Introduction
The incidence of pancreatitis and pancreatic cancer is increased with obesity [
1,
2]. Although the mechanism underlying this association is unknown, as the incidence of several other malignancies is increased with obesity [
3], it has been considered to be a possible consequence of chronic inflammation. We reported increased pancreatic duct cell replication in Sprague–Dawley human islet amyloid polypeptide transgenic (HIP) rats fed a high-fat diet [
4]. HIP rats are a model of type 2 diabetes [
5,
6]. In common with type 2 diabetes, the HIP rat develops diabetes because of impaired beta cell function and loss of beta cell mass through endoplasmic-reticulum-stress-induced apoptosis.
We also noted that pancreatic duct cell replication in the high-fat-fed HIP rat increased as a function of blood glucose. While pancreatitis and pancreatic cancer can cause diabetes, there is some evidence to suggest that the converse may be true [
1,
2]. A possible underlying mechanism to account for an increased risk of pancreatic cancer in people with obesity and/or diabetes is chronically increased pancreatic duct cell replication. Increased pancreatic duct cell replication is a characteristic of both pancreatitis and pancreatic cancer [
7‐
9].
We sought to address the following hypotheses. First, that pancreatic duct cell replication is increased in obese vs lean humans. Second, that pancreatic duct cell replication is increased in humans with type 2 diabetes compared with non-diabetic individuals. To address these hypotheses we examined the frequency of pancreatic duct cell replication in pancreas obtained at autopsy from lean and obese humans with or without type 2 diabetes. In addition we studied pancreas obtained at surgery from nine individuals who underwent pancreatic surgery for resection of pancreatic ductal adenocarcinoma (eight cases) and an intraductal papillary mucinous neoplasm (one case). The surgical tissue studied from each case was not from the tumour itself but from adjacent pancreas. In seven cases the pancreas was negative for tumour but did show signs of chronic pancreatitis. In two cases there was invasive adenocarcinoma in the sample.
Discussion
We report that pancreatic duct cell replication is increased in obese humans. Moreover, we report that type 2 diabetes is associated with an increase in duct cell replication that is more obvious in lean than in obese individuals.
Although obesity is recognised as a risk factor for pancreatitis and pancreatic cancer, the mechanisms remain elusive [
1]. To our knowledge, this is the first report documenting increased pancreatic duct cell replication in obese and type 2 diabetes patients who do not have histological evidence of pancreatitis. Increased pancreatic duct cell replication is considered a risk factor for pancreatitis and pancreatic cancer [
7‐
9,
11,
12]. We affirm that exocrine ductal replication is increased in pancreas obtained from individuals with pancreatitis associated with pancreatic cancer, and to an even greater extent in malignantly transformed ductal cells (Fig.
2). A limitation of the present study is that pancreas samples from the pancreatic cancer cases were obtained surgically while samples obtained from the other groups were removed at autopsy. To the extent that sensitivity for detection of Ki67 differs between pancreas obtained at surgery vs autopsy, this comparison might be flawed. To limit any effect, pancreas with autolysis was excluded from both groups.
While the current data provide a potential explanation for the increased risk of pancreatitis and pancreatic cancer in obesity and type 2 diabetes, respectively, an obvious limitation of an autopsy study is that it cannot reveal the molecular mechanisms to explain why ductal replication is increased in obesity and type 2 diabetes. Little is known about the regulation of pancreatic duct cell replication. Candidates that might regulate pancreatic duct cell replication include hormones secreted by the gastrointestinal neuroendocrine system in response to food intake, including incretin hormones such as glucagon-like peptide 1 (GLP-1) [
13]. While controversial, it has been proposed that exocrine ducts house progenitor cells that are capable of transdifferentiation into endocrine cells to form new islets (so called islet neogenesis) [
14]. It is conceivable that obesity and type 2 diabetes promote increased formation of cells from pancreatic progenitors. Treatment of rodents with GLP-1 mimetics or dipeptidyl peptidase-IV inhibitors results in increased islet cell clusters in relation to pancreatic ducts, which is often interpreted as evidence of neogenesis [
14].
We observed an increase in pancreatic duct cell replication in the high-fat-fed HIP rat model of type 2 diabetes compared with non-diabetic wild-type rats, and duct cell replication was further increased with treatment with the dipeptidyl peptidase-IV inhibitor sitagliptin [
4]. Of concern, we also noted ductal metaplasia in three HIP rats treated with sitagliptin, and pancreatitis in one. These findings led us to suggest that the possible link between GLP-1-based therapy and pancreatitis might be an unintended action of GLP-1 to promote pancreatic duct cell replication. GLP-1 receptors are present in pancreatic ducts [
4].
In the present study we had no pancreas available to us from humans treated with GLP-1 mimetics or dipeptidyl peptidase-IV inhibitors as these have become available only relatively recently. In the future, it will be important to carefully evaluate the effects of this class of drugs on the exocrine pancreas in humans. In the present study, the individuals with type 2 diabetes had been treated with diet, sulfonylurea or insulin therapy. There was no discernible difference in duct cell replication between these treatments.
In summary, we report that both obesity and type 2 diabetes are associated with increased pancreatic duct cell replication in humans. These data are consistent with the hypothesis that the increased risk of pancreatitis and pancreatic cancer in obesity and type 2 diabetes is driven by chronically increased pancreatic duct cell replication. It will be of interest to establish the signals that foster increased pancreatic duct cell replication in humans. In addition, the present data lend caution to the use of therapeutic strategies that act to increase pancreatic duct cell replication. In HIP rats, GLP-1-based therapy appears to provoke increased pancreatic duct cell replication.
Acknowledgements
This study was supported by funding from the NIH (DK059579, DK077967) and the Larry L. Hillblom Foundation. We are grateful to our colleagues A. Bhushan and S. Georgia in the Larry Hillblom Islet Research Center for their excellent suggestions. We acknowledge B. Lui for excellent administrative assistance.