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Diacylglycerol acyl...
Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects : a randomized clinical trial
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Denison, H (author)
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Nilsson, C (author)
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Löfgren, L (author)
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Himmelmann, A (author)
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Mårtensson, G (author)
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Knutsson, M (author)
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Al-Shurbaji, A (author)
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Tornqvist, H (author)
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- Eriksson, Jan W (author)
- Uppsala universitet,Endokrin diabetes och metabolism
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(creator_code:org_t)
- 2013-10-31
- 2014
- English.
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In: Diabetes, obesity and metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 16:4, s. 334-343
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- AIM:Inhibition of diacylglycerol acyltransferase 1 (DGAT1) is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. This randomized, placebo-controlled, phase 1 study in 62 overweight men explored the effects and tolerability of AZD7687, a reversible and selective DGAT1 inhibitor.METHODS:Multiple doses of AZD7687 (1, 2.5, 5, 10 and 20 mg/day, n = 6 or n = 12 for each) or placebo (n = 20) were administered for 1 week. Postprandial serum triacylglycerol (TAG) was measured for 8 hours after a standardized 45% fat meal. Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured and a paracetamol challenge was performed to assess gastric emptying.RESULTS:Dose-dependent reductions in postprandial serum TAG were demonstrated with AZD7687 doses ≥5 mg compared with placebo (p < 0.01). Significant (p < 0.001) increases in plasma GLP-1 and PYY levels were seen at these doses, but no clear effect on gastric emptying was demonstrated at end of treatment. With AZD7687doses >5 mg/day, gastrointestinal (GI) side effects increased; 11/18 of these participants discontinued treatment owing to diarrhoea.CONCLUSIONS:Altered lipid handling and hormone secretion in the gut were demonstrated during 1-week treatment with the DGAT1 inhibitor AZD7687. However, the apparent lack of therapeutic window owing to GI side effects of AZD7687, particularly diarrhoea, makes the utility of DGAT1 inhibition as a novel treatment for diabetes and obesity questionable.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
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- ref (subject category)
- art (subject category)
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- By the author/editor
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Denison, H
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Nilsson, C
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Löfgren, L
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Himmelmann, A
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Mårtensson, G
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Knutsson, M
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show more...
-
Al-Shurbaji, A
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Tornqvist, H
-
Eriksson, Jan W
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
- Articles in the publication
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Diabetes, obesit ...
- By the university
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Uppsala University
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Karolinska Institutet