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Diabetes Pathophysiology
Figure 4: Nuclear Magnetic Resonance Analysis of Flux
this pathway in regulating HGP is debatable. In a study by Edgerton et
Through the Gluconeogenic Pathway in Perfused Livers
al.,
14
dogs were subjected to a pancreatic clamp with portal replacement
Isolated from Transgenic Mice with Varying Amounts of
of basal levels of insulin and glucagon and maintenance of euglycemia.
PEPCK Protein Content
Insulin infusion was then switched to a peripheral vessel (resulting in
systemic hyperinsulinemia, but also hepatic hypoinsulinemia). This
0.7
lox/lox
resulted in the elevation of HGP (via increased glycogenolysis) and
pck
0.6
marked hyperglycemia. Thus, hyperinsulinemia at the brain (and all
del/w
pck
tissues supplied with arterial blood) could not appropriately inhibit HGP
0.5
lox/neo
pck
when insulin levels at the liver were deficient. This clearly illustrates that
0.4
lox + neo/del the liver’s direct effect is dominant in reducing HGP.
pck
0.3
Metabolic control coefficient = 0.18
Re-evaluating the Dogma—
0.2
Does PEPCK Control GNG Flux to G6P?
PEPCK flux (µmol/min/gww)
0.1
The notion that PEPCK is the chief rate-limiting enzyme in the
lox/lox + AlbCre
pck
gluconeogenic pathway is based largely on several early in vitro and in
0.0
0.0 0.2 0.4 0.6 0.8 1.0
vivo studies in rats. The compound 3-mercapopicolinate (3-MP) inhibited
Fraction of hepatic PEPCK protein content
glucose formation from lactate, pyruvate, and alanine in perfused
liver slices.
67
Oral or intravenous administration of 3-MP caused
Only in livers with 100% PEPCK deletion is flux through the pathway markedly inhibited.
71
Data originally presented by Burgess et al., 2007.
hypoglycemia in vivo in several model systems, including rats, mice,
and guinea pigs.
67–69
Cross-over plot analysis of liver metabolite
was maintained at this lower rate despite an eventual 60% reduction in concentrations suggested PEPCK was the target of inhibition, which was
PEPCK protein after five hours.
54
Thus, PEPCK appears to have poor supported by the observation that hepatic oxaloacetate levels increased
control strength over the gluconeogenic pathway during the acute during 3-MP treatment.
68,69
These studies were typically performed after a
response to insulin. long fasting period (a condition in which liver glycogen levels were
depleted and glycogenolysis was assumed to be zero). This led to the
In several recent rodent studies, the inhibition of gluconeogenesis and conclusion that 3-MP inhibited gluconeogenesis by pharmacological
suppression of gluconeogenic gene expression (via a pathway that blockade of PEPCK.
required the vagus nerves and hepatic STAT3) was observed in response
to hyperinsulinemia in the brain.
7–9
Data in dogs, however, have indicated Other evidence casts doubt on the degree of control that PEPCK
that hepatic denervation does not blunt insulin’s ability to inhibit HGP,
63
exerts on GNG flux to G6P. Metabolic control analysis of the pathway
which is similar to what has been observed in humans with liver using rat hepatocytes determined that PEPCK has poor control
transplants.
64
Furthermore, insulin introduced into the third ventricle of strength on the gluconeogenic process under various conditions
the brain in dogs during a basal pancreatic clamp, in the same manner in vitro.
70
A recent study evaluated the gluconeogenic pathway in
and at the same rate as was used in rodents, could not bring about any perfused livers (isolated from transgenic mice) with different amounts
effect on HGP.
12
Thus, the question arises as to whether the insulin– of PEPCK protein content (see Figure 4). Only in the almost complete
brain–liver axis that acutely regulates GNG flux to G6P in rodents is absence of PEPCK protein was the gluconeogenic process markedly
conserved in large animals. It is possible that the sensitivity and inhibited.
71
This is in line with the results observed with 3-MP, which
mechanism of insulin-mediated inhibition of HGP may be species- presumably resulted in a virtually complete blockade of PEPCK at the
dependent. Rodents have five to 10 times the basal HGP rates of large enzymatic level. These observations
71
are also in agreement with
animals and they exhaust liver glycogen stores after a relatively short the physiological regulation of PEPCK protein by insulin. Here even
fast. Canines and humans, on the other hand, maintain a significant marked, sustained hyperinsulinemia (16-fold for five hours) was only
amount of liver glycogen even after several days of fasting.
65,66
It is able to reduce the amount of protein by ~60% and thus was unable to
therefore conceivable that the drive to maintain GNG flux to G6P during alter GNG flux to G6P.
54
Thus, acute physiological hyperinsulinemia
hyperinsulinemia differs between species. does not suppress PEPCK protein expression to a large enough extent
to alter GNG flux to G6P in vivo. This supports the view that the
Alternatively, the insulin–brain regulation of GNG flux to G6P in the cited pathway is active and important in glycogen formation during
rodent studies may have been due to the experimental design the post-prandial (hyperinsulinemic) state.
56–59
The only evidence that
employed.
7–9
Hyperinsulinemia was brought about via insulin infusion in a physiological elevation in insulin can suppress the GNG flux to G6P
a peripheral vein, resulting in elevated insulin at the brain (and comes from rodent studies
7–9
in which the effect was observed in
periphery) but basal insulin levels at the liver. At same time, glucagon decidedly non-physiological circumstances.
was not replaced during the clamp protocol, thus depriving the liver of
one of its primary physiological signals. Whether hypothalamic Elevated HGP in the diabetic state is associated with increased
hyperinsulinemia can regulate HGP in a physiological circumstance (in gluconeogenesis and also typically increased levels of PEPCK mRNA
the presence of hepatic hyperinsulinemia and physiological levels of expression in animal models. This supports the belief that this enzyme
glucagon) has not been demonstrated. Even if the insulin–brain–liver has a rate-limiting influence on GNG flux to G6P in a chronic, insulin-
signaling axis does exist in large animals and humans, the relevance of resistant state.
72
A recent study, however, demonstrated that in rat
38 US ENDOCRINOLOGY
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