Metabolic Effects of Ketohexokinase Inhibition on Individuals With Non-alcoholic Fatty Liver Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- Hepatic insulin sensitivity
研究概览
简要总结
Fructose is a big contributor to the development of non-alcoholic fatty liver disease (NAFLD). Inhibiting ketohexokinase (KHK), the enzyme catalyzing the first committed step in fructose metabolism, is thought to reduced intrahepatic lipid (IHL) content. Pharmacological inhibition of KHK resulted in a decrease in IHL content in NAFLD patients, but additional health effects are still unknown. In this study the investigators aim to look at additional health effects following KHK inhibition (KHKi).
详细描述
Rationale: NAFLD is a highly prevalent (~30%) disease that is histologically characterized by simple steatosis, steatohepatitis and/or fibrosis in the absence of alcohol abuse. Liver fibrosis can progress to cirrhosis, which is a risk factor for endstage liver disease and hepatocellular carcinoma. Of interest, recent studies have shown that NAFLD is also a risk factor for systemic diseases, such as type 2 diabetes, which is probably mediated by hepatic insulin resistance. Previous research showed that inhibition of KHK, the first step in fructose metabolism, reduces IHL content in individuals with NAFLD. KHK is predominantly expressed in the gut, kidney, and liver where it facilitates the phosphorylation of fructose to fructose-1P, and thereby entrapment and subsequent metabolism within the cell. KHKi in the liver, therefore, impairs entrapment of ingested fructose and, consequently, conversion into fat which might lead to improvements in hepatic insulin sensitivity. However, studies investigating the effect of KHKi on hepatic insulin sensitivity are lacking. Objective: The primary objective of this study is to assess the effect of KHKi on hepatic insulin sensitivity in overweight/obese individuals with non-alcoholic fatty liver disease. The secondary objective includes the assessment of KHKi on fat distribution, adipose tissue insulin sensitivity, and fat oxidation in overweight/obese individuals with non-alcoholic fatty liver disease.
Explorative objectives are the assessment of in vivo KHK activity, gut microbiota composition and alternative metabolic pathways upon KHK inhibition. Study design: The present study is a randomized, double-blinded, placebo-controlled cross over trial (RCT).
Study population: 14 overweight/obese (BMI: 27-35 kg/m2
), male and (postmenopausal) female participants, aged 45 - 70 years with non-alcoholic fatty liver disease (IHL ≥ 5.56%) will participate in this study. From experience with similar studies, the investigators estimate a drop-out rate of 20% and a screening failure of 50% (due to the strict inclusion criteria), resulting in maximally 17 subjects that have to be included and 36 subjects that have to be screened (maximally).
Intervention (if applicable): Participants receive once daily (in the morning) 300 mg in tablet form.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 45 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Participants are able to provide signed and dated written informed consent prior to any study specific procedures
- •Men and (postmenopausal) woman
- •Aged ≥ 45 and ≤ 70 years
- •Body mass index (BMI) 27 - 35 kg/m2
- •Hepatic steatosis (i.e. IHL ≥ 5.56%)
- •Stable dietary habits (no weight loss or gain > 3 kg in the past 3 months)
排除标准
- •Type 2 diabetes
- •Patients with congestive heart failure and and/or severe renal and or liver insufficiency
- •Uncontrolled hypertension
- •Any contra-indication for MRI scanning
- •Alcohol consumption of >3 servings per day for man and >2 servings per day for woman
- •Unstable body weight (weight gain or loss > 3kg in the last 3 months)
- •Engagement in structured exercise activities > 2 hours a week
- •Previous enrolment in a clinical study with an investigational product during the last 3 months or as judged by the investigator which would possibly hamper our study results
- •Use of drugs that inhibit organic anion transporting polypeptide (OATP) transporters (e.g. rifampicin, gemfibrozil, cyclosporine, erythromycin and clarithromycin)
- •Subjects who do not want to be informed about unexpected medical findings
研究组 & 干预措施
PF-06835919
KHKi
干预措施: Ketohexokinase inhibition (Drug)
Placebo
Placebo
干预措施: Placebo (Other)
结局指标
主要结局
Hepatic insulin sensitivity
时间窗: 42 days
insulin-mediated suppression of endogenous glucose production (EGP) in µmol/kg/min measured during the 2- step hyperinsulinemic-euglycemic clamp
次要结局
- Subcutaneous adipose tissue(41 days)
- Intrahepatic lipid content(41 days)
- Liver lipid content composition(41 days)
- Visceral adipose tissue(41 days)
- Insulin-mediated suppression of free fatty acids(42 days)
- Inflammatory markers like adiponectin, interleukin-6, hsCRP, TNF-α(42 days)
- Resting energy expenditure (REE)(42 days)
- Sleeping metabolic rate(42 days)
- Body composition(42 days)