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.
