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. 2021 Mar 15:14:1129-1139.
doi: 10.2147/DMSO.S300048. eCollection 2021.

Gene Expression Profiling of Apoptotic Proteins in Circulating Peripheral Blood Mononuclear Cells in Type II Diabetes Mellitus and Modulation by Metformin

Mohammed Al Dubayee  1   2   3 , Awad Alshahrani  1   2   3 , Dana Aljada  4 , Mahmoud Zahra  5 , Ahmed Alotaibi  1 , Ibrahim Ababtain  1 , Malik Alnaim  1 , Ali Alahmari  1 , Abdullah Aljarallah  1 , Muhammad Affan Elahi  5 , Hana M A Fakhoury  5
Affiliations

Gene Expression Profiling of Apoptotic Proteins in Circulating Peripheral Blood Mononuclear Cells in Type II Diabetes Mellitus and Modulation by Metformin

Mohammed Al Dubayee et al. Diabetes Metab Syndr Obes. .

Abstract

Introduction: Insulin resistance in obesity and type 2 diabetes mellitus (T2DM) is associated with cardiovascular complications such as atherosclerosis. On the other hand, the reduction of apoptosis in macrophages has been linked with accelerated atherosclerosis. Apoptosis is controlled by a different family of proteins including Bcl-2 and caspases.

Methods: To examine apoptosis in insulin resistance, we assessed the mRNA expression by qRT-PCR of several Bcl-2 family members, as well as caspase-3, -7, -8, and -9 in peripheral blood mononuclear cells (PBMCs) isolated from lean, obese, diabetic, and diabetic on metformin individuals.

Results: PBMCs of diabetic individuals exhibited reduced expression of caspase-7 and increased expression of Bcl-10, Bad, Bax, Bid, and caspase-3. T2DM on metformin group had significantly higher Bad, Bax, and caspase-7 expression.

Discussion: The moderate up-regulation of pro-apoptotic Bcl-10, Bax, Bad, Bid, and the effector caspase-3 coupled with inhibition of caspase-7 in circulating PBMCs of T2DM could be the result of increased inflammation in T2DM. Metformin treatment significantly inhibited the expression of Bcl-10, Bid, and caspase-3 and upregulated Bad/Bax/caspase-7 pathway suggesting the activation of Bad/Bax/caspase-7 apoptotic pathway. Further studies are warranted to elicit the underlying apoptotic pathways of PBMCs in T2DM and following metformin treatment.

Keywords: BCl-10; BCl-2; PBMC; T2DM; apoptosis; caspase; peripheral blood mononuclear cells.

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Conflict of interest statement

The authors report no conflicts of interest for this work and declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest.

Figures

Figure 1
Figure 1
mRNA expression of Bcl-2 in PBMC of lean, obese, T2DM, and T2DM on metformin. Results are presented as mean ± S.E.M.
Figure 2
Figure 2
mRNA expression of three members of the Bcl-2 family that promote apoptosis in PBMC of lean, obese, T2DM, and T2DM on metformin: (A) Bak; (B) Bax; and (C) Bcl-10. Results are presented as mean ± S.E.M. *P < 0.05 vs lean subjects; σP < 0.05 vs obese subjects; δP < 0.05 vs T2DM subjects.
Figure 3
Figure 3
mRNA expression of three members of apoptotic BH3 domain-only proteins that bind and regulate the anti-apoptotic Bcl-2 proteins in PBMC of lean, obese, T2DM, and T2DM on metformin: (A) Bad; (B) Bid; and (C) Bim. Results are presented as mean ± S.E.M. *P < 0.05 vs lean subjects; σP < 0.05 vs obese subjects; δP < 0.05 vs T2DM subjects.
Figure 4
Figure 4
mRNA expression of three caspases in PBMC of lean, obese, T2DM and T2DM on metformin: (A) CASP3; (B) CASP7; (C) CASP8; and (D) CASP9. Results are presented as mean ± S.E.M. *P < 0.05 vs lean subjects; σP < 0.05 vs obese subjects; δP < 0.05 vs T2DM subjects.
Figure 5
Figure 5
Apoptotic protease activating factor 1 (Apaf1) mRNA expression in PBMC of lean, obese, T2DM, and T2DM on metformin. Results are presented as mean ± S.E.M.
Figure 6
Figure 6
This figure schematizes steps in the proposed effect of metformin on apoptotic proteins in PBMCs examined in this study. The steps are depicted in a sequence proceeding from right to left. Hyperglycaemia presents in diabetes induces NF-κB pathway by reactive oxygen species (ROS). The low to moderate up-regulation of inflammatory Bcl-10, Bax, Bad, Bid, and the effector caspase-3 coupled with inhibition of caspase-7 in circulating PBMCs of T2DM could be a result of activated NF-κB pathway in T2DM.
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