Bone quality assessment in type 2 diabetes mellitus.

UNLABELLED: The increased risk for fractures in type 2 diabetes mellitus (T2DM) despite higher average bone density is unexplained. This study assessed trabecular bone quality in T2DM using the trabecular bone score (TBS). The salient findings are that TBS is decreased in T2DM and low TBS associates with worse glycemic control. INTRODUCTION: Type 2 diabetes mellitus is a risk factor for osteoporotic fractures despite high average bone mineral density (BMD). The aim of this study was to compare BMD with a noninvasive assessment of trabecular microarchitecture, TBS, in women with T2DM. METHODS: In a cross-sectional study, trabecular microarchitecture was examined in 57 women with T2DM and 43 women without diabetes, ages 30 to 90 years. Lumbar spine BMD was measured by dual-emission x-ray absorptiometry (DXA), and TBS was calculated by examining pixel variations within the DXA images utilizing TBS iNsight software. RESULTS: Mean TBS was lower in T2DM (1.228 ± 0.140 vs. 1.298 ± 0.132, p = 0.013), irrespective of age. Mean BMD was higher in T2DM (1.150 ± 0.172 vs. 1.051 ± 0.125, p = 0.001). Within the T2DM group, TBS was higher (1.254 ± 0.148) in subjects with good glycemic control (A1c ≤ 7.5 %) compared to those (1.166 ± 0.094; p = 0.01) with poor glycemic control (A1c > 7.5 %). CONCLUSION: In T2DM, TBS is lower and associated with poor glycemic control. Abnormal trabecular microarchitecture may help explain the paradox of increased fractures at a higher BMD in T2DM. Further studies are needed to better understand the relationship between glycemic control and trabecular bone quality.

L-histidine augments the response to 1-deamino-8-D-arginine vasopressin in Brattleboro homozygous (di/di) rats.

Studies in vitro have shown that L-histidine increases the hydroosmotic response to vasopressin. We examined whether this phenomenon occurs also in vivo. Homozygous Brattleboro rats (di/di) were fed a regular diet (0.5% histidine) or a diet enriched with histidine and received 1 ng of 1-deamino-8-D-arginine vasopressin (dDAVP) daily. Addition of histidine (1% by weight) increased post-dDAVP urine osmolality to a level higher than that of control (502 +/- 62 vs. 316 +/- 36 mosmol/kg, P less than 0.05). Similar results were seen with 3.0% and 5.5% dietary histidine. There were significant increases in free-water reabsorption and in the ratio of free-water reabsorption to osmolar clearance, but no difference in osmolal clearance. No significant effect was found with supplemental histidine of 0.5% or less. The cause for these findings appears not to be the metabolism of histidine, since the nonmetabolizable D-histidine had a significant, albeit smaller, effect, and the isonitrogenous addition of albumin, alanine, arginine, or glutamine was ineffective. In part, histidine may operate by increasing cAMP since the renal cAMP content in response to vasopressin is increased in histidine-fed rats (13.1 +/- 0.9 vs. 9.8 +/- 0.8 nmol/g dry weight, P less than 0.01). The role of prostaglandins appears less clear. Histidine greatly decreased urinary PGE2 during baseline (1.5 +/- 0.3 vs. 7.0 +/- 2.3 micrograms/mg creatinine, P less than 0.001), but it profoundly augmented urinary prostaglandin excretion after dDAVP stimulation (40.0 +/- 4.2 vs. 7.0 +/- 2.0 micrograms/mg creatinine, P less than 0.001).

Clofibrate-induced antidiuresis.

Normal subjects and patients with antidiuretic hormone (ADH) deficiency were studied to determine the mechanism of the antidiuretic action of clofibrate. Before clofibrate treatment, the patients' ability to concentrate urine with a standardized dehydration procedure correlated with the amount of ADH which was excreted. During clofibrate administration all six patients with ADH deficiency developed an antidiuresis which was like that of ADH, since there was no change in sodium, potassium, total solute, or creatinine excretion. There was a correlation between the patients' ability to concentrate urine during dehydration and the subsequent response to clofibrate, and the excretion of ADH during dehydration correlated with the excretion of ADH on clofibrate therapy. Clofibrate-induced antidiuresis in these patients was partially overcome by ethanol and by water loading. Clofibrate interfered with the ability of patients and subjects to excrete a water load and prevented the water load from inhibiting ADH excretion in the normal subjects. These studies suggested that clofibrate was acting through endogenous ADH and this thesis was supported by the failure of clofibrate to produce an antidiuresis when injected into rats with total ADH deficiency (Brattleboro strain) although an antidiuresis was produced in water-loaded normal rats. When the drug was injected into Brattleboro rats with exogenous ADH, clofibrate either did not alter or it inhibited the action of the ADH. The data demonstrate that clofibrate has a significant ADH-like action. This action appears to be mediated through the release of endogenous ADH.

Action of cortisol on sodium transport in canine erythrocytes.

Incubation of blood from deoxycorticosterone-treated, adrenalectomized dogs with glucose, (22)NaCl, and cortisol, added in vitro, revealed log dose-related acceleration of sodium influx, of glucose utilization, and of lactate formation by cortisol in concentrations between 150 and 1000 microg/liter. Addition of 2-deoxyglucose, or preincubation of the blood until blood glucose concentration had fallen below 2.0 mg per 100 ml, reduced or abolished the acceleratory action of added cortisol on sodium influx but had no effect on sodium influx in the absence of added cortisol. Cortisol did not change the ATP or ATPase content of erythrocytes, or the metabolism of glucose via the pentose phosphate pathway, or the rate of efflux of (22)Na from the erythrocytes. The acceleratory actions of cortisol on sodium, influx, glucose utilization, and lactate formation were significantly correlated. Cortisol (1000 microg/liter) enhanced sodium influx by approximately 8.7 mmole per liter erythrocytes per hour for each 1 mmole cortisol-induced increment in ATP production. It is concluded that sodium influx in canine erythrocytes comprises a passive component, unchanged by cellular metabolism, and a second component which is accelerated and inhibited in proportion to prevailing plasma concentrations of cortisol and aldosterone, and which (for cortisol) depends upon accelerated ATP production via glycolysis. These steroid actions probably result from effects on enzyme activity rather than on new enzyme induction.

Secondary hyperparathyroidism caused by oral contraceptives.

Secondary hyperparathyroidism developed on two separate occasions in a patient taking an oral contraceptive (OC) in a mixture of norethindrone and mestranol (Ortho-Novum 1/80). The probable cause of this condition is an estrogenic inhibition of the calcium mobilizing effect of parathyroid hormone (PTH) or vitamin D. The possible consequences of OC therapy in this patient and patients like her include those of milk hypocalcemia, moderate hypophosphatemia, or the neurotoxic actions of excessive levels of circulating PTH. One should also consider the possible role of OC therapy in patients with unexplained parathyroid hyperplasia and with tertiary hyperparathyroidism.

Inhibition of hormonal activation of hepatic phosphorylase by chlorpropamide: evidence for an intracellular site of drug action.

Phosphorylase a activity was measured in hepatocytes from fed rats, some of which received ip chlorpropamide injections for 5 days preceding death (20 mg/100 g BW X day for 5 days). Chlorpropamide treatment significantly depressed basal phosphorylase a activity and lessened the increments in the activity of this enzyme induced by 10(-10) -10(-8) M glucagon and arginine vasopressin. The reductions in phosphorylase a activity after treatment with chlorpropamide were more than sufficient to explain the accompanying decreases in hepatic glucose production. Since glucagon and arginine vasopressin stimulate alternate pathways of phosphorylase activation and since chlorpropamide antagonizes both hormones, it is likely that the drug acts at or distal to the intracellular site (phosphorylase kinase) at which the two activation pathways converge.

Augmentation by chlorpropamide of 1-deamino-8-D-arginine vasopressin-induced antidiuresis and stimulation of renal medullary adenylate cyclase and accumulation of adenosine 3',5'-monophosphate.

The effect of chlorpropamide was determined in Brattleboro diabetes insipidus (DI) rats that were injected with 1-deamino-8-D-arginine vasopressin (dDAVP). Chlorpropamide augmented the antidiuretic responses to 0.78 and 1.56 ng dDAVP but not to larger doses. In an effort to explain this observation we investigated the effect of chlorpropamide on renal medullary adenylate cyclase activation by dDAVP and on phosphodiesterase activity. We found that the injection of chlorpropamide increased adenylate cyclase activation by dDAVP added in vitro to renal medullary cell membrane preparations from Brattleboro DI rats but had no effect on phosphodiesterase activity. When kidneys from Brattleboro DI rats, treated and not treated with chlorpropamide, were perfused in vitro, we found that 10(-4) M dDAVP increased the concentration of cAMP in comparison to untreated and chlorpropamide-treated groups, and that chlorpropamide plus dDAVP resulted in a greater concentration of renal cAMP than was found with dDAVP alone. We believe that treatment with chlorpropamide increases dDAVP-stimulated renal medullary adenylate cyclase activity without altering phosphodiesterase activity and that this leads to increased renal cAMP concentrations. This, in turn, causes an augmented antidiuresis in response to dDAVP.

Further studies on the mechanism by which chlorpropamide alters the action of vasopressin.

The injection of chlorpropamide into Brattleboro homozygous rats (di/di) has previously been shown to result in enhanced activation of renal medullary adenylate cyclase activity and increased renal medullary content of cAMP in response to 1-desamino-8-D-arginine vasopressin (dDAVP). In contrast, in vivo chlorpropamide did not alter GTP, guanylylimidodiphosphate, or fluoride-stimulated adenylate cyclase activities in these renal membranes. We have now found that the effect of in vivo chlorpropamide in enhancing dDVAP-stimulated adenylate cyclase activity involves lowering the Km for ATP. We have also found that dDAVP increases urinary prostaglandin E2 (PGE2) excretion, and treatment with chlorpropamide causes an even greater PGE2 response to dDAVP. In contrast, in vivo chlorpropamide treatment did not increase vascular responses to arginine vasopressin (AVP) in the perfused kidney preparation and, in fact, inhibited the AVP-induced decrease in the glomerular filtration rate. Chlorpropamide, therefore, enhances the renal responses to dDAVP in terms of the cAMP and PG systems, while not increasing responses to postreceptor stimuli of the adenylate cyclase system or vascular responses to AVP. These observations support the concept that in vivo chlorpropamide acts at the receptor of the vasopressin-sensitive part of the tubule to augment responsiveness to vasopressin. In addition, in vivo chlorpropamide may inhibit certain vascular responses to AVP.

Albright's osteodystrophy in a patient with renal hypercalciuria.

We have investigated an 18-yr-old hypercalciuric female with features of both renal hypercalciuria and pseudohypoparathyroidism. She had increased circulating parathyroid hormone levels, which are common to both diseases. She also had a modest hypocalcemia and low normal basal cAMP excretion, both of which are more likely to occur in pseudohypoparathyroidism. She also had Albright's osteodystrophy, which is frequent in patients with pseudohypoparathyroidism and has never been reported in patients with renal hypercalciuria. In contrast to patients with pseudohypoparathyroidism, her serum 1,25-dihydroxycholecalciferol level was increased and her renal responses to parathyroid hormone infusion, including renal calcium reabsorption, were normal. This patient, therefore, raises the possibility that some patients with renal hyperalciuria may have a forme fruste of pseudohypoparathyroidism.

Marked hypotonic polyuria resulting from nephrogenic diabetes insipidus with partial sensitivity to vasopressin.

We studied two women with severe hypotonic polyuria whose symptoms dated from infancy. We eliminated the possibility of central diabetes insipidus (DI) and primary polydipsia, and established the presence of nephrogenic DI on the basis of: 1) the interrelationships between plasma osmolality, urine osmolality, and urinary AVP; and 2) impaired antidiuretic responses to AVP and 1 deamino-8-D-arginine vasopressin. Though 25-50 times as resistant to 1 deamino-8-D-arginine vasopressin nasal spray as patients with central DI, these patients could be treated effectively with large doses of the nasal spray. One patient has been so treated for more than a year with dramatic improvement in her polydipsia, polyuria, and sense of well-being.

Proposed cause of marked vasopressin resistance in a female with an X-linked recessive V2 receptor abnormality.

Almost all cases of congenital nephrogenic diabetes insipidus (NDI) are transmitted in an X-linked recessive manner by an asymptomatic carrier female to her affected son. Severe symptomatic NDI has not previously been reported in a female with X-linked recessive NDI. Each of the three members of this family has an abnormal V2 receptor gene, which results in truncation of the V2 receptor beginning at arginine-337. This prematurely terminates the receptor at the carboxy-terminal tail and very likely disrupts receptor function. The son has an abnormal V2 receptor gene on his X-chromosome, whereas the mother and daughter have one normal and one abnormal gene for the V2 receptor. The infusion of desmopressin into the mother and son reveals a total lack of antidiuretic response, whereas the daughter increases urinary osmolality normally. The plasma factor VIII concentration after the infusion of desmopressin in the son does not rise, whereas the mother and daughter have half of the normal factor VIII response, similar to asymptomatic female carriers of NDI. These responses to desmopressin in daughter and son are those of a typical carrier female and male affected with NDI. In contrast, the mother acts as an NDI patient when the urine concentration is measured, but acts as a carrier in terms of the factor VIII response to desmopressin. We postulate that the renal tubular cells of the mother demonstrate extreme lyonization of X-chromosome inactivation, whereas in the tissue that subserves the hematological response to desmopressin, X-chromosome inactivation followed a more typically random distribution.

Effects of sodium intake, furosemide, and infusion of atrial natriuretic peptide on the urinary and metabolic clearances of arginine vasopressin in normal subjects.

Arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) have important influences on water and electrolyte metabolism, and studies on the interactions between these hormones may have important implications. We have investigated the effects of sodium intake, furosemide, and infusion of ANP on the urinary and metabolic (nonurinary) clearances of AVP in hydrated normal subjects. On a high sodium diet there was an increase in urine volume, sodium excretion, osmolal clearance, plasma ANP concentration, and urinary clearance and fractional excretion of AVP, with a decrease in PRA. The infusion of furosemide increased urine volume, sodium excretion, osmolal clearance, and PRA, but decreased circulating ANP levels and urinary clearance and fractional excretion of AVP. Since there was a positive correlation between circulating ANP and urinary clearance of AVP in these experiments, we infused human alpha ANP in physiological amounts and found increases in the urinary and metabolic (nonurinary) clearances of AVP. The changes in urinary clearance of AVP in all three experiments occurred even in relation to creatinine clearance. These observations demonstrate that urinary clearance of AVP does not correlate with urine volume, sodium or solute excretion, or PRA. The observations support a physiological role for ANP in modulating the renal action of AVP, probably at the level of the renal tubules, and indicate a need for caution when using plasma or urinary AVP as an indicator of AVP release from the neurohypophysis.

Two distinct pathophysiological mechanisms in congenital nephrogenic diabetes insipidus.

V1 and V2 vasopressin receptor functions were studied in 2 patients with congenital nephrogenic diabetes insipidus. V1 receptor-mediated functions (increase in urinary prostaglandin E2 excretion and plasma cortisol levels) and Gs (guanine nucleotide-binding stimulatory protein) activity of erythrocyte membranes were normal in both patients. After infusion of 0.4 micrograms/kg dDAVP, a 57-yr-old male patient had no increase in plasma factor VIII coagulant, ristocetin cofactor, or fibrinolytic activity or change in von Willebrand factor multimers. In addition, he had no vasodilatory response to dDAVP, a response that occurs in normal subjects and patients with central diabetes insipidus. In contrast, a 25-yr-old female patient had normal hemostatic and vasodilatory responses to the infusion of dDAVP. These observations indicate that the cellular abnormalities in patients with congenital nephrogenic diabetes insipidus may be either at the V2 receptor or in the postreceptor (and Gs activity) cascade of events that mediate vasopressin-induced antidiuresis. Therefore, heterogeneity exists in the biochemical cause(s) of congenital nephrogenic diabetes insipidus in man.

Antidiuretic responses to injected desmopressin, alone and with indomethacin.

Desmopressin (dDAVP) is a synthetic analog of arginine vasopressin which generally has been very effective, used intranasally, in the treatment of diabetes insipidus. There are several clinical situations, however, where a parenteral route of administration would be preferable. Using 6 patients with diabetes insipidus, we have shown a dose-response relationship between 0.5 and 4 microgram of dDAVP injected sc. The nonsteroidal, antiinflammatory agent, indomethacin, augments the magnitude, but not the duration, of the response to 0.5 microgram dDAVP. These observations suggest that injected dDAVP, generally in the amount of 1 or 2 microgram, would be a valuable agent in the treatment of diabetes insipidus and that combined therapy with indomethacin is probably not warranted.

Evidence for bone remodeling but lack of calcium mobilization response to parathyroid hormone in pseudohypoparathyroidism.

Twenty-eight patients with hypoparathyroidism were classified into PTH-deficient (HP; n = 14) or PTH-resistant [pseudohypoparathyroid (PHP); n = 14] groups on the basis of serum PTH level and urinary cAMP response to PTH infusion. Bone density (BD; bone mineral content/bone width) was determined by 125I photon absorptiometry in the distal third of the radius of each patient. After 3 days of equilibration on a constant diet, fasting serum Ca, 1,25-dihydroxyvitamin D [1,25-(OH)2D] and 24-h urinary hydroxyproline (OHP) were measured during 4 control days and 4 treatment days [Lilly Parathyroid Extract (PTE); 100 U, im, every 6 h]. In HP, the mean BD was 0.772 +/- 0.016 (+/- SE) g/cm2, which was similar to the value obtained in a normal control group matched for age, sex, and race. In PHP, the mean BD was 0.633 +/- 0.017 g/cm2, which was 15 +/- 2% less than the normal value (P less than 0.005). Diminished BD was present in all patients with PHP, even in the absence of radiographic changes. Mean basal OHP excretion in PHP was more than twice that in HP (34.9 +/- 5.5 vs. 13.8 +/- 1.3 mg/day; P less than 0.005). Both groups had significant and comparable increases in urinary OHP excretion in response to PTE (9.1 +/- 2.1 mg/day for HP; 8.1 +/- 2.2 mg/day for PHP; P less than 0.005 for each). However, unlike the patients with HP, those with PHP did not have increases in serum 1,25-(OH)2D or a normal calcemic response to PTE. Thus, the bone-remodeling response to PTH remains intact in the majority of patients with PHP, but the mineral mobilization response, which may require 1,25-(OH)2D, is defective.

Altered osmotic threshold for vasopressin release and impaired thirst sensation: additional abnormalities in Kallmann's syndrome.

Seven subjects with Kallmann's syndrome were studied to determine whether they had disturbances of fluid homeostasis. Simultaneous measurements of urine and plasma osmolality (Uosm and Posm, respectively) were made during free access to fluids. The Uosm-Posm relationship was abnormal in five patients on at least one occasion. Patient 2 was frequently overhydrated (Posm less than or equal to 280 mosmol/kg) and patient 5 excreted a dilute urine when his Posm was 290 mosmol/kg. The three subjects (1, 5, and 7) tending to have an increased Psom (greater than or equal to 300 mosmol/kg) were able to concentrate their urine (Uosm greater than 800 mosmol/kg) and denied polyuria and polydipsia. Their elevated Posms could be explained by impairment of thirst, rather than increased excretion of water, because the patients concentrated their urines at normal Posms during fluid deprivation. The osmotic threshold for vasopressin release was decreased (Posm = 270.6 mosmol/kg) in one patient and increased (Posm greater than or equal to 295 mosmol/kg) in two others of the seven patients. The elevated osmotic threshold was not due to chronic hyperosmolality or a generalized defect in vasopressin secretion. In the patient with the highest osmotic threshold (Posm = 296 mosmol/kg) and Posms between 289--301 mosmol/kg during free access to fluid, the osmotic threshold decreased to only 293 mosmol/kg after 6 weeks of adequate hydration and desmopressin acetate. However, in response to hypotension induced by trimethaphan, he increased his plasma vasopressin from 1--26 microU/ml. In conclusion, some patients with Kallmann's syndrome may have osmoreceptor dysfunction and abnormal thirst regulation, indicating more extensive hypothalamic involvement than previously appreciated.

Evidence for normal antidiuretic responses to endogenous and exogenous arginine vasopressin in patients with guanine nucleotide-binding stimulatory protein-deficient pseudohypoparathyroidism.

In six patients with pseudohypoparathyroidism (PHP) who were deficient in guanine nucleotide-binding stimulatory protein (Ns) activity, the response to endogenous arginine vasopressin (AVP) was tested during water deprivation. Hourly plasma osmolality (Posm), urinary osmolality (Uosm), and urinary AVP (UAVP) values were compared to those in normal subjects. The Uosm vs. Posm and the UAVP vs. Uosm relationships of the patients were all within the normal range. Four patients with Ns-deficient PHP were subjected to maintained water loads and infused with AVP at three different rates for 1 h each to assess their responses to exogenous AVP. Urinary volume and osmolality values from the final 30 min of each infusion rate were measured. All volume values except 1 were within 1.6 SD of normal, and all osmolality values except 1 were within 1.1 SD of normal. In conclusion, these studies indicate that these six patients with Ns-deficient PHP are not resistant to the antidiuretic (cAMP-mediated) action of endogenous or exogenous AVP, in contrast to the previously documented resistance of patients with Ns-deficient PHP to the actions of PTH, TSH, glucagon, and gonadotropins.

Reproductive dysfunction in women with Albright's hereditary osteodystrophy.

Most individuals with Albright's hereditary osteodystrophy (AHO) have deficient expression or function of G(s alpha), the alpha subunit of the guanine nucleotide binding protein that stimulates adenylyl cyclase, and are resistant to parathyroid hormone (PTH) and other hormones that act via stimulation of adenylyl cyclase. To determine the incidence and etiology of ovarian dysfunction in women with AHO, we examined the reproductive history and hypothalamic-pituitary-ovarian axis in 17 affected women aged 17-43 yr. All patients had typical PTH resistance and an approximately 50% reduction in erythrocyte G(s alpha) activity, (0.43 +/- 0.03 vs. 0.92 +/- 0.08 for normal control subjects, P < 0.001). Fourteen of the 17 patients (76%) were oligomenorrheic or amenorrheic, more than half had delayed or incomplete sexual development, and only two had a history of earlier pregnancy. Most women were mildly hypoestrogenic, with normal to slightly elevated serum gonadotropin levels. Computer analysis of 24 hour LH measurement showed that the frequency of LH peaks/24 h in AHO women varied widely, but as a group they were not statistically different from a group of normal women studied in the early follicular phase. Administration of 100 microg synthetic GnRH produced normal FSH and LH responses. We conclude that reproductive dysfunction is common in women with AHO and probably represents partial resistance to gonadotropins.

Renal responses to PTH in patients with hormone-resistant (pseudo) hypoparathyroidism.

Five patients with pseudohypoparathyroidism were compared to normal subjects and patients with hypoparathyroidism in their ability to respond to the infusion of parathyroid hormone (PTH) by altering excretion of calcium, sodium, potassium, phosphate and bicarbonate. In patients with pseudohypoparathyroidism, impairment in renal responses to PTH was more generalized than has been recognized. The patterns of response varied from patient to patient. The most commonly observed abnormality, aside from lack of increase in urinary cyclic adenosine 5'-monophosphate (AMP) was failure to decrease the calcium to sodium clearance ratio, and indication of impaired renal calcium reabsorption. The responses which most closely approximated normal, including a normal decrease in the calcium to sodium clearance ratio, occurred in a patient (Case 1) who had the largest, although impaired, response in cyclic AMP excretion. Conversely, the most abnormal responses occurred in three patients (Cases 2, 4 and 5) who had the smallest increases in cyclic AMP excretion after the administration of PTH. The impaired renal reabsorption of calcium after the administration of PTH (lack of decrease in calcium to sodium clearance ratio) may, when present, be in part responsible for hypocalcemia.

Fulminating hypercalcemia and markedly increased nephrogenous cyclic AMP in a patient with transitional cell carcinoma of the bladder.

Refractory hypercalcemia developed suddenly in a patient who had undergone a radical cystectomy for an anaplastic transitional cell carcinoma of the bladder. A normal serum parathyroid hormone (PTH) value was obtained by immunoassay while the patient had hypercalcemia and unimpaired renal function. This normal PTH value in the presence of hypercalcemia was consistent with his hypercalcemia being secondary to excessive amounts of circulating PTH. The finding of increased nephrogenous cyclic AMP, however, provided the definitive diagnosis of hyyperparathyroidism. Since autopsy revealed that there was no residual tumor in the bladder area, only evidence of metastatic disease, and since the parathyroid glands were not hyperplastic or adenomatous, we attributed this patient's hypercalcemia to hyperparathyroidism due to the ectopic production of PTH by a metastasis from the transitional cell carcinoma of the bladder.