Langenbecks Arch Surg (2005) 390:66–72 DOI 10.1007/s00423-004-0469-8
M. Yalniz P. M. Pour
Received: 22 January 2004 Accepted: 22 January 2004 Published online: 9 April 2004 Springer-Verlag 2004
M. Yalniz is the recipient of a fellowship from the Turkish Gastroenterology Foundation M. Yalniz · P. M. Pour ()) UNMC Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA e-mail:
[email protected] Tel.: +1-402-5594495
NEW SURGICAL HORIZONS
Diabetes mellitus: a risk factor for pancreatic cancer?
Abstract The relationship between pancreatic cancer (PC) and diabetes is controversial. While some investigators assume that type II diabetes is a predisposition to PC, recent data argue that diabetes and altered glucose metabolism are a consequence of PC, and yet, the clinical presentation of the altered glucose metabolism in these patients varies considerably. Around 70% of patients with PC have impaired glucose tolerance (IGT) or frank diabetes. Of these, nearly 60% show an improvement of IGT or diabetes after surgery, whereas the rest show only mild or no improvement. It appears that biologically there are three types of PC: (1) PC not associated with IGT or diabetes; (2) PC associated with IGT or diabetes in which the abnormality improves postoperatively; (3) PC
Introduction Despite progress in the clinical and biological aspects of pancreatic cancer (PC), the disease has remained lethal [1]. Its 5-year survival rate is still below 5% [2]. Early diagnostic efforts have failed and the standard and modern therapeutic approaches have become disappointing. The only effective therapy, surgery, is still limited to about 25% of the patients and, even in these patients, cancer recurrence has remained unavoidable [2]. These problems are based on our inability to understand the natural course and biology of the disease. Epidemiological studies have not shed light on the etiology of PC and the reported data have remained unsettled. The link between PC and smoking, although
associated with IGT or diabetes in which the abnormality does not improve postoperatively. Based on our own studies, we suggest that the reason for impaired glucose metabolism in most patients is the alteration of islet cells either by the carcinogen directly, or by diabetogenic substances released by cancer cells. The extent of the islet alteration (i.e. focal or diffuse) may determine whether the removal of tumor alone can improve the metabolic alteration. The elucidation of the mechanism is of immense importance for providing an early tumor marker and for developing preventative or therapeutic modalities. Keywords Pancreatic · Cancer · Glucose metabolism · Diabetes · Islet cell · Surgery
confirmed by most studies, is weakened by the recent findings that tobacco seems to promote rather than initiate pancreatic carcinogenesis. The controversy on the relationship between diabetes and PC still exists. Although a link between PC and diabetes was recognized in 1833 [3], it is yet unclear whether diabetes is the cause or the consequence of PC.
Diabetes as a risk factor for pancreatic cancer One school of thought considers diabetes to be a predisposing factor for PC. In many retrospective case–control and prospective cohort studies, an association between longstanding diabetes and an increased rate of subsequent
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death from PC was indicated [4, 5, 6, 7]. In recent studies, however, when the latency period between the onset of diabetes and PC was considered, the issue became muddled. In some studies, when the patients with short latency periods were excluded from the sample size, the relative risk of diabetes for PC was markedly diminished [8, 9]. In another population-based case–control study, a significant positive trend in risk for PC was detected (p=0.016) in patients with diabetes diagnosed 10 or more years prior to cancer detection [10]. The meta-analysis of more than 20 epidemiologic studies indicated the relative risk of PC for diabetics diagnosed at least 5 years prior to the diagnosis of cancer to be 2.0 [11]. In two prospective cohort studies with more than 20 years’ follow-up, an increased risk was found among subjects with high post-load plasma glucose levels [12, 13]. In the latter study, the risk was 2.2-fold higher for participants whose post-load glucose level was at least 200 mg/dl at baseline than for those with the levels equal or less than 119 mg/dl. These studies evidently show that glucose intolerance may precede the onset of PC rather than just be a consequence. In a recent study the increased risk for PC in longstanding diabetes was investigated with regard to treatment administered to patients. It was found that the increased risk for PC persisted only for patients treated with insulin [14]. The mechanism responsible for this was not elucidated. The exact risk of PC in longstanding diabetic patients may be underestimated due to the death of diabetic patients without a PC diagnosis. The mechanism of the association between diabetes and PC is elusive and includes metabolic, hormonal, and immunologic alterations, which may influence PC growth. Insulin has been shown to have a direct, dosedependent, growth-promoting effect on PC cell lines in vitro [15]. Hence, the hyperinsulinemic state and alterations in islets during type II diabetes can expose the exocrine cells to unusually high concentrations of insulin and trigger neoplastic growth. Ishikawa et al. reported that cells in the main pancreatic duct are vulnerable to hyperplastic and neoplastic changes in patients with a history of diabetes of more than 2 years [16]. Experimentally, induction of peripheral insulin resistance has promoted pancreatic carcinogenesis [17, 18]. Alterations during the hyperinsulinemic state, as described above, may make the diabetic pancreas more susceptible to the hormonal changes associated with diabetes as well as carcinogenesis, and may play a role in the induction or promotion of PC [19]. The onset of both diabetes and PC is insidious. Noninsulin-dependent diabetes mellitus may take more than 7 years before it is clinically diagnosed [20]. The latency of PC is also unclear, and the development of some cancers seems to take as long as 10 years [21]. Diabetes or PC may proceed for many years without diagnosis. For these reasons, estimation of the exact duration needed to con-
clude that the diabetes occurred before the development of PC, is difficult. Over the course of time, chronic complications such as angiopathies may develop in diabetic patients. The existence of these complications could be used as accurate evidence for longstanding disease, because the development of these complications takes a long time. In the literature, diabetic angiopathies were examined in only one study [22] and were not found in patients with PC. The authors suggested that the duration of diabetes is too short for marked diabetic angiopathies to develop and that the survival period in patients with invasive ductal PC with diabetes is short compared with patients without diabetes. Also, PC and other complications may develop from different pathophysiologic pathways. In fact, other complications of diabetes might be expected in longstanding diabetic patients with PC and could be investigated properly in the relevant studies. In our own experience, pancreatic islet cell alterations, characteristic for diabetes, were never observed in a series of over 100 PC patients with diabetes. It must be emphasized that the possible link between diabetes and PC exists only for type II diabetes mellitus. There are no reports on the association between PC and type I diabetes. Whetherthis lack of association is due to the short survival of patients with type I diabetes remains unanswered. Nevertheless, the notion that diabetes is a predisposing factor for PC remains questionable. The establishment of a potential causal association between hyperglycemia and PC could help with prevention studies of this dismal malignancy.
Diabetes as a symptom of PC Nearly 80% of PC patients have impaired glucose metabolism, either frank diabetes or impaired glucose tolerance (IGT) [23, 24], and the majority of diabetes associated with PC is diagnosed either concomitantly or during the 2 years before the diagnosis of PC [8]. Karmody and Kyle reported that PC was diagnosed within 1 year from the onset of the diabetes in 40 out of 51 patients (78.4%) [25]. According to Gullo et al. [9], diabetes in patients with PC is frequently (56.1%) of the recent onset type and is presumably caused by the tumor. In this study, in 43.9% of the patients, the diagnosis of diabetes preceded the diagnosis of PC by 3 years and in 37.2% it was 5 years or more. In a more recent study, the diagnosis of PC and diabetes was made concomitantly or shortly before the tumor diagnosis in 65% of the patients [26]. Presently, a number of investigators consider diabetes to be a clinical manifestation of PC rather than a risk factor for the disease.
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Primary alterations of islet cells in PC patients is the foundation for altered glucose metabolism Based on the published data and our experience, glucose intolerance is a PC-associated symptom and is the result of the primary alteration of islet cell function and differentiation in response to causative carcinogens. Experimentally, the development of glucose intolerance and peripheral insulin resistance coincides with the appearance of microscopic pancreatic tumors [27, 28] and changes occurring in islet hormones, at this stage, of carcinogenesis in PC patients [23, 29]. Also IGT or diabetes has been noticed in small, localized and early PC in humans [30, 31]. In Japanese patients, IGT was the only clinical abnormality in small (<2 cm) PC cases [30]. When we studied the pattern of islet cells in PC specimens, we found that 10 out of 14 cancer specimens showed a significant loss of b-cells in the islet [32]. Of the ten cases, IGT was known in four cases but no information was available about the glucose metabolism in the rest. The occurrence of islet cell alterations in 72% of the cases correlates with the frequency of abnormal glucose metabolism in PC patients. Notably, most altered islet cells were in the vicinity of the cancer. In only one case was the abnormality also found in an area remote from the cancer. Since tumor-free pancreatic tissues were available in only five cases, the frequency of islet-cell alteration in the teletumoral area could not be determined. Another noteworthy finding associated with this abnormality was the sign of altered islet-cell differentiation, including the formation of intra-insular ductular structures and the expression of tumor-associated antigens (CA19–9, TAG-72, and/or DU-PAN-2) in islet cells and in intrainsular ductular cells [33, 34] (Fig. 1). This finding indicates that islet cells have the ability to form an abnormal cell population in these patients. The potential of islet cells to transdifferentiate into a variety of pancreatic and extrapancreatic cells, including hepatocytes, has been well documented [34, 35, 36, 37, 38, 39, 40]. In culture, both human and hamster islet cells gradually lose the endocrine markers and assume markers for ductal, acinar and intermediary cells and express tumor-associated antigens CA19–9, TAG-72, and DU-PAN-2, as well as nestin, a suggested marker for stem cells [34, 35, 41, 42]. As in the hamster model, intrainsular ductular structures could be found in PC patients, close to or remote from cancer. There is a school of thought, however, that islet-cell abnormalities and the altered glucose metabolism are caused by substances released from the cancer cells. It has been proposed that amylin, a peptide with a molecular weight of 2030, or other yet unknown substances released from cancer cells are responsible for the development of IGT [43, 44, 45, 46, 47]. Because we believe that most cancers arise from altered islet cells, the
Fig. 1a–c Alterations of islet cells in pancreatic cancer patients. a Expression of tumor-associated antigens CA19-9 (blue) and TAG-72 (red) in an islet. Note that in some cells both antigens are expressed (arrows). b CA19-9 expression in an islet of normal size (left), in an atrophic islet (middle) and in cancer cells (right). c Expression of DU-PAN-2 antigen in many islet cells and in intrainsular ductular cells. In experimental studies, most cancers develop from similar intra-insular ductules. Multilabeling immunohistochemistry using ABC method: a, c120: b 75
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production of these substances from cancer cells is selfexplanatory. Cancer cells are known to inherit some of the biological properties of the cells from which they are derived. Indeed, several studies show the expression of neuroendocrine markers in PC cells [48, 49, 50]. From the pathophysiological point of view, the production of diabetogenic material from islet cells appears more plausible, as it is well known that islet cells have the potential to produce many different pancreatic and extrapancreatic peptides simultaneously. They also have the ability to shift the synthesis of one hormone to another [51, 52, 53, 54, 55, 56]. A good example is the co-production and corelease of insulin and amylin, the synchrony of which is altered in PC [45, 51]. The improvement of IGT and diabetes after tumor resection by a 70% pancreatectomy or curative resection [43, 44, 45, 57, 58] by no means indicates that the tumor produced the diabetogenic substances, because, together with the cancer tissue, the altered islet cells that, in reality, may produce the diabetogenic material are also removed. Moreover, we must be aware that nearly all well-differentiated PC contain endocrine cells [49, 50], sometimes in remarkably high numbers, which could also be the source of altered hormone production and are also removed with the cancer. For example, although the extracts of tumors from diabetic patients with PC showed a marked reduction of glycogen synthesis in skeletal muscles, examination of the tumor revealed that the tumor tissue contained islet hormones [44]. Although, from a clinical standpoint, the issue of whether the diabetogenic material is produced by cancer cells or altered islet cells is trivial, the elucidation of the mechanism is crucial to understanding the biology of the disease and in planning future diagnostic and therapeutic modalities. As discussed, islet cells and peripheral insulin resistance are emphasized as the most probable responsible factors for the development of abnormal glucose metabolism in PC, whether it is the result or the cause of the disease. Insulin resistance is also found in non-diabetic or glucose intolerant PC patients, though to a lesser degree [44]. Studies concerned with the mechanism of insulin resistance in PC patients have shown that the insulin signaling cascade in skeletal muscle is impaired at multiple steps [44, 59, 60, 61]. Recent studies, however, point to a complicated path of peripheral insulin resistance. Although earlier reports implicated skeletal muscle as the major site of insulin resistance [62], adipose tissue is now recognized by many as the primary site [63]. Recent studies have disclosed that the adipose tissue is not merely a fat-storing tissue but also an endocrine organ that produces various cytokines, e.g., TNF-a, releases leptin, and modulates glucose and fatty acid metabolism and insulin sensitivity in various stromal and epithelial cells [64, 65, 66].
Fig. 2 Three subsets of PC patients (IGT impaired glucose tolerance, IGT PC patients without IGT or diabetes, IGT+ PC patients with IGT or diabetes, IGT+/ PC patients whose glucose intolerance or diabetes improves postoperatively, IGT+/+ patients in whom the abnormality improves only slightly or not at all after the tumor resection)
Differences in the clinical presentation of PC with regard to altered glucose abnormalities One of the most striking findings is that only 60–70% of PC patients develop IGT or diabetes (Fig. 2) [23, 30, 43, 44, 56, 57, 58, 67, 68, 69, 70, 71, 72]. Although IGT improves in many patients after surgery [43, 45, 57], in some it either does not improve [44, 45, 57, 58] or it worsens [57]. There are conflicting reports and inadequate information on the incidence of peripheral insulin resistance, IGT and diabetes before and after surgery. According to Fogar et al. [57], 59% of PC patients with either diabetes (45%) or IGT (14%) show improvement after curative surgery. On the other hand, studies by Permert et al. [43], using a hyperglycemic clamp method, show the normalization of IGT and improvement of diabetes in around 60% of the patients. Consequently, it can be assumed that 10–40% of PC patients either do not show any improvement of the abnormality after surgery or their IGT becomes worse [57]. It is unclear whether the observed improvement is just a temporary situation or whether the abnormality reappears at the time of tumor recurrence. Although many factors could be responsible for the lack of the postoperative improvement of glucose metabolism in the subset of patients, it is highly possible that either the altered islet cells producing the diabetogenic substances exist in the teletumoral area not removed by surgery, or some hidden (metastatic) tumors are left behind, for example in the liver [73].
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Since the glucose homeostasis increasingly worsened in patients who did not have curative surgery [57], in a follow-up study the extent of the tumor and/or altered islets seems to be responsible for the glucose metabolism. There are, as yet, no studies examining the extent of islet cell alteration within, around, and remote from cancer. Also there are limited follow-up studies of the patients after surgery. It is puzzling that around 20–30% of PC patients do not develop a glucose metabolic abnormality. Is this related to the different biology of cancer as has been suggested previously, where a correlation was found between the degree of IGT severity and the histological type of cancer [16]? Is this because tumors develop from islets in patients with IGT or diabetes and, in a minority of the patients, from other cells? Or could this be related to the severity and extent of islet-cell damage? Nevertheless, the data suggest that, with regard to the glucose metabolic alteration, there are at least three subsets of PC patients, possibly with tumors of different biology. The published data and our own experience suggests the following subsets: (1) PC patients without IGT or diabetes (IGT; ~20–30%); (2) PC patients with IGT or diabetes (IGT+; ~70–80%), whose glucose intolerance or diabetes improves postoperatively (IGT+/); (3) patients in whom the abnormality does not improve or improves only slightly (IGT+/+) after the tumor resection. Early detection and prevention, in established tumors, needs to be emphasized. Despite advances in diagnostic imaging, most pancreatic cancers continue to be recognized at a late stage [74, 75]. The onset of diabetes could be a manifestation of occult PC and recently developed glucose intolerance, or diabetes may be an early sign of PC. Identifying this group would permit early detection and a potential cure. Karmody and Kyle considered unstable hyperglycemia and glucosuria “a valuable early warning sign” of carcinoma of the pancreas, because only 3 out of 51 patients had developed any other symptoms of PC before their diabetes in their study [25]. In some
studies, atypical diabetes is depicted as diabetes in a patient with an onset after age 55 years, without obesity, no family history and deterioration of diabetes or loss of body weight despite strict medical control [76, 77]. Efficient criteria for selecting the group at high risk of PC development among patients with diabetes mellitus have not yet been established. In a recent study performed in patients with diabetes, early diagnosis of PC in high-risk groups was investigated [77]. Although a high diagnostic rate of PC was found in patients within 3 years after the onset of diabetes, the selection of diabetic patients with high risk did not lead to the early diagnosis of PC. The criteria for the selection of diabetic patients at high-risk of PC development in early phases of the disease must be improved. Diabetic patients with PC tend to present a more advanced stage of the disease and a shorter survival than their non-diabetic counterparts [78]. In another confirmative study, the survival period was found to be significantly lower in PC patients with diabetes than in those without diabetes [22]. On the contrary, TalarWojnarowski et al. [79] could not find any significant impact of diabetes as a presenting symptom on the survival of patients with PC. In summary, the overwhelming data suggest that diabetes is a consequence of PC. A correlation between the duration of diabetes and the occurrence of diabetes cannot be made without the knowledge of the latency of tumors, which may take over 10 years to become noticeable. Since type II diabetes usually starts with peripheral insulin resistance, most probably associated with the compensatory islet cell proliferation, the predisposition of islet cells to malignancy at this stage cannot be ruled out entirely. Acknowledgements This work was supported by the National Cancer Institute Grant, 5ROICA60479 and SPORE Grant P50CA72712, the National Cancer Institute Laboratory Cancer Research Center Support Grant CA367127, and the American Cancer Special Institutional Grant.
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