diabetes research and clinical practice 106 (2014) 590–596

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Diabetes Research and Clinical Practice jou rnal hom ep ag e: w ww.e l s e v i er . c om/ loca te / d i ab r es

The association between ectopic fat in the pancreas and subclinical atherosclerosis in type 2 diabetes Mee Kyoung Kim a, Hyun Ji Chun a, Jin Hee Park a, Dong Myung Yeo b, Ki-Hyun Baek a, Ki-Ho Song a, Dong Jin Chung b,**, Hyuk-Sang Kwon a,* a b

Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea Department of Radiology, The Catholic University of Korea, Seoul, Republic of Korea

article info

abstract

Article history:

Aims: Evidence that pancreatic fat accumulation has a role in obesity, metabolic syndrome

Received 18 July 2014

and type 2 diabetes mellitus (DM) is emerging. However, data on the influence of pancreatic

Received in revised form

steatosis on subclinical atherosclerosis are lacking.

8 September 2014

Methods: We examined 198 patients with type 2 DM. Pancreatic computed tomography (CT)

Accepted 17 September 2014

attenuations were assessed using CT imaging. Obesity was defined as BMI  25 kg/m2

Available online 30 September 2014

according to the Asian-specific BMI cut-offs. We defined pancreatic steatosis as pancreatic

Keywords:

Results: The pancreatic attenuations was significantly correlated with age (r =

0.302,

Pancreatic fat

p < 0.001), visceral fat area (r =

0.242,

attenuations below median levels.

Diabetes mellitus

0.194, p = 0.006) and vascular stiffness (r =

p = 0.001). In the non-obese group (BMI < 25 kg/m2), pancreatic steatosis was associated

Atherosclerosis

with a higher prevalence of carotid artery plaque and vascular stiffness. In the non-obese

Ectopic fat

group, patients with pancreatic steatosis, compared with those without, had an odds ratio (OR) of 3.1 (95% CI 1.2–8.1) for carotid atherosclerosis, after adjusting for age, gender and BMI. However, significant associations between pancreatic steatosis and atherosclerosis were not found in the obese group. Conclusion: Ectopic fat in the pancreas is strongly associated with carotid atherosclerosis in non-obese subjects with type 2 DM. This finding highlights the importance of pancreatic fat deposits related to a higher risk of cardiovascular disease, especially in non-obese subjects. # 2014 Elsevier Ireland Ltd. All rights reserved.

1.

Introduction

Obesity is a major risk factor for developing type 2 diabetes mellitus (DM) and its related complications [1]. Current data suggest that fat distribution is a better marker of metabolic

risk than obesity itself [2]. Body shape and how regional adipose tissue handles and stores excess dietary energy have substantial cardiometabolic implications [3]. Several studies have investigated the correlation of either visceral adipose tissue or subcutaneous adipose tissue with cardiometabolic risk and concluded that visceral adipose tissue is a stronger

* Corresponding authors at: Department of Internal Medicine, Yeouido St. Mary’s Hospital, The Catolic University of Korea, 10 Yuksamro Youngdeungpo-gu, Seoul 150-713, Republic of Korea. Tel.: +82-2-3779-1039; fax: +81-2-780-3132. ** Corresponding authors at: Department of Radiology, Yeouido St. Mary’s Hospital, The Catholic University of Korea, 10 Yuksam-ro Youngdeungpo-gu, Seoul 150-713, Republic of Korea. Tel.: +82-2-3779-1270; fax: +82-2-783-5288. E-mail addresses: [email protected] (D.J. Chung), [email protected] (H.-S. Kwon). http://dx.doi.org/10.1016/j.diabres.2014.09.005 0168-8227/# 2014 Elsevier Ireland Ltd. All rights reserved.

diabetes research and clinical practice 106 (2014) 590–596

correlate of cardiometabolic risk than subcutaneous adipose tissue [4]. Accumulation of fat in specific locations or as ectopic fat may partially contribute to the association of adiposity with cardiometabolic risk. Ectopic fat accumulation in muscle and liver is related to insulin resistance, and lipid accumulation in the pancreas has been suggested to impair insulin secretion from b-cells in the islets of Langerhans [5]. In 112 unselected autopsies of adult patients without known pancreatic disease, lipomatosis (defined as fat in the pancreas >25%) is not limited to patients with general obesity. Moreover, there were significant correlations between fat in the pancreas of more than 25% and DM and severe generalized atherosclerosis [6]. Although the association is inconsistent, the role of pancreatic fat in the pathogenesis of type 2 DM or b-cell dysfunction has been reported in several studies [7]. Previous studies mainly focused on the effect of pancreatic fat depots on b-cell dysfunction, as a locally acting fat depot. Therefore, we hypothesized that the presence of fat in the pancreas might influence atherosclerosis. In the present study, we investigated whether pancreatic steatosis was associated with subclinical atherosclerosis in patients with type 2 DM.

2.

Methods

2.1.

Subjects

One hundred ninety-eight consecutive patients with type 2 DM in whom conventional outpatient treatment with either diet or any combination of oral antidiabetic agents had failed were referred to the inpatient diabetes service. All study patients were hospitalized only for glycemic control. The criteria for this study included age > 20 years and a diagnosis of type 2 DM. The exclusion criteria included a history of type 1 or secondary diabetes, positive anti-glutamic acid decarboxylase antibody, pancreatitis or pancreatic cancer, liver cirrhosis, renal failure (serum creatinine > 2 mg/dL), systemic infection, the use of corticosteroids, or pregnancy. This study was approved by the Institutional Review Board.

2.2.

Pancreas attenuations

Computed tomography (CT) images were acquired using the standard clinical abdominal CT protocol utilizing a multi-slice CT scanner. Pancreatic CT attenuations were determined by calculating the mean Hounsfield unit (HU) of three pancreatic regions (head, body and tail) [5,8]. The measurement of pancreatic CT attenuations was performed by two experienced radiologists. A CT scan at the L4–5 level was performed to measure the cross-sectional areas of total abdominal fat, visceral abdominal fat and subcutaneous abdominal fat using previously described methods [9]. First, the total area of abdominal adipose tissue was measured at 190 to 30 HUs. The visceral fat area (VFA) was distinguished from the subcutaneous fat area (SFA) by manually tracing the abdominal muscular wall separating the two adipose tissue compartments. The VFA was measured, and the SFA was calculated by subtracting the VFA area from the total abdominal fat area.

2.3.

591

Anthropometric and laboratory measurements

Body weight and height were measured while the subjects were barefoot and wearing light clothing, and were used to calculate the body mass index (BMI). Waist circumference was measured to the nearest 0.1 cm at the narrowest point between the lower limit of the ribcage and the iliac crest. Obesity was defined as BMI  25 kg/m2 according to the Asian-specific BMI cut-off values from the World Health Organization report [10,11]. HbA1c levels were measured using an automated HPLC analyzer (HLC-723 G7, Tosoh Corporation, Tokyo, Japan). Apolipoprotein A1 (Apo-A1) and apolipoprotein B levels were determined by immunoturbidometry using a Hitachi-7600 analyzer (Sekisui Chemical). Serum C-peptide was measured before and 6 min after intravenous injection of 1 mg of glucagon using an immunoradiometric assay (Institute of Isotopes Co. Ltd, Budapest, Hungary).

2.4.

Evaluation of atherosclerosis

Brachial-ankle pulse wave velocity (PWV) was measured using a Colin waveform analyzer (VP2000; Colin, Komaki, Japan). After a 5-min rest in the supine position, the PWV of each subject was measured and calculated as the mean of the left (left upper arm to left ankle) and right (right upper arm to right ankle) PWV values. Hypertension/European Society of Cardiology guidelines [12], subclinical atherosclerosis in the carotid artery was defined as either an abnormally increased carotid intima media thickness (C-IMT) (0.9 mm) or the presence of carotid plaque.

2.5.

Statistical analysis

For analyzing the association of ectopic fat and diabetic complications in patients with type 2 DM, pancreatic attenuations and visceral to subcutaneous fat ratios were designated as high or low based upon the median levels. The median pancreatic attenuation was 36.0 HU. The median visceral to subcutaneous fat ratio was 0.74. We defined pancreatic steatosis as a pancreatic attenuation below the median level and visceral obesity as a visceral to subcutaneous fat ratio above the median level. Subject characteristics were compared among groups stratified by the presence or absence of pancreatic steatosis and obesity by independentsample Student’s t-tests for continuous measures and x2 tests for categorical measures. Pearson’s correlation coefficients between pancreatic attenuations and various parameters were calculated. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using binary logistic regression analysis to assess the associations between pancreatic steatosis and subclinical atherosclerosis. All data were analyzed using SAS version 9.1 for Windows software (SAS Institute Inc., Cary, NC, USA). Data are presented as the means  standard deviation (SD) unless otherwise stated. A p-value < 0.05 was considered significant.

3.

Results

3.1.

Clinical characteristics of study subjects

The data of 198 patients were analyzed. All patients were treated with oral hypoglycemic agents or insulin. The mean age

592

diabetes research and clinical practice 106 (2014) 590–596

was 59.1  14.7 years, and the mean BMI was 25.9  4.1 kg/m2. The mean duration of diabetes was 15.0  9.4 years, and the mean HbA1c level was 9.5  2.1%.

3.2. Correlation between pancreatic attenuations and clinical parameters Pancreatic attenuations were negatively correlated with age (r = 0.302, p < 0.001), diabetes duration (r = 0.216, p = 0.005), waist circumference (r = 0.262, p = 0.001), total abdominal fat area (r = 0.227, p = 0.001), and VFA (r = 0.194, p = 0.006). The pancreatic attenuation was positively correlated with levels of Apo-A1 (r = 0.214, p = 0.003) and high-density lipoprotein (HDL) cholesterol (r = 0.170, p = 0.016). The pancreatic attenuation was negatively correlated with vascular stiffness (PWV; r = 0.242, p = 0.001) and this association remained constant after adjusting for age (Table 1). No significant associations of pancreatic attenuations with abdominal SFA or C-peptide levels were observed (Table 1). The VFA to SFA ratio was positively correlated with age (r = 0.253, p < 0.001), fasting (r = 0.264, p < 0.001) and stimulated C-peptide (r = 0.213, p = 0.003), serum triglyceride (r = 0.213, p = 0.003) and vascular stiffness (r = 0.254, p = 0.001). The VFA to SFA ratio and BMI were not significantly correlated (r = 0.029, p = 0.683). We performed multiple stepwise linear regression analyzes with pancreatic CT attenuations as the dependent variables and potential predictors (age, diabetes duration, BMI, HDL-C, visceral fat area, PWV, carotid IMT, and carotid plaques) as independent variables. Age ( p = 0.002), BMI ( p = 0.02) and PWV ( p = 0.04) were independently related to pancreatic steatosis in all patients with type 2 diabetes.

3.3. Association of pancreatic fat with subclinical atherosclerosis according to the presence or absence of obesity Table 2 shows the participants’ characteristics stratified by the presence or absence of pancreatic steatosis and obesity. In the non-obese group, subjects with pancreatic steatosis were older (64.2  12.9 vs. 53.2  14.7 years, p < 0.001) and had lower levels of HDL cholesterol (39.1  10.2 vs. 45.9  12.8 mg/dL, p = 0.004) and Apo-A1 (115.2  22.4 vs. 124.8  23.3 mg/dL, p = 0.047). Waist circumference (86.9  6.6 vs. 83.3  6.1 cm2, p = 0.018)

and VFA (116.7  48.2 vs. 101.2  43.8 cm2, p = 0.099) tended to be higher in subjects with pancreatic steatosis than in those without steatosis. However, BMI, gender distribution, fasting and stimulated C-peptide levels did not differ significantly between the two groups. In the non-obese group, pancreatic steatosis was associated with a higher prevalence of subclinical atherosclerosis (Fig. 1A) and vascular stiffness (Table 2). To assess whether pancreatic fat deposit is associated with diabetic complications independent of confounding factors, we adjusted our model for age, gender and BMI. In the nonobese group, patients with pancreatic steatosis, compared with those without, had an OR of 3.1 (95% CI 1.2–8.1) for subclinical atherosclerosis, after adjusting for age, gender and BMI (Table 3). Age, gender and BMI-adjusted means of PWV were also significantly higher in subjects with pancreatic steatosis (1800  655 vs. 1660  310 cm/s, p = 0.042). In the obese group, the prevalence of subclinical atherosclerosis was not different according to the presence or absence of pancreatic steatosis (Fig. 1B). In the obese group, there was no significant difference between the two groups according to the variables except for age: patients with pancreatic steatosis were older.

3.4. Association of pancreatic fat with subclinical atherosclerosis according to the presence or absence of visceral obesity The vascular stiffness (PWV) was significantly higher in subjects with pancreatic steatosis than in those without, regardless of visceral obesity. In the non-visceral obesity group, pancreatic steatosis was associated with a higher prevalence of subclinical atherosclerosis ( p = 0.003; Supplementary Table 1). The differences in the prevalence of subclinical atherosclerosis between the groups remained significant after adjusting for age, gender and BMI (OR 2.9, 95% CI 1.1–7.6). Pancreatic steatosis was not significantly associated with carotid artery plaque in patients with visceral obesity (Supplementary Table 1).

4.

Discussion

We found that pancreatic steatosis was associated with increased atherosclerosis in non-obese subjects with type 2

Table 1 – Correlation between pancreatic computed tomography (CT) values and various parameters. Pancreatic CT values Age (years) DM duration (years) BMI (kg/m2) Waist circumference (cm) Fasting C-peptide (ng/mL) Stimulated C-peptide (ng/mL) Total abdominal fat area (cm2) Visceral fat area (cm2) Subcutaneous fat area (cm2) Pulse wave velocity (cm/s) Apolipoprotein A-1(mg/dL) Apolipoprotein B (mg/dL) HDL cholesterol (mg/dL) Log triglyceride (mg/dL)

Unadjusted R 0.302 0.216 0.179 0.262 0.014 0.002 0.227 0.194 0.073 0.242 0.214 0.051 0.170 0.014

P-value

The association between ectopic fat in the pancreas and subclinical atherosclerosis in type 2 diabetes.

Evidence that pancreatic fat accumulation has a role in obesity, metabolic syndrome and type 2 diabetes mellitus (DM) is emerging. However, data on th...
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