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31.
Ho RH Tirona RG Leake BF Glaeser H Lee W Lemke CJ Wang Y Kim RB 《Gastroenterology》2006,130(6):1793-1806
BACKGROUND & AIMS: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, target liver HMG-CoA and are of proven benefit in the prevention of coronary heart disease. Rosuvastatin is an effective statin notable for liver selectivity and lack of significant metabolism. We assessed the extent and relevance of hepatic transporters to rosuvastatin uptake. METHODS: Transporters involved in rosuvastatin uptake were determined through heterologous expression of multiple human and rat uptake transporters. Human organic anion transporting polypeptide (OATP) 1B1 and sodium-dependent taurocholate cotransporting polypeptide (NTCP) allelic variants were also assessed. Expression of OATP and NTCP messenger RNA and protein was determined from a bank of human liver samples. RESULTS: Multiple OATP family members, including 1B1, 1B3, 2B1, and 1A2, were capable of rosuvastatin transport. Naturally occurring polymorphisms in OATP1B1, including *5, *9, *15, and *18, were associated with profound loss of activity toward rosuvastatin. Interestingly, the major human hepatic bile acid uptake transporter NTCP, but not rat Ntcp, also transported rosuvastatin. Human hepatocyte studies suggested that NTCP alone accounted for approximately 35% of rosuvastatin uptake. Remarkably, NTCP*2, a variant known to have a near complete loss of function for bile acids, exhibited a profound gain of function for rosuvastatin. Quantitative messenger RNA analysis revealed marked intersubject variability in expression of OATPs and NTCP. CONCLUSIONS: Multiple transporters mediate the overall hepatic uptake of rosuvastatin, and NTCP may be a heretofore unrecognized transporter important to the disposition of rosuvastatin and possibly other drugs/statins in clinical use. Accordingly, transporter expression and polymorphisms may be key determinants of intersubject variability in response to statin therapy in general. 相似文献
32.
Dr. F. K. Gorus J. -C. Sodoyez D. G. Pipeleers B. Keymeulen A. Foriers C. F. H. Van Schravendijk 《Diabetologia》1992,35(11):1080-1086
Summary A radiobinding assay for the detection of autoantibodies against islet amyloid polypeptide was developed, analytically validated, and -in parallel with a similar assay for the detection of autoantibodies against insulin — applied to sera from recent-onset Type 1 (insulin-dependent) diabetic patients and from age- and sex-matched control subjects. There was no difference in islet amyloid polypeptide autoantibody titres between patient groups and matched control subjects, nor within subject groups according to age. At onset of Type 1 diabetes, elevated islet amyloid polypeptide-autoantibody levels (> 97th percentile of control subjects) were only detected in 1 of 30 patients aged 0–19 years and in 2 of 35 patients aged 20–39 years. By contrast, insulin autoantibodies were frequently demonstrated, in particular at onset of diabetes under age 20 (0–19 years: 18 of 30 patients; 20–39 years: 10 of 35 patients; p < 0.01 vs matched control subjects). Islet amyloid polypeptide autoantibodies were not detectable in 3 insulinoma patients nor in 37 patients (aged 33–70 years) with Type 2 diabetes (vs 1 of 40 in matched control subjects). In positive serum, adsorption onto protein A-Sepharose removed islet amyloid polypeptide binding activity, hereby confirming its antibody nature. In conclusion, Type 1 diabetes is associated with an age-dependent autoantibody reaction against insulin but not against islet amyloid polypeptide. Conditions associated with amyloid deposition in islets (Type 2 diabetes, insulinoma and ageing) do not favour the formation of autoantibodies against islet amyloid polypeptide. 相似文献
33.
Kyoko Miyasaka MD Kazunori Miyazaki MD Akihiro Funakoshi MD Kenichi Kitani MD 《Digestive diseases and sciences》1989,34(3):474-480
The possibility of the involvement of pancreatic polypeptide (PP) release in luminal feedback regulation in the conscious rat was examined. Pancreatic secretion in the intestinal phase in the rat is regulated by negative feedback control so that a decrease in luminal protease activities produced by a diversion of bile-pancreatic juice (BPJ) from the intestine stimulates pancreatic secretion. Plasma concentration of rat PP and the effect of exogenous infusion of rat PP on pancreatic secretions during BPJ diversion were determined. Plasma PP concentration significantly increased with BPJ diversion and peaked at 90 min after BPJ diversion began, almost paralleling changes in protein output. Exogenous PP infusion (1, 2, and 10 g/kg/hr) inhibited pancreatic protein and fluid outputs but not the bicarbonate output during BPJ diversion. PP was shown to be physiologically released in the intestinal phase of pancreatic secretion; however, the physiological role of endogenous PP remains unknown.This study was supported in part by the Uehara Memorial Foundation and a grant in aid from the Japanese Ministry of Education. 相似文献
34.
《Journal of the American College of Cardiology》2020,75(11):1341-1350
Millions of individuals in the United States require long-term treatment with an oral anticoagulant. For decades, vitamin K antagonists were the only oral option available; however, they have a number of well-known limitations. Introduction of the direct oral anticoagulants (DOACs) has long been considered a major therapeutic advance, largely because they lack the need for therapeutic monitoring. Despite this, DOACs, like vitamin K antagonists, can still cause major and clinically relevant nonmajor bleeding, even when used appropriately. Drug-drug interactions (DDIs) involving the DOACs represent an important contributor to increased bleeding risk. Awareness of these DDIs and how best to address them is of critical importance in optimizing management while mitigating bleeding risk. This review provides an overview of DOAC metabolism, the most common drugs likely to contribute to DOAC DDIs, their underlying mechanisms, and how best to address them. 相似文献
35.
Summary Islet amyloid polypeptide or amylin is a polypeptide secreted mainly from the pancreatic beta cells together with insulin upon stimulation. High levels of islet amyloid polypeptide have also been shown to increase the peripheral insulin resistance and consequently a role for islet amyloid polypeptide in the glucose homeostasis has been suggested. We have studied the glucose homeostasis in a patient with a malignant endocrine pancreatic tumour producing large amounts of an islet amyloid polypeptide-like molecule (about 400 times the upper reference level for islet amyloid polypeptide). This patient developed insulin-requiring diabetes mellitus shortly after the tumour diagnosis. Both intravenous and oral glucose tolerance tests revealed inhibited early responses in insulin and C-peptide release, but the insulin and C-peptide response to glucagon stimulation was less affected. Aneuglycaemic insulin clamp showed normal insulin-mediated glucose disposal. In vitro experiments, where isolated rat pancreatic islets were cultured with serum from the patient, showed a moderately decreased islet glucose oxidation rate and glucose-stimulated insulin release compared to islets cultured with serum from healthy subjects. However, culture of rat islets with normal human serum supplemented with synthetic rat islet amyloid polypeptide did not affect the glucose-stimulated insulin release. In conclusion, the observed effects show that the diabetic state in this patient was associated with an impaired glucose-stimulated insulin release but not with an increased peripheral insulin resistance. Thus, the results suggest that if islet amyloid polypeptide has diabetogenic effects they are more likely to be exerted at the level of insulin secretion than at the level of peripheral insulin sensitivity. 相似文献
36.
Summary Systematic sampling of human necropsy pancreases has revealed that pancreatic polypeptide (PP) cells are not distributed equally in the gland. PP-cells are the most abundant cell type in the posterior part of the pancreatic head while they are scarce or absent in the remainder of the gland. The PP-rich part of the head can be separated by blunt dissection from the pancreas as a discrete lobe. This lobe probably originates from the ventral pancreatic bud during embryogenesis. A quantitative study of the immunofluorescent endocrine cell types (insulin, glucagon, somatostatin and pancreatic polypeptide cells) in PP-rich and PP-poor regions of pancreases in 8 subjects with ages ranging from 33 fetal weeks to 80 years, showed that the proportions of the cell types were different in youngs and adults. 相似文献
37.
Dr. I. R. Jones D. R. Owens A. J. Moody S. D. Luzio T. Morris T. M. Hayes 《Diabetologia》1987,30(9):707-712
Summary The effects of porcine glucose-dependent insulinotropic polypeptide given by continuous intravenous infusion in normal subjects (n=6) and Type 2 (non-insulin-dependent) diabetic patients (n=6) have been investigated. The subjects were studied on 2 separate days after overnight fasts. On each day 25 g of glucose was infused from 0–30 min plus an infusion of either porcine glucose-dependent insulinotropic polypeptide (0.75 pmol·kg–1·min–1) or control solution. During the glucose-dependent insulinotropic polypeptide infusion plasma glucose values were reduced in normal subjects from 30–60 min (p<0.01) and in Type 2 diabetic patients at 45 and 60 min (p<0.05). In the normal subjects insulin concentrations were greater from 10–35 min (p<0.01) following glucose-dependent insulinotropic polypeptide infusion and peak values were increased by 123%. In the Type 2 diabetic patients following glucose-dependent insulinotropic polypeptide infusion insulin levels were increased from 4–40 min (p<0.01) but peak values were only increased by 27%. In the normal subjects C-peptide values were greater from 25–45 min (p<0.01) following glucose-dependent insulinotropic polypeptide infusion and peak C-peptide levels were increased by 82%. In the Type 2 diabetic patients following the glucose-dependent insulinotropic polypeptide infusion C-peptide levels were increased from 6–55 min (p<0.01) and peak values were increased by 20%. Plasma glucose-dependent insulinotropic polypeptide levels were within the physiological post prandial range during the glucose-dependent insulinotropic polypeptide infusion. Glucose-dependent insulinotropic polypeptide is insulinotropic in normal subjects and Type 2 diabetic patients at physiological concentrations and results in improved glucose tolerance. This insulinotropic effect is less marked in the diabetic patients and may represent insensitivity of the B cell to glucose-dependent insulinotropic polypeptide. 相似文献
38.
Alpha-naphthylisothiocyanate (ANIT) induces intra-hepatic cholestasis mixed with hepatocellular injury mainly by bile ductular damage. However, its direct effect on hepatic parenchymal cells (hepatocytes) is unclear. Sandwich-cultured rat hepatocytes (SCRH) were applied to clarify this question. Though cytotoxicity was not observed (0–180 μM) in ANIT-treated SCRH, metabonomics analysis of the hepatocytes revealed a shift in the metabolic pattern and a decrease in cellular cholesterol level, accompanied by an increase in total bile acids after 48 h ANIT (5–45 μM) treatment. To assess the function of major hepatic bile acid transporters, the accumulation and efflux of [D-Pen2,5]-enkephalin (DPDPE), 5 (and 6)-carboxy-2′,7′-dichlorofluorescein (CDF) diacetate promoiety and deuterium-labeled sodium taurocholate (d8-TCA) were measured. ANIT incubation for either 30 min or 48 h led to dose-dependent decreases in the biliary excretion index (BEI) of DPDPE and CDF, as well as the intracellular accumulation of d8-TCA, CDF and DPDPE. The basolateral efflux of d8-TCA was also decreased with its BEI barely changed. mRNA expression of multiple uptake transporters and bile acid synthesizing enzymes was down-regulated after 48 h incubation. In conclusion, ANIT could directly induce retention of bile acids in hepatocytes by inhibiting the function of bile acid transporters, which might contribute to its cholestatic effect. 相似文献
39.
胰岛淀粉样多肽是2型糖尿病的重要致病原因之一.为了研究胰岛淀粉样多肽的生物学作用及其应用范围,本文拟通过文本挖掘技术来对胰岛淀粉样多肽生化用专业试剂和试剂盒检测的研究发展趋势进行探测. 相似文献
40.
Summary Considerable disagreement exists regarding the levels of immunoreactive glucose dependent insulinotropic polypeptide in patients with Type 2 (non-insulin-dependent) diabetes mellitus. Glucose dependent insulinotropic polypeptide levels were therefore studied during oral glucose and mixed meal tolerance tests in normal subjects (n=31) and newly presenting previously untreated patients with Type 2 diabetes mellitus (n=68). The tests were performed in random order after overnight fasts and blood samples were taken at 30 min intervals for 4 h. During the oral glucose tolerance test plasma glucose dependent insulinotropic polypeptide levels increased in the normal subjects from a fasting value of 20±3 pmol/l to a peak of 68±5 pmol/l at 30 min and in the Type 2 diabetic patients from a similar fasting level of 27±3 pmol/l to a higher peak value of 104±6 pmol/l at 30 min (p<0.001). Glucose dependent insulinotropic polypeptide levels were significantly higher in the diabetic patients compared with the normal subjects from 30–90 min (p<0.01–0.001) following oral glucose. During the meal tolerance test glucose dependent insulinotropic polypeptide levels increased in the normal subjects from a pre-prandial value of 22±4 pmol/l to a peak of 93±6 pmol/l at 90 min and in the Type 2 diabetic patients from a similar basal level of 25±2 pmol/l to a higher peak of 133±7 pmol/l at 60 min. Glucose dependent insulinotropic polypeptide concentrations were significantly higher in Type 2 diabetic patients compared with the normal subjects at 30 min (p<0.001), 60 min (p<0.01) and from 210–240 min (p<0.05) during the meal tolerance test. The groups were subdivided on the basis of degree of obesity and glucose dependent insulinotropic polypeptide concentrations were still higher in the diabetic subgroups compared with the normal subjects matched for weight. Type 2 diabetes mellitus is associated with an exaggerated glucose dependent insulinotropic polypeptide response to oral glucose and mixed meals which is independent of any effect of obesity. 相似文献