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 Oral Glucose Tolerance Test
(FPG) - (cheap, fast) (OGTT)
*fasting B.G.L. 100-125 mg/dl *tested for 2 hrs after
signals pre-diabetes glucose-
*>126 mg/dl signals diabetes rich drink
*140-199 mg/dl signals pre-
diabetes
*>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

 Stored as β granules

Zn

This light micrograph of a section 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 of the body.
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
 Insulin is a small protein consisting of an A
A chain 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:
amino acids protein
 It stimulates skeletal muscle fibers. uptake synthesis

 It stimulates liver cells.

glycogen
glucose
synthesis
 It acts on fat cells uptake

 It inhibits production of certain fat

enzyme. synthesis

In each case, insulin triggers

these effects by binding to the enzyme glycogen
insulin receptor. production 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® insullin-
zinc 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/ A21 B3 B28 B29 B30 B31
Type And
B32
Human Asn Asn Pro Lys Thr
Aspart Asn Aspartic Lys Thr
acid
Lispro Asn Lys Pro Thr rapid-acting
Glulisin Asn Lys Pro Glu Thr
e
Glargine Gly Pro Lys Thr Arg
long-acting
Detemir Lys Myristic
acid
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
 1st generation
2-(p-aminobenzenesulfonamido)-5-isopropyl -thiadiazole (IPTD)
– (1)Orinase (tolbutamide)
bind to protein

was used in treatment of typhoid fever in 1940’s  hypoglycemia

– (3)Tolinase (tolazamide) Currently > 12,000

– (6)Diabinese (chlorpropamide)
 may become dislodged  delayed activity

 2nd generation
Rel. Potency

– (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 -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
move glucose into cells (esp. muscle)
R
R R
N N

R R
N N N
H
N N R R

 Metformin H
N N N
- Glucophage®, Fortamet®, H
H H
Riomet®
+ 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
& O
NH
S O
O
H
N N

&
N N N
H
H H
O
O NH + HCl

Cl
1-[[ p-[ 2-( 5-chloro-o-anisamido) ethyl] phenyl] sulfonyl]-3-cyclohexylurea
Thiazolidinediones (TZD’s) : make
cells more sensitive to insulin (esp. fatty cells)
O
N O

 Pioglitazone 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 H
O
O
O
H N

O O
H H
1-(2-Hydroxy-ethyl)-2-hydroxymethyl-
piperidine-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 stimulate β cells
 Biguanides 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://en.wikipedia.org/wiki/Prandin
 
 
http://www.diabetes.org/about-diabetes.jsp
http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=APRD00593.txt
 
 
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