Methodological and physiological test-retest reliability of¹³C-MRS glycogen measurements in liver and in skeletal muscle of patients with type 1 diabetes and matched healthy controls

Abstract

Glycogen is a major substrate in energy metabolism and particularly important to prevent hypoglycemia in pathologies of glucose homeostasis such as type 1 diabetes mellitus (T1DM). (13) C-MRS is increasingly used to determine glycogen in skeletal muscle and liver non-invasively; however, the low signal-to-noise ratio leads to long acquisition times, particularly when glycogen levels are determined before and after interventions. In order to ease the requirements for the subjects and to avoid systematic effects of the lengthy examination, we evaluated if a standardized preparation period would allow us to shift the baseline (pre-intervention) experiments to a preceding day. Based on natural abundance (13) C-MRS on a clinical 3 T MR system the present study investigated the test-retest reliability of glycogen measurements in patients with T1DM and matched controls (n = 10 each group) in quadriceps muscle and liver. Prior to the MR examination, participants followed a standardized diet and avoided strenuous exercise for two days. The average coefficient of variation (CV) of myocellular glycogen levels was 9.7% in patients with T1DM compared with 6.6% in controls after a 2 week period, while hepatic glycogen variability was 13.3% in patients with T1DM and 14.6% in controls. For comparison, a single-session test-retest variability in four healthy volunteers resulted in 9.5% for skeletal muscle and 14.3% for liver. Glycogen levels in muscle and liver were not statistically different between test and retest, except for hepatic glycogen, which decreased in T1DM patients in the retest examination, but without an increase of the group distribution. Since the CVs of glycogen levels determined in a "single session" versus "within weeks" are comparable, we conclude that the major source of uncertainty is the methodological error and that physiological variations can be minimized by a pre-study standardization. For hepatic glycogen examinations, familiarization sessions (MR and potentially strenuous interventions) are recommended. Copyright © 2016 John Wiley & Sons, Ltd.

Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride

“…Definite proof that rs4841132 is glycogenic requires measurement of hepatic glycogen in humans. (33) To our knowledge, hepatic glycogen has not been measured in a large enough sample to detect modest effects. Potential methods to quantitate hepatic glycogen include histology (periodic acid Schiff staining), biochemical measurement in liver biopsies, or 13 C-MRS of the liver in vivo.…”

“…There are limitations to our study that merit consideration. Definite proof that rs4841132 is glycogenic requires measurement of hepatic glycogen in humans . To our knowledge, hepatic glycogen has not been measured in a large enough sample to detect modest effects.…”

“…To our knowledge, hepatic glycogen has not been measured in a large enough sample to detect modest effects. Potential methods to quantitate hepatic glycogen include histology (periodic acid Schiff staining), biochemical measurement in liver biopsies, or 13 C‐MRS of the liver in vivo . Assessing the sample size required to detect an association between rs4841132 and hepatic glycogen content is complicated because the effect size of the variant and the natural variation of hepatic glycogen content in human populations are not known.…”

“…Potential methods to quantitate hepatic glycogen include histology (periodic acid Schiff staining), biochemical measurement in liver biopsies, or 13 C-MRS of the liver in vivo. (33) Assessing the sample size required to detect an association between rs4841132 and hepatic glycogen content is complicated because the effect size of the variant and the natural variation of hepatic glycogen content in human populations are not known. Previous studies found that a 1% increase in biochemically measured hepatic glycogen content increases hepatic x-ray attenuation by 3 HU.…”

The competitive athlete with type 1 diabetes

“…2). Individuals with type 1 diabetes can have normal levels of muscle and liver glycogen content if they are adequately fed, take insulin and have good glycaemic control (HbA 1c <58 mmol/mol [7.5%]) [12,13]. Hepatic glycogen levels are lowered by poor glycaemic control in individuals with type 1 diabetes [14], with only a partial restoration with short-term improvements in glycaemic control [15].…”