Glucagon
Clinical background
Hypoglycaemia is an important
complication of insulin therapy in patients with diabetes. At the onset of the
disease most patients recognize the symptoms (Fig. 42d) and are able to take
remedial action, but ‘hypoglycaemia awareness’ decreases with the duration of
insulin treatment so that after 20 years of diabetes up to a half of patients
may have lost their awareness of the symptoms. Severe hypoglycaemia, requiring
the assistance of another person for treatment, is an important cause of
morbidity and mortality in insulin treated diabetics. Family members, friends
or school staff should be educated in recognition of the symp- toms and how to
treat it. Early symptoms can be treated with oral carbohydrate; if the patient
is unable to swallow intramuscular glucagon is helpful as is buccal glucose
gel. Patients and their relatives can be trained to administer intramuscular
glucagon. If there is evidence of impaired consciousness medical advice should
be sought and the patient treated with intravenous glucose.
Biosynthesis, storage and secretion
Glucagon is synthesized
principally in the pancreatic α-cell, and is cleaved from a much larger
precursor molecule, preproglucagon (179 amino acids in humans). The
preproglucagon gene in humans is located on chromosome 2. Preproglucagon yields
proglucagon (Fig. 42a). The N-terminal fragment of proglucagon is termed
glicentin-related polypeptide fragment (GRPP), so-called because it contains
glicentin (glucagon-like immunoreactivity-1), an intestinal glucagon
sequence-containing polypeptide. GRPP and glucagon are stored together in the
cell in granules, and released together in approximately equimolar quantities.
Both these peptides are also stored
and released from cells in the gut, and glucagon and GRPP form part of a larger
family of gut hormones (see Chapter 43). The glucagon content of a healthy
human adult pancreas ranges from about 3–5 μg/g of net pancreas weight.
Chemically, glucagon is a polypeptide
of molecular weight of about 3.5 kDa, consisting of 29 amino acids. The amino
acid sequence of glucagon has been well conserved throughout evolution, and the
whole amino acid sequence is required for full biological activity. If the
N-terminal histidine is replaced, the molecule loses biological activity.
Insulin, on the other hand, depends for its action more on the integrity of its
three-dimensional structure, rather than an absolute dependence on the amino
acid sequence. Unlike insulin, glucagon does not have a stable
three-dimensional structure in physiological solutions, but may acquire this
when it binds to its receptor.
Secretion of glucagon (Fig. 42b). Glucagon is rapidly secreted when
plasma glucose concentrations fall, and secretion is inhibited when glucose
concentrations rise. Secretion is inhibited also by other energy substrates,
such as ketone bodies and fatty acids. Amino acids, particularly arginine,
stimulate glucagon secretion (as they do insulin). In this situation, where
both insulin and glucagon are released simultaneously, the effect may be to
allow insulin to promote protein synthesis without a disturbance of normal
glucose homeostasis.
Insulin inhibits glucagon secretion
(Fig. 42b), perhaps through a paracrine reciprocal interaction between the
pancreatic α and β cells. Glucagon secretion is affected by gut hormones (see
Chapter 43), being stimulated by cholecystokinin (CCK) and vasointestinal
peptide (VIP). Somatostatin, another hormone secreted by the pancreas, among
many other tissues, inhibits the secretion of both glucagon and insulin.
The nervous system mediates glucagon
release, which is effected by cholinergic and β-adrenergic stimulation.
Electrical stimulation of the ventromedial hypothalamus in experimental animals
increases glucagon release.
Once released into the circulation,
glucagon circulates unbound to any plasma protein, and exists in several forms.
The hormone has a short half-life of about 5 minutes, being rapidly degraded,
especially in the kidney and liver. In the liver, glucagon binds to a specific
membrane receptor, after which it is degraded, a degradation process apparently
peculiar to glucagon.
Mechanism of action
Glucagon binds to a membrane receptor
on the target cell and activates the adenylate cyclase second messenger system
(Fig. 42c). It was through the study of glucagon action on gluconeogenesis that
the second messenger system of cellular response was first discovered. Glucose
up-regulates glucagon receptor expression while glucagon and agents that
increase intracellular cAMP down-regulate glucagon receptor expression. Glucagon
receptor antagonists have now been identified and may become available for
controlling circulating glucose in patients.
Effects of glucagon
Glucagon has the opposite effects to
those exerted by insulin. In the liver, the hormone promotes the
formation of glucose from the breakdown of glycogen. Glucagon, through cAMP,
blocks the enzyme cascade leading to glycogen synthesis at the level of the
enzyme activities between fructose-6-phosphate and fructose-1,6-diphosphate,
and between pyruvate and phosphoenolpyruvate. The glycolytic action of glucagon
is essential for maintaining short-term glucose blood levels, especially in the
fed state, when glycogen stores are high. In the liver, glucagon promotes the
conversion of amino acids to glucose. The hormone also promotes the conversion
of free fatty acids to ketone bodies.
Within the hepatocyte, glucagon
is lipolytic, liberating free fatty acids and glycerol, but its actions on the
hepatocyte may only be significant when insulin concentrations are low, since
insulin is a potent inhibitor of hepatocyte lipolysis.
Glucagon receptor mutations
Like mutations in the insulin
receptor, mutations in the glucagon receptor gene have been reported to be
linked to Type 2 diabetes. A single heterozygous missense mutation in exon 2 of
the glucagon receptor gene, which changes a glycine to a serine (Gly40Ser), was
associated with diabetes in a population of patients with Type 2 diabetes. The
mutated receptor was studied in vitro and the mutant receptor bound
glucagon with an approximately three-fold lower affinity compared with the wild
type receptor. Furthermore, the production of cAMP in response to glucagon was
decreased in cells expressing the mutant receptor compared with those
expressing the wild type.
