mechanisms of CsA- and FK506-induced inhibition of insulin release.

Measurement of parathyroid hormone.

Interpretation of serum immunoreactive PTH measurements requires an understanding of the secretion, metabolism, and heterogeneity of circulating immunoreactive PTH. Both intact hormone and biologically inactive carboxyl fragments containing the middle and C-terminal regions are secreted by the parathyroid glands. Inactive fragments also are produced peripherally by metabolism of intact hormone by liver and kidney. Inactive fragments represent 75 to 95% of the total immunoreactivity in serum, a consequence of their long half-life in vivo as compared with intact hormone. Immunoassays for PTH can be divided into those measuring intact hormone (N-terminal, intact) and those measuring both inactive fragments and intact hormone (mid-region, C-terminal, polyvalent). The latter principally measures inactive fragments because of their greater concentration as compared with intact hormone in peripheral serum. The clinical utility of PTH assays varies considerably because of differences in their specificity and sensitivity. Serum PTH levels have been more often observed to be elevated in individuals with primary hyperparathyroidism with the use of research quality radioimmunoassays that recognize both inactive fragments and intact hormone than with conventional N-terminal or intact assays. Homologous mid-region assays have provided exceptional clinical sensitivity in confirming primary hyperparathyroidism. Comparison of a sensitive mid-region radioimmunoassay with a recently developed two-site, noncompetitive chemiluminescent immunoassay for intact PTH indicated that both methods were highly useful in the differential diagnosis of hypercalcemia. The mid-region assay provided the best diagnostic sensitivity in primary hyperparathyroidism with more elevated levels of PTH. The sensitivity of the intact assay was good, a significant improvement over conventional N-terminal and intact assays. The specificity of the intact assay was clearly superior, with measured PTH levels found to be suppressed to below normal in most subjects with hypercalcemia associated with malignancy. In contrast, measured levels were primarily normal with the mid-region assay. The higher levels of immunoreactive PTH observed in nonparathyroid hypercalcemia with the mid-region assay are in agreement with the measurement of biologically inactive carboxyl fragments, which continue to be secreted in hypercalcemia.

Sex differences in the concentrations of glucocorticoid receptors in rat liver and thymus.

The effects in rats of adrenalectomy, hypophysectomy, ovariectomy or combinations of these operations on the concentrations of glucocorticoid receptors in the cytosol of liver and thymus were measured. The concentrations of glucocorticoid receptors were lower in cytosols from liver and thymus of female than of male rats. After adrenalectomy, there was a significant increase in the concentrations of receptors measured in the cytoplasm from the liver and thymus of female rats and from the liver of male rats. After adrenalectomy or hypophysectomy, there was no sex difference in the concentration of glucocorticoid receptors in cytosols of liver or thymus. After ovariectomy, the concentration of receptors in cytosols from the thymus, but not from the liver, increased. Ovariectomized rats responded to adrenalectomy in the same way as intact male rats. The different responses shown by male and female rats to endocrine manipulation probably depend upon associated changes in plasma corticosterone concentrations which are influenced by the ovary. Differences in response between the liver and thymus probably reflect a preferential distribution of corticosterone to the liver rather than to the thymus.