azd7687 has been researched along with Insulin-Resistance* in 2 studies
1 trial(s) available for azd7687 and Insulin-Resistance
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Proof of mechanism for the DGAT1 inhibitor AZD7687: results from a first-time-in-human single-dose study.
Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which catalyses the final step in triacylglycerol (TAG) assembly, is suggested as a treatment for type 2 diabetes and obesity based on animal data indicating insulin sensitization and weight reduction. This first-time-in-human single ascending dose study explored the safety, tolerability, pharmacokinetics and pharmacodynamics of the selective DGAT1 inhibitor AZD7687.. Eighty healthy male subjects were enrolled. In each of 10 cohorts, six subjects received the same dose of AZD7687 orally (range across cohorts 1-60 mg) and two placebo. Plasma AZD7687 exposure was measured repeatedly. Postprandial serum TAG excursion was measured during 8 h after a standardized mixed meal with fat energy content of 60% (SMM 60%; five cohorts, 1-20 mg), before (baseline) and after dosing, to assess effects on gut DGAT1 activity.. AZD7687 markedly reduced postprandial TAG excursion with a steep concentration-effect relationship. Incremental TAG AUC (area under the serum concentration vs. time curve) following SMM 60% was decreased >75% from baseline at doses ≥5 mg (p < 0.0001 vs. placebo). Serum levels of diacylglycerol, specifically measured with mass spectrometry, did not increase after AZD7687 administration. Nausea, vomiting and diarrhoea were reported with increasing doses and they limited dose escalation. Lowering of SMM fat content to 45 or 30% in five cohorts gradually reduced the frequency of gastrointestinal symptoms at a given dose of AZD7687.. The attenuating effect of AZD7687 on postprandial TAG excursion provides proof of mechanism with respect to gut DGAT1 inhibition. However, dose and diet-related gastrointestinal side effects may impact further development of DGAT1 inhibitors. Topics: Acetates; Adult; Area Under Curve; Cohort Studies; Diabetes Mellitus, Type 2; Diacylglycerol O-Acyltransferase; Diglycerides; Dose-Response Relationship, Drug; Humans; Insulin Resistance; Intestinal Absorption; Male; Mass Spectrometry; Postprandial Period; Pyrazines; Treatment Outcome; Triglycerides | 2013 |
1 other study(ies) available for azd7687 and Insulin-Resistance
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Pharmacological inhibition of DGAT1 induces sebaceous gland atrophy in mouse and dog skin while overt alopecia is restricted to the mouse.
Diacylglycerol O-acyltransferase 1 (DGAT1) plays an important role in synthesizing lipids, and inhibitors of DGAT1 have been investigated as potential treatments for diabetes and metabolic diseases. DGAT1 knockout (-/-) mice are resistant to obesity, have increased sensitivity to insulin, and exhibit sebaceous gland atrophy and alopecia. Prolonged pharmacological inhibition of DGAT1 with AZD7687 in mice results in the same skin phenotype, including sebaceous gland atrophy and alopecia, as seen in the skin of DGAT1 (-/-) mice. AZD7687-mediated effects on the skin were dose- and time-dependent and reversible. They occurred only at substantial levels of continuous DGAT1 inhibition. Prolonged treatment of dogs with AZD7687 also resulted in sebaceous gland atrophy but did not result in the more adverse skin changes of hair loss and skin lesions. Our findings highlight a significant risk of generating the same lesions that were seen in mouse skin during clinical development of DGAT1 inhibitors in humans and also reveal a species difference in the effects on the skin, indicating that the mouse may be an especially sensitive species. Therefore, although human therapeutic doses may not have the same influence on skin morphology as seen in mice, monitoring of skin changes will be essential in clinical trials with DGAT1 inhibitors. Topics: Acetates; Alopecia; Animals; Diacylglycerol O-Acyltransferase; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Insulin Resistance; Male; Mice; Mice, Inbred ICR; Mice, Knockout; Pyrazines; Sebaceous Glands; Skin | 2015 |