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- 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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- 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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- Vilsboll, T., et al.
(författare)
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Dapagliflozin Plus Saxagliptin Add-on Therapy Compared With Insulin in Patients With Type 2 Diabetes Poorly Controlled by Metformin With or Without Sulfonylurea Therapy: A Randomized Clinical Trial
- 2019
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 42:8, s. 1464-1472
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE This study evaluated whether an oral combination of a sodium-glucose cotransporter 2 inhibitor and a dipeptidyl peptidase 4 inhibitor achieved glycemic control similar to basal insulin in patients with type 2 diabetes, poorly controlled with metformin, without increasing hypoglycemia or body weight. RESEARCH DESIGN AND METHODS In a multinational, open-label, randomized, phase 3 trial ( reg. no. ), adults with type 2 diabetes inadequately controlled on metformin, with or without sulfonylurea, were randomized (1:1) to receive dapagliflozin (DAPA) plus saxagliptin (SAXA) or titrated insulin glargine (INS). The primary end point was change in glycated hemoglobin A(1c) (HbA(1c)) from baseline to week 24. DAPA + SAXA treatment was tested for noninferiority versus INS. RESULTS The efficacy data set included 643 patients (mean +/- SD HbA(1c), 9.1 +/- 1.0% [75 +/- 11 mmol/mol]). At week 24, DAPA + SAXA treatment versus INS resulted in noninferior reductions in HbA(1c) (adjusted mean +/- SE change, -1.7 +/- 0.1% vs. -1.5 +/- 0.1% [18.3 +/- 0.7 mmol/mol vs. 16.8 +/- 0.7 mmol/mol]; P = 0.118), significantly different body weight change (between-group difference, -3.64 kg [95% CI -4.20 to -3.09]; P < 0.001), fewer patients with confirmed hypoglycemia (21.3% vs. 38.4%, P < 0.001), more patients achieving HbA(1c) <7.0% (53 mmol/mol) without hypoglycemia (20.9% vs. 13.1%, P = 0.008), and a similar proportion of patients achieving HbA(1c) <7.0% (33.2% vs. 33.5%, P = 0.924). Mean reductions in 24-h glucose measurements from baseline to week 2 were greater with DAPA + SAXA than with INS (P < 0.0001). No patients in the DAPA + SAXA group and three patients (0.9%) in the INS group experienced severe hypoglycemia. CONCLUSIONS Adding DAPA + SAXA to insulin-naive patients with poorly controlled type 2 diabetes achieved similar glycemic control, a lower risk of hypoglycemia, and a clinically relevant body weight difference compared with basal INS.
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