Integration of Metabolism 1 Regulation of Energy Metabolism

Integration of Metabolism 1

Regulation of Energy Metabolism • Energy reserves: – Molecules that can be oxidized for energy are derived from storage molecules (glycogen, protein, and fat). Insert fig. 19. 2 • Circulating substrates: – Molecules absorbed through small intestine and carried to the cell for use in cell respiration. 2

Metabolic Effects of Insulin and Glucagon 3

• Four major organs play a dominant role in fuel metabolism: • liver • adipose • muscle • brain v Each organ is specialized for the storage, use, and generation of specific fuels. 4

• These tissues do not function in isolation, • One tissue may provide substrates to another, or process compounds produced by other organs. • Communication between tissues is mediated by the nervous system, by the availability of circulating substrates, and by variation in the levels of plasma hormones. 5

Balance Between Anabolism and Catabolism • The rate of deposit and withdrawal of energy substrates, and the conversion of 1 type of energy substrate into another; are regulated by hormones. Insert fig. 19. 4 6

• The integration of energy metabolism is controlled primarily by the actions of two peptide hormones: 1. insulin 2. glucagon with the catecholamines epinephrine and norepinephrine playing a supporting role. 7

• This chapter describes the: 1. structure, 2. secretion, 3. metabolic effects of insulin & Glucagon that most profoundly affect energy metabolism. 8

Insulin 9

Structure of Insulin • Composed of 51 amino acids arranged in two polypeptide chains, designated A and B, linked together by two disulfide bridges. • Pig and beef insulin differ from human insulin at one and three amino acid positions, respectively. • Each can be used in humans for the treatment of diabetes; however, antibodies to these foreign proteins can develop. 10

Pancreatic Islets (Islets of Langerhans) • Alpha cells secrete glucagon. – Stimulus is decrease in blood [glucose]. – Stimulates glycogenolysis and lipolysis. – Stimulates conversion of fatty acids to ketones. • Beta cells secrete insulin. – Stimulus is increase in blood [glucose]. – Promotes entry of glucose into cells. – Converts glucose to glycogen and fat. – Aids entry of amino acids into cells. 11

Energy Regulation of Pancreas • Islets of Langerhans contain 3 distinct cell types: – a cells: • Secrete glucagon. – b cells: • Secrete insulin. – D cells: • Secrete somatostatin. 12

Regulation of Insulin and Glucagon • Mainly regulated by blood [glucose]. • Lesser effect: blood [amino acid]. – Regulated by negative feedback. 13

Synthesis of Insulin • The biosynthesis involves two inactive precursors, preproinsulin and proinsulin, • They are sequentially cleaved to form the active hormone plus the connecting or Cpeptide. 14

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Regulation of Insulin and Glucagon (continued) • When blood [glucose] increases: – Glucose binds to GLUT 2 receptor protein in b cells, stimulating the production and release of insulin. • Insulin: – Stimulates skeletal muscle cells and adipocytes to incorporate GLUT 4 (glucose facilitated diffusion carrier) into plasma membranes. • Promotes anabolism. 16

Oral Glucose Tolerance Test • Measurement of the ability of b cells to secrete insulin. • Ability of insulin to lower blood glucose. • Normal person’s rise in blood [glucose] after drinking solution is reversed to normal in 2 hrs.

Oral Glucose Tolerance Test Insert fig. 19. 8 18

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Inhibition of Insulin Secretion • Synthesis and release of insulin are decreased when there is: 1. a decrease in dietary fuels, 2. during periods of stress (for example, fever or infection). These effects are mediated primarily by epinephrine, which is secreted in response to stress, trauma, or extreme exercise. 20

• Under these conditions, epinephrine is controlled largely by the nervous system. • Epinephrine has the result of rapid mobilization of stored energy (glycogenolysis, gluconeogenesis and lipolysis). • In addition, epinephrine can override the normal glucose-stimulated release of insulin. • Thus, in emergency situations, the nervous system largely replaces the plasma glucose concentration as the controlling influence over β-cell secretion. 21

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Metabolic effects of insulin 1. Effects on carbohydrate metabolism: • The effects of insulin on glucose metabolism promote its storage and are most prominent in three tissues: liver, muscle, and adipose. • • In the liver and muscle, insulin increases glycogen synthesis. In the muscle and adipose, insulin increases glucose uptake by increasing the number of glucose transporters (GLUT-2) in the cell membrane. 23

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• The intravenous administration of insulin thus causes an immediate decrease in the concentration of blood glucose. • In the liver, insulin decreases the production of glucose through the inhibition of glycogenolysis and gluconeogenesis 26

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Effects on lipid metabolism: • Adipose tissue responds within minutes to administration of insulin, which causes a significant reduction in the release of fatty acids. – Decreased triacylglycerol degradation: Insulin decreases the level of circulating fatty acids by inhibiting the activity of hormone-sensitive lipase in adipose tissue. 28

– Increased triacylglycerol synthesis: § Insulin increases the transport and metabolism of glucose into adipocytes, providing the substrate glycerol 3 -phosphate for triacylglycerol synthesis. § It also increases the lipoprotein lipase activity of adipose tissue by increasing the enzyme's synthesis, thus providing fatty acids for esterification. 29

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Effects on protein synthesis: • In most tissues, insulin stimulates the entry of amino acids into cells, and protein synthesis. 31

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Glucagon • Glucagon is a polypeptide hormone secreted by the α cells of the pancreatic islets of Langerhans. • Glucagon, along with epinephrine, cortisol, and growth hormone (the “counter-regulatory hormones”), opposes many of the actions of insulin. - Most importantly, glucagon acts to maintain blood glucose levels by activation of hepatic glycogenolysis and gluconeogenesis. 33

Structure of Glucagon: • Glucagon is composed of 29 amino acids arranged in a single polypeptide chain. • It is synthesized as a large precursor molecule that is converted to glucagon through a series of selective proteolytic cleavages. 34

Inhibition of glucagon secretion • Glucagon secretion is significantly decreased by elevated blood glucose and by insulin. • Both substances are increased following ingestion of glucose or a carbohydrate-rich meal. 35

Glucagon Effects on carbohydrate metabolism 36

Effects on lipid metabolism 37

Effects on protein metabolism • Glucagon increases uptake of amino acids by the liver, resulting in increased availability of carbon skeletons for gluconeogenesis. • As a consequence, plasma levels of amino acids are decreased. 38

Hypoglycemia • Hypoglycemia is characterized by: 1. central nervous system (CNS) symptoms, including confusion, aberrant behavior, or coma 2. a simultaneous blood glucose level equal to or less than 40 mg/dl 3. symptoms being resolved within minutes following the administration of glucose. 39

• Hypoglycemia is a medical emergency because the CNS has an absolute requirement for a continuous supply of bloodborne glucose to serve as fuel for energy metabolism. • Transient hypoglycemia can cause cerebral dysfunction, • whereas severe, prolonged hypoglycemia causes brain death. 40

• The body has multiple overlapping mechanisms to prevent or correct hypoglycemia. • The most important hormone changes in combating hypoglycemia are elevated glucagon and epinephrine, combined with the diminished release of insulin. 41

Types of hypoglycemia 1. Insulin-induced hypoglycemia: - Hypoglycemia occurs frequently in patients with diabetes who are receiving insulin treatment. - particularly those striving to achieve tight control of blood glucose levels. - Mild hypoglycemia in fully conscious patients is treated by oral administration of carbohydrate. 42

2. Postprandial hypoglycemia: • This is the second most common form of • • • hypoglycemia. caused by an exaggerated insulin release following a meal, prompting transient hypoglycemia with mild adrenergic symptoms. The plasma glucose level returns to normal even if the patient is not fed. The only treatment usually required is that the patient eat frequent small meals rather than the usual three large meals 43

3. Fasting hypoglycemia: § Low blood glucose occurring during fasting is rare, but is more likely to present as a serious medical problem. § Fasting hypoglycemia, which tends to produce neuroglycopenia symptoms, may result from a reduction in the rate of glucose production by the liver. 44

• Low blood glucose levels are often seen in patients with hepatocellular damage, or in fasting individuals who have consumed large quantities of ethanol. • Alternately, fasting hypoglycemia may be the result of an increased rate of glucose use by the peripheral tissues, most commonly due to elevated insulin resulting from a pancreatic β-cell tumor. • If left untreated, a patient with fasting hypoglycemia may lose consciousness and experience convulsions and coma. 45