Modulation of Human Myocardial Metabolism by GLP-1 Dose Response
The objective of this proposal is to provide quantitative dose-response data for effects of GLP-1 on myocardial glucose uptake in healthy control subjects and obese type 2 diabetic subjects, in support of the design of later studies evaluating therapeutic applications of GLP-1 to heart disease.
Aim 1: To measure the effects of GLP-1 infusion on myocardial fuel selection in lean healthy humans under fasting (fatty acid-dominant) conditions. Four groups of 10 lean healthy subjects will be studied during infusions of 0 (saline control), 0.5, 1.5, and 4.0 pmol/kg/min GLP-1 (one study per subject). Cardiac metabolism will be measured using PET, using a dual-tracer approach which allows measurement of myocardial glucose uptake (the primary endpoint) along with total oxidation rate and myocardial perfusion (secondary endpoints). In concert with measures of circulating metabolites and regulatory hormones, the investigators will produce the most comprehensive assessment of actions of GLP-1 on myocardial metabolism in humans to date. Effects of each dose will be compared to the saline control, plus the investigators will combine all data and use nonlinear curve-fitting to derive sensitivity (ED50) and maximal responses for GLP-1 effects on myocardial glucose uptake.
Aim 2: To measure the effects of GLP-1 infusion on myocardial fuel selection in obese type 2 diabetic humans under fasting (fatty acid-dominant) conditions Four groups of 10 obese type 2 diabetic subjects will be studied during infusions of 0, 0.5, 1.5, and 4.0 pmol/kg/min GLP-1 as under Aim 1. Analyses will be parallel to those described under Aim 1. Results from Aims 1 and 2 will be combined to allow direct comparison of the dose-response between nondiabetic control and type 2 diabetic subjects.
No literature has been published to inform dose selection in the design of clinical trials of GLP-1 for modulation of heart fuel selection. With our expertise and experience in PET measurement of heart metabolism in diabetes, the investigators are uniquely positioned to fill this gap in knowledge. These studies are a necessary preamble to further evaluation of the potential for GLP-1 based treatments in heart disease.
調査の概要
研究の種類
入学 (実際)
段階
- フェーズ2
- フェーズ 3
連絡先と場所
研究場所
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Indiana
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Indianapolis、Indiana、アメリカ、46202
- Indiana Clinical Research Center
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参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
Inclusion Criteria:
- Age 18-60
- Lean subjects will be defined as having a BMI <25 kg/m2, in good general health, taking no regular medications
- Diabetic subjects will be obese (BMI >30 kg/m2 but <40 kg/m2), HbA1c 7.0-10.0%, treated with diet and exercise plus oral agents or injected insulin. All diabetic subjects will be treated with injected insulin for 2 weeks prior to study, to avoid potential confounding effects of other antidiabetic agents.
Exclusion Criteria:
- Chronic illnesses or infections (other than type 2 diabetes)
- Known coronary artery disease or abnormal ECG on screening evaluation
- Blood pressure > 160/100 mmHg on two occasions during screening evaluations. Current use of 3 or fewer blood pressure medications with blood pressure below this cutpoint will be acceptable.
- Total cholesterol > 240 mg/dL. Current use of 2 or fewer lipid lowering agents with cholesterol below this cutpoint will be acceptable.
- Diabetic subjects: Treatment with a GLP-1 agonist or DPP4 inhibitor within the past 6 months
- Known intolerance to injected GLP-1 agonist
- Treatment with PPAR gamma agonists currently or within the past 6 months
- Recognized microvascular complications (retinopathy, nephropathy, neuropathy)
- Unwillingness or inability to use injected insulin for the purposes of this study
- Chronic pain or other physical conditions which limit ability to remain supine for the duration of the study protocol
- History of claustrophobia, musculoskeletal or other factors which would result in an inability to comfortably remain within PET scanner gantry for the duration of the imaging protocol
- Occupational, investigational or other known radiation exposure which, together with the planned radiologic studies, will result in greater than 500 mrem total exposure in a contiguous 12 month period
- For female participants, current pregnancy
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：非ランダム化
- 介入モデル：並列代入
- マスキング：独身
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
|
他の：Saline
12 hour saline (control) infusion prior to PET study
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Normal saline placebo infusion for 12 hours prior to PET study
他の名前：
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実験的：GLP-1 Low dose
GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study
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0.5mmol/kg/hr GLP-1 for 12 hours prior to PET study
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|
実験的：GLP-1 Mid-Range Dose
GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study
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1.5mmol/kg/min for 12 hours prior to PET study
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実験的：GLP-1 High Dose
GLP-1 High Dose: 4.0 pmol/kg/min for 12 hours prior to PET study
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4.0mmol/kg/min GLP-1 for 12 hours prior to PET study
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Myocardial Glucose Uptake.
時間枠：After 12 hours of glucagon-like peptide 1 (GLP-1) exposure
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Myocardial glucose uptake measured using 18FDG PET, quantified using a 3-compartment model with a lumped constant of 1.0.
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After 12 hours of glucagon-like peptide 1 (GLP-1) exposure
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Myocardial Blood Flow
時間枠：After 12 hours of GLP-1 exposure
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Myocardial perfusion derived from acetate kinetics
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After 12 hours of GLP-1 exposure
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Myocardial Total Oxidation Rate
時間枠：After 12 hours of GLP-1 exposure
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MVO2 derived from acetate kinetics
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After 12 hours of GLP-1 exposure
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Cardiac Index
時間枠：After 12 hours of GLP-1 exposure
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Impedance cardiography-derived measurement of cardiac index, assessed following 12 hour exposure to treatment condition concurrent with the PET measurements.
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After 12 hours of GLP-1 exposure
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GLP-1 Concentrations
時間枠：After 12 hours of GLP-1 exposure
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Achieved GLP-1 concentrations at the end of the 12 hour treatment exposure
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After 12 hours of GLP-1 exposure
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協力者と研究者
スポンサー
捜査官
- 主任研究者：Kieren J Mather, MD、Indiana University
研究記録日
主要日程の研究
研究開始
一次修了 (実際)
研究の完了 (実際)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (見積もり)
学習記録の更新
投稿された最後の更新 (見積もり)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
キーワード
追加の関連 MeSH 用語
その他の研究ID番号
- 1010002497
- R21HL092799 (米国 NIH グラント/契約)
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