Transcript Diabetes Mellitus Overview and Treatments Andrew P. Vogt Chemistry 6116 Diabetes Mellitus : a group of diseases characterized by high levels of blood glucose resulting.

Diabetes Mellitus
Overview and Treatments
Andrew P. Vogt
Chemistry 6116
Diabetes Mellitus :
a group of diseases characterized by high levels of blood glucose
resulting from defects in insulin production, insulin action, or both
 20.8 million in US ( 7% of population)
 estimated 14.6 million diagnosed (only 2/3)
 Consists of 3 types:
1) Type 1 diabetes
2) Type 2 diabetes
3) Gestational diabetes
 Complications :
- Stroke
- Heart attack
- Kidney disease
- Eye Disease
- Nerve Damage
Diabetes Mellitus
 Type 1 Diabetes
- cells that produce insulin are
destroyed
- results in insulin dependence
- commonly detected before 30
 Type 2 Diabetes
- blood glucose levels rise due to
1) Lack of insulin
production
2) Insufficient insulin
action (resistant cells)
- commonly detected after 40
- effects > 90%
- eventually leads to β-cell failure
(resulting in insulin dependence)
Gestational Diabetes
3-5% of pregnant women in the US
develop gestational diabetes
Testing :
Fasting Plasma Glucose Test
(FPG) - (cheap, fast)
*fasting B.G.L. 100-125 mg/dl
signals pre-diabetes
*>126 mg/dl signals diabetes
Oral Glucose Tolerance Test
(OGTT)
*tested for 2 hrs after
glucoserich drink
*140-199 mg/dl signals prediabetes
*>200 mg/dl signals diabetes
A.K.A.: Glycated Hemoglobin tests
A1C

80 to 90 mg per 100 ml, is the normal fasting blood glucose
concentration in humans and most mammals which is
associated with very low levels of insulin secretion.
Diabetes - Insulin
 Discovered in 1921 by Banting
~
and Best
 Consist of A & B chains linked
by 2 disulfide bonds
(plus additional disulfide in A)
A = 21amino acids B = 30 amino acids
Diabetes – Insulin
(synthesis, storage, secretion)
 Produced within the pancreas by β
cells  islets of Langerhans
 insulin mRNA is translated as a
single chain precursor called
preproinsulin
 removal of signal peptide during
insertion into the endoplasmic
reticulum generates proinsulin
 Within the endoplasmic reticulum,
proinsulin is exposed to several
specific endopeptidases which
excise the C peptide, thereby
generating the mature form of
insulin
This light micrograph of a section
 Stored as β granules
of the human pancreas shows
one of the islets of Langerhans,
center, a group of modified
glandular cells. These cells
secrete insulin, a hormone that
helps the body metabolize
sugars, fats, and starches. The
blue and white lines in the islets
of Langerhans are blood vessels
that carry the insulin to the rest
Zn
Diabetes – Insulin
(Biochemical Role)
-Tyrosine Kinase
receptors are the locks
in which the insulin
key fits
- Involved in signal
transduction
(insulin hormone being 1st messenger)
In the case of type 1 diabetes, insulin levels
are grossly deficient. Thus type 1 diabetes is
invariably treated with insulin
Type 2 diabetes is frequently associated with
obesity. Serum insulin levels are normal or
elevated, so this is a disease of insulin
resistance. A number of treatment options
may be employed.
 Animation showing overview of diabetes:
 http://www.healthscout.com/animation/1/34
/main.html
 Animation showing mechanism of action of
insulin:
 http://www.vivo.colostate.edu/hbooks/pathp
hys/endocrine/pancreas/insulin_phys.html
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.
amino acids
uptake
protein
synthesis
 It stimulates liver cells.
 It acts on fat cells
glucose
uptake
 It inhibits production of certain
fat
synthesis
enzyme.
In each case, insulin triggers
these effects by binding to the
insulin receptor.
glycogen
synthesis
enzyme
production
glycogen
breaking
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
culture the recombinant 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-
B- chain Position
chai
n
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
Glulisin
e
Asn
Pro
Glu
Thr
Glargine
Gly
Pro
Lys
Thr
Lys
Myristic
acid
Detemir
Lys
B31
And
B32
rapid-acting
Arg
long-acting
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
Diabetes – Oral Medications
6 Classes :
 Sulfonylureas
 Biguanides
 Sulfonylureas and biguanide combination
drugs
 Thiazolidinediones
 Alpha-glycosidase inhibitors
 Meglitinides
Sulfonylureas : stimulate β cells to produce
more insulin
Rel. Potency
bind to protein
 1st generation
–
–
(1)Orinase
(tolbutamide)
(3)Tolinase (tolazamide)
(6)Diabinese (chlorpropamide)
2-(p-aminobenzenesulfonamido)-5-isopropyl -thiadiazole (IPTD)
was used in treatment of typhoid fever in 1940’s  hypoglycemia
Currently > 12,000
–
 may become dislodged  delayed activity
 2nd generation
–
–
–
–
(75)Glucotrol
(glipizide)
(150)Glucotrol XL (ex. rel. glipizide)
(150)Micronase, Diabeta (glyburide)
(250)Glynase (micronized glyburide)
 3rd generation
–
(350)Amaryl
(glimepiride)
*Hydroxylation of the aromatic ring appears to be the most favored metabolic pathway
*Hydroxylated derivatives have much lower hypoglycemic activity
Mechanism of Action
 Sulfonylureas interact with receptors on
pancreatic b-cells to block ATP-sensitive
potassium channels
 This, in turn, leads to opening of calcium
channels
 Which leads to the production of insulin
Biguanides : improves insulin’s ability to
R
move glucose into cells (esp. muscle)
R
N
R
N
R
R
N
H
 Metformin
N
R
N
N
N
R
H
- Glucophage®, Fortamet®,
Riomet®
N
N
H
H
N
H
+
HCl
- mechanism improves insulin sensitivity by increasing peripheral glucose
uptake and utilization.
- Zhou et al (2001) showed that metformin stimulates the hepatic enzyme
AMP-activated protein kinase
- Metformin was first described in the scientific literature in 1957 (Unger et al).
- It was first marketed in France in 1979 but did not receive FDA approval for Type
2 diabetes until 1994.
Metformin is a widely used monotherapy, and also used in combination with
the sulfonylureas in treatment of type 2 diabetes
*only anti-diabetic drug that has been proven to reduce the complications of diabetes, as evidenced in a large study of overweight patients with
diabetes (UKPDS 1998).
Sulfonylurea & Biguanide
Combo drugs/ Cocktails
 Glucovance® (Glyburide & Metformine HCl)
NH
&
NH
O
S
O
O
H
N
N
H
&
N
N
H
H
N
H
O
O
NH
Cl
1-[[ p-[ 2-( 5-chloro-o-anisamido) ethyl] phenyl] sulfonyl]-3-cyclohexylurea
+
HCl
Thiazolidinediones (TZD’s) : make
cells more sensitive to insulin (esp. fatty cells)
O
 Pioglitazone
- Actos®, Avandia®
N
O
S
NH
O
5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-thiazolidine-2,4-dione
- binds to and activates the gamma isoform of the peroxisome proliferator-activated receptor (PPARγ).
- PPARγ is a member of the steroid hormone nuclear receptor superfamily, and is found in adipose tissue,
cardiac and skeletal muscle, liver and placenta
- upon activation of this nuclear receptor by a ligand such as a TZD,
PPARγ–ligand complex binds to a specific region of DNA and thereby
regulates the transcription of many genes involved in glucose and fatty
acid metabolism.
- Marketed in USA in August of 1999
PPAR - γ
Αlpha – glycosidase inhibitors :
Block enzymes that help digest starches  slowing
the rise in B.G.L.
 AGI’s
- Precose ® (acarbose),
- Glyset ® (miglitol)
H
O
H
O
H
O
N
H
O
O
H
1-(2-Hydroxy-ethyl)-2-hydroxymethylpiperidine-3,4,5-triol
Meglitinides : Stimulate more insulin
production ; dependant upon level of glucose present
 Meglitinides
O
- Prandin ® (repaglinide)
N
O
OH
NH
O
2-Ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid
- Starlix ® (nateglinide)
NH
O
O
OH
2-[(4-Isopropyl-cyclohexanecarbonyl)-amino]-3-phenyl-propionic acid
Diabetes – Oral Medications
Summary
6 Classes :
 Sulfonylureas
 Biguanides
stimulate β cells
improves insulin’s ability to move glucose
 Sulfonylureas and biguanide combination
drugs BOTH
 Thiazolidinediones cells more sensitive to insulin
 Alpha-glycosidase inhibitors Block enzymes that help
digest starches
 Meglitinides
stimulate β cells (dependant upon glucose conc.)
In Conclusion :
 2 major types of diabetes
(3 with Gestational)
 Type 1 => insulin dependant (5-10%)
 Type 2 => may treat with oral medication
which may alter insulin production &/or
sensitivity ; disease often succumbs to
insulin dependence (>90%)
References:
http://www.webmd.com/content/article/59/66840
http://en.wikipedia.org/wiki/Actos
http://hms.harvard.edu/public/disease/diabetes/diabetes.html
http://www.answers.com/topic/peroxisome-proliferator-activated-receptor
http://focus.hms.harvard.edu/2005/May20_2005/immunology.shtml
http://www.mja.com.au/public/issues/176_08_150402/omo10828_fm.html
http://diabetes.niddk.nih.gov/dm/pubs/medicines_ez/index.htm
http://www.univgraph.com/bayer/inserts/precose.pdf
http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin_struct.html http://www.drugs.com/pdr/ACARBOSE.html
http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin.html
http://www.pfizer.com/pfizer/download/uspi_glyset.pdf
http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/moaction/surface.html
http://www.rxlist.com/cgi/generic2/miglitol.htm
http://www.cancure.org/insulin_potentiation_therapy.htm
http://www.diabetes.org/about-diabetes.jsp
http://www.diabetesnet.com/diabetes_treatments/sulfonylureas.php
http://www.people.vcu.edu/~urdesai/sulf.htm
http://en.wikipedia.org/wiki/Glucohexal
http://www.drkoop.com/druglibrary/93/glucovance-warnings_precautions.html
http://en.wikipedia.org/wiki/Prandin
http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=APRD00593.txt