Monitoring of liver glycogen synthesis in diabetic patients using carbon-13 MR spectroscopy

Tomiyasu, Moyoko; Obata, Takayuki; Nishi, Yukio; Nakamoto, Hiromitsu; Nonaka, Hiroi; Takayama, Yoshiaki; Autio, Joonas; Ikehira, Hiroo; Kanno, Iwao

doi:10.1016/j.ejrad.2008.10.019

Cited by 13 publications

(14 citation statements)

References 18 publications

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“…In T2D, glycogen metabolism has received more attention, showing increased glycogen metabolism and fragility of the α‐particles of glycogen . However, as the glycogen content in diabetes varies between the studies depending on the type (1 or 2) and the state (early or established) of diabetes, and the diurnal cycle, accelerated glycogen metabolism and the structure of glycogen molecules seem to be better biomarkers for pathogenic glucose metabolism than the glycogen content itself.…”

Section: Discussionmentioning

confidence: 99%

“…Glucose is stored in tissues as glycogen, but liver is the only organ capable of producing glucose from glycogen (reviewed by Kowalski et al). The role of hepatic glycogen in the pathogenesis of diabetes is controversial and unclear in many aspects . However, increased glycogenolysis and glycogen cycling have been associated with diabetes in both rodents and humans .…”

Section: Introductionmentioning

confidence: 99%

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Metformin normalizes the structural changes in glycogen preceding prediabetes in mice overexpressing neuropeptide Y in noradrenergic neurons

Ailanen

Bezborodkina

Virtanen

et al. 2018

Pharmacology Res & Perspec

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Hepatic insulin resistance and increased gluconeogenesis are known therapeutic targets of metformin, but the role of hepatic glycogen in the pathogenesis of diabetes is less clear. Mouse model of neuropeptide Y (NPY) overexpression in noradrenergic neurons (OE‐NPYD βH) with a phenotype of late onset obesity, hepatosteatosis, and prediabetes was used to study early changes in glycogen structure and metabolism preceding prediabetes. Furthermore, the effect of the anti‐hyperglycemic agent, metformin (300 mg/kg/day/4 weeks in drinking water), was assessed on changes in glycogen metabolism, body weight, fat mass, and glucose tolerance. Glycogen structure was characterized by cytofluorometric analysis in isolated hepatocytes and mRNA expression of key enzymes by qPCR. OE‐NPYD βH mice displayed decreased labile glycogen fraction relative to stabile fraction (the intermediate form of glycogen) suggesting enhanced glycogen cycling. This was supported by decreased filling of glucose residues in the 10th outer tier of the glycogen molecule, which suggests accelerated glycogen phosphorylation. Metformin reduced fat mass gain in both genotypes, but glucose tolerance was improved mostly in wild‐type mice. However, metformin inhibited glycogen accumulation and normalized the ratio between glycogen structures in OE‐NPYD βH mice indicating decreased glycogen synthesis. Furthermore, the presence of glucose residues in the 11th tier together with decreased glycogen phosphorylase expression suggested inhibition of glycogen degradation. In conclusion, structural changes in glycogen of OE‐NPYD βH mice point to increased glycogen metabolism, which may predispose them to prediabetes. Metformin treatment normalizes these changes and suppresses both glycogen synthesis and phosphorylation, which may contribute to its preventive effect on the onset of diabetes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metformin normalizes the structural changes in glycogen preceding prediabetes in mice overexpressing neuropeptide Y in noradrenergic neurons

Ailanen

Bezborodkina

Virtanen

et al. 2018

Pharmacology Res & Perspec

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“…Insulin‐mediated hepatic glucose uptake was impaired in patients with more severe metabolic conditions, including type 2 diabetes or morbid obesity, and is improved after bariatric surgery or glitazone treatment . Recent [ 13 C]MRS‐based studies highlight an important role of post–glucose load hepatic glycogen storage in modulating the subsequent fasting glycemia . An overflow of fatty acids to the liver was able to impair insulin‐mediated glucose uptake and promote glucose release by the liver, but hepatic steatosis seems an unlikely mediator, as it weakly correlates with liver glucose uptake .…”

Section: Obesity‐related Complicationsmentioning

confidence: 99%

“…153 Recent [ 13 C]MRS-based studies highlight an important role of post-glucose load hepatic glycogen storage in modulating the subsequent fasting glycemia. 154 An overflow of fatty acids to the liver was able to impair insulin-mediated glucose uptake 155 and promote glucose release by the liver, but hepatic steatosis seems an unlikely mediator, as it weakly correlates with liver glucose uptake. 156 Overall, our studies suggest that oxidative metabolism, generating free radicals and oxidative stress, deserves attention as an early and direct candidate marker of liver dysfunction.…”

Section: Nonalcoholic Fatty Liver Diseasementioning

confidence: 99%

Metabolic imaging in obesity: underlying mechanisms and consequences in the whole body

Iozzo

2015

Annals of the New York Academy of Sciences

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Obesity is a phenotype resulting from a series of causative factors with a variable risk of complications. Etiologic diversity requires personalized prevention and treatment. Imaging procedures offer the potential to investigate the interplay between organs and pathways underlying energy intake and consumption in an integrated manner, and may open the perspective to classify and treat obesity according to causative mechanisms. This review illustrates the contribution provided by imaging studies to the understanding of human obesity, starting with the regulation of food intake and intestinal metabolism, followed by the role of adipose tissue in storing, releasing, and utilizing substrates, including the interconversion of white and brown fat, and concluding with the examination of imaging risk indicators related to complications, including type 2 diabetes, liver pathologies, cardiac and kidney diseases, and sleep disorders. The imaging modalities include (1) positron emission tomography to quantify organ-specific perfusion and substrate metabolism; (2) computed tomography to assess tissue density as an indicator of fat content and browning/ whitening; (3) ultrasounds to examine liver steatosis, stiffness, and inflammation; and (4) magnetic resonance techniques to assess blood oxygenation levels in the brain, liver stiffness, and metabolite contents (triglycerides, fatty acids, glucose, phosphocreatine, ATP, and acetylcarnitine) in a variety of organs.

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“…From the time that natural abundance 13 C MRS measurements of hepatic glycogen levels were first suggested [53], the technique has been validated multiple times [7,54] . Stephenson et al [30] also tested measurement repeatability at high field (3T) and reported a single-session coefficient of variation in hepatic 13 C MRS measurement of 13% making this a feasible technique for many studies comparing the effects of nutritional intake or exercise [55] and also the differences between healthy volunteers and patients [56] . The low natural abundance of 13 C also allows for study designs that specifically track the uptake of consumed or infused 13 C labelled substrates.…”

Section: Mrs Measurements Of Liver Glycogenmentioning

confidence: 99%

Current and Future Magnetic Resonance Technologies for Assessing Liver Disease in Clinical and Experimental Medicine

Bawden

Scott²,

Aithal³

2017

Dig Dis

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Background: In the past decades, a number of non-invasive methods have emerged for detecting and estimating liver fibrosis; these include both serum-based panels and imaging-based technology. Some of these methods are now being incorporated in clinical practice. However, the limitations of the current techniques include lack of organ specificity, sampling errors and limited ability to reflect the efficacy of interventions. Key Messages: Novel magnetic resonance (MR)-based techniques provide an opportunity to bring about further changes in the investigations and management of patients with liver diseases. Multimodal quantitative MR techniques enable the estimation of fat, iron accumulation, degree of liver injury/inflammation and fibrosis within the whole liver without the need for administering contrast agents. Architectural changes within the liver can be evaluated concurrently with portal haemodynamic changes allowing non-invasive assessment of portal hypertension and effects of interventions. A combination ultra-high field (7T) provides greater sensitivity with a potential to distinguish inflammation from fibrosis on imaging and determine specific types of fats (saturated vs. unsaturated) present within the liver using MR spectroscopy. ¹³C MR spectroscopy can estimate glutathione flux and rate of beta oxidation in-vivo providing novel tools for experimental studies that evaluate the efficacy of interventions as well as underlying mechanisms. Conclusions: Translational research should focus on converting the potentials of these innovative methodologies into clinical applications for the benefit of patients.

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Monitoring of liver glycogen synthesis in diabetic patients using carbon-13 MR spectroscopy

Cited by 13 publications

References 18 publications

Metformin normalizes the structural changes in glycogen preceding prediabetes in mice overexpressing neuropeptide Y in noradrenergic neurons

Metformin normalizes the structural changes in glycogen preceding prediabetes in mice overexpressing neuropeptide Y in noradrenergic neurons

Metabolic imaging in obesity: underlying mechanisms and consequences in the whole body

Current and Future Magnetic Resonance Technologies for Assessing Liver Disease in Clinical and Experimental Medicine

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