Irisin is related to insulin resistance and metabolic disorders. The physiologic effects of irisin are partially mediated through peroxisome proliferator-activated receptor-
The prevalence of type 2 diabetes mellitus (T2DM) is rapidly increasing, and many patients suffer from diabetes-related cardiovascular complications, which are the major cause of death in patients with T2DM. Efforts have been made to reduce the risk of cardiovascular complications, and many previous clinical trials have demonstrated meaningful reduction in the incidence of cardiovascular disorders in T2DM patients after multifactorial risk factor modifications [
The dyslipidemia in T2DM is characterized by increased low-density lipoprotein cholesterol (LDL-C), elevated triglycerides (TG), and decreased high-density lipoprotein cholesterol (HDL-C), and it is associated with an increased risk of coronary artery disease [
Fenofibrate is known as an important peroxisome proliferator-activated receptor-
Irisin is a newly identified hormone secreted by myocytes. It reportedly mediates the beneficial effects of exercise and influences multiple metabolic pathways, such as lipid and glucose metabolism [
Recent studies have demonstrated that the physiologic effects of irisin are, at least in part, mediated through PPAR-
All participants (both genders) ranging in age from 30 to 70 years were recruited from September 2013 to January 2014.
Twenty-five type 2 diabetes mellitus patients with hypertriglyceridemia (group A) were recruited for this study from a group of outpatients at the Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China. Patients diagnosed with type 2 diabetes mellitus, as defined by the World Health Organization (WHO) criteria, and with stable hypoglycemic treatment for at least 3 months, fasting blood glucose (FBG) levels < 9 mmol/L and glycosylated hemoglobin (HbA1c) levels < 8%, were eligible for the study. Additionally, the patients had been treated with 20 mg/day atorvastatin for more than 3 months; however, their TG levels were still greater than 1.7 mmol/L. The following exclusion criteria for group A were applied: known type 1 and other specific types of diabetes (e.g., genetic defects of the
Forty healthy people (group B) were recruited as the control group from the community or from the group of people undergoing routine medical check-ups. None of them had a history of prediabetes (including impaired glucose tolerance and impaired fasting glucose), diabetes, hyperlipidemia, or cardiovascular disease.
Moreover, people with hypertension, endocrine disease, systemic inflammatory disease, infectious disease, cancer, chronic kidney disease (i.e., serum creatinine [CR] > 120
Participants in group A were required to attend 3 study visits: the screening visit, visit 1, and visit 2 (spaced 8 weeks apart), while participants in group B attended the screening visit. Starting at visit 1, the group A participants who fulfilled the inclusion criteria (without any exclusion criteria) were administered fenofibrate 200 mg/day for 8 weeks. The capsules were counted at visit 2, and compliance was considered to be satisfactory if > 90% of capsules were taken.
Blood samples and the data on the medical history, height, weight, and blood pressure were collected at the screening visit (groups A and B) and at visit 2 (group A) (under fasting conditions, as described below). At visit 1, each participant in group A received instructions to maintain his/her usual nutritional and exercise habits and to not modify any drug treatment throughout the study. Participants in group A were asked to immediately report the development of unusual muscle soreness or pain throughout the study. In addition, any adverse event in each group A participant was recorded at visit 2.
The study protocol was approved by the Medicine and Pharmacy Ethics Committee of Beijing Chao-Yang Hospital, Capital Medical University. Written informed consent was obtained from each participant prior to the performance of any study procedure.
A complete medical history, including duration and treatment of any disease, was obtained for each participant; height and weight were determined using a standardized protocol. Body mass index (BMI) was calculated as weight (kg)/[height (m)]2. Blood pressure was measured using a calibrated standard mercury sphygmomanometer. All readings were measured after a 5 min rest, with the patients in the sitting position.
Fasting blood samples were collected in the morning after an 8-hour overnight fast. FBG, total cholesterol (TC), HDL-C, TG, CR, AST, ALT, CK, and HbA1c were measured in the central laboratory of Beijing Chao-Yang Hospital, Capital Medical University. LDL-C was calculated using the Friedewald formula (LDL = CHOL − [TG/5 + HDL]). Serum samples from all participants were stored at −80°C. Serum irisin concentrations were measured in duplicate at the same time using enzyme-linked immunosorbent assay (ELISA) kits (Phoenix Pharmaceuticals Science, Inc., USA) for quantitative detection with an automated ELISA reader (VARIOSKAN FLASH-5250040, Thermo Scientific, USA).
Adverse events were recorded throughout the study. The safety parameters included serum CR, AST, ALT, and CK.
All analyses were performed with Statistical Package for Social Sciences version 19.0 (SPSS, Inc., Chicago, IL, USA). Data were expressed as the mean ± SD. Comparisons of the baseline clinical and biochemical markers, as well as the irisin levels, between groups A and B were performed using an independent sample
The baseline clinical characteristics of the study participants are listed in Table
Baseline clinical characteristics of the study participants.
Parameters | Group A |
Group B |
|
---|---|---|---|
Sex (M/F) | 19/6 | 28/12 | 0.599 |
Age (years) | 53.76 ± 8.89 | 49.10 ± 10.57 | 0.071 |
BMI (kg/m2) | 26.46 ± 4.60 | 24.63 ± 3.71 | 0.083 |
SBP (mmHg) | 125.00 ± 7.65 | 123.63 ± 9.00 | 0.529 |
DBP (mmHg) | 74.24 ± 8.74 | 73.75 ± 6.13 | 0.808 |
FBG (mmol/L) | 7.43 ± 1.01 | 5.06 ± 0.50 | <0.001 |
TC (mmol/L) | 4.62 ± 0.66 | 4.49 ± 0.74 | 0.461 |
HDL (mmol/L) | 1.25 ± 0.29 | 1.61 ± 0.29 | <0.001 |
LDL (mmol/L) | 2.80 ± 0.53 | 2.45 ± 0.62 | 0.023 |
TG (mmol/L) | 3.05 ± 0.86 | 0.92 ± 0.37 | <0.001 |
HbA1c (%) | 6.88 ± 0.72 | 5.42 ± 0.33 | <0.001 |
Group A, type 2 diabetes mellitus patients with hypertriglyceridemia; group B, control subjects; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fasting blood glucose; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides; HbA1c, glycosylated hemoglobin.
The fasting serum levels of irisin were significantly higher in group A than in group B (45.15 ± 10.48 versus 35.38 ± 9.97 ng/mL,
Baseline serum irisin levels in the study participants. The values are expressed as the means ± SD. Group A: type 2 diabetes patients with hypertriglyceridemia (
The following parameters were found to be significantly correlated with the serum irisin levels: BMI (
Correlation and multiple regression analyses of the baseline parameters associated with serum irisin levels.
Parameters | Correlation | Multiple regression | ||
---|---|---|---|---|
|
|
|
|
|
Age (years) | 0.215 | 0.085 | ||
BMI (kg/m2) | 0.314 | 0.011 | ||
SBP (mmHg) | 0.126 | 0.316 | ||
DBP (mmHg) | −0.107 | 0.395 | ||
FBG (mmol/L) | 0.399 | 0.001 | 5.615 | <0.001 |
TC (mmol/L) | 0.256 | 0.040 | ||
HDL (mmol/L) | 0.247 | 0.047 | 19.483 | <0.001 |
LDL (mmol/L) | 0.109 | 0.387 | ||
TG (mmol/L) | 0.230 | 0.065 | ||
HbA1c (%) | 0.239 | 0.055 |
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fasting blood glucose; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides; HbA1c, glycosylated hemoglobin. The following variables were included in the multiple stepwise regression analysis: age, sex, BMI, SBP, DBP, FBG, TC, HDL-C, LDL-C, TG, and HbA1c.
Multiple stepwise regression analysis was performed to determine the parameters that were independently associated with serum irisin. The results showed that only FBG (beta coefficient 5.615, SE 0.903, standard beta coefficient 0.691,
The pretreatment and posttreatment (with fenofibrate) clinical parameters in group A are summarized in Table
Pretreatment and posttreatment clinical characteristics of type 2 diabetes patients with hypertriglyceridemia treated with fenofibrate.
Parameters | Pretreatment |
Posttreatment |
|
---|---|---|---|
BMI (kg/m2) | 26.46 ± 4.60 | 26.37 ± 4.59 | 0.209 |
SBP (mmHg) | 125.00 ± 7.56 | 125.48 ± 6.76 | 0.668 |
DBP (mmHg) | 74.24 ± 8.74 | 73.92 ± 7.30 | 0.831 |
FBG (mmol/L) | 7.42 ± 1.01 | 7.32 ± 1.00 | 0.215 |
TC (mmol/L) | 4.62 ± 0.66 | 4.83 ± 0.69 | 0.145 |
HDL (mmol/L) | 1.25 ± 0.29 | 1.47 ± 0.27 | <0.001 |
LDL (mmol/L) | 2.80 ± 0.53 | 2.82 ± 0.66 | 0.845 |
TG (mmol/L) | 3.05 ± 0.86 | 1.84 ± 0.76 | <0.001 |
AST (U/L) | 22.08 ± 7.33 | 23.84 ± 9.04 | 0.322 |
ALT (U/L) | 26.00 ± 5.69 | 24.44 ± 11.64 | 0.518 |
CR ( |
71.92 ± 13.74 | 76.10 ± 17.29 | 0.164 |
CK (U/L) | 84.64 ± 27.69 | 91.20 ± 37.28 | 0.307 |
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fasting blood glucose; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CR, creatinine; CK, creatine kinase.
After 8 weeks of fenofibrate treatment, the serum irisin levels in group A were significantly decreased compared with the baseline levels (from 45.15 ± 10.48 ng/mL at pretreatment to 38.74 ± 12.54 ng/mL after treatment,
Serum irisin levels in type 2 diabetes patients with hypertriglyceridemia after 8 weeks of fenofibrate treatment compared with the baseline levels. The values are expressed as the means ± SD (
All participants completed the study, and no serious adverse effects were observed throughout the study.
Skeletal muscle tissue is an important organ for lipid and glucose metabolism. It secretes cytokines and peptides that are classified as “myokines” [
In this study, we demonstrated that serum irisin levels were significantly higher in the T2DM patients with hypertriglyceridemia compared with the controls, and serum irisin was positively correlated with BMI, FBG, TC, and HDL, suggesting that irisin could play an important role in the delicate balance of energy metabolism and insulin resistance.
Our findings are in contrast to some recent studies indicating that circulating irisin was significantly lower in patients with T2DM [
Moreover, the reported results on the association between irisin, obesity, and metabolic parameters have been controversial. The majority of previous studies align with our findings that circulating irisin levels were positively associated with FBG levels [
Accumulating evidence has demonstrated that PPAR-
Importantly, we report for the first time here that fenofibrate treatment administered to T2DM patients with hypertriglyceridemia for 8 weeks resulted in a significant decrease in serum irisin levels, although fenofibrate was reported to increase irisin gene expression in diet-induced male obese mice [
In addition, it has been observed that the overexpression of PPARr coactivator-1alpha (PGC-1
Furthermore, our result that the serum irisin levels were significantly decreased after the 8-week fenofibrate treatment suggests that fenofibrate might protect against cardiovascular diseases, except for a lipid-lowering effect [
Atherosclerosis remains a major risk factor for cardiovascular diseases. PPAR-
Reduction of serum irisin levels through fenofibrate treatment may partially explain the beneficial effects of PPAR-
Further study is required to determine whether the protective effects of fenofibrate against the cardiovascular complications of diabetes are related to irisin. Our findings in the present study may provide one possible pathway to protect against the cardiovascular complications of diabetes with fenofibrate treatment.
Many studies have been published with irisin levels changing widely in human serum or plasma measured by commercial ELISA kits from different companies. The ELISA kits used in our study were from Phoenix Pharmaceuticals, and these kits were reported to have high sensitivity and excellent specificity for detection of human irisin with no significant cross-reactivity or interference. Therefore, they have been widely used in human and animal studies. However, a recent study has questioned the existence of circulating human irisin both because human FNDC5 has a noncanonical ATA translation start and because many human irisin antibodies used in commercial ELISA kits are based on polyclonal antibodies (pAbs) which are not previously tested for cross-reacting serum proteins and lack required specificity [
The limitations of our study are identified as follows. Firstly, our study population was limited to the Chinese. Therefore, our findings may not be directly applicable to other populations. Secondly, our sample size was relatively small so that our findings were not powerful enough to account for potentially confounding factors in our analysis, and our results could be improperly influenced by some outliers due to the sample size. Thirdly, the insulin levels were not examined in the present study. Thus, the points that circulating irisin levels were positively associated with insulin resistance and that fenofibrate improved insulin resistance were supported by the previous studies rather than our study. Fourthly, the cross-sectional design of the study does not allow us to determine a causal relationship, but it can certainly raise credible hypotheses to be confirmed and extended by future prospective cohort and mechanistic studies. Finally, since commercial ELISA kits of irisin are mostly based on pAbs which relatively lack specificity and are not previously tested for cross-reacting serum proteins, the values of human irisin measured by ELISA might be at high levels [
We reported the novel finding of a significant increase of serum irisin, a novel myokine, in type 2 diabetes mellitus patients with hypertriglyceridemia. More importantly, we presented novel data that fenofibrate treatment significantly decreased serum irisin levels in type 2 diabetes mellitus patients with hypertriglyceridemia. These results indicate that PPAR-
The study was approved by the Medicine and Pharmacy Ethics Committee of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
The authors declare no conflict of interests.
This work was supported by grants from the Major National Basic Research Program of China (no. 2011CB503904), the Chinese National Natural Science Foundation (nos. 81270369, 81070244, and 30770873), and the Beijing Natural Science Foundation (no. 7142060) to Guang Wang.