2352.3 PST Increase Hepatic Glycogen Catabolism and Inhibits
Insulin-Stimulated Glucose Uptake
In vivo, PST seems to exert direct effects on the liver metabolism stimulating glyco-
genolysis, while the basal levels of insulin and glucagon remained unchanged. The
mechanism mediating the glycogenolytic effect of PST was studied in rat isolated
hepatocytes. The glycogenolytic effect of PST turned out to be mediated by a
cAMP-independent and Ca2+−dependent mechanism. Moreover, the glycogenolytic
effect of PST is related to the increase of cytosolic calcium concentration in a dose-
dependent manner (Sanchez et al. 1992 ).
On the other hand, insulin stimulated glycogen synthesis was also inhibited by
PST, in a similar way to the effect of glucagon, increasing the ratio of glycolysis on
insulin-stimulated hepatocytes to 25%. But unlike glucagon, PST did not affect the
basal rate of glycolysis. In addition, PST inhibits glucagon-stimulated insulin
release enhancing the net hyperglycemia. However, only high concentrations of
PST and insulin were able to induce insulin-stimulated glycolysis, which proposes
that PST could play some role in insulin resistance (Sanchez-Margalet and Goberna
1994a, b). As a result, PST causes hyperglycemia by increasing glucose release
from the liver (Sanchez et al. 1990 ).
Using CGA knockout mice, more recent animal studies have found that the lack
of CGA expression reduces hepatic gluconeogenesis, improves insulin sensitivity,
and results in low glycemia, despite of elevated plasma catecholamines and corticos-
terone levels. The mice has also hypertension, which could result from the loss of the
catestatin fragment of CGA. These results may indicate that in CGA KO mice, the
lack of PST could increase insulin sensitivity, contributing to maintain euglycemia
by relieving inhibition from IRS1/2-PI 3-kinase-Akt signaling (achieved through
suppression of cPKC and NOS activity) leading to increased suppression of hepatic
gluconeogenesis. Thus, in normal condition, PST boosts the gluconeogenesis,
through the inhibition of insulin signaling (Gayen et al. 2009 ; Valicherla et al. 2013 ).
Taken together, these findings indicate that PST could be an important modulator
of hepatic glucose metabolism, an effect that may be mediated by an inhibitory
cross-talk with insulin signaling pathway.
2.4 In Adipocyte, PST Enhances Energy Metabolism
and Stimulates Protein Synthesis
In adipocytes PST has a similar role than in hepatocytes, exhibiting an increment of
the energy expenditure and anti-insulin properties. In isolated white adipocytes we
found a dose-dependent inhibition of both basal and insulin-stimulated glycogen
synthesis, lactate production and glucose transport (Sanchez-Margalet and
Gonzalez-Yanes 1998 ).
Action and Mechanisms of Action of the Chromogranin A Derived Peptide Pancreastatin