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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 166-172

Oxidative stress injury and glucolipotoxicity in type 2 diabetes mellitus: The potential role of metformin and sitagliptin


Department of Pharmacology, Toxicology and Medicine, College of Medicine, Almustansiriya University, Baghdad, Iraq

Date of Submission28-Jan-2020
Date of Acceptance25-Feb-2020
Date of Web Publication17-Jun-2020

Correspondence Address:
Prof. Hayder Mutter Al-Kuraishy
Department of Pharmacology, Toxicology and Medicine, College of Medicine, Almustansiriya University, P. O. Box 14132, Baghdad
Iraq
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_7_20

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  Abstract 


Objective: The objective of this study was to explore the potential effects of metformin and/or sitagliptin on the oxidative stress (OS) and antioxidant capacity in patients with type 2 diabetes mellitus (T2DM). Materials and Methods: In this cross-sectional study, 64 patients with T2DM compared with 32 healthy controls, they divided into three groups: Group A: 32 healthy controls, Group B: 33 patients with T2DM on metformin therapy, and Group C: 31 patients with T2DM on metformin plus sitagliptin therapy. Fasting blood glucose, glycated hemoglobin, fasting serum insulin, insulin resistance, lipid profile, cardiac indices, and anthropometric measurements were determined. As well, OS parameters which include total oxidant status (TOS), total antioxidant status (TAS), and OS index (OSI) were measured in patients with T2DM and healthy controls. Data analysis was done using SPSS; for significance testing, unpaired Student's t-test and analysis of variance were used. Pearson correlation was also used to detect the level of correlations. Results: Patients with T2DM have a high risk of diverse cardiometabolic changes compared with the controls (P = 0.0001). TOS was high in diabetic patients (36.89 ± 4.71 μmole/L) compared with the controls (12.74 ± 3.81 μmole/L) (P = 0.0001), TAS was low in diabetic patients (1145.89 ± 293.51 μmole/L) compared with the controls (1237.61 ± 383.74 μmole/L) (P = 0.0001), and OSI was high in diabetic patients (3.21 ± 1.99) compared with the controls (1.02 ± 0.92) (P = 0.0001). Patients with T2DM on metformin plus sitagliptin illustrated low OSI compared with T2DM on metformin monotherapy (P = 0.04). Conclusion: Metformin and/or sitagliptin attenuate T2DM-induced OS through potentiation of TAC and reduction of TOC and OSI. Therefore, a combination of metformin and sitagliptin is recommended to reduce glucolipotoxicity and related OS injury.

Keywords: Oxidative stress index, total antioxidant status, total oxidant status, type 2 diabetes mellitus


How to cite this article:
Abdul-Hadi MH, Naji MT, Shams HA, Sami OM, Al-Harchan NA, Al-Kuraishy HM, Al-Gareeb AI. Oxidative stress injury and glucolipotoxicity in type 2 diabetes mellitus: The potential role of metformin and sitagliptin. Biomed Biotechnol Res J 2020;4:166-72

How to cite this URL:
Abdul-Hadi MH, Naji MT, Shams HA, Sami OM, Al-Harchan NA, Al-Kuraishy HM, Al-Gareeb AI. Oxidative stress injury and glucolipotoxicity in type 2 diabetes mellitus: The potential role of metformin and sitagliptin. Biomed Biotechnol Res J [serial online] 2020 [cited 2020 Jul 7];4:166-72. Available from: http://www.bmbtrj.org/text.asp?2020/4/2/166/286850




  Introduction Top


Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia, glycosuria, polyuria, and polydipsia due to defects in insulin action and/or secretion.[1] Chronic hyperglycemia in T2DM leads to the induction of oxidative stress (OS) through the formation of free radicals by glucose autoxidation. As well, protein glycosylation by hyperglycemia and cellular metabolism are regarded as another source of reactive oxygen species (ROS).[2] On the other hand, levels of endogenous antioxidant capacity, mainly superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH), are reduced in patients with T2DM. Therefore, high ROS and low total body antioxidant capacity in T2DM increase the risk of oxidative injury which per se leads to diabetic complications.[3] Pancreatic β-cells have a low antioxidant defense, so it is highly susceptible to the risk of oxidative injury.[4] It has been reported that OS is implicated in the pathogenesis and complications of T2DM. OS causes lipid peroxidation, endothelial dysfunction, insulin resistance (IR), and impaired pancreatic β-cells.[5] Lahera et al.[6] found that inflammation, OS, and endothelial dysfunction are interrelated factors in the development of cardiovascular complications in patients with T2DM. Monnier et al. illustrated that there are four main pathways involved in hyperglycemia-induced microvascular complications which are an accumulation of sorbitol and fructose within endothelium through activation of polyol pathway, activation of the formation of advanced glycation end-product, activation of protein kinase C (PKC) and nuclear factor-κB as well as activation of hexosamine pathway. These pathways provoke overproduction of free radicals by the mitochondrial electron transport chain leading to vascular damage and endothelial dysfunction.[7]

Indeed, chronic hyperglycemia activates ROS and reactive nitrogen species which are collectively named reactive species (RS) causing reversible or irreversible oxidative effects. RS-induced oxidative injury is mediated through activation of mitogen-activated protein (MAP) and c-Jun N-terminal kinase.[8]

Animal model studies revealed that liver and adipose tissue are the major sources of OS in obese, prediabetic, and diabetic conditions. High hydrogen peroxide generated by adipose tissue is linked with a reduction in SOD, CAT, and GSH during the development of T2DM. Besides, triglyceride (TG) accumulation in the liver induces lipid peroxidation and causing hepatic IR.[9],[10]

Human studies demonstrated that OS in T2DM leads to lipid peroxidation, depletion of antioxidant capacity, DNA, and protein damage since systemic OS is correlated with hyperglycemia and blood glucose variability.[11],[12]

In T2DM, both glucotoxicity and lipotoxicity impair pancreatic β-cells through the generation of ROSs which cause the suppression of insulin mRNA, insulin concentration, and induction of apoptosis. Therefore, antioxidant therapy improves glucose tolerance in diabetic mice through reduction of the baneful effect of RS on pancreatic β-cells.[13] In addition, the reduction of circulating free fatty acids by acipimox improves insulin secretion and pancreatic β-cell function in obese participants with a history of T2DM.[14] Therefore, these facts give a clue about glucolipotoxicity during T2DM.

On the other hand, diabetic pharmacotherapy has been changed noticeably in the last decade. This pharmacotherapy and drugs reduce hyperglycemia by primary effect (inhibition of hepatic gluconeogenesis) or by secondary effect (increasing of insulin sensitivity).[15] Metformin is a biguanide drug used as a first-line therapy of T2DM which also has an antioxidant effect.[16] Besides, sitagliptin which is incretin-related drug acts through inhibition of dipeptidyl peptidase-4 (DPP-4) leading to prolongation of the half-life of glucagon-like peptide (GLP) which induces suppression of glucagon and stimulation of insulin with a significant antioxidant effect.[17]

Thus, the rationale of the present depends on the notion that glucolipotoxicity is the leading cause of OS in T2DM, and thus, diabetic pharmacotherapy due to their antioxidant effects may attenuate OS.

Therefore, the objective of the present study was to explore the potential effects of metformin and/or sitagliptin on the OS and antioxidant capacity in patients with T2DM.


  Materials and Methods Top


In this cross-sectional study, 64 patients with T2DM (22 females and 42 males, ages ranging 49–71 years) were randomly recruited from the Departments of Internal Medicine and National Endocrinology Center during routine visits compared with 32 healthy controls (17 males and 15 females) matched with age and body weight. Full history and general physical examination with routine investigations were done by an internist physician and endocrinologist. The study protocol divided the participants into:

  • Group (A): 32 healthy controls
  • Group (B): 33 patients with T2DM on metformin therapy
  • Group (C): 31 patients with T2DM on metformin plus sitagliptin therapy.


Inclusion criteria

Patients with T2DM for more than 6 months were included in this study.

Exclusion criteria

Pregnant and lactating women; patients with psychiatric and mental disorders, hepatic dysfunction, end-stage kidney disease, and thyroid disorders; patients with T2DM on antidiabetic medication other than metformin or sitagliptin; and patients on medications of dopamine agonists, active infection, and sepsis were excluded from the study.

Biochemical measurements

Glycemic indices

Fasting blood glucose (FBG) was determined by a glucose oxidase method. Glycated hemoglobin (HbA1c) was measured by a specific kit (human HbA1c AIi1c, GHbA1c, MBS702379). Fasting insulin was measured by ELISA kit method (insulin human ELISA kit, Catalog number: KAQ1251). IR and pancreatic β-cell function were determined by homeostatic model assessment (HOMA-2).





Lipid profile and cardiac indices

A blood sample (10 mL) was get from patients and matched controls which centrifugated at 3000 rpm and stored till the time of analysis.

Lipid profiles (total cholesterol [TC], TG, and high-density lipoprotein [HDL]) were measured by colorimetric ELISA kit method (Abcam, 65390, USA). Very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), atherogenic index (AI), AI = log (TG/HDL), and cardiac risk ratio (CRR), CRR = TC/HDL, non-HDL-c = TC-HDL-c, and cardiovascular risk index (CVRI) = TG/HDL were measured according to Al-Kuraishy et al.[19]

Anthropometric measurements

Blood pressure was measured at the supine position from the left arm by digital automated blood pressure monitoring 2 h apart. Pulse pressure (PP) = Systolic blood pressure − diastolic blood pressure (SBP − DBP) and mean arterial pressure (MAP),. Body mass index (BMI) was estimated by explicit equation BMI = weight (kg)/height (cm2).[20]

Measurements of oxidative stress parameters

Total oxidant status (TOS) measures overall body oxidant status, total antioxidant status (TAS) measures overall body antioxidant status, and OS index (OSI) is the ratio of TOS to TAS which reflects body oxidative stress.[21]

TOS was measured by ELISA kit method (human total oxidant, MBS162650, MyBioSource).

TAS was measured by ELISA kit method (human total antioxidant, MBS168358, MyBioSource).

Both TAS and TAS are expressed as μmole/L, .

Statistical analysis

Data analysis was done using SPSS (IBM SPSS Statistics for Windows version 20.0, 2014 Armonk, NY, IBM, Corp, USA). Unpaired Student's t-test was used to test the level of significance between two study groups. Analysis of variance followed by Bonferroni post hoc test was used to compare the results of different groups. Pearson correlation was used to detect the level of correlations. The level of significance was regarded when P < 0.05.


  Results Top


Study characteristics

The present study demonstrated that 64 patients with T2DM with age of 61.56 ± 7.83 years and 65.62% of them were males compared to 34.37% female also, 56.25% of them were active smokers. The duration of T2DM was 7.81 ± 3.43 years which associated with other concomitant diseases such as dyslipidemia (75.00%), hypertension (79.68%) and previous myocardial infarction (9.37%), diabetic neuropathy (45.31%), diabetic retinopathy (35.39), and diabetic nephropathy (42.18%). Regarding current pharmacotherapy of diabetic patients, 51.56% were on metformin therapy and 48.43% on metformin and sitagliptin, and other therapies are listed in [Table 1].
Table 1: Characteristics of patients with type 2 diabetes mellitus

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Cardiometabolic and oxidative stress changes in patients with type 2 diabetes mellitus

Patients with T2DM of the present study have a high risk of diverse cardiometabolic changes compared with healthy controls. BMI of diabetic patients was slightly higher than of controls but not significant (P = 0.08). Blood pressure changes (SBP, DBP, PP, and MAP) were high in diabetic patients compared with the controls (P < 0.01). Glycemic indices (FBG, HbA1c, HOMA-IR, and HOMA-β cell function) were high in diabetic patients compared with the controls (P < 0.01). As well, lipid profiles were high (LDL, VLDL, TC, and TG) and low HDL in diabetic patients compared with the controls (P < 0.01) for all lipid profiles except of LDL (P = 0.02). Moreover, cardiac indices (CRR, AI, and CVRI) were high in diabetic patients compared with the controls (P < 0.01). Oxidative parameters were disorganized in patients with T2DM; TOS was high in diabetic patients (36.89 ± 4.71 μmole/L) compared with controls (12.74 ± 3.81 μmole/L) (P < 0.01), whereas TAS was low in diabetic patients (1145.89 ± 293.51 μmole/L) compared with controls (1237.61 ± 383.74 μmole/L) (P < 0.01). Furthermore, OSI was high in diabetic patients (3.21 ± 1.99) compared with controls (1.02 ± 0.92) (P < 0.01), [Table 2].
Table 2: Cardiometabolic differences in patients with type 2 diabetes mellitus compared with controls

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Relationship of oxidative stress index with cardiometabolic changes in patients with type 2 diabetes mellitus

OSI of patients with T2DM was not significantly correlated with patients' BMI (r = 0.22, P = 0.08). On the other hand, OSI was significantly correlated with blood pressure profiles and glycemic and cardiac indices. In this correlation, OSI was positively correlated with all of those variables, but it was negatively correlated with HOMA-β, HDL, and TAS [Table 3].
Table 3: Pearson correlations of oxidative stress index with cardiometabolic changes in patients with type 2 diabetes mellitus

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Effects of metformin and/or sitagliptin on the oxidative stress index

OSI was high in patients with T2DM on metformin monotherapy (3.19 ± 1.37) compared with healthy controls (1.02 ± 0.43) (difference = 2.17, 95% confidence interval [CI] =1.5460–2.7940, P = 0.0001). Furthermore, OSI was high in patients with T2DM on metformin plus sitagliptin (2.55 ± 1.01) compared with healthy controls (difference = 1.53, 95% CI = 0.9060–2.1540, P = 0.0001). Patients with T2DM on metformin plus sitagliptin illustrated low OSI compared with T2DM on metformin monotherapy (difference = 0.64, 95% CI = 1.2640–0.0160, P = 0.04), [Figure 1].
Figure 1: Oxidative stress index in patients with type 2 diabetes mellitus regarding the effects of diabetic pharmacotherapy

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  Discussion Top


The present study illustrated that patients with T2DM had cardiometabolic complications including hypertension, dyslipidemia, and OS compared with healthy controls as revealed by Tangyarasittichai[3] study that showed OS causing hypertension and dyslipidemia, and also, it is regarded as the underlying cause of T2DM-induced complications.

It has been reported that hyperglycemia in T2DM is the main cause of OS through induction of the generation of free radicals which cause various diabetic complications such as endothelial dysfunction and systemic hypertension.[22] These findings correspond with our results since high SBP, DBP, PP, and MAP were observed in patients with T2DM compared with the controls. As well, our findings revealed that systemic hypertension was correlated with the level of OS. Montezano et al.[23] illustrated that OS promotes vascular damage, inflammation, vascular remodeling, and endothelial dysfunction which eventually cause hypertension due to macrovascular complications.

T2DM-induced OS leads to impairment of endothelial nitric oxide (NO) production with induction of inducible NO synthase (NOS) which provokes the production peroxynitrite instead of NO. Peroxynitrite leads to the activation of polyl-ADP-ribose polymerase (PARP) and depletion of endothelial NOS and tetrahydrobiopterin. These changes lead to vasoconstriction, endothelial dysfunction, and vascular damage through the upregulation of different adhesion molecules and pro-inflammatory cytokines.[24]

Moreover, variability of blood glucose (high and low) in T2DM may provoke the PARP pathway with induction of the expression of interleukin-6 and other pro-inflammatory adhesion molecules. Therefore, inhibition of PARP prevents hyperglycemia-induced cardiovascular complications.[25] In our study, pro-inflammatory adhesion molecules and PARP were not estimated as well, and blood glucose variability was not evaluated.

Besides, our results illustrated that glycemic indices FBG, HbA1c, fasting serum insulin (FSI), HOMA-IR, and HOMA-β were strictly affected and correlated with OSI in patients with T2DM. Saif-Elnasr et al.[26] demonstrated that hyperglycemia and hyperinsulinemia are implicated in the generation of free radicals and induction of OS which per se leading to IR, impairment of pancreatic-β cell function and insulin release. In the present study, high FSI and HOMA-β were to overcome the developed IR.

Moreover, in the current study, there was noteworthy dyslipidemia which also correlated with OSI in patients with T2DM, as revealed by Yu and Lyons study.[27] It has been accounted that small dense LDL, IDL, and chylomicron remnants are prone to oxidation with induction of lipid peroxidation and induction of OS. Oxidized LDL when binds to its receptors induces the release of chemokines and pro-inflammatory cytokines from activated macrophage. In turn, circulated and disseminated oxidized lipids play a role in the induction of OS.[28] Thus, dyslipidemia together with OS contributes to cardiovascular complication in patients with T2DM which were seen noticeably in our study through high CRR, CVRI, and AI as revealed in a previous study.[29]

Further, in our study, we observed low TAS and high TOS and OSI in patients with T2DM compared with healthy controls as reported by Rani and Mythili.[30] This decrease of TAS among diabetic patients could be ascribed to hyperglycemia-induced OS and lipid peroxidation. Similarly, the reduction of TAS reflects the activity of potential endogenous capacity to fight and stop underling oxidative injury. TAS provides a complete picture about the endogenous and exogenous antioxidant capacity; thus, it is more accurate than measuring a single antioxidant as they act synergistically against OS.[31] Exogenous antioxidant capacity is also impaired in patients with T2DM. In chronic oxidative reaction, Vitamins C and E and SOD are slightly increased in T2DM due to the adaptive response of body antioxidant capacity against OS, whereas in acute diabetic complications such as diabetic ketoacidosis, body antioxidant capacity is relentlessly reduced.[32] In addition, Savu et al.[33] found that body antioxidant capacity is increased despite high OS in patients with uncomplicated T2DM due to the increase of copper and ceruloplasmin which together act as pro-oxidant and antioxidant depending on redox reactions.

In the present study, diabetic neuropathy, retinopathy, and nephropathy were observed within patients with T2DM which were linked to the risk of OS. It has been documented that OS leads to the diabetic microvascular and macrovascular complications through induction of malondialdehyde (MDA) a byproduct of lipid peroxidation. MDA is a highly toxic oxidant lipid biomarker that leads to alteration of lipoprotein metabolism, induction of pro-inflammatory cytokines, and activation of PKC. Besides, MDA reacts reversibly or irreversibly with phospholipids and proteins leading to microvascular complications.[34]

Regarding the effect of current diabetic pharmacotherapy in the present study, metformin or metformin plus sitagliptin might affect the oxidant and antioxidant status. Patients with T2DM that were treated with metformin plus sitagliptin illustrated low OSI compared with diabetic patients treated with metformin alone. Bonnefont-Rousselot et al.[35] found that metformin therapy in T2DM has a potent antioxidant effect through direct scavenge of ROS or indirectly by inhibition of the production of superoxide anion, inhibition of intracellular NADPH oxidase, increasing the concentration of Vitamin E, improvement of endogenous antioxidant capacity, suppression of glucose autoxidation, and PARP pathway. Thus, metformin improves oxidative parameters as seen in our study. Similarly, metformin inhibits oxidative phosphorylation, thereby reducing cellular ATP levels, production of ROS, and induction of DNA repair.[36]

On the other hand, sitagliptin and other DDP4 inhibitors prevent hyperglycemia-induced OS with a significant antioxidant effect through reversing of ROS and endoplasmic reticulum stress.[37] Moreover, Wang et al.[38] illustrated that sitagliptin improves endothelial dysfunction in experimental rats through promoting of autophagy and reduction of peroxynitrite serum levels. Furthermore, metformin plus sitagliptin produces more antioxidant and anti-inflammatory effects with reduction of OS in doxorubicin-induced cardiotoxicity.[39]

Moreover, 56.25% of our patients were active smokers which might be an additional factor in the induction of OS that led to high TOS and OSI. Kamceva et al.[40] confirmed that cigarette smoking leads to the induction of OS and reduction of endogenous antioxidant capacity.

Besides, other drugs such as statins, fenofibrate, and ACEI that were used by our diabetic patients might affect body oxidant and antioxidant status. Effects of those drugs were excluded in the present since these drugs as documented from patients history were used in an irregular pattern as most of those patients regarded these drugs are not essential in the management of T2DM.

It inspiring to cognize that glucolipotoxicity is interrelated with OS in the initiation of T2DM-induced complications through wide vicious cycle; thus, break-off components of this cycle by metformin and/or sitagliptin might be of great value in prevention and attenuation of oxidative injury. Therefore, metformin and/or sitagliptin in addition to their potent antidiabetic effects, they improve TAC and reduce TOC and OSI in patients with T2DM.

The present study has some limitations including a cross-sectional study with a small sample size which might limit the interpretation of the results, dose-dependent effect of metformin or sitagliptin was not evaluated, and individual biomarkers of OS were not estimated. As well, gender differences and risk of OS in T2DM were not eliminated sufficiently. Nevertheless, our study is regarded as a prelude outlook to a large-scale study to assess the potential effect of metformin and sitagliptin on the molecular basis of their antioxidant and ROS scavenging effects.


  Conclusion Top


Metformin and/or sitagliptin attenuate T2DM-induced OS through potentiation of TAC and reduction of TOC and OSI. Therefore, a combination of metformin and sitagliptin is recommended to reduce glucolipotoxicity and related OS injury.

Research quality and ethics statements

The authors of this manuscript declare that this scientific work obeys and complies with known formatting, quality, and reproducibility guidelines forth by EQUATOR Network. As well, the authors demonstrate that these scientific and clinical investigations were required the Institutional Review Board, Ethics Committee review, and specific approval by the Medical Research Jury in College of Medicine, Al-Mustansiriyia University, Baghdad, Iraq.

Acknowledgments

We thank the registry database team and all medical staff members in the Department of Clinical Endocrinology for their cooperation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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