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

Pharmacol Res Perspect. 2018 Mar 8;6(2):e00389. doi: 10.1002/prp2.389. eCollection 2018 Apr.


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.

Keywords: glycogen structure; metformin; neuropeptide Y; prediabetes.

MeSH terms

  • Adrenergic Neurons / drug effects*
  • Adrenergic Neurons / metabolism
  • Animals
  • Diabetes Mellitus, Experimental / metabolism*
  • Glycogen / biosynthesis*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hypoglycemic Agents / pharmacology*
  • Male
  • Metformin / pharmacology*
  • Mice, Transgenic
  • Neuropeptide Y / genetics*
  • Phosphorylation
  • Prediabetic State / metabolism*
  • Up-Regulation


  • Hypoglycemic Agents
  • Neuropeptide Y
  • Glycogen
  • Metformin