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Hormonal Regulation
and Integration of
Mammalian Metabolism
S-266
1. Peptide Hormone Activity Explain how two peptide hormones as structurally similar as oxytocin and
vasopressin can have such different effects (see Fig. 23–9).
2. ATP and Phosphocreatine as Sources of Energy for Muscle During muscle contraction, the con-
centration of phosphocreatine in skeletal muscle drops while the concentration of ATP remains fairly
constant. However, in a classic experiment, Robert Davies found that if he first treated muscle with
1-fluoro-2,4-dinitrobenzene (p. 98), the concentration of ATP declined rapidly while the concentration
of phosphocreatine remained unchanged during a series of contractions. Suggest an explanation.
3. Metabolism of Glutamate in the Brain Brain tissue takes up glutamate from the blood, transforms
it into glutamine, then releases it into the blood. What is accomplished by this metabolic conversion?
How does it take place? The amount of glutamine produced in the brain can actually exceed the
amount of glutamate entering from the blood. How does this extra glutamine arise? (Hint: you may
want to review amino acid catabolism in Chapter 18; recall that NH
3
is very toxic to the brain.)
chapter
23
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4. Proteins as Fuel during Fasting When muscle proteins are catabolized in skeletal muscle during a
fast, what are the fates of the amino acids?
5. Absence of Glycerol Kinase in Adipose Tissue Glycerol 3-phosphate is required for the biosyn-
thesis of triacylglycerols. Adipocytes, specialized for the synthesis and degradation of triacylglycerols,
cannot use glycerol directly because they lack glycerol kinase, which catalyzes the reaction
Glycerol ⫹ATP 88n glycerol 3-phosphate ⫹ADP
How does adipose tissue obtain the glycerol 3-phosphate necessary for triacylglycerol synthesis?
6. Oxygen Consumption during Exercise A sedentary adult consumes about 0.05 L of O
2
in 10 sec-
onds. A sprinter, running a 100 m race, consumes about 1 L of O
2
in 10 seconds. After finishing the
race, the sprinter continues to breathe at an elevated (but declining) rate for some minutes, consum-
ing an extra 4 L of O
2
above the amount consumed by the sedentary individual.
(a) Why does the need for O
2
increase dramatically during the sprint?
(b) Why does the demand for O
2
remain high after the sprint is completed?
7. Thiamine Deficiency and Brain Function Individuals with thiamine deficiency show some charac-
teristic neurological signs and symptoms, including loss of reflexes, anxiety, and mental confusion.
Why might thiamine deficiency be manifested by changes in brain function?
8. Potency of Hormones Under normal conditions, the human adrenal medulla secretes epinephrine
(C
9
H
13
NO
3
) at a rate sufficient to maintain a concentration of 10
⫺10
M
in circulating blood. To appreci-
ate what that concentration means, calculate the diameter of a round swimming pool, with a water
depth of 2.0 m, that would be needed to dissolve 1.0 g (about 1 teaspoon) of epinephrine to a concen-
tration equal to that in blood.
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9. Regulation of Hormone Levels in the Blood The half-life of most hormones in the blood is
relatively short. For example, when radioactively labeled insulin is injected into an animal, half of the
labeled hormone disappears from the blood within 30 min.
(a) What is the importance of the relatively rapid inactivation of circulating hormones?
(b) In view of this rapid inactivation, how is the level of circulating hormone kept constant under
normal conditions?
(c) In what ways can the organism make rapid changes in the level of a circulating hormone?
Answer
10. Water-Soluble versus Lipid-Soluble Hormones On the basis of their physical properties, hor-
mones fall into one of two categories: those that are very soluble in water but relatively insoluble in
lipids (e.g., epinephrine) and those that are relatively insoluble in water but highly soluble in lipids
(e.g., steroid hormones). In their role as regulators of cellular activity, most water-soluble hormones do
not enter their target cells. The lipid-soluble hormones, by contrast, do enter their target cells and
ultimately act in the nucleus. What is the correlation between solubility, the location of receptors, and
the mode of action of these two classes of hormones?
11. Metabolic Differences between Muscle and Liver in a “Fight or Flight” Situation When an
animal confronts a “fight or flight” situation, the release of epinephrine promotes glycogen breakdown
in the liver, heart, and skeletal muscle. The end product of glycogen breakdown in the liver is glucose;
the end product in skeletal muscle is pyruvate.
(a) What is the reason for the different products of glycogen breakdown in the two tissues?
(b) What is the advantage to an animal that must fight or flee of these specific glycogen breakdown
routes?
Answer
12. Excessive Amounts of Insulin Secretion: Hyperinsulinism Certain malignant tumors of the pan-
creas cause excessive production of insulin by the bcells. Affected individuals exhibit shaking and trem-
bling, weakness and fatigue, sweating, and hunger.
(a) What is the effect of hyperinsulinism on the metabolism of carbohydrates, amino acids, and lipids
by the liver?
(b) What are the causes of the observed symptoms? Suggest why this condition, if prolonged, leads
to brain damage.
13. Thermogenesis Caused by Thyroid Hormones Thyroid hormones are intimately involved in regu-
lating the basal metabolic rate. Liver tissue of animals given excess thyroxine shows an increased rate
of O
2
consumption and increased heat output (thermogenesis), but the ATP concentration in the tissue
is normal. Different explanations have been offered for the thermogenic effect of thyroxine. One is that
excess thryroxine causes uncoupling of oxidative phosphorylation in mitochondria. How could such an
effect account for the observations? Another explanation suggests that the thermogenesis is due to an in-
creased rate of ATP utilization by the thyroxine-stimulated tissue. Is this a reasonable explanation? Why?
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S-270 Chapter 23 Hormonal Regulation and Integration of Mammalian Metabolism
14. Function of Prohormones What are the possible advantages in the synthesis of hormones as prohor-
mones?
15. Sources of Glucose during Starvation The typical human adult uses about 160 g of glucose per
day, 120 g of which is used by the brain. The available reserve of glucose (~20 g of circulating glucose
and ~190 g of glycogen) is adequate for about one day. After the reserve has been depleted during
starvation, how would the body obtain more glucose?
16. Parabiotic ob/ob mice By careful surgery, researchers can connect the circulatory systems of two
mice so that the same blood circulates through both animals. In these parabiotic mice, products re-
leased into the blood by one animal reach the other animal via the shared circulation. Both animals are
free to eat independently. If an ob/ob mouse (both copies of the OB gene are defective) and a normal
OB/OB mouse (two good copies of the OB gene) were made parabiotic, what would happen to the
weight of each mouse?
17. Calculation of Body Mass Index A portly biochemistry professor weighs 260 lb (118 kg) and is
5 feet 8 inches (173 cm) tall. What is his body mass index? How much weight would he have to lose to
bring his body mass index down to 25 (normal)?
18. Insulin Secretion Predict the effects on insulin secretion by pancreatic cells of exposure to the
potassium ionophore valinomycin (Fig. 11⫺44). Explain your prediction.
19. Effects of a Deleted Insulin Receptor A strain of mice specifically lacking the insulin receptor
of liver is found to have mild fasting hyperglycemia (blood glucose ⫽132 mg/dL, vs. 101 mg/dL in
controls) and a more striking hyperglycemia in the fed state (glucose ⫽363 mg/dL, vs. 135 mg/dL in
controls). The mice have higher than normal levels of glucose 6-phosphatase in the liver and elevated
levels of insulin in the blood. Explain these observations.
20. Decisions on Drug Safety The drug Avandia (rosiglitazone) is effective in lowering blood glucose in
patients with type 2 diabetes, but also seems to carry an increased risk of heart attack. If it were your
responsibility to decide whether this drug should remain on the market (labeled with suitable warnings
of its side effects) or should be withdrawn, what factors would you weigh in making your decision?
21. Type 2 Diabetes Medication The drugs acarbose (Precose) and miglitol (Glyset), used in the
treatment of type 2 diabetes mellitus, inhibit ␣-glucosidases in the brush border of the small intestine.
These enzymes degrade oligosaccharides derived from glycogen or starch to monosaccharides.
Suggest a possible mechanism for the salutary effect of these drugs on individuals with diabetes.
What side effects, if any, would you expect from these drugs. Why? (Hint: Review lactose
intolerance, p. 561⫺562).
Data Analysis Problem
22. Cloning the Pancreatic -Cell Sulfonylurea Receptor Glyburide, a member of the sulfonylurea
family of drugs is used to treat type 2 diabetes. It binds to and closes the ATP-gated K
⫹
channel
shown in Figures 23–27 and 23–28.
(a) Given the mechanism shown in Figure 23–27, would treatment with glyburide result in increased
or decreased insulin secretion by pancreatic cells? Explain your reasoning.
(b) How does treatment with glyburide help reduce the symptoms of type 2 diabetes?
(c) Would you expect glyburide to be useful for treating type 1 diabetes? Why or why not?
Aguilar-Bryan and coauthors (1995) cloned the gene for the sulfonylurea receptor (SUR)
portion of the ATP-gated K
⫹
channel from hamsters. The research team went to great lengths to
ensure that the gene they cloned was in fact the SUR-encoding gene. Here we explore how it is
possible for researchers to demonstrate that they have actually cloned the gene of interest rather
than another gene.
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The first step was to obtain pure SUR protein. As was already known, drugs such as glyburide
bind SUR with very high affinity (K
d
⬍10 n
M
), and SUR has a molecular weight of 140 to 170 kDa.
Aguilar-Bryan and coworkers made use of the high-affinity glyburide binding to tag the SUR protein
with a radioactive label that would serve as a marker to purify the protein from a cell extract. First,
they made a radiolabeled derivative of glyburide, using radioactive iodine (
125
I):
(d) In preliminary studies, the
125
I-labeled glyburide derivative (hereafter, [
125
I]glyburide) was shown
to have the same K
d
and binding characteristics as unaltered glyburide. Why was it necessary to
demonstrate this (what alternative possibilities did it rule out)?
Even though [
125
I]glyburide bound to SUR with high affinity, a significant amount of the la-
beled drug would probably dissociate from the SUR protein during purification. To prevent this,
[
125
I]glyburide had to be covalently cross-linked to SUR. There are many methods for covalent
cross-linking; Aguilar-Bryan and coworkers used UV light. When aromatic molecules are exposed
to short-wave UV, they enter an excited state and readily form covalent bonds with nearby mole-
cules. By cross-linking the radiolabeled glyburide to the SUR protein, the researchers could simply
track the
125
I radioactivity to follow SUR through the purification procedure.
Aguilar-Bryan and colleagues treated hamster HIT cells (which express SUR) with [
125
I]gly-
buride and UV light, purified the
125
I-labeled 140 kDa protein, and sequenced its amino-terminal
25 amino acid segment; they found the sequence PLAFCGTENHSAAYRVDQGVLNNGC. The inves-
tigators then generated antibodies that bound to two short peptides in this sequence, one that
bound to PLAFCGTE and the other to HSAAYRVDQGV, and showed that these antibodies bound
the purified
125
I-labeled 140 kDa protein.
(e) Why was it necessary to include this antibody-binding step?
Next, the researchers designed PCR primers based on the sequences above, and cloned a
gene from a hamster cDNA library that encoded a protein that included these sequences (see
Chapter 9 on biotechnology methods). The cloned putative SUR cDNA hybridized to an mRNA of
the appropriate length that was present in cells known to contain SUR. The putative SUR cDNA
did not hybridize to any mRNA fraction of the mRNAs isolated from hepatocytes, which do not
express SUR.
(f) Why was it necessary to include this putative SUR cDNA–mRNA hybridization step?
Finally, the cloned gene was inserted into and expressed in COS cells, which do not normally
express the SUR gene. The investigators mixed these cells with [
125
I]glyburide with or without a
large excess of unlabeled glyburide, exposed the cells to UV light, and measured the radioactivity
of the 140 kDa protein produced. Their results are shown in the table.
125I
NHCH2CH2SN
HN
H
O
O
O
OH
O
[125I]5-Iodo-2-hydroxyglyburide
Added Added excess
125
I label
Cell putative SUR unlabeled in 140 kDa
Experiment type cDNA? glyburide? protein
1 HIT No No ⫹⫹⫹
2 HIT No Yes ⫺
3 COS No No ⫺
4 COS Yes No ⫹⫹⫹
5 COS Yes Yes ⫺
(g) Why was no
125
I-labeled 140 kDa protein found in experiment 2?
(h) How would you use the information in the table to argue that the cDNA encoded SUR?
(i) What other information would you want to collect to be more confident that you had cloned the
SUR gene?
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