1. Hello, everyone. My name is Minsoo Choi. I’m
in a laboratory for Systems Biology and Bio-inspired Engineering. I will give you the lecture of
front part of chapter 11: therapeutic hormone. 2.
First, I will introduce you about a general definition of hormone. Then we will discuss
3 endocrine hormone, Insulin, glucagon and growth hormone for a detail.
3. Originally, the term hormone was defined as
a substance synthesized and released from a specific gland in the body to generate a
change in that target cell by interacting with a receptor. Hormones travel to the target
cell via the circulatory system. In this lecture, we will introduce 3 endocrine hormones including
insulin, glucagon and GH. . 4.
As you can see a left figure, insulin is a polypeptide hormone produced by the beta cells
of the pancreatic islets of Langerhans. Its most important targets are skeletal muscle
fibres, hepatocytes and adipocytes. It plays a central role in regulating blood glucose
levels.Insulin orchestrates a suitable metabolic response to the absorption of glucose and
other nutrients in a number of ways: it stimulates glucose transport into cells and reducing
their blood concentration and intracellular anabolic such as glycogen synthesis Furthermore,
insulin inhibits catabolic pathways, such as glycogenolysis
5. Failure of the body to synthesize sufficient
insulin results in the development of insulin-dependent diabetes mellitus (IDDM). This is also known
as type-1 diabetes. This picture describes a contrasting situation in normal and IDDM
condition. IDDM is caused by T-cell-mediated autoimmune destruction of the insulin-producing
β-pancreatic islet cells in genetically predisposed individuals.
6. Insulin was first identified as an anti-diabetic
factor in 1921, and was introduced clinically the following year. Preproinsulin is transcribed
as a 110 amino acid chain and proinsulin is produced by the removal of the signal peptide.
Proinsulin is proteolytically processed in the coated secretory granules. , yielding
mature insulin and a 34-amino acid connecting peptide(C peptide). Removal of the connecting
C peptide chain produces mature Insulin. The C peptide is further proteolytically modified
by removal of a dipeptide from each of its ends. The insulin is stored in the form of
a characteristic zinc–insulin hexamer, consisting of six molecules of insulin stabilized by
two zinc atoms. Mature insulin consists of two polypeptide chains connected by two interchain
disulfide linkages. The A-chain contains 21 amino acids, whereas the larger B-chain is
composed of 30 residues. 7.
The insulin receptor has two alpha subunits and two beta subunits. These are held together
by disulfide linkages. Binding of insulin to its receptor promotes the autophosphorylation
of three specific tyrosine residues in the tyrosine kinase domain. Activation of the
beta-subunit’s tyrosine kinase activity in turn results in the phosphorylation of
various intracellular substrates which trigger the mitogen-activated protein kinase and the
phosphoinositide (PI-3) kinase pathway responsible for inducing insulin’s mitogenic and metabolic
effects. This table shows the list of insulin-sensitive genes.
8. Traditionally, commercial insulin preparations
were produced by direct extraction from pancreatic tissue of slaughterhouse pigs and cattle.
However, the use of animal-derived product had a number of potential disadvantages such
as Immunogenicity and Availability. These issues and concerns result in the development
of recombinant human insulin products, now routinely used in the management of diabetes.
9. The initial approach to recombinant insulin
production taken entailed inserting the nucleotide sequence coding for the insulin A- and B-chains
into two different E. coli cells. It was termed ‘human insulin crb’. An alternative method
entails inserting a nucleotide sequence coding for human proinsulin into recombinant E. coli.
This approach has become more popular due to the requirement for a single fermentation
and subsequent purification scheme. Such preparations have been termed ‘human insulin prb’.
A right picture shows a purification scheme for human insulin prb. A final RP-HPLC ‘polishing’
step yields a highly pure product. 10.
Insulin may be formulated in a number of ways, generally in order to alter its pharmacokinetic
profile. This graph shows subtypes and approximate durations of action of different insulin formulations.Rapid
(short)-acting insulins are those preparations that yield an elevated blood insulin concentration
relatively quickly after their administration. On the other hand, long-acting insulins enter
the circulation much more slowly from the depot site. Therapy consists of injections
of slow- and fast-acting insulins, as appropriate, or a mixture of both. In order to prolong
the duration of insulin action, soluble insulin may be formulated to generate insulin suspensions.
This is generally achieved in one of two ways: Addition of zinc or proteamine
11. Recombinant DNA technology facilitates native
and engineered human insulin product. By generating the engineered insulin, it is possible to
make faster-acting, slower-acting insulins or super-potent insulin forms. This table
is about the native and engineered human insulin preparations that have gained approval for
general medical use. 12.
There have been attempts to improve upon the mode of administering insulin, as many people
find injection inconvenient and generally painful. Insulin is usually taken as subcutaneous injections
There is an alternative means like inhalable insulin.‘open-loop system’ consists of
an infusion pump. Blood glucose levels are monitored manually and the infusion rate is
programmed accordingly. They have not as yet become popular in practice, mainly due to
inconvenience. The closed-loop system (it is often termed the ‘artificial pancreas’)
consists of a pump, infusion device, an integral glucose sensor and computer. The system imitates
the feedback loop inherent to the pancreatic beta cells to control glucose levels. Transplantation of
insulin-producing pancreatic cells is being investigated.
13. The left picture shows the intimate relationship
both insulin and glucagon have to each other. The major biological actions of glucagon tend
to oppose those of insulin. When blood glucose concentrations decrease, insulin levels decrease
and the catabolic effects of glucagon become more prominent. The prominent metabolic effect
is to increase blood glucose levels. Glucagon initiates its metabolic effects by binding
to a specific cell surface receptor. Then a membrane-bound adenylate kinase is activated.
This promotes activation of a cyclic adenosine monophosphate (cAMP)-dependent protein kinase.
The kinase phosphorylates key regulatory enzymes in carbohydrate metabolism.
14. As you can see, Growth hormone (GH) is an
anabolic hormone made and secreted by the pituitary gland. GH is a large polypeptide
thought to encourage growth indirectly by stimulating the release of growth factors
from the liver and muscle. These growth factors create the cascade of events typically associated
with higher GH concentrations. GH is released in response to growth hormone releasing hormone
(GHRH) produced by the hypothalamus. GH primarily displays an anabolic activity. It partially
stimulates the growth of bone, muscle and cartilage cells directly.
During the years of active body growth, deficiency in the secretion of hGH results in pituitary
dwarfism. On the other hand, overproduction of hGH results in gigantism. After primary
body growth, hGH overproduction has occurred results in acromegaly.
15. As you can see the left table, GH has a potentially
wide range of therapeutic uses. GH is now produced by recombinant DNA technology and
is prescribed for a variety of reasons. The right table shows rhGH preparations approved
for general medical use.