Biology & Life Sciences Chapter 23 Homework Sources Glucose During Starvation The Typical Human

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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

is very toxic to the brain.)

chapter

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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

in 10 sec-

onds. A sprinter, running a 100 m race, consumes about 1 L of O

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

above the amount consumed by the sedentary individual.

(a) Why does the need for O

increase dramatically during the sprint?

(b) Why does the demand for O

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

) at a rate sufficient to maintain a concentration of 10

⫺10

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?

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

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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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?

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

⬍10 n

), 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

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

[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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