Metformin normalizes the structural changes in glycogen preceding prediabetes in mice overexpressing neuropeptide Y in noradrenergic neurons.
| Title: | Metformin normalizes the structural changes in glycogen preceding prediabetes in mice overexpressing neuropeptide Y in noradrenergic neurons. |
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| Authors: | Ailanen L; Institute of Biomedicine Research Center for Integrative Physiology and Pharmacology and Turku Center for Disease Modelling University of Turku Turku Finland.; Drug Research Doctoral Program University of Turku Turku Finland.; Bezborodkina NN; Laboratory of Cellular Pathology Institute of Cytology of the Russian Academy of Sciences St. Petersburg Russia.; Virtanen L; Institute of Biomedicine Research Center for Integrative Physiology and Pharmacology and Turku Center for Disease Modelling University of Turku Turku Finland.; Ruohonen ST; Institute of Biomedicine Research Center for Integrative Physiology and Pharmacology and Turku Center for Disease Modelling University of Turku Turku Finland.; Malova AV; Laboratory of Cellular Pathology Institute of Cytology of the Russian Academy of Sciences St. Petersburg Russia.; Okovityi SV; Department of Pharmacology and Clinical Pharmacology Saint-Petersburg State Chemical Pharmaceutical Academy St. Petersburg Russia.; Chistyakova EY; Department of Pharmacology and Clinical Pharmacology Saint-Petersburg State Chemical Pharmaceutical Academy St. Petersburg Russia.; Savontaus E; Institute of Biomedicine Research Center for Integrative Physiology and Pharmacology and Turku Center for Disease Modelling University of Turku Turku Finland.; Unit of Clinical Pharmacology Turku University Hospital Turku Finland. |
| Source: | Pharmacology research & perspectives [Pharmacol Res Perspect] 2018 Mar 08; Vol. 6 (2), pp. e00389. Date of Electronic Publication: 2018 Mar 08 (Print Publication: 2018). |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 101626369 Publication Model: eCollection Cited Medium: Internet ISSN: 2052-1707 (Electronic) Linking ISSN: 20521707 NLM ISO Abbreviation: Pharmacol Res Perspect Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Hoboken, NJ] : John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics, [2013]- |
| MeSH Terms: | Adrenergic Neurons/*drug effects ; Diabetes Mellitus, Experimental/*metabolism ; Glycogen/*biosynthesis ; Hypoglycemic Agents/*pharmacology ; Metformin/*pharmacology ; Neuropeptide Y/*genetics ; Prediabetic State/*metabolism; Adrenergic Neurons/metabolism ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Animals ; Male ; Mice, Transgenic ; Phosphorylation ; Up-Regulation |
| Abstract: | 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-NPYDβH) 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-NPYDβH 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-NPYDβH 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-NPYDβH 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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| Contributed Indexing: | Keywords: glycogen structure; metformin; neuropeptide Y; prediabetes |
| Substance Nomenclature: | 0 (Hypoglycemic Agents); 0 (Neuropeptide Y); 9005-79-2 (Glycogen); 9100L32L2N (Metformin) |
| Entry Date(s): | Date Created: 20180316 Date Completed: 20181119 Latest Revision: 20240314 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC5842371 |
| DOI: | 10.1002/prp2.389 |
| PMID: | 29541475 |
| Database: | MEDLINE |
Journal Article