Control Of Metabolic Fuels - pediagenosis
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Tuesday, March 21, 2023

Control Of Metabolic Fuels

Control Of Metabolic Fuels

Control Of Metabolic Fuels

Animal cells utilize glucose and fatty acids as fuels to generate the energy-rich molecule adenosine triphosphate (ATP) (Chapter 3). The blood levels of these molecules must be carefully controlled to ensure a steady supply of fuel to active tissues, a task that is complicated by the tendency of many animals (not ruminants) to eat discrete meals rather than continuously. Immediately after a meal, circulating levels of fuel molecules rise and any excess to immediate requirements is stored. This requires the transport of the molecules into cells (primarily liver, skeletal muscle and the fat-storing cells of adipose tissues) and the synthesis of storage molecules, such as glycogen, a polymer of glucose, triglycerides (fats) and, to a lesser extent, proteins. As time after a meal increases, the consumption of blood glucose and fatty acids necessitates the activation of tissue energy stores. Glycogen is broken down into glucose, triglycerides are converted into free fatty acids and ketone bodies and, if the fast is prolonged, proteins are catabolized to provide a supply of amino acids that can be converted to glucose (gluconeogenesis). The body thus alternates between two states, which can be described as anabolic, in which storage molecules are manufactured, and catabolic in which the same molecules are broken down (Fig. 43a). Switching between these states is controlled mainly by hormones, with the pancreatic proteins insulin and glucagon being the prime movers of the anabolic and catabolic processes, respectively. In addition, growth hormone (Chapter 47), cortisol, adrenaline (epinephrine) and noradrenaline (norepinephrine) (Chapter 49) can stimulate catabolic processes (Fig. 43a). There is growing evidence that hormones produced from fat (e.g. leptin) and the gut (e.g. ghrelin from the stomach) are involved in energy homeostasis, including controlling food intake, energy expenditure and adiposity.

Insulin and glucagon
These hormones are made in the endocrine tissues of the pancreas, known as the islets of Langerhans. Three main types of cell have been identified within the islets: peripherally located A (also known as α) cells, which manufacture and secrete glucagon; centrally located B (or β) cells for the production and release of insulin; and D (δ) cells that synthesize and liberate somatostatin. The exact role of somatostatin has not been established, but it may be involved in controlling the release of the other two hormones. Insulin release is stimulated initially during eating by the parasympathetic nervous system and gut hormones, such as secretin (Chapter 39), but most output is driven by the rise in plasma glucose concentration that occurs after a meal (Fig. 43a,b). Circulating fatty acids, ketone bodies and amino acids augment the effect of glucose. The major action of insulin is to stimulate glucose uptake, with the subsequent manufacture of glycogen and triglycerides by adipose, muscle and liver cells. Its effects are mediated by a receptor tyrosine kinase (RTK; Fig. 43c; Chapter 47). The enzyme activates an intracellular pathway that results in the translocation of the glucose transporter GLUT-4 and to a lesser extent GLUT-1 to the plasma membrane of the affected cell, to facilitate the entry of glucose (Fig. 43c). Insulin thus decreases plasma glucose. Insulin release is reduced as the blood glucose concentration falls, and is further inhibited by catecholamines (Chapter 49) acting at B-cell α2- adrenoceptors (Chapters 7 and 49). Glucagon release patterns tend to be the mirror image of those of insulin. Low blood glucose initiates glucagon release directly and also drives nervous and hormonal release of catecholamines, which activate β-adrenoceptors (Chapters 7 and 49) on A cells to augment glucagon release. Glucagon acts on guanosine triphosphate-binding protein (G-protein)-coupled receptors that stimulate the production of intracellular cyclic adenosine monophosphate (cAMP) (Chapter 4). In liver cells, this results in the inhibition of glycogen synthesis and the activation of glycogen breakdown systems. Similar effects are obtained in muscle cells to increase circulating levels of glucose. There are interactions between glucagon and insulin within the islets: insulin inhibits A-cell release of glucagon, but glucagon stimulates the release of insulin, an effect that ensures a basal level of insulin release irrespective of glucose levels. The two hormones operate as part of a classical negative feedback system (Fig. 43a; Chapter 1), in which the A and B cells act as combined sensors comparators, and their hormones activate the effector tissues.

Diabetes mellitus
This disease is caused by failure of B-cell function, either by autoimmune attack, in which the immune system (Chapter 10) misidentifies the cells as non-self and destroys them, or by pathologies, such as obesity, that impair insulin release. The former type of disease is usually early onset and is treated with insulin (insulin-dependent diabetes), whereas the latter develops later and is treated by diets that lower blood glucose levels or drugs that stimulate insulin release (non–insulin-dependent diabetes). Untreated, the condition leads to chronically high levels of plasma glucose (hyperglycaemia), over-loading of the kidney glucose transporters (Chapter 33) so that sugar begins to appear in the urine. The osmotic effect of glucose leads to excess production of urine (polyuria) that tastes sweet (this used to be the diagnostic test for diabetes, and gives the disease its name; Latin mellitus = sweet). Long-term hyperglycaemia drives excessive lipolysis by liver cells, leading to a build-up of ketone bodies and the condition known as ketoacidosis. This disrupts brain function, causing coma and eventually death. A sharp fall in blood glucose (hypoglycaemia) caused by excessive insulin administration starves the brain of its main metabolic fuel and, by a sad  irony,  can  also  lead  to coma and death (Fig. 43a). The main symptoms of hyper- and hypoglcaemia are shown in Table 43. Long-term complications of diabetes include damage to small blood vessels, especially in the retina and renal nephron (diabetic retinopathy and nephropathy). This is at least partly due oxidative stress as a result of the hyperglycaemia.

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