CLINICAL CASES
203
pyruvate kinase (PK; direct effect). Glycolytically derived pyruvate could
potentially undergo one of two fates in the liver, namely, full oxidation (via
Krebs cycle and oxidative phosphorylation) and/or entry into the fatty acid
synthesis pathway. However, humans on a Western diet, in which excess calo-
ries are more often a mixture of carbohydrate and fat, tend to use ingested car-
bohydrate as a fuel, while fatty acids are stored as triglyceride in adipose
tissue. The latter is driven by insulin.
When blood glucose levels begin to decline (e.g., during an overnight fast),
so too does insulin secretion. In contrast, circulating levels of glucagon
increase. The latter targets primarily hepatic glucose metabolism in humans,
increasing glucose production and decreasing glucose utilization. On binding
to its cell surface receptors, glucagon increases the activity of protein kinase
A (PKA; Figure 22-2b). In turn, PKA stimulates net glycogen breakdown
(glycogenolysis) through phosphorylation of phosphorylase kinase (increases
activity) and glycogen synthase (decreases activity). The former phosphory-
lates and activates glycogen phosphorylase. PKA further antagonizes the
effects of insulin through inactivation of PP1. PKA phosphorylates the glyco-
gen binding subunit at specific serine residues, causing the release of PP1 from
the glycogen particle. Once released, PP1 binds to inhibitor 1, further inacti-
vating PP1 activity. This PP1-inhibitor 1 association is promoted by PKA-
mediated phosphorylation of inhibitor 1. Gluconeogenesis is also stimulated
Glucagon
O -------- PKA ©
/ / \
IT
?
G ly c o g e ifô //
\
G IF
Glucose ^
Glucose
G6P
F6P
n ,6BisP
HoBisPase
PK
PEP
ruvate
Monti
Hepatocyte
Figure 22-2b. Glucagon promotion of glycogenolysis and gluconeogenesis in
the liver. Glucagon binding leads to the activation of protein kinase A, which
activates glycogen phosphorylase and fructose-1,6-bisphosphatase, while
inhibiting glycogen synthase, pyruvate kinase, and protein phosphatase 1.
Abbreviations: protein kinase A (PKA); the rest are the same as in Figure 22-2a.
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