| 1. |
- Bronden, A., et al.
(författare)
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Glucose-lowering effects and mechanisms of the bile acid-sequestering resin sevelamer
- 2018
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Ingår i: Diabetes Obesity & Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 20:7, s. 1623-1631
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Tidskriftsartikel (refereegranskat)abstract
- Aims Sevelamer, a non-absorbable amine-based resin used for treatment of hyperphosphataemia, has been demonstrated to have a marked bile acid-binding potential alongside beneficial effects on lipid and glucose metabolism. The aim of this study was to investigate the glucose-lowering effect and mechanism(s) of sevelamer in patients with type 2 diabetes. Materials and Methods In this double-blinded randomized controlled trial, we randomized 30 patients with type 2 diabetes to sevelamer (n = 20) or placebo (n = 10). Participants were subjected to standardized 4-hour liquid meal tests at baseline and after 7 days of treatment. The main outcome measure was plasma glucagon-like peptide-1 excursions as measured by area under the curve. In addition, blood was sampled for measurements of glucose, lipids, glucose-dependent insulinotropic polypeptide, C-peptide, glucagon, fibroblast growth factor-19, cholecystokinin and bile acids. Assessments of gastric emptying, resting energy expenditure and gut microbiota composition were performed. Results Sevelamer elicited a significant placebo-corrected reduction in plasma glucose with concomitant reduced fibroblast growth factor-19 concentrations, increased de novo synthesis of bile acids, a shift towards a more hydrophilic bile acid pool and increased lipogenesis. No glucagon-like peptide-1-mediated effects on insulin, glucagon or gastric emptying were evident, which points to a limited contribution of this incretin hormone to the glucose-lowering effect of sevelamer. Furthermore, no sevelamer-mediated effects on gut microbiota composition or resting energy expenditure were observed. Conclusions Sevelamer reduced plasma glucose concentrations in patients with type 2 diabetes by mechanisms that seemed to involve decreased intestinal and hepatic bile acid-mediated farnesoid X receptor activation.
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| 2. |
- Guiastrennec, Benjamin, et al.
(författare)
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Mechanism-Based Modeling of Gastric Emptying Rate and Gallbladder Emptying in Response to Caloric Intake
- 2016
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Ingår i: CPT. - : Wiley. - 2163-8306. ; 5:12, s. 692-700
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Tidskriftsartikel (refereegranskat)abstract
- Bile acids released postprandially modify the rate and extent of absorption of lipophilic compounds. The present study aimed to predict gastric emptying (GE) rate and gallbladder emptying (GBE) patterns in response to caloric intake. A mechanism-based model for GE, cholecystokinin plasma concentrations, and GBE was developed on data from 33 patients with type 2 diabetes and 33 matched nondiabetic individuals who were administered various test drinks. A feedback action of the caloric content entering the proximal small intestine was identified for the rate of GE. The cholecystokinin concentrations were not predictive of GBE, and an alternative model linking the nutrients amount in the upper intestine to GBE was preferred. Relative to fats, the potency on GBE was 68% for proteins and 2.3% for carbohydrates. The model predictions were robust across a broad range of nutritional content and may potentially be used to predict postprandial changes in drug absorption.
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| 3. |
- Ohlsson, Bodil, et al.
(författare)
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Continuous infusion of cholecystokinin leads to down-regulation of the cholecystokinin-A receptor in the rat pancreas
- 2000
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 35:6, s. 612-618
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Infusion of sulphated cholecystokinin-8 (CCK-8S) in rats transiently increased the proliferation of pancreatic acinar cells, whereas the CCK-A receptor antagonist devazepide decreased such proliferation. This effect ceased after 3 days. CCK-8S or devazepide injected twice daily induced a persistent effect on the cell proliferation involving the major cells of the exocrine pancreas. The aim of this study was to examine the effect of continuous infusion of CCK-8S and devazepide on CCK-A receptor gene expression. METHODS: Male Sprague-Dawley rats received subcutaneous continuous infusion of 5 microg/kg/h CCK-8S, 200 microg/kg/h devazepide, or 1% bovine serum albumin (BSA) by means of osmotic minipumps. The rats were killed after 4 days; I h before being killed they received 5-bromo-2-deoxyuridine (BrdU) intraperitoneally. Plasma was collected for analysis of CCK. The pancreas was dissected, and indirect immunofluorescence for BrdU and CCK-A receptor was performed. In situ hybridization to CCK-A receptor mRNA was performed for examination and semiquantification of receptor gene expression. RESULTS: Continuous infusion of CCK-8S led to a sixfold increase in plasma CCK and a 40% increase in pancreatic weight. Devazepide did not affect the CCK level but decreased the pancreatic weight by 24% compared with BSA-infused rats. The BrdU labeling indicated that CCK-8S had no effect on cell proliferation. Immunofluorescence for the CCK-A receptor showed a decreased labeling intensity after CCK-8S infusion. The mean optical density of in situ hybridization labeling of the sections from CCK-8S-treated rats was decreased to 37% +/- 3% of that in controls. Devazepide did not affect the CCK-A receptor gene expression. CONCLUSIONS: Continuous stimulation of the CCK-A receptor led to a downregulation of the receptor gene expression in pancreatic acinar cells and decreased labeling of the receptor at immunohistochemistry. The results suggest that down-regulation of the receptor is a protective mechanism against overstimulation.
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| 4. |
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| 5. |
- Donges, Jonathan F., et al.
(författare)
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Non-linear regime shifts in Holocene Asian monsoon variability : potential impacts on cultural change and migratory patterns
- 2015
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Ingår i: Climate of the Past. - : Copernicus GmbH. - 1814-9324 .- 1814-9332. ; 11:5, s. 709-741
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Tidskriftsartikel (refereegranskat)abstract
- The Asian monsoon system is an important tipping element in Earth's climate with a large impact on human societies in the past and present. In light of the potentially severe impacts of present and future anthropogenic climate change on Asian hydrology, it is vital to understand the forcing mechanisms of past climatic regime shifts in the Asian monsoon domain. Here we use novel recurrence network analysis techniques for detecting episodes with pronounced non-linear changes in Holocene Asian monsoon dynamics recorded in speleothems from caves distributed throughout the major branches of the Asian monsoon system. A newly developed multi-proxy methodology explicitly considers dating uncertainties with the COPRA (COnstructing Proxy Records from Age models) approach and allows for detection of continental-scale regime shifts in the complexity of monsoon dynamics. Several epochs are characterised by non-linear regime shifts in Asian monsoon variability, including the periods around 8.5-7.9, 5.7-5.0, 4.1-3.7, and 3.0-2.4 ka BP. The timing of these regime shifts is consistent with known episodes of Holocene rapid climate change (RCC) and high-latitude Bond events. Additionally, we observe a previously rarely reported non-linear regime shift around 7.3 ka BP, a timing that matches the typical 1.0-1.5 ky return intervals of Bond events. A detailed review of previously suggested links between Holocene climatic changes in the Asian monsoon domain and the archaeological record indicates that, in addition to previously considered longer-term changes in mean monsoon intensity and other climatic parameters, regime shifts in monsoon complexity might have played an important role as drivers of migration, pronounced cultural changes, and the collapse of ancient human societies.
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| 6. |
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| 7. |
- Lindqvist, Andreas, et al.
(författare)
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The impact of Roux-en-Y gastric bypass surgery on normal metabolism in a porcine model
- 2017
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- Background A growing body of literature on Roux-en-Y gastric bypass surgery (RYGB) has generated inconclusive results on the mechanism underlying the beneficial effects on weight loss and glycaemia, partially due to the problems of designing clinical studies with the appropriate controls. Moreover, RYGB is only performed in obese individuals, in whom metabolism is perturbed and not completely understood. In an attempt to isolate the effects of RYGB and its effects on normal metabolism, we investigated the effect of RYGB in lean pigs, using sham-operated pair-fed pigs as controls. Two weeks post-surgery, pigs were subjected to an intravenous glucose tolerance test (IVGTT) and circulating metabolites, hormones and lipids measured. Bile acid composition was profiled after extraction from blood, faeces and the gallbladder. A similar weight development in both groups of pigs validated our experimental model. Despite similar changes in fasting insulin, RYGB-pigs had lower fasting glucose levels. During an IVGTT RYGB-pigs had higher insulin and lower glucose levels. VLDL and IDL were lower in RYGB-than in sham-pigs. RYGB-pigs had increased levels of most amino acids, including branched-chain amino acids, but these were more efficiently suppressed by glucose. Levels of bile acids in the gallbladder were higher, whereas plasma and faecal bile acid levels were lower in RYGB-than in sham-pigs. In a lean model RYGB caused lower plasma lipid and bile acid levels, which were compensated for by increased plasma amino acids, suggesting a switch from lipid to protein metabolism during fasting in the immediate postoperative period.
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| 8. |
- Madsen, O. D., et al.
(författare)
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Cloned cell lines from a transplantable islet cell tumor are heterogeneous and express cholecystokinin in addition to islet hormones
- 1986
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Ingår i: Journal of Cell Biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 103:5, s. 2025-2034
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Tidskriftsartikel (refereegranskat)abstract
- A liver metastasis (MSL) with a remarkable in vitro proliferation potential has been identified in an NEDH rat carrying a transplantable x-ray-induced islet cell tumor. Two insulin-secreting cell lines, MSL-G and MSL-H, with doubling times of 3-5 d were established by repeated limiting dilution cloning. In vivo inoculation of MSL-G cells induced severe hypoglycemia caused by a small but highly heterogeneous tumor as revealed by immunocytochemistry. Whereas most cells stained for the islet hormones, insulin, glucagon, and somatostatin, clustered cells were discovered to contain cholecystokinin (CCK). Additional in vitro-limiting dilution cloning, followed by immunocytochemical characterization, clearly demonstrated the capacity of single cell clones to simultaneously express the same four hormones. Radioimmunoassays with a panel of site-specific antisera of culture supernatants and purified cell extracts showed the MSL-G2 cells to produce, store, and secrete readily detectable amounts of processed and unprocessed CCK. Gastrin was not detected while coexpression of glucagon and CCK were demonstrated. Mutant clones selected for resistance to 6-thioguanine (frequency, 2 x 10-7) and checked for HAT (hypoxanthine, aminopterin, thymidine) sensitivity retained the capacity for multihormone expression. We propose that the MSL tumor contains pluripotent endocrine stem cells. The MSL tumor and the MSL-G2 cells in particular will allow studies of not only CCK biosynthesis and processing but also of mechanisms involved in tumor and islet cell differentiation.
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| 9. |
- Ohlsson, Bodil, et al.
(författare)
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CCK stimulates growth of both the pancreas and the liver
- 1999
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Ingår i: International journal of surgical investigation. - 1607-8519. ; 1:1, s. 47-54
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The pancreas is the main target of the trophic effect of cholecystokinin (CCK), with a transient increase in cell proliferation and persistent effect on DNA content and weight gain when given continuously. Whether CCK exerts similar effects on the liver and biliary tract is not known. Most studies on this subject have hitherto been done in the rat. The aim of the present experiments was therefore to study the possible concomitant trophic effects of CCK on these three organs in a gallbladder-bearing animal, the hamster. METHODS: CCK-8S or the CCK-A receptor antagonist devazepide were infused subcutaneously by osmotic minipumps for 4 weeks in 11 and 7 hamsters, respectively. Fifteen animals served as untreated controls. One hour before sacrifice tritiated thymidine was injected intraperitoneally. Plasma was collected for determination of CCK and the pancreas, liver, common bile duct and gallbladder were excised. The pancreas and liver were weighed and processed for the contents of protein, DNA and water. Tissue specimens were taken for autoradiography. RESULTS: The concentration of CCK in plasma increased fourfold during the infusion of CCK-8S. The pancreas and, to a lesser extent, the liver increased in weight, DNA and protein contents after infusion of CCK-8S, whereas the pancreas, but not the liver, decreased in weight and protein content after infusion of devazepide. Pancreatic amylase content was increased after CCK-8S treatment, but unaffected by devazepide. Labelling index of pancreatic acinar cells, hepatocytes and gallbladder epithelium was no different from that of controls after four weeks of infusion of CCK-8S or devazepide. A correlation was found between the concentration of plasma CCK on one hand and the weights and DNA contents in pancreas and liver on the other. CONCLUSION: The results suggest that CCK stimulates growth of both the pancreas and the liver in the hamster.
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| 10. |
- Ohlsson, Bodil, et al.
(författare)
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Cholecystokinin does not affect the pancreatic contents of epidermal growth factor or its receptor
- 2000
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Ingår i: Pancreas. - 0885-3177. ; 21:4, s. 385-391
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Tidskriftsartikel (refereegranskat)abstract
- Cholecystokinin (CCK) is a hormone with well-known secretory and trophic effects on the pancreas. This also is true for epidermal growth factor (EGF), which acts in a paracrine and autocrine way. The aim was to study the influence of CCK on cell proliferation in rat pancreas with special reference to the expression of EGF, the EGF receptor, and phosphorylated tyrosine. Twenty-four male Sprague-Dawley rats received either one single injection, or injections twice daily for 3 days of 6 microg sulfated CCK-8 (CCK-8S) subcutaneously in the neck. The same number of rats received injections of 1% bovine serum albumin (BSA) in the same way. The rats were killed 1, 3, or 6 hours after the last injection. One hour before killing, they received 50 mg/kg of bromodeoxyuridine (BrdU) intraperitoneally. Plasma was collected for analysis of CCK. The pancreas was dissected, and in situ hybridization using a probe for EGF mRNA was performed for semiquantification of gene expression. Immunocytochemistry using antibodies against the EGF receptor and phosphotyrosine was performed to examine the expression of the proteins, and against BrdU for measuring the cell proliferation. A single injection of CCK-8S led to hyperCCKemia at 1 and 3 hours afterward. After 6 hours, plasma CCK had returned to the same levels as in control rats. The cell proliferation was unaffected. The rats that received CCK-8S injections for 3 days still had hyperCCKemia 6 hours after the last injection. The cell proliferation was increased by CCK, as indicated by the BrdU labeling. However, neither body weight nor pancreatic weight was affected. In controls, EGF was expressed all over the gland, but its receptor and phosphotyrosine were expressed only in ductal cells and in the islet cells of endocrine pancreas. There was no difference in the pancreatic staining of EGF, its receptor, or phosphotyrosine at the different time points studied. There was no difference in the staining of EGF and its receptor between CCK-8S- and BSA-treated animals, but phosphotyrosine staining was detectable in acinar cells after 3 days of CCK-8S injections. Thus CCK-8S causes hyperCCKemia with ensuing enhanced cell proliferation in rat pancreas. This effect on the cell proliferation seems to be a direct effect of CCK and not mediated by changes in the tissue levels of EGF or its receptor.
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