Non Invasive Assessment of Liver Glycogen Kinetics and ATP Synthesis in Type1 Diabetics

NCT00481598 | Completed DMC

• 1 other identifier: JDRF Grant Number: 1-2006-74
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

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 \[6,6-2H2\]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.

Conditions

Type 1 Diabetes Mellitus

Outcome Measures

Primary Outcomes (1)

• glycogen metabolism, gluconeogenesis, after 3 months of treatment;

  August 2008

Interventions

magnet resonance spectroscopy PROCEDURE

magnet resonance spectroscopy

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Landsteiner Institut: lead
• University of Coimbra: collaborator

Study Sites (1)

Landsteiner Institute for Endocrinology and Metabolic Diseases, Hanusch Hospital Heinrich Collin Straße 30

Vienna, Vienna, 1140, Austria

Location

Related Publications (1)

• Kacerovsky M, Brehm A, Chmelik M, Schmid AI, Szendroedi J, Kacerovsky-Bielesz G, Nowotny P, Lettner A, Wolzt M, Jones JG, Roden M. Impaired insulin stimulation of muscular ATP production in patients with type 1 diabetes. J Intern Med. 2011 Feb;269(2):189-99. doi: 10.1111/j.1365-2796.2010.02298.x.

  PMID: 21205021 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Michael Roden, Professor Dr.

  Landsteiner Institute

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: June 1, 2007
• First Posted: June 4, 2007
• Study Start: January 1, 2006
• Primary Completion: July 1, 2008
• Study Completion: September 1, 2008
• Last Updated: September 12, 2008

Record last verified: 2008-09

Locations

AU (1)