Biochemical Structure &

function of Glucagon &

Somatostatin

By Dr Namrah Zubair
Demonstrator Biochemistry LCMD
Glucagon
Glucagon is a peptide hormone, produced by 
alpha cells of the pancreas. It works to raise the
concentration of glucose and fatty acids in the
bloodstream, and is considered to be the main 
catabolic hormone of the body. Its effect is
opposite to that of insulin, which lowers
extracellular glucose. It is produced from 
proglucagon, encoded by the GCG gene.
Structure of Glucagon
Glucagon is a 29-amino acid polypeptide.
It is a peptide hormone.
It is generated from the cleavage of 
proglucagon by pro-protein convertase 2 in
pancreatic islet α cells. In intestinal L cells, 
proglucagon is cleaved to the alternate
products, GLP-1 (an incretin), and GLP-2
 (promotes intestinal growth).
Mechanism Of Action
The pancreas releases glucagon when the amount
of glucose in the bloodstream is too low. Glucagon
causes the liver to convert stored glycogen into 
glucose, which is released into the bloodstream .
So, glucagon and insulin are part of a feedback
system that keeps blood glucose levels stable.
Glucagon increases energy expenditure and is
elevated under conditions of stress . Glucagon
belongs to the secretin family of hormones.
Glucagon binds to the glucagon receptor, a G protein-coupled receptor
, located in the plasma membrane. The conformation change in the
receptor activates G proteins, a heterotrimeric protein with α, β, and γ
subunits. When the G protein interacts with the receptor, it undergoes
a conformational change that results in the replacement of the GDP
 molecule that was bound to the α subunit with a GTP molecule. This
substitution results in the releasing of the α subunit from the β and γ
subunits. The alpha subunit specifically activates the next enzyme in
the cascade, adenylate cyclase.
Adenylate cyclase manufactures cyclic adenosine monophosphate
 (cyclic AMP or cAMP), which activates protein kinase A (cAMP-
dependent protein kinase). This enzyme, in turn, activates 
phosphorylase kinase, which then phosphorylates 
glycogen phosphorylase b (PYG b), converting it into the active form
called phosphorylase .
 This regulates primary regulatory step of glycolysis by slowing the rate
of its formation, thereby inhibiting the flux of the glycolysis pathway
and allowing gluconeogenesis to predominate. This process is
reversible in the absence of glucagon.
Secretion of Glucagon

Secretion of Liver
Dec blood Glucagon from • Glycogenolysis
glucose pancreas • Gluconeogenesis
• Ketone synthesis

Increase glucose Blood glucose

back to basal
Increase ketones level
Regulation of Glucagon secretion

Secretion of glucagon is stimulated by:

1. Hypoglycemia
2. Epinephrine (via β2, α2,and α1 adrenergic
receptors)
3. Arginine
4. Alanine (often from muscle-derived
pyruvate/glutamate transamination)
5. Acetylcholine
6. Cholecystokinin
7. Gastric inhibitory polypeptide
Secretion of glucagon is inhibited by:
1. Somatostatin
2. Amylin 
3. Insulin 
4. Increased free fatty acids and keto acids into
the blood.
5. Increased urea production
6. Glucagon-like peptide-1
Diseases
Glucagonoma :Abnormally elevated levels of glucagon may be
caused by pancreatic tumor, symptoms of which include reduced
amino acids, and hyperglycemia. It may occur alone or in the
context of multiple endocrine neoplasia type 1.
Elevated glucagon is the main contributor to hyperglycemic
ketoacidosis in undiagnosed or poorly treated type 1 diabetes.
As the beta cells cease to function, insulin and pancreatic GABA
are no longer present to suppress the free running output of
glucagon. As a result, glucagon is released from the alpha cells
at a maximum, causing rapid breakdown of glycogen to glucose
and fast ketogenesis .
The absence of alpha cells (and hence glucagon) is thought to
be one of the main influences in the extreme volatility of blood
glucose in the setting of a total pancreatectomy.
Somatostatin
Somatostatin, also known as growth
hormone-inhibiting hormone (GHIH), is a 
peptide hormone that regulates the 
endocrine system and affects neurotransmission
 and cell proliferation via interaction with 
G protein-coupled somatostatin receptors and
inhibition of the release of numerous secondary
hormones. Somatostatin inhibits insulin and
glucagon secretion.
Structure:
Somatostatin has two active forms produced by
the alternative cleavage of a single preproprotein:
one consisting of 14 amino acids 
 other consisting of 28 amino acids.
Nomenclature :
Synonyms of "somatostatin" include:
1. growth hormone–inhibiting hormone (GHIH)
2. growth hormone release–inhibiting hormone
(GHRIH)
3. somatotropin release–inhibiting factor (SRIF)
4. somatotropin release–inhibiting hormone (SRIH)
Production
Digestive system
Somatostatin is secreted by delta cells at
several locations in the digestive system,
namely the 
1. pyloric antrum
2. duodenum 
3. pancreatic islets.
Mechanism Of action
 Somatostatin released in the pyloric antrum travels via the portal
venous system to the heart, then enters the systemic circulation to
reach the locations where it will exert its inhibitory effects.
 In the stomach, it acts directly on the acid-producing parietal cells
 via a G-protein coupled receptor (which inhibits adenylate cyclase,
thus effectively antagonizing the stimulatory effect of histamine) to
reduce acid secretion. Somatostatin can also indirectly decrease
stomach acid production by preventing the release of other
hormones, including gastrin and histamine which effectively slows
down the digestive process.
 In addition, somatostatin release from delta cells can act in a 
paracrine manner.
Brain:
Somatostatin is produced by neuroendocrine
 neurons of the ventromedial nucleus of the 
hypothalamus. It is carried to the 
anterior pituitary gland, where it inhibits the
secretion of growth hormone from somatotrope
 cells.
Somatostatin is also produced by several other
populations that project centrally e.g the arcuate
nucleus, the hippocampus, and the brainstem 
nucleus of the solitary tract.
 Anterior
GI system
pituitary
Inhibit release of glucagon
Inhibiting adenylyl cyclase in parietal cells

Suppresses the release of pancreatic

hormones
Inhibiting the release of thyroid-stimulating
hormone (TSH)
Decreases the rate of gastric emptying,
and reduces smooth muscle contractions
and blood flow within the intestine
Inhibiting the release of growth hormone
(GH)
Somatostatin suppresses the release of GI
hormones

Inhibiting the release of prolactin (PRL) Somatostatin release is triggered by the

beta cell peptide urocortin3 to inhibit
insulin release.
Synthetic Substitute
Octreoride (brand name Sandostatin,) is an octapeptide that
mimics natural somatostatin pharmacologically, though is a
more potent inhibitor of growth hormone, glucagon, and insulin
than the natural hormone, and has a much longer half-life
 (about 90 minutes, compared to 2–3 minutes for somatostatin).
It is indicated for symptomatic treatment of carcinoid syndrome
 and acromegaly. It is also finding increased use in polycystic
diseases of the liver and kidney.
Lanreotide (Somatuline,) is a medication used in the
management of acromegaly and symptoms caused by
neuroendocrine tumors, most notably carcinoid syndrome. It is
a long-acting analog of somatostatin.
Pancreatic Polypeptide
Pancreatic polypeptide (PP) is a polypeptide secreted
by PP cells in the endocrine pancreas predominantly in
the head of the pancreas. It consists of 36 amino acid.
The function of PP is to self-regulate pancreatic secretion
activities (endocrine and exocrine). It also has effects on
hepatic glycogen levels and gastrointestinal secretions.
Its secretion in humans is increased after a protein meal, 
fasting, exercise, and acute hypoglycemia, and is
decreased by somatostatin and intravenous glucose.
Plasma PP has been shown to be reduced in conditions
associated with increased food intake and elevated in 
anorexia nervosa.. It is the antagonist of cholecystokinin
 and inhibits the pancreatic secretion which is stimulated
by cholecystokinin.