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

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‐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.

Revisiting Glycogen in Cancer: A Conspicuous and Targetable Enabler of Malignant Transformation

“…These processes can be targeted with AMPK activators such as metformin and resveratrol, anti-diabetic agents that are becoming more widely studied in cancer (9,114,115). Metformin functions by inducing glycogenolysis via insulin signaling, downstream of GSK activity, as well as by AMPK activation (9,17,(116)(117)(118). Pharmacological disruption of processes downstream the glycogen debranching enzyme AGL has also been attempted.…”

Evaluation of the Effectiveness of Metformin and Black Rice Ethanol Extract Combination in Reducing Blood Glucose Levels and Protecting Kidney, Liver, and Pancreatic Cells

“…The dry extract was obtained by adding 10:1 desiccant to the BRB extract to enrich it with C3G content. 12,16 Modeling hyperglycemic animals Male white rats, which had been adapted to the experimental environment and had set initial parameters as baseline values, were induced with ALX 150 mg/kg BW (0.3% in saline) intraperitoneally. Treatment was administered to animals whose blood glucose levels were above 200 mg/dL on the fourth day following induction.…”

Механізми Дії Метформіну За Діабету Та Пов’язаних Із Діабетом Патологій

“…Також постулюється вплив МФ на мікробіом кишечника [6]. Лікування МФ нормалізує метаболізм глікогену та пригнічує як синтез глікогену, так і фосфорилювання, що може сприяти його профілактичному впливу на виникнення ЦД2 [7].…”