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The Role of Insulin in the Regulation of PEPCK and Gluconeogenesis In Vivo
Intracellular G6P has three major cellular fates:
Figure 1: The Sources and Fates of G6P in the Hepatocyte
dephosphorylation by the enzyme G6Pase and export as glucose into
the systemic circulation;
Glycogen
entry into the glycolytic pathway that generates lactate, pyruvate and
CO
Glycogen Glycogen
2
(essentially the reverse of GNG flux to G6P); and
flux synthetic flux
deposition in liver glycogen (see Figure 1).
Production
(GLY/GNG)
A rise in insulin can therefore inhibit glucose output derived from
Glucose G6P
gluconeogenesis in several ways. Hyperinsulinemia can:
Uptake
suppress the activity of gluconeogenic enzymes, thereby reducing
GNG Glycolytic
GNG flux to G6P;
flux to G6P flux
promote the activity of glycolytic enzymes, thereby increasing CO
2
Pyruvate
glycolytic flux (and decreasing the net GNG flux to G6P); and/or
+
lactate
enhance the deposition of gluconeogenically derived G6P in glycogen.
GNG
In the latter two scenarios, hyperinsulinemia can reduce gluconeogenesis
precursors
without modifying the rate of GNG flux to G6P. The distinction between
gluconeogenesis and GNG flux to G6P is therefore crucial in the
There are three sources that feed into the glucose-6 phosphate (G6P) pool: glucose is taken up
from circulation (white); G6P is derived from glycogenolytic flux (red); and G6P is derived from
interpretation of insulin’s effects on the pathway. Insulin can also regulate
the gluconeogenic pathway (gluconeogenesis [GNG] flux to G6P, blue). There are a number of
hepatic gluconeogenesis indirectly by mediating events in non-hepatic
fates for G6P molecules from this pool, each of which can include G6P derived from all three
sources (depicted by a mixture of white, red, and blue): deposition into glycogen, entrance into
tissues (see Figure 2) such as fat,
15,16
muscle,
17
the pancreatic alpha cell,
18
glycolysis, and exit into circulation as glucose. Note that net hepatic glycogenolytic flux
and the brain.
7–9
represents the difference between glycogenolytic flux and glycogen synthetic flux. Net hepatic
gluconeogenic flux represents the difference between GNG flux to G6P and glycolytic flux. Net
hepatic glucose production (consisting of both gluconeogenesis and glycogenolysis) is the
Cellular Mechanisms of Insulin
difference between glucose uptake and release.
Action in the Liver
Regulation of Cyclic Adenosine
Figure 2: A Physiological Rise in Insulin Can
Suppress GNG Flux to G6P by Mediating Effects in
Monophosphate Concentration
Non-hepatic Tissues
Insulin, upon binding to its hepatic receptor, activates an intricate
signaling cascade that can regulate the enzymes related to glucose
A. Hypothalamus
uptake and release, gluconeogenesis, glycolysis, and glycogen Modify vagal drive
metabolism (see
b2up Hepatic STAT3
Figure 3). Cyclic adenosine monophosphate (cAMP) is
phosphorylation
the second messenger responsible for glucagon’s stimulatory effects on b2down GNG gene expression
glucose production
19–21
in vitro and in vivo.
22,23
Insulin opposes glucagon’s
action, in part by decreasing the concentration of hepatic cAMP,
presumably by activating a phosphodiesterase.
24
P
STAT3
Inhibition of
Glucokinase and G6Pase Expression
B. Pancreatic α-cell
gluconeogenesis
b2down Inhibit glucagon secretion
Insulin can stimulate the transcription of glucokinase
25
and inhibit the
expression of G6Pase,
26
leading to long-term changes in the levels of
b2down GNG precursors
b2down FFA oxidation
glucokinase and G6Pase protein that favor glucose uptake. The genetic
regulation of glucokinase and G6Pase can be modified rapidly in
response to insulin in the rat
5,27
and dog,
28
but it has been observed that
D. Adipose
C. Muscle b2down Glycerol release
it takes several hours for the corresponding protein levels to change in
b2down Amino acid release b2down FFA release
the dog model.
28
It is therefore clear that this genetic regulation is not
involved in the acute suppression of HGP by hyperinsulinemia, which Note that the rise in insulin at the liver is usually several-fold that of other organs.
occurs within minutes. On the other hand, the translocation of
Hyperinsulinemia results in: hypothalamic signaling that alters vagal input to the liver,
resulting in STAT3 phosphorylation and reduction of gluconeogenesis (GNG) gene expression
glucokinase from the nucleus to the cytoplasm (where it can function in (A); reduced glucagon secretion from the pancreatic α cell (B); β-protein synthesis and
glucose phosphorylaton) is stimulated within minutes by insulin
β proteolysis in muscle and reduction of amino acid (GNG substrate) release to liver (C); and
in vivo,
29
inhibition of lipolysis and reduction of release of both glycerol (GNG substrate) and free fatty
and may be involved in the rapid transition of the liver from an organ of acids (FFAs) (which stimulate gluconeogenesis and inhibit glycolysis) to the liver (D).
glucose production to one of glucose uptake.
enzyme that has long been thought of as the rate-determining enzyme
Transcriptional Regulation of PEPCK controlling GNG flux to G6P.
3,5,6,26
The genetic control of PEPCK by insulin
Insulin can also potently and rapidly (within minutes) inhibit the is complex and involves many signaling intermediates that are also
transcription of phosphoenolpyruvate carboxykinase (PEPCK), an involved in the regulation of G6Pase expression. Studies frequently use
US ENDOCRINOLOGY 35
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