Background: In pancreatic cancer-associated diabetes mellitus (PC-DM) an altered liver and muscle glucose metabolism occurs. NO modifies glucose release by isolated hepatocytes. Our aims were to verify whether PC-DM determines in the liver: 1. an increased NO production, 2. an altered action and/or mRNA levels of the glycolytic enzyme GAPDH, which catalyzes a critical reaction in gluconeogenesis and which could be inhibited by NO. Patients and Methods: 23 patients with pancreatic cancer (PC, n 17) or chronic pancreatitis (CP; n 6) were studied. In liver tissue homogenates the following were assayed: GAPDH mRNA (quantitative RT-PCR, BioSource, USA), l-glucose, l-lactate, l-urea, l-nitrite and l-nitrate (Roche, Italy)(indirect indices of NO production), and l-GAPDH activity. Results: DM was diagnosed in 12 PC and 3 CP. No significant association was observed between DM and disease diagnosis (X2 1.75, p:ns). None of the parameters evaluated varied in relation to the presence of PC or CP. Considering patients with PC only, higher mean levels of GAPDH mRNA (t 2.15, p 0.05), l-nitrite (t 2.30, p 0.05), l-lactate (t 2.2, p 0.05), l-urea (t 2.38, p 0.05) and l-glucose (t 2.00, p 0.064) were found in patients with than in those without DM. In PC the variations of GAPDH mRNA copies were correlated with the serum levels of fasting glucose (r 0.78, p 0.001) and with l-GAPDH activity (r 0.508, p 0.05); l-nitrite levels correlated with l-glucose (r 0.594, p 0.05), l-lactate (r 0.654, p 0.01) and l-urea (r 0.758, p 0.01) levels. The variations of l-glucose were correlated with those of l-lactate (r 0.913, p 0.001) and of l-urea (r 0.559, p 0.05). Conclusion: In the liver of patients with PC-DM, NO synthesis is induced; this increased production does not inhibit, as expected, GAPDH activity nor urea production. The increased levels of liver GAPDH mRNA copies in PC-DM might be a physiological response to hyperglycemia, while the increased urea content in the same patients might be a consequence of an enhanced proteolysis which parallels glucose metabolic alterations.

Pancreatic cancer-associated diabetes is correlated with increased liver nitric oxide (NO)

BASSO, DANIELA;FOGAR, PAOLA;VALERIO, ANNA CANDIDA;ZAMBON, CARLO-FEDERICO;GRECO, ELIANA;PEDRAZZOLI, SERGIO;PLEBANI, MARIO
2002

Abstract

Background: In pancreatic cancer-associated diabetes mellitus (PC-DM) an altered liver and muscle glucose metabolism occurs. NO modifies glucose release by isolated hepatocytes. Our aims were to verify whether PC-DM determines in the liver: 1. an increased NO production, 2. an altered action and/or mRNA levels of the glycolytic enzyme GAPDH, which catalyzes a critical reaction in gluconeogenesis and which could be inhibited by NO. Patients and Methods: 23 patients with pancreatic cancer (PC, n 17) or chronic pancreatitis (CP; n 6) were studied. In liver tissue homogenates the following were assayed: GAPDH mRNA (quantitative RT-PCR, BioSource, USA), l-glucose, l-lactate, l-urea, l-nitrite and l-nitrate (Roche, Italy)(indirect indices of NO production), and l-GAPDH activity. Results: DM was diagnosed in 12 PC and 3 CP. No significant association was observed between DM and disease diagnosis (X2 1.75, p:ns). None of the parameters evaluated varied in relation to the presence of PC or CP. Considering patients with PC only, higher mean levels of GAPDH mRNA (t 2.15, p 0.05), l-nitrite (t 2.30, p 0.05), l-lactate (t 2.2, p 0.05), l-urea (t 2.38, p 0.05) and l-glucose (t 2.00, p 0.064) were found in patients with than in those without DM. In PC the variations of GAPDH mRNA copies were correlated with the serum levels of fasting glucose (r 0.78, p 0.001) and with l-GAPDH activity (r 0.508, p 0.05); l-nitrite levels correlated with l-glucose (r 0.594, p 0.05), l-lactate (r 0.654, p 0.01) and l-urea (r 0.758, p 0.01) levels. The variations of l-glucose were correlated with those of l-lactate (r 0.913, p 0.001) and of l-urea (r 0.559, p 0.05). Conclusion: In the liver of patients with PC-DM, NO synthesis is induced; this increased production does not inhibit, as expected, GAPDH activity nor urea production. The increased levels of liver GAPDH mRNA copies in PC-DM might be a physiological response to hyperglycemia, while the increased urea content in the same patients might be a consequence of an enhanced proteolysis which parallels glucose metabolic alterations.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/2526239
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