Ignite Creation Date:
2024-05-05 @ 11:53 AM
Last Modification Date:
2024-10-26 @ 9:15 AM
Study NCT ID:
NCT00168519
Status:
COMPLETED
Last Update Posted:
2009-12-15
First Post:
2005-09-14
Brief Title:
Contraction Exercise Mediated Glucose Uptake as a Therapeutic Target in Type 2 Diabetes
Sponsor:
Baker Heart Research Institute
Organization:
Baker Heart Research Institute
Study Overview
Official Title:
Contraction Mediated Glucose Uptake as a Therapeutic Target in Type 2 Diabetes
Status:
COMPLETED
Status Verified Date:
2009-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purpose of this project is to determine whether glucose metabolism can be improved by administering a substance nitric oxide donor normally released by muscles during exercise
Detailed Description:
Aim 1 To determine whether acute infusion of sodium nitroprusside an NO donor increases leg glucose uptake at rest in patients with type 2 diabetes
Twenty male type 2 diabetic patients aged between 30 and 60 years will be recruited from our clinic and through advertisement The inclusion criteria
non-smokers
free of overt coronary disease stress ECG
body mass index 35 kgm-2
fasting plasma glucose 7 mmolL-1 and or post 75 gm oral glucose load plasma glucose levels of 111 mmolL-1
unmedicated diet controlled
The leg blood flow thermodilution and glucose uptake responses arterial-venous differences to three cumulative doses of sodium nitroprusside 01 03 and 06 ugkg-1min-1 10 mins per dose infused into the femoral artery using techniques established in our laboratory will be assessed Doses are based on our extensive unpublished observations and have been calculated to lie on the linear part of the dose-response curve and to induce local and not systemic hemodynamic effects As a control we will also assess responses to the nitrate independent vasodilator Verapamil Isoptin 1 3 and 6 ugkg-1min-1 Doses Verapamil is a calcium channel antagonist which causes vasodilatation by direct actions on the smooth muscle Doses will be titrated to give similar blood flow responses and the two drugs will be administered in randomized order with a 60 min wash-out period Verapamil doses will be determined in pilot experiments Vastus lateralis biopsies will be performed at baseline and after the highest dose of each drug and cGMP and GLUT-4 translocation measured
A single Vastus lateralis biopsy will be performed as a comparison against type 2 diabetics
Significance This study will determine whether acute NO supplementation stimulates muscle GLUT-4 translocation and glucose uptake in patients with type 2 diabetes
Pilot Study To determine whether oral nitrates increase exhaled NO levels in healthy volunteers to compare isosorbide mononitrate ISMN with pentaerythritol tetranitrate PETN to determine which drug is more effective in increasing exhaled NO
Fifteen healthy male volunteers as determined via a medical screening aged between 18 and 65 years will be recruited through advertisement The inclusion criteria for healthy controls will be
non-smokers
free of overt coronary disease ECG
body mass index 30 kgm-2
fasting plasma glucose 61 mmolL-1
unmedicated
Blood samples will be obtained and an oral glucose tolerance test OGTT performed Baseline exhaled nitric oxide NO and pulmonary blood flow will be measured in collaboration with Dr Bruce Thompson from the Alfred Respiratory Department Sodium nitroprusside SNP is a known NO donor and will be used as a positive control Following baseline measurements participants will receive an intravenous forearm vein infusion of SNP titrated from 03ugkgmin to a maximum of 3 ugkgmin over 30 minutes Blood pressure will be monitored throughout using an automated sphygmomanometer Post infusion exhaled NO and pulmonary blood flow will be measured
Participants will then commence the second phase of the study to determine whether ISMN and PETN increase exhaled NO levels and to determine which drug is more potent in this regard
Visit 2 3 4 Participants will receive each of the following study medications in a randomised Latin square design
Placebo administered once on the morning of Visit 2 3 or 4
extended release ISMN mononitrate 120mg administered once on the morning of Visit 2 3 or 4
pentaerythritol tetranitrate 160mg administered once on the morning of Visit 2 3 or 4
There will be a 7-day wash-out period between each treatmentvisit Participants will undergo repeated measures of exhaled NO pulmonary blood flow and OGTT three hours after each study drug has been administered Blood will be taken prior to and every hour after the participant has taken each drug for measurement of NO metabolites eg nitritenitrate nitrosothiols nitrosohemoglobin Nitrate drugs are occasionally associated with headache and dizziness Headaches can be treated with paracetamol
Endpoints at baseline and post treatments will be
Post 75g oral glucose load
Exhaled NO levels
Pulmonary blood flow
Significance Once the most effective NO donor has been determined it will be utilized in the chronic nitrate study described in Aim 2
Aim 2 To determine whether chronic nitrate therapy for 12 weeks improves glucose tolerance and HbA1c in patients with type 2 diabetes
Twenty male type 2 diabetic subjects aged between 30 and 60 years and meeting the inclusion criteria specified in Aim 1 will be recruited from our clinics and through advertisement Patients will be randomized to 12 weeks of treatment with both long-acting nitrate therapy isosorbide mononitrate 60mg daily Imdur and placebo cross-over design Primary endpoints will be
glycated haemoglobin HbA1c
whole body glucose uptake at rest stable glucose tracer methodology 39-41
whole body glucose uptake after 0-2 hrs a 75 gm oral glucose load tracer methodology
skeletal muscle cGMP and GLUT-4 translocation vastus lateralis muscle biopsy before and after glucose load
skeletal muscle glycogen lactate phosphocreatine creatine and ATP Significance This study will determine whether chronic nitrate therapy increases GLUT-4 translocation glucose uptake and has beneficial effects on glycaemic control in patients with type 2 diabetes
Aim 3
To determine whether acute infusion of AICAR an AMP analogue increases leg glucose uptake at rest in patients with type 2 diabetes
Twenty healthy males and twenty male type 2 diabetics aged between 30 and 60 years will be recruited from our clinic and through advertisement The inclusion criteria for the diabetics will be
non-smokers
free of overt coronary disease stress ECG
body mass index 35 kgm-2
fasting plasma glucose 7 mmolL-1 and or post 75 gm oral glucose load plasma glucose levels of 111 mmolL-1
unmedicated diet controlled
The leg blood flow thermodilution and glucose uptake arterial-venous differences response to a 60 minute intra-femoral infusion of AICAR 1 mgkg-1min-1 Clinalfa Switzerland using techniques established in our laboratory will be assessed As a control we will also measure responses to vehicle saline infusion prior to commencing the dose response curve 60 min Plasma free fatty acids glycerol triglycerides and lactate will be determined and blood gases will be measured to assess respiratory quotient Vastus lateralis biopsies will be performed at baseline and after AICAR and the following parameters quantitated
AMPK activity
nNOS phosphorylation
NOS activity
GLUT-4 translocation
Twenty male type 2 diabetic patients aged between 30 and 60 years will be recruited from our clinic and through advertisement The inclusion criteria
non-smokers
free of overt coronary disease stress ECG
body mass index 35 kgm-2
fasting plasma glucose 7 mmolL-1 and or post 75 gm oral glucose load plasma glucose levels of 111 mmolL-1
unmedicated diet controlled
The leg blood flow thermodilution and glucose uptake responses arterial-venous differences to three cumulative doses of sodium nitroprusside 01 03 and 06 ugkg-1min-1 10 mins per dose infused into the femoral artery using techniques established in our laboratory will be assessed Doses are based on our extensive unpublished observations and have been calculated to lie on the linear part of the dose-response curve and to induce local and not systemic hemodynamic effects As a control we will also assess responses to the nitrate independent vasodilator Verapamil Isoptin 1 3 and 6 ugkg-1min-1 Doses Verapamil is a calcium channel antagonist which causes vasodilatation by direct actions on the smooth muscle Doses will be titrated to give similar blood flow responses and the two drugs will be administered in randomized order with a 60 min wash-out period Verapamil doses will be determined in pilot experiments Vastus lateralis biopsies will be performed at baseline and after the highest dose of each drug and cGMP and GLUT-4 translocation measured
A single Vastus lateralis biopsy will be performed as a comparison against type 2 diabetics
Significance This study will determine whether acute NO supplementation stimulates muscle GLUT-4 translocation and glucose uptake in patients with type 2 diabetes
Pilot Study To determine whether oral nitrates increase exhaled NO levels in healthy volunteers to compare isosorbide mononitrate ISMN with pentaerythritol tetranitrate PETN to determine which drug is more effective in increasing exhaled NO
Fifteen healthy male volunteers as determined via a medical screening aged between 18 and 65 years will be recruited through advertisement The inclusion criteria for healthy controls will be
non-smokers
free of overt coronary disease ECG
body mass index 30 kgm-2
fasting plasma glucose 61 mmolL-1
unmedicated
Blood samples will be obtained and an oral glucose tolerance test OGTT performed Baseline exhaled nitric oxide NO and pulmonary blood flow will be measured in collaboration with Dr Bruce Thompson from the Alfred Respiratory Department Sodium nitroprusside SNP is a known NO donor and will be used as a positive control Following baseline measurements participants will receive an intravenous forearm vein infusion of SNP titrated from 03ugkgmin to a maximum of 3 ugkgmin over 30 minutes Blood pressure will be monitored throughout using an automated sphygmomanometer Post infusion exhaled NO and pulmonary blood flow will be measured
Participants will then commence the second phase of the study to determine whether ISMN and PETN increase exhaled NO levels and to determine which drug is more potent in this regard
Visit 2 3 4 Participants will receive each of the following study medications in a randomised Latin square design
Placebo administered once on the morning of Visit 2 3 or 4
extended release ISMN mononitrate 120mg administered once on the morning of Visit 2 3 or 4
pentaerythritol tetranitrate 160mg administered once on the morning of Visit 2 3 or 4
There will be a 7-day wash-out period between each treatmentvisit Participants will undergo repeated measures of exhaled NO pulmonary blood flow and OGTT three hours after each study drug has been administered Blood will be taken prior to and every hour after the participant has taken each drug for measurement of NO metabolites eg nitritenitrate nitrosothiols nitrosohemoglobin Nitrate drugs are occasionally associated with headache and dizziness Headaches can be treated with paracetamol
Endpoints at baseline and post treatments will be
Post 75g oral glucose load
Exhaled NO levels
Pulmonary blood flow
Significance Once the most effective NO donor has been determined it will be utilized in the chronic nitrate study described in Aim 2
Aim 2 To determine whether chronic nitrate therapy for 12 weeks improves glucose tolerance and HbA1c in patients with type 2 diabetes
Twenty male type 2 diabetic subjects aged between 30 and 60 years and meeting the inclusion criteria specified in Aim 1 will be recruited from our clinics and through advertisement Patients will be randomized to 12 weeks of treatment with both long-acting nitrate therapy isosorbide mononitrate 60mg daily Imdur and placebo cross-over design Primary endpoints will be
glycated haemoglobin HbA1c
whole body glucose uptake at rest stable glucose tracer methodology 39-41
whole body glucose uptake after 0-2 hrs a 75 gm oral glucose load tracer methodology
skeletal muscle cGMP and GLUT-4 translocation vastus lateralis muscle biopsy before and after glucose load
skeletal muscle glycogen lactate phosphocreatine creatine and ATP Significance This study will determine whether chronic nitrate therapy increases GLUT-4 translocation glucose uptake and has beneficial effects on glycaemic control in patients with type 2 diabetes
Aim 3
To determine whether acute infusion of AICAR an AMP analogue increases leg glucose uptake at rest in patients with type 2 diabetes
Twenty healthy males and twenty male type 2 diabetics aged between 30 and 60 years will be recruited from our clinic and through advertisement The inclusion criteria for the diabetics will be
non-smokers
free of overt coronary disease stress ECG
body mass index 35 kgm-2
fasting plasma glucose 7 mmolL-1 and or post 75 gm oral glucose load plasma glucose levels of 111 mmolL-1
unmedicated diet controlled
The leg blood flow thermodilution and glucose uptake arterial-venous differences response to a 60 minute intra-femoral infusion of AICAR 1 mgkg-1min-1 Clinalfa Switzerland using techniques established in our laboratory will be assessed As a control we will also measure responses to vehicle saline infusion prior to commencing the dose response curve 60 min Plasma free fatty acids glycerol triglycerides and lactate will be determined and blood gases will be measured to assess respiratory quotient Vastus lateralis biopsies will be performed at baseline and after AICAR and the following parameters quantitated
AMPK activity
nNOS phosphorylation
NOS activity
GLUT-4 translocation
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None