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Liraglutide treatment causes upregulation of adiponectin and downregulation of resistin in Chinese type 2 diabetes
DIAB-6427; No. of Pages 5 diabetes research and clinical practice xxx (2015) xxx–xxx
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Liraglutide treatment causes upregulation of adiponectin and downregulation of resistin in Chinese type 2 diabetes Dongmei Li a, Xiaohua Xu a, Ying Zhang a, Jian Zhu a, Lei Ye b, Kok Onn Lee c, Jianhua Ma a,* a
Department of Endocrinology, Nanjing Medical University Affiliated Nanjing First Hospital, No. 68 Changle Road, Nanjing, China b Department of Medicine, University of Minnesota, Minneapolis, MN, USA c Department of Medicine, National University of Singapore, Singapore, Singapore
article info
abstract
Article history:
Aims: To assess the effect of 16 weeks of liraglutide administration on the plasma levels of
Received 30 September 2014
adiponectin and resistin in Chinese patients diagnosed with type 2 diabetes mellitus
Received in revised form
(T2DM).
13 May 2015
Methods: Forty-four subjects were recruited and randomly assigned to once-a-day dosage of
Accepted 28 May 2015
either liraglutide, or glimepiride (4 mg) in a double-blinded double-dummy active-controlled
Available online xxx
study. All treatments were administered in combination with metformin (1 g, twice daily).
Keywords:
adiponectin and resistin in the plasma before and after the 16-week treatment.
Type 2 diabetes mellitus
Results: The plasma level of adiponectin was significantly increased (0.74 0.19 ng/ml,
The efficacy of liraglutide was estimated by measuring and comparing the levels of HbA1c,
Liraglutide
p < 0.05) and resistin was significantly lowered ( 1.34 0.34 pg/ml, p < 0.05) in a dose-
Glimepiride
dependent manner in the liraglutide group when compared with the glimepiride group
Adiponectin
( 0.44 0.09 ng/ml of adiponectin and 0.14 0.41 pg/ml of resistin). In contrast, we found
Resistin
no differences in the decrease in HbA1c between the two groups (8.3 1.2% to 7.2 1.1% in NGSP units vs. 8.3 1.0% to 7.3 1.2% in NGSP units; 67 13 mmol/mol to 55 12 mmol/ mol vs. 67 11 mmol/mol to 56 13 mmol/mol in IFCC units). Conclusions: In Chinese T2DM patients, liraglutide treatment led to increased adiponectin and decreased resistin levels compared to glimepiride-treated subjects, while inducing similar glycemic changes. # 2015 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
Cardiovascular diseases are the major cause of morbidity and mortality in patients diagnosed with type 2 diabetes mellitus
(T2DM), while the latter itself is considered a cardiovascular disease risk equivalent. Recent evidence from various studies suggests that the anti-diabetic drug glucagon-like peptide-1 (GLP-1) may have positive effects on the cardiovascular system. Subsequently, several large-scale studies have
* Corresponding author. Tel.: +86 13905187504; fax: +86 25 52887016. E-mail address: [email protected] (J. Ma). http://dx.doi.org/10.1016/j.diabres.2015.05.051 0168-8227/# 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Li D, et al. Liraglutide treatment causes upregulation of adiponectin and downregulation of resistin in Chinese type 2 diabetes. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.051
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diabetes research and clinical practice xxx (2015) xxx–xxx
Table 1 – Clinical characteristics of patients subjected to a 14-week treatment with liraglutide or glimepiride in combination with metformin. Group(case/male)
Age (years) Duration (years) BMI (kg/m2) Waist circumference (cm) Hip circumference (cm) Waist-to-hip ratio Waist-to-height ratio SBP (mmHg) DBP (mmHg) HbA1c (%) (mmol/mol) FBG (mmol/l) PBG(mmol/l) Fasting insulin (mmol/l) Fasting C-peptide (mmol/l) Adiponection (ng/ml) Resistin (pg/ml) *
Baseline Glimepiride (11/6)
Liraglutide (33/21)
Glimepiride (11/6)
Liraglutide (33/21)
57.0 11.6 4.3 3.6 24.8 3.7 90.1 12.9 98.5 6.4 0.91 0.08 0.54 0.07 130 20 81 8 8.3 1.0 67 11 9.95 2.35 12.7 3.4 51.0 (19.0–84.0) 0.844 (0.602–1.215) 2.33 (2.06–3.86) 5.88 (3.96–10.36)
55.2 8.4 6.4 4.9 25.3 3.3 92.2 10.1 99.8 8.5 0.92 0.05 0.56 0.07 131 16 81 8 8.3 1.2 67 13 9.6 2.64 12.0 3.2 35.0 (15.0–48.0) 0.775 (0.497–1.011) 2.25 (1.49–3.78) 6.42 (4.69–8.26)
25.6 3.8 92.3 12.3 101.9 6.1 0.90 0.07 0.56 0.06 138 17 86 10 7.3 1.2* 56 13 8.14 2.91* 9.7 2.3* 92.5 (47.5–108.0) 1.002 (0.789–1.294)* 2.82 (1.93–3.40) 4.91 (4.56–9.5)
24.9 3.1 90.3 8.9 100.3 7.7 0.90 0.05 0.55 0.06 134 15 83 10 7.2 1.1* 55 12 7.97 2.28* 10.1 2.7* 48.0 (23.0–79.5) 0.861 (0.630–1.117)* 3.08 (2.22–4.53)* 5.52 (4.09–7.29)*
Compared with baseline, p < 0.01.
focused on the cardiovascular outcome of other novel antidiabetic drugs that either mimic GLP-1 or increase its physiological function [26,27]. Liraglutide is one such compound, identified recently as a GLP-1 mimetic that shares 97% homology with human GLP-1, and is likely to have a beneficial effect on cardiovascular conditions [18]. The severity of cardiovascular diseases is often estimated from the levels of two critical adipocytokines, adiponectin and resistin, both of which have been linked to the pathogenesis of such conditions [7,21]. Lower adiponectin and higher resistin levels in the plasma have been observed in T2DM as well as cardiovascular diseases [20,22,23,25,30]. A recent study demonstrated a significant increase in adiponectin in non-diabetic obese patients treated with liraglutide [1]. In European patients diagnosed with type 2 diabetes, liraglutide treatment was shown to have a positive effect on circulating adipocytokines [10]. In this study, we measured and compared the plasma levels of these two adipocytokines, in response to liraglutide, and compared the latter’s efficacy with glimepiride treatment. Our findings suggest that liraglutide might significantly improve the cardiovascular defects observed in T2DM patients.
2.
After treatment
Patients and methods
We conducted a 16-week, double-blind, double-dummy, and active-control clinical trial in 44 Asian patients (27 males and 17 females) diagnosed with T2DM (www.ClinicalTrials.gov; NCT00614120) [31]. The inclusion criterion were: received oral antidiabetic drugs for at the least 3 months, HbA1c level at 7.0–11.0% (National Glycohemoglobin Standardization Program [NGSP]_ units, or 53–97 mmol/mol in International Federation of Clinical Chemistry [IFCC] units) for those receiving monotherapy, or 7.0–10.0% (NGSP unit, or 53– 86 mmol/mol in IFCC unit). Patients who were administered insulin in the previous 3 months, or diagnosed with liver or
renal disease or an unstable heart condition within that past 6 months were excluded. All patients were recruited from the Nanjing First Hospital, Nanjing. Plasma was collected before and after withdrawal of therapy. None of the subjects had a history of cardiovascular diseases. This study was approved by the institutional review board of Nanjing First Hospital. All subjects were required to provide a written informed consent before commencement of the study (Table 1). The patients were first maintained for a 3-week washout period on a metformin dosage regiment (up to 2000 mg/day— 1000 mg twice a day). Following this, they were randomly assigned to two experimental groups—1. Liraglutide treatment group (once-a-day dosage of either 0.6, 1.2 or 1.8 mg/day, injected subcutaneously in combination with metformin; Novo Nordisk, Bagsvaerd, Denmark; n = 33, 21 males); 2. Glimepiride treatment group (administered once-a-day (4 mg/day) together with metformin; n = 11, 6 males). The double-dummy design required that subjects in liraglutide group received a glimepiride placebo, while subjects in the glimepiride group received a liraglutide placebo once daily. Patients were randomized into three groups that received a liraglutide dosage of 0.6 (n = 11, 7 males), 1.2 (n = 12, 8 males) or 1.8 mg per day (n = 10, 6 males). In case of subjects who received the high doses of 1.2 and 1.8 mg per day, the dosage was gradually titrated at increments of 0.6 mg per day each week of the treatment. In the glimepiride group, titration was carried out at increments of 1 mg per day during the first week, 2 mg per day during the second week, and 4 mg per day starting from the third week. Laboratory analyses were performed by MDS Pharma Services in Beijing, China. HbA1c levels were measured by high performance liquid chromatography (HPLC), certified by the National Glycohemoglobin Standardization Program. Serum insulin and C-peptide levels were determined using a chemiluminescence immunoassay. Adiponectin and resistin levels in the plasma were determined by an enzyme-linked
Please cite this article in press as: Li D, et al. Liraglutide treatment causes upregulation of adiponectin and downregulation of resistin in Chinese type 2 diabetes. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.051
DIAB-6427; No. of Pages 5 diabetes research and clinical practice xxx (2015) xxx–xxx
immunoassay (USCNLIFE Co. Ltd., USA) according to the manufacturers’ recommendations. The features of these assays are as follows—(1) Adiponectin intra-assay Coefficient of Variability (CV) = 3.4%, inter-assay CV = 5.7%, detection range = 0.156–10 ng/ml; (2) resistin intra-assay CV < 6%, interassay CV < 7%, detection range = 0–500 pg/ml). Distribution of variables was analyzed using the Kolmogorov–Smirnov tests. Data are presented as mean SD for parametric variables and as median (interquartile ranger) for nonparametric variables. Quantifiable variables with normal distribution were analyzed using a two-tailed T-test. Nonparametric variables were analyzed using the Friedman test. GLM analysis of variance for repeated measurements (SPSS) was used to determine the statistical significance of the differences in the changes in adiponectin and resistin levels in the various experimental groups (glimepiride group, liraglutide group (and its three subgroups). A regression analysis was used to identify factors likely to be associated with changes in the levels of adiponectin or resistin before and after liraglutide administration. Patients were grouped according to whether or not they received liraglutide therapy, and analyzed to determine if changes in adiponectin and resistin levels correlated with liraglutide activity. Significant correlations were determined using the Pearson test. A p-value <0.05 was considered significant.
3.
Results
Forty-four patients at age 55.7 9.2 years and a disease duration of 5.9 4.7 years, displayed basal HbA1c levels of 8.3 1.1% (NGSP; IFCC: 67 12 mmol/mol) and a BMI of 25.2 3.4 kg/m2. The plasma adiponectin and resistin levels at baseline were 2.73 (1.98–3.87) ng/ml and 5.88 (4.48–7.91) pg/ ml. We found no significant differences between the various experimental groups before the start of the study. First, we detected a significant decrease in HbA1c levels in liraglutide (from 8.3 1.2% to 7.2 1.1% in NGSP units, or from 67 13 mmol/mol to 55 12 mmol/mol in IFCC units, p < 0.05) and glimepiride (from 8.3 1.0% to 7.3 1.2% in NGSP units, or from 67 11 mmol/mol to 56 12 mmol/mol in IFCC units, p < 0.05) treatment groups. There was no significant difference in the decrease of HbA1c between the glimepiride and liraglutide groups. The reduction in HbA1c was recorded as 0.7 0.7% (IFCC: 8 7 mmol/mol), 1.2 0.9% (IFCC: 13 10 mmol/mol) and 1.4 0.9% (IFCC: 15 10 mmol/mol) at liraglutide dosage of 0.6 mg, 1.2 mg and 1.8 mg, respectively. However, administration of liraglutide led to a significant reduction in body weight (baseline: 68.7 10.3 kg; after treatment: 68.3 10.1 kg; difference: 0.4 0.6 kg, p < 0.05) and the circumference of the waist (baseline: 92.2 10.1 cm; after treatment: 90.3 8.9 cm; difference: 1.95 0.80 cm). In contrast, administration of glimepiride caused an increase in body weight (baseline: 68.3 13.6 kg; after treatment: 70.5 14.2 kg; difference: +2.2 0.8 kg, p < 0.05) and the circumference of the waist (baseline: 90.1 12.9 cm; after treatment: 92.3 12.3 cm; difference: +2.14 1.49 cm, p < 0.05). The extent of weight loss showed a tendency of correlation with the dosage in the liraglutide group. 0.1 2.7 kg, Specifically we recorded a weight loss of
3
0.3 3.4 kg and 0.8 3.3 kg in the 0.6 mg, 1.2 mg and 1.8 mg dosage groups, respectively. Next, we measured the plasma levels of adiponectin and resistin in all treatment groups. We found a significant increase in adiponectin in a dose-dependent manner in the liraglutide group, with an overall increase of 0.74 0.19 ng/ml (baseline: 2.25 (1.49– 3.78) ng/ml; after treatment: 3.08 (2.22–4.53) ng/ml), p < 0.05). Specifically, we recorded an increase of 0.67 0.16 ng/ml (baseline: 3.35 (2.32–4.50) ng/ml, after treatment: 2.56 (1.47– 4.08) ng/ml) in the 1.2 mg dosage subgroup ( p < 0.05), 1.01 0.40 ng/ml (baseline: 3.34 (2.70–5.52) ng/ml, after treatment: 2.38 (1.99–4.16) ng/ml) in the 1.8 mg dosage subgroup ( p < 0.05), and 0.57 0.38 ng/ml (baseline: 2.18 (1.39–2.46) ng/ ml, after treatment: 2.92 (1.64–3.92) ng/ml) in the 0.6 mg dosage group ( p = 0.10). On the other hand, glimepiride treatment did not significantly change adiponectin concentration in the plasma ( 0.44 0.09 ng/ml, baseline: 2.33 (2.06–3.86) ng/ml; after treatment: 2.82 (1.93–3.40) ng/ml, p > 0.05) (Fig. 1). In addition, the levels of resistin in the plasma were significantly reduced, in a dose-dependent manner, in patients who received liraglutide, with an overall decrease of 1.34 0.34 pg/ml (baseline: 6.42 (4.69–8.26) pg/ml; after treatment 5.52 (4.09–7.29) pg/ml, p < 0.05). While the levels of resistin didn’t change significantly in glimepiride group (0.14 0.41 pg/ml, baseline: 5.88 (3.96–10.36) pg/ml; after treatment 4.91(4.56–9.5) pg/ml). Specifically, we recorded a decrease of 0.49 0.25 pg/ml (baseline: 5.79 (4.48–5.78) pg/ ml, after treatment: 5.26 (3.62–6.78) pg/ml) in the 0.6 mg dosage subgroup, 1.63 0.58 pg/ml (baseline: 7.47 (4.66– 9.92) pg/ml, after treatment: 5.74 (3.77–8.69) pg/ml) in the 1.2 mg dosage subgroup, and 1.94 0.78 pg/ml (baseline: 6.46
Fig. 1 – Effect of liraglutide and glimepiride on plasma level of adiponectin and resistin before and after treatment.
Please cite this article in press as: Li D, et al. Liraglutide treatment causes upregulation of adiponectin and downregulation of resistin in Chinese type 2 diabetes. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.051
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(4.71–9.51) pg/ml, after treatment: 5.35 (4.41–7.01) pg/ml) in the 1.8 mg dosage subgroup. Our results show that liraglutide therapy is linearly correlated with the plasma levels of adiponectin (r = 0.357; p = 0.017) and resistin (r = 0.314, p = 0.038). Specifically, liraglutide therapy leads to increased adiponectin and decreased resistin levels. Multiple regression analysis showed that the change in adiponectin levels correlated with the change in waist-to-hip ratio ( 0.477, 95% confidence intervals [CI]: 0.934 to 0.020, p = 0.041), HDL levels (2.259, 95% CI: 0.444 to 4.074, p = 0.017) and administration of liraglutide therapy (r = 0.701, 95% CI: 0.207 to 1.195, p = 0.033). On the other hand, the change in resistin levels correlated with changes in total cholesterol (0.114, 95% CI: 0.011 to 0.217, p = 0.032), fasting C peptide ( 0.003, 95% CI: 0.005 to 0, p = 0.032) as well as administration of liraglutide therapy ( 1.820, 95% CI: 3.476 to 0.165, p = 0.033).
4.
Discussion
In this study, we have demonstrated that administration of liraglutide can significantly increase plasma adiponectin levels and decrease resistin levels in a dose-dependent manner in T2DM patients, when compared with glimepiride treatment. Our data provides evidence supporting recent speculation that liraglutide is likely to improve cardiovascular outcomes in Chinese T2DM patients, especially in contrast to glimepiride and possibly other sulphonylurea drugs. Our study further shows that the beneficial effect of liraglutide is independent of the mechanism of action of the lowering of blood glucose levels, and could therefore be the consequence of the direct influence of GLP-1 on the specific markers of cardiovascular risk analyzed in this study. The GLP-1 analogue therapy, an alternative strategy to treat T2DM, has been reported in several studies to be associated with increased levels of adiponectin (anti-inflammatory adipokine) and decreased levels of inflammatory cytokines [4,13] and resistin [8,9]. Clinically, liraglutide therapy significantly reduces body weight, fat mass, fat percentage [14] and intrahepatic lipid content [6] in T2D patients. In experimental studies, it has been shown that liraglutide induces adipocyte formation by promoting the proliferation of pre-adipocytes and inhibiting their apoptosis [5]. In addition, liraglutide can stimulate brown adipose tissue thermogenesis resulting in the formation of brown adipose tissue [2] and can directly promote adiponectin secretion from adipocytes [16], to assist glucose regulation. Resistin is positively associated with insulin resistance [12] and may have potent proinflammatory properties [3]. Because liraglutide can improve insulin resistance [11] and inflammatory response [19,28], it was proposed that decreased blood resistin levels following liraglutide administration could partially account for the beneficial effects of liraglutide on glucose metabolism. In addition to the effects on glucose metabolism, increased circulating adiponectin levels are reported to be associated with decreased incidence [17] and severity [24] of cardiovascular diseases. On the other hand, resistin is known to directly promote the activity of endothelial cells, and can increase the risk of cardiovascular disease [29]. Therefore, the interaction
between resistin and adiponectin could play a role in determining the inflammation status of vascular tissues, and in turn indicate the progress of atherosclerosis [15]. Accordingly, it has been proposed that the beneficial influence on the relative levels of adiponectin and resistin by GLP-1 analogue therapy may also ameliorate the progression of cardiovascular pathophysiology. Although the exact mechanism underlying the effect of liraglutide on adiponectin and resistin expression in T2DM patients is unclear, our findings emphasize the need for further studies to understand the potential effects of GLP-1 on the cardiovascular pathophysiology of diabetes patients.
5.
Conclusions
In this study, we show that in a group of Chinese patients diagnosed with T2DM, those treated with liraglutide and metformin displayed increased adiponectin and decreased resistin levels when compared to the glimepiride and metformin-treated patients, although there was a similar HbA1c reduction in both groups. Whether the changes in adipokine levels following liraglutide therapy suggest a potential role of glucagon-like peptide-1 treatment for preventing cardiovascular complications in diabetes needs further investigation.
Conflict of interest statement The authors declared no conflicts of interest.
Funding None.
references
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Please cite this article in press as: Li D, et al. Liraglutide treatment causes upregulation of adiponectin and downregulation of resistin in Chinese type 2 diabetes. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.051
5
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Liraglutide treatment causes upregulation of adiponectin and downregulation of resistin in Chinese type 2 diabetes Dongmei Li a, Xiaohua Xu a, Ying Zhang a, Jian Zhu a, Lei Ye b, Kok Onn Lee c, Jianhua Ma a,* a
Department of Endocrinology, Nanjing Medical University Affiliated Nanjing First Hospital, No. 68 Changle Road, Nanjing, China b Department of Medicine, University of Minnesota, Minneapolis, MN, USA c Department of Medicine, National University of Singapore, Singapore, Singapore
article info
abstract
Article history:
Aims: To assess the effect of 16 weeks of liraglutide administration on the plasma levels of
Received 30 September 2014
adiponectin and resistin in Chinese patients diagnosed with type 2 diabetes mellitus
Received in revised form
(T2DM).
13 May 2015
Methods: Forty-four subjects were recruited and randomly assigned to once-a-day dosage of
Accepted 28 May 2015
either liraglutide, or glimepiride (4 mg) in a double-blinded double-dummy active-controlled
Available online xxx
study. All treatments were administered in combination with metformin (1 g, twice daily).
Keywords:
adiponectin and resistin in the plasma before and after the 16-week treatment.
Type 2 diabetes mellitus
Results: The plasma level of adiponectin was significantly increased (0.74 0.19 ng/ml,
The efficacy of liraglutide was estimated by measuring and comparing the levels of HbA1c,
Liraglutide
p < 0.05) and resistin was significantly lowered ( 1.34 0.34 pg/ml, p < 0.05) in a dose-
Glimepiride
dependent manner in the liraglutide group when compared with the glimepiride group
Adiponectin
( 0.44 0.09 ng/ml of adiponectin and 0.14 0.41 pg/ml of resistin). In contrast, we found
Resistin
no differences in the decrease in HbA1c between the two groups (8.3 1.2% to 7.2 1.1% in NGSP units vs. 8.3 1.0% to 7.3 1.2% in NGSP units; 67 13 mmol/mol to 55 12 mmol/ mol vs. 67 11 mmol/mol to 56 13 mmol/mol in IFCC units). Conclusions: In Chinese T2DM patients, liraglutide treatment led to increased adiponectin and decreased resistin levels compared to glimepiride-treated subjects, while inducing similar glycemic changes. # 2015 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
Cardiovascular diseases are the major cause of morbidity and mortality in patients diagnosed with type 2 diabetes mellitus
(T2DM), while the latter itself is considered a cardiovascular disease risk equivalent. Recent evidence from various studies suggests that the anti-diabetic drug glucagon-like peptide-1 (GLP-1) may have positive effects on the cardiovascular system. Subsequently, several large-scale studies have
* Corresponding author. Tel.: +86 13905187504; fax: +86 25 52887016. E-mail address: [email protected] (J. Ma). http://dx.doi.org/10.1016/j.diabres.2015.05.051 0168-8227/# 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Li D, et al. Liraglutide treatment causes upregulation of adiponectin and downregulation of resistin in Chinese type 2 diabetes. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.051
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Table 1 – Clinical characteristics of patients subjected to a 14-week treatment with liraglutide or glimepiride in combination with metformin. Group(case/male)
Age (years) Duration (years) BMI (kg/m2) Waist circumference (cm) Hip circumference (cm) Waist-to-hip ratio Waist-to-height ratio SBP (mmHg) DBP (mmHg) HbA1c (%) (mmol/mol) FBG (mmol/l) PBG(mmol/l) Fasting insulin (mmol/l) Fasting C-peptide (mmol/l) Adiponection (ng/ml) Resistin (pg/ml) *
Baseline Glimepiride (11/6)
Liraglutide (33/21)
Glimepiride (11/6)
Liraglutide (33/21)
57.0 11.6 4.3 3.6 24.8 3.7 90.1 12.9 98.5 6.4 0.91 0.08 0.54 0.07 130 20 81 8 8.3 1.0 67 11 9.95 2.35 12.7 3.4 51.0 (19.0–84.0) 0.844 (0.602–1.215) 2.33 (2.06–3.86) 5.88 (3.96–10.36)
55.2 8.4 6.4 4.9 25.3 3.3 92.2 10.1 99.8 8.5 0.92 0.05 0.56 0.07 131 16 81 8 8.3 1.2 67 13 9.6 2.64 12.0 3.2 35.0 (15.0–48.0) 0.775 (0.497–1.011) 2.25 (1.49–3.78) 6.42 (4.69–8.26)
25.6 3.8 92.3 12.3 101.9 6.1 0.90 0.07 0.56 0.06 138 17 86 10 7.3 1.2* 56 13 8.14 2.91* 9.7 2.3* 92.5 (47.5–108.0) 1.002 (0.789–1.294)* 2.82 (1.93–3.40) 4.91 (4.56–9.5)
24.9 3.1 90.3 8.9 100.3 7.7 0.90 0.05 0.55 0.06 134 15 83 10 7.2 1.1* 55 12 7.97 2.28* 10.1 2.7* 48.0 (23.0–79.5) 0.861 (0.630–1.117)* 3.08 (2.22–4.53)* 5.52 (4.09–7.29)*
Compared with baseline, p < 0.01.
focused on the cardiovascular outcome of other novel antidiabetic drugs that either mimic GLP-1 or increase its physiological function [26,27]. Liraglutide is one such compound, identified recently as a GLP-1 mimetic that shares 97% homology with human GLP-1, and is likely to have a beneficial effect on cardiovascular conditions [18]. The severity of cardiovascular diseases is often estimated from the levels of two critical adipocytokines, adiponectin and resistin, both of which have been linked to the pathogenesis of such conditions [7,21]. Lower adiponectin and higher resistin levels in the plasma have been observed in T2DM as well as cardiovascular diseases [20,22,23,25,30]. A recent study demonstrated a significant increase in adiponectin in non-diabetic obese patients treated with liraglutide [1]. In European patients diagnosed with type 2 diabetes, liraglutide treatment was shown to have a positive effect on circulating adipocytokines [10]. In this study, we measured and compared the plasma levels of these two adipocytokines, in response to liraglutide, and compared the latter’s efficacy with glimepiride treatment. Our findings suggest that liraglutide might significantly improve the cardiovascular defects observed in T2DM patients.
2.
After treatment
Patients and methods
We conducted a 16-week, double-blind, double-dummy, and active-control clinical trial in 44 Asian patients (27 males and 17 females) diagnosed with T2DM (www.ClinicalTrials.gov; NCT00614120) [31]. The inclusion criterion were: received oral antidiabetic drugs for at the least 3 months, HbA1c level at 7.0–11.0% (National Glycohemoglobin Standardization Program [NGSP]_ units, or 53–97 mmol/mol in International Federation of Clinical Chemistry [IFCC] units) for those receiving monotherapy, or 7.0–10.0% (NGSP unit, or 53– 86 mmol/mol in IFCC unit). Patients who were administered insulin in the previous 3 months, or diagnosed with liver or
renal disease or an unstable heart condition within that past 6 months were excluded. All patients were recruited from the Nanjing First Hospital, Nanjing. Plasma was collected before and after withdrawal of therapy. None of the subjects had a history of cardiovascular diseases. This study was approved by the institutional review board of Nanjing First Hospital. All subjects were required to provide a written informed consent before commencement of the study (Table 1). The patients were first maintained for a 3-week washout period on a metformin dosage regiment (up to 2000 mg/day— 1000 mg twice a day). Following this, they were randomly assigned to two experimental groups—1. Liraglutide treatment group (once-a-day dosage of either 0.6, 1.2 or 1.8 mg/day, injected subcutaneously in combination with metformin; Novo Nordisk, Bagsvaerd, Denmark; n = 33, 21 males); 2. Glimepiride treatment group (administered once-a-day (4 mg/day) together with metformin; n = 11, 6 males). The double-dummy design required that subjects in liraglutide group received a glimepiride placebo, while subjects in the glimepiride group received a liraglutide placebo once daily. Patients were randomized into three groups that received a liraglutide dosage of 0.6 (n = 11, 7 males), 1.2 (n = 12, 8 males) or 1.8 mg per day (n = 10, 6 males). In case of subjects who received the high doses of 1.2 and 1.8 mg per day, the dosage was gradually titrated at increments of 0.6 mg per day each week of the treatment. In the glimepiride group, titration was carried out at increments of 1 mg per day during the first week, 2 mg per day during the second week, and 4 mg per day starting from the third week. Laboratory analyses were performed by MDS Pharma Services in Beijing, China. HbA1c levels were measured by high performance liquid chromatography (HPLC), certified by the National Glycohemoglobin Standardization Program. Serum insulin and C-peptide levels were determined using a chemiluminescence immunoassay. Adiponectin and resistin levels in the plasma were determined by an enzyme-linked
Please cite this article in press as: Li D, et al. Liraglutide treatment causes upregulation of adiponectin and downregulation of resistin in Chinese type 2 diabetes. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.051
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immunoassay (USCNLIFE Co. Ltd., USA) according to the manufacturers’ recommendations. The features of these assays are as follows—(1) Adiponectin intra-assay Coefficient of Variability (CV) = 3.4%, inter-assay CV = 5.7%, detection range = 0.156–10 ng/ml; (2) resistin intra-assay CV < 6%, interassay CV < 7%, detection range = 0–500 pg/ml). Distribution of variables was analyzed using the Kolmogorov–Smirnov tests. Data are presented as mean SD for parametric variables and as median (interquartile ranger) for nonparametric variables. Quantifiable variables with normal distribution were analyzed using a two-tailed T-test. Nonparametric variables were analyzed using the Friedman test. GLM analysis of variance for repeated measurements (SPSS) was used to determine the statistical significance of the differences in the changes in adiponectin and resistin levels in the various experimental groups (glimepiride group, liraglutide group (and its three subgroups). A regression analysis was used to identify factors likely to be associated with changes in the levels of adiponectin or resistin before and after liraglutide administration. Patients were grouped according to whether or not they received liraglutide therapy, and analyzed to determine if changes in adiponectin and resistin levels correlated with liraglutide activity. Significant correlations were determined using the Pearson test. A p-value <0.05 was considered significant.
3.
Results
Forty-four patients at age 55.7 9.2 years and a disease duration of 5.9 4.7 years, displayed basal HbA1c levels of 8.3 1.1% (NGSP; IFCC: 67 12 mmol/mol) and a BMI of 25.2 3.4 kg/m2. The plasma adiponectin and resistin levels at baseline were 2.73 (1.98–3.87) ng/ml and 5.88 (4.48–7.91) pg/ ml. We found no significant differences between the various experimental groups before the start of the study. First, we detected a significant decrease in HbA1c levels in liraglutide (from 8.3 1.2% to 7.2 1.1% in NGSP units, or from 67 13 mmol/mol to 55 12 mmol/mol in IFCC units, p < 0.05) and glimepiride (from 8.3 1.0% to 7.3 1.2% in NGSP units, or from 67 11 mmol/mol to 56 12 mmol/mol in IFCC units, p < 0.05) treatment groups. There was no significant difference in the decrease of HbA1c between the glimepiride and liraglutide groups. The reduction in HbA1c was recorded as 0.7 0.7% (IFCC: 8 7 mmol/mol), 1.2 0.9% (IFCC: 13 10 mmol/mol) and 1.4 0.9% (IFCC: 15 10 mmol/mol) at liraglutide dosage of 0.6 mg, 1.2 mg and 1.8 mg, respectively. However, administration of liraglutide led to a significant reduction in body weight (baseline: 68.7 10.3 kg; after treatment: 68.3 10.1 kg; difference: 0.4 0.6 kg, p < 0.05) and the circumference of the waist (baseline: 92.2 10.1 cm; after treatment: 90.3 8.9 cm; difference: 1.95 0.80 cm). In contrast, administration of glimepiride caused an increase in body weight (baseline: 68.3 13.6 kg; after treatment: 70.5 14.2 kg; difference: +2.2 0.8 kg, p < 0.05) and the circumference of the waist (baseline: 90.1 12.9 cm; after treatment: 92.3 12.3 cm; difference: +2.14 1.49 cm, p < 0.05). The extent of weight loss showed a tendency of correlation with the dosage in the liraglutide group. 0.1 2.7 kg, Specifically we recorded a weight loss of
3
0.3 3.4 kg and 0.8 3.3 kg in the 0.6 mg, 1.2 mg and 1.8 mg dosage groups, respectively. Next, we measured the plasma levels of adiponectin and resistin in all treatment groups. We found a significant increase in adiponectin in a dose-dependent manner in the liraglutide group, with an overall increase of 0.74 0.19 ng/ml (baseline: 2.25 (1.49– 3.78) ng/ml; after treatment: 3.08 (2.22–4.53) ng/ml), p < 0.05). Specifically, we recorded an increase of 0.67 0.16 ng/ml (baseline: 3.35 (2.32–4.50) ng/ml, after treatment: 2.56 (1.47– 4.08) ng/ml) in the 1.2 mg dosage subgroup ( p < 0.05), 1.01 0.40 ng/ml (baseline: 3.34 (2.70–5.52) ng/ml, after treatment: 2.38 (1.99–4.16) ng/ml) in the 1.8 mg dosage subgroup ( p < 0.05), and 0.57 0.38 ng/ml (baseline: 2.18 (1.39–2.46) ng/ ml, after treatment: 2.92 (1.64–3.92) ng/ml) in the 0.6 mg dosage group ( p = 0.10). On the other hand, glimepiride treatment did not significantly change adiponectin concentration in the plasma ( 0.44 0.09 ng/ml, baseline: 2.33 (2.06–3.86) ng/ml; after treatment: 2.82 (1.93–3.40) ng/ml, p > 0.05) (Fig. 1). In addition, the levels of resistin in the plasma were significantly reduced, in a dose-dependent manner, in patients who received liraglutide, with an overall decrease of 1.34 0.34 pg/ml (baseline: 6.42 (4.69–8.26) pg/ml; after treatment 5.52 (4.09–7.29) pg/ml, p < 0.05). While the levels of resistin didn’t change significantly in glimepiride group (0.14 0.41 pg/ml, baseline: 5.88 (3.96–10.36) pg/ml; after treatment 4.91(4.56–9.5) pg/ml). Specifically, we recorded a decrease of 0.49 0.25 pg/ml (baseline: 5.79 (4.48–5.78) pg/ ml, after treatment: 5.26 (3.62–6.78) pg/ml) in the 0.6 mg dosage subgroup, 1.63 0.58 pg/ml (baseline: 7.47 (4.66– 9.92) pg/ml, after treatment: 5.74 (3.77–8.69) pg/ml) in the 1.2 mg dosage subgroup, and 1.94 0.78 pg/ml (baseline: 6.46
Fig. 1 – Effect of liraglutide and glimepiride on plasma level of adiponectin and resistin before and after treatment.
Please cite this article in press as: Li D, et al. Liraglutide treatment causes upregulation of adiponectin and downregulation of resistin in Chinese type 2 diabetes. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.051
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(4.71–9.51) pg/ml, after treatment: 5.35 (4.41–7.01) pg/ml) in the 1.8 mg dosage subgroup. Our results show that liraglutide therapy is linearly correlated with the plasma levels of adiponectin (r = 0.357; p = 0.017) and resistin (r = 0.314, p = 0.038). Specifically, liraglutide therapy leads to increased adiponectin and decreased resistin levels. Multiple regression analysis showed that the change in adiponectin levels correlated with the change in waist-to-hip ratio ( 0.477, 95% confidence intervals [CI]: 0.934 to 0.020, p = 0.041), HDL levels (2.259, 95% CI: 0.444 to 4.074, p = 0.017) and administration of liraglutide therapy (r = 0.701, 95% CI: 0.207 to 1.195, p = 0.033). On the other hand, the change in resistin levels correlated with changes in total cholesterol (0.114, 95% CI: 0.011 to 0.217, p = 0.032), fasting C peptide ( 0.003, 95% CI: 0.005 to 0, p = 0.032) as well as administration of liraglutide therapy ( 1.820, 95% CI: 3.476 to 0.165, p = 0.033).
4.
Discussion
In this study, we have demonstrated that administration of liraglutide can significantly increase plasma adiponectin levels and decrease resistin levels in a dose-dependent manner in T2DM patients, when compared with glimepiride treatment. Our data provides evidence supporting recent speculation that liraglutide is likely to improve cardiovascular outcomes in Chinese T2DM patients, especially in contrast to glimepiride and possibly other sulphonylurea drugs. Our study further shows that the beneficial effect of liraglutide is independent of the mechanism of action of the lowering of blood glucose levels, and could therefore be the consequence of the direct influence of GLP-1 on the specific markers of cardiovascular risk analyzed in this study. The GLP-1 analogue therapy, an alternative strategy to treat T2DM, has been reported in several studies to be associated with increased levels of adiponectin (anti-inflammatory adipokine) and decreased levels of inflammatory cytokines [4,13] and resistin [8,9]. Clinically, liraglutide therapy significantly reduces body weight, fat mass, fat percentage [14] and intrahepatic lipid content [6] in T2D patients. In experimental studies, it has been shown that liraglutide induces adipocyte formation by promoting the proliferation of pre-adipocytes and inhibiting their apoptosis [5]. In addition, liraglutide can stimulate brown adipose tissue thermogenesis resulting in the formation of brown adipose tissue [2] and can directly promote adiponectin secretion from adipocytes [16], to assist glucose regulation. Resistin is positively associated with insulin resistance [12] and may have potent proinflammatory properties [3]. Because liraglutide can improve insulin resistance [11] and inflammatory response [19,28], it was proposed that decreased blood resistin levels following liraglutide administration could partially account for the beneficial effects of liraglutide on glucose metabolism. In addition to the effects on glucose metabolism, increased circulating adiponectin levels are reported to be associated with decreased incidence [17] and severity [24] of cardiovascular diseases. On the other hand, resistin is known to directly promote the activity of endothelial cells, and can increase the risk of cardiovascular disease [29]. Therefore, the interaction
between resistin and adiponectin could play a role in determining the inflammation status of vascular tissues, and in turn indicate the progress of atherosclerosis [15]. Accordingly, it has been proposed that the beneficial influence on the relative levels of adiponectin and resistin by GLP-1 analogue therapy may also ameliorate the progression of cardiovascular pathophysiology. Although the exact mechanism underlying the effect of liraglutide on adiponectin and resistin expression in T2DM patients is unclear, our findings emphasize the need for further studies to understand the potential effects of GLP-1 on the cardiovascular pathophysiology of diabetes patients.
5.
Conclusions
In this study, we show that in a group of Chinese patients diagnosed with T2DM, those treated with liraglutide and metformin displayed increased adiponectin and decreased resistin levels when compared to the glimepiride and metformin-treated patients, although there was a similar HbA1c reduction in both groups. Whether the changes in adipokine levels following liraglutide therapy suggest a potential role of glucagon-like peptide-1 treatment for preventing cardiovascular complications in diabetes needs further investigation.
Conflict of interest statement The authors declared no conflicts of interest.
Funding None.
references
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