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A Phase I Study on the Pharmacokinetics and Pharmacodynamics of DJT1116PG, a Novel Selective Inhibitor of Sodium-glucose Cotransporter Type 2, in Healthy Individuals at Steady State.
Zhang, H, Liu, J, Zhu, X, Li, X, Chen, H, Wu, M, Li, C, Ding, Y
Clinical therapeutics. 2020;(5):892-905.e3
Abstract
PURPOSE DJT1116PG, which selectively inhibits renal glucose reabsorption by inhibiting sodium-glucose cotransporter type 2, was developed as an insulin-independent treatment for type 2 diabetes mellitus. This Phase I trial evaluated the pharmacokinetic and pharmacodynamic properties of DJT1116PG at steady state in healthy Chinese individuals. METHODS This was a multiple ascending dose study of DJT1116PG (20, 50, and 100 mg once daily for 7 days) that included 36 healthy individuals. FINDINGS There were no serious adverse events or deaths in these studies, and no adverse event led to study discontinuation. Oral DJT1116PG was rapidly absorbed with a Tmax of 0.75-1.5 h and a t½ of 12-16.2 h. Systemic exposure (Cmax and AUC) of DJT1116PG and its inactive metabolites (T1444, T1454, and T1830) increased in a dose-dependent manner. Urinary glucose excretion (UGE) plateaued at 50 mg of DJT1116PG in a previous single ascending dose study and on day 1 of this study. UGE plateaued at 20 mg of DJT1116PG on day 7 of this study. Serum glucose parameters were similar in individuals who received DJT1116PG or placebo. IMPLICATIONS DJT1116PG was well tolerated in healthy Chinese individuals. At steady state, UGE plateaued at 20 mg of DJT1116PG in these individuals. These findings will inform the selection of doses for further early-stage clinical trials of DJT1116PG. Chinese Drug Trial Identifier: CTR20160986.
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Gut microbiota metabolites, amino acid metabolites and improvements in insulin sensitivity and glucose metabolism: the POUNDS Lost trial.
Heianza, Y, Sun, D, Li, X, DiDonato, JA, Bray, GA, Sacks, FM, Qi, L
Gut. 2019;(2):263-270
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Abstract
OBJECTIVE Alterations in gut microbiota have been linked to host insulin resistance, diabetes and impaired amino acid metabolism. We investigated whether changes in gut microbiota-dependent metabolite of trimethylamine N-oxide (TMAO) and its nutrient precursors (choline and L-carnitine) were associated with improvements in glucose metabolism and diabetes-related amino acids in a weight-loss diet intervention. DESIGN We included 504 overweight and obese adults who were randomly assigned to one of four energy-reduced diets varying in macronutrient intake. The 6-month changes (Δ) in TMAO, choline and L-carnitine levels after the intervention were calculated. RESULTS Greater decreases in choline and L-carnitine were significantly (p<0.05) associated with greater improvements in fasting insulin concentrations and homeostasis model assessment of insulin resistance (HOMA-IR) at 6 months. The reduction of choline was significantly related to 2-year improvements in glucose and insulin resistance. We found significant linkages between dietary fat intake and ΔTMAO for changes in fasting glucose, insulin and HOMA-IR (pinteraction <0.05); a greater increase in TMAO was related to lesser improvements in the outcomes among participants who consumed a high-fat diet. In addition, ΔL-carnitine and Δcholine were significantly related to changes in amino acids (including branched-chain and aromatic amino acids). Interestingly, the associations of ΔTMAO, Δcholine and ΔL-carnitine with diabetes-related traits were independent of the changes in amino acids. CONCLUSION Our findings underscore the importance of changes in TMAO, choline and L-carnitine in improving insulin sensitivity during a weight-loss intervention for obese patients. Dietary fat intake may modify the associations of TMAO with insulin sensitivity and glucose metabolism. TRIAL REGISTRATION NUMBER NCT00072995.