Role of Fatty Acid Oxidation Defects in Insulin Sensitivity
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 41
- 试验地点
- 1
- 主要终点
- Glucose Disposal Rate (Rd)- the Rate of Glucose Infusion to Maintain Euglycemia During Steady State Insulin Infusion in mg/Min
研究概览
简要总结
The purpose of this study is to learn more about what causes insulin resistance. It has been suggested that proper breakdown of fat into energy (oxidation) in the body is important to allow insulin to keep blood sugar in the normal range. The investigators want to know if having one of the fatty acid oxidation disorders could have an influence on insulin action. Fatty acid oxidation disorders are genetic disorders that inhibit one of the enzymes that converts fat into energy. The investigators will study both normal healthy people and people with a long-chain fatty acid oxidation disorder.
详细描述
The overall goal of this proposal is to investigate the effects of disordered mitochondrial fatty acid oxidation on insulin resistance in humans. Mitochondrial dysfunction has been implicated in the development of insulin resistance and type 2 diabetes during excess dietary fat intake and from increased release of endogenous free fatty acids , such as occurs in obesity. Controversy exists, however, as to whether this insulin resistance results from intrinsic defects in mitochondrial energy utilization or from abnormalities resulting from excess free fatty acid flux, as well as the role that subsequent accumulation of cellular metabolic intermediates play in impaired insulin signaling.
To address these controversies, the investigators will study a unique population of patients with inherited defects in each of the three mitochondrial enzymes in the fatty acid oxidation pathway: 1) very long-chain acyl-CoA dehydrogenase (VLCAD); 2) trifunctional protein (TFP, which includes long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)); and 3) medium-chain acyl-CoA dehydrogenase (MCAD). These proteins are required for the oxidation of sequentially shorter fatty acids . The investigators will test the hypothesis that intrinsic defects in mitochondrial function involving oxidation of long-chain, but not medium-chain, fatty acids are sufficient to prevent intralipid-induced insulin resistance.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •confirmed diagnosis of VLCAD, LCHAD, TFP or MCAD deficiency or same gender, age and BMI as a subject with a fatty acid oxidation disorder
- •ability to travel to Oregon Health & Science University, Portland, Oregon
- •ability and willingness to complete the protocol
排除标准
- •hemoglobin <10g/dl, international normalized ratio (INR) >1.2 Prothrombin time (PTT) >36 sec, Platelets <150K/mm3
- •pregnant or lactating females
- •endocrine disorder such as diabetes or untreated thyroid disease
- •cardiovascular disease or elevated plasma lipids
- •regularly taking meds that strongly affect bleeding, bruising or platelets
研究组 & 干预措施
glycerol/saline FAOD
Glycerol/Saline co-infusion hyperinsulinemic euglycemic clamp among subjects with a fatty acid oxidation disorder (FAOD)
干预措施: Glycerol/Saline (Drug)
glycerol/saline FAOD
Glycerol/Saline co-infusion hyperinsulinemic euglycemic clamp among subjects with a fatty acid oxidation disorder (FAOD)
干预措施: Hyperinsulinemic euglycemic clamp (Drug)
intralipid FAOD
Intralipid/Heparin co-infusion hyperinsulinemic euglycemic clamp among subjects with a fatty acid oxidation disorder (FAOD)
干预措施: Intralipid/Heparin (Drug)
intralipid FAOD
Intralipid/Heparin co-infusion hyperinsulinemic euglycemic clamp among subjects with a fatty acid oxidation disorder (FAOD)
干预措施: Hyperinsulinemic euglycemic clamp (Drug)
glycerol/saline Control
Glycerol/Saline co-infusion hyperinsulinemic euglycemic clamp among normal matched control subjects (control)
干预措施: Glycerol/Saline (Drug)
glycerol/saline Control
Glycerol/Saline co-infusion hyperinsulinemic euglycemic clamp among normal matched control subjects (control)
干预措施: Hyperinsulinemic euglycemic clamp (Drug)
intralipid Control
Intralipid/Heparin co-infusion hyperinsulinemic euglycemic clamp among normal matched control subjects (control)
干预措施: Intralipid/Heparin (Drug)
intralipid Control
Intralipid/Heparin co-infusion hyperinsulinemic euglycemic clamp among normal matched control subjects (control)
干预措施: Hyperinsulinemic euglycemic clamp (Drug)
结局指标
主要结局
Glucose Disposal Rate (Rd)- the Rate of Glucose Infusion to Maintain Euglycemia During Steady State Insulin Infusion in mg/Min
时间窗: Calculated during the last 30 minutes of a 300 minute clamp.
Insulin infusion induces glucose disposal into muscle and adipose tissue in insulin sensitive participants. During the glycerol co-infusion, glucose disposal will be high. Intralipid co-infusion can induce a temporary insulin resistant state. During the intralipid co-infusion, glucose disposal will be decreased. We are comparing how intralipid dampens glucose disposal between participants with a FAOD and matched control participants. Glucose disposal is measured by measuring the ratio of deuterated glucose to unlabeled glucose at the beginning and end of the clamp. The calculated glucose disposal rate or RD is mg of glucose taken into muscle and adipose tissue per minute.
次要结局
- Endogenous Glucose Production (Ra) - Calculated by the Equations of Steele During Steady State in mg/Min(Calculated during the last 30 minutes of a 300 minute clamp.)
研究者
Melanie B Gillingham
Associate Professor
Oregon Health and Science University