**4. Pathophysiology of T3cDM associated with sporadic pancreatic cancer**

The pathophysiological relationship between T3cDM and SPC remains largely unknown. The high proportion of patients who develop T3cDM as the first clinical symptom of SPC (about 74% patients developing diabetes up to 24 months prior to SPC diagnosis) suggests that the tumor is the cause of the diabetes [28]. In addition, the prevalence of diabetes in patients with SPC is much higher (68%) compared to diabetes that develops in association with other cancers (up to 24%) [29].

#### **4.1. β-cell dysfunction and insulin resistance**

New-onset diabetes associated with SPC is a paraneoplastic phenomenon that is characterized by impaired insulin secretion and insulin resistance [30]. Impaired glucoregulation develops gradually. Approximately 15–20% SPC patients are normoglycemic with normal β-cell function but increased insulin resistance. Subjects with impaired glucose tolerance have disturbed β-cell function, but the insulin resistance is not significantly different from the preceding group. The changes in β-cells associated with SPC are initially functional as previously supposed in experimental study [31]. In contrast, morphological changes or a decrease of their counts are associated with other diseases of the exocrine pancreas, that is, chronic pancreatitis, cystic fibrosis, tropical pancreatitis, and hemochromatosis [32].

Several findings support the hypothesis that β-cell dysfunction is caused by substances overproduced by the cancer cells [21], which may impair glucose-stimulated insulin release and contribute to glucose dysregulation. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine which affects both inflammation and glucose homeostasis. Its overproduction by pancreatic cancer cells has been observed, and its effect on the inhibition of glucose-stimulated insulin release from β-cells as well as from isolated islets, through regulation of Ca2+ channels, has also been demonstrated [33]. In addition, increased serum levels of MIF have been found in new-onset diabetic patients with pancreatic cancer while no such increase has been seen in patients with pancreatic cancer without diabetes or in non-cancer new-onset Type 2 diabetic patients [33]. Cancer cells have also been shown to upregulate adrenomedullin, a potent inhibitor of insulin secretion (see below) [34, 35].

In addition to β-cell dysfunction, a significant increase in insulin resistance develops in SPC patients with diabetes [36]. Peripheral insulin resistance was confirmed by hyperinsulinemic clamps in patients with pancreatic cancer and was found to be higher in those with diabetes than in nondiabetic subjects [37]. Improved insulin sensitivity was observed after surgical removal of the pancreatic cancer [37]. Insulin resistance was found to be associated with reduced glycogen synthesis in muscles, which was also confirmed *in vitro* [37]. Impaired glycogen synthesis and glycogen storage in muscles were caused by defects at the post-receptor 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).

#### *4.1.1. Adrenomedullin*

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

The pathophysiological relationship between T3cDM and SPC remains largely unknown. The high proportion of patients who develop T3cDM as the first clinical symptom of SPC (about 74% patients developing diabetes up to 24 months prior to SPC diagnosis) suggests that the tumor is the cause of the diabetes [28]. In addition, the prevalence of diabetes in patients with SPC is much higher (68%) compared to diabetes that develops in association with other can-

New-onset diabetes associated with SPC is a paraneoplastic phenomenon that is characterized by impaired insulin secretion and insulin resistance [30]. Impaired glucoregulation develops gradually. Approximately 15–20% SPC patients are normoglycemic with normal β-cell function but increased insulin resistance. Subjects with impaired glucose tolerance have disturbed β-cell function, but the insulin resistance is not significantly different from the preceding group. The changes in β-cells associated with SPC are initially functional as previously supposed in experimental study [31]. In contrast, morphological changes or a decrease of their counts are associated with other diseases of the exocrine pancreas, that is, chronic pan-

Several findings support the hypothesis that β-cell dysfunction is caused by substances overproduced by the cancer cells [21], which may impair glucose-stimulated insulin release and contribute to glucose dysregulation. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine which affects both inflammation and glucose homeostasis. Its overproduction by pancreatic cancer cells has been observed, and its effect on the inhibition of glucose-stimulated insulin release from β-cells as well as from isolated islets, through regulation of Ca2+ channels, has also been demonstrated [33]. In addition, increased serum levels of MIF have been found in new-onset diabetic patients with pancreatic cancer while no such increase has been seen in patients with pancreatic cancer without diabetes or in non-cancer new-onset Type 2 diabetic patients [33]. Cancer cells have also been shown to upregulate

In addition to β-cell dysfunction, a significant increase in insulin resistance develops in SPC patients with diabetes [36]. Peripheral insulin resistance was confirmed by hyperinsulinemic clamps in patients with pancreatic cancer and was found to be higher in those with diabetes than in nondiabetic subjects [37]. Improved insulin sensitivity was observed after surgical removal of the pancreatic cancer [37]. Insulin resistance was found to be associated with reduced glycogen synthesis in muscles, which was also confirmed *in vitro* [37]. Impaired glycogen synthesis and glycogen storage in muscles were caused by defects at the post-receptor

creatitis, cystic fibrosis, tropical pancreatitis, and hemochromatosis [32].

adrenomedullin, a potent inhibitor of insulin secretion (see below) [34, 35].

recent-onset diabetes were suggested to develop pancreatic cancer within 3 years [27].

**4. Pathophysiology of T3cDM associated with sporadic pancreatic** 

**cancer**

cers (up to 24%) [29].

56 Advances in Pancreatic Cancer

**4.1. β-cell dysfunction and insulin resistance**

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

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 malignant tumors [47]. In additional to the peripheral insulin resistance expressed in skeletal muscles, impaired insulin action has been found in the liver where similar pathogenic mechanisms may be present [32].

The role of DPP4 and FAP alpha has been studied in the context of various malignancies, including pancreatic cancer. Expression of both proteases is increased in SPC tissues and SPC patients with recent onset diabetes or prediabetes have increased plasma DPP4 enzymatic activity [51]. Increased expression and activity of these proteases may thus lead to decreased bioavailability of their substrates and thus contribute to impaired glucose homeostasis in SPC. In summary, pancreatic cancer cells dysregulate the production of various substances with hormonal or enzymatic activities, which lead to impaired functioning of both the endocrine pancreas and other organs. New-onset T3cDM is therefore a consequence of impaired glucose

Sporadic Pancreatic Cancer: Glucose Homeostasis and Pancreatogenic Type 3 Diabetes

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

59

Early diagnosis of impaired glucose homeostasis is the first important step in the proper diagnosis of T3cDM associated with SPC. At this stage, the patient is usually without any clinical symptoms and a small decrease in body weight is frequently overlooked or considered unrelated. Determination of blood glucose every 2 years in patients over 50 years is highly recommended as a part of regular preventive examinations by general practitioners. A finding of impaired fasting glucose (IFG) or increased random blood glucose should initiate the next level of examination (i.e., oral glucose tolerance test or HbA1c), which can confirm a diagnosis

The main task for physicians is to distinguish T3c diabetes from the more common Type 2 or Type 1 diabetes, since in general practice only the latter two types are usually considered without any suspicion of T3c. Several indicators can be used for a better evaluation. Firstly, changes in body weight differ in subjects with T2DM vs. T3cDM after the appearance of diabetes. A decrease in body weight at the diagnosis of prediabetes or diabetes is significantly more frequent in patients with T3cDM than with T2DM, likely due to the tumor induced loss of subcutaneous fat tissue [45]. In SPC, the decrease in body weight usually precedes other systemic and local symptoms. T2DM frequently begins with increased body weight associated with insulin resistance and hyperinsulinemia and BMI is often higher compared to T3cDM [8]. A family history of diabetes is common in T2DM but not in T3cDM associated with SPC. The absence of markers of autoimmune disease may help exclude Type 1 diabetes. Therefore, an association of newly diagnosed prediabetes or diabetes with progressive weight loss should lead to the suspicion of T3cDM. Basic laboratory and clinical data that differenti-

The plasma pancreatic polypeptide (PP) concentration in the fasting state and after meal-stimulation may also help discriminate between T2DM and T3cDM [8, 52]. The test is based on increased PP secretion after 30 min of nutritional stimulation in healthy controls and T2DM patients (usually by more than 100% of the baseline value); this increase is missing in T3cDM patients. The discriminative value of this test was found to be higher in cancer of the pancreatic head than in the other regions of the gland [53], since PP-cells are predominantly located

homeostasis caused by the cancer cells.

**5. Diagnosis of T3cDM**

of prediabetes or diabetes.

ates T2DM and T3cDM are presented in **Table 2**.

within the head of the pancreas.

#### *4.1.2. Dipeptidyl peptidase 4 and fibroblast activation protein alpha*

The membrane-bound proteases dipeptidyl peptidase 4 (DPP4, EC 3.4.14.5, CD26) and fibroblast activation protein alpha (FAP alpha, EC 3.4.21.B28, seprase) may represent other factors contributing to impaired glucoregulation in SPC [48]. DPP4 is a membrane glycoprotein expressed on the surface of many cell types including endothelial and epithelial cells, fibroblasts, and activated lymphocytes. Its soluble form is also present in the serum and other body fluids. FAP alpha is a close structural homolog of DPP4 with 52% amino acid sequence identity. Under physiological conditions, the expression of FAP alpha is restricted to alpha cells of pancreatic islets and stromal cells in the uterus. During carcinogenesis, FAP alpha is upregulated in the stromal fibroblasts of various malignancies [49]. FAP alpha positive fibroblasts have been found in primary and secondary cancerous lesions, whereas benign epithelial lesions rarely contain FAP alpha positive stromal cells.

DPP4 and FAP alpha are multifunctional proteins that exhibit both enzyme activity dependent and enzyme activity independent biological functions. The catalytic activity of DPP4 and FAP alpha cleaves off the N-terminal dipeptide from peptides and proteins containing proline or alanine in the penultimate position. In addition, FAP alpha also possesses endopeptidase enzymatic activity, with the potential to cleave among others FGF21 [49]. A number of DPP4 and FAP alpha substrates are related to the regulation of glucose metabolism and energy homeostasis (**Table 1**). The proteolytic cleavage significantly modifies the biological activity of the targets leading to inactivation, modified receptor preference, or increased susceptibility to cleavage by other proteases [50].


GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide 1; PYY – peptide YY; NPY, neuropeptide Y; FGF21, fibroblast growth factor 21; VIP, vasoactive intestinal peptide; PACAP, pituitary adenylate cyclase-activating peptide.

**Table 1.** Biopeptides involved in glucose and energy homeostasis that are cleaved by DPP4\* and/or FAP\*\*. The role of DPP4 and FAP alpha has been studied in the context of various malignancies, including pancreatic cancer. Expression of both proteases is increased in SPC tissues and SPC patients with recent onset diabetes or prediabetes have increased plasma DPP4 enzymatic activity [51]. Increased expression and activity of these proteases may thus lead to decreased bioavailability of their substrates and thus contribute to impaired glucose homeostasis in SPC.

In summary, pancreatic cancer cells dysregulate the production of various substances with hormonal or enzymatic activities, which lead to impaired functioning of both the endocrine pancreas and other organs. New-onset T3cDM is therefore a consequence of impaired glucose homeostasis caused by the cancer cells.
