| HORMONAL REGULATION OF HEPATIC GLYCOGENOLYSIS
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The study of glycogen metabolism is best approached by first addressing the regulation of glycogenolysis. Glycogenolysis is activated in liver in response to a demand for blood glucose , either because of its utilization during the post-absorptive state or in preparation for increased glucose utilization in response to stress. There are three major hormonal activators of glycogenolysis: glucagon, epinephrine (adrenaline), and cortisol (Table 12.2).
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| Glucagon is a peptide hormone (3500 Da), secreted from the α-cells of the endocrine pancreas. Its primary function is to activate hepatic glycogenolysis for maintenance of normoglycemia. It has a short half-life in plasma, about 5 min, as a result of receptor binding, renal filtration, and proteolytic inactivation in liver. Glucagon concentration in plasma therefore changes rapidly in response to the need for blood glucose. Blood glucagon increases between meals, decreases during a meal, and is chronically increased during fasting or on a low-carbohydrate diet.
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Glycogenolysis is also activated in response to both acute and chronic stress. The stress may be:
- physiologic, e.g. in response to increased blood glucose utilization during prolonged exercise;
- pathologic, e.g. as a result of blood loss;
- psychological, e.g. in response to acute or chronic threats.
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| VON GIERKE'S DISEASE: GLYCOGEN STORAGE DISEASE CAUSED BY GLC-6-PASE DEFICIENCY |
| A baby girl was chronically cranky, irritable, sweaty, and lethargic, and demanded food frequently. Physical evaluation indicated an extended abdomen, resulting from an enlarged liver. Blood glucose, measured 1 h after feeding, was 3.5 mmol/L (70 mg/dL) normal value ∼5 mmol/L (100 mg/dL). After 4 h, when the child was exhibiting irritability and sweating, her heart rate was increased (pulse = 110), and blood glucose had declined to 2 mmol/L (40 mg/dL). These symptoms were corrected by feeding. A liver biopsy showed massive deposition of glycogen particles in the liver cytosol. |
| Comment. This child has a deficiency in glycogen mobilization. Because of the severity of hypoglycemia, the most likely mutation is in hepatic Glc-6-Pase, which is required for glucose production by both glycogenolysis and gluconeogenesis. Treatment involves frequent feeding with slowly digested carbohydrate, e.g. uncooked starch, and nasogastric drip-feeding during the night. |
| Acute stress, regardless of its source, causes an activation of glycogenolysis through the action of the catecholamine hormone, epinephrine, released from the adrenal medulla. During prolonged exercise, both glucagon and epinephrine contribute to the stimulation of glycogenolysis.
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| Increased blood concentrations of the adrenocortical steroid hormone cortisol also induce glycogenolysis. Levels of the glucocorticoid cortisol vary diurnally in plasma, but may be chronically elevated under continuously stressful conditions, including psychological and environmental (e.g., cold) stress. Glucagon serves as a general model for the mechanism of action of hormones that act by way of cell-surface receptors. Cortisol, which acts at the level of gene expression, will be discussed later in Chapter 37.
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