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Diabetes Mellitus Overview and Treatments

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Title: Diabetes Mellitus Overview and Treatments


1
Diabetes Mellitus Overview and Treatments
  • Andrew P. Vogt
  • Chemistry 6116

2
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

3
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 gt 90
  • - eventually leads to ß-cell failure
  • (resulting in insulin dependence)

Gestational Diabetes 3-5 of pregnant women in
the US develop gestational diabetes
4
Testing
Fasting Plasma Glucose Test (FPG) - (cheap,
fast) fasting B.G.L. 100-125 mg/dl signals
pre-diabetes gt126 mg/dl signals diabetes
Oral Glucose Tolerance Test (OGTT) tested for
2 hrs after glucose- rich drink 140-199 mg/dl
signals pre- diabetes gt200 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.

5
Diabetes - Insulin
  • Discovered in 1921 by Banting and Best
  • Consist of A B chains linked by 2 disulfide
    bonds
  • (plus additional disulfide in A)





6
Diabetes Insulin(synthesis, storage, secretion)
  • Produced within the pancreas by ß 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 ß 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.
7
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)

8
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.

9
  • Animation showing overview of diabetes
  • http//www.healthscout.com/animation/1/34/main.htm
    l
  • Animation showing mechanism of action of insulin
  • http//www.vivo.colostate.edu/hbooks/pathphys/endo
    crine/pancreas/insulin_phys.html

10
Pancreatic Hormones and Insulin Receptor Agonists
  • Hongmei Li
  • Mar. 21th, 2006

11
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.
12
  • Pancreatic Hormones
  • Insulin
  • Amylin
  • Glucagon
  • Somatostatin
  • Pancreatic Polypeptide

13
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.
A chain
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
14
  • Insulin affects many organs
  • It stimulates skeletal muscle fibers.
  • It stimulates liver cells.
  • It acts on fat cells
  • It inhibits production of certain enzyme.
  • In each case, insulin triggers
  • these effects by binding to the
  • insulin receptor.

15
  • The insulin receptor (IR) is a transmembrane
    glycoprotein, composed of 2a and 2ß domains.
  • .
  • Its intracellular tyrosine kinase domain is
    activated by binding of insulin, leading to a
    cascade of signaling events.

16
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

17
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.
18
  • 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.
19
  • Types of insulin
  • Regular insulins
  • Insulin analogs
  • Pre-mixed insulin
  • Short peptide mimics

20
  • Regular insulins
  • Human insulin Humulin (from E.coli),
  • Novalin (from yeast)
  • NPH - neutral protamine Hagedorn (NPH),
  • protamine mixed.
  • Lente insulin / Ultralente insullin-
  • zinc added

21
  • Types of insulin
  • Regular insulins
  • Insulin analogs
  • Pre-mixed insulin
  • Short peptide mimics

22
  • 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)

23
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24
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25
References
  • Renuka C. P. et.al (2002) J. Biol. Chem. 277,
    225904
  • 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

26
Diabetes Oral Medications
6 Classes
  • Sulfonylureas
  • Biguanides
  • Sulfonylureas and biguanide combination drugs
  • Thiazolidinediones
  • Alpha-glycosidase inhibitors
  • Meglitinides

27
Sulfonylureas stimulate ß cells to produce more
insulin
  • 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 1940s ? hypoglycemia
Currently gt 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

28
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

29
Biguanides improves insulins ability to move
glucose into cells (esp. muscle)
  • Metformin
  • - Glucophage, Fortamet,
  • Riomet

- 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).
30
Sulfonylurea Biguanide Combo drugs/ Cocktails
  • Glucovance (Glyburide Metformine HCl)



31
Thiazolidinediones (TZDs) make cells more
sensitive to insulin (esp. fatty cells)
  • Pioglitazone
  • - Actos, Avandia

- 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 - ?
32
?lpha glycosidase inhibitors Block enzymes
that help digest starches ? slowing the rise in
B.G.L.
  • AGIs
  • - Precose (acarbose),
  • - Glyset (miglitol)

33
Meglitinides Stimulate more insulin production
dependant upon level of glucose present
  • Meglitinides
  • - Prandin (repaglinide)
  • - Starlix (nateglinide)

34
Diabetes Oral Medications Summary
6 Classes
  • Sulfonylureas stimulate ß cells
  • Biguanides improves insulins 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 ß cells (dependant upon
    glucose conc.)

35
In Conclusion
  • 2 major types of diabetes
  • (3 with Gestational)
  • Type 1 gt insulin dependant (5-10)
  • Type 2 gt may treat with oral medication which
    may alter insulin production /or sensitivity
    disease often succumbs to insulin dependence
    (gt90)

36
References
  • http//www.webmd.com/content/article/59/66840
  •  
  • http//hms.harvard.edu/public/disease/diabetes/dia
    betes.html
  •  
  • http//focus.hms.harvard.edu/2005/May20_2005/immun
    ology.shtml
  •  
  • http//diabetes.niddk.nih.gov/dm/pubs/medicines_ez
    /index.htm
  •  
  • http//www.vivo.colostate.edu/hbooks/pathphys/endo
    crine/pancreas/insulin_struct.html
  •  
  • http//www.vivo.colostate.edu/hbooks/pathphys/endo
    crine/pancreas/insulin.html
  •  
  • http//www.vivo.colostate.edu/hbooks/pathphys/endo
    crine/moaction/surface.html
  •  
  • http//www.cancure.org/insulin_potentiation_therap
    y.htm
  •  
  • http//www.diabetes.org/about-diabetes.jsp
  •  
  • http//www.diabetesnet.com/diabetes_treatments/sul
    fonylureas.php

http//en.wikipedia.org/wiki/Actos   http//www.an
swers.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/pfiz
er/download/uspi_glyset.pdf   http//www.rxlist.co
m/cgi/generic2/miglitol.htm   http//en.wikipedia.
org/wiki/Prandin   http//redpoll.pharmacy.ualbert
a.ca/drugbank/cgi-bin/getCard.cgi?CARDAPRD00593.t
xt      
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