Chapter Summary, Questions Answers - Metabolic Effects of Insulin and Glucagon

CHAPTER SUMMARY

The integration of energy metabolism is controlled primarily by insulin and the opposing actions of glucagon and the catecholamines, particularly epinephrine (Figure 23.17). Changes in the circulating levels of these hormones allow the body to store energy when food is abundant or to make stored energy available in times of physiologic stress (for example, during “survival crises,” such as famine). Insulin is a peptide hormone produced by the β cells of the islets of Langerhans of the pancreas. It consists of disulfide-linked A and B chains. A rise in blood glucose is the most important signal for insulin secretion. The catecholamines, secreted in response to stress, trauma, or extreme exercise, inhibit insulin secretion. Insulin increases glucose uptake (by muscle and adipose) and the synthesis of glycogen, protein, and triacylglycerol: it is an anabolic hormone. These actions are mediated by binding to its tyrosine kinase receptor. Binding initiates a cascade of cell-signaling responses, including phosphorylation of a family of proteins called insulin receptor substrate proteins. Glucagon is a monomeric peptide hormone produced by the α cells of the pancreatic islets (both insulin and glucagon synthesis involves formation of inactive precursors that are cleaved to form the active hormones). Glucagon, along with epinephrine, norepinephrine, cortisol, and growth hormone (the “counterregulatory” hormones), opposes many of the actions of insulin. Glucagon acts to maintain blood glucose during periods of potential hypoglycemia. Glucagon increases glycogenolysis, gluconeogenesis, fatty acid oxidation, ketogenesis, and uptake of amino acids: it is a catabolic hormone. Glucagon secretion is stimulated by low blood glucose, amino acids, and the catecholamines. Its secretion is inhibited by elevated blood glucose and by insulin. Glucagon binds to high-affinity receptors of hepatocytes. Binding results in the activation of adenylyl cyclase, which produces the second messenger cyclic adenosine monophosphate (cAMP). Subsequent activation of cAMP-dependent protein kinase A results in the phosphorylation-mediated activation or inhibition of key regulatory enzymes involved in carbohydrate and lipid metabolism. Both insulin and glucagon affect gene transcription. Hypoglycemia is characterized by low blood glucose accompanied by adrenergic and neuroglycopenic symptoms that are rapidly resolved by the administration of glucose. Insulin-induced, postprandial, and fasting hypoglycemia result in release of glucagon and epinephrine. The rise in nicotinamide adenine dinucleotide (NADH) that accompanies ethanol metabolism inhibits gluconeogenesis, leading to hypoglycemia in individuals with depleted stores. Alcohol consumption also increases the risk for hypoglycemia in patients using insulin. Chronic alcohol consumption can cause fatty liver disease.

Figure 23.17 Key concept map for the metabolic effects of insulin and glucagon, and hypoglycemia. IRSs = insulin receptor substrates.

Study Questions
Choose the ONE best answer.

23.1 Which of the following statements is true for insulin but not for glucagon?

A. It is a peptide hormone secreted by pancreatic cells.

B. Its actions are mediated by binding to a receptor found on the cell membrane of liver cells.

C. Its effects include alterations in gene expression.

D. Its secretion is decreased by the catecholamines.

E. Its secretion is increased by amino acids.

F. Its synthesis involves a nonfunctional precursor that gets cleaved to yield a functional molecule.

Correct answer = D. Secretion of insulin by pancreatic β cells is inhibited by the catecholamines, whereas glucagon secretion by the α cells is stimulated by them. All of the other statements are true for both insulin and glucagon.

23.2 In which one of the following tissues is glucose transport into the cell insulin dependent?

A. Adipose

B. Brain

C. Liver

D. Red blood cells

Correct answer = A. The glucose transporter (GLUT-4) in adipose (and muscle) tissue is dependent on insulin. Insulin results in transport of GLUT-4 from intracellular vesicles to the cell membrane. The other tissues in the list contain GLUTs that are independent of insulin because they are always located on the cell membrane.

23.3 A 39-year-old woman is brought to the emergency room complaining of weakness and dizziness. She recalls getting up early that morning to do her weekly errands and had skipped breakfast. She drank a cup of coffee for lunch and had nothing to eat during the day. She met with friends at 8 p.m. and had a few drinks. As the evening progressed, she soon became weak and dizzy and was taken to the hospital. Laboratory tests revealed her blood glucose was 45 mg/dl (normal = 70– 99). She was given orange juice and immediately felt better. The biochemical basis of her alcohol-induced hypoglycemia is an increase in:

A. fatty acid oxidation.

B. the ratio of the reduced-to-oxidized forms of nicotinamide adenine dinucleotide.

C. oxaloacetate and pyruvate.

D. use of acetyl coenzyme A in fatty acid synthesis.

Correct answer = B. The oxidation of ethanol to acetate by dehydrogenases is accompanied by the reduction of nicotinamide adenine dinucleotide (NAD⁺) to NADH. The rise in NADH shifts pyruvate to lactate and oxaloacetate (OAA) to malate, decreasing the availability of substrates for gluconeogenesis and resulting in hypoglycemia. The rise in NADH also reduces the NAD⁺ needed for fatty acid oxidation. The decrease in OAA shunts any acetyl coenzyme A produced to ketogenesis. Note that the inhibition of fatty acid degradation results in their reesterification into triacylglycerol that can result in fatty liver.

23.4 A patient is diagnosed with an insulinoma, a rare neuroendocrine tumor, the cells of which are derived primarily from pancreatic β cells. Which of the following would logically be characteristic of an insulinoma?

A. Decreased body weight

B. Decreased connecting peptide in the blood

C. Decreased glucose in the blood

D. Decreased insulin in the blood

Correct answer = C. Insulinomas are characterized by constant production of insulin (and, therefore, of C-peptide) by the tumor cells. The increase in insulin drives glucose uptake by tissues such as muscle and adipose that have insulin-dependent glucose transporters, resulting in hypoglycemia. The hypoglycemia is insufficient to suppress insulin production and secretion, however. Insulinomas, then, are characterized by increased blood insulin and decreased blood glucose. Insulin, as an anabolic hormone, results in weight gain.

23.5 In a patient with an even rarer glucagon-secreting tumor derived from the α cells of the pancreas, how would the presentation be expected to differ relative to the patient in Question 23.4?

A glucagon-secreting tumor of the pancreas (glucagonoma) would result in hyperglycemia, not hypoglycemia. The constant production of glucagon would result in constant gluconeogenesis, using amino acids from proteolysis as substrates. This results in loss of body weight.