**5. Diagnosis of T3cDM**

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

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

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

**Biopeptide Main physiological functions References** GIP\* Stimulation of insulin and glucagon secretion [78]

> Regulation of food intake, adipogenesis, energy homeostasis, glucose-stimulated insulin secretion, lipolysis and blood pressure. Involved in stress reaction and

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

Glucagon\* Increase of glycemia and ketogenesis [79, 82, 83] FGF21\*,\*\* Stimulation of glucose uptake in adipocytes, increase of energy expenditure [84–86]

, PACAP\* Regulation of insulin and glucagon secretion, regulation of body weight, energy and lipid metabolism. Gastrointestinal motility. Immunomodulation

**Table 1.** Biopeptides involved in glucose and energy homeostasis that are cleaved by DPP4\*

[78]

[78–81]

[87, 88]

and/or FAP\*\*.

GLP-1\* Stimulation of glucose-stimulated insulin secretion, inhibition of glucagon

mechanisms may be present [32].

58 Advances in Pancreatic Cancer

to cleavage by other proteases [50].

secretion

pain perception

PYY\*,\*\* NPY\*,\*\*

VIP\*

peptide.

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

epithelial lesions rarely contain FAP alpha positive stromal cells.

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 of prediabetes or diabetes.

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

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 within the head of the pancreas.


stage IA/IB/IIA from healthy controls [59]. This panel had the predictive power to detect early-stage pancreatic cancer and may have clinical utility for early detection of surgically resectable pancreatic ductal adenocarcinoma. In another study, a surface enhanced Raman spectroscopy (SERS) based immunoassay of CA 19–9 in combination with matrix metalloproteinase (MMP7) and mucin (MUC4) in serum had significantly enhanced sensitivity and

Sporadic Pancreatic Cancer: Glucose Homeostasis and Pancreatogenic Type 3 Diabetes

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

61

**MicroRNAs**, small non-coding molecules circulating in blood, have been tested in patients with pancreatic cancer and healthy controls. They play roles in regulation of cell physiology, tumorigenesis, apoptosis, proliferation, invasion, metastasis, and chemoresistance. Many miRNAs found in serum have been suggested as reliable biomarkers of early SPC detection [61]. Combining several miRNAs with CA19–9 in a composite panel could improve diagnosis compared to a single biomarker. This was documented with six miRNAs (including miR-20a, miR-21, miR-25, miR-155, miR-196a, and miR-210), and CA19–9 [62]. The panels had a high specificity for pancreatic cancer compared to other gastrointestinal cancers and they showed better sensitivity and specificity than CA19–9 alone. A panel of miRNAs could be used to differentiate patients with new-onset diabetes with SPC, healthy controls, and new-onset Type 2 diabetes without SPC [63, 64]. MiRNAs were also analyzed using weighted gene co-expression network analysis (WGCNA). This method better discriminates between healthy and cancer patients and demonstrates that miRNAs can serve as prognostic biomarkers [65]. On the other hand, a set of 15 selected miRNAs was able to discriminate SPC patients from controls at the time of diagnosis but could not be used in earlier stages because their alterations only

Another area of investigation provides new data from **metabolomic** studies that are based on metabolic differences between new-onset diabetes with and without pancreatic cancer as well as in comparison with Type 2 diabetes [67]. Sixty-two metabolites, from several hundred, were analyzed using liquid chromatography/mass spectrometry. The results were able to discriminate between the three abovementioned groups, although the procedure is not yet suitable for routine use. In another study, using a metabolomic profile of 206 metabolites, most significant changes were found in oleanolic acid, palmitic acid, taurochenodeoxycholate, and d-sphingosine, discriminating between healthy controls and pancreatic cancer patients [68]. T3cDM caused by pancreatic cancer is characterized by **abnormal concentrations of several hormones** which participate in glucose homeostasis. In cases where basal plasma concentrations of the hormone are within normal limits, the impairment may be disclosed after mixed-nutrient stimulation [52]. The determination of insulin, pancreatic polypeptide (PP), or glucose-dependent insulinotropic peptide (GIP) during the "meal test" may confirm their

**Exosomes** bring new possibilities to the detection of SPC [69]. The proteins, miRNAs, and mRNAs transferred by these vesicles originating in cancer cells can be used as biomarkers. Several body fluids like serum, urine, and saliva were demonstrated to contain pancreatic cancer-derived exosomes [70]. Exosomes may improve early diagnosis of pancreatic cancer in stage I and IIA when the tumor is still localized [71]. Two miRNAs, miR-196a and miR-1246, were found to be highly enriched in pancreatic cancer exosomes and elevated in plasma exosomes of patients with localized pancreatic cancer. Exosomes can be examined

decreased levels, which would demonstrate their altered dynamics [19].

could be a promising tool for liquid biopsy diagnostics [60].

appeared in the later stages of the disease [66].

**Table 2.** Clinical and laboratory characteristics differentiating new-onset Type 2 from Type 3c diabetes associated with SPC.
