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

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

Interventions

PROCEDURE

magnet resonance spectroscopy

magnet resonance spectroscopy

Sponsors & Collaborators

• University of Coimbra

  collaborator OTHER

• Landsteiner Institut

  lead OTHER

Principal Investigators

• Michael Roden, Professor Dr. · Landsteiner Institute

Study Design

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

50 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2006-01-31

Primary Completion

2008-07-31

Completion

2008-09-30

Countries

• Austria

Study Locations