Insulin and Glucagon

Steroid Hormones
Images

Pancreas

Exocrine pancreas
Digestive enzymes

Endocrine pancreas
Insulin
Glucagon
Somatostatin
Pancreatic polypeptide

The pancreas contains two distinctly different tissues. The bulk

of the mass is exocrine tissue and associated ducts which
produce an alkaline fluid with digestive enzymes that is delivered
to the small intestine. Scattered throughout the exocrine tissues
are clusters of endocrine cells which produce, among others, the
hormones insulin and glucagon.

Cell types in the endocrine pancreatic Islets of Langerhans

Cell types

Secretory Products

A cell ()

Glucagon, proglucagon, glucagon-like

peptides (GLP-1, GLP-2)

B cell ()

Insulin, C peptide, proinsulin, amylin,

-aminobutyric acid (GABA)

D cell ()

Somatostatin

F cell (PP cell) Pancreatic polypeptide

Beta cells usually

occupy the central
portion of an islet
and are surrounded
by alpha and delta
cells.

Three Islets of Langerhans in the

pancreas of a horse

In 1916 Nicolae Paulescu, a Romanian professor of physiology,

developed an aqueous pancreatic extract which, when injected
into a diabetic dog, proved to have a normalizing effect on blood
sugar levels. He had to interrupt his experiments because the
World War I and in 1921 he wrote four papers about his work
carried out in Bucharest and his tests on a diabetic dog. Later that
year, he detailed his work by publishing an extensive whitepaper
on the effect of the pancreatic extract injected into a diabetic
animal, which he called: "Research on the Role of the Pancreas in
Food Assimilation.

The Nobel Prize committee in 1923 credited the practical

extraction of insulin to a team at the University of Toronto and
awarded the Nobel Prize to two men: Frederick Banting and J.J.R.
Macleod.

Synthesis and secretion

of insulin

Processing of Insulin
Preproinsulin
Preproinsulin is a long-chain polypeptide (MW 11,500) produced
by mRNA-directed translation in the rough endoplasmic reticulum.
Proinsulin
Preproinsulin is cleaved immediately after synthesis to proinsulin
(MW 9000). Proinsulin is transported to the Golgi and packaged into
secretory granules.
Insulin and C peptide
Maturation of the secretory granule involves proteolytic cleavage of
proinsulin into insulin and C peptide. Normal mature secretory
granules contain these in equimolar amounts and only small
quantities of proinsulin.

Proinsulin consists of a single chain of 86 amino acids which

includes the A and B chains of insulin, and a connecting
segment of 35 amino acids.

Insulin hexamer
with two Zn atoms

The hexameric form of insulin

is thought to exist in the
secretory granules of the
pancreatic B cells.

Glucose Transporters
All cells require proteins to transport glucose across the lipid
bilayers into the cytosol.
The intestine and kidney have an energy dependent
Na+/glucose cotransporter.
All other cells have non-energy dependent transporters that
facilitate diffusion of glucose from a higher concentration to a
lower concentration across cell membranes. At least five
facilitative glucose transporters have been described, and
these have different affinities for glucose (GLUT1, GLUT2,
GLUT3, GLUT4, and GLUT5).

Human glucose transporters

Transporter

Major sites of expression

Affinity for
glucose

GLUT1

Brain vasculature, red blood cells, all

tissues

High

GLUT2

Liver, pancreatic B cells, serosal

surfaces of gut and kidney

Low

GLUT3

Brain neurons, all tissues

High

GLUT4

Muscle, fat cells

Medium

GLUT5

Jejunum, liver, spermatozoa

Medium

GLUT1 is present in all tissues especially brain vascular system

(blood-brain barrier). Its high affinity for glucose ensures
adequate uptake even at low blood glucose levels (basal levels).
GLUT3 is the main neuronal glucose transporter. It has a very
high affinity for glucose and is responsible for transferring
glucose from the cerebrospinal fluid into neuronal cells.
GLUT2 has a low affinity for glucose. It is the major
transporter in the liver and pancreatic B cells. This insures that
insulin is secreted only when blood glucose levels are high. It
also prevents hepatic uptake when levels are basal or low as
during fasting.

GLUT4 is found in two major insulin-targeted tissues,

muscle and adipose tissue. It is not present to a great
extent on the cell surface until an insulin signal relocates
these transporters to the cell membrane. Thus GLUT4
functions primarily after a high carbohydrate meal when
insulin is secreted.
GLUT5 appears to function biochemically as a fructose
transporter.

Stimulus for insulin secretion

Glucose is the most potent simulate to pancreatic B cells for
insulin secretion.
Glucose enters B cells through GLUT2 (low affinity for glucose).
The metabolism of glucose is apparently required for insulin
secretion. The rate limiting step for glucose utilization in the B
cells is phosphorylation to glucose-6-phosphate by the lowaffinity enzyme glucokinase.
Glucose induces cAMP formation in B cells. However,
increased [cAMP] will not induce insulin in the absence of
glucose.
Insulin release also requires Ca2+ ( microtubules that
contract in response to Ca2+ may play a role in the ejection
of insulin granules).

Multiphasic response of the in vitro perfused pancreas

during constant stimulation with glucose

Insulin Receptors
Insulin action begins with the binding to specific cell surface
receptors.
Insulin receptors are membrane glycoproteins composed of
two subunits: a larger subunit which extends beyond the
cell surface and is involved in the binding of insulin, and a
smaller subunit which is predominately intracellular and
contains tyrosine kinase activity.
Upon insulin binding, signal transduction results in
autophosphorylation of the receptor tyrosine kinase. This
now activated complex, interacts with and phosphorylates a
network of as many as nine intracellular proteins.

The insulin receptor is a

tyrosine-specific kinase

Upon insulin binding, signal

transduction causes
autophosphorylation of the receptor,
activating the complex. The target
proteins, IRS-1 and IRS-2, are then
phosphorylated.

The immediate targets for the activated insulin receptor tyrosine

kinase are insulin receptor substrate-1 (IRS-1) and insulin
receptor substrate-2 (IRS-2).
IRS-1 becomes the point of nucleation for a complex of proteins
that carry the signal from the insulin receptor to end targets in
both the cytosol and the nucleus.

Abbreviations used in previous figure

IRS-1: insulin receptor substrate-1
PI-3K: phosphatidylinositiol 3-kinase (phosphorylates
phosphatidylinositol-4,5-bisphosphate (PIP2) to form
phosphatidylinositol-3,4,5-trisphsophate (PIP3).
PKB: protein kinase B
PDK1: a protein kinase
GSK3: glycogen synthase kinase 3
GS: glycogen synthase
GluT4: glucose transporter 4

Metabolic effects of insulin

The major function of insulin is to promote storage of ingested
nutrients. Blood glucose is converted to glycogen (muscle and
liver) and into triacylglycerols (adipose tissue).
Liver
Promotes glucose storage as glycogen
Increases triglyceride synthesis and VLDL formation
Inhibits glycogen breakdown
Inhibits conversion of fatty acids and amino acids to keto
acids
Inhibits conversion of amino acids to glucose

Muscle
Increases ribosomal protein synthesis
Increases amino acids uptake
Increases glucose transport
Increases glycogen synthesis and inhibits glycogen breakdown
Adipose tissue
Increases triglyceride storage
Inhibits intracellular lipase
Promotes uptake of fatty acids
Increases glucose transport
Reduces fatty acid flux to the liver

Metabolic effects of insulin

Metabolic effect

Target enzyme

Glucose uptake (muscle)

Glucose transporter

Glucose uptake (liver)

Glucokinase

Glycogen synthesis (liver, muscle)

Glycogen synthase

Glycogen breakdown (liver, muscle)

Glycogen phosphorylase

Glycolysis, acetyl-CoA production

(liver, muscle)

Phosphofructokinase-1,
pyruvate dehydrogenase
complex

Fatty acid synthesis (liver)

Acetyl-CoA carboxylase

Triacylglycerol synthesis (adipose)

Lipoprotein lipase

Glucagon
Synthesized in the A cells of the Islets of Langerhans, the
precursor molecule, proglucagon, is composed of 160 amino
acids. Within this prohormone are several other peptides
connected in tandem:
glicentin-related polypeptide (GRPP)
glucagon
glucagon-like peptide-1 (GLP-1)
glucagon-like peptide-2 (GLP-2)

Levels of GLP-1 and GLP-2 both increase after meals.

A truncated derivative of GLP-1 (residues 7-37) is an
extremely potent stimulator of pancreatic B cells. This
molecule is thought to be the major physiological gut
factor which potentiates glucose-induced insulin secretion.
Intact GLP-1 and GLP-2 do not stimulate insulin secretion.

Tissue specific secretory products of human proglucagon

Secretion of glucagon
The release of glucagon is controlled primarily through suppression
by glucose and insulin.
Glucagon secretion is inhibited by glucose. This may be direct, or
indirect via the release of insulin and somatostatin.
Several hours after the intake of dietary carbohydrates, blood
glucose levels fall below 4.5 mM and trigger the secretion of
glucagon. Basically, this signal says: glucose is gone.

Other substances that stimulate glucagon release:

catecholamines (epinephrine)
the gastrointestinal hormones (cholecystokinin,
gastrin, and gastrin-inhibitory peptide)
glucocorticoids (cortisol)
High levels of fatty acids are associated with suppression of
glucagon release.
Many amino acids stimulate glucagon release:
Arginine: releases both insulin and glucagon
Leucine, a good stimulant for insulin release, does
not release glucagon.
Alanine stimulates glucagon primarily.

Glucagon Receptors
The liver is one of the major target organs for glucagon.
Glucagon binds to hepatic receptors in the cell membrane
and stimulates adenylyl cyclase and thus increases the
intracellular concentration of cAMP.

Metabolic effects of glucagon

Glucagon acts to maintain fuel availability in the absence of
dietary glucose.
Glucagon stimulates the breakdown of stored glycogen,
maintains hepatic output of glucose from amino acid
precursors (gluconeogenesis), and promotes hepatic output
of ketone bodies from fatty acid precursors (ketogenesis).
Uptake of alanine by liver cells is facilitated by glucagon and
fatty acids are directed away from reesterification to
triacylglycerols and toward ketogenic pathways.

Metabolic effects of glucagon

Metabolic effect

Target enzyme

Glycogen breakdown (liver)

Glycogen phosphorylase

Glycogen synthesis (liver)

Glycogen synthase

Glycolysis (liver)

Phosphofructokinase-1

Gluconeogenesis (liver)

Fructose-1,6-bisphosphatase
Pyruvate kinase

Fatty acid mobilization

(adipose tissue)

Triacylglycerol lipase

Blood glucose, insulin, and

glucagon levels after a high
carbohydrate meal.

Release of insulin and

glucagon after a high
protein meal (100
grams of protein after
an overnight fast)

Insulin levels do not increase

nearly as much as after a
high carbohydrate meal.
Glucagon increases above
fasting levels.

Steroid hormones
production

Images