| MOBILIZATION OF HEPATIC GLYCOGEN BY EPINEPHRINE
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| McARDLE'S DISEASE: A GLYCOGEN STORAGE DISEASE THAT REDUCES CAPACITY FOR EXERCISE |
A 30-year-old man consulted his physician because of chronic arm and leg muscle pains and cramps during exercise. He indicated that he had always had some muscle weakness and, for this reason, was never active in scholastic sports, but the problem did not become severe until he recently enrolled in an exercise program to improve his health. He also noted that the pain generally disappeared after about 15-30 min, and then he could continue his exercise without discomfort. His blood glucose concentration was normal during exercise, but serum creatine kinase (MM isoform) was elevated, suggesting muscle damage. Blood glucose declined slightly during 15 min of exercise, but unexpectedly blood lactate also declined, rather than increased, even when he was experiencing muscle cramps. A biopsy indicated an unusually high level of glycogen in muscle, suggesting a glycogen storage disease. |
| Comment. This patient suffers from McArdle's disease, a rare deficiency of muscle phosphorylase activity. The actual enzyme deficiency must be confirmed by enzyme assay, since a number of other mutations could also affect muscle glycogen metabolism. During the early periods of intense exercise, the muscle obtains most of its energy by metabolism of glucose, derived from glycogen. During cramps, which normally occur during oxygen debt, much of the pyruvate produced by glycolysis is excreted into blood as lactate. In this case, however, the patient did not excrete lactate, suggesting a failure to mobilize muscle glycogen. His recovery after about 0.5 h results from epinephrine-mediated physiologic responses that provide fuels, both glucose and fatty acids, from blood, overcoming the deficit in muscle glycogenolysis. Treatment of McArdle's disease usually involves exercise avoidance or, if necessary, carbohydrate consumption prior to exercise. Otherwise, the course of the disease is uneventful. |
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Table 12-4.
Major classes of glycogen-storage diseases. |
| Body_ID: None |
| Glycogen storage diseases |
| Body_ID: T012004.50 |
| Type | Name | Enzyme deficiency | Structural or clinical consequences |
| Body_ID: T012004.100 |
| I | von Gierke's | Glc-6-Pase | severe postabsorptive hypoglycemia, lactic acidemia, hyperlipidemia |
| Body_ID: T012004.150 |
| II | Pompe's | lysosomal α-glucosidase | glycogen granules in lysosomes |
| Body_ID: T012004.200 |
| III | Cori's | debranching enzyme | altered glycogen structure, hypoglycemia |
| Body_ID: T012004.250 |
| IV | Andersen's | branching enzyme | altered glycogen structure |
| Body_ID: T012004.300 |
| V | McArdle's | muscle phosphorylase | excess muscle glycogen deposition, exercise-induced cramps and fatigue |
| Body_ID: T012004.350 |
| VI | Hers' | liver phosphorylase | hypoglycemia, not as severe as Type I |
| Body_ID: T012004.400 |
| Epinephrine works through several distinct receptors on different cells. The best studied of these receptors are the α- and β-adrenergic receptors; they bind epinephrine with different affinities and work by different mechanisms. During severe hypoglycemia, glucagon and epinephrine work together to magnify the glycogenolytic response in liver. However, even when blood glucose is normal, epinephrine is released in response to real or perceived threats, causing an increase in
blood glucose to support a 'fight or flight' response. Caffeine in coffee and theophylline in tea are inhibitors of phosphodiesterase and also cause an increase in hepatic cAMP and blood glucose. Like epinephrine, caffeine, administered in the form of a few strong cups of coffee, can also make us alert, responsive, and aggressive.
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| CHILD BORN OF MALNOURISHED MOTHER MAY HAVE HYPOGLYCEMIA |
| A baby girl was born at 39 weeks of gestation to a young, malnourished mother. The child was also thin and weak at birth and, within 1 h after birth, was showing signs of distress, including rapid heartbeat and respiration. Her blood glucose was 3.5 mmol/L (63 mg/dL) at birth, and declined rapidly to 1.5 mmol/L (27 mg/dL) by 1 h, when she was becoming unresponsive and comatose. Her condition was markedly improved by infusion of a glucose solution, followed by a carbohydrate-rich diet. She improved gradually over the next 2 weeks before discharge from the hospital. |
| Comment. During development in utero, the fetus obtains glucose exogenously, from the placental circulation. However, following birth, the child relies at first on mobilization of hepatic glycogen, and then on gluconeogenesis for maintenance of blood glucose. Because of the malnourished state of the mother, this child was born with negligible hepatic glycogen reserves. Thus, she was unable to maintain blood glucose homeostasis postpartum and rapidly declined into hypoglycemia, initiating a stress response. After surviving the transient hypoglycemia, she probably still lacked adequate muscle mass to provide a sufficient supply of amino acids for gluconeogenesis. Infusion of glucose, followed by a carbohydrate-rich diet, would address these deficits, but may not correct more serious damage from prolonged malnutrition during fetal development. |
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| Epinephrine action on hepatic glycogenolysis proceeds by two pathways. One of these, through the epinephrine β-adrenergic receptor, is similar to that for glucagon, involving a plasma-membrane epinephrine-specific receptor, G-proteins, and cAMP. The epinephrine response augments the effects of glucagon during severe hypoglycemia, and also explains, in part, the rapid heartbeat, sweating, tremors, and anxiety associated with hypoglycemia. Epinephrine also works simultaneously through an α-receptor, but by a different mechanism. Binding to α-receptors also involves G-proteins, common elements in hormone signal transduction, but in this case the G-protein is specific for activation of a membrane isozyme of phospholipase C (PLC), which is specific for cleavage of a membrane phospholipid, phosphatidylinositol bisphosphate (PIP2) (Fig. 12.5). Both products of PLC action, diacylglycerol (DAG) and inositol trisphosphate (IP3), act as second messengers of epinephrine action. DAG activates protein kinase C (PKC), which, like PKA, initiates a series of protein-phosphorylation reactions. IP3 promotes the transport of Ca2+ into the cytosol. Ca2+ then binds to the cytoplasmic protein calmodulin, which binds to and activates phosphorylase kinase, leading to phosphorylation and activation of phosphorylase, providing glucose for blood. A Ca2+-calmodulin-dependent protein kinase and other enzymes are also activated, either by phosphorylation
or by association with the Ca2+-calmodulin complex. Thus, a range of metabolic pathways is activated in response to stress, especially those involved in the mobilization of energy reserves.
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