Two special features of glucose metabolism in animals are dominant.224 The first is the storage of
glycogen for use in providing muscular energy rapidly. This is a relatively short-term matter but the rate of glycolysis can be intense: The entire glycogen content of muscle could be exhausted in only 20 s of anaerobic fermentation or in 3.5 min of oxidative metabolism.225
There must be a way to turn on glycolysis quickly and to turn it off when it is no longer needed. At the same time, it must be possible to reconvert lactate to glucose or glycogen (gluconeogenesis). The glycogen stores of the muscle must be repleted from glucose of the blood. If insufficient glucose is available from the diet or from the glycogen stores of the liver, it must be synthesized from amino acids.
The second special feature of glucose metabolism is that certain tissues, including brain, blood cells, kidney medulla, and testis, ordinarily obtain most of
A. Activity increased Enzymes of glycolysis
Glucokinase Transcription induced
Phosphofructokinase via 2,6-fructose P2
Pyruvate kinase Dephosphorylation
6-Phosphofructo-2-kinase Dephosphorylation
Enzymes of glycogen synthesis
Glucokinase Transcription
Glycogen synthase (muscle) Dephosphorylation
Enzymes of lipid synthesis
Pyruvate dehydrogenase (adipose) Dephosphorylation (Eq. 17-9)
Acetyl-CoA carboxylase Dephosphorylation
ATP-citrate lyase Phosphorylation
Fatty acid synthase Lipoprotein lipase
Hydroxymethylglutaryl-CoA reductase B. Activity decreased
Enzymes of gluconeogenesis Pyruvate carboxylase
PEP carboxykinase Transcription inhibited
Fructose 1,6-bisphosphate Glucose 6-phosphatase Enzymes of lipolysis
Triglyceride lipase
(hormone-sensitive lipase) Dephosphorylation
Enzymes of glycogenolysis Glycogen phosphorylase C. Other proteins affected by insulin
Glucose transporter GLUT4 Redistribution
Ribosomal protein S6 Phosphorylation by p90rsk
IGF-II receptor Redistribution
Transferrin receptor Redistribution
Calmodulin Phosphorylation
TABLE 17-3
Some Effects of Insulin on Enzymes
Name of Enzyme Type of Regulation
A clue to another possible unrecognized mecha- nism of action for insulin comes from the observation that urine of patients with non-insulin-dependent diabetes contains an unusual isomer of inositol,
D-chiro-inositol.233,234
Plasma of such individuals contains an antagonist of insulin action, an inositol phosphoglycan containing
myo-inositol as a cyclic 1,2-phosphate
ester and galactosamine and man- nose in a 1:1:3 ratio.235 This appears
to be related to the glycosyl phos- phatidylinositol (GPI) membrane anchors (Fig. 8-13). It has been suggested that such a glycan, perhaps containing chiro-inositol, is released in response to insulin and serves as a second messenger for insulin.235–236a
This hypothesis remains unproved.237
However, insulin does greatly stim- ulate a GPI-specific phospholipase C, at least in yeast.237a Another
uncertainty surrounds the possible cooperation of chromium (Chapter 16) in the action of insulin.
How do the insulin-secreting pancreatic β cells sense a high blood glucose concentration? Two specialized proteins appear to be involved. The sugar transporter GLUT2 allows the glucose in blood to equilibrate with the free glucose in the β cells,237bwhile glucokinase
(hexokinase IV or D) apparently serves as the glucose sensor.228,238
Despite the fact that glucokinase is a monomer, it displays a coopera- tive behavior toward glucose bind- ing, having a low affinity at low [glucose] and a high affinity at high [glucose]. Mutant mice lacking the glucokinase gene develop early onset diabetes which is mild in hetero- zygotes but severe and fatal within a week of birth for homozygotes.239,240 These facts alone do not explain
how the sensor works and there are doubtless other components to the signaling system.
HO OH HO OH OH OH 1 OH OH OH HO 4 3 6 myo-Inositol (numbered as d) 1 2 3 4 5 6 d-chiro-Inositol OH 2 HO 5
A current theory is that the increased rate of glucose catabolism in the β cells when blood [glucose] is high leads to a high ratio of [ATP]/[ADP] which induces closure of ATP-sensitive K+ channels and opening of
voltage-gated Ca2+ channels.241 This could explain the
increase in [Ca2+] within β cells which has been associ-
ated with secretion of insulin242,243 and which is
thought to induce the exocytosis in insulin storage granules. The internal [Ca2+] in pancreatic islet cells
is observed to oscillate in a characteristic way that is synchronized with insulin secretion.243
Glucagon. This 29-residue peptide is the principal hormone that counteracts the action of insulin. Gluca- gon acts primarily on liver cells (hepatocytes) and adipose tissue and is secreted by the α cells of the islets of Langerhans in the pancreas, the same tissue whoseβ cells produce insulin, if the blood glucose concentration falls much below 2 mM.244– 250 Like the
insulin-secreting β cells, the pancreatic α cells contain glucokinase, which may be involved in sensing the drop in glucose concentration. However, the carrier GLUT2 is not present and there is scant information on the sensing mechanism.248
Glucagon promotes an increase in the blood glu- cose level by stimulating breakdown of liver glycogen, by inhibiting its synthesis, and by stimulating gluco- neogenesis. All of these effects are mediated by cyclic AMP through cAMP-activated protein kinase (Fig. 11-4) and through fructose 2,6-P2 (Fig. 11-4 and next section). Glucagon also has a strong effect in promoting the release of glucose into the bloodstream. Adrenaline has similar effects, again mediated by cAMP. However, glucagon affects the liver, while adrenaline affects many tissues. Glucocorticoids such as cortisol (Chapter 22) also promote gluconeogenesis and the accumulation of glycogen in the liver through their action on gene transcription.
The release of glucose from the glycogen stores in the liver is mediated by glucose 6-phosphatase, which is apparently embedded within the membranes of the endoplasmic reticulum. A labile enzyme, it consists of a 357-residue catalytic subunit,251,252 which
may be associated with other subunits that participate in transport.252,253 A deficiency of this enzyme causes
the very severe type 1a glycogen storage disease (see Box 20-D).251,253 Only hepatocytes have significant
glucose 6-phosphatase activity.
2. Phosphofructo-1-Kinase in the Regulation