Insulin-induced hypoglycemia suppresses plasma parathyroid hormone levels in patients with adrenal insufficiency.

Hypoglycemia has been reported to cause suppression of parathyroid hormone (PTH) levels in serum in normal subjects. It is possible that increasing cortisol levels in response to hypoglycemia was responsible. To examine this possibility the acute PTH response to insulin administration and resulting hypoglycemia was examined in patients with adrenal insufficiency. The possible acute impact of insulin-induced hypoglycemia on bone formation and bone resorption in the absence of an endogenous cortisol response was also examined. A prospective open study was undertaken to examine the acute effects of insulin and resulting hypoglycemia on PTH levels, on bone formation as indicated by serum levels of aminoterminal propeptide of type 1 procollagen (PINP), and on bone resorption as indicated by serum levels of beta carboxy terminal telopeptide of type 1 collagen (beta-CTx). Seven patients with adrenal insufficiency participated. These patients were studied on 3 occasions under different conditions: (1) when insulin was administered to induce hypoglycemia while the patients received their routine glucocorticoid replacement; (2) when the patients received their routine glucocorticoid replacement, but were not rendered hypoglycemic; and (3) when they did not receive glucocorticoid replacement and were not rendered hypoglycemic, ie, untreated. This facilitated isolation of the PTH response to insulin and hypoglycemia from the effects of the normal increase in endogenous cortisol levels in response to hypoglycemia. Blood samples were taken at baseline and after 3 hours while the subjects continued fasting for measurement of plasma glucose, serum ionized calcium (Cai), magnesium, phosphate, PINP, PTH, and beta-CTx. Insulin 0.075 IU/kg body weight was given intravenously after the first blood sample. The usual morning glucocorticoid replacement dose was given 20 minutes after the baseline blood sample was obtained. After the administration of insulin, plasma glucose decreased from 4.8 +/- 0.5 to 2.7 +/- 0.5 mmol/L, mean +/- SD (P < .0001). PTH was not influenced by time or glucocorticoid treatment, but decreased in response to insulin-induced hypoglycemia (P < .05). Serum levels of PINP and beta-CTx decreased when untreated between 9 AM and 12 PM (P < .05), but were not independently influenced by insulin-induced hypoglycemia or glucocorticoid treatment. Serum levels of Cai increased and serum phosphate levels decreased in response to insulin-induced hypoglycemia, while serum phosphate levels were also independently influenced by time decreasing between 9 AM and 12 PM (P < .05). There was no effect of time, insulin-induced hypoglycemia, or glucocorticoid treatment on serum levels of magnesium. Possible mechanisms involved in the acute decrease in serum PTH observed include a direct effect of insulin or hypoglycemia or an indirect effect, eg, increased sympathomimetic activity on PTH secretion or on calcium or phosphate intercompartmental shifts.

The impact of different glucocorticoid replacement schedules on bone turnover and insulin sensitivity in patients with adrenal insufficiency.

OBJECTIVE: Optimization of physiological replacement of glucocorticoid in patients with adrenal insufficiency is controversial. The present study was undertaken to compare the relative impact of three different regimes of glucocorticoid replacement in patients with adrenal insufficiency on parameters of bone turnover and insulin sensitivity. PATIENTS: Six female and three male patients with adrenal insufficiency and 17 female and 14 male control subjects participated. DESIGN: This was an open study conducted in a university teaching hospital. Schedule 1 (S1) consisted of hydrocortisone 10 mg with breakfast and 5 mg with lunch. S2 was similar to S1 with the addition of 5 mg hydrocortisone with the evening meal. S3 utilized dexamethasone 0.1 mg/15 kg body weight given per day with breakfast only. Each schedule was given for at least 4 weeks in random sequence to nine patients with adrenal insufficiency. METHODS: Blood was obtained at 0900 h (fasting) and at 1300 h for measurement of the ionized calcium (Cai), PTH, 25-hydroxyvitamin D and the bone formation markers intact osteocalcin and amino-terminal propeptide of type 1 procollagen (PINP). Timed urine collections were made under standardized conditions, that is while fasting between 0700 and 0900 h (basal) and between 0900 and 1300 h for measurement of the bone resorption markers, free deoxypyridinoline (FDPD) and cross-linked N-telopeptide of type 1 collagen (NTX). Blood was drawn for measurement of fasting plasma glucose and serum insulin levels. Insulin (0.075 IU/kg) was administered i.v. while the patient was fasting prior to the first glucocorticoid replacement dose on each study day. Plasma glucose was measured before and 3, 6, 9, 12 and 15 min after insulin administration to calculate the glucose disappearance rate (Kitt). Insulin resistance (IR) and beta-cell function were estimated using the homeostasis model assessment (HOMA). Glucocorticoid dosage was given according to the various schedules at approximately 0930 h. RESULTS: During all three treatment schedules the serum Cai level was significantly lower than that seen in control subjects. PTH levels in patients taking the three replacement schedules and in normal subjects were similar. Serum 25-hydroxyvitamin D levels were not suppressed in the patients during any of the three treatment schedules. The bone resorption marker urinary FDPD under basal conditions was significantly lower during S3 (dexamethasone) than during either hydrocortisone schedules, S1 or S2. Urinary NTX values were not significantly different in the three study groups. The bone formation markers intact osteocalcin and PINP were similar in the three replacement schedules. The indices of IR and beta-cell function tended to be higher during treatment with dexamethasone than with S1 or S2 but did not achieve statistical significance. CONCLUSIONS: These data indicate that all three replacement schedules were associated with low serum ionized calcium levels without evidence of a compensatory increase in PTH levels. These findings are consistent with direct or indirect suppression of the bone remodelling cycle and suppression of PTH levels. Bone turnover in patients with adrenal insufficiency treated with schedule 3, dexamethasone, was associated with lower bone turnover than patients treated with hydrocortisone schedules 1 or 2. While indices of insulin sensitivity measured during schedules 1, 2 and 3 did not achieve statistical significance, there was an obvious trend for greater insulin resistance to occur with schedules 3 using dexamethasone.

Use of the gas exchange threshold to noninvasively determine the lactate threshold in patients with cystic fibrosis.

OBJECTIVE: The anaerobic threshold (AT) is a submaximal index related to endurance exercise performance, which is usually determined by the measurement of blood lactate concentration during an incremental exercise test (lactate threshold [LT]). The LT, and thus the AT, can also be detected noninvasively in normal subjects by means of the gas exchange threshold (GET). This study was undertaken to validate the use of GET in patients with cystic fibrosis (CF) with a wide range of disease severity, and to assess the reproducibility of this index. METHODS: In patients with CF (FEV(1) range, 23 to 118% of predicted) and control subjects, gas exchange was measured breath by breath during the incremental exercise tests to allow determination of the GET. Arterialized-venous blood was sampled for determination of the LT. The GET and LT were determined in a blinded manner. RESULTS: The mean differences (GET - LT) for control subjects (n = 18) and patients with CF (n = 23) were - 40 mL/min and + 10 mL/min, respectively, neither being significantly different from zero. The limits of agreement were +/- 550 mL/min and +/- 410 mL/min, respectively. The mean test-retest differences in GET for control subjects (n = 14) and patients with CF (n = 12) were - 50 mL/min and 0 mL/min, respectively, neither being significantly different from zero; the respective limits of reproducibility were +/- 450 mL/min and +/- 350 mL/min. CONCLUSIONS: This study demonstrates that in patients with CF, the GET can be used to obtain an unbiased estimate of the LT, and that the GET is reproducible.