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PubMed1987

Periodic gallbladder contraction maintains bile acid circulation during the fasting period: a canine study.

Using a canine model we have studied the relationship between the interdigestive cycle in the small intestine, motility changes in the biliary tract and bile acid output into the duodenum from direct hepatic secretion and gallbladder emptying. Under anaesthesia catheters were inserted into the gallbladder, common bile duct and duodenum, and electrodes were attached to the small intestine in five dogs. These animals were subsequently studied conscious and fasting. A double marker technique was used to measure bile acid output from the gallbladder and liver while pressure in the gallbladder and common bile duct and electrical activity in the small intestine were monitored. Four complete interdigestive cycles were recorded in each dog. Output of bile acids from the gallbladder fluctuated with the phases of the cycle: being lowest in phase I (3.9 +/- 0.7 mumol/min); increasing significantly (P less than 0.005) in phase II (9.8 +/- 1.0 mumol/min); remaining elevated in phase III (13.9 +/- 1.7 mumol/min); and falling significantly (P less than 0.05) in phase IV (8.4 +/- 1.8 mumol/min). In contrast, hepatic secretion of bile acids directly into the duodenum remained fairly constant. Intraluminal pressure in the biliary tract paralleled the fluctuation in gallbladder bile acid output, being significantly increased (P less than 0.05) in phases II and III. Periodic contraction of the gallbladder would, therefore, appear to be the principal mechanism for the phasic output of bile during fasting.

Animals↗

PubMed1988

Gallbladder non-filling: an indication for cholecystectomy after endoscopic sphincterotomy.

The place of endoscopic sphincterotomy in the treatment of common duct stones leaving the gallbladder in situ remains controversial. Over a 3-year period, 20 elderly high-operative-risk patients with stones in the common duct and intact biliary tree were treated by endoscopic sphincterotomy leaving the gallbladder in situ. Two patients underwent cholecystectomy for persistent symptoms after endoscopic sphincterotomy, and 18 patients were discharged from hospital, with the gallbladder intact. Of the 18 patients, 6 developed recurrent gallbladder problems, with 3 of the 6 dying as a result of these problems. On review of our data, these six patients were in a group of eight who, at the time of original endoscopic retrograde cholangiography (ERC), were shown to have an obstructed cystic duct. The other 10 patients, with a patent cystic duct and discharged with gallbladder in situ, remained symptom free over a median follow-up period of 9 (range 2-42) months. We conclude that if the gallbladder does not fill at ERC (indicating probable cystic duct obstruction), cholecystectomy is warranted. When the gallbladder fills, regular follow-up alone is justified in the absence of symptoms.

Aged↗

PubMed2002

Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma.

BACKGROUND: To the authors' knowledge, the significance of postoperative adjuvant chemotherapy in pancreaticobiliary carcinoma has not yet been clarified. A randomized controlled study evaluated the effect of postoperative adjuvant therapy with mitomycin C (MMC) and 5-fluorouracil (5-FU) (MF arm) versus surgery alone (control arm) on survival and disease-free survival (DFS) for each specific disease comprising resected pancreaticobiliary carcinoma (pancreatic, gallbladder, bile duct, or ampulla of Vater carcinoma) separately. METHODS: Between April 1986 and June 1992, a total of 508 patients with resected pancreatic (n = 173), bile duct (n = 139), gallbladder (n = 140), or ampulla of Vater (n = 56) carcinomas were allocated randomly to either the MF group or the control group. The MF group received MMC (6 mg/m(2) intravenously [i.v.]) at the time of surgery and 5-FU (310 mg/m(2) i.v.) in 2 courses of treatment for 5 consecutive days during postoperative Weeks 1 and 3, followed by 5-FU (100 mg/m(2)orally) daily from postoperative Week 5 until disease recurrence. All patients were followed for 5 years. RESULTS: After ineligible patients were excluded, 158 patients with pancreatic carcinoma (81 in the MF group and 77 in the control group), 118 patients with bile duct carcinoma (58 in the MF group and 60 in the control group), 112 patients with gallbladder carcinoma (69 in the MF group and 43 in the control group), and 48 patients with carcinoma of the ampulla of Vater (24 in the MF group and 24 in the control group) were evaluated. Good compliance (> 80%) was achieved with MF treatment. The 5-year survival rate in gallbladder carcinoma patients was significantly better in the MF group (26.0%) compared with the control group (14.4%) (P = 0.0367). Similarly, the 5-year DFS rate of patients with gallbladder carcinoma was 20.3% in the MF group, which was significantly higher than the 11.6% DFS rate reported in the control group (P = 0.0210). Significant improvement in body weight compared with the control was observed only in patients with gallbladder carcinoma. There were no apparent differences in 5-year survival and 5-year DFS rates between patients with pancreatic, bile duct, or ampulla of Vater carcinomas. Multivariate analyses demonstrated a tendency for the MF group to have a lower risk of mortality (risk ratio of 0.654; P = 0.0825) and recurrence (risk ratio of 0.626; P = 0.0589). The most commonly reported adverse drug reactions were anorexia, nausea/emesis, stomatitis, and leukopenia, none of which were noted to be serious. CONCLUSIONS: The results of the current study indicate that gallbladder carcinoma patients who undergo noncurative resections may derive some benefit from systemic chemotherapy. However, alternative modalities must be developed for patients with carcinomas of the pancreas, bile duct, or ampulla of Vater.

Adult↗

PubMed1998

Effects of long-term ursodeoxycholate administration on expression levels of secretory low-molecular-weight phospholipases A2 and mucin genes in gallbladders and biliary composition in patients with multiple cholesterol stones.

Group IIA phospholipase A2 (PLA2), a secretory low-molecular-weight PLA2, may play a critical role in the process of gallbladder mucosal inflammation in multiple cholesterol stones, which in turn may produce biliary pronucleating proteins as well as mucin. On the other hand, ursodeoxycholate (UDC) decreases biliary levels of various pronucleating proteins, possibly because of its membrane-protective effects on the inflamed gallbladder mucosa. To elucidate that beneficial effect of UDC, the expression levels of low-molecular-weight PLA2s, group IIA PLA2 (PLA2-IIA), and group V PLA2 (PLA2-V), and mucin core polypeptide genes in the gallbladders were studied for UDC-treated patients and untreated patients with multiple cholesterol stones. Furthermore, the results were correlated with alterations in biliary composition. With long-term administration of UDC, the PLA2-IIA protein mass (2.7 +/- 0.5 vs. 5.0 +/- 0.4 ng/mg x protein [mean +/- SEM]; P < .01) and steady-state mRNA level, as well as the PLA2-V mRNA level, were significantly decreased in the gallbladders, where the prostaglandin E2 (PGE2) level was concomitantly decreased (190.7 +/- 27.9 vs. 393.6 +/- 55.3 pg/mg x protein; P < .01). In the gallbladder bile, the immunoradiometrically determined PLA2-IIA levels were significantly decreased in the UDC-treated patients (43 +/- 4 ng/dL; P < .01) in comparison with untreated patients (78 +/- 6 ng/dL). Significant decreases were similarly found for total protein, mucin, and free arachidonate concentrations, as well as nucleation activity in the bile. The degree of the changes was found to be rather small in solitary stones. In contrast to the decreased mucin concentration, however, there were no significant changes in the expression levels of mucin core polypeptide genes (MUC1-MUC6) between the UDC-treated and untreated patients. Long-term UDC administration was observed to lower the increased PLA2-IIA protein mass and mRNA level, as well as the PLA2-V mRNA level, in the gallbladders of patients with multiple cholesterol stones, which in turn may be of therapeutic importance in improving the gallbladder mucosal inflammation. Effects of UDC on secretory low-molecular-weight PLA2s as inflammatory mediators may relate to the reported efficacy of UDC treatment in cholesterol gallstone disease.

Arachidonic Acid↗

PubMed2000

Apolipoprotein E genotype and the risk of gallbladder disease in pregnancy.

The E4 allele of apolipoprotein E (apoE4) has previously been associated with symptomatic gallstone disease. The aim of this study was to determine if apoE4 is associated with the development of gallbladder sludge and/or stones during pregnancy. We conducted a nested case-control study based on an ongoing cohort study of gallbladder disease in pregnancy. Women in this study receive gallbladder ultrasounds in each trimester of pregnancy. Cases (n = 52) were defined as women with incident gallbladder sludge or stones diagnosed at the third trimester ultrasound. Controls (n = 104) were defined as women without gallbladder sludge or stones on any of 3 study ultrasounds. ApoE genotyping was performed from stored white blood cell pellets. Data were analyzed by stratified analysis and multivariate logistic regression. Cases and controls were similar in baseline characteristics. Forty-two women had sludge, 6 had gallstones, and 4 had both sludge and stones. After adjusting for risk factors such as age, parity, and body mass index, the odds ratio (OR) for the association between heterozygosity or homozygosity for the apoE4 allele and incident gallbladder sludge or stones was 0.91 (95% confidence interval [CI], 0.41-2.02). Further adjustment for family medical history and serum lipid levels did not substantially change these results (OR, 0.73; 95% CI, 0.29-1.82). In conclusion, apoE4 appears to have little or no overall association with the development of new gallbladder sludge or stones in pregnancy. However, an effect could not be ruled out in certain subgroups, such as blacks or women who are homozygous for apoE4.

Apolipoprotein E4↗

PubMed2002

Association of chili pepper consumption, low socioeconomic status and longstanding gallstones with gallbladder cancer in a Chilean population.

We explored the risk factors for gallbladder cancer and explanations for its sharp and constant incidence increase in Chile since the 1970s. We compared 114 consecutive patients with verified gallbladder cancer, diagnosed 1992-1995, to 114 matched hospital patients with gallstones, using conditional logistic regression analysis. Low education showed a nonsignificant positive relationship with gallbladder cancer [odds ratio (OR) = 2.3, 95% confidence interval (CI) 0.8-6.2], and low socioeconomic level showed a significant relationship (OR = 5.0, 95% CI 1.5-17.3). A very long history of gallstone disease was significantly more prevalent among cases (OR = 11.0, 95% CI 1.4-85.2). Significant red chili pepper consumption was observed in gallbladder cancer patients (OR = 2.9, 95% CI 1.6-5.2). Low intake of both fresh fruit and sugar as soft drinks was associated with gallbladder cancer, with ORs of 6.4 (95% CI 1.4-30.3) and 3.6 (95% CI 1.3-10.1), respectively. Multivariate analysis kept only a very low socioeconomic status and red chili pepper consumption as significant independent risk factors for gallbladder cancer, ORs of 6.3 (95% CI 1.7-23.0) and 3.2 (95% CI 1.7-5.9). Longstanding gallstone cases were removed from the multivariate model because all were in the low and very low socioeconomic groups, reinforcing the association. Patients with gallbladder cancer differed from matched controls by exhibiting lower socioeconomic levels, having a much longer history of gallstone disease and presenting a dietary pattern characterized by high red chili pepper consumption and low fresh fruit intake.

Adult↗

PubMed2005

Volume changes in the gallbladder in association with various radiologic examinations.

PURPOSE: Our aim was to evaluate with sonography the volume changes of the gallbladder after intravenous administration of nonionic, iodinated contrast agents with or without ingestion of contrast agent or water. METHODS: A total of 191 patients received intravenous injection of 50 ml of nonionic contrast agent (Group A), intravenous injection of 100 ml of contrast medium (Group B), intravenous injection of 100 ml of contrast medium together with ingestion of 1000 ml of a dilute solution of contrast medium (Group C), or 1000 ml of water taken orally (Group D). The gallbladder volume was measured by ultrasonography in the fasting state in all groups, 15 minutes after intravenous injection of contrast medium in Groups A, B, and C and 30 minutes after water ingestion in Group D. RESULTS: In all groups, the volume of the gallbladder was statistically lower after the procedure than before. There was no significant difference among the groups in terms of this gallbladder volume change. CONCLUSIONS: Intravenous injection of nonionic, iodinated contrast medium or ingestion of water or a dilute solution of contrast medium for various radiological examinations results in contraction of the gallbladder. Contrast-enhanced radiological examinations may interfere with sonographic evaluation of the gallbladder. If necessary, gallbladder ultrasonographic examination should be repeated with the patient in a fasting state. (c) 2005 Wiley Periodicals, Inc. J Clin Ultrasound 33:214-217, 2005.

Administration, Oral↗

PubMed1998

The basis for progesterone impairment of gallbladder contractility in male guinea pigs in vitro.

Progesterone suppresses gallbladder smooth muscle function but its exact mechanism is unknown. We sought to determine the cellular site where progesterone impairs gallbladder smooth muscle. Sixty-four adult male guinea pigs were injected with either progesterone (2 mg/kg/day sc) or normal saline (controls) for 7 days. Dose-response curves of gallbladder strips to cholecystokinin (CCK), bethanechol, and potassium (K+) were constructed in vitro. To better define the basis for the progesterone effect, gallbladder contractile response was determined to specific agonists: aluminum fluoride and mastoparan (direct G-protein activators), cyclopiazonic acid (CPA), and a calcium ionophore (A-23187). Gallbladder from animals on progesterone exhibited a marked decrease in contractile response to CCK and bethanechol compared with controls (P < 0.05). Further, gallbladder contraction remained depressed (P < 0.05) in progesterone-treated animals, when the G protein was directly activated with aluminum fluoride and mastoparan. In contrast, the responses to K+ (acting independent of receptor G-protein) and to A-23187 and CPA (agonists that bypassed the membrane) were comparable in both groups (NS). It is concluded that progesterone directly inhibits gallbladder smooth muscle contractility in vitro to a standard hormone, CCK, and a cholinergic agent. Such depressed contraction is not due to an altered contractile machinery, since it is normal with agonists that act independently of G-protein activation. Progesterone thus interferes with signaling through the G-protein, either by directly becoming closely associated with the cell membrane or by indirectly perturbing its receptor products.

Animals↗

PubMed1995

Laparoscopic cholecystectomy for gallbladder volvulus.

Torsion of the gallbladder is a rare entity. Approximately 300 cases have been reported since it was first described in 1898 by Wendel (Ann. Surg. 1898; 27:199). The condition occurs most often in the elderly. Although the etiology is unknown, a constant finding is the presence of the gallbladder on a mobile mesentery ("floating" gallbladder). Torsion, or volvulus, of the gallbladder occurs when this gallbladder twists axially, with subsequent occlusion of bile and/or blood flow. We present a case of gallbladder volvulus diagnosed and treated laparoscopically. This is the first reported laparoscopic cholecystectomy for volvulus of the gallbladder.

Aged↗

PubMed1989

Histochemistry of glycoconjugates in the gallbladder epithelium of ten animal species.

A battery of seven lectins and several conventional mucin histochemical techniques were used to identify the epithelial mucins of the gallbladder of ten species: man, rabbit (Oryctolagus cuniculus, mammalia), hamster (Mesocricetus auratus, mammalia), chicken (Gallus gallus, bird), sparrow (Passer domesticus, bird), moorish gecko (Tarentola mauritanica, reptilia), ladder snake (Elaphe scalaris, reptilia), lake frog (Rana perezi, amphibia), natterjack toad (Bufo calamita, amphibia) and gilthead sea bream (Sparus auratus, fish). Glycogen was found in the epithelial lining of the reptilian and amphibian gallbladders. Sulphate and carboxyl groups were frequently found in the same species, except in the ladder snake and natterjack toad gallbladders where only sulphate groups were identified. Sialic acid residues were detected in man, rabbit, bird, T. mauritanica, R. perezi and fish gallbladders. ConA binding pattern was similar in the ten species studied. In the human gallbladder only PNA failed to label the luminal surface, while the glands were only unreactive to DBA. The human gallbladder showed a large variety of saccharides. The present results suggest that no relation exists between the composition of the gallbladder mucins and the situation of the species in the phylogenetic scale.

Animals↗

PubMed1986

[Bacteria in the gallbladder wall and gallstones--indications for cholecystectomy].

After cholecystectomy the bacterial content of the bile, gallbladder wall and gallstones was studied in 40 patients. Bacteria could be found in 9 cases in the gallbladder wall, in 8 cases in the gallstones and in 3 cases in the bile. In chronic inflammatory thickened gallbladder wall bacteria were positive in 8 of 14 cases whereas in normal gallbladders bacteria were found only in 3 of 26 cases (difference statistically significant, P = 0.01). It is concluded that in gallstone disease bacteria are not only present in bile but also in the gallbladder wall and within the gallstones. As bacteria are mostly present in a gallbladder wall with chronical inflammatory changes a thickened gallbladder should be removed even in asymptomatic or slightly symptomatic cases of gallstone disease in order to prevent relapsing cholecystitis.

Adult↗

PubMed1992

Effect of small doses of somatostatin analog, octreotide, on gallbladder contractility in normal Chinese adults.

The acute effects of single different doses of the somatostatin analog octreotide on the contractility of the gallbladder stimulated by fatty meal were studied in six healthy Chinese volunteers. Gallbladder contraction after a fatty meal was significantly suppressed by octreotide at doses of 50, 25, 12.5, and 5 micrograms. Mean duration of suppression lasted for more than 10 hr at doses of 25 and 50 micrograms, after which the gallbladder contractility was restored at 24 hr in three and four, respectively, of the six subjects. The percentage of relative gallbladder contraction (PRGC) in all subjects receiving 12.5 and 5 micrograms octreotide returned to pretreatment values at 10 hr but had not returned to normal 6 hr after the injection of 5 micrograms octreotide. In summary, octreotide inhibits the contraction of the gallbladder even with a dose as low as 5 micrograms. It appears that it may not be possible to avoid gallbladder dysfunction during long-term octreotide therapy by decreasing the dose. Further studies including modalities to increase the contractility of the gallbladder are recommended.

Adult↗

PubMed1982

Abnormal gallbladder emptying in patients with gallstones.

In this study, gallbladder and gastric emptying were compared in 15 normal subjects and 15 patients with gallstones. A noninvasive technique which used two gamma-emitting radiopharmaceutical agents to image the gallbladder and stomach simultaneously was employed. Technetium-99m-HIDA was used as a gamma-emitting marker for the gallbladder and indium-111-DTPA was mixed with a standard liquid meal in order to stimulate gallbladder emptying and to measure gastric emptying. In patients with gallstones, gallbladder emptying was diminished significantly compared to normal subjects. In contrast, emptying of the stomach was normal. The gallbladder emptying responses to octapeptide of cholecystokinin, administered either as bolus or infusion doses, were similar in normal subjects and patients with gallstones. These studies suggest that gallbladder emptying may be abnormal in patients with gallstones. The explanation for this abnormality and its relationship to the development of gallstones has not been determined.

Adult↗

PubMed1988

Gallbladder kinetics in obese patients. Effect of a regular meal and low-calorie meal.

Gallbladder contractility has been studied in 21 obese patients (greater than 130% ideal weight) and 30 nonobese subjects before and at regular intervals after the administration of a regular solid-liquid meal, and after a low-calorie, low-fat meal used conventionally for weight-loss purposes (Modifast). Gallbladder volume was determined by means of real-time ultrasonography, using a linear array scanner with a 3.5 MHZ probe. In seven of the obese patients, gallbladder contractility was also evaluated after a 10-day regimen with Modifast. The obese group showed a statistically significant greater gallbladder fasting volume and blunted contractility than controls both after the ordinary and the low-calorie meal. The 10-day low-calorie regimen was associated with a statistically significant increment in fasting gallbladder volume, while the percent volume reduction after Modifast did not change. It is suggested that, in addition to metabolic factors, gallbladder hypocontractility in the obese may contribute to the high incidence of cholesterol gallstones noted in these patients. A low-calorie, low-fat diet augmenting gallbladder volume may favor bile stasis and therefore the likelihood of developing gallstones.

Adult↗

PubMed1990

Duodenal osmolality drives gallbladder emptying in humans.

The effect of duodenal osmoreceptor stimulation on gallbladder motility was evaluated in 18 normal subjects during intraduodenal infusion of 280, 560 and 840 mosm/liters NaCl solutions. Gallbladder emptying was found to be dose-dependent between 560 and 840 mosm/liter (P less than 0.01 vs basal volume). The effect of duodenal infusion of hypertonic saline on gallbladder emptying was prevented by atropine and partially antagonized by naloxone, indicating that cholinergic and endorphinergic pathways may be involved in regulating this reflex. Since proglumide, a cholecystokinin (CCK) antagonist, did not affect gallbladder emptying induced by hypertonic saline, it seems likely that CCK is not released by increasing duodenal osmolality. A significant reduction in gallbladder volume was obtained when hyperosmolar saline was delivered into the duodenum, whereas no emptying was seen when infused into the gastric antrum or the jejunum, suggesting that osmoreceptors that activate gallbladder emptying are located only in the duodenum. Additionally, all subjects manifested central symptoms (nausea or vomiting) during duodenal infusion of hypertonic saline, suggesting that central mechanisms might be activated by a change in duodenal osmolality. Our data indicate that the osmolality of duodenal contents might regulate gallbladder motility by neural atropine- and naloxone-sensitive pathways.

Adult↗

PubMed1982

Changes in gallbladder motor function during the female cycle--a risk factor leading to gallstone formation?

The gallbladder volume of eight women with stable cycles was determined by sonography. Furthermore, gallbladder contraction--following an orally administered fatty meal and the spontaneous refilling of the empty gallbladder--was quantitatively examined. The formula of a rotation ellipsoid, which has been proven to be adequately accurate in in vitro studies, was used for calculating the gallbladder volume. In the gestagen phase (21st or 22nd day) the intraindividual studies showed greater fasting volumes, higher residual volumes after contraction, slower gallbladder emptying, and retarded refilling of the empty gallbladder as compared to the estrogen phase (12th or 13th day). The hormonally modified contraction behavior and the differing course of gallbladder filling may play a major role in the pathogenesis of gallstone formation.

Cholelithiasis↗

PubMed1995

Gallbladder mucosal protein secretion during development of experimental cholecystitis.

The development of experimental cholecystitis produced by lysophosphatidylcholine is associated with reversal of the normal absorptive characteristics of gallbladder mucosa, resulting in the intraluminal accumulation of water, glycoprotein, and protein. The purpose of the present study was to attempt to ascertain if the protein leaks into the lumen because of the cytolytic properties of lysophosphatidylcholine or if it is due to an active secretory process and to characterize the protein produced. Experiments were performed on anesthetized cats undergoing gallbladder perfusion with and without lysophosphatidylcholine. The amount of protein in the perfusate was measured and albumin clearance from blood to gallbladder lumen was calculated with and without the administration of vesicular transport inhibitors. In separate experiments, control and lysophosphatidylcholine (LPC) produced gallbladder perfusates were collected and the protein subjected to SDS-PAGE to ascertain the nature of the protein secreted. Inhibitors of both microtubular and microfilament activity decreased the protein accumulation and clearance produced by lysophosphatidylcholine. Gallbladder white blood cell accumulation and inflammation as evaluated by beta-glucuronidase and prostaglandin E levels were not significantly altered by cytochalasin or colchicine administration. Lysophosphatidylcholine also produced significant increases in perfusate LDH levels. The protein produced was primarily a 66-kDa protein. Transfer of the protein to a nitrocellulose membrane and immunoblotting with anti-albumin antibody demonstrated that the protein was albumin. The results suggest that during the development of cholecystitis, lysophosphatidylcholine produces albumin accumulation in the gallbladder primarily by inducing an active secretory process resulting in gallbladder distension.

Albumins↗

PubMed1994

Effect of intravenous glucose on intravenous amino acid-induced gallbladder contraction and CCK secretion.

The present study was undertaken to investigate the effect of acute hyperglycemia on the gallbladder contraction induced by intravenous administration of high doses of amino acids (Vamin 18, 250 mg protein/kg/hr). Six healthy volunteers were studied in random order on two occasions during normoglycemia and hyperglycemia with blood glucose levels stabilized at 15 mmol/liter. Gallbladder volumes, measured with ultrasonography, were studied for 60 min before and for 120 min during intravenous infusion of amino acids (IVAA). Administration of IVAA resulted in a significant reduction (P < 0.05) in gallbladder volume from 32 +/- 5 cm3 to 17 +/- 2 cm3 during normoglycemia. During hyperglycemia no significant changes in gallbladder volume were observed in response to IVAA. No significant changes in plasma CCK concentration, the major hormonal stimulus for gallbladder contraction, occurred in response to IVAA. During hyperglycemia, pancreatic polypeptide (PP) secretion, as an indirect measure of vagal cholinergic tone, in response to IVAA was significantly (P < 0.05) reduced compared to normoglycemia. It is concluded that: (1) administration of high doses of IVAA results in significant gallbladder contraction, (2) high doses of IVAA do not stimulate CCK secretion, (3) acute hyperglycemia inhibits IVAA-induced gallbladder contraction, and (4) acute hyperglycemia inhibits basal and stimulated plasma PP secretion, suggesting impaired vagal-cholinergic tone during hyperglycemia.

Adult↗