3. Type II diabetes
In 2001, 7.9% of the American population was
living with diabetes mellitus; this population is
expected to almost double by the year 2010.
Diabetes mellitus is the result of metabolic
dysfunction. Onset starts with the overproduction
of unutilized glucose that leads to abnormal
insulin resistance and impaired insulin secretion.
Islet B-cells that produce and secrete insulin
eventually cannot keep up with the need for
insulin and become dysfunctional resulting in
their degradation.
5. Effects of Diabetes Mellitus
• Usually the first symptom is inception of hyperglycemia
caused by a deficiency in insulin secretion.
• This is often in conjunction with effects such as;
dyslipidemia, abnormalities in carbohydrates, fat, and
protein metabolism, resulting in weight gain, and an
elevation in blood pressure.
• Over time these dysfunctions can cause irreversible
damage to; kidneys, eyes, heart, blood vessels, and
nerves.
• This damage can lead to blindness, vascular clotting,
myocardial infarction, stroke, amputation and even
death.
6. Insulin Analogues
• When developing an insulin analogue,
researcher seek to alleviate side effects of
past therapies such as nocturnal
hypoglycemia and metabolic control.
• At the present there are two short-acting
analogues on the market, insulin aspart
and insulin lispro.
8. Long acting Analogues
• Unlike short acting analogues, glargine
has a constant action of up to 24 hours
• Structural changes make the analogue
less soluble at a physiological PH, thus
mimicking basal insulin release
9. Side effects of insulin analogues
Thus far, no negative side effects have been
found in human cases of analogue usage.
Side effects have been shown in animal studies
with both long and short term action analogues
revealing an elevated risk of mammary gland
tumors.
Research on these particular analogues was
abandoned and no other analogues have shown
similar side effects in humans.
10. Peroxisome Proliferator-activated
Receptors (PPARS)
• Belong to the steroid/thyroid retinoid receptor
superfamily, and therefore, are expected to
effect metabolic functions involved in diabetes.
• They form active heterodimers with the 9-cis-retinoic
acid receptor allowing them to regulate
target genes in DNA.
• Two important subtypes PPAR alpha and PPAR
gamma are involved in regulating lipid
metabolism and energy balance.
11. PPAR alpha and PPAR gamma
• PPAR alphas are lipoprotein regulators
expressed in catabolic tissues such as the liver,
kidney, heart and skeletal muscles
• PPAR gamma is primarily expressed in adipose
tissue, however, it is occasionally active in
skeletal muscle, kidney, and intestine
• PPAR gamma’s activation is known to be
accompanied with the modulation of genes
involved in fat derived hormones that effect body
metabolism.
12. PPAR
• Differences between the PPAR alpha and
gamma binding sites lie within the exchange of
the Tyrosine in PPAR alpha and substitution for
a histadine in PPAR gamma.
• Ligands with bulky head groups such as TZDs
have shown more affinity to the PPAR alphas
because of interaction with the larger tyrosine
group resulting in a disruption of the hydrogen
bonding with the other amino acids.
13. Dual agonists
• Researchers hypothesised that a dual agonist
for these receptors, can potential exhibit the
positive effects of both.
• KRP-297 and Tesaglitazar are dual agonists that
are still in clinical trials .
• Studies of these agonists are fairly recent and
therefore, no dual agonist are on the market at
this time, but they give strong possibilities for the
treatment of diabetes in the future
14. TZDs
• Patent testing has shown that oral TZD treatment
enhances the effects of insulin on glucose.
• The correct mechanism for the action of TZD is still not
know but drugs such as rosiglitazone and pioglitazone
are on the market and shown effective in patients.
• Like any drug these agents have side effects such as
weight gain and an increase in subcutaneous fat
mass.
• For most patients, weight increase is minimal but
sometimes the weight gain is accompanied with an
increase in plasma volume resulting in edema
15. GLP-1
• GLP-1 is a hormone released from L- cells in the
intestine as a reaction to meal ingestion. This
release causes the inhibition of gastric motility
and gastric acid secretions. GLP-1 is
responsible for enhanced insulin secretions after
oral ingestion of glucose by the release of islet
B-cells in the pancreas.
16. Exendin-4
• An agonist currently studied
is the exendin-4 peptide
which is isolated from the
venom of a Gila monster.
• Exendin-4 has a 9 amino
acid proline-rich C-terminal
tail, which is thought to
stabilize the molecule at the
receptor binding site.
• Exendin-4 is a very potent
peptide with potency up to
10 times greater than that of
natural GLP-1 and has a
longer half-life.
17. Liraglutide
• Liraglutide is a series of
acylated derivatives of GLP-1
that have long acting effects.
• Liraglutide works by self-association
and noncovalent
binding of plasma albumin fatty
acid binding sites
• Albumin acts as a buffer
reservoir to insure the binding
of liraglutide to the active site.
• This binding causes a
pharmacokinetic profile with
slow absorption and a long
half-life of eight hours
• Administered intravenously
once a day
18. Dipeptidyl Pepidase 4 (DPP4)
• Dipeptidyl peptidase 4 (DPP4) is a “nonclassical
serine protease” that is ubiquitously expressed in
increased levels in the kidney and in lower levels in
many areas including; the liver, pancreas, placenta,
thymus, spleen, epithelium cells, vascular
endoplasm, and lymphoid and myeloid cells
• DPP-IV works by cleaving the N-terminal two amino
acids causing GLP-1 to give an inactive amide.
Through these trials it was determined that an
amine at position two is absolutely required for
inhibition. Two N-substituted glycine derivatives;
DPP728 and LAF237 have been studied in depth for
their inhibitory effects.
20. DPP728
• DPP728 was given on a trial basis to
patients for a period of a month on a daily
dosage of 300mg.
• It showed a decrease in fasting and
prandial glucose over a period of twenty-four
hours.
• Transient pruritus localized to the palms
was noted in some subjects though the
reason for this effect is not known.
21. LAF237
• LAF237’s efficient once a day
doses.
• This inhibitor was also
administered over a period of
four weeks with a dosage of
100mg. Fasting was also
decreased, along with
postprandial glucose, and
postprandial glucagon levels.
The presence of Pruritus of the
palms was not shown over the
course of this trial.
22. Future focuses for treatment of
Diabetes mellitus
• Now that many of the mechanisms for metabolic
dysfunction are understood, researchers can develop
better drugs to alleviate adverse effects.
• Future drug development aims to increase the duration
of drug action thus decreasing the amount of times the
drug needs to be administered for effectiveness.
• Researchers are also focused on developing the most
efficient and easy method of admission to target areas.
By improving these current problems with the
development of new drugs, hopefully future treatment of
the diabetes mellitus will be a more efficient and
satisfying experience for patients.
