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Diabetes Pathophysiology
Figure 3: Hepatic Loci of Regulation in Which Insulin Can
Insulin also stimulates the dephosphorylation of the bifunctional
Inhibit Hepatic Gluconeogenesis (Glucose Release Derived
enzyme 6-phosphofructokinase-2 (PFK-2)/fructose-2,6-bisphosphatase
from GNG Flux to G6P)
(FBPase-2), increasing its PFK-2 activity while inhibiting its FBPase-2
activity. PFK-2 and FBPase-2 regulate the synthesis and degradation,
respectively, of F2,6PGlycogen
2
, a metabolite that potently stimulates glycolytic
– +
and inhibits gluconeogenic enzymes in vitro.
4,21,35
Thus, it is conceivable
Glycogen Glycogen
phosphorylase synthase that insulin can inhibit GNG flux to G6P in vivo by increasing hepatic
B
+ F2,6P
2
concentration.
Glucokinase
Glycogen Metabolism
Glucose G6PA
Glycogen phosphorylase (GP) and glycogen synthase (GS) regulate the
+

C
balance between hepatic glycogen breakdown and deposition and are
F2,6P
2
G6Pase
reciprocally regulated by insulin. In the fasted state, GP and GS
– +
are phosphorylated, permitting GP activity and inhibiting GS activity, theFBP-1 PFK-1
net of which favors glycogenolysis.
38,39
Hyperinsulinemia mediates
Phosphoenolpyruvate
the rapid dephosphorylation of both GP and GS, facilitating the transition
from net glycogenolysis to net glycogen synthesis
38
in vitro and in vivo.
40
+

PyruvateD
PEPCK
kinase
Non-hepatic Mechanisms of Insulin-mediated
Regulation of Gluconeogenesis
CO
2
+
Pyruvate
The Alpha Cell
lactate
In addition to reducing the concentration of hepatic cAMP, insulin can
also counter glucagon’s ability to stimulate HGP by inhibiting glucagonGNG
precursors
secretion from alpha-cells.
18
Arrows marked in red and blue depict pathways that are stimulated and inhibited, respectively,
Gluconeogenic Precursor Flux
by hyperinsulinemia. Insulin can: mediate transcriptional regulation of both G6Pase iand
Insulin can regulate the availability of gluconeogenic precursors to the
glucokinase h to inhibit the dephosphorylation of G6P and stimulate GK translocation (A);
reciprocally regulate glycogen phosphorylase iand glycogen synthase h to divert
liver through its effects on peripheral tissues.
20
Insulin has anabolic
gluconeogenically derived G6P into glycogen (B); stimulate the formation of F2,6P , a metabolite2
effects in muscle and fat, inhibiting proteolysis
41
as well as lipolysis,
42
that regulates key enzymes in the gluconeogenic iand glycolytic pathway h, respectively (C);
and regulate the balance between pyruvate and phosphoenolpyruvate by suppressing the
thereby decreasing the availability of gluconeogenic amino acids
transcription of PEPCK (considered to be the rate-limiting enzyme in the gluconeogenic
(GNGAA) and glycerol to the liver. Glucose formation from glycerol
formation of G6P) and stimulating activity of the glycolytic enzyme pyruvate kinase (D).
accounts for about 3% of hepatic glucose output in 12–14-hour fasted
PEPCK and G6Pase messenger RNA (mRNA) as indices of insulin’s humans.
43
Thus, the reduction of glycerol flux to the liver can be
hepatic action. In the fasting state, the transcription factor FOXO1 considered to have only a minor influence in the overall gluconeogenic
interacts with the protein PGC1α at the promoter of the gluconeogenic rate. Insulin stimulates hepatic amino acid transport into the liver,
44
genes PEPCK and G6Pase, driving their mRNA expression.
30–32
PGC1α thereby increasing the net hepatic fractional extraction of GNGAAs so
expression, in turn, is regulated by the protein TORC2.
33,34
A rise in that the effect on reduction in the flow of GNGAAs from muscle to liver
hepatic insulin causes the phosphorylation of FOXO1 and TORC2, is somewhat offset. Lactate is quantitatively the most important
leading to their nuclear exclusion and resulting in suppression of GNG gluconeogenic precursor during fasting. However, lactate production by
mRNA expression.
30–34
In addition, recent studies in rodents have peripheral tissues (muscle, fat, skin, red blood cells, and the central
indicated that hyperinsulinemia in the brain can play a role in the nervous system), and therefore the availability of lactate to the liver,
suppression of gluconeogenic mRNA expression.
7–9
does not appear to substantially change during physiological
hyperinsulinemia.
17,45
Hepatic lactate metabolism, on the other hand, can
Stimulation of Glycolysis be significantly altered by insulin in a manner that is secondary to the
Unlike the long-term (hours to days) genetic control that insulin exerts hormone’s inhibition of lipolysis.
on the enzymes of the gluconeogenic pathway, hyperinsulinemia can
modify the activity of enzymes in the glycolytic pathway in rapid Inhibition of Lipolysis
(minute-to-minute) fashion.
4,35,36
There are metabolically specialized During fasting, lipolysis supplies free fatty acids (FFAs) and glycerol to
hepatocytes within the liver,
37
and GNG flux to G6P (in periportal the liver. While FFAs are not gluconeogenic substrates, they are potent
hepatocytes) and glycolytic flux (in perivenous hepatocytes) can occur stimulators of gluconeogenesis
46
in vitro and in vivo.
47
The oxidation of
simultaneously. Glycolytic flux is essentially the reverse of GNG flux to fatty acids by the liver generates energy while preserving circulating
G6P, so hyperinsulinemia may inhibit G6P formation in the net sense by glucose for other tissues.
48
Fatty acid oxidation in the liver increases the
stimulating the reverse, glycolytic reaction. concentration of citrate, adenosine triphosphate (ATP), nicotinamide
adenine dinucleotide (reduced form) (NADH), and acetyl-CoA.
49
Citrate is
Pyruvate kinase is believed to be one of the rate-controlling enzymes in a potent inhibitor of glycolysis,
50
while ATP and NADH are energy
glycolysis and insulin facilitates its desphosphorylation and activation.
36
equivalents that can be used to fuel gluconeogenesis.
49
Acetyl-CoA
36 US ENDOCRINOLOGY
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