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The Role of Insulin in the Regulation of PEPCK and Gluconeogenesis In Vivo
allosterically stimulates activity of the gluconeogenic enzyme pyruvate al.
15,16
brought about a small (~two-fold) selective rise in either systemic
carboxylase.
51
The liver in humans fasted for 12–14 hours or longer
52
and (with no alteration in insulin at the liver and, presumably, no alteration
in dogs fasted for 22 hours or longer
53
exhibits net lactate uptake, with in F2,6P
2
) or hepatic (with no alteration in peripheral insulin and,
lactate used primarily for gluconeogenesis. A rise in insulin markedly presumably, an increase in F2,6P
2
) insulin in the dog. Hyperinsulinemia
and rapidly (within 30 minutes) suppresses lipolysis,
54
resulting in at the liver rapidly inhibited glycogenolysis, but did not alter NHGNG
reduction of FFA supply to and FFA oxidation by the liver and the flux (the net of glycolytic flux and GNG flux to G6P). Peripheral
removal of cues (citrate, ATP, NADH, and acetyl-CoA) that, at least in hyperinsulinemia, on the other hand, brought about a decrease in HGP
vitro, stimulate the gluconeogenic pathway and inhibit glycolytic flux. that was attributed to reduced NHGNG flux. Interestingly, the time-
Thus, glycolysis is promoted (as is carbon efflux from the liver in the course of this inhibition correlated with the switch of the liver from an
form of lactate), resulting in a consequent decrease of net hepatic organ of net lactate uptake to an organ of lactate output, an increase in
lactate uptake. glycolysis, and the inhibition of lipolysis. This observation led to the
hypothesis that the fall in FFA was responsible for the decrease in
Insulin–Brain–Liver Axis NHGNG flux. In support of this concept, peripheral hyperinsulinemia did
In recent years it has been suggested that hyperinsulinemia in the brain not bring about a decrease in NHGNG flux or an alteration in net lactate
is sufficient to suppress HGP
7–9
strictly by reducing the gluconeogenic balance when the fall in circulating FFA was prevented with intravenous
rate, with no alteration in glycogenolysis or glucose utilization.
8,9
These intralipid infusion.
16
Thus, insulin-mediated suppression of NHGNG flux
observations led the authors to suggest that insulin action in the was due to the indirect effect of insulin on lipolysis and was not likely
hypothalamus alters vagal input to the liver, resulting in a hepatic event, related to changes in hepatic F2,6P
2
, although F2,6P
2
was not assayed
suggested to be STAT3 phosphorylation, that causes the reduction of in these studies.
gluconeogenic mRNA expression and suppression of gluconeogenesis.
7–9
As one would predict, this genetic regulation takes several hours to bring It must be noted that these experiments
15,16
were performed in a setting
about decreased HGP. in which the normal relationship between arterial and portal vein insulin
was disrupted. It has recently been confirmed that an eight-fold increase
Integrating Cellular Effects with Regulation of in portally administered insulin (which establishes a physiological
GNG Flux to G6P In Vivo gradient of hyperinsulinemia between the periphery and at the liver) can
While there is an abundance of in vitro data suggesting that insulin can cause a rapid increase in F2,6P
2
in concert with a profound inhibition of
regulate the gluconeogenic pathway via suppression of PEPCK gene fat oxidation by the liver.
28
Although these changes increased glycolysis,
transcription, data in whole animals are conflicting. Certain studies GNG flux to G6P was unaltered. During physiological hyperinsulinemia
suggest that GNG flux to G6P can be inhibited by insulin in rodents,
7–9
associated with refeeding in the rat, the F2,6P
2
concentration was rapidly
while other rodent studies suggest that flux through the pathway increased, yet GNG flux to G6P was not altered.
55
Conversely, insulin-
continues unaltered during hyperinsulinemia.
55–57
In humans and dogs, mediated increases in F2,6P
2
stimulated glycolysis in mice
60
and rats.
61,62
physiological hyperinsulinemia suppresses glucose output (derived from Thus, in agreement with findings, it appears that glycolysis is far more
glycogenolytic and gluconeogenic sources) by inhibiting glycogenolytic sensitive to insulin (and F2,6P
2
) in vivo than is GNG flux to G6P. While
flux, without altering GNG flux to G6P. This suggests that gluconeogenically increased F2,6P
2
and decreased fat oxidation were observed in response
derived carbon is redirected into glycogen.
1,10–14
The GNG formation of G6P to four-, eight-, and 16-fold hyperinsulinemia in the dog, only the 16-fold
has been shown to be important in post-prandial glycogen deposition in rise in insulin (which caused a ~three-fold higher elevation of F2,6P
2
than
humans, dogs, and rodents.
56–59
This is in agreement with the concept that observed in response to four- or eight-fold insulin) caused a decrease in
GNG flux to G6P is not sensitive to insulin. GNG flux to G6P.
28,54
Since fat oxidation was similarly suppressed in
response to four-, eight-, and 16-fold hyperinsulinemia, it is possible that
In the dog, two-,
13
four-,
54
and eight-fold
28
increases in insulin have 16-fold hyperinsulinemia may have elevated F2,6P
2
to a level sufficient to
substantial effects on glycogen metabolism without altering GNG flux to inhibit the gluconeogenic enzyme FBP-1 (see Figure 3), whereas four-
G6P. A recent study demonstrated that a supraphysiological dose of and eight-fold hyperinsulinemia did not.
insulin (16-fold rise) can reduce GNG flux to G6P rapidly (within 30
minutes) in the canine. This inhibition, however, was still modest relative Recent data from the authors’ laboratory have shown that the molecular
to the effect on glycogen metabolism.
54
Furthermore, while PEPCK inhibition of gluconeogenic gene expression is conserved and intact in
mRNA levels were substantially reduced after five hours, the reduction large animals, but these signaling events do not correlate to the acute
in PEPCK protein did not occur fast enough to explain the rapid regulation of GNG flux to G6P in vivo.
28,54
Furthermore, the time-course of
inhibition of GNG flux to G6P.
54
insulin-mediated events suggests that the bulk of inhibition of PEPCK
and G6Pase mRNA expression is a result of insulin’s direct effects at the
The rapid suppression of HGP (within 30 minutes) by physiological liver (mediated through FOXO1). It also suggests that the inhibiton
hyperinsulinemia in vivo is associated with reciprocal changes in GP occurs hours prior to regulation through the insulin–brain–liver axis
and GS activity that modulate glycogen metabolism and cause a (through STAT3).
28
In response to eight-fold hyperinsulinemia, GNG flux
transient increase in glycolytic flux.
28
Glycolysis is essentially the to G6P is not altered after four hours despite a ~50% reduction in PEPCK
reverse of GNG flux to G6P. Insulin can thus reduce net hepatic GNG flux protein.
28
In response to 16-fold hyperinsulinemia, GNG flux to G6P was
to G6P (NHGNG flux; see Figure 1) by either increasing hepatic F2,6P
2
or suppressed by 30 minutes, but this reduction was too rapid to be
decreasing lipolysis, both of which stimulate glycolysis. Sindelar et explained by a change in PEPCK protein.
54
Furthermore, GNG flux to G6P
US ENDOCRINOLOGY 37
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