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Published online March 3, 2008
Diabetes Care 31:1105-1111, 2008
DOI: 10.2337/dc07-2015
© 2008 by the American Diabetes Association
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Clinical Care/Education/Nutrition/Psychosocial Research
Original Research

Proliferation of Colo-357 Pancreatic Carcinoma Cells and Survival of Patients With Pancreatic Carcinoma Are Not Altered by Insulin Glargine

Saskia Erbel, PHD1, Christina Reers, PHD1, Volker W. Eckstein, PHD2, Jörg Kleeff, MD3, Markus W. Büchler, MD3, Peter P. Nawroth, MD1 and Robert A. Ritzel, MD1

1 Department of Internal Medicine I, University of Heidelberg, Heidelberg, Germany
2 Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
3 Department of General Surgery, University of Heidelberg, Heidelberg, Germany

Corresponding author: Robert A. Ritzel, MD, Department of Internal Medicine I and Clinical Chemistry, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. E-mail: robert_ritzel{at}uni-heidelberg.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS
 CONCLUSIONS--
 References
 
OBJECTIVE—It was reported that the long-acting insulin analogue glargine induces cell proliferation in a human osteosarcoma cell line and therefore might induce or accelerate tumor growth. Induction of cell proliferation would be particularly relevant for insulin treatment of subjects with diabetes and the potential of bearing tumor cells (e.g., a history of a malignant disease).

RESEARCH DESIGN AND METHODS—Proliferation, apoptosis, and the expression levels of insulin receptor, IGF-I receptor, and insulin receptor substrate (IRS) 2 were analyzed in human pancreatic cancer cells (Colo-357) after incubation (72 h) with insulin glargine or regular human insulin at 0–100 nmol/l. A total of 125 subjects, after partial or total pancreatectomy due to pancreatic carcinoma, were analyzed over a median follow-up period of 22 months.

RESULTS—There was no significant difference between glargine and regular human insulin with respect to regulation of proliferation and apoptosis of Colo-357 cells. The expression levels of insulin receptor, IGF-I receptor, and IRS2 as a downstream molecule of both receptor signaling pathways were not altered at any concentration tested. The insulin receptor was downregulated to a similar degree by glargine and regular human insulin at high insulin concentrations (P < 0.0001 for glargine, P = 0.002 for regular human insulin). The median survival time after pancreatic surgery was 15 months. Survival analysis showed that the time-dependent proportion of patients who survived was identical in patients receiving insulin glargine versus insulin treatment without glargine and control subjects without diabetes after surgery (P = 0.4, three-sample comparison).

CONCLUSIONS—Regular human insulin and insulin glargine may be used to treat diabetes in patients with pancreatic cancer.

Abbreviations: IRS, insulin receptor substrate


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS--
 RESULTS
 CONCLUSIONS--
 References
 
Diabetes is a chronically progressive disease (1) characterized by insulin deficiency that often requires exogenous insulin therapy. To more closely reproduce endogenous insulin dynamics, several insulin molecules with structural modifications and either a shortened or prolonged action profile (insulin analogues) have been developed for clinical use (2). Replacement of basal insulin in patients with diabetes is usually performed with either NPH insulin or a long-acting insulin analogue like insulin glargine (3). Two modifications of the human insulin structure at the C-terminus of the β-chain and at position 21 in the {alpha}-chain lead to the prolonged action profile of insulin glargine because precipitation of the modified insulin molecule in the subcutaneous compartment delays absorption. However, structural modifications of the amino acid sequence of the human insulin molecule might also induce changes of the biological effects of insulin. Insulin is an important regulator of glucose metabolism, protein metabolism, platelet activation, and apoptosis, as well as cell growth (4–7). Insulin initiates its effects via the insulin receptor but can also cross-activate the IGF-I receptor (8). Based on in vitro studies, it has been hypothesized that insulin glargine has an enhanced affinity to the IGF-I receptor and might be mitogenic (7).

Enhanced cell proliferation due to IGF-I receptor signaling would be particularly relevant for subjects with diabetes and the potential of bearing tumor cells (e.g., with a history of a malignant disease). After partial or total pancreatectomy, patients with pancreatic cancer and diabetes often require insulin therapy. Pancreatic cancer is an aggressive disease with poor prognosis and a 5-year survival rate of <4%. When surgery is a therapeutic option, the median survival is 14–20 months and the 5-year survival increases to 20–25% (9). After total pancreatectomy, insulin therapy is mandatory, while after partial pancreatic resection, depending on different surgical techniques and function of the remnant pancreas, up to ~50% of patients require insulin therapy (10). Therefore, it is important to know whether insulin therapy in these patients requires differential considerations. We therefore posed the following questions: 1) Does insulin glargine induce cell proliferation in human pancreatic carcinoma cells? 2) Does insulin glargine affect the survival of patients after surgery for pancreatic carcinoma?


   RESEARCH DESIGN AND METHODS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
RESULTS
 CONCLUSIONS--
 References
 
Human pancreatic cancer cells (Colo-357) were incubated for 72 h in RPMI culture medium and treated with either insulin glargine (Sanofi-Aventis, Frankfurt, Germany) or regular human insulin (Novo Nordisk, Bagsværd, Denmark) at the following concentrations: 0, 0.01, 0.1, 1, 10, and 100 nmol/l. After static incubation, Colo-357 cells were either analyzed by flow cytometry or immunoblotting. Colo-357 cells were maintained in RPMI culture medium supplemented with 10% fetal bovine serum, penicillin G (100 units/ml), and streptomycin (100 µg/ml) at 37°C in humidified air containing 5% CO2. Colo-357 cells are characterized by a high expression level of insulin receptor substrate (IRS) 2, which is implicated in mitogenic signaling after activation of the insulin or IGF-I receptor. Prior reports showed that Colo-357 cells are insulin-responsive cells (11). In contrast to this and other studies, we did not use serum-free medium for preconditioning/cell cycle synchronization of the cells because serum starvation does not represent a condition that occurs physiologically to cancer cells in vivo.

To corroborate the in vitro data, 125 patients were retrospectively examined, in whom total or partial pancreatectomy had been performed due to pancreatic carcinoma. Patients were divided into three groups: 1) control group without diabetes after pancreatectomy, 2) patients with diabetes and subcutaneous insulin glargine, and 3) patients with diabetes and subcutaneous insulin without glargine. All data were updated by contacting each patient's primary care physician. Survival in the groups was compared by Kaplan-Meier survival analysis.

Flow cytometric analysis
After insulin treatment for 72 h, Colo-357 cells were harvested and washed with PBS. Cells (2.5 x 105 cells) from each sample were used for the measurement of replication (Ki-67) or apoptosis (annexin-V). For detection of replication, cells were permeabilized with a Fix&Perm Cell Permeabilization Kit (An der Grub, Kaumberg, Austria) followed by an immunofluorescent staining with an antibody to Ki-67 antigen (Ki-67 R-phycoerythrin–conjugated mouse anti-human monoclonal antibody set; BD Pharmingen, Heidelberg, Germany). Apoptotic cells were quantified using annexin-V–fluorescein isothiocyanate (Invitrogen, Karlsruhe, Germany). In addition, every sample was stained with propidium iodide (BD Pharmingen) to detect nonviable cells. Antibody labeling as well as annexin-V and propidium iodide staining were done according to the manufacturers directions. Each sample was processed using a standard FACScan flow cytometer (Becton Dickinson, San Jose, CA).

Immunoblotting
After appropriate incubations, Colo-357 cells were lysed with mammalian protein extraction reagent combined with protease and phosphatase inhibitors (Pierce, Rockford, IL). Cell lysates (30 µg) were subjected to 10% SDS-PAGE and electro-transferred to immobilon-P membranes (Millipore, Billerica, MA). Membranes were incubated with antibodies against the insulin receptor, IGF-I receptor, and pan actin as a loading control (Cell Signaling Technology, Danvers, MA) at dilutions of 1:2,000. IRS2 and phosphoinsulin receptor β-antibodies (Cell Signaling Technology) were used at a dilution of 1:1,000. Corresponding secondary horseradish-conjugated antibodies were diluted to 1:5,000. Bound antibodies were visualized using chemiluminescence (ECL Western blotting detection reagents; Amersham, Buckinghamshire, U.K.).

Statistical analysis
Changes in the mean rates of replication, apoptosis, and the expression levels of insulin receptor, IGF-I receptor, and IRS2 after each treatment were determined by the Student's t test. Changes at different concentrations of both insulin treatments were examined by ANOVA. P < 0.05 was considered to denote significant differences. Survival analysis (Kaplan-Meier) was performed as a three-sample comparison with the software Statistica (version 6.1).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS
CONCLUSIONS--
 References
 
Flow cytometric analysis
After 72 h static incubation of Colo-357 cells with either insulin glargine or regular human insulin, flow cytometric analysis was performed to determine proliferation and apoptosis (Fig. 1). Colo-357 cells are characterized by a homogenous autofluorescence, confirming that this cell type is an appropriate model for flow cytometric analysis (Fig. 1A). The fraction of propidium iodide–positive (nonviable) cells was always <5% (data not shown). Cells positive for Ki-67 or annexin-V separated clearly from the unstained cell population (Fig. 1B and C). The replication rate (percentage of Ki-67–positive cells) was 0.55–3.11%, and the number of apoptotic cells (percentage of annexin-V–positive cells) was in the range of 0.94–4.84% (data not shown). There was no concentration-dependent change in cell proliferation after incubation with human insulin or insulin glargine (P = 0.3 and P = 0.4 by ANOVA, respectively) (Fig. 1D). Furthermore, there was no significant difference in cell replication after incubation with human insulin or insulin glargine at any of the individual concentrations tested (P = NS). Similarly, there is no interaction between insulin concentrations and apoptosis for both insulins (P = 0.9 for insulin glargine, P = 0.2 for human insulin by ANOVA) (Fig. 1E), and there were no differences comparing individual concentrations (P = NS).


Figure 1
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  		Figure 1— Flow cytometric analysis of Colo-357 after 72 h incubation with insulin glargine or regular human insulin. Representative dot plots showing the size and granularity of the cells in region R1 (FSC, forward scatter; SSC, sideward scatter) (A), Ki-67–positive cells in the tagged region R2 (labeled with phycoerythrin) (B), and annexin-V–positive cells in the lower right area (labeled with fluorescein) (C). Mean numbers of Ki-67–positive cells as a marker for replication (D) and of annexin-V–positive cells as a marker for apoptosis (E) from six independent experiments of each insulin glargine and regular human insulin treatment are shown. For D and E data are means ± SE. *P < 0.05 insulin glargine vs. regular human insulin and different concentrations of each insulin versus control.

 
Immunoblotting
To demonstrate that Colo-357 cells respond to exogenous insulin, the phosphorylation level of the insulin receptor was measured by immunoblotting using a monoclonal phospho-specific antibody to the insulin receptor β-subunit. After incubation for 30 min, the phosphorylation level of the insulin receptor was increased to a similar degree with regular human insulin or insulin glargine (Fig. 2A and B). Expression levels of insulin receptor, IGF-I receptor, and IRS2 were characterized in additional experiments by immunoblotting using specific rabbit polyclonal antibodies against the β-subunit of the IGF-I receptor and total IRS2 and a monoclonal antibody against the insulin receptor β-subunit (Fig. 2C). The pattern of the expression levels of the IGF-I receptor and IRS2 were similar with both types of insulin (Fig. 2D). There were no differences of the IGF-I receptor expression across the wide spectrum of insulin concentrations. IRS2 expression was downregulated at high concentrations of regular human insulin. Increasing insulin glargine concentrations did not induce changes in the expression levels of total IRS2. Expression of the insulin receptor was downregulated at high concentrations of insulin glargine as well as regular human insulin (Fig. 2D). However, comparing both insulins, the expression levels did not show a significant difference at any of the concentrations tested.


Figure 2
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  		Figure 2— Colo-357 cells were grown for 48 h in culture medium and then incubated for 30 min with regular human insulin (RHI) or insulin glargine (G) at indicated concentrations (A and B). For long-term incubation, Colo-357 cells were incubated with either regular human insulin or insulin glargine for 72 h (C and D). After the treatment, whole-cell lysates were prepared and 30 µg total protein was immunoblotted using antibodies against the phosphorylated insulin receptor β and the total insulin receptor β as a loading control or the insulin receptor, IGF-I receptor, or IRS2 and pan actin as a loading control. Representative Western blots from two (A) or six (C) independent experiments are shown. Densitometric quantification of the data, corrected for the intensity of either the insulin receptor (B) or pan actin expression (D), is shown in the bottom panels. Data represent means ± SE. *P < 0.05; **P < 0.01; ***P < 0.001, insulin glargine vs. regular human insulin and different concentrations of each insulin versus control.

 
Survival analysis
To extend the analysis of the long-acting insulin analogue glargine into the clinical context of pancreatic cancer, we examined the survival of patients after surgery due to pancreatic carcinoma. Subjects were analyzed over a median follow-up period of 22 months after surgery (total n = 125). Strategies of insulin therapy were equally distributed among both groups with diabetic patients (Table 1). There were no differences regarding sex, age, tumor stage, and histomorphology of the tumors between the subject groups. Similarly, the surgical techniques and status of resection, which have an important impact on patients’ survival, did not differ in the three groups. The median survival time was 15 months (Fig. 3A). Survival analysis (Kaplan-Meier) showed that the time-dependent proportion of patients who survived was not altered by insulin glargine (P = 0.4, three-sample comparison) (Fig. 3B) compared with treatment with regular human insulin and subjects without diabetes after pancreatectomy.


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  		Table 1— Characteristics of patients after partial or total pancreatectomy due to pancreatic carcinoma, classified by the insulin treatment

 

Figure 3
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  		Figure 3— Survival analysis (Kaplan-Meier) of 125 patients after pancreatectomy due to pancreatic carcinoma with or without diabetes. Patients were divided into three different groups relating to the insulin treatment: 1= control group without any insulin therapy, 2 = patients who received insulin glargine, and 3 = patients who received an insulin therapy without insulin glargine. The survival time of the whole cohort is shown (A) as well as the distribution of the three different groups and their individual run of the curve (B).

 

   CONCLUSIONS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS
 CONCLUSIONS--
References
 
In the present study, we sought to investigate the influence of insulin glargine on proliferation of pancreatic cancer cells in comparison with regular human insulin and whether treatment with insulin glargine has an impact on the survival of patients with pancreatic carcinoma. These questions were addressed using a human pancreatic cancer cell line for the in vitro studies and additionally analyzing patients after pancreatectomy due to pancreatic carcinoma. Short-term incubation studies confirmed that the cells used in the present projects respond to exogenous insulin. We report that the turnover of human pancreatic cancer cells is not altered by insulin glargine. There were also no significant differences of the expression patterns of the insulin and IGF-I receptor compared with regular human insulin. Unchanged cell proliferation after prolonged incubation might be partially due to downregulation of the insulin receptor. With low (0.01–1 nmol/l) and high (10–100 nmol/l) insulin concentrations, we reproduced physiological and supraphysiological conditions. This was necessary because insulin selectively activates the insulin receptor at physiological concentrations, whereas at high concentrations it cross-activates the IGF-I receptor (8). Survival after surgery because of pancreatic carcinoma was not influenced by the type of insulin used for therapy of diabetes.

Prior receptor-binding studies using different types of insulin demonstrated that structural modifications of the insulin molecule at its C-terminus are responsible for an altered affinity to the IGF-I receptor (12). Accordingly, an about sixfold higher affinity of insulin glargine to the IGF-I receptor was observed (7). It was hypothesized that mitogenic effects of insulin are mainly mediated through IGF-I receptor stimulation at high insulin concentrations. In an experimental model, the proliferation of human osteosarcoma cells directly correlated with the increased affinity of insulin glargine to the IGF-I receptor (7). From these studies it was inferred that treatment with insulin glargine might induce cell proliferation in various tissues. However, an increased mitogenic potential has not been supported in other studies. In comparison to regular human insulin, the proliferation of insulin glargine–treated cells was not significantly different in human coronary artery endothelial and smooth muscle cells (13), skeletal muscle cells (14), rat fibroblasts (15), cardiac myoblasts, and adult rat ventricular cardiomyocytes (16). One in vivo study (17) in rats and mice reported no significant difference between insulin glargine and NPH insulin with regard to the development of mammary tumors.

In the present study, we extended the experimental evidence into the context of pancreatic cancer and report that insulin glargine does not induce proliferation of pancreatic cancer cells compared with regular human insulin. It is established that the development of pancreatic cancer is associated with diabetes. However, an exact mechanism has not been identified. On the one hand, type 2 diabetes is considered a risk factor for several types of cancer (e.g., of the pancreas [18], breast [19], endometrium [20], liver [21], bladder [22], colon, and rectum [23–25]). Therefore, it was postulated that the increased risk is mainly constituted by elevated concentrations of circulating insulin (26) compared with insulin levels in lean nondiabetic humans. On the other hand, there is also evidence from case-control studies to suggest that pancreatic cancer triggers the development of diabetes because there is a significant association between the two conditions if diabetes is diagnosed concomitantly or within 2 years before the diagnosis of cancer (27). These studies allow the conclusion that glucose metabolism might be influenced by the tumor itself or a secreted product from the tumor with effects on insulin sensitivity (28). Consistent with this hypothesis, it has been reported that insulin sensitivity may be improving after resection of pancreatic tumors (29). Pancreatic ductal adenocarcinoma, which is the most common form of pancreatic cancer in general and in our group of patients, is believed to originate from pancreatic progenitor or stem cells (30,31) and not from pancreatic β-cells (32), which are exposed to the highest local insulin concentrations. When pancreatic progenitor or stem cells can be readily identified and are available for experimental applications, it would be interesting to analyze the concentration-dependent effects of insulin in these cells with respect to tumor formation. Clinically, this would be relevant for patients with diabetes before development of pancreatic cancer. The present result that survival of patients with pancreatic carcinoma is not influenced by diabetes is consistent with other reports showing that survival in patients with pancreatic carcinoma and a palliative therapeutic concept (33) or after surgical resection is not associated with metabolic status (34). However, median survival is short in the present group of patients. Therefore, it might be interesting to perform similar analyses with patients undergoing surgery at earlier tumor stages than T3 and with longer survival.

In summary, we demonstrated that regular human insulin as well as insulin glargine did not influence proliferation and apoptosis in human pancreatic cancer cells. Moreover, therapy with both insulins was not associated with altered survival of patients after pancreatectomy due to pancreatic carcinoma. Based on these results, regular human insulin and insulin glargine may be safely used to treat patients with pancreatic cancer and diabetes.


   Acknowledgments
 
These studies were funded by the Deutsche Forschungsgemeinschaft, DFG (Ri 1055/3-1). P.P.N. and M.W.B. were supported by the Lautenschläger Foundation.


   Footnotes
 
Published ahead of print at http://care.diabetesjournals.org on 3 March 2008. DOI: 10.2337/dc07-2015.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

Received for publication October 18, 2007. Accepted for publication February 20, 2008.


   References
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS
 CONCLUSIONS--
 References
 

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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum