Abstract
Introduction
A wide range of antidiabetic therapies have been developed to manage diabetes and limit its lifespan but each of them have adverse long-term drug reactions. This study was performed for the investigation of the possible association of antidiabetic therapy with shortened telomere length in middle-aged Type 2 diabetic patients.
Materials and methods
The subjects in this case–control study included 100 non-diabetic patients and 300 patients with Type 2 diabetes with ages in the range of 30–50 years. The treated patients were further subdivided into diabetic patients using Doanil, those using insulin and those using both the therapies. The mean telomere length was determined using the southern-blotting technique. A logistic regression analysis was performed to predict the relationship between antidiabetic therapy and shortened telomere length.
Results
The results revealed a significant increase (P < 0.01) in the fasting blood glucose and lipid profile in non-treatment diabetic patients compared to diabetic patients with treatment, and also in diabetic patients with insulin therapy, compared to diabetic patients with Doanil or both therapies. The results showed that non-treatment diabetic patients had shorter telomere length, compared to the diabetic patients with treatment, and patients treated with insulin therapy had shorter telomere length, compared to the diabetic patients with Doanil or both therapies. The logistic regression analysis confirmed that insulin therapy was closely related to diabetic risk factors and shortened telomere length.
Conclusions
The results revealed that Doanil therapy was more effective in managing diabetic risk and limiting the shortening telomere length than insulin therapy.
Keywords: Antidiabetic therapy, Type 2 diabetes, Telomere length
Introduction
Many diseases have reached epidemic proportions worldwide, but among the most important is Type 2 diabetes mellitus [1]. A primary cause of diabetes is the lack of insulin secretion or its action, which leads to dyslipidaemia and other complications [2]. It has been shown that poor glycaemic control is related to cardiac risk factors such as dyslipidaemia, obesity and metabolic syndrome [3, 4]. Moreover, glycaemic disorder and insulin resistance in patients with Type 2 diabetes have been shown to be associated with increased free fatty acid flux and oxidative stress which cause heart disease and accelerated aging [5, 6]. The most important biological aging marker is the telomere which is composed of a repetitive sequence at the terminal of linear chromosomes to prevent loss of genomic DNA and protect the chromosome stability [7]. Moreover, insulin deficiency decreases the glucose transport into the target organ and decreases the number of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) receptors with increased free fatty acid levels and hepatic very-low-density lipoprotein (VLDL-TG) secretion which results in hyperglycaemia and dyslipidaemia [8, 9]. Insulin deficiency enhances oxidative damage of DNA and shorter telomere length [10, 11]. Their length is known to shorten with several diseases, such as cardiovascular disease [12], obesity [13], diabetes [14] and metabolic syndrome [15]. This attrition happens in all cells except immortal, carcinomatous and germ cells due to the end-replication phenomenon and oxidative stress associated with age-related diseases [16]. The end-replication phenomenon weakens the DNA polymerase and prevents it from fully replicating the 3′end of chromosomes with every cell division [17]. Besides, oxidative stress weakens the telomerase activity to counteract telomere erosion and prevents cells from entering senescence [18]. In diabetes and its complication, it is well reported that hyperglycaemia induces the replication of β-cells to match the increased demand for insulin secretion, which leads to excessive telomere attrition in the β-cells [19]. Moreover, oxidative stress induced by high-glucose conditions may selectively cause telomerase dysfunction in the β-cells [20]. These diabetic complications can be prevented by using anti-diabetic drugs and through lifestyle modifications [21].
Antidiabetic drugs can be divided into oral and insulin therapy. Oral antidiabetic drugs are classified according to insulin sensitisation and insulin secretion. One of the classes of these drugs is the sulphonylureas, drugs that are often used to treat Type 2 diabetes [22]. Doanil (glibenclamide) is one of the most frequently used sulphonylureas that have a key role in the management of Type 2 diabetes and increasing insulin release from the β-cells [23]. Doanil treatment improves blood glucose and dyslipidaemia and reduces the risk of complications; however, given the long-term damage of the β-cell function and low response towards insulin in target cells with oral treatment, it becomes necessary to use insulin therapy [22, 24]. Insulin therapy regulates glucose and lipid profile levels by decreasing glucose production in the liver, increasing infusion of glucose to peripheral tissues and regulating liver production of apolipoprotein and enzyme activities of hepatic lipase [22]; however, with long-term use of insulin therapy, patients have symptoms of hypoglycaemia and weight gain [21]. According to previous studies, none of the antidiabetic therapies have been shown to completely cure this disease and the optimisation of this therapy by the prevention of deterioration in diabetic patients is essential [21, 22, 24]. Few studies have examined the association of antidiabetic therapy and shortened telomere length in diabetic patients [25–27]. However, there is currently no study regarding the relationship between antidiabetic therapy and telomere length in middle-aged Type 2 diabetic patients. Therefore, the present study was conducted to assess the effect of antidiabetic therapy on shortened telomere length in middle-aged Type 2 diabetic patients.
Methods
Study population and anthropometric measurements
A case–control study was performed including 100 non-diabetic and 300 Types 2 diabetic patients (75 non-treatment group, 80 using Doanil, 70 using insulin and 75 with both therapies), with aged in the range of 30–50 years during the period of March 2020 to October 2020. Diabetic patients were recruited from the Diabetic centre in Mergan hospital, Babylon province, while the non-diabetic control participants were from the general Iraqi population. Smokers, alcoholics, pregnant women, individuals with high blood pressure, and patients with diabetes complications were excluded. A questionnaire was taken for each patient and included age, diabetes duration, types of anti-diabetic therapy, and use of hormone replacement therapy. Patients who had been using diabetes medications including Doanil, those using insulin and those using both the therapies for 3 years or more were assigned to treatment groups. Body Mass Index (BMI) was calculated according to the BMI formula = weight (kg)/ height2 (m2) and classify into underweight, normal and overweight (BMI < 18.5 kg/m2), BMI (18.5 ≥ BMI < 25 kg/m2) and overweight (BMI ≥ 25 kg/m2), respectively [28]. The waist circumference in the torso was calculated at its narrowest point in terms of width, specifically directly above the belly button, and it is ≤ 102 cm for men and ≤ 88 cm for women [29].
Biochemical determinations
Blood samples (5 mL) were collected from each study subject after 8–12 h of fasting and then used to assay glycated hemoglobin (HbA1c) and telomere length while the sera were collected for biochemical assay including fasting blood glucose (FBG) and lipid profile. Fasting serum glucose was determined by the glucose oxidase method. Low-density lipoprotein cholesterol (LDL-C) was measured using the Fredwald formula [30], while the remaining lipid profile was determined by the enzymatic colorimetric method.
Telomere length
Genaid kit was used to isolate genomic DNA from whole blood and was quantified by Nanodrop. The southern-blotting technique was used to measure the terminal restriction fragment (TRF) lengths [31, 32]. Briefly, 2 µg of DNA was digested for 2 h at 37 °C with two restriction enzymes including HinfI and RsaI (Roche) with a concentration (20 U) for each to produce TRFs. The TRFs were loading on 0.8% agarose gel then denatured with 0.5 M NaOH/1.5 M NaCl and neutralized for 30 min in 0.5 M Tris and 1.5 M NaCl. The capillary transfer was used overnight to transfer DNA to a nylon membrane positively charged. The nylon membranes were then hybridized for 3 h in the hybridization solution with telomeric probe digoxigenin. Wash the blotting membrane 3 times with 2 × SSC (3 M NaCl, 0.3 M Sodium citrate, pH 7.0). The telomeric probe was revealed by the digoxigenin luminescent procedure after exposed to X-ray film.
Statistical analysis
The SPSS v23.0 (IBM, NY, USA) was used to perform statistical analysis of the data. Values were presented as mean ± standard deviation (SD) and least-square means ± standard error (LSM ± SE). The normalized data were tested with the Kolmogorov–Smirnov test. The student's t-test was used to compare the two groups, Chi-squared tests for categorical data and one-way ANOVA was used to determine the differences in the studied characteristics for antidiabetic drugs. Multiple pairwise comparisons between main factors were performed using a Tukey-Krammer test. The logistic regression analysis was used to assess the association between risk factors with telomere length and the significance was set at P ≤ 0.05.
Results
The baseline characteristics of the study population
The baseline variables of the study population are presented in Table 1. Subjects with diabetic showed a significant increase (P < 0.01) in the age, waist, FBG, HbA1c, total cholesterol (TC), triglyceride (TG), LDL-C with a lower high-density lipoprotein cholesterol (HDL-C) and telomere length compared to the non-diabetic subjects.
Table 1.
The baseline variables of the study population
| Characteristic | Non-diabetic (N = 100) | Diabetic (N = 300) | P-value |
|---|---|---|---|
| Gender (M/F) | 58/42 | 151/149 | 0.12 |
| Age (year) | 41.09 ± 1.12 | 45.55 ± 1.80 | 0.01* |
| DM duration (years) | – | 5.39 ± 1.09 | |
| BMI (kg/m2) | 27.78 ± 1.11 | 29.82 ± 0.95 | 0.46 |
| WC (cm) | 90.50 ± 2.14 | 102.24 ± 1.83 | 0.01* |
| FBG (mmol/L) | 4.86 ± 0.55 | 11.56 ± 0.50 | 0.001** |
| HbA1c (%) | 5.07 ± 0.13 | 7.50 ± 0.27 | 0.001** |
| TC (mmol/L) | 4.43 ± 0.22 | 5.55 ± 0.31 | 0.03* |
| TG (mmol/L) | 1.56 ± 0.03 | 2.87 ± 0.02 | 0.04* |
| HDL-C (mmol/L) | 1.13 ± 0.05 | 0.84 ± 0.04 | 0.03* |
| LDL-C (mmol/L) | 2.73 ± 0.02 | 3.89 ± 0.01 | 0.02* |
| Telomere length (kb) | 14.24 ± 0.95 | 11.23 ± 0.87 | 0.001** |
Values are mean ± Standard deviation (SD),* (P ≤ 0.05), ** (P ≤ 0.01)
DM diabetes mellitus, BMI body mass index, WC waist circumference, FBG fasting blood glucose, HbA1c hemoglobin A1c, TC total cholesterol, TG triglycerides, HDL-C HDL cholesterol, LDL-C LDL cholesterol
Comparison of the clinico-biochemical parameters
The clinical and biochemical parameters of diabetic patients have been shown in Tables 2 and 3. There was a significant increase (P < 0.01) in the clinical profiles including FBG, and total cholesterol, triglyceride, LDL-C and a lower HDL-C in non-treatment diabetic patients, compared to diabetes patients with treatment, and also in diabetic patients with insulin therapy, compared to diabetic patients with Doanil therapy or both therapies. The results showed that non-treatment diabetic patients had shorter telomere length, compared to the diabetic patients with treatment, and patients treated with insulin therapy had shorter telomere length, compared to the diabetes patients treated with Doanil or both therapies. Scatter plots showing all values of the terminal restriction fragment (TRF) lengths in the study sample and the TRF lengths according to the diabetes treatment status has been shown in Figs. 1 and 2.
Table 2.
Comparison of diabetic indices to the treated and untreated diabetic patients
| Characteristic | Diabetic with treatment (N = 225) (LSM ± SE) | Non-treatment group (N = 75) (LSM ± SE) | P-value |
|---|---|---|---|
| Gender (M/F) | 112/113 | 39/36 | 0.25 |
| Age (year) | 41.32 ± 1.26 | 41.63 ± 1.64 | 0.32 |
| BMI (kg/m2) | 29.74 ± 0.98 | 30.16 ± 1.24 | 0.64 |
| WC (cm) | 98.82 ± 1.76 | 102.41 ± 1.34 | 0.42 |
| FBG mmol/L) | 10.35 ± 0.84 | 12.99 ± 1.38 | 0.03* |
| HbA1c (%) | 8.03 ± 0.61 | 9.74 ± 0.61 | 0.21 |
| TC (mmol/L) | 4.89 ± 0.04 | 5.89 ± 0.04 | 0.03* |
| TG (mmol/L) | 2.36 ± 0.006 | 3.14 ± 0.004 | 0.03* |
| HDL-C (mmol/L) | 1.60 ± 0.003 | 0.69 ± 0.006 | 0.01* |
| LDL-C (mmol/L) | 2.84 ± 0.007 | 3.23 ± 0.007 | 0.03* |
| Telomere length (kb) | 11.14 ± 0.45 | 9.77 ± 0.65 | 0.003** |
SM ± SE, Least square means ± Standard error, *(P ≤ 0.05), ** (P ≤ 0.01)
DM diabetes mellitus, BMI body mass index, WC waist circumference, FBG fasting blood glucose; HbA1c hemoglobin A1c, TC total cholesterol, TG triglycerides, HDL-C HDL cholesterol, LDL-C LDL cholesterol
Table 3.
Comparison of diabetic indices according to the anti-diabetic drugs of diabetic patients
| Characteristic | Diabetic using Doanil (N = 80) (LSM ± SE) |
Diabetic using insulin (N = 70) (LSM ± SE) |
Diabetic using both (N = 75) (LSM ± SE) |
P-value |
|---|---|---|---|---|
| Gender (M/F) | 38/42 | 34/36 | 37/38 | 0.32 |
| Age (year) | 41.09 ± 1.12 | 41.24 ± 1.35 | 40.12 ± 1.21 | 0.43 |
| BMI (kg/m2) | 28.31 ± 1.31 | 29.56 ± 0.75 | 28.14 ± 1.01 | 0.87 |
| WC (cm) | 98.44 ± 2.77 | 100.10 ± 1.59 | 97.26 ± 1.31 | 0.91 |
| FBG mmol/L) | 9.67 ± 0.99 | 11.74 ± 0.57 | 10.27 ± 0.69 | 0.04* |
| HbA1c (%) | 7.05 ± 0.42 | 8.51 ± 0.43 | 7.89 ± 0.24 | 0.09 |
| TC (mmol/L) | 4.60 ± 0.03 | 5.67 ± 0.02 | 4.96 ± 0.03 | 0.05* |
| TG (mmol/L) | 1.99 ± 0.004 | 2.94 ± 0.001 | 2.63 ± 0.002 | 0.04* |
| HDL-C (mmol/L) | 1.54 ± 0.008 | 0.71 ± 0.004 | 1.02 ± 0.003 | 0.03* |
| LDL-C (mmol/L) | 2.44 ± 0.003 | 3.01 ± 0.003 | 2.67 ± 0.002 | 0.05* |
| Telomere length (kb) | 12.16 ± 0.84 | 10.03 ± 0.76 | 11.12 ± 0.42 | 0.001** |
LSM ± SE, Least square means ± Standard error, *(P ≤ 0.05), ** (P ≤ 0.01)
DM diabetes mellitus, BMI body mass index, WC waist circumference, FBG fasting blood glucose, HbA1c hemoglobin A1c, TC total cholesterol, TG triglycerides, HDL-C HDL cholesterol, LDL-C LDL cholesterol
Fig. 1.
Scatter plots showing all values of the terminal restriction fragment (TRF) lengths in the study sample. In each graph, diamonds represent distinct values depending on the normality
Fig. 2.
Terminal restriction fragment (TRF) lengths according to the diabetes treatment status. M; Refers to DNA size marker, lane 1 represent the non-treatment diabetic patients, lane 2 represent the diabetic patients using Doanil and insulin therapies, lane 3 represent the diabetic patients using insulin therapy and lane 4 represent the diabetic patients using Doanil therapy
Association analyses of diabetic risk and shortened telomere length
To further clarify the association between diabetic risk factors and shortened telomere length, the univariate regression analysis was performed (Table 4). All these risk factors were also included in multiple regression analysis to predict the higher risk factors, which showed that the telomere shortening was 3 times higher in patients with insulin therapy.
Table 4.
Logistic regression analysis of risk factors associated with telomere length in Type 2 diabetic patients
| Characteristic | Univariate logistic regression | Multivariate logistic regression | ||||
|---|---|---|---|---|---|---|
| Estimate | Odds ratio (95% Cl) | P-value | Estimate | Odds ratio (95% Cl) | P-value | |
| Gender | −0.12 | 0.38 (0.09–1.62) | 0.32 | |||
| Age (year) | 0.22 | 0.08 (0.01–1.02) | 0.41 | |||
| DM duration (years) | −0.04 | 0.53 (0.02–0.87) | 0.16 | |||
| BMI (kg/m2) | 0.12 | 0.84 (0.64–1.10) | 0.21 | |||
| WC (cm) | 0.08 | 1.10 (0.97–1.24) | 0.12 | |||
| FBG (mg/dl) | 0.86 | 1.25 (1.01–2.56) | 0.03* | 0.27 | 0.05 (0.01–0.56) | 0.24 |
| HbA1c (%) | −0.43 | 0.97 (0.60–1.56) | 0.92 | |||
| TC (mmol/L) | 0.18 | 2.00 (1.30–4.55) | 0.03* | 0.09 | 0.54 (0.64–1.90) | 0.15 |
| TG (mmol/L) | 0.10 | 2.22 (1.05–3.90) | 0.03* | 0.13 | 0.08 (0.03–0.52) | 0.11 |
| HDL-C (mmol/L) | −0.31 | 0.25 (0.01–1.16) | 0.40 | |||
| LDL-C (mmol/L) | 0.21 | 1.47 (0.98–2.94) | 0.04* | 0.16 | 0.09 (0.05–0.26) | 0.31 |
| Daonil therapy | 2.23 | 1.96 (0.56–4.23) | 0.01* | 2.42 | 2.07 (1.13–2.90) | 0.004** |
| Insulin therapy | −3.41 | 2.96 (0.56–5.23) | 0.001** | -2.99 | 3.14 (1.05–5.90) | 0.001** |
| Daonil and insulin | 1.41 | 0.27 (0.06–1.08) | 0.04* | 1.53 | 1.62 (1.21–2.01) | 0.006** |
For antidiabetic therapy, non-treatment was scored 0. The P-value with statistical significance are indicated in bold numbers
CL confidence interval
Discussion
Age significantly influences the prevalence and pathogenesis of diabetes mellitus [33]. The prevalence of diabetes in middle age is associated with hyperglycaemia and atherogenic indices in diabetic women [34]. Besides, middle age is the primary risk factor of diabetes and insulin resistance because the visceral fat and subcutaneous abdominal fat increase with aging and reach peak values at middle age [35, 36]. The present study is congruent with the results of Al Mansour [37] that refer to the prevalence of diabetes in middle-aged diabetic patients.
Regarding clinico-biochemical parameters and telomere length, this study showed a significant increase in waist circumference, FBG, HbA1c and lipid profile with lower HDL and shortened telomere length in diabetic patients, compared to the non-diabetic subjects, and in diabetic non-treatment patients compared to the diabetic patients treated with antidiabetic therapy. Results of previous studies conducted by Wu et al. [14] and Al Shehri [1] align with those of our study that have revealed that Type 2 diabetes is associated with elevated HbA1c, cholesterol, triglyceride, LDL with lower HDL and shortened telomere length, compared to the control group. Hyperglycaemia and dyslipidaemia increase reactive oxygen species (ROS) from the mitochondrial electron transport chain in Type 2 diabetes and diabetes-associated complications. This oxidative stress is increased in not only leukocytes but also pancreatic β-cells [19]. Oxidative stress accelerates the rate of telomere attrition in different cell types because the high guanine content of telomeres makes them particularly vulnerable to reactive oxygen species [38]. Moreover, oxidative stress promotes DNA double-strand breaks (DSBs), particularly at telomeric regions, resulting in telomere shortening with each cell division [39]. Consequently, this may lead to premature senescence of mammalian cells and the loss of functional cells [40]. Furthermore, another report has shown that oxidative stress weakens the telomerase activity of an enzyme that prevents telomere shortening and consists of the telomere reverse transcriptase (TERT) and a telomerase RNA component (TERC) [19]. It has been proposed that the decrease of telomerase activity lowers the replication capacity of β-cells and thereby leads to a reduced islet mass and the failure to produce adequate amounts of insulin in response to glucose stimulation [41].
Concerning antidiabetic therapy, the result of the present study revealed remarkable differences between diabetic patients with antidiabetic therapy compared to the non-treatment groups in terms of clinico-biochemical parameters and telomere length. Diabetic patients with antidiabetic therapy exhibited better glycaemic control and reduced telomere attrition, which is congruent with the result of Liu et al. [25] that refer to the good glycaemic control and complication rates with reduced telomere attrition in patients with antidiabetic therapy compared to those who did not use therapy. Besides, the result revealed a remarkable decrease in levels of FBG, lipid profile measures and shortened telomere length of diabetic patients with Doanil (glibenclamide) therapy compared to those treated with insulin and both therapies. Appropriate diabetic therapy can be predicted from glycemic control and good lipid management [42]. Glibenclamide was reported to have caused hypoglycaemia and stimulated insulin release from pancreatic β-cells by binding with sulfonylurea (SUR) receptors on the β-cell plasma membrane [43, 44]. This binding causes the closure of adenosine triphosphate (ATP)-sensitive potassium channels, preventing potassium efflux, which leads to the depolarisation of the cell membrane and the opening of voltage-gated channels. These movements increase the influx of calcium in β-cells and then stimulate insulin secretion to the cell surface [44–46]. Moreover, glibenclamide therapy reduces plasma glucagon, gluconeogenesis and free fatty acid concentrations, by increasing GLUT4 and GLUT1 expression [47]. Further, good glycaemic control by using this therapy may alleviate oxidative stress and subsequently prevent the shortening of telomere length [26]. However, despite its potential, it cannot achieve or maintain glycaemic control for the long term, which necessitates insulin therapy [48]. Insulin therapy remains the most potent and final treatment option for Type 2 diabetic patients, although many diabetic patients avoid initiating insulin therapy because of multiple disadvantages such as weight gain, needle pain, time constraints and hypoglycaemic episodes [49]. Moreover, Zeng et al. [26] demonstrated for the first time that insulin therapy accelerates telomere attrition. This is perhaps associated with the weight gain which aggravates insulin resistance, promotes oxidative stress and subsequently shortens the telomere length [15]. Marín-Peñalver et al. [50] and ALrefai et al. [51] revealed that the combination of oral antidiabetic drugs with insulin therapy strongly improved glycaemia and lipid profile levels in diabetic patients, with less weight gain. From the above-mentioned, none of the antidiabetic therapies appear to be able to completely cure this disease, but according to the currently findings oral antidiabetic therapy is more effective through the attenuation of telomere attrition and prevention of deterioration in diabetic patients. For the predicted deleterious effect of insulin therapy on shortened telomere length and diabetic risk, the optimisation of this therapy by combination with oral antidiabetic medication and a lifestyle with diet modification is essential.
In conclusion, the results revealed that Doanil therapy was more effective in managing the diabetic risk and limiting the risk factor for the long term and shortening of telomere length. A high prevalence of hyperglycaemia and shortened telomere length was observed with insulin therapy, which suggests the optimal effect of insulin therapy on telomere attrition that should be considered by physicians when prescribing antidiabetic therapy. The optimal care of diabetic patients with insulin therapy can improve glycaemic disorder in tandem with the attenuation of telomere attrition.
Acknowledgements
The authors express deep thanks to all the participants.
Author contribution
All the works is done by the single author.
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Code availability
Not applicable.
Declarations
Ethics approval and consent to participate
The study was performed following the Helsinki Declaration and after ethics approval from the University of Al-Qasim Green (Approval No.12.10.15), and the informed consent form signed by all participants before the study.
Consent for publication
Not applicable.
Competing interests
The author declare that they have no competing interests.
Footnotes
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Not applicable.