Abstract
Previous studies have shown that dipeptidyl peptidase (DPP)-4, is released from adipocytes in a differentiation-dependent manner and a marker for insulin resistance in obese individuals who have particularly high circulating DPP-4/soluble CD26 (sCD26) concentrations. In this study, we have evaluated the effects of short-term hospitalization with calorie restriction on body composition and circulating DPP-4/sCD26 concentrations in patients with type 2 diabetes. A total of 47 Japanese adults with type 2 diabetes were recruited to the study (age; 56.6 ± 13.0 years, body mass index (BMI); 27.3 ± 5.6 kg/m2). Body composition, circulating DPP-4/sCD26 concentrations and metabolic parameters were assessed upon admission and at discharge from hospital (average of the period: 13.0 ± 2.5 days). Visceral fat area (VFA) was also assessed by dual impedance method. During hospitalization, there was a significant reduction in body weight, BMI, lean body mass, VFA and circulating DPP-4/sCD26 concentrations, but not in body fat mass. Fasting circulating DPP-4/sCD26 concentrations were significantly correlated with fasting insulin, aspartate aminotransferase, γ-glutamyltransferase (γ-GTP) levels, and HOMA-IR (r = 0.477, 0.423, 0.415, 0.548, respectively), but not with VFA (r = − 0.056) by liner regression analyses at base line. It was also observed a positive correlation between changes in circulating DPP-4/sCD26 concentrations and γ-GTP level, HOMA-IR, and a negative correlation between the changes in circulating DPP-4/sCD26 concentrations and VFA significantly (r = 0.300, 0.633, − 0.343, respectively). In conclusion, our observations suggest that liver enzymes as well as VFA might be associated with the response of DPP-4/sCD26 concentrations.
Keywords: DPP-4, Soluble CD26, Type 2 diabetes, Body composition, Visceral fat
Introduction
Both obesity and type 2 diabetes are associated with insulin resistance [1]. Chronic nutrient excess leads to visceral adipose tissue expansion and dysfunction in an active process that involves the adipocytes, their supporting matrix, and immune cell infiltrates [2]. Visceral adipose tissue secretes a number of adipokines and cytokines leading to a proinflammatory, procoagulant and insulin resistance collectively known as the metabolic syndrome [3]. Thus, greater visceral adiposity is associated with subsequent insulin resistance [4–6]. However, there are several studies to report that subcutaneous fat accumulation is more closely related to insulin resistance in general and diabetic population [7–11]. Although normalizing overweight should lead to improve metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension, the weight loss is often accompanied by a loss in lean body mass [12]. Therefore, it should be important to consider a change in each component of the body composition as well as visceral adipose fat, when we investigate whether those components would be associated with insulin resistance and glucose metabolism.
Metabolic syndrome is associated with abdominal obesity, dyslipidemia, inflammation, insulin resistance or full-blown diabetes, and risk of developing cardiovascular diseases [3]. The visceral fat area (VFA) has been quantitatively evaluated by computed tomography (CT) or magnetic resonance imaging (MRI) until several years ago. However, these methods have some problems such as risk of radiation, higher costs and they also require radiologists’ cooperation, which comprises an obstacle in the prevention, improvement and treatment of lifestyle related diseases. Recently, a dual bioelectrical analysis (Dual BIA) that can determine VFA by measuring truncal impedance and surface impedance at the abdomen separately has been developed. As the change in estimated VFA by Dual BIA is highly correlated with that by CT, Dual BIA is useful and important for the early detection and prevention cardiovascular risks and evaluation of effectiveness of weight reduction therapy in obese patients [13].
Dipeptidyl peptidase (DPP)-4 is also known as cell surface antigen CD26 that has a costimulatory function in the immune system [14]. A soluble form of CD26 (sCD26), which lacks the cytoplasmic tail and transmembrane domain, is found in serum and it possesses DPP-4/sCD26 enzymatic activity that removes X-Pro and X-Ala dipeptides from substrates [15]. DPP-4/CD26 gene is widely expressed in many organs, including adipose and liver tissues [16]. Previous studies have shown that DPP-4/sCD26 is released from adipocytes in a differentiation-dependent manner [17] and a marker for insulin resistance in obese individuals, who have particularly high concentrations of circulating DPP-4/sCD26 [18]. On the other hand, the activity of serum DPP-4/sCD26 and the expression level of DPP-4/CD26 in liver were correlated with histopathological grade of nonalcoholic steatohepatitis (NASH) and hepatosteatosis [19]. Moreover, mice lacking DPP-4 displayed a protective effect from diet-induced hepatic steatosis and insulin resistance [20].
Interestingly, high circulating DPP-4/sCD26 concentrations may be associated with reduced efficacy of a DPP-4 inhibitor, sitagliptin [21]. It is possible that reduction in circulating DPP-4/sCD26 concentrations may enhance the efficacy of incretin related agents. In this study, our purpose is to evaluate the changes in each component of body composition, including those in VFA measured by Dual BIA, under short-term hospitalization with calorie restriction and the effects on insulin secretion and sensitivity, lipid metabolism and circulating DPP-4/sCD26 concentrations in type 2 diabetic patients, thereby specifying an influence factor which influences the response of DPP-4/sCD26 concentrations.
Materials and methods
Study population
All subjects were adult Japanese with type 2 diabetes who underwent hospitalization for glycemic control. The protocol of the following studies was approved by the ethical committee on human research at Dokkyo Medical University Saitama Medical Center (approval number: 1431) according to the Declaration of Helsinki. Written informed consent was obtained from all subjects prior to enrollment.
The sample size was calculated as follows; suppose one wishes to detect a simple correlation r (r = 0.4) of N observations. Using a two-sided test, 5% significance level test (α = 0.05) with 80% power (β = 0.2), the required sample size is approximate 47 (n = 47) [22]. A total of 47 patients were recruited to this study. They were eligible to participate if they were ≥ 20 years old and had inadequate glycemic control (Hemoglobin A1c (HbA1c) ≥ 7.0%) required medical care and self-management education under hospitalization. Subjects who had already been diagnosed with type 1 diabetes, gestational diabetes and diabetes in pregnancy, and who had any acute complications such as diabetic ketoacidosis were excluded from the study.
Study protocol
All subjects were placed under calorie restriction with 25 to 30 kcal per kilogram (kg) of ideal body weight, corresponding to body mass index (BMI) of 22, per day (carbohydrate: 50–60% of total calories) during hospitalization. Body composition, circulating DPP-4/sCD26 concentrations and hemodynamic parameters were assessed upon admission and at discharge from hospital. After overnight fasting, blood samples were obtained from each subject and metabolic parameters were measured. Body composition was assessed by bioelectrical impedance analysis using multi frequency segmental body composition analyzer, MC-780 (Tanita corporation, Tokyo, Japan). Abdominal VFA was also assessed by dual impedance method using visceral fat monitor system, HDS-2000 DUALSCAN (Omron Healthcare Co., Ltd., Kyoto, Japan). Circulating DPP-4/sCD26 concentrations were measured with enzyme-linked immunosorbent assay kit (Human sCD26 platinum ELISA; Bender MedSystems GmbH, Vieena, Austria). Fasting plasma glucose (FPG) was evaluated using Glucose Auto Stat GA1160® (Arkray, Kyoto, Japan). HbA1c was evaluated by Norudia N HbA1c (Sekisui Medical Inc., Tokyo, Japan) and the normal range was 4.5–6.2% [NGSP: national glycohemoglobin standardization program]. Serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and serum triglyceride (TG) were measured using enzymatic assays. The Determiner L TC II® and Determiner L TG® reagents (Kyowa Medics, Tokyo, Japan) were used for measurements of TC and TG, respectively. HDL-C and LDL-C were directly measured by Cholestest N HDL-C® and Cholestest LDL® (Daiichi Pure Chemicals, Tokyo, Japan), respectively. Fatty acids including malondialdehyde-modified LDL (MDA-LDL), remnant like particles cholesterol (RLP-C), dihomo γ-linolenic acid (DHLA), and arachidonic acid (AA) were assessed using the gas-chromatograph method (SRL inc. Tokyo, Japan). Plasma insulin was measured by a chemiluminescent enzyme immunoassay (CLEIA) using the lumipulse Presto Insulin Kit ® (Fujirebio, Tokyo, Japan). HOMA-IR was used as an indicator of insulin resistance and was calculated as follows: HOMA-IR = FPG (mg/dL) × fasting immunoreactive insulin (μU/mL)/405 [23].
Statistics
Data are expressed as the mean ± SD. Statistical evaluation of the differences between two groups was performed by unpaired t test. The relationships between fasting circulating DPP-4/sCD26 concentrations and metabolic and hemodynamic parameters were examined by linear regression and Spearman’s correlation coefficient analyses. For multiple regression analyses, we used the stepwise regression method to find a model that is appropriate for these data. Serious multicollinearity was not detected among included factors (Variance inflation factors < 10). Statistical analyses were performed using IBM SPSS Statictics 25 (IBM, Armonk, NY, USA) and R version 3.0.2 (R Foundation for Statistical Computing, http://www.r-project.org/). All P values were two-tailed.
Results
Changes in various variables at baseline and at 2 weeks after hospitalization in patients with type 2 diabetes are presented in Table 1. During the period, a significant decrease was obtained in FPG, fasting immunoreactive insulin (IRI), fasting C-peptide and HOMA-IR by the optimization of the treatment for diabetes including the calorie restriction. A significant decrease was also obtained in body weight, BMI, VFA and lean body mass. However, no significant changes were observed in body fat mass and body fat weight during the period. We also found that the circulating DPP-4/sCD26 concentrations were significantly decreased after a 2 week-hospitalization (Table 2). As shown in Table 1, administration of sodium/glucose cotransporter 2 (SGLT2) inhibitors was initiated for 7 patients with diabetes. A recent study has demonstrated that a SGLT2 inhibitor, dapagliflozin, reduced serum levels of DPP-4/sCD26 in people with Type 2 diabetes [24]. In this study, significant reductions of DPP-4/sCD26 concentrations were observed in both groups with and without administration of SGLT2 inhibitors during the hospitalization (with SGLT2 inhibitor: at baseline 1161.3 ± 176.0 ng/ml, after 2 weeks 900.4 ± 143.9 ng/ml, P = 0.04, without SGLT2 inhibitor: at baseline 973.4 ± 416.9 ng/ml, after 2 weeks 890.5 ± 430.8 ng/ml, P = 0.03). Interestingly, changes of DPP-4/sCD26 concentrations were greater in a group with SGLT-2 inhibitors than in that with SGLT-2 inhibitors, however this difference was not significant (P = 0.09). Then, there was a significant reduction in γ-glutamyltransferase (γ-GTP), LDL-C, HDL-C, TG, MDA-LDL, RLP-C, DHLA, and AA after a 2 week-hospitalization.
Table 1.
Clinical characteristics of study population
| Baseline | After 2 weeks | P value | |
|---|---|---|---|
| N (male/female) | 47 (34/13) | ||
| Age (years) | 56.6 ± 13.0 | ||
| Height (cm) | 165.3 ± 9.5 | ||
| Weight (Kg) | 75.3 ± 19.6 | 73.7 ± 18.6 | 2.11 × 10–7 |
| BMI | 27.3 ± 5.6 | 26.8 ± 5.3 | 8.05 × 10–8 |
| Body fat mass (%) | 28.8 ± 9.5 | 28.8 ± 9.2 | 0.995 |
| Body fat weight (kg) | 22.5 ± 11.3 | 22.0 ± 10.8 | 0.11 |
| Lean body weight (kg) | 52.8 ± 12.3 | 51.7 ± 11.3 | 0.001 |
| Visceral fat area (cm2) | 104.0 ± 52.5 | 96.3 ± 46.2 | 0.009 |
| FPG (mg/dl) | 172.6 ± 53.2 | 111.1 ± 17.2 | 9.57 × 10–11 |
| HbA1c (%) | 10.2 ± 2.4 | ||
| Fasting IRI (μU/ml) | 10.4 ± 7.3*** | 9.7 ± 5.2* | 0.006 |
| Fasting C-peptide (ng/ml) | 2.2 ± 1.3 | 1.8 ± 1.2** | 0.002 |
| HOMA-IR | 4.3 ± 3.6*** | 2.8 ± 1.8* | 0.0002 |
| Diabetic therapy | |||
| DP/BG/TZ/SU/GL/AG/SG | 29/20/1/9/1/7/0 | 32/27/11/4/7/10/7 | |
| INS/GLP-1/NONE | 8/1/6 | 22/3/2 | |
Data are mean ± SD
DP, DPP-4 inhibitors; BG, biguanide; TZ, thiazolidine; SU, sulfonylureas; GL, glinides; AG, α glucosidase inhibitors; SG, SGLT-2 inhibitors; INS, insulin; GLP-1, GLP-1 receptor agonist
*n = 18
**n = 44
***n = 36
Table 2.
Changes in circulating DPP-4/sCD26 concentrations and metabolic parameters
| Baseline | After 2 weeks | P value | |
|---|---|---|---|
| AST (IU/L) | 32.3 ± 23.1 | 30.4 ± 18.9 | 0.48 |
| ALT (IU/L) | 43.1 ± 38.9 | 39.9 ± 30.9 | 0.47 |
| γ-GTP (IU/L) | 59.6 ± 66.9 | 47.9 ± 51.7 | 0.004 |
| LDL-C (mg/dl) | 118.0 ± 31.9 | 104.2 ± 28.8 | 0.00008 |
| HDL-C (mg/dl) | 41.3 ± 9.3 | 39.0 ± 8.1 | 0.004 |
| TG (mg/dl) | 159.2 ± 86.1 | 133.8 ± 60.5 | 0.02 |
| MDA-LDL (U/L) | 136.2 ± 49.7 | 115.2 ± 35.6 | 0.00003 |
| RLP-C (mg/dl) | 7.4 ± 5.8 | 5.4 ± 3.4 | 0.02 |
| DHLA (μg/ml) | 38.4 ± 16.5 | 30.1 ± 8.4 | 0.0002 |
| AA (μg/ml) | 207.3 ± 58.9 | 192.7 ± 45.2 | 0.003 |
| EPA (μg/ml) | 60.2 ± 35.6 | 57.2 ± 27.0 | 0.36 |
| DHA (μg/ml) | 139.8 ± 50.9 | 137.3 ± 43.7 | 0.54 |
| EPA/AA | 0.30 ± 0.20 | 0.31 ± 0.16 | 0.80 |
| hsCRP (mg/dl) | 0.25 ± 0.34 | 0.22 ± 0.36 | 0.90 |
| DPP-4/sCD26 (ng/ml) | 1002.6 ± 393.9 | 892.0 ± 399.4 | 0.003 |
MDA-LDL, malondialdehyde-modified LDL; RLP-C, remnant like particls cholesterol; DHLA, dihomo γ-linolenic acid; AA, arachidonic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid
At baseline analysis, circulating DPP-4/sCD26 concentrations were positively correlated with AST, γ-GTP, fasting IRI levels and HOMA-IR (r = 0.423, 0.415, 0.477, 0.548, P = 0.004, 0.005, 0.004, 0.001, respectively), but not with abdominal VFA (r = − 0.056, P = 0.72). There are no significant correlations between circulating DPP-4/sCD26 concentrations and each lipid profile. We performed a stepwise regression analysis that included all significant variables. In a model explaining 45.6% (R2 = 0.456) of the variation of circulating DPP-4/sCD26 concentrations in our 35 patients, HOMA-IR (β = 0.308, P = 0.05) and γ-GTP (β = 0.462, P = 0.005) were independent determinants of circulating DPP-4/sCD26 concentrations (Table 3).
Table 3.
Correlation analysis between clinical traits and circulating DPP-4 concentrations (at baseline)
| Single correlation | Multiple regression (n = 35) | |||
|---|---|---|---|---|
| Independent parameter | r | P | β | P |
| BMI | − 0.061 | 0.69 | – | – |
| Visceral fat area | − 0.056 | 0.72 | – | – |
| Body fat mass | − 0.017 | 0.91 | – | – |
| Lean body weight | 0.006 | 0.97 | – | – |
| AST | 0.423 | 0.004 | – | – |
| ALT | 0.248 | 0.10 | – | – |
| γ-GTP | 0.415 | 0.005 | 0.462 | 0.005 |
| IRI | 0.477 | 0.004 | – | – |
| HOMA-IR | 0.548 | 0.001 | 0.308 | 0.05 |
During hospitalization, changes in circulating DPP-4/sCD26 concentrations were positively correlated with changes in γ-GTP levels and HOMA-IR (r = 0.300, 0.633, P = 0.04, 0.005, respectively), and negatively correlated with changes in VFA (r = − 0.343, P = 0.02). There are no significant correlations between changes in circulating DPP-4/sCD26 concentrations and changes in each lipid profiles. We also performed a stepwise regression analysis that excluded fasting IRI levels and HOMA-IR because approximately 50% of patients were received insulin injection therapy at the end point of this study. In a model explaining 19.9% (R2 = 0.199) of the variation in changes in circulating DPP-4/sCD26 concentrations in our 43 patients, VFA (β = − 0.302, P = 0.05) were independent determinants of changes in circulating DPP-4/sCD26 concentrations (Table 4).
Table 4.
Correlation analysis between changes in clinical traits and circulating DPP-4 concentrations during a 2 week-hospitalization
| Single correlation | Multiple regression (n = 43) | |||
|---|---|---|---|---|
| r | P | β | P | |
| ∆BMI | 0.223 | 0.13 | 0.245 | 0.12 |
| ∆Visceral fat area | − 0.343 | 0.02 | -0.302 | 0.05 |
| ∆Body fat mass | − 0.056 | 0.71 | – | – |
| ∆Lean body weight | 0.104 | 0.49 | – | – |
| ∆AST | 0.067 | 0.65 | – | – |
| ∆ALT | 0.030 | 0.84 | – | – |
| ∆γ-GTP | 0.300 | 0.04 | 0.173 | 0.27 |
| ∆IRI | 0.366 | 0.11 | Not included | Not included |
| ∆HOMA-IR | 0.633 | 0.005 | Not included | Not included |
Discussion
In this study, we evaluated that the effects of a 2 week-hospitalization of type 2 diabetic patients on the changes in body composition including VFA and related clinical parameters including circulating DPP-4/sCD26 concentrations. We observed that body weight, BMI and lean body mass were significantly decreased, but body fat mass was not changed. These results indicate that the change in lean body mass, rather than that of body fat mass, may be the major factor, which contributed to body weight loss under the short-term hospitalization with calorie restriction. It may be resulted from the reduction of physical activity during the hospitalization with bed rest, because the physical activity has been shown to be vitally important for maintaining muscle mass and function [25].
A previous study has reported that DPP-4/sCD26 expression levels in both subcutaneous and visceral adipose tissues were positively correlated with BMI [18]. However, any significant correlations between the circulating DPP-4/sCD26 concentrations and BMI were not found at baseline or after the hospitalization in this study, suggesting that the circulating DPP-4/sCD26 concentrations may not necessarily reflect local DPP-4/sCD26 expression levels in adipose tissues.
It has been also shown that circulating DPP-4/sCD26 concentrations in obese subjects with insulin resistance are higher than those without insulin resistance [18]. Our data showed that the circulating DPP-4/sCD26 concentrations were not correlated with HOMA-IR at baseline. However, the changes in circulating DPP-4/sCD26 concentrations were positively correlated with those in HOMA-IR during the hospitalization, indicating that the circulating DPP-4/sCD26 concentrations can be one of markers for insulin resistance.
A previous report showed that the DPP-4/sCD26 expression in visceral adipose tissue was significantly higher than that in subcutaneous adipose tissue and positively correlated with BMI in non-diabetic population [18]. However, in the current study, we found no significant correlation between circulating DPP-4/sCD26 concentrations and BMI. There is a possibility that the treatment for diabetes during hospitalization may affect the circulating DPP-4/sCD26 concentrations in our study. Another previous report showed that circulating DPP-4/sCD26 concentrations were positively and specifically associated with the accumulation of visceral fat evaluated by CT and the presence of metabolic syndrome in 135 men with type 2 diabetes [26]. On the other hand, we could not find any significant association between the baseline circulating DPP-4/sCD26 concentrations and VFA or between the changes in those during hospitalization, which might be attributed to the smaller participants in our study.
Regarding the expression and secretion of DPP-4/sCD26 in liver, a previous study reported that the serum DPP-4/sCD26 activity was higher in patients with NASH than controls, and correlated with the histopathological grade and hepatosteatosis but not with DPP-4/CD26 positive staining [19]. Furthermore, another previous study showed that the high circulating DPP-4/sCD26 concentrations were correlated with liver function but not with FPG or HbA1c in nonalcoholic fatty liver disease (NAFLD) [27]. It is suggested that improving NAFLD and NASH by calorie restriction may lead to suppress the expression of DPP-4 in liver, reduce circulating DPP-4/sCD26 concentrations, and ameliorate the efficacy of DPP-4 inhibitors. A meta regression analysis also showed that the baseline BMI is significantly correlated with the HbA1c lowering efficacy of DPP-4 inhibitors [28], because obese patients should be under a situation with NAFLD or NASH, thereby with possibly high circulating DPP-4/sCD26 concentrations.
It is not clear that how the glucose-lowering effects of DPP-4 inhibitors could be attenuated in patients with elevated circulating DPP-4/sCD26 concentration. There is a possibility that the therapeutic dose of DPP-4 inhibitors may be insufficient to inhibit DPP-4 activity in type 2 diabetic patients with high circulating DPP-4/sCD26 concentrations. Considering another possibility, a negative correlation between circulating DPP-4/sCD26 and postprandial serum C peptide was observed in a previous report [21]. A high circulating DPP-4/sCD26 promotes degradation of active incretin, and might be associated with impaired postprandial insulin secretion.
There are several limitations in this study. First, this study was conducted at a single institute. Second, all subjects were diabetic patients with severe hyperglycemia, which were required hospitalization, and healthy subjects were not enrolled. Therefore, the participants enrolled in this study might have relatively severe diabetes and might not be representative of all Japanese diabetic patients. Third, every participant received different treatments. For example, approximate 50% participants received insulin injection therapy and several participants received the treatment of SGLT-2 inhibitor at discharge from the hospital. It may affect varying changes in the body composition during the hospitalization. Fourth, we used HOMA-IR for a marker of insulin resistance, although patients receiving insulin therapy at both baseline and the end of the study were excluded from this analysis. However, there is a possibility that the evaluation of insulin resistance is inaccurately at baseline, because all subjects needed to be hospitalized for glycemic control and showed high fasting glucose levels. Fifth, we have tried to specify an influence factor which influences the response of DPP-4/sCD26 concentrations, but the R-squared value of the multivariate analysis was substantially low. There can be a problem with the regression model and included independent variables did not explain much in the variation of DPP-4/sCD26 concentration.
In conclusion, circulating DPP-4/sCD26 concentrations are positively associated with liver enzymes but not with fat mass and VFA. However, changes in circulating DPP-4/sCD26 concentrations are negatively and independently associated with VFA and positively with γ-GTP. Further clinical observations in subjects with various metabolic disorders should be necessary to clarify the role of circulating DPP-4/sCD26.
Acknowledgements
This work was supported in part by Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (JSPS) [Grant Numbers 19K09018 (K.H.)]; Takeda Science Foundation (K.H.).
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Compliance with ethical standards
Conflict of interest
The authors declare no competing interests.
Ethical statement
The authors have nothing to disclose.
Human rights statement
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (the Institutional Review Boards of Dokkyo Medical University Saitama Medical Center, approval date: Nov. 19, 2014, approval number: 1431) and with Helsinki Declaration of 1964 and later versions.
Informed consent
All informed consent or substitute for it was obtained from all patients for being included in the study.
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 data that support the findings of this study are available from the corresponding author upon reasonable request.