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. 2023 Jun;1869(5):166668.
doi: 10.1016/j.bbadis.2023.166668. Epub 2023 Feb 21.

GLUT4 degradation by GLUTFOURINH® in mice resembles moderate-obese diabetes of human with hyperglycemia and low lipid accumulation

Sang R Lee  1 , Su Hee Jeong  1 , Moeka Mukae  1 , Kang Joo Jeong  1 , Hyo-Jung Kwun  1 , Eui-Ju Hong  2
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Free article

GLUT4 degradation by GLUTFOURINH® in mice resembles moderate-obese diabetes of human with hyperglycemia and low lipid accumulation

Sang R Lee et al. Biochim Biophys Acta Mol Basis Dis. 2023 Jun.
Free article

Abstract

Backgrounds and aims: Type 2 diabetes mellitus (T2D) is a chronic disease characterized by insulin resistance and hyperglycemia. To investigate T2D, genetic and chemical induced hyper-obese rodent models have been experimentally developed. However, establishment of moderate-obese diabetes model will confer diverse opportunities for translational studies. In this study, we found the chemical, GLUTFOURINH® (GFI), induces post-translational degradation of glucose transporter 4 (GLUT4). We aimed to establish novel diabetic model by using GFI.

Methods and results: Low plasma membrane GLUT4 (pmGLUT4) levels by GFI resulted in reduction of intracellular glucose uptake and TG, and increase of intracellular FFA in A204 cells. Likewise, GFI treatment decreased intracellular TG and increased intracellular FFA levels in Hep3B and 3T3-L1 cells. Mice were administered with GFI (16 mg/kg) for short-term (3-day) and long-term (28- and 31-day) to compared with vehicle injection, HFD model, and T2D model, respectively. Short-term and long-term GFI treatments induced hyperglycemia and hyperinsulinemia with low pmGLUT4 levels. Compared to HFD model, long-term GFI with HFD reduced adipose weight and intracellular TG accumulation, but increased plasma FFA. GFI treatment resulted in insulin resistance by showing low QUICKI and high HOMA-IR values, and low insulin response during insulin tolerance test. Additionally, low pmGLUT4 by GFI heightened hyperglycemia, hyperinsulinemia, and insulin resistance compared to T2D model.

Conclusions: In summary, we report GLUT4 degradation by novel chemical (GFI) induces moderate-obese diabetes representing hyperglycemia, insulin resistance and low intracellular lipid accumulation. The GLUT4 degradation by GFI has translational value for studying diseases related to moderate-obese diabetes.

Keywords: Diabetes; Glut4; Glut4 degradation; Hyperglycemia; Insulin resistance.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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