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. 2024 Jul 16;12(10):7177-7185.
doi: 10.1002/fsn3.4267. eCollection 2024 Oct.

The effect of myo-inositol supplementation on AMPK/PI3K/AKT pathway and insulin resistance in patients with NAFLD

Taha Aghajani  1 , Sara Arefhosseini  2 , Mehrangiz Ebrahimi-Mameghani  3 , Reza Safaralizadeh  1
Affiliations

The effect of myo-inositol supplementation on AMPK/PI3K/AKT pathway and insulin resistance in patients with NAFLD

Taha Aghajani et al. Food Sci Nutr. .

Abstract

Insulin resistance (IR) is the pivotal pathological hit in non-alcoholic fatty liver disease (NAFLD). There is specific attention to combination/conjugated therapies for NAFLD management. As myo-inositol (MI) has been shown to improve IR in animal and human trials, this study aimed to investigate the influence of MI supplementation on glycemic response and IR through AMPK/PI3K/AKT signaling pathway in obese patients with NAFLD. This double-blinded placebo-controlled randomized clinical trial was conducted on 48 obese (BMI = 30-40 kg/m2) patients with NAFLD who were randomly assigned to receiving either MI (4 g/day) or placebo (maltodextrin 4 g/day) group for 8 weeks. Before and after the trial, weight, height, serum glycemic parameters (inc. fasting glucose and insulin) as well as IR indices were assessed. Moreover, the mRNA expression levels of AMPK, AKT, and PDK-1 in peripheral blood mononuclear cells (PBMCs) were determined. MI supplementation resulted in significant increases in the fold changes of AMPK, AKT, and PDK-1 genes (p = .019, p = .049, and p = .029, respectively). Indeed, IR improved in terms of all IR indices in MI group (p < .05) after adjusting for the confounders, apart from quantitative insulin sensitivity check index (QUICKI). The results showed that MI supplementation not only upregulated AMPK, AKT, and PDK-1 mRNA in PBMCs but also improved IR in obese patients with NAFLD.

Keywords: gene expression; insulin resistance; myo‐inositol; non‐alcoholic fatty liver disease.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

FIGURE 1
FIGURE 1
Trial profile.
FIGURE 2
FIGURE 2
Result of intervention. Fold change of AMPK, AKT, and PDK‐1 mRNAs expression. Values are the mean of fold change ± SEM. Data analysis was done using the one sample t‐test and ANCOVA. *p < .05 versus baseline. **p < .05 versus Placebo. p < .05 statistically significant. AMPK, adenosine monophosphate‐activated protein kinase; AKT, protein kinase‐B; PDK‐1, phosphoinositide‐dependent kinase 1.
FIGURE 3
FIGURE 3
Possible triggered molecular pathways by MI supplementation, leading to the treatment of IR in patients with NAFLD. MI participates in intra‐cellular pool of phosphatidylinositols and activates IPMK which phosphorylates LKB1 and thereby upregulates AMPK. On the other side, increased generation of MI‐IPGs and DCI–IPGs directly upregulate IRS, PDK‐1, and AKT. AKT activation results in the phosphorylation of Rab and facilitating the translocation of GLUT‐4 and lowering blood glucose levels (S12). AKT stimulates glucose synthase (GS) activity, resulting in reduced hepatic glucose synthesis. AKT, protein kinase‐B; AMPK, adenosine monophosphate‐activated protein kinase; DCI‐IPGs, d‐chiro inositol containing inositol phosphoglycans; GLUT‐4 glucose transporter 4; GS, glycogen synthase; IMPK, inositol phosphate multikinase; INS, inositols; MI, myo‐inositol; MI‐IPGs, Myo‐inositol containing inositol phosphoglycans; PDK‐1 phosphoinositide‐dependent kinase 1; PI3K, phosphoinositide 3 kinase IRS insulin receptor substrates; PIP2, Phosphatidylinositol‐4,5‐bisphphosphate; PIP3, phosphatidylinositol‐3,4,5‐triphphosphate; SMIT, sodium/myo‐inositol transporter.
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