CA19-9 is a tumor-associated antigen. It is also a marker of pancreatic tissue damage that might be caused by diabetes. Long-term poor glycemic control may lead to pancreatic beta cell dysfunction which is reflected by elevated serum CA19-9 level. Intracellular cholesterol accumulation leads to islet dysfunction and impaired insulin secretion which provide a new lipotoxic model. This study firstly found total cholesterol was one of the independent contributors to CA19-9. Elevated serum CA19-9 level in diabetic patients may indicate further investigations of glycemic control, pancreatic beta cell function, and total cholesterol level.
CA19-9 is a tumor-associated antigen that was originally defined by a monoclonal antibody produced by a hybridoma prepared from murine spleen cells immunized with a human colorectal cancer cell line. Although increased serum CA19-9 level is known to be associated with pancreatic cancer. In particular, it has been also shown to increase in many malignant diseases such as upper gastrointestinal tract, ovarian, and hepatocellular and colorectal cancer. In addition, various studies have reported increased serum CA19-9 levels in benign diseases such as inflammatory conditions of the hepatobiliary system, thyroid disease [
CA19-9 is used in the diagnosis of pancreatic cancer, but it is also a marker of pancreatic tissue damage that might be caused by diabetes. Benhamou et al. [
The aim of this study was to evaluate serum CA19-9 levels in patients with DM in comparison with age- and sex-matched control subjects. In addition, we aimed to find out whether serum CA19-9 level was related with metabolic control and pancreas pancreatic beta cell function in these subjects.
71 type 1 DM, 866 type 2 DM patients, and 122 healthy volunteers who examined and treated in our outpatient clinic and inpatient department were enrolled in this cross-sectional study. The local ethical committee approval was obtained. Patients with malignant disease, with history of chemotherapy or radiotherapy, and with acute or chronic pancreatitis were excluded. Patients with diabetes who have any coexistent disease related to high CA19-9 levels were also excluded. CA19-9 levels were measured in all subjects. Cases with high CA19-9 levels were evaluated with abdominal ultrasonography and CT imaging. Upper gastrointestinal endoscopy and colonoscopy were performed when needed. Duration of diabetes was calculated by years. Heights and weights of the participants were measured, and their body mass indexes (BMI) [weight (kg)/square of height (m2)] were calculated.
Plasma glucose was assayed by glucose oxidase method. Serum C peptide concentration was measured by radioimmunoassay (RIA) (Linco Research, United States). HbA1c was determined by high-performance liquid chromatography (Bio-Rad Inc., Hercules, USA). GA was measured by enzymatic method (LUCICA GA-L, Asahi KASEI, Tokyo). Alanine aminotransferase (ALT) was measured by UV method. Alanine aminotransferase (AST) was measured by Szasz-Persijn method. Serum triglyceride (TG), TC, high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c) were measured by enzymatic procedures using an autoanalyzer (Hitachi 7600-020, automatic analyzer, Japan). Serum CA19-9 level was measured using chemiluminescence method and access GI monitor kit (Siemens Immulite 2000, Siemens Healthcare Diagnostics; and Immulite 2000, Beckman Coulter, Brea, CA). Normal ranges for serum CA19-9 level were 0 to 35 U/mL, and the levels above higher range were accepted as abnormal.
All analyses were performed with Statistical Package for Social Sciences 11.0 software (SPSS, Chicago, USA). Data were expressed as mean ± SD except skewed variable which was presented as medium (interquartile range 25%–75%), and the data that were not normally distributed were logarithmically transformed before analysis. Clinical characteristics were compared among the three groups using one-way ANOVA test, and several variables without data of control group were compared with independent samples
The general characteristics and clinical parameters of the cross-sectional study are summarized in Table
Demographic and clinical characteristics of study subjects.
Variables | Control ( |
T1DM ( |
T2DM ( |
|
---|---|---|---|---|
Gender (M/F) | 64/58 | 34/37 | 507/359 | — |
Age (y) |
|
|
|
<0.001 |
Duration (y) | — | 5.00 (1.00–8.00)## | 8.00 (3.88–13.00) | 0.008 |
ALT (U/L) | 18.2 (13.00–26.75) | 17.00 (11.00–27.50) | 18.0 (13.00–29.00) | 0.722 |
AST (U/L) | 21.0 (17.00–25.00) | 18.00 (15.00–25.00) | 19.0 (15.00–24.00) | 0.332 |
TC (mmol/L) |
|
|
|
0.401 |
TG (mmol/L) | 1.20 (0.87–1.79) | 0.90 (0.71–1.33)*## | 1.52 (1.06–2.20)** | <0.001 |
HDL (mmol/L) |
|
|
|
<0.001 |
LDL (mmol/L) |
|
|
|
0.256 |
BUN (mmol/L) |
|
|
|
<0.001 |
Cr ( |
67.00 (58.00–78.00) | 65.50 (51.25–79.75) | 66.00 (54.00–80.00) | 0.855 |
FPG (mmol/L) |
|
|
|
<0.001 |
2hPG (mmol/L) |
|
|
|
<0.001 |
HbA1c (%) |
|
|
|
<0.001 |
GA (%) | — |
|
|
0.001 |
CP0 (ng/mL) | 6.84 (5.08–9.85) | 0.25 (0.05–0.80)**## | 1.62 (1.04–2.31)** | <0.001 |
CP120 (ng/mL) | 36.80 (22.44–57.97) | 0.40 (0.48–1.42)** | 3.37 (2.05–5.29)** | <0.001 |
|
28.84 (16.43–52.42) | 0.08 (0.00–0.62)**## | 1.59 (0.77–2.77)** | <0.001 |
CA19-9 (KU/L) | 4.69 (2.66–9.65) | 18.59 (11.68–39.28)**## | 12.07 (6.72–21.57)** | <0.001 |
Data represent means ± S.D. or median (interquartile range), *
ALT, aspartate aminotransferase; AST, alanine aminotransferase; BUN, blood urea nitrogen; Cr, creatinine; FPG, fasting plasma glucose; 2hPG, 2h plasma glucose; HbA1c, glycated hemoglobin A1C; GA, glycated serum albumin; TG, total triglycerides; TC, total cholesterol; HDL, high-density lipoprotein; LDL, low-density lipoprotein; CP0, C Peptide of 0 min; CP120, C Peptide of 120 min;
As is shown in Table
Basic clinical and biochemical characteristics by quartiles of CA19-9.
Variables |
CA19-9 quartile |
|
|||
---|---|---|---|---|---|
1 (Lowest) | 2 | 3 | 4 (Highest) | ||
Age (y) |
|
|
|
|
0.023 |
Duration (y) | 8.0 (3.0–12.0) | 9.0 (4.0–12.5) | 8.0 (3.0–13.0) | 8.0 (3.0–13.0) | 0.327 |
ALT (U/L) | 17.00 (13.00–26.00) | 19.00 (13.75–30.00) | 17.00 (13.00–75.00) | 19.00 (12.00–29.00) | 0.398 |
AST (U/L) | 19.00 (15.00–24.00) | 19.00 (16.00–24.75) | 18.50 (16.00–24.00) | 19.00 (16.00–25.00) | 0.508 |
TC (mmol/L) |
|
|
|
|
0.001 |
TG (mmol/L) | 1.45 (0.99–2.08) | 1.43 (1.04–2.04) | 1.47 (0.93–2.07) | 1.44 (0.97–2.21) | 0.739 |
HDL (mmol/L) |
|
|
|
|
0.167 |
LDL (mmol/L) |
|
|
|
|
0.168 |
BUN (mmol/L) |
|
|
|
|
0.056 |
Cr ( |
67.00 (57.00–78.25) | 68.00 (57.00–81.00) | 64.00 (54.00–77.00) | 63.00 (51.75–80.50) | 0.363 |
FPG (mmol/L) |
|
|
|
|
<0.001 |
2hPG (mmol/L) |
|
|
|
|
<0.001 |
HbA1c (%) |
|
|
|
|
<0.001 |
GA (%) |
|
|
|
|
<0.001 |
CP0 (ng/mL) | 2.195 (1.383–4.228) | 1.80 (1.18–2.695)* | 1.705 (1.04–2.553)** | 1.29 (0.64–2.03)**# | <0.001 |
CP120 (ng/mL) | 5.32 (2.85–15.05) | 4.21 (2.53–5.82)** | 3.27 (1.76–5.44)**# | 2.38 (1.31–4.15)**# | <0.001 |
|
2.76 (1.34–9.388) | 2.09 (0.94–3.41)** | 1.55 (0.53–2.77)**# | 1.00 (0.41–2.06)**#▲ | <0.001 |
Data represent means ± S.D. or median (interquartile range), *
In whole participants the correlation analysis (Table
Correlation analysis of serum CA19-9 with variables as follows.
Variables | Serum CA19-9 | |
---|---|---|
|
| |
Age | 0.045 | 0.142 |
Duration | 0.004 | 0.904 |
ALT | 0.029 | 0.35 |
AST | 0.038 | 0.217 |
TC | 0.129** | <0.001 |
TG | 0.048 | 0.125 |
HDL | −0.002 | 0.961 |
LDL | 0.068* | 0.028 |
BUN | 0.057 | 0.07 |
Cr | −0.064* | 0.041 |
FPG | 0.309** | <0.001 |
2hFPG | 0.284** | <0.001 |
HbA1c | 0.486** | <0.001 |
GA | 0.389** | <0.001 |
CP0 | −0.229** | <0.001 |
CP120 | −0.365** | <0.001 |
|
−0.359** | <0.001 |
*
To further determine which variables were independently associated with serum CA19-9, multiple stepwise regression analysis was performed (Table
Multiple stepwise regression analysis showing variables independently associated with serum CA19-9.
Independent variables enter the model |
|
S.E.M | Standardized |
|
|
95% CI for |
---|---|---|---|---|---|---|
HbA1c | 0.068 | 0.005 | 0.433 | 13.223 | <0.001 | 0.058 to 0.078 |
Type of diabetes | −0.139 | 0.043 | −0.099 | −3.235 | 0.001 | −0.223 to −0.055 |
TC | 0.028 | 0.009 | 0.091 | 3.02 | 0.003 | 0.010 to 0.046 |
|
−0.019 | 0.007 | −0.084 | −2.547 | 0.011 | −0.033 to −0.004 |
The parameters which significantly correlated with serum CA19-9 level showed in Table
This is the first study which demonstrated that increased serum CA19-9 level significantly correlated with serum total cholesterol and pancreatic beta cell function in diabetic patients.
CA19-9 is a tumor marker mainly used for the diagnosis of pancreatic cancer. However, it is well known that high serum CA19-9 levels can also be found in various diseases, such as nonmalignant obstructive jaundice, thyroid disease, and ovarian diseases. In limited numbers of studies with small sample sizes, patients with diabetes were shown to have increased CA19-9 levels compared with control groups [
HbA1c is a marker of chronic glucose toxicity. Significant correlation was also defined between serum CA19-9 levels and HbA1c. In a previous study [
The mechanism of increased serum CA19-9 levels in diabetic patients remains unclear. One of them is that the rise of serum CA19-9 level only reflects cellular dysfunction. The lack of insulin could result in a pancreatic exocrine deficiency and release of CA19-9 by ductal cells [
Diabetes is often accompanied by abnormal blood lipid and lipoprotein levels, but most studies on the link between dyslipidemia and diabetes have focused on TG and free fatty acids (FFAs). More recently, the accumulating data suggested that cholesterol homeostasis is a major regulator of pancreatic beta cell function [
The elevated serum CA19-9 level in diabetic patients may indicate further investigations of glycemic control, pancreatic beta cell function, and TC level. One limitation of the present study should be noted that it was a cross-sectional study. A long-term follow-up study of these subjects should be undertaken to further determine the correlation of serum CA19-9 level with pancreatic beta cell function and TC level.
The authors declare that they have no conflict of interests.
H. Yu and R. Li contributed equally to this work.
This study was supported by Grants from the National Natural Science Foundation of China (81070649) and Shanghai Municipal Hospitals’ Project of Chronic Disease Prevention and Treatment (no. SHDC12007316).