Effect of Metformin on Vascular and Mitochondrial Function in Type 1 Diabetes (MeT1)
研究概览
研究类型
注册 (实际的)
阶段
- 第四阶段
联系人和位置
学习地点
-
-
Colorado
-
Aurora、Colorado、美国、80045
- University of Colorado Denver
-
-
参与标准
资格标准
适合学习的年龄
接受健康志愿者
有资格学习的性别
描述
Inclusion Criteria:
- Age 20-59 years of age,
- Type 1 diabetes based on antibody-positivity, rapid persistent conversion to insulin requirement after diagnosis, absent C-peptide, or DKA at diagnosis, or a clinical course consistent with T1D,
- HbA1c 6.0 - 9.5, and
- Willing and able to commit to two 6 week-long periods of blinded medication followed by hyperinsulinemic euglycemic clamp, vascular testing, and muscle biopsies.
Exclusion Criteria:
Any comorbid condition associated with:
- inflammation,
- insulin Resistance, or
dyslipidemia including:
- cancer,
- heart failure,
- active or end stage liver disease,
- kidney disease, or
- rheumatological disease;
- Tobacco use;
- Pregnancy or women who are breastfeeding;
- Steroid use;
- Scheduled strenuous physical activity >3 days a week;
- Angina, known CAD, or any other cardiovascular or pulmonary disease;
- A history of COPD or asthma;
- Presence of systolic blood pressure >190 at rest or >250 with exercise, or diastolic pressure >95 at rest or >105 with exercise;
- Untreated thyroid disease;
- Proteinuria (urine protein >200 mg/dl) or a creatinine > 1.5 mg/dl (males) or 1.4 mg/dL (females), suggestive of severe renal disease;
- Severe Proliferative retinopathy;
- Niacin treatment;
- Administration of experimental agent for T1D within 30 days prior to screening;
- Recent (prior 6 months) or current metformin or thiazolidenedione use;
- Hypoglycemia unawareness or recurrent severe hypoglycemia (no symptoms of hypoglycemia with FSBS<40 and episodes of this severity >1 per week);
- Weight instability (weight change >5% in last 6 months);
- History of any organ transplant, including islet cell transplant;
- Current or prior infection with HIV, hepatitis B or hepatitis C or hepatic -insufficiency (AST or ALT > 2x the upper limits of normal);
- Any condition, medical or otherwise that would, in the opinion of the investigator, prevent complete participation in the study, or that would pose a significant hazard to the subject;
- History of substance abuse within the 12 months prior to screening.
学习计划
研究是如何设计的?
设计细节
- 主要用途:治疗
- 分配:随机化
- 介入模型:交叉作业
- 屏蔽:双倍的
武器和干预
参与者组/臂 |
干预/治疗 |
---|---|
安慰剂比较:安慰剂
|
Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
|
实验性的:二甲双胍
|
Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention.
If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.
其他名称:
|
研究衡量的是什么?
主要结果指标
结果测量 |
措施说明 |
大体时间 |
---|---|---|
Insulin Sensitivity by Hyperinsulinemic Euglycemic Clamp
大体时间:End of each 6 week intervention period
|
Determine the effect of metformin on insulin sensitivity in T1D.
Reported measure is glucose infusion rate during hyperinsulinemic euglycemic clamp normalized to total body weight.
For this measure, insulin was infused at 40 mU/m2 surface area.
Blood sugar wass checked every 5 minutes and glucose infusion adjusted to maintain glucose level at 90 mg/dL for 2 hours.
The glucose infusion rate for the final 30 minutes is reported as GIR (aka M-value or glucose disposal rate) in mg glucose/kg*min.
A higher value corresponds to greater sensitivity to insulin.
There is no strictly defined normal range.
|
End of each 6 week intervention period
|
Flow-mediated Brachial Artery Dilation
大体时间:End of each 6 week intervention period
|
Measure of endothelial function by brachial ultrasound of the percent dilation after 5 minutes of occlusion.
|
End of each 6 week intervention period
|
次要结果测量
结果测量 |
措施说明 |
大体时间 |
---|---|---|
Arterial Stiffness by PWV
大体时间:End of each 6 week intervention period
|
Pulse wave velocity by Sphygmacor as a measure of aortic stiffness in m/sec.
|
End of each 6 week intervention period
|
Arterial Stiffness by AI@75
大体时间:End of each 6 week intervention period
|
Augmentation index by Sphygmacor is a measure of aortic arterial stiffness.
AI@75 is the ratio of augmented pressure/pulse pressure adjusted to a heart rate of 75.
|
End of each 6 week intervention period
|
Mitochondrial Measures: Oxygen Consumption
大体时间:End of each 6 week intervention period
|
Oxygen consumption rate with various substrates and max uncoupled O2 consumption. Measure is performed on permeabilized muscle fibers from biopsy tissue from the vastus lateralis using the Oroboros OxygraphO2k high resolution respirometer. State 3 is full coupled oxygen flux using PMG or PMGS (pyruvate, malate, glutamate, +/- succinate) or OCMS (octanyl carnitine, malate, +/- succinate) as substrates. state 4 is after addition of oligomycin to inhibit the ATP synthase and thus corresponds to the maximum leak state where O2 consumption is limited by the buildup of the proton gradient and can only proceed as fast as the protons can leak back across the membrane. FCCP is added as an uncoupler, allowing free leakage of protons across the inner membrane, and thus measures maximum possible O2 flux. There are no defined normal ranges, but higher state 3 and uncoupled flux indicate better mitochondrial function, while state 4 is needed to correct state 3 to the fully coupled flux. |
End of each 6 week intervention period
|
Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes
大体时间:End of each 6 week intervention period
|
Mito content by Western Blotting of electron transport chain complexes I, II, III, and V. complex 1 utilizes NADH from pyruvate/malate/glutamate while complex II utilizes FADH from succinate.
complex III is the cytochrome c reductase while complex V is the ATP synthase.
|
End of each 6 week intervention period
|
Inflammatory Marker: hsCRP
大体时间:End of each 6 week intervention period
|
hsCRP (mg/L) by Beckman Coulter assay
|
End of each 6 week intervention period
|
Heart Rate Variability
大体时间:End of each 6 week intervention period
|
measure of autonomic function: ratio of fastest to slowest heart rate during valsalva maneuver
|
End of each 6 week intervention period
|
Continuous Glucose Monitor Measures of Mean Glucose
大体时间:Last Week of each 6 Week Intervention Period (over 7 days)
|
Mean Glucose & Glucose Standard Deviation (Glycemic Variability) by Dexcom CGM
|
Last Week of each 6 Week Intervention Period (over 7 days)
|
Continuous Glucose Monitor Measures of Hypoglycemia
大体时间:Last Week of each 6 Week Intervention Period (over 7 days)
|
Percent of time less than 70 mg/dL during the final week of each phase by Dexcom CGM.
|
Last Week of each 6 Week Intervention Period (over 7 days)
|
Metabolic Markers: Glucagon
大体时间:End of each 6 week intervention period
|
Glucagon (pg/ml); baseline on AM of each phase final study visit.
|
End of each 6 week intervention period
|
Metabolic Markers: Glucose, Triglycerides, Cholesterol
大体时间:End of each 6 week intervention period
|
Glucose (mg/dL), triglycerides (mg/dL), cholesterol (mg/dL) at baseline after each phase
|
End of each 6 week intervention period
|
Metabolic Markers: Fatty Acids
大体时间:End of each 6 week intervention period
|
fatty acids (microeq/L) at baseline after each phase in the AM of the final visit
|
End of each 6 week intervention period
|
Metabolic Markers: Glycerol
大体时间:End of each 6 week intervention period
|
glycerol (micromol/L) at baseline after each phase in the AM of the final phase visit
|
End of each 6 week intervention period
|
Metabolic Markers: Insulin
大体时间:End of each 6 week intervention period
|
insulin (microIU/ml) at baseline after each phase in the AM of the final phase visit
|
End of each 6 week intervention period
|
Metabolic Markers: Lactate
大体时间:End of each 6 week intervention period
|
lactate (mmol/L) at baseline after each phase in the AM of the final phase visit
|
End of each 6 week intervention period
|
Metabolic Markers: Adiponection
大体时间:End of each 6 week intervention period
|
adiponection (microg/ml) at baseline after each phase in the AM of the final phase visit
|
End of each 6 week intervention period
|
Vascular Markers: Endothelin-1 (pg/ml)
大体时间:End of each 6 week intervention period
|
endothelin-1 at baseline after each phase in the AM of the final phase visit by peninsula labs radioimmunoassay
|
End of each 6 week intervention period
|
In Vivo Mitochondrial Function: Ratio of the Amount of ATP Generated Per Unit of Oxygen Consumed
大体时间:End of each 6 week intervention period
|
Measured by 31P-mass spec.
This ratio measures mitochondrial efficiency.
The higher the ratio, the more efficiently the individual converts metabolic substrates into ATP, with the ATP then available for energy-demanding cellular processes such as protein synthesis and biomass production
|
End of each 6 week intervention period
|
In Vivo Mitochondrial Function: Time Constants
大体时间:End of each 6 week intervention period
|
Measured by 31P-mass spec.
ADP time constant and phosphocreatine time constant.
ADP time constant is a measure of the time required to convert ADP → ATP and is a measure of muscle mitochondrial health (energy metabolism).
A faster recovery is a better outcome; a slower recovery is a worse outcome.
Similarly for phosphocreatine.
|
End of each 6 week intervention period
|
In Vivo Mitochondrial Function: QMax, VPCr
大体时间:End of each 6 week intervention period
|
Measured by 31P-mass spec. For each measure, a higher value indicates better mitochondrial function. All re calculated from multiple measures from the MRS spectra. These are relatively new research measures and normal values are not known or generally accepted.
|
End of each 6 week intervention period
|
In Vivo Mitochondrial Function: Oxidative Phosphorylation
大体时间:End of each 6 week intervention period
|
Measured by 31P-mass spec.
A higher value indicates better mitochondrial function.
All re calculated from multiple measures from the MRS spectra.
These are relatively new research measures and normal values are not known or generally accepted.
Oxidative Phosphorylation measures the rate at which electron transport activity generates phosphorylated energy sources (ATP and PCr)
|
End of each 6 week intervention period
|
In Vivo Mitochondrial Function:AnGly
大体时间:End of each 6 week intervention period
|
Measured by 31P-mass spec.
Anaerobic glycolysis measures the amount of anaerobic ATP generation for energy.
It is generally felt that a higher value here reflects impaired mitochondrial function necessitating greater reliance on anaerobic metabolism.
|
End of each 6 week intervention period
|
Cardiac Function
大体时间:End of each 6 week intervention period
|
Cardiac output
|
End of each 6 week intervention period
|
其他结果措施
结果测量 |
措施说明 |
大体时间 |
---|---|---|
Vascular Markers: PAI-1
大体时间:End of each 6 week intervention period
|
PAI-1 exploratory thromobotic marker.
|
End of each 6 week intervention period
|
Vascular Markers: Exploratory
大体时间:End of each 6 week intervention period
|
ICAM
|
End of each 6 week intervention period
|
Oxidative Stress Markers
大体时间:End of each 6 week intervention period
|
TBARs, GSSG:GSH ratio
|
End of each 6 week intervention period
|
Mitochondrial Measures: Oxidant Generation
大体时间:End of each 6 week intervention period
|
oxidant generation
|
End of each 6 week intervention period
|
Inflammatory Markers: Exploratory
大体时间:End of each 6 week intervention period
|
IL6, TNF alpha
|
End of each 6 week intervention period
|
Mitochondrial Oxidant Generation
大体时间:after each 6 week intervention
|
exploratory measure looking at H2O2 production.
not performed due to equipment not available.
|
after each 6 week intervention
|
合作者和调查者
调查人员
- 首席研究员:Irene Schauer, MD, PhD、University of Colorado, Denver
研究记录日期
研究主要日期
学习开始
初级完成 (实际的)
研究完成 (实际的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (估计)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
此信息直接从 clinicaltrials.gov 网站检索,没有任何更改。如果您有任何更改、删除或更新研究详细信息的请求,请联系 register@clinicaltrials.gov. clinicaltrials.gov 上实施更改,我们的网站上也会自动更新.
1 型糖尿病的临床试验
-
Oxford Brookes UniversityUniversity of Oxford完全的体力活动 | 心理健康 1 | 认知功能 1,社交 | Academic Attainment | Fitness Testing英国
-
Merck Sharp & Dohme LLC招聘中非小细胞肺癌 | 实体瘤 | 程序性细胞死亡-1(PD1、PD-1) | 程序性细胞死亡 1 配体 1(PDL1, PD-L1) | 程序性细胞死亡 1 配体 2(PDL2、PD-L2)日本
-
Amsterdam UMC, location VUmcRadboud University Medical Center; Maastricht University Medical Center; GGZ inGeest; Neurocare; M... 和其他合作者招聘中
-
Calliditas Therapeutics ABEurofins Optimed; York Bioanalytical Solution完全的
Metformin的临床试验
-
Poznan University of Medical SciencesUniversity of California, San Diego未知
-
Boehringer IngelheimEli Lilly and Company完全的
-
Boehringer IngelheimEli Lilly and Company完全的