摘要:

The Second International Islet Transplantation Symposium was held at UCLA in January, 1993. The symposium, sponsored by the Jerry's Foundation for Diabetes Research was focused on the issues in clinical islet transplantation. The leaders from each of the clinically active programs around the world were invited to discuss their clinical results and ways to achieve higher success rates. The Islet Transplantation Registry revealed there have been 178 islet transplants in human subjects worldwide: 11% of the patients have achieved insulin-independence; however, 20% of the patients have achieved insulin-independence during 1990–1992; 20% of the patients have functioning islet grafts as determined by circulating C-peptide levels: however 65% have functioning grafts during 1990–1992. These patients still require exogenous insulin; however, many demonstrate improved glucose control and decreased insulin requirements, and are considered to have a partially successful transplant. The major issues for clinical success are islet preparation, donor islet number, and prevention of rejection. We are hopeful that islet transplantation will realize its full potential this decade and await the advance in technology that will result in clinical success rates approaching that of solid organ transplantation.

ISSN:0885-3177    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

It has recently been suggested that gastric inhibitory polypeptide (GIP) may block the risk factors associated with both hypo- and hyperglycemia by either suppressing or enhancing (depending on the prevailing glucose conditions) insulin release. In the present study we examined, through the use of isolated perifused mu-rine islets, the effect of GIP on insulin secretion that was stimulated by polyunsaturated fatty acids (PUFA) in the presence of low or high glucose concentrations. For each experiment, islets were preperifused at the rate of 1 ml/ min for I h at 37°C with Krebs-Ringer bicarbonate buffer pH 7.4 that was continuously gassed with 95%/5%, O2CO2and which contained 5.5mM(basal) glucose, 2% bovine albumin, and 100 kIU/ml trasylol. Basal samples were then taken before PUFA were added to the perifu-sate of 5.5 or 27.7 mM glucose, in the absence (control) or presence of synthetic human GIP, and in 20-min perifu-sion cycles. Solutions were changed using a stopcock, and effluent samples collected on ice were stored frozen until radioimmunoassay for insulin. The addition of a mixture of 10 mM linoleic acid (18:2, w6) and 5 mM lin-olenic acid (18:3, w3), to basal glucose perifusate stimulated insulin secretion from a mean basal rate of 61 5 2 to 220 t 21 pg/islet/min (p < 0.001, n = 5). When GIP concentrations of either 1 × 10−9or 1 × 1o−8M were added to the fatty acid perifusate, insulin secretion stimulated by PUFA was significantly attenuated in a dose-dependent manner, but was completely restored after withdrawal of GIP. This suppressive effect of GIP upon insulin secretion stimulated by the PUFA mixture was also observed when the stimulatory effect of 10 mM li-noleate alone rather than the mixture of linoleic and lin-olenic acids was examined. In contrast, when islets were perifused with PUFA in the presence of 27.7 mM glucose, PUFA-induced insulin release was observed. Thus, the mean rate of insulin release rose from a basal 59 2 1 to 120 * 5 pgfisletimin and 166 2 5 pgfisletimin (p< 0.001) in the presence of 10 mM linoleate alone or with GIP, respectively, and fell to 105 2 2 pg/islet/min (p< 0.001, n = 5), following withdrawal of GIP from the fatty acid perifusate. In control experiments to monitor temporal changes over the course of these perifusions, maximally stimulated insulin secretion in the presence of 10 mM linoleate remained in a steady state throughout the study. In conclusion, this study suggests that GIP may act to inhibit PUFA-stimulated insulin output by isolated perifused islets, in the presence of low but not high glucose conditions.

ISSN:0885-3177    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The influence of extrapancreatic nerves on the inhibition of meal- and secretogogue-induced pancreatic secretion by galanin was studied in conscious dogs. Chronic pancreatic fistulae were created in five mongrel dogs and a second group of five dogs also underwent complete pancreatic denervation. After recovery, galanin dose response (150-1,200 pmol/kg/h) revealed that 600 pmoYkgih was the lowest dose of galanin to significantly inhibit pancreatic exocrine secretion. Pancreatic responses to a mixed meal, cholecystokinin (CCK) dose response (12.5-200 ng/kg/h), and secretin dose response (16–500 ng/kg/h) were determined. The experiments were then replicated with a continuous background infusion of galanin (600 pmol/kg/h). Galanin inhibited meal-, CCK-, and secretin-induced bicarbonate outputs in both the innervated and denervated pancreas. Galanin also inhibited meal- and CCK-induced protein responses in both groups. We conclude that extrapancreatic nerves do not mediate the inhibitory effects of galanin.

ISSN:0885-3177    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

An experiment was conducted on 54 male Wistar rats (36 experimental, 18 controls) to study adverse effects of monosodium L-glutamate (MSG) on pancreatic acinar cells by measuring the qualitative and quantitative changes in acid phosphatase (ACPase) in these cells. Various concentrations of aqueous MSG were given to rats for various durations (Group I, 1% MSG for 1 month; Group II, 1% MSG for 1 week; Group III, 0.5% MSG for 1 week; Group IV, 0.2% MSG for 1 week; Group V, 0.1% MSG for 1 week; Group VI, 0.05% MSG for 1 week). The pancreas was then removed from each specimen for electron microscopic examination, cyto-chemical localization of ACPase, and cell fractionation for quantitative measurement of ACPase. Serum level of ACPase was determined in these animals before removal of the pancreas. The ultrastructural changes in pancreatic acinar cells revealed an increase in the number and size of autophagic vacuoles and various sizes of myelin figures in the cytoplasm and interstitial space. Dilatation of rough endoplasmic reticulum, swollen mitochondria, and altered zymogen granules were occasionally found. These changes occurred most often in Group I rats, which ingested 1% MSG for 1 month. The changes became less prominent as the dose of MSG administered was lessened. A reaction product of ACPase could also be seen in autophagic vacuoles in Group I rats. Regarding quantitative measurement, the serum level of ACPase for Group I rats was markedly higher than that of the controls and was statistically significant (20.52 ± 4.92 vs. 12.62 ± 4.13 U/L;p< 0.05). Although it was not remarkable in other experimental rats, the activity of ACPase in pancreas ho-mogenate, supernatant, and pellets of experimental Groups I and II rats was higher, although not statistically significant, than that of the controls. The altered ultra-structure of pancreatic acinar cells and increased activities of acid phosphatase found led to the conclusion that long-term ingestion of large doses of MSG will induce damage to pancreatic acinar cells.

ISSN:0885-3177    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The prophylactic and therapeutic effects of a potent cholecystokinin (CCK) receptor antagonist, L-364,718, on acute pancreatitis induced by caerulein were evaluated, analyzing morphologic and functional pancreatic parameters jointly. Edematous pancreatitis was induced by four subcutaneous injections of caerulein (20 μkg) in rats at 1-h intervals. Prophylactic administration of L-364,718 (0.1 mg/kg) prevented rise in serum amylase levels, interstitial edema, vacuolization, and impairment of pancreatic enzyme secretion that accompany caerulein-induced acute pancreatitis. After 7 days, a spontaneous regression of the morphologic alterations caused by caerulein-induced acute pancreatitis occurs; however, recovery of the secretory function of the pancreas was only reached after this period of time when L-364,718 was administered therapeutically (0.1 mg/kg/ day). Prophylactically or therapeutically administered, L-364,718 exerts a beneficial effect on caerulein-induced acute pancreatitis, indicating that CCK (exogenous or endogenous) plays an important role in the development of this pathology.

ISSN:0885-3177    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Interleukin-1, tumor necrosis factor, and in-terleukind inhibit insulin release and may be cytotoxic to isolated pancreatic islets. These cytokines have been postulated to play an important role in the β cell destruction characteristic of type 1 diabetes. The present study was designed to investigate the effect of the above cytokines on insulin, glucagon, somatostatin, and thyrotropin-releasing hormone secretion by isolated human islets. In addition, we have investigated if cytokine-induced modifications in hormone secretion are accompanied by modifications in the ab initio synthesis of any specific lipidic fraction. All three cytokines studied, although not modifying insulin and somatostatin release to glucose 5 mmol/L, inhibited the response of both hormones to glucose 20 mmol/L. On the other hand, the cytokines almost completely blocked islet basal glucagon release, without affecting thyrotropin-releasing hormone secretion. The added cytokines also suppressed 20 mmol/L [U-14C]glu-cose incorporation into both phospholipids and diacyl-glycerol. Our results demonstrate a p-, a-, and & cell, sensitivity to cytokine action. Additionally, they suggest that ab initio lipid synthesis might be implicated in the mechanism of insulin release in human islets.

ISSN:0885-3177    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Biochemical and pharmacologic characteristics of a newly developed benzodiazepine derivative (S)-N-[l-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxo-pyrrolo-[3,2,1 -jk] [1,4]benzodiazepine-3-yl]-lH-indole-2-carboxamide (FK480) as a cholecystokinin (CCK) receptor antagonist were examined in the isolated rat pancreatic acini and compared with those of MK-329 and loxiglumide. FK480, MK-329, and loxiglumide inhibited CCK octapeptide (CCK-8)-stimulated amylase release and binding of [125I]CCK-8 in a concentration-dependent manner, with a half-maximal inhibition (ID50) at 1.30 ± 0.12 nM, 1.33 ± 0.21 nM, and 1.27 ± 0.23 μM, respectively, for amylase release, and 0.40 2 0.06 nM, 0.68 ± 0.08 nM, and 0.38 ± 0.03 μM, respectively, for [125I]CCK-8 binding. The antagonism was competitive in nature because these three compounds caused a parallel rightward shift of the dose-response curve for CCK-8-stimulated amylase secretion, without altering the maximal increase. The antagonism produced by FK480 was specific for CCK in that the effects of other receptor secretagogues or agents bypassing receptors were not altered. FK480 not only prevented but also reversed CCK-&stimulated amylase release. This compound caused a residual inhibition of the action of CCK-8. When acini were preincubated with 100 nM FK480 for 30 min, the subsequent dose-response curve to CCK-8 was shifted 10-fold toward higher concentration. Similar results were obtained with MK-329 but not with loxiglumide. FK480 appeared to be bound to the receptors on acinar cells in a slowly dissociating state. These results demonstrate that FK480 is a potent, competitive, and specific antagonist of CCK's stirnulatory action on the exocrine pancreas.

ISSN:0885-3177    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

To evaluate β-cell function in patients with pancreatic cancer, the glucagon stimulation test was performed in seven patients with pancreatic adenocarcinoma, seven patients with type I diabetes mellitus, seven patients with type II diabetes mellitus, and in seven healthy controls. C-peptide serum levels were determined before and after a 1-mg i.v. glucagon injection. Basal C-peptide values were normal or slightly increased in pancreatic cancer and type II diabetic patients and low in type I diabetic patients. Following glucagon stimulation, no significant increase was observed in C-peptide values of type I diabetics and pancreatic cancer patients, whereas significant increases occurred in controls and type II diabetics. It is concluded that the altered p-cell function found in pancreatic cancer patients may lead to hyperglycemia, which is frequently associated with this tumor type.

ISSN:0885-3177    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Plasma levels of fibrinogen, a,-acid glycoprotein (AG) and albumin, pancreatic insulitis quantitative scores, and erythrocyte velocity in the mesoappendix mi-crovessels were measured in BB diabetic (BBD) and streptozotocin-diabetic rats (WSTZ) in order to answer the following questions: (a) Does hyperfibrinogenemia or increase in AG plasma level occur in BBD and WSTZ rats, and if so, are these alterations secondary to the hy-perglycemia or to an inflammatory process such as insulitis? (b) Is there a decrease in microcirculatory flow in the BBD and WSTZ rats, and if so, is it secondary to the hyperfibrinogenemia and/or the hyperglycemia? Insulitis was present in the BBD rats after 5 weeks of disease (with a score of 2.9 ± 0.1 vs. 1.4 ± 0.6 in the normoglycemic controls), but absent in WSTZ rats after 5 months of disease (1.2 ± 0.06 vs. 1.1 ± 0.06). Increase in fibrinogen and AG plasma levels was observed in the BBD rats only and appears linked to the insulitis. The major acute phase protein AG level is increased in BBD rats already on the first day of appearance of glycosuria. In the WSTZ rats, without insulitis, chronic hyperglycemia alone did not induce an increase in fibrinogen and AG plasma levels. A decreased microcirculatory erythrocyte velocity has been found in both BBD and WSTZ rats. Thus an increase in fibrinogen or AG plasma levels is not necessary for inducing a decrease in erythrocyte velocity. Hyperglycemia is probably the main factor responsible for the decrease in microcirculatory flow in the BBD and WSTZ rats.

ISSN:0885-3177    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We studied the difference in the susceptibility to neonatal streptozotocin (STZ) diabetes between spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Two-day-old female SHR and WKY were injected intraperitoneally with 75.0 mg/kg of STZ or vehicle for control. Hyperglycemia developed in both strains at 4 days of age, but SHR were more hyperglycemic. Overt hyperglycemia developed in SHR with aging after a partial recovery from initial hyperglycemia at 10 days of age, whereas WKY did not develop significant hyperglycemia except shortly after STZ treatment. Percentage of insulin-positive B cells in total islet cells and pancreatic immunoreactive insulin (IRI) content were measured at 4 days, 10 days, 4 weeks, and 12 weeks of age. B cells per islet and pancreatic IRI content were significantly reduced in STZ-treated groups as compared with control in both SHR and WKY at 4 days of age, but later they increased significantly with aging in both strains. However, the reduction in pancreatic IRI content relative to control was significantly greater in SHR than in WKY from 4 days (−94.5 ± 3.5%, −84.1 ± 4.8%;p< 0.01) to 12 weeks (−97.1 ± 2.1%, −28.0 ± 2.5%;p< 0.05), and the reduction in B cells per islet was also greater in SHR at 4 weeks of age. These results indicated that the initial destruction of pancreatic B cells induced by STZ was greater, and the following regeneration was less in SHR than in WKY. The association of the susceptibility to neonatal STZ diabetes with the development of genetic hypertension in SHR remained to be elucidated.

ISSN:0885-3177    

出版商:OVID    

年代:1994

数据来源: OVID