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Both myo-inositol to chiro-inositol epimerase activities and chiro-inositol to myo-inositol ratios are decreased in tissues of GK type 2 diabetic rats compared to Wistar controls
Abstract
Previous data from our and other labs demonstrated a decreased chiro-inositol content in urine and tissues of human subjects and animals with type 2 diabetes. In urine this decrease in chiro-inositol was accompanied by an increase in myo-inositol content. Decreased urine levels of chiro-inositol in monkeys were next correlated with the severity of underlying insulin resistance determined by five separate assays. To investigate the decreased chiro-inositol and the accompanying increased myo-inositol excretions in urine in humans and monkeys, we postulated a defect in the epimerization of myo-inositol to chiro-inositol. [(3)H]Myo-inositol was then shown to be converted to [(3)H]chiro-inositol in rats in vivo and in fibroblasts in vitro in a process stimulated by insulin. We next demonstrated that the conversion of [(3)H]myo-inositol to [(3)H]chiro-inositol in vivo was markedly decreased in GK type 2 diabetic rats compared to Wistar controls in liver, muscle, and fat, insulin sensitive tissues. Decreases of 20-25% conversion to baseline levels of under 5% conversion were observed. In the present work, we initially compared the total contents of myo-inositol and chiro-inositol in GK type 2 diabetic rat kidney, liver, and muscle compared to Wistar controls. We demonstrated a consistent decreased total chiro-inositol to myo-inositol ratio in kidney, liver, and muscle compared to controls. We next established the presence of a myo-inositol to chiro-inositol epimerase activity in rat liver cytosol. Enzyme activity was shown to be time and enzyme concentration dependent with a broad pH optimum. It required NADH and NADPH for full activity, which is compatible with its action via an oxido-reductive mechanism. Lastly, we demonstrated that the epimerase enzyme bioactivity was significantly decreased in muscle, liver, and fat cytosolic extracts of GK type 2 diabetic rats versus Wistar controls. Decreased myo-inositol to chiro-inositol epimerase activity may therefore play a role in explaining the decreased chiro-inositol to myo-inositol urine and tissue ratios observed here and in previous animal and human studies. Further it may also possibly play a role in the underlying insulin resistance.
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“Insulin stimulates unidirectional conversion of MI to D-chiro-inositol (DCI) (10)”
From Inositol for Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis to Inform the 2023 Update of the International Evidence-based PCOS Guidelines (2024) · cites this paper as [10]
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Metadata
- Authors
- Sun, T.-H., Heimark, D. B., Nguygen, T., Nadler, J. L., & Larner, J.
- Affiliations
- Insmed (United States) (US)
- University of Virginia Medical Center (US)
- Corresponding author
- Larner, Joseph
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2002-05
- Volume
- 293
- Issue
- 3
- Pages
- 1092-1098
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2081776150
- Cited by
- 144
- References
- 20
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 7 · 2023: 16 · 2022: 6 · 2021: 9 · 2020: 15 · 2019: 7 · 2018: 10 · 2017: 6 · 2016: 15 · 2015: 5 · 2014: 7 · 2013: 5 · 2012: 7
- FWCI
- 0.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK055240)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- myo-inositol, chiro-inositol, epimerization, type 2 diabetes, insulin resistance, Goto-Kakizaki rats, liver cytosol, muscle, kidney, fats, NADPH-dependent enzyme
- MeSH terms
- Adipose Tissue, Animals, Cell Extracts, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Inositol, Kidney, Liver, Male, Rats, Mutant Strains, Sugar Alcohol Dehydrogenases, Rats, Wistar, Muscle, Skeletal, Rats
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