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Effects of KDT501 on Metabolic Parameters in Insulin-Resistant Prediabetic Humans.

ABSTRACT: Context:KDT501 is an isohumulone drug that has demonstrated beneficial effects on metabolic parameters in mice. Objective:This study was intended to examine potential improvements in metabolism in humans. Design and Setting:Changes in carbohydrate and lipid metabolism, along with inflammatory markers, were evaluated in prediabetic humans in a clinical research center. Participants:Nine obese patients participated. All had prediabetes or normal glucose tolerance plus three features of metabolic syndrome. Intervention:All participants were treated with escalating doses of KDT501 to a maximum dose of 1000 mg every 12 hours for a total of 28 days. Outcome Measures:Changes in carbohydrate metabolism were measured with oral glucose tolerance, homeostatic model of insulin resistance, and euglycemic clamp; changes in plasma lipids and response to a lipid tolerance test; and changes in plasma inflammatory markers. Results:The drug was well tolerated. After KDT501 treatment, plasma triglycerides were reduced at 4 hours during a lipid tolerance test. Furthermore, plasma adiponectin and high-molecular-weight adiponectin increased significantly, and plasma tumor necrosis factor-? decreased significantly. There were no significant changes in oral glucose tolerance test results or insulin sensitivity measures. Conclusions:Despite the small sample size and the short duration of therapy, KDT501 administration reduced measures of systemic inflammation and improved postmeal plasma triglyceride levels, which may be beneficial in participants with insulin resistance or metabolic syndrome.

SUBMITTER: Kern PA

PROVIDER: S-EPMC5686568 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Effects of KDT501 on Metabolic Parameters in Insulin-Resistant Prediabetic Humans.

Kern Philip A PA Finlin Brian S BS Ross Dorothy D Boyechko Tania T Zhu Beibei B Grayson Neile N Sims Robert R Bland Jeffrey S JS

Journal of the Endocrine Society 20170421 6

<h4>Context</h4>KDT501 is an isohumulone drug that has demonstrated beneficial effects on metabolic parameters in mice.<h4>Objective</h4>This study was intended to examine potential improvements in metabolism in humans.<h4>Design and setting</h4>Changes in carbohydrate and lipid metabolism, along with inflammatory markers, were evaluated in prediabetic humans in a clinical research center.<h4>Participants</h4>Nine obese patients participated. All had prediabetes or normal glucose tolerance plus ...[more]

PMID: 29264518

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Project description:Inhibition of cannabinoid receptor 1 (CB1) has shown efficacy in reducing body weight and improving metabolic parameters, with the effects correlating with target engagement in the brain. Recently, the peripheral effects of inhibiting the CB1 receptor has been appreciated through studies in diet-induced obese and liver-specific CB1 KO mice. In this report, we systematically investigated gene expression changes in peripheral tissues of DIO mice treated with the CB1 inverse agonist AM251. CB1 receptor inhibition led to down-regulation of genes within the de novo fatty acid and cholesterol synthetic pathways, including SREBP-1 and -2, and their downstream targets in both liver and adipose tissue. In addition, genes involved in fatty acid Beta-oxidation were up-regulated with AM251 treatment, probably through the activation of PPARalpha. In adipose tissue, CB1 receptor inhibition led to the down-regulation of genes in the TNFalpha signal transduction pathway and possibly to the activation of PPARgamma, both of which would result in improved insulin sensitivity. CB1-/- mice were obtained from A. Zimmer (University of Bonn) (Zimmer et al., 1999) and back-crossed onto C57BL/6J genetic background for ten generations by A. Zimmer before homozygous CB1-/- mice were re-derived at Taconic Farms (German Town, NY) onto the C57BL/6N genetic background. Male CB1-/- mice and control littermates (n=5-7 in each group) at 2 months of age were fed with regular chow (Teklad 7012, 13 % kcal from fat, 3.41 kcal/g, Harlan Laboratories, Indianapolis, IN, USA) or high fat diet (S3282, 59.4% kcal from fat; 24.5% kcal from carbohydrate; 16.2% kcal from protein; 5.29 kcal/g, Bio-Serv, Frenchtown, NJ, USA) for 14 weeks, and were individually caged 1 week before drug treatment. Vehicle (0.5% methylcellulose) or AM251 (10 mg/kg, Sigma, St Louis, MO, USA) were dosed by oral gavage at 5:00 PM daily for 2 days. Body weight was measured at 5:00 PM on day 1 and 2, and at 10:00 AM on day 3 before tissue collection. Food was measured at 5:00 PM on day 1 and at 10:00 AM on day 3 before tissue collection. Food intake is calculated as the difference in food weight at the start minus at the end of the study. Mice were euthanized by CO2 asphyxiation at 10:00 AM following the second dose.

Dataset Information

Effects of KDT501 on Metabolic Parameters in Insulin-Resistant Prediabetic Humans.

Publications

Effects of KDT501 on Metabolic Parameters in Insulin-Resistant Prediabetic Humans.

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