Beta 2-adrenergic responsiveness in vivo during abdominal surgery

We have studied adrenergic function in vivo during anaesthesia and surgery. Epinephrine 50 ng kg-1 min-1 was given by i.v. infusion over 30 min to 10 healthy adult volunteers and to 10 patients undergoing abdominal operations. The cAMP response to stimulation by epinephrine, which was obtained as the area under the curve (AUC) for plasma cAMP concentration divided by the AUC for plasma concentration of epinephrine, was more pronounced during surgery (mean ratio 3.5) than in the control situation (ratio 1.4; P < 0.02). This resulted in greater hypokalaemic and hyperglycaemic responses (ratios -0.67 and 4.5) than in the control group (ratios -0.33 and 1.6, respectively; P < 0.004). Mean arterial pressure decreased in the control group while it increased in the study group, and serum cortisol concentration was higher in those who underwent surgery (P < 0.02). These results are consistent with an increased adrenergic response during abdominal surgery.      

Acid-base homeostasis during chronic PTH excess in humans

The chronic renal and systemic acid-base effects of hyperparathyroidism in humans remain controversial and unresolved. The present studies evaluated the acid-base response of normal human subjects to a 13-day intravenous infusion of synthetic b(1-34) PTH sufficient to result in sustained hypercalcemia and hypophosphatemia. The acid-base response was biphasic: an initial transient renal acidosis developed on the first day of PTH infusion, followed by a prompt increase in net acid excretion and plasma [HCO3-] of sufficient magnitude to result in a steady state of mild metabolic alkalosis. The results indicate that: 1) sustained, continuous, experimentally produced hyperparathyroidism results in a steady state of mild metabolic alkalosis; 2) the alkalosis is both generated and maintained, at least in part, by renal mechanisms; and 3) reported renal acidosis in sustained clinical conditions of primary hyperparathyroidism is not attributable to either direct or indirect effects of PTH excess when present for a 2-week period, an interval sufficient to re-establish a new steady state of renal and systemic acid-base equilibrium.     

Alpha 1-adrenergic blockade raises epinephrine-arrhythmia threshold in halothane-anesthetized dogs in a dose-dependent fashion

The authors determined whether increasing alpha 1-adrenergic blockade resulted in progressively less arrhythmic activity in the canine halothane-epinephrine arrhythmia model. Dogs (n = 7) were anesthetized with halothane (1.5%) in oxygen. Stepwise increases in steady-state plasma levels of either of two alpha 1-adrenoceptor antagonists (droperidol, doxazosin) were produced by applying Wagnerian principles to the known pharmacokinetic parameters of these drugs. At each steady state plasma level of these antagonists, the extent of the alpha 1-adrenergic blockade produced was assessed by defining a phenylephrine (PE) dose pressor response curve. The degree of alpha 1-blockade produced was quantitated as the dose of PE that caused a 25-mmHg increase in mean arterial pressure (ED25) as derived by polynomial regression analysis. By analysis of variance (ANOVA) the ED25 increased significantly for each targeted steady state plasma level of either droperidol (P less than 0.001) or doxazosin (P less than 0.001). For an assessment of the antiarrhythmic activity of these alpha 1-antagonists, the arrhythmogenic dose of epinephrine (ADE) was determined at each of the states of alpha 1-adrenergic blockade previously defined. By ANOVA there was a significant increase in the ADE over the range of alpha blockade produced for either droperidol (P less than 0.001) or doxazosin (P less than 0.001). A close correlation (r2) existed between the ED25 and the ADE for the target steady state levels that were achieved for either droperidol (0.99) or doxazosin (0.74).(ABSTRACT TRUNCATED AT 250 WORDS)     

Nonselective Beta-adrenergic blockade augments fasting hyperkalemia in hemodialysis patients

BACKGROUND/AIM: Fasting hyperkalemia in patients with end-stage renal failure is a well-documented phenomenon. Both a decreased secretion of insulin and decreased beta-adrenergic receptor sensitivity may take part in this effect. METHODS: Twelve anuric, long-term (6.4 +/- 2.7 years; mean +/- SD) hemodialysis patients underwent three periods of 18-hour fasting (from 6 p.m. to 12 a.m.). At the beginning of each fasting period a single dose of the nonselective beta-blocker, nadolol (80 mg), or the beta(1)-selective blocker, betaxolol (20 mg), or placebo were given in a random order and in blinded fashion. The wash-out period was 7 days. RESULTS: The mean decrease in blood pressure was similar after nadolol and betaxolol (18 +/- 10 vs. 19 +/- 11 mm Hg) as was a decrease in heart rate (20 +/- 3 and 19 +/- 6, respectively). Serum potassium was not different before each of the fasting periods. The increase in serum potassium during fasting was highly significant in each case. The mean increase in serum potassium was 1.2 +/- 0.4 mmol/l after nadolol, 0.9 +/- 0.6 after betaxolol and 0.6 +/- 0.6 after placebo. This effect was significantly larger after nadolol than after placebo (p = 0.01), but this relation was not significant with respect to betaxolol (p = 0.30). Serum insulin as well as glucose decreased significantly and to a similar extent during each fasting period. Plasma aldosterone was unchanged. CONCLUSION: Nonselective beta-adrenergic blockade increases the hyperkalemic effect of fasting in hemodialysis patients.     

Dynamics of PTH secretion in hemodialysis patients as determined by the intact and whole PTH assays

BACKGROUND: Renal hyperparathyroidism is assessed by measurement of parathyroid hormone (PTH) levels. The intact PTH assay (I-PTH) not only reacts with 1-84 PTH but also with large, truncated fragments of non-1-84 PTH. Because the whole PTH assay (W-PTH) is specific for 1-84 PTH, non-1-84 PTH is determined by subtracting W-PTH from I-PTH values. These large circulating PTH fragments may exert a hypocalcemic effect by contributing to skeletal resistance to 1-84 PTH. METHODS: The dynamic secretion of both 1-84 PTH and non-1-84 PTH was evaluated during the induction of hypo- and hypercalcemia in eight hemodialysis patients. RESULTS: The basal ionized calcium concentration was 1.23 +/- 0.03 mmol/L at which time I-PTH, W-PTH, and non-1-84 PTH values were 276 +/- 78 pg/mL, 164 +/- 48 pg/mL, and 102 +/- 28 pg/mL, respectively. The induction of hypo- and hypercalcemic changes resulted in a sigmoidal response for all three PTH moieties, I-PTH, W-PTH, and non-1-84 PTH. During hypocalcemia, maximal values of W-PTH were greater than those of non-1-84 PTH. But during hypercalcemia, minimal values of W-PTH and non-1-84 PTH were similar. Neither the set points nor the basal/maximal ratios for W-PTH, I-PTH, and non-1-84 PTH were different. At the baseline ionized calcium concentration, the W-PTH (1-84 PTH)/non-1-84 PTH ratio was 1.53 +/- 0.15. Changes in ionized calcium resulted in a sigmoidal relationship with hypocalcemia, increasing this ratio to a maximum of 2.01 +/- 0.30 and hypercalcemia decreasing this ratio to a minimum of 1.18 +/- 0.15 (P < 0.01 vs baseline for both hypo- and hypercalcemia). CONCLUSION: Although acute changes in serum calcium produce similar secretory responses in 1-84 PTH and non-1-84 PTH, the secretory responses are not proportional for these PTH moieties. Changes in the serum calcium concentration modulate the ratio of 1-84 PTH/non-1-84 PTH in a sigmoidal pattern with hypocalcemia maximizing this ratio. Whether changes in the 1-84 PTH/non-1-84 PTH ratio specifically modulate the calcemic action and other biologic effects of 1-84 PTH remain to be determined.     

Intraoperative and postoperative PTH secretion mode in patients with hyperparathyroidism

The development of a sensitive 2-site immunoradiometric assay which detects only intact human PTH (1–84) enabled us to study kinetics of PTH secretion intraoperatively. In a prospective study, we assessed the PTH (1–84) secretion mode intraoperatively in 54 patients with adenomas, in 14 patients with tertiary hyperparathyroidism (HPT), and in 2 patients with persistent HPT. After the removal of adenomatous or hyperplastic tissue, a significant drop of PTH (1–84) concentration was seen. A 50% decrease in the basal PTH concentration was reached significantly earlier for adenomas than for hyperplasias. In the 2 cases with unrevealing neck exploration, the PTH (1–84) concentrations showed hardly any change. The recovery of PTH secretion was studied in 23 patients, 20 of whom had a single adenoma; in 2 cases, a hyperplasia was present and 1 patient showed the clinical signs of a toxic HPT. We found an initial drop of PTH concentration 4 hours postoperatively below the limit of detection and a rapid recovery within 24 hours postoperatively. The PTH concentration values were well within the normal range after 48–72 hours.

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Resumen El desarrollo de una muy sensible determinación inmunoradiométrica capaz de detectar exclusivamente la HPT (1–84) humana nos ha permitido realizar un estudio de la cinética de la secreción intraoperatoria de hormona paratiroidea (PTH). En un estudio prospectivo hemos hecho la determinación del modo de secreción de PTH (1–84) en 54 pacientes con adenomas, en 14 con hiperparatiroidismo terciario, y en 2 con hiperparatiroidismo persistente. Una vez resecado el tejido adenomatoso o hiperplásico, se observó un descenso significativo de la concentración sérica de PTH (1–84). Un descenso de 50% en el nivel de la concentración basal de PTH apareció, en forma significativa, más precozmente en los adenomas que en las hiperplasias. En los 2 casos con exploración cervical negativa, la concentración de PTH (1–84) prácticamente no exhibió modificación. La recuperación de la secreción de PTH fue estudiada en 23 pacientes, 20 de los cuales tenían adenoma único, 2 hiperplasia y 1 exhibía signos clínicos de hiperparatiroidismo tóxico. Encontramos un descenso inicial de la concentración de PTH a valores por debajo del nivel de detección a las 4 horas postoperatorias y una recuperación rápida dentro de las primeras 24 horas. Las concentraciones de PTH regresaron a valores normales a las 48–72 horas.

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Résumé Le perfectionnement d'un dosage immunoradiométrique à 2 sites, sensible, qui ne détecte que la parathormone humaine intacte (PTH 1–84) a permis d'étudier les cinétiques de la sécrétion peropératoire de ia PTH. Dans une étude prospective, nous avons évalué la sécrétion peropératoire de PTH 1–84 chez 54 patients ayant un adénome, chez 14 patients ayant une hyperparathyroïdie tertiaire (HPT), et chez 2 patients ayant une HPT persistante. On a observé une chute significative de PTH 1–84 après l'ablation de tissus athéromateux ou hyperplasiques. La réduction de la sécrétion de base de PTH de 50% était atteinte plus tôt de façon significative pour les adénomes que pour les hyperplasies. Dans les 2 cas où l'exploration cervicale était négative, les concentrations en PTH 1–84 sont restées pratiquement inchangées. La reprise de la sécrétion en PTH a été étudiée chez 23 patients, dont 20 avaient un adénome solitaire; dans 2 cas, on a découvert une hyperplasie, et chez 1 patient, il y avait des signes cliniques de HPT toxique. La chute initiale de PTH 4 heures après l'opération n'était pas sensible et la reprise était rapide, moins de 24 heures après l'intervention. La PTH était dans les limites de la normale après 48–72 heures.

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Presented at the International Association of Endocrine Surgeons in Toronto, Ontario, Canada, September, 1989.     

Effects of endothelin-1 and endothelin-1-receptor blockade on renal function in humans.

BACKGROUND: In patients with renal or cardiac failure, renal function may be endangered by elevated plasma concentrations of the vasoconstrictor endothelin-1 (ET-1). To mimic effects of pathologically increased plasma ET-1, we gave intravenous ET-1 in healthy subjects and examined whether simultaneous infusion of the ETA-receptor antagonist VML 588 would prevent the effects of ET-1 on the kidney. METHODS: Nine healthy men received on four separate days intravenous infusion of ET-1 (2.5 ng/kg/min) superimposed on vehicle (saline) or on VML 588 infusion (0.05, 0.20 and 0.40 mg/kg/h) in randomized order to assess the effects on renal function and renal haemodynamics. RESULTS: At resting plasma ET-1, infusion of VML 588 alone had no significant effects on renal function. Infusion of ET-1 alone decreased glomerular filtration rate by 11% and this reduction was not reversed by co-infusion of VML 588. ET-1 reduced renal blood flow by 35% and VML 588 reduced this decrease by one-third, in a dose-independent fashion. ET-1 increased the filtration fraction by 34% and VML 588 reduced this increase dose-independently by one-half. ET-1 increased renal vascular resistance by 59% and VML 588 reduced this increase dose-independently by one-half. Finally, ET-1 decreased sodium excretion by 58% and VML 588 reduced this decrease dose-independently by two-thirds. CONCLUSIONS: ET-1-induced reductions in renal function were partially but not completely prevented in a dose-independent manner by the ETA-receptor antagonist VML 588.     

Action of vitamin D metabolites on PTH secretion in man

We have examined the effects of metabolites of vitamin D [25OHD3, 1,25(OH)2D3, 24,25(OH)2D3, and 25,26(OH)2D3] on serum calcium and iPTH in human deficient-D osteomalacia. The four metabolites decreased iPTH, but only for 1,25(OH)2D3 was a significant correlation between increase of serum calcium and decrease of iPTH observed. The 24,25(OH)2D3 and 25,26(OH)2D3 decreased iPTH despite a decrease of serum calcium at the beginning of treatment. The 25OHD decreased iPTH before increased serum calcium. These results could be interpreted as a direct effect of metabolites of vitamin D on PTH secretion. However, the conversion of other metabolites and the calcium concentration in parathyroid cells must be determined before this hypothesis can be accepted.     

Action of vitamin D metabolites on PTH secretion in man

Summary We have examined the effects of metabolites of vitamin D [25OHD₃, 1,25(OH)₂D₃, 24,25(OH)₂D₃, and 25,26(OH)₂D₃] on serum calcium and iPTH in human deficient-D osteomalacia. The four metabolites decreased iPTH, but only for 1,25(OH)₂D₃ was a significant correlation between increase of serum calcium and decrease of iPTH observed. The 24,25(OH)₂D₃ and 25,26(OH)₂D₃ decreased iPTH despite a decrease of serum calcium at the beginning of treatment. The 25OHD decreased iPTH before increased serum calcium. These results could be interpreted as a direct effect of metabolites of vitamin D on PTH secretion. However, the conversion of other metabolites and the calcium concentration in parathyroid cells must be determined before this hypothesis can be accepted.     

ZP2307, a novel, cyclic PTH(1-17) analog that augments bone mass in ovariectomized rats

Daily injections of human parathyroid hormone (1-34), hPTH(1-34), provide a highly effective treatment option for severe osteoporosis. However, PTH analogs shorter than 28 amino acids do not retain any bone augmenting potential. Here, we present ZP2307 ([Ac₅c¹, Aib³, Leu⁸, Gln¹⁰, Har¹¹, Ala¹², Trp¹⁴, Asp¹⁷]PTH(1-17)-NH₂), a novel, chemically modified and cyclized hPTH(1-17) analog, that augments bone mass in ovariectomized, osteopenic rats. Subcutaneous administration of this structurally constrained, K¹³-D¹⁷ side-chain-to-side-chain cyclized peptide reversed bone loss and increased bone mineral density (BMD) up to or above baseline levels in rat long bones and vertebrae. Highly significant effects of ZP2307 were achieved at doses of 40–320 nmol/kg. Micro-CT and histomorphometric analyses showed that ZP2307 improved quantitative and qualitative parameters of bone structure. Biomechanical testing of rat femora confirmed that ZP2307 dramatically increased bone strength. Over a broad maximally effective dose range (40–160 nmol/kg) ZP2307 did not increase serum concentrations of ionized free calcium above normal levels. Only at the highest dose (320 nmol/kg) ZP2307 induced hypercalcemic calcium levels in the ovariectomized rats.To our knowledge ZP2307 is the smallest PTH peptide analog known to exert augmentation of bone. Our findings suggest that ZP2307 has the potential to effectively augment bone mass over a broad dose range without a concomitant increase in the serum concentration of ionized free calcium above the normal range.     

Nitrous oxide potentiates vecuronium neuromuscular blockade in humans

This study was designed to measure the potency of vecuronium with and without nitrous oxide. Anaesthesia was induced with thiopentone and fentanyl in 56 adult patients. The subjects were randomly assigned to receive nitrous oxide, 70%, or intermittent boluses of thiopentone and fentanyl for maintenance of anaesthesia. Train-of-four stimulation was applied to the ulnar nerve every 20 sec, and the force of contraction of the adductor pollicis muscle was measured. Vecuronium, 20, 30 or 40 micrograms.kg-1 was given by random allocation five minutes after induction of anaesthesia. Maximum depression of the first response (T1) in the train-of-four was measured, and dose-response curves were constructed. In the absence of nitrous oxide, the ED50 and ED95 were mean +/- standard error of the mean (SEM), 29.2 +/- 1.8 and 59.3 +/- 3.6 micrograms.kg-1, respectively. In the group receiving nitrous oxide, these values were 25.3 +/- 1.2 and 42.3 +/- 2.0 micrograms.kg-1 respectively. By analysis of covariance, the dose-response curves were shown to be shifted with respect to one another (P less than 0.05). Administration of nitrous oxide was associated with a 19.5% increase in potency (95% confidence limits: 1.7 to 40.4%). It is concluded that nitrous oxide has a slight potentiating effect on neuromuscular blockade, and that this effect occurs within five to ten minutes after the beginning of its administration.     

Alterations in the pulsatile properties of gonadotropin secretion in alcoholic men

The functional characteristics of the hypothalamic-pituitary-testicular axis were examined quantitatively in 10 chronic alcoholic men without hepatic dysfunction or clinical nutritional deficiencies. Spontaneous gonadotropin pulsatility was analyzed in blood sampled every 20 minutes over a 24-hour period 3 to 16 days after abstinence from alcohol and again 29 to 39 days later. The numbers of LH and FSH pulses per 24 hours were normal in these alcoholic men compared with controls. However, we found increased mean 24-hour concentrations of immunoactive LH (P = 0.012) and FSH (P = 0.018), increased peak heights for LH (P = 0.035) and FSH (P = 0.004), decreased fractional LH (P = 0.002) and FSH (P = 0.044) pulse amplitudes and increased interpulse valley mean LH (P = 0.010) and FSH (P = 0.018) concentrations. Serum levels of total testosterone, total estradiol and estrone were normal, whereas concentrations of free testosterone and free estradiol were increased. Pituitary release of LH and FSH was normal in response to low (5-micrograms) and high (95-micrograms) doses of GnRH given intravenously. The present observations indicate that in chronically alcoholic men, acute abstinence from ethanol is associated with elevated circulating concentrations of immunoactive gonadotropins in the presence of intact spontaneous gonadotropin pulsatility, preserved pituitary responsiveness to exogenous GnRH, and increased concentrations of free testosterone and free estradiol. Such findings are consistent with alterations in the endogenous feedback actions of sex steroid hormones in this setting.     

Effects of fasting on physiologically pulsatile insulin release in healthy humans

Insulin is released as secretory bursts superimposed on basal release. The overall contribution of secretory bursts was recently quantified as at least 75%, and the main regulation of insulin secretion is through perturbation of the amount of insulin released and the frequency of these secretory bursts. The mode of delivery of insulin into the circulation seems important for insulin action, and therefore physiological conditions that alter the pattern of insulin release may affect insulin action through this mechanism. To assess the mechanisms by which fasting changes the amount of insulin released and the frequency, amplitude, and overall contribution of pulsatile insulin secretion, we used a validated deconvolution model to examine pulsatile insulin secretion during 10 and 58 h of fasting in seven healthy subjects. The subjects were studied for 75 min before (0-75 min) and 75 min during (115-190 min) a glucose infusion (2.5 mg.kg(-1).min(-1)). We found that the pulsatile insulin release pattern was preserved and that, at fasting, overall insulin release is adjusted to needs by a reduced amount of insulin released (10.1 +/- 1.7 vs. 16.0 +/- 3.2 pmol/l/pulse, P < 0.05) but similar frequency (6.3 +/- 0.4 vs. 6.1 +/- 0.4 min/pulse) of the insulin secretory bursts. In both states, glucose infusion caused an increase (P < 0.05) in amount (100-200%) and frequency (approximately 20%). The impact of increased glucose concentration on pulse frequency seems distinct for in vivo versus in vitro pulsatile insulin secretion and may indicate the presence of a glucose-sensitive pacemaker, which initiates the coordinated secretory bursts. Increased insulin/C-peptide ratio at long-term fasting (6.0 vs. 9.1%, P < 0.01) indicates that the changes in insulin release patterns may be accompanied by changes in hepatic insulin extraction.     

Circulating 1-84 PTH and large C-terminal PTH fragment levels in uremia

Background. The so-called intact parathyroid hormone (iPTH) assay detects large C-terminal PTH fragments that are lacking several N-terminal amino acid residues in addition to 1-84 PTH molecules.Methods. Blood samples were obtained from 65 predialysis patients (male, 35; female, 30) and 109 dialysis patients (male, 73; female, 36). The plasma 1-84 PTH levels were determined by a specific immunoradiometric assay (IRMA).Results. The ratio of 1-84 PTH/iPTH did not show a significant correlation with glomerular filtration rate (GFR) among patients with a GFR of more than 80ml/min, while it showed a positive correlation with GFR among patients with a GFR of less than 80ml/min. The ratio of 1-84 PTH/iPTH demonstrated a significant tendency to decrease in the order of patients with normal renal function (0.928 ± 0.182), those with renal dysfunction (0.836 ± 0.186; P < 0.05 vs patients with GFR > 80ml/min [i.e., normal renal function]), and those with maintenance hemodialysis (0.618 ± 0.123; P < 0.01 vs patients with GFR > 80ml/min). The plasma levels of 1-84 PTH and conventional iPTH showed a close correlation in dialysis patients. Neither 1-84 PTH levels nor secondary parameters calculated from them showed a better correlation with bone metabolic markers than iPTH levels.Conclusions. Circulating large C-terminal PTH fragment levels are increased in uremic patients. However, this noninvasive study failed to demonstrate the superiority of the specific 1-84 assay compared with the conventional iPTH assay to evaluate bone metabolism.     

Opioid receptor blockade prevents exercise-associated autonomic failure in humans

Hypoglycemia and exercise both induce the release of β-endorphin, which plays an important role in the modulation of the autonomic response during subsequent events. Because opioid receptor (OR) blockade during antecedent hypoglycemia has been shown to prevent hypoglycemia-associated autonomic failure, we hypothesized that OR blockade during exercise would prevent exercise-associated autonomic failure (EAAF). We studied 8 healthy subjects on 2 consecutive days, each of whom participated in three different studies in random order. The protocol on day 1 involved one of the following: 1) two 90-min hyperinsulinemic-euglycemic clamps plus naloxone infusion (control); 2) two 90-min hyperinsulinemic-euglycemic clamps with exercise at 60% Vo(2max), plus naloxone infusion (N+); or 3) same protocol as in the N+ group, but with saline infusion only (N-). On day 2, all were studied with stepped hyperinsulinemic-hypoglycemic clamps, using hormone concentrations and glucose turnover as indicators of hypoglycemia counterregulation. Compared with control, N- studies resulted in significantly blunted epinephrine and norepinephrine responses to subsequent hypoglycemia. Conversely, the N+ group exhibited unimpaired hypoglycemia counterregulation, characterized by appropriate increases in epinephrine, norepinephrine, and endogenous glucose production. Thus, OR blockade with naloxone during antecedent exercise prevents the development of acute EAAF by improving the catecholamine responses and by restoring endogenous glucose production.     

Nitrous oxide potentiates succinylcholine neuromuscular blockade in humans.

Sixty ASA physical status I and II adults received 0.3 mg/kg succinylcholine to determine the effect of prolonged administration of thiopental and that of nitrous oxide on succinylcholine neuromuscular blockade. Succinylcholine was administered either 1 min (group 1) or 6 min (groups 2 and 3) after induction of anesthesia with thiopental. In group 2, anesthesia was maintained with thiopental and the patients' lungs were ventilated with oxygen. In group 3, anesthesia was maintained with only 70% nitrous oxide in oxygen. Train-of-four stimulation of the ulnar nerve was started 30 s before the administration of succinylcholine and repeated every 12 s. The force of contraction of the adductor pollicis muscle was measured. Maximum blockade (mean +/- SEM) did not vary significantly between group 1, where thiopental had been administered for 1 min, and group 2, where it had been administered for 6 min (group 1: 61% +/- 6%; group 2: 54% +/- 8%). However, the addition of nitrous oxide increased neuromuscular blockade (group 3: 80% +/- 6%; P less than 0.05 compared with group 2). The degree of twitch augmentation, i.e., greater than maximal response, and times to twitch augmentation and to maximum blockade did not vary significantly among the groups. It is concluded that nitrous oxide increases succinylcholine neuromuscular blockade and that this is manifest within 6 min. This effect is not due to the duration of the anesthetic because thiopental, administered over a similar time period, did not potentiate succinylcholine.     

Gastric bypass surgery enhances glucagon-like peptide 1-stimulated postprandial insulin secretion in humans

OBJECTIVE

Gastric bypass (GB) surgery is associated with postprandial hyperinsulinemia, and this effect is accentuated in postsurgical patients who develop recurrent hypoglycemia. Plasma levels of the incretin glucagon-like peptide 1 (GLP-1) are dramatically increased after GB, suggesting that its action contributes to alteration in postprandial glucose regulation. The aim of this study was to establish the role of GLP-1 on insulin secretion in patients with GB.

RESEARCH DESIGN AND METHODS

Twelve asymptomatic individuals with previous GB (Asym-GB), 10 matched healthy nonoperated control subjects, and 12 patients with recurrent hypoglycemia after GB (Hypo-GB) had pre- and postprandial hormone levels and insulin secretion rates (ISR) measured during a hyperglycemic clamp with either GLP-1 receptor blockade with exendin-(9–39) or saline.

RESULTS

Blocking the action of GLP-1 suppressed postprandial ISR to a larger extent in Asym-GB individuals versus control subjects (33 ± 4 vs.16 ± 5%; P = 0.04). In Hypo-GB patients, GLP-1 accounted for 43 ± 4% of postprandial ISR, which was not significantly higher than that in Asym-GB subjects (P = 0.20). Glucagon was suppressed similarly by hyperglycemia in all groups but rose significantly after the meal in surgical individuals but remained suppressed in nonsurgical subjects. GLP-1 receptor blockade increased postprandial glucagon in both surgical groups.

CONCLUSIONS

Increased GLP-1–stimulated insulin secretion contributes significantly to hyperinsulinism in GB subjects. However, the exaggerated effect of GLP-1 on postprandial insulin secretion in surgical subjects is not significantly different in those with and without recurrent hypoglycemia.Surgery to induce weight loss has become increasingly common (1) as obesity has become pandemic (2). Roux-en-Y gastric bypass (GB), which is associated with substantial and durable weight loss (3), has been reported to cause near complete remission of diabetes within days—before any significant weight loss (4,5). The mechanisms for these metabolic benefits independent of weight loss are still unknown, but it is clear that the insulin response to meal ingestion is exaggerated after surgery (6). Postprandial insulin secretion is augmented by the actions of hormones released from the gastrointestinal (GI) tract, primarily glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (7), and GB subjects have elevated plasma concentrations of GLP-1 (6,8–13). These findings are the basis for a popular but as yet unproven hypothesis that increased GLP-1 secretion is responsible for the improvement in glucose regulation following GB.Moreover, in recent years there have been increasing reports of severe hyperinsulinemic hypoglycemia occurring in patients several years after GB (14,15). Affected individuals have exaggerated insulin and GLP-1 responses to meal consumption compared with asymptomatic individuals with GB (16). These observations raise the question as to whether an amplified GLP-1 effect, either from higher plasma levels or increased sensitivity to the peptide, accounts for the syndrome of post-GB hypoglycemia.In the current study, exendin-(9–39) (Ex-9), a specific GLP-1 receptor (GLP-1r) antagonist (17), was used to test the hypothesis that GB-associated hyperinsulinemia is mediated by increased GLP-1 action and to determine whether enhanced GLP-1 action accounts for greater β-cell stimulation in subjects with postsurgical hypoglycemia.     

Effects of high concentrations of glucose on PTH secretion in parathyroid cells

We examined the effects of high concentrations of glucose on PTH secretion from cultured bovine parathyroid cells. Increasing medium concentration of glucose caused suppression of PTH secretion. A significant suppression of PTH secretion was found within 48 hours of incubation with as little as 15 mM glucose. The addition of choline chloride to the medium did not suppress PTH secretion, although the osmolality was the same as that of the medium containing 50 mM glucose. When cells previously exposed to 50 mM glucose were reincubated in the medium containing 5 mM glucose for another 48 hours, a complete recovery of PTH secretion was observed. In the cells exposed to 50 mM glucose, the magnitude of the response of PTH secretion to 10(-6) M isoproterenol was blunted. Acid-urea gel electrophoresis revealed that the pattern of intact PTH and fragments secreted from cells exposed to high concentration of glucose was similar to that from control cells. Removal of insulin from the medium resulted in a suppression of PTH secretion similar to changes observed with high concentrations of glucose. The suppressive effects of high concentrations of glucose and lack of insulin were additive. However, we cannot exclude from the present studies whether the suppressive effects of the lack of insulin on PTH secretion was secondary to the fact that insulin may be required for the maintenance of parathyroid cells. The present studies demonstrate that glucose directly modulates PTH secretion in primary parathyroid cell culture.     

Ultradian oscillations of insulin secretion in humans

Ultradian rhythmicity appears to be characteristic of several endocrine systems. As described for other hormones, insulin release is a multioscillatory process with rapid pulses of about 10 min and slower ultradian oscillations (50--120 min). The mechanisms underlying the ultradian circhoral oscillations of insulin secretion rate (ISR), which arise in part from a rhythmic amplification of the rapid pulses, are not fully understood. In humans, included in the same period range is the alternation of rapid eye movement (REM) and non-REM (NREM) sleep cycles and the associated opposite oscillations in sympathovagal balance. During sleep, the glucose and ISR oscillations were amplified by about 150%, but the REM-NREM sleep cycles did not entrain the glucose and ISR ultradian oscillations. Also, the latter were not related to either the ultradian oscillations in sympathoagal balance, as inferred from spectral analysis of cardiac R-R intervals, or the plasma fluctuations of glucagon-like peptide-1 (GLP-1), an incretin hormone known to potentiate glucose-stimulated insulin. Other rhythmic physiological processes are currently being examined in relation to ultradian insulin release.