**3. Sporadic pancreatic cancer and diabetes mellitus**

The association between diabetes mellitus and pancreatic cancer has been repeatedly observed, and several case–control and cohort studies have been analyzed in meta-analyses [6]. The relationship between diabetes and SPC is reciprocal. While long-term diabetes is considered an etiologic/risk factor of SPC, new-onset diabetes may be the first manifestation of SPC [7] as recently summarized by D.K. Andersen [8].

#### **3.1. Type 2 diabetes and obesity: important risk factors**

*Long-term Type 2 diabetes* is a risk factor of SPC with a latency of more than 5 years, and an incidence that is approximately doubled [9, 10]. However, Type 2 diabetes develops from prediabetes and is frequently symptom-free for several years without clinical manifestations, which allows it to go undiagnosed. Exposure to the protumorgenic effects of Type 2 diabetes is in reality often longer than would be expected based on the time point at which the diagnosis was established. Hyperglycemia is the main factor inducing a cluster of events like higher oxidative stress, formation of advanced glycation end products, and inflammation. Such changes increase proliferation, invasiveness, and metastatic potential of pancreatic cancer [11]. Stimulation of receptors for advanced glycation end products (RAGE) promotes pancreatic cancer development, whereas their inhibition was reported to have opposite effects [12, 13]. Hyperinsulinemia exists in prediabetes and in the initial phase of Type 2 diabetes as a consequence of obesity and insulin resistance. Higher intrapancreatic insulin concentrations may stimulate proliferation of pancreatic tumor cells by activating insulin-like growth factor receptors (IGF-1R) and the downstream PI3K/Akt/mTOR signaling pathway [14].

The clinical diagnostics of SPC starts now much as it did in the middle of the past century, that is, after the appearance of local and/or systemic symptoms. They include abdominal and back pain, fatigue, loss of body weight, painless jaundice, anemia, peripheral phlebitis, and

High-resolution imaging methods (HRIMs: CT, MRI, MRCP, EUS) and histomorphology provide information suitable for diagnostics; nevertheless, their impact on patient prognosis is limited as they are typically ordered at an advanced disease stage. Radical surgery may only be suitable for 15–20% of patients. The relapses are frequent as well as early, and chemotherapy is basically palliative. This confluence of factors results in very low 5-year survival rates

We recently recommended a screening program for early SPC detection based on cooperation

Pancreatic carcinogenesis begins with the transformation of pancreatic cells and evolution of the precancerous lesions (precursors). At present, six precursors with different morphologies and malignant potential are distinguished [serous microcystic adenoma (SMA); intraductal papillary mucinous neoplasm (IPMN); intraductal tubulopapillary neoplasm (ITPN); mucinous cystic neoplasm (MCN); pancreatic intraepithelial neoplasm (PanIN); and solid pseudopapillary neoplasm (SPN)] [3, 4]. The development of SPC based on the gradual accumulation of genetic and epigenetic alterations consists of three stages: (1) time prior to the invasive lesion, (2) time to the development of the metastatic subclone, and (3) time period of metastatic dissemination that leads to patient death. The average duration of the first two time periods is estimated to be about 18 years. Early detection must be concentrated during these

The association between diabetes mellitus and pancreatic cancer has been repeatedly observed, and several case–control and cohort studies have been analyzed in meta-analyses [6]. The relationship between diabetes and SPC is reciprocal. While long-term diabetes is considered an etiologic/risk factor of SPC, new-onset diabetes may be the first manifestation of

*Long-term Type 2 diabetes* is a risk factor of SPC with a latency of more than 5 years, and an incidence that is approximately doubled [9, 10]. However, Type 2 diabetes develops from prediabetes and is frequently symptom-free for several years without clinical manifestations, which allows it to go undiagnosed. Exposure to the protumorgenic effects of Type 2

cachexia. These symptoms are nevertheless also harbingers of advanced disease.

of primary care physicians with gastroenterologists and other specialists [2].

**2. Sporadic pancreatic cancer development**

two periods, when patients are often without any symptoms [5].

**3. Sporadic pancreatic cancer and diabetes mellitus**

SPC [7] as recently summarized by D.K. Andersen [8].

**3.1. Type 2 diabetes and obesity: important risk factors**

of only 3–6% of patients [1].

54 Advances in Pancreatic Cancer

Long-term Type 2 diabetes is frequently associated with *obesity*, which by itself is another independent factor increasing the risk of pancreatic cancer development. Fat tissue as an endocrine organ produces and secretes hormones (adipokines) including leptin and adiponectin, which have been linked to cancer development. The key signaling pathway linking obesity and cancer is the PI3K/Akt/mTOR cascade which regulates cell proliferation and survival [15]. Leptin is positively correlated with adipose stores and nutritional status. It induces cancer progression by activating the PI3K, MAPK, and STAT3 signaling pathways [16]. In contrast to leptin, adiponectin is inversely associated with adiposity, hyperinsulinemia, and inflammation. It exhibits anticancer effects by decreasing insulin/insulin-like growth factor (IGF-1) and mTOR signaling via activation of 5′AMP-activated protein kinase (AMPK) and exerting anti-inflammatory actions via the inhibition of the nuclear kappa-light-chain enhancer of activated B-cells (NF-κB) [17]. Activation of NF-κB complex by stimulated RAGE is a possible mechanism through which inflammation may stimulate pancreatic cancer development [18]. In addition, obesity is frequently associated with hyperinsulinemia and may therefore through complex mechanism increase the risk of pancreatic cancer.

#### **3.2. New-onset T3c diabetes: an early symptom of sporadic pancreatic cancer**

Newly developed impairment of glucose homeostasis represented either by prediabetes (impaired fasting glucose or impaired glucose tolerance) or diabetes develops as the sole early symptom of SPC and is called pancreatogenic diabetes Type 3c (T3cDM), which appears up to 24 months (or even 36 months according to some investigators) before the clinical manifestation of SPC [19–21]. The relative probability of an already existing undiagnosed SPC is the highest in patients who were diagnosed with impairment of glucose homeostasis within the last 12 months (RR 5.4: 95% CI 3.5–8.3) [22]. A causal relationship between SPC and T3c diabetes is supported by the observation that diabetes resolves after surgical removal of the tumor in more than 50% of patients [23]. However, improvement of glucose homeostasis may be linked to the surgical procedure itself since it has also been demonstrated that subtotal pancreatoduodenectomy similarly improved diabetes in patients with or without pancreatic cancer [24].

T3c diabetes, which represents up to 8% of the total number of patients with diabetes mellitus, can occur secondary to other pancreatic disorders like chronic pancreatitis, hemochromatosis, or cystic fibrosis; however, in these cases, clinical manifestation of exocrine insufficiency usually precedes the development of pancreatic endocrine dysfunction [25]. Pancreatic cancers occur in about 9% of patients with T3cDM [26]. Therefore, one case of SPC per roughly 140 patients with new-onset diabetes can be expected. Patients with new-onset diabetes are associated with a 4- to 7-fold increase in risk of pancreatic cancer, such that 1–2% of patients with recent-onset diabetes were suggested to develop pancreatic cancer within 3 years [27].

level [38]. No changes in receptor tyrosine kinase activity, insulin-receptor substrate (IRS-1), or glucose transporter GLUT-4 were found in skeletal muscle biopsies of pancreatic cancer patients as compared to healthy controls [38]. Muscle insulin resistance was also unrelated to weight loss, plasma free fatty acids, or the energy status of cells and medium conditioned by pancreatic cancer cells did not induce insulin resistance in muscle cells in vitro [39]. Hepatic insulin resistance as determined by HOMA-IR indexes was observed in patients with pancreatic cancer [36]. Hepatic insulin resistance seems to be caused by pancreatic polypeptide deficiency and administration of pancreatic polypeptide has the potential to improve insulin sensitivity in the liver [40, 41]. In addition, adrenomedullin and tumor-derived exosomes may significantly contribute to the development of insulin resistance in SPC patients (see below).

Sporadic Pancreatic Cancer: Glucose Homeostasis and Pancreatogenic Type 3 Diabetes

http://dx.doi.org/10.5772/intechopen.75740

57

Adrenomedullin secreted by pancreatic cancer cells was found to be an important factor influencing β-cell function. It was first identified in 1993 in a pheochromocytoma as a hypotensive peptide [42]. It binds with three types of specific receptors (ADMR), which belong to the 7-transmembrane superfamily of G-protein-coupled receptors. One of them, the calcitonin receptor-like receptor (CRLR), is modulated by the receptor activity modifying protein (RAMP) [43]. Adrenomedullin is released by pancreatic cancer cells in **exosomes.** These membrane-bound vesicles contain proteins, miRNAs, and other molecules and traffic molecular cargo from the cell-of-origin to target sites in the body. After endocytosis or macro-pinocytosis of adrenomedullin-containing exosomes, adrenomedullin binds to its receptors, initiates endoplasmic reticulum (ER) stress and consequently the intracellular increase of reactive oxygen/nitrogen species (ROS/RNS) that can lead to β-cell dysfunction and death [30]. These observations provide new insights into the relationship between pancreatic cancer and newonset diabetes. The SPC-associated diabetes was therefore proposed to be an example of an

Body weight loss is another symptom frequently accompanying new-onset diabetes associated with SPC. It usually starts shortly after the onset of diabetes, precedes the development of other symptoms, and progresses up to the diagnosis of SPC. Weight loss varies extensively among individual patients with an average loss of between 4 and 5 kg. Weight loss may have a similar paraneoplastic origin as T3cDM. The adrenomedullin-containing exosomes secreted from pancreatic cancer cells interact with adipose cells and are internalized by endocytosis. Adrenomedullin via its receptors activates p38 and ERK1/2 MAPKs and promotes lipolysis through phosphorylation of hormone sensitive lipase [45]; thus, the loss of subcutaneous fat observed in SPC may be a paraneoplastic symptom mediated by exosomal adrenomedullin. Exosome induced β-cell dysfunction and lipolysis could be inhibited by adrenomedullin receptor blockade [30, 45], which underscores the role of adrenomedullin in the development of new-onset diabetes and weight loss in SPC. Nevertheless, exosomes are involved in several other aspects of cancer development including angiogenesis, stromal remodeling, chemo-resistance, and genetic intercellular exchange [46]. Cancer-derived exosomes can also enter muscle cells and inhibit insulin and PI3K/Akt signaling, leading to impaired GLUT 4 trafficking [47]. This effect leading to skeletal muscle insulin resistance may be mediated by microRNAs carried by exosomes [47]. This interaction between pancreatic cancer cells and normal cells represents another example of a "metabolic crosstalk" in

"exosomopathy," a novel exosome-based disease mechanism [44].

*4.1.1. Adrenomedullin*
