Diabetes Mellitus

Overview and Treatments

Diabetes Mellitus :
a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both

j 20.8 million in US ( 7% of population) j estimated 14.6 million diagnosed (only 2/3) j Consists of 3 types:

1) Type 1 diabetes 2) Type 2 diabetes 3) Gestational diabetes

j Complications :

- Stroke - Heart attack - Kidney disease - Eye Disease - Nerve Damage

Diabetes Mellitus
j Type 1 Diabetes
- cells that produce insulin are destroyed - results in insulin dependence - commonly detected before 30

j 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 -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

j

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
j Discovered in 1921 by Banting

and Best j Consist of A & B chains linked by 2 disulfide bonds (plus additional disulfide in A) jA = 21amino acids B = 30 amino acids

Diabetes Insulin
(synthesis, storage, secretion)
j Produced within the pancreas by

cells islets of Langerhans j insulin mRNA is translated as a single chain precursor called preproinsulin j removal of signal peptide during insertion into the endoplasmic reticulum generates proinsulin j 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
j Stored as

Zn

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 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.

j Animation showing overview of diabetes: j http://www.healthscout.com/animation/1/34

/main.html j Animation showing mechanism of action of insulin: j 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
j Insulin j Amylin j Glucagon j Somatostatin j Pancreatic Polypeptide

A chain

Insulin is a small protein consisting of an A chain of 21 amino acids linked by two disulfide (SS) 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:

j It stimulates skeletal muscle fibers. j It stimulates liver cells. j It acts on fat cells j It inhibits production of certain

amino acids uptake

protein synthesis

glucose uptake

glycogen synthesis

enzyme. In each case, insulin triggers these effects by binding to the insulin receptor.

fat synthesis

enzyme production

glycogen breaking

The insulin receptor (IR) is a transmembrane glycoprotein, composed of 2 and 2 domains. . Its intracellular tyrosine kinase domain is activated by binding of insulin, leading to a cascade of signaling events.

Who need insulin medicine

j Type I (insulin dependent) diabetes patients whose body

produces no insulin. j 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.

j 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:
j Human insulin: Humulin (from E.coli),

Novalin (from yeast) j NPH - neutral protamine Hagedorn (NPH), protamine mixed. j Lente insulin / Ultralente insullinzinc added

Types of insulin

Regular insulins Insulin analogs Pre-mixed insulin

Short peptide mimics

Insulin Analogs:
j Fatty Acid Acylated insulins j Insulin Lispro (Humalog) (1996)

j Insulin Aspart (NovoLog) (2000) j Insulin Glargine (Lantus) (2002) j Insulin Detemir (Levemir) (Jun.,2005) j Insulin Glulisine (Apidra) (Jan., 2006)

Amino Acid Substitutons

Achai n Position
Source/ Type Human Aspart Lispro Glulisin e Glargine Detemir A21 Asn Asn Asn Asn Gly Lys B3 Asn

B- chain Position

B28 Pro

B29 Lys

B30 Thr Thr Thr Thr Thr Myristic acid

B31 And B32

Aspartic Lys acid Lys Pro Pro Pro Glu Lys Lys

rapid-acting

Arg

long-acting

References
j Renuka C. P. et.al (2002) J. Biol. Chem. 277, 225904 j Zoltan V. AND William C. D. (2001) Pharm. Rev. 52, 1-9 j Lauge S. et. Al (2003) PNAS 100, 4435-9 j Mark R. B. (1997) J. of Clin. Endoc.& Met. 82, 3-7 j Gianni C. (1992) FEBS 307, 66-70 j Irl B. H., (2001) Clin. Diabetes 19, 146-7 j BRUCE W. B. and POUL S. (2001) Diabetes care 24,69-72 j http://www.indstate.edu/thcme/mwking/diabetes.html

Diabetes Oral Medications

6 Classes :
j Sulfonylureas j Biguanides j Sulfonylureas and biguanide combination

drugs j Thiazolidinediones j Alpha-glycosidase inhibitors j Meglitinides

Sulfonylureas : stimulate
more insulin
j 1st generation
r tein

cells to produce

(1)Orinase

@ may become dislodged

(tolbutamide) (3)Tolinase (tolazamide) (6)Diabinese (chlorpropamide)

delayed activity

2-(p-aminobenzenesulfonamido)-5-isopropyl -thiadiazole (IPTD) was used in treatment of typhoid fever in 1940s hypoglycemia Currently > 12,000

j 2nd generation
(75)Glucotrol

tenc

ind t

(glipizide) (150)Glucotrol XL (ex. rel. glipizide) (150)Micronase, Diabeta (glyburide) (250)Glynase (micronized glyburide)

Rel.

j 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
j Sulfonylureas interact with receptors on

pancreatic F-cells to block ATP-sensitive potassium channels j This, in turn, leads to opening of calcium channels j Which leads to the production of insulin

Biguanides : improves insulins ability to

move glucose into cells (esp. muscle)
R N
N N N N

R R N N N R N R R R

- 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).

- Glucophage, Fortamet, Riomet

j Metformin

Sulfonylurea & Biguanide Combo drugs/ Cocktails

j Glucovance (Glyburide & Metformine HCl)

NH

&

O S

NH O O
H N H N N H N H H

&
O O NH

HCl

ido) et

l]

enyl] s lfonyl]- -cyclohexyl rea

Cl -[[ -[ -( -c l r - - nis

Thiazolidinediones (TZDs) : make

cells more sensitive to insulin (esp. fatty cells)
O

j Pioglitazone
- Actos, Avandia
  

O S NH

O 5-{ -[ -(5- thyl- yridin- -yl)-ethoxy]- enzyl}-thiazolidine- , -dione

- binds to and activates the gamma isoform of the peroxisome proliferator-activated receptor (PPAR ). - PPAR 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, PPAR 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 -

lpha glycosidase inhibitors :

Block enzymes that help digest starches slowing the rise in B.G.L.

j AGIs
- Precose (acarbose),

- Glyset (miglitol)
H O H O N O H

H 1-(2-Hydroxy-ethyl)-2-hydroxymethylpiperidine-3,4,5-triol

Meglitinides : Stimulate more insulin

production ; dependant upon level of glucose present

j Meglitinides
O

- Prandin (repaglinide)

N NH

O O

OH

- Starlix (nateglinide)
NH O O OH 2-[( -Isopropyl-cyclohexanecar onyl)-amino]- -phenyl-propionic acid

2- thoxy- -{[ - ethyl- -(2- i e ridin- -yl- henyl)-

%$

"

##

"

tylcar amoyl]-methyl}- enzoic acid

Diabetes Oral Medications

Summary

6 Classes :
j Sulfonylureas j Biguanides
stimulate cells improves insulins ability to move glucose

j Sulfonylureas and biguanide combination

drugs BOTH j Thiazolidinediones cells more sensitive to insulin j Alpha-glycosidase inhibitors Block enzymes that help
digest starches

j Meglitinides

stimulate

cells (dependant upon glucose conc.)

In Conclusion :
j 2 major types of diabetes

(3 with Gestational) j Type 1 => insulin dependant (5-10%) j 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://hms.harvard.edu/public/disease/diabetes/diabetes.html http://focus.hms.harvard.edu/2005/May20_2005/immunology.shtml http://diabetes.niddk.nih.gov/dm/pubs/medicines_ez/index.htm http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin_struct.html http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin.html http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/moaction/surface.html 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/Actos http://www.answers.com/topic/peroxisome-proliferator-activated-receptor http://www.mja.com.au/public/issues/176_08_150402/omo10828_fm.html http://www.univgraph.com/bayer/inserts/precose.pdf http://www.drugs.com/pdr/ACARBOSE.html http://www.pfizer.com/pfizer/download/uspi_glyset.pdf http://www.rxlist.com/cgi/generic2/miglitol.htm http://en.wikipedia.org/wiki/Prandin http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=APRD00593.txt