Non Invasive Assessment of Liver Glycogen Kinetics and ATP Synthesis in Type1 Diabetics
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 28
- 试验地点
- 2
- 主要终点
- glycogen metabolism, gluconeogenesis, after 3 months of treatment;
研究概览
简要总结
Patients with Type 1 diabetes (T1DM) suffer from impaired postprandial hepatic glycogen storage and breakdown, if they are under poor glycaemic control. Poor glycogen storage in the liver puts these patients at risk of fasting hypoglycaemia. Amelioration of glycaemic control could improve these abnormalities and thereby reduce the risk of hypoglycaemia in these patients. The "gold standard" technique for the assessment of hepatic glycogen metabolism in humans, 13 C magnetic resonance spectroscopy (13C-MRS), is expensive and limited to a few centers worldwide. Furthermore, treated type 1 diabetic patients exhibit skeletal muscle insulin resistance when treated insufficiently. This condition can also be reversed by improvement of glycaemic control. Recent studies link skeletal muscle insulin resistance to impaired mitochondrial function. Up to date, the impact of glycaemic control on skeletal muscle mitochondrial function has not yet been assessed.
Aim 1 of our project is to establish a new assessment method for glycogen metabolism. This new method is based on oral administration of 2H2O and acetaminophen.
Our second aim is to examine the impact of improvements of glycaemic control on skeletal muscle mitochondrial function in type 1 diabetic patients.
Our third aim is to assess the ATP-synthesis in T1DM.
We will conduct a prospective study on 14 patients with type 1 diabetes and 14 healthy controls.
On the respective study day, participants will be served three standardized meals, blood sugar will be controlled hourly and blood samples will be drawn at timed intervals to determine glucoregulatory hormones, metabolites and enrichments of [6,6-2H2]glucose.
During the night, four 13C-MRS-measurements will be performed in combination with [6,6-2H2]glucose infusion to assess glucose production, glycogen breakdown and gluconeogenesis.
In addition, patients will drink 3g/kg bodyweight 2H2O and acetaminophen will be administered. Thus the new 2H2O-acetaminophen method will be applied simultaneously with the "gold standard" method.
The following morning, mitochondrial function will be assessed in skeletal muscle from unidirectional flux through ATP synthase by 31P MRS.
TIDM patients will be studied twice. First, under conditions of insufficient glycaemic control and the second time after three months of intensified insulin treatment using CSII pumps aiming at optimized metabolic control. Healthy controls will be studied only once.
To assess muscular mitochondrial function in T1DM we will measure ATP synthesis in a calf muscle with magnetic resonance spectroscopy. First, we will conduct a basal measurement. Thereafter, we will start a hyperinsulinaemic euglycemic calmp to stimulate the ATP synthesis and measure again.
This study will provide information on rates of post absorptive glycogen breakdown, gluconeogenesis, and postprandial glycogen storage in the liver and on the skeletal muscle mitochondrial function under conditions of optimized glycaemic control for 3 months.
Finally, this study will demonstrate whether or not poorly controlled type 1 diabetic patients exhibit abnormalities in muscle mitochondrial function and to what extent those alterations can be reversed by optimized glycaemic control. We expect to validate the 2H2O-acetaminophen method, which will provide justification for a broad scale in clinical studies.
详细描述
Non-Invasive Assessment of Liver Glycogen-Kinetics in Type1 Diabetics
Background:
Hepatic glycogen is the principal short-term reserve for circulating glucose in humans. Up to 50-60% of endogenous glucose production is derived from hepatic glycogenolysis during overnight fasting. In healthy subjects, deprivation of hepatic glycogen by prolonged fasting (60-65 hours) depresses fasting glucose production and plasma glucose levels approach the hypoglycemic range. T1DM were shown to have lower rates of hepatic glycogen synthesis during feeding and lower rates of glycogenolysis during fasting. Thus, this dangerous condition may develop during overnight fasting.
Importantly, defective hepatic glycogen metabolism in T1D can be therapeutically restored, suggesting that measurements of glycogen kinetics could be useful for evaluating both new and existing therapies of glycemic control.
The accepted "gold standard" for hepatic glycogenolysis measurements in humans involves a direct measurement of the natural abundance 13C hepatic glycogen signal using localized 13C NMR on a high-field clinical whole body magnetic resonance system. This method is only available in a handful of clinical research centers around the world.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Type 1 Diabetes Mellitus
- •HbA1c at the beginning of the trial between 8,5% and 10%
- •Age: 18-50 years
- •BMI <30 kg/m2 (due to limited MR diameter)
- •Normal routine lab tests (blood cell count, kidney, liver, pancreas, thyroid and neuromuscular function)
- •Availability within the local area throughout the study
- •Ability to understand and sign the consent forms
排除标准
- •Current smoking
- •Present drug treatment
- •Contraindications for MRS studies: claustrophobia and metalliferous implants
- •Pregnancy
- •HIV or Hepatitis
- •acute disease 2 weeks previous to the examination
- •Heart disease
- •Hypertension (RR>140/95)
- •Liver disease
- •Kidney disease
- •Pulmonary disease
- •Thyroid disease
结局指标
主要结局
glycogen metabolism, gluconeogenesis, after 3 months of treatment;
时间窗: August 2008
次要结局
未报告次要终点