Download Pancreatic Hormones and Insulin Receptor Agonists

Pancreatic Hormones and
Insulin Receptor Agonists
Hongmei Li
Mar. 21th, 2006
The bulk of the pancreas is an exocrine gland
secreting pancreatic fluid into the duodenum
after a meal.
Inside the pancreas are millions of clusters of
cells called islets of Langerhans. The islets are
endocrine tissue containing four types of cells.
In order of abundance, they are:
beta cells, which secrete insulin and amylin;
alpha cells, which secrete glucagon;
delta cells, which secrete somatostatin
gamma cells, which secrete a polypeptide.
Pancreatic Hormones





Insulin
Amylin
Glucagon
Somatostatin
Pancreatic Polypeptide
A chain
Insulin is a small protein consisting of an A
chain of 21 amino acids linked by two disulfide
(S—S) bridges to a B chain of 30 amino acids.
Beta cells have channels in their plasma
membrane that serve as glucose
detectors. Beta cells secrete insulin in
response to a rising level of circulating
glucose.
B chain
Insulin affects many organs:
 It stimulates skeletal muscle
fibers.
 It stimulates liver cells.
amino acids
uptake
glucose
uptake
protein
synthesis
glycogen
synthesis
 It acts on fat cells
fat
synthesis
 It inhibits production of certain
enzyme.
In each case, insulin triggers
these effects by binding to the
insulin receptor.
enzyme
production
glycogen
breaking
Pancreatic Hormones





Insulin
Amylin
Glucagon
Somatostatin
Pancreatic Polypeptide
 Amylin
 Amylin is a peptide of 37 amino acids.
 It inhibits the secretion of glucagon;
 It slows the emptying of the stomach;
 It sends a satiety signal to the brain.
All of its actions tend to supplement those
of insulin, reducing the level of glucose in
the blood.
Pancreatic Hormones





Insulin
Amylin
Glucagon
Somatostatin
Pancreatic Polypeptide
Glucagon
Glucagon, a polypeptide of 29 amino acids, acts
principally on the liver.
 It stimulates the conversion of glycogen into glucose.
 It stimulates the conversion of fat and protein into
intermediate metabolites that are ultimately
converted into glucose.
Glucagon secretion is stimulated by low levels of
glucose in the blood; inhibited by high levels, and
inhibited by amylin.
Pancreatic Hormones





Insulin
Amylin
Glucagon
Somatostatin
Pancreatic Polypeptide
 Somatostatin
Somatostatin consists of two polypeptides,
one of 14 amino acids and the other of 28.
They work together to reduce the rate at
which food is absorbed in the intestine.
Pancreatic Hormones





Insulin
Amylin
Glucagon
Somatostatin
Pancreatic Polypeptide
Pancreatic Polypeptide by Gamma Cells
The gamma cells of the islets secrete a 36amino-acid pancreatic polypeptide, which
reduces appetite.
The insulin receptor (IR)
is a transmembrane
glycoprotein, composed
of 2α and 2β domains.
.
Its intracellular tyrosine
kinase domain is
activated by binding of
insulin, leading to a
cascade of signaling
events.
Who need insulin medicine
 Type I (insulin dependent) diabetes patients
whose body produces no insulin.
 Type 2 diabetes patients that do not always
produce enough insulin.
Treatment
 subcutaneous injection
Insulin drug evolution
Stage 1 Insulin was extracted from the glands of
cows and pigs. (1920s)
Stage 2 Convert pig insulin into human insulin by
removing the one amino acid that distinguishes them
and replacing it with the human version.
 Stage 3 Insert the human
insulin gene into E. coli and
c ul t ure t he rec om b in a n t
E.coli to produce insulin
(trade name = Humulin ® ).
Yeast is also used to produce
insulin (trade name =
Novolin®) (1987).
Recombinant DNA technology has also made it possible to
manufacture slightly-modified forms of human insulin that
work faster (Humalog® and NovoLog®) or slower
(Lantus®) than regular human insulin.
Types of insulin
•
Regular insulins
•
Insulin analogs
•
Pre-mixed insulin
Short peptide mimics
Regular insulins:
 Human insulin: Humulin® (from E.coli),
Novalin® (from yeast)
 NPH - neutral protamine Hagedorn (NPH),
protamine mixed.
 Lente® insulin / Ultralente® insullinzinc added
Types of insulin
•
Regular insulins
•
Insulin analogs
•
Pre-mixed insulin
Short peptide mimics
Insulin Analogs:
 Fatty Acid Acylated insulins
 Insulin Lispro (Humalog®) (1996)
 Insulin Aspart (NovoLog®) (2000)
 Insulin Glargine (Lantus®) (2002)
 Insulin Detemir (Levemir®) (Jun.,2005)
 Insulin Glulisine (Apidra®) (Jan., 2006)
Amino Acid Substitutons
A- chain
Position
B- chain Position
Source/
Type
A21
B3
B28
B29
B30
Human
Asn
Asn
Pro
Lys
Thr
Aspart
Asn
Aspartic
acid
Lys
Thr
Lispro
Asn
Lys
Pro
Thr
Glulisine
Asn
Pro
Glu
Thr
Glargine
Gly
Pro
Lys
Thr
Lys
Myristic
acid
Detemir
Lys
B31
And
B32
rapid-acting
Arg
long-acting
Types of insulin
•
Regular insulins
•
Insulin analogs
•
Pre-mixed insulin
Short peptide mimics
Types of insulin
•
Regular insulins
•
Insulin analogs
•
Pre-mixed insulin
Short peptide mimics
Short surrogate peptides
IR
Insulin receptors
were used as targets
to screen surrogate
peptides in random
peptide phage
display libraries.
Short surrogate peptides
H2C-D117: 14 a.a.
RP9-S371: 16 a.a.
20E2-D118: 24 a.a.
Future Directions for new IR agonists






Increased Stability
Less Variability
High Selective Action
Ultra Rapid Onset
Ultra Long Activity
W/O side effects
References








Renuka C. P. et.al (2002) J. Biol. Chem. 277, 22590–4
Zoltan V. AND William C. D. (2001) Pharm. Rev. 52, 1-9
Lauge S. et. Al (2003) PNAS 100, 4435-9
Mark R. B. (1997) J. of Clin. Endoc.& Met. 82, 3-7
Gianni C. (1992) FEBS 307, 66-70
Irl B. H., (2001) Clin. Diabetes 19, 146-7
BRUCE W. B. and POUL S. (2001) Diabetes care 24,69-72
http://www.indstate.edu/thcme/mwking/diabetes.html