Transcript Diabetes Mellitus Overview and Treatments

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)
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
Biguanides : improves insulin’s ability to
R
move glucose into cells (esp. muscle)
R
N
R
N
R
R
N
N
N
H
 Metformin
N
R
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.
*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
N
O
S
NH
- Actos®, Avandia®
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