Ignite Creation Date:
2024-05-05 @ 5:35 PM
Last Modification Date:
2024-10-26 @ 9:33 AM
Study NCT ID:
NCT00481598
Status:
COMPLETED
Last Update Posted:
2008-09-12
First Post:
2007-06-01
Brief Title:
Non Invasive Assessment of Liver Glycogen Kinetics and ATP Synthesis in Type1 Diabetics
Sponsor:
Landsteiner Institut
Organization:
Landsteiner Institut
Study Overview
Official Title:
Non Invasive Assessment of Liver Glycogen Kinetics and ATP Synthesis in Type1 Diabetics
Status:
COMPLETED
Status Verified Date:
2008-09
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:
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 66-2H2glucose
During the night four 13C-MRS-measurements will be performed in combination with 66-2H2glucose infusion to assess glucose production glycogen breakdown and gluconeogenesis
In addition patients will drink 3gkg 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
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 66-2H2glucose
During the night four 13C-MRS-measurements will be performed in combination with 66-2H2glucose infusion to assess glucose production glycogen breakdown and gluconeogenesis
In addition patients will drink 3gkg 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
Detailed Description:
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
Our proposed measurement is highly practical and relatively inexpensive since it involves oral administration of a small amount of deuterated water 2H2O tracer and a standard dose of Acetaminophen This new method is based on the analysis of deuterium enrichment of urinary glucuronide which is derived from the glucose moiety of hepatic UDP-glucose the immediate hexose precursor pool of glycogen synthesis
To date there have been no direct comparisons of the 2H2O measurement and clinical 13C MR methods for quantifying rates of fasting glycogenolysis in T1D subjects
Mitochondrial dysfunction assessed by impaired myocellular ATP synthesis is associated with insulin resistance in relatives of T2DM in patients with overt T2DM and T1DM with poor glycemic control However it is yet unknown to what extend alterations in hyperglycemia contribute to this abnormality Our hypothesis is that improvement of hyperglycemia in type 1 diabetic patients who do dot suffer from genetically induced insulin resistance will increase myocellular ATP synthesis Thus this study will examine basal myocellular ATP synthetic flux in patients with type 1 diabetes mellitus before and after improvement of glycemic control In addition we will perform hyperinsulinaemic euglycemic clamp tests to stimulate mitochondrial ATP synthesis
Clinical Protocols
Simultaneous in vivo 13C NMR and 2H2O-glucuronide measurements of hepatic glycogenolysis Vienna
A total of 24 subjects consisting of 12 healthy controls and 12 TID patients first in insufficient metabolic control HbA1c 85-100 and again after 3 months of intensified insulin treatment using continuous subcutaneous insulin infusion CSII pump aiming at optimized metabolic control HbA1c 75 will be studied following informed consent at the MR Centre-of-Excellence Medical University of Vienna
All measurements will either take place in the Hanusch Hospital Heinrich Collin Straße 30 A-1140 Vienna or the MR Center-of-Excellence at the General Hospital of ViennaLazerettgasse 14 A-1090 Vienna
For a 24 hour period before the study T1D patients will be instructed to omit NPH or Zn-insulin and only use regular insulin to control blood glucose concentrations
On day 1 staring in the Hanusch Hospital subjects will ingest 3 standard mixed meals 60 CHO 20 protein and 20 fat 720kcal 710kcal and 800kcal at 0800 1300 and 1840 The last meal will be served after transferring to the MR-Centre-of-Excellence and the first MR-measurement
Blood sugar will be controlled hourly and blood samples will be drawn at timed intervals to determine glucoregulatory hormones and metabolites
Subjects will be transferred periodically to the magnetic resonance spectroscopy unit where in vivo 13C NMR spectra lasting 1 hour will be performed at 1730-1830 before dinner 2330-030 0200-0300 and 0650-0750 There will be performed an additional 31P NMR measurement to assess the intramyocellular ATP synthesis of the right leg between 0530-0630
At 2230 a 8-hour primed infusion of 66-2H2glucose will be started The priming dose of 5 mgkg will be adjusted according to fasting blood glucose levels and will be followed by a constant infusion of 005 mgkgmin Plasma samples will be collected twice before the infusion starts and then from 030 -050 310 - 330 and 630-650 in ten minutes intervals respectively to quantify enrichment of plasma 66-2H2glucose
At 2300 subjects will ingest 2H2O to 03 body water and at 0300 they will ingest 1000 mg Acetaminophen Paracetamol
At 600 the participants are instructed to void This Urine will be collected as Urine 1 Between 0600 and 0800 Urine will be collected for recovery of Acetaminophen glucuronide Urine2 at which point the study will finish The urine will be evaporated frozen and sent to Coimbra for analysis
After day one intensified insulin treatment using continuous subcutaneous insulin infusion CSII pump will start Patients will be re-measured after three month according to the same protocol
Healthy controls will be examined only once
ATP-synthesis will be measured on a separate study day Patients and healthy controls will be admitted to the MR-Centre-of-Excellence at 600 am First there will be a basal measurement of ATP-synthesis Thereafter the clamp will be started and conducted for 4 hours Then the second 31P NMR measurement will be performed to assess whether ATP synthesis can be stimulated in T1DM patients
Participants will be released after a meal at 1500
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
Our proposed measurement is highly practical and relatively inexpensive since it involves oral administration of a small amount of deuterated water 2H2O tracer and a standard dose of Acetaminophen This new method is based on the analysis of deuterium enrichment of urinary glucuronide which is derived from the glucose moiety of hepatic UDP-glucose the immediate hexose precursor pool of glycogen synthesis
To date there have been no direct comparisons of the 2H2O measurement and clinical 13C MR methods for quantifying rates of fasting glycogenolysis in T1D subjects
Mitochondrial dysfunction assessed by impaired myocellular ATP synthesis is associated with insulin resistance in relatives of T2DM in patients with overt T2DM and T1DM with poor glycemic control However it is yet unknown to what extend alterations in hyperglycemia contribute to this abnormality Our hypothesis is that improvement of hyperglycemia in type 1 diabetic patients who do dot suffer from genetically induced insulin resistance will increase myocellular ATP synthesis Thus this study will examine basal myocellular ATP synthetic flux in patients with type 1 diabetes mellitus before and after improvement of glycemic control In addition we will perform hyperinsulinaemic euglycemic clamp tests to stimulate mitochondrial ATP synthesis
Clinical Protocols
Simultaneous in vivo 13C NMR and 2H2O-glucuronide measurements of hepatic glycogenolysis Vienna
A total of 24 subjects consisting of 12 healthy controls and 12 TID patients first in insufficient metabolic control HbA1c 85-100 and again after 3 months of intensified insulin treatment using continuous subcutaneous insulin infusion CSII pump aiming at optimized metabolic control HbA1c 75 will be studied following informed consent at the MR Centre-of-Excellence Medical University of Vienna
All measurements will either take place in the Hanusch Hospital Heinrich Collin Straße 30 A-1140 Vienna or the MR Center-of-Excellence at the General Hospital of ViennaLazerettgasse 14 A-1090 Vienna
For a 24 hour period before the study T1D patients will be instructed to omit NPH or Zn-insulin and only use regular insulin to control blood glucose concentrations
On day 1 staring in the Hanusch Hospital subjects will ingest 3 standard mixed meals 60 CHO 20 protein and 20 fat 720kcal 710kcal and 800kcal at 0800 1300 and 1840 The last meal will be served after transferring to the MR-Centre-of-Excellence and the first MR-measurement
Blood sugar will be controlled hourly and blood samples will be drawn at timed intervals to determine glucoregulatory hormones and metabolites
Subjects will be transferred periodically to the magnetic resonance spectroscopy unit where in vivo 13C NMR spectra lasting 1 hour will be performed at 1730-1830 before dinner 2330-030 0200-0300 and 0650-0750 There will be performed an additional 31P NMR measurement to assess the intramyocellular ATP synthesis of the right leg between 0530-0630
At 2230 a 8-hour primed infusion of 66-2H2glucose will be started The priming dose of 5 mgkg will be adjusted according to fasting blood glucose levels and will be followed by a constant infusion of 005 mgkgmin Plasma samples will be collected twice before the infusion starts and then from 030 -050 310 - 330 and 630-650 in ten minutes intervals respectively to quantify enrichment of plasma 66-2H2glucose
At 2300 subjects will ingest 2H2O to 03 body water and at 0300 they will ingest 1000 mg Acetaminophen Paracetamol
At 600 the participants are instructed to void This Urine will be collected as Urine 1 Between 0600 and 0800 Urine will be collected for recovery of Acetaminophen glucuronide Urine2 at which point the study will finish The urine will be evaporated frozen and sent to Coimbra for analysis
After day one intensified insulin treatment using continuous subcutaneous insulin infusion CSII pump will start Patients will be re-measured after three month according to the same protocol
Healthy controls will be examined only once
ATP-synthesis will be measured on a separate study day Patients and healthy controls will be admitted to the MR-Centre-of-Excellence at 600 am First there will be a basal measurement of ATP-synthesis Thereafter the clamp will be started and conducted for 4 hours Then the second 31P NMR measurement will be performed to assess whether ATP synthesis can be stimulated in T1DM patients
Participants will be released after a meal at 1500
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