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Lecture Schedule

Integration of Metabolism

Learning Objectives and Guiding Questions

Reading assignment: Ace the Boards, Chapter 19 (handout)

Important note: This is to correct the statements made in lecture that glucagon has no effect on adipose tissue. After digging around a little I found that glucagon does have an effect on adipose tissue, although it is not as pronounced as epinephrine. Most textbooks do not mention this effect, but including it in the metabolic diagrams does help explain the mobilization of FFA during fasting a little better. Another important concept that was not emphasized enough concerns the importance of the ratio of insulin/glucagon rather that the independent effects of each hormone. You should always think in terms of the insulin/glucagon ratio.

1. Describe the overall effect on metabolism of a high insulin/glucagon ratio compared to a low insulin/glucagon ratio.

A. What is the general effect of glucagon on its target tissue? Just what is its target tissue?

B. What is the general effect of insulin on its target tissues? And…what are its major target tissues? How does it affect the phosphorylation state of the cell?

C. Could we say that when insulin stimulates phosphatase activity producing dephosphorylation that enzymes involved in energy storage are activated and energy mobilizing enzymes are inactivated? Could we likewise say that when glucagon stimulates protein kinase A phosphorylation that enzymes involved in energy mobilization are activated and enzymes involved in energy storage are inactivated? You bet we can.

2. Describe the pathways involved in the storage of energy in the liver in the well-fed state.

A. How is glycogen synthesis stimulated?

B. How is the pentose phosphate pathway stimulated? What is the main regulator of the pentose phosphate pathway? How is it consumed in the well-fed state?

C. What is the major path for acetyl CoA carbons?

D. How is PFK activated? How is PFK-2 involved in regulating PFK activity? How is PFK-2 affected by insulin?

E. How is pyruvate dehydrogenase activated?

F. How are the FFA transported to the adipose tissue?

G. What characteristics of glucokinase allow it to maximize the amount of glucose removed by the liver after a meal?

3. Describe the metabolism of glucose and triglycerides that are transported to adipose tissue in the well-fed state.

A. How do triglycerides from the diet reach the adipose cell in the well-fed state? What if they were synthesized in the liver from excess glucose?

B. Which lipase releases FFA to enter the adipose cell? Which glycolytic intermediate is needed to esterify the FFA for storage in the adipose cell?

4. Describe the source of fuel for the brain in the well-fed, fasting, starvation, and diabetic states.

A. Does the brain ever use fats as a source of energy? How about ketones? When?

B. Will the brain use ketones for energy if glucose is available?

C. Does the brain store significant amounts of glycogen?

D. Why does the brain try to spare glucose in the starvation state? What critical negative allosteric effector of hemoglobin in red cells requires an active glycolytic pathway for its synthesis?

5. Describe the metabolism of glucose, FFA, and amino acids in muscle in the well-fed state.

A. Other than supporting a basal rate of glycolysis, what else happens to glucose 6-phosphate?

B. What is the overall effect of insulin on protein synthesis? How does insulin affect eIF4 in skeletal muscle?

C. Are FFA a significant source of energy in skeletal muscle?

6. Describe the effect of glucagon on liver metabolism.

A. How is PFK activity affected by glucagon? How about fructose 2,6-bisphosphatase?

B. How is all this gluconeogenic activity paid for, i.e. where does the energy come from?

C. What's happening with the urea cycle during fasting? Why? What is the alanine cycle? How does that work?

D. There is another cycle like the alanine cycle that occurs during exercise and even during inactive periods to a lesser extent. It's called the Cori cycle and it involves lactate. How do you think the Cori cycle works, if it's just like the alanine cycle? (pg 659 and fig. 29.16)

7. Describe the events in adipose tissue during fasting.

A. What stimulates the hormone sensitive lipase? What is the effect of decreasing insulin levels?

B. What happens to the glycerol that is released?

8. What are the events in skeletal muscle during fasting?

A. What happens to the nitrogen of the amino acids that are produced by the breakdown of muscle protein?

B. Can skeletal muscle glycogen be used to help maintain blood sugar concentrations.

C. What is the primary source of energy in the muscle cell?

9. Describe the way metabolism changes in starvation to conserve blood glucose and to spare protein from continued degradation.

A. Does muscle protein continue to breakdown in starvation as a source of carbon skeletons for glucose synthesis? What does muscle use as a source of energy during starvation? How is b-hydroxybutyrate converted to acetoacetate? How is acetoacetate converted to acetyl CoA?

B. Does metabolism in adipose tissue during starvation differ from the fasting state?

C. Does metabolism in brain during starvation differ from the fasting state? How?

D. Is liver actively synthesizing glucose during starvation? What is the source of carbon skeletons for this process and what tissue does it come from?

E. What is the main output of the liver during starvation? What tissue is able to use ketone bodies during starvation?

F. What tissue (cell type) needs the glucose that is spared by ketone metabolism? Why?

10. Describe the differences between the metabolism in an uncontrolled type I diabetic and a patient who is in starvation.

A. How does the insulin/glucagon ratio compare between diabetes and starvation?

B. How does the liver respond to diabetes compared to starvation? (Remember that one big difference between a starving person and a diabetic is that the diabetic is eating regular meals, and therefore has a source of amino acids for gluconeogenesis. Although muscle wasting does occur, this alternate source of amino acids makes muscle wasting a much slower process.) How do the rates of glucose output compare? How do the rates of ketone body output compare? (pg195, Ace handout)

C. How does adipose tissue metabolism in diabetes compare to starvation?

D. With all of those ketones available, does the brain switch to ketone metabolism in diabetes like it does in starvation?

E. What are the two causes of hyperglycemia in diabetes?

F. How does insulin administration correct the metabolism in diabetic liver? In adipose tissue? In muscle?

11. Describe the mechanism by which insulin increases the uptake of glucose in adipose tissue and skeletal muscle.

A. In what two places are the glucose transporter molecules located in the cell?

B. How does insulin change the distribution of the glucose transporters?

12.Describe three ways that ethanol metabolism can contribute to acidosis.

A. What two carbon metabolite is produced from ethanol oxidation in the cytoplasm? What two carbon metabolite is produced by further oxidation in the mitochondrion?

B. What is the effect of ethanol oxidation on the NADH levels in the cell? How does this affect pyruvate levels?

C. What are the three types of acids produced from ethanol metabolism?

13. Explain how ethanol metabolism can produce hypoglycemia.

A. How does ethanol metabolism affect the levels of pyruvate as a precursor for gluconeogenesis?

B. What is the only other source of glucose from the liver?

14. Explain why ethanol metabolism can lead to an elevation in VLDL.

Last revised 11/28/99