Transcript Protein kinase A

Chapter 7
Companion site for Basic Medical Endocrinology, 4th Edition
Author: Dr. Goodman
FIGURE 7.1
Cytoarchitecture of a typical human pancreatic islet as revealed in immunostained confocal
scanning microscopic images. Endocrine cells are closely but randomly associated with vascular
cells. Most insulin- (red), glucagon- (green), and somatostatin- (cyan) immunoreactive cells are in
close proximity to vascular cells immunoreactive for smooth muscle cell actin (blue). Endocrine
cells are aligned along the blood vessels in a random order. (From Cabrera, O., Berman, D.M.,
Kenyon, N.S., Ricordi, C., Berggren, P.O., and Caicedo, A. (2006) The unique cytoarchitecture of
human pancreatic islets has implications for islet cell function. Proc. Natl. Acad. Sci. USA 103:
2334–2339, with permission.)
Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman
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FIGURE 7.2
Biochemical pathways of glucose metabolism in hepatocytes. Reactions that are accelerated in the
presence of glucagon are shown in green. Broken red arrows indicate reactions that are inhibited
by protein kinase A catalyzed phosphorylation. The hexose-monophosphate shunt is indirectly
inhibited. Roman numerals indicate substrate cycles.
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FIGURE 7.3
Role of protein kinase A (cyclic AMP-dependent protein kinase) in glycogen metabolism.
Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman
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FIGURE 7.4
Regulation of fructose-1,6-bisphosphate metabolism by protein kinase A (cyclic AMP-dependent
protein kinase). Formation of fructose-1,6-bis phosphate is accelerated by the metabolite fructose2,6-bisphosphate, which stimulates phosphofructokinase and inhibits fructose-1,6-phosphatase.
Protein kinase A lowers the concentration of fructose-2,6-bisphosphate by catalyzing
phosphorylation of the bifunctional enzyme 6 phosphofructose-2 kinase/fructose-2,6bisphosphatase, which promotes its phosphatase activity. The resulting decrease in fructose-2,6bisphosphate concentration removes the stimulation of phosphofructokinase, and the inhibition of
fructose-1,6-phosphatase, and drives substrate flow from fructose-1,6-bisphosphate to fructose-1phosphate.
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FIGURE 7.5
Regulation of phosphoenol pyruvate (PEP) formation by protein kinase A (PKA, cyclic AMPdependent protein kinase). Protein kinase A catalyzes the phosphorylation and, hence, inactivation
of pyruvate kinase whose activity limits the conversion of PEP to pyruvate.
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FIGURE 7.6
Protein kinase A (cyclic AMP-dependent protein kinase) indirectly stimulates ketogenesis by
decreasing the formation of malonyl CoA, thus removing a restriction on accessibility of fatty acids
to intramitochondrial oxidative enzymes.
Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman
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FIGURE 7.7
Stimulatory and inhibitory signals for glucagon secretion.
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FIGURE 7.8
Post-translational processing of preproinsulin. The leader sequence is removed and the molecule
folds in a way that lines up cyteines so that disulfide bonds can form. After packaging into secretory
granules prohormone convertases excise the connecting peptide.
Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman
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FIGURE 7.9
Idealized glucose tolerance tests in normal and diabetic subjects. Subjects are given a
standardized solution of glucose to drink and blood samples are taken at the indicated times
thereafter. An impairment of glucose disposition results in a greater than normal and prolonged
increase in blood glucose concentration.
Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman
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FIGURE 7.10
Carbohydrate and lipid metabolism in adipose tissue. Reactions enhanced by insulin (green
arrows) are as follows: (1) transport of glucose into adipose cell; (2) conversion of excess glucose
to glycogen; (3) decarboxylation of pyruvate; (4) initiation of fatty acid synthesis; (5) uptake of fatty
acids from circulating lipoproteins. Breakdown of triglycerides is inhibited by insulin (dashed red
arrows). Esterification of fatty acids to triglycerides follows from availability of -glycerol phosphate.
Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman
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FIGURE 7.11
Confocal fluorescent microscope images of cultured mouse adipocytes that were transfected with
GLUT4 linked to green fluorescent protein and then incubated in the absence (A) or presence (B) of
insulin for 30 min. Insulin stimulation results in the translocation of GLUT4 from intracellular storage
sites to the plasma membrane. (From Watson, R.T., Kanzaki, M., and Pessin, J. (2004) Regulated
membrane trafficking of the insulin-responsive glucose transporter 4 in adipocytes. Endocr. Revs.
25: 177–204, with permission.)
Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman
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FIGURE 7.12
Metabolism of carbohydrate and lipid in muscle. Rate-limiting reactions accelerated by insulin
(green arrows) are: (1) transport of glucose into muscle cells; (2) phosphorylation of glucose by
hexokinase; (3) storage of glucose as glycogen; (4) addition of the second phosphate by
phosphofructokinase; (5) inhibition of fatty acid entry into mitochondria by malonyl CoA. Red arrows
indicate reactions that are inhibited.
Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman
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FIGURE 7.13
Effects of insulin on protein turnover in muscle. Reactions stimulated by insulin are shown in green.
The dashed red arrows indicate reactions inhibited by insulin.
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FIGURE 7.14
Insulin decreases hepatic production of glucose and ketone bodies by actions exerted on muscle
and adipose tissue that limit availability of precursors.
Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman
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FIGURE 7.15
Changes in insulin and glucagon in plasma and carbohydrate metabolism in normal subjects
following ingestion of a liquid meal rich in carbohydrate. Although secretion of both insulin and
glucagon was stimulated, insulin increased about twenty-fivefold while glucagon increased only
threefold so that the ratio of glucagon to insulin fell dramatically. Plasma glucose increased
transiently, but release of glucose from the liver fell precipitously, and liver glycogen increased.
(From Taylor, R., Magnusson, I., Rothman, D.L., Cline, D.W., Caumo, A., Cobelli, C., and Shulman,
G.L. (1996) Direct assessment of liver glycogen storage by 13C nuclear magnetic resonance
spectroscopy and regulation of glucose homeostasis after a mixed meal in normal subjects. J. Clin.
Invest. 97: 126–132, with permission.)
Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman
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FIGURE 7.16
Effects of insulin on glucose metabolism in hepatocytes. Green arrows indicate reactions that are
increased, and dashed red arrows indicate reactions that are decreased.
Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman
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FIGURE 7.17
Effects of insulin on lipogenesis in hepatocytes. Green arrows indicate reactions that are increased,
and the dashed red arrow indicates a reaction that is decreased. 1. Pyruvate kinase. 2. Pyruvate
dehydrogenase. 3. Acetyl CoA carboxylase. 4. Fatty acid synthase.
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FIGURE 7.18
The insulin receptor.
Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman
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FIGURE 7.19
Simplified model of insulin signaling pathways. The insulin receptor proteins (IRS 1,2,3,4), Cbl,
Shc, and the  subunits of the insulin receptor are phosphorylated on tyrosine residues by the
insulin receptor kinase and serve as anchoring sites for cytosolic proteins that form signaling
cascades. Proteins shown in blue boxes are serine/threonine kinases. Specific isoforms and/or
subunits are not shown nor are the relevant phosphatases. Shc = Src homology containing protein;
Cbl = Cacitas B lineage lymphoma protein; PI3K = phosphoinositol-3-kinase; PDK =
phosphoinositide dependent kinase; PKC =  isoform of protein kinase C; PKB = protein kinase
B; PDE = phosphodiesterase; RAS = Ras oncogene, a small G-protein; mTOR = mammalian target
of rapamycin; GSK = glycogen synthase kinase; ERK = extracellular receptor kinase.
Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman
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FIGURE 7.20
Changes in the concentrations of plasma glucose, immunoreactive glucagon (IRG), and
immunoreactive insulin (IRI) throughout the day. Values are the mean  SEM (n = 4). (From Tasaka,
Y., Sekine, M., Wakatsuki, M., Ohgawara, H., and Shizume, K. (1975) Levels of pancreatic
glucagon, insulin and glucose during twenty-four hours of the day in normal subjects. Horm. Metab.
Res. 7: 205–206.)
Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman
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FIGURE 7.21
Insulin secretion by isolated human pancreatic islets in response to increasing concentrations of
glucose. A. Stimulus:response curve. The threshold for increased secretion in vivo may be
somewhat higher than between 1 and 3 mM/L shown here. B. Insulin secretion in response to a
sudden rise in glucose concentration has two phases: an early transient spike followed by a
sustained plateau. (Drawn from the data of Henquin, J.C., Dufrane, D., and Nenquin, M. (2006)
Nutrient control of insulin secretion in isolated normal human islets. Diabetes 55: 3470–3477.)
Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman
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FIGURE 7.22
Metabolic, hormonal, and neural influences on insulin secretion.
Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman
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FIGURE 7.23
Triggering of insulin secretion by glucose. A. “Resting” beta cell (blood glucose  100 mg/dl).
ADP/ATP ratio is high enough so that ATP-sensitive potassium channels (KATP) are open, and the
membrane potential is about 70 mv. Voltage-sensitive calcium channels (VSCC) and calciumsensitive potassium channels (CSKC) are closed. B. Beta cell response to increased blood
glucose. Increased entry and metabolism of glucose decreases the ratio of ADP/ATP, and KATP
channels close. Voltage-sensitive calcium channels (VSCC) are activated; calcium enters and
stimulates insulin secretion. Mitochondrial metabolites formed in response to glucose and calcium
amplify secretion. Influx of calcium inhibits voltage-sensitive calcium channels and activates
calcium-sensitive and voltage-sensitive potassium channels, thereby allowing the cell membrane to
repolarize and calcium channels to close. Calcium is extruded by membrane calcium ATPase.
Persistence of high glucose results in repeated spiking of electrical discharges and oscillation of
intracellular calcium concentrations.
Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman
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FIGURE 7.24
Major acute cellular actions of incretins. GLP-1 (glucagons-like peptide 1) and GIP (glucosedependent insulinotropic peptide) acting through G peptide-coupled receptors activate adenylyl
cyclase to increase intracellular concentrations of cyclic AMP (cAMP). Cyclic AMP increases the
activity of protein kinase A or binds to a GTP (guanosine triphosphate) exchange factor to increase
cytosolic calcium and enhance the effects of calcium of insulin secretion. KATP = ATP-sensitive
potassium channels; KV = voltage sensitive potassium channels: VSCC = voltage sensitive calcium
channels; RP = reserve pool of secretory granules; ER = endoplasmic reticulum. See text for
details.
Companion site for Basic Medical Endocrinology, 4th Edition. by Dr. Goodman
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