Glucagon/insulin ratio as a potential biomarker for pancreatic cancer in patients with new-onset diabetes mellitus

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with an overall 5-year survival rate of less than 5%. This dismal prognosis is largely due to the advanced stage of the disease at presentation, i.e., the late diagnosis. Therefore, early detection would have the potential to significantly improve the overall prognosis of PDAC patients. Diabetes mellitus (DM) has a high prevalence in PDAC patients and is frequently of new onset. The aim of this study was to analyze whether DM can be utilized as an early disease marker in PDAC. Quantitative RT-PCR analysis and immunohistochemistry for insulin and glucagon was performed in 22 PDAC and 16 normal pancreas tissues. Blood samples of 66 patients suffering from PDAC, 35 DM type 2 patients, and 29 healthy donors were analyzed for insulin, glucagon, C-peptide and glucose levels. Quantitative RT-PCR showed a two-fold increase of the glucagon/insulin ratio in pancreatic cancer tissues in comparison to the normal pancreas. By immunohistochemistry a shift in the expression pattern of glucagon and insulin, i.e., a higher glucagon/insulin ratio was found in PDAC associated islets compared to islets in the normal pancreas. Fasting insulin levels in PDAC patients were lower compared to DM patients. The calculated serum glucagon/ insulin ratio was significantly different between PDAC and DM patients. At a cut-off of 7.4 ng/mU glucagon/insulin, pancreatic cancer induced new-onset DM could be discriminated from type 2 DM with 77% sensitivity and 69% specificity. In conclusion, the suggested serum glucagon/insulin ratio showed significant differences in patients with PDAC related DM and type 2 DM. Therefore, this analysis might help to identify PDAC in patients with new-onset DM in the age group at risk. Larger clinical trials have to confirm these findings.

Identification of plasma protease derived metabolites of glucagon and their formation under typical laboratory sample handling conditions

“…Endogenous glucagon levels in healthy patients are reported between 25-80 pg/mL, which may be raised by about 10pg/mL in pancreatic cancer patients, and can reach up to 160 pg/mL in diabetic patients [1] .…”

“…It is also a biomarker for pathologies such as diabetes, pancreatic cancer or certain neuroendocrine tumours [1] .…”

“…For example, glucagon , glucagon , and glucagon [1][2][3][4][5][6][7][8][9][10][11][12][13] are formed by hepatocytes in the liver [4] [5] . Glucagon [1][2][3][4][5][6][7][8][9][10][11][12][13] and glucagon [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] , and the minor metabolites glucagon [1][2][3][4][5][6][7][8]…”

“…Glucagon [1][2][3][4][5][6][7][8][9][10][11][12][13] and glucagon [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] , and the minor metabolites glucagon [1][2][3][4][5][6][7][8][9][10] , glucagon [14][15][16][17][18][19][20][21][22][23][24][25] and glucagon [23][24]…”

“…For example, although the C-terminal region of glucagon improves receptor binding, peptides lacking this region, such as glucagon and glucagon [1][2][3][4][5][6] , are essentially fully active glucagon derivatives, but with lower potency [12] . In contrast, modifications at the amino-terminus of glucagon, including removal of the His residue, have a greater effect on receptor binding affinity and biological activity [13] .…”