INCRETINS: ANTIOBESITY AND ANTIDIABETIC BLOCKBUSTERS

www.wjpps.com Vol 4, Issue 04, 2015. 640
Amit. World Journal of Pharmacy and Pharmaceutical Sciences
INCRETINS: ANTIOBESITY AND ANTIDIABETIC BLOCKBUSTERS
Amit Gangwal*
Smriti College of Pharmaceutical Education, Indore, M. P.
ABSTRACT
Incretins are a group of specialized hormones secreted in
gastrointestinal tract (usually post - meal) that play crucial role in
feeding behavior directly or indirectly. They stimulate a decrease in
blood glucose levels. Incretins increases insulin release from the beta
cells of the islets of Langerhans of pancreas, post meal so that blood
glucose levels remains in check. They also minimize the rate of
absorption of nutrients into the blood stream by reducing gastric
emptying and may directly reduce food intake by providing a feeling
of satiety. Their gastric emptying delay also causes slower entry of
glucose in blood. They also inhibit glucagon release from the
alphacells of the Islets of Langerhans. Glucagon-like peptide-1 (GLP-1) and gastric inhibitory
peptide (also known as: glucose-dependent insulinotropic polypeptide or GIP) are two major
candidate molecules that fulfill criteria for an incretin. Both GLP-1 and GIP are rapidly
inactivated by enzyme dipeptidyl peptidase- IV (DPP- IV). This led to the concept of DPP -
IV inhibitors as anti diabetic agents. Few insulinotropic activity possessing incretins which
are available in marker for treatment of diabetes are exenatide, liraglutide, exenatide
(extended-release). There are reports of incretins being explored for their role in management
of obesity. This article summarizes potential role of incretins in discovery of antidiabetic and
antiobesity molecule. Article also throws light on recent developments in incretin research.
KEYWORDS: Incretins, GLP-1, Amylin, Exenatide, Gila monster, Diabetes, Obesity, DPP-
4 inhibitors.
INTRODUCTION
Incretins are gut-derived peptide molecules secreted post meal to act on food.[1]
The major
incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide
(GIP)1
. GLP-1 is secreted by neuroendocrine L cells of the ileum and colon and GIP is
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Article Received on
25 Jan 2015,
Revised on 18 Feb 2015,
Accepted on 14 March 2015
*Correspondence for
Author
Dr. Amit Gangwal
1635-b, Scheme no 71
Indore, 452009, M.P,
India.

produced by K cells of the duodenum and jejunum. GLP-1 and GIP stimulate insulin release
from pancreatic beta cells in a glucose-dependent fashion. GLP-1 also lessens secretion of
glucagon, a hormone that causes conversion of glycogen into glucose (responsible for
opposing the effects of insulin and amylin) in liver. GLP-1 also slows down gastric emptying
and makes person feel full for an extended time.[2]
In this way he consumes less. The incretin
hormones; GLP-1 and glucose-dependent insulinotropic polypeptide GIP are now widely
recognized as important contributors to the maintenance of glucose homeostasis.[3]
This class
of drugs is not very old and much of the research work is focused on incretins as researchers
are exploring them from antiobesity point of view also. This article reviews currently
available GLP-1 analogues (GLP-1 mimetics) which mimic incretins e. g. Exenatide, DPP –
IV inhibitors (sitagliptin), and closely related category, amylins.[3]
Latest in the domain of
incretins is also being discussed here.
GLP-1/Incretin mimetics
Two incretin hormones identified first are GIP and GLP-1. Levels of these hormones rise
post prandial and shown to rise rapidly shortly after nutrient intake and then fall suddenly
shortly thereafter as a result of inactivation by the enzyme DPP – IV. GLP-1 is secreted in
greater concentrations.[4]
GLP-1 has been reported to enhance glucose-dependent insulin
secretion, suppress postprandial glucagon secretion from pancreatic alpha-cells, slow gastric
emptying, and reduce food intake and body weight. It may also preserve/enhance beta-cell
mass, by promoting beta-cell proliferation, and by decreasing beta-cell death.[5]
In addition to
its effects on the core defects in type 2 diabetes, GLP-1 also appears to have direct effects on
other body tissues.[6-11]
The first synthetic agonist at GLP-1 receptor is Exenatide. Exenatide
(a drug available with the brand name Byetta) is a synthetic analogue of a substance
(exendin-4) found in Gila monster (Heloderma suspectum) saliva, led to healthy sustained
glucose levels and progressive weight loss among type 2 diabetics who took part in a three-
year study. Gila monster is a large venomous lizard native to the southwestern United States
and northwestern Mexico. The lizard hormone is about 50 percent identical to GLP-1. It was
approved by the USFDA in April 2005 to treat type 2 diabetes in patients who were finding it
difficult to lower their raise blood glucose level despite of using couple of oral hypoglycemic
agents. GLP-1 receptor agonists are the among the newest categories of anti diabetic drugs.
Exenatide (manufactured by Amylin Pharmaceuticals Inc. in collaboration with Eli Lilly and
Company, comes in a prefilled pen. The reptile version of this hormone remains effective
much longer than the human version and thus its synthetic form helps diabetics keep their

blood sugar levels from getting too high. Exenatide also slows the emptying of the stomach
and causes a decrease in appetite, which is how it leads to weight loss. John Eng, an
endocrinologist at the Bronx Veterans Affairs Medical Center in New York City, was looking
at studies of people who developed pancreatitis after being bitten by venomous animals. Eng
wanted to find the connection, so he procured various animals’ venoms, including that of the
Gila monster. He explored these venoms for their effect on pancreas. Then he concluded that
Gila monster secretes a hormone in its saliva called exendin-4. This hormone, which aids
digestion in the lizard, is similar to a human digestive hormone called GLP-1. This finding
encouraged researchers to develop more successful agonists of GLP-1.[12-16]
The beauty of
Exenatide is that it is resistant to DPP- IV degradation, and is cleared by kidneys.[17]
Dipeptidyl Peptidase - IV Inhibitors (DPP – IV inhibitors)
Physiological incretins are short-lived owing to their rapid degradation by the enzyme DPP -
IV. DPP- IV is widely available in body and circulates in a soluble form. Endogenous GLP-1
has a short half-life (2 minutes). Inhibitors of DPP – IV are available to prevent the
inactivation of GLP-1 and lengthen the activity of the endogenously released hormone. The
drugs currently available are sitagliptin, saxagliptin, and vildagliptin as sole agents and also
combined with metformin. They act on other bioactive peptides like neuropeptide Y, gastrin
releasing peptide, substance P, and various chemokines.[18]
Oral inhibitors of DPP - IV are
recommended for patients with type 2 diabetes mellitus. They decrease the activity of the
enzyme close to 80% for up to 24 hours. By doing this they enhance post meal circulating
level of GLP-1 and GIP. Unlike GLP-1 mimetics, DPP – IV inhibitors increase effective
incretin levels into a more physiological range.[19]
They increase insulin secretion in response
to dietary glucose and suppress glucagon secretion.[20]
Glucagon like
Peptide – 1 secretion
from intestinal L cell
Enhanced glucose-
dependent insulin
secretion from
pancreatic beta -cells
Suppress ion of
postprandial glucagon
secretion from
pancreatic alpha-cells
Slowing of gastric
emptying,
reduction in food intake
and body weight
Events followed by
meal

*Got positive response from USFDA on 09/09/2014, but final approval is still not
granted, marketing authorization may be granted very soon. Novo Nordisk is looking to
get Saxenda approved for chronic weight management in patients with either a BMI of
≥30 kg/m2, or a BMI of ≥27 kg/m2 plus at least one weight-related comorbid condition.
Induce satiety and satiation
(locally/centrally);
involvement of incretins
Strategies
to combat
obesity
Burn deposited fat
(in body only; non exercise stuff)
Decrease food/fat
absorption
Increase energy expenditure
(Exercise etc.)
Serotonin/noradrenalin
reuptake inhibitor
e. g. Sibutramine (withdrawn
from US)
Gastric and pancreatic
lipase inhibitor
e. g. Orlistat
Serotonin 2C agonist
e. g. Belviq®
(Lorcaserin)
(Only in USA), approved in
2012
Noradrenalin releaser
and anti-convulsant
e. g. Qsymia®
(Phentermine with Topiramate)
(Only in USA), approved in
2012
Noradrenalin releaser,
sympaticomimetic
e. g. Phentermine
Norepinephrine/dopamine
reuptake inhibitor
e. g. Contrave®
(Bupropion/
Naltrexone), approved in September
2014
GLP-1 analogue*
e. g. Liraglutide (Saxenda®)
Saxenda
Currently available drug
to treat obesity
(withdrawn from non US
market not included & off
label claims drugs not
covered).
As the boxes clearly indicate only two broad categories are there neurotransmitters
augmenting agents and agents reducing the digestion and absorption (Only orlistat)

Current options
and mode of
action of
antidiabetics
drugs
Alpha-glucosidase inhibitors
They delay the digestion and absorption of
carbohydrates; hence reduce the blood sugar
elevation after a meal.
e.g. Acarbose, Miglitol.
Sulphonylureas
They increase insulin secretion.
e. g. Tolbutamide,
Chlorpropamide, Glibenclamide,
Glipizide, Gliclazide, Glimiperide
Biguanides
e. g. MetforminGlucagon like peptide (GLP-1) analogues
Mimics incretins, the peptides that are secreted
when a person eats; incretins stimulate insulin
production and help the person feel full by
delaying emptying of the stomach.
e. g. Exenatide
Dipeptidyl peptidase-4 (DPP-4) inhibitors
e. g. Sitagliptin DPP-4 inhibitors reduce
glucagon and blood glucose levels by
blocking DPP-4, which breaks down GLP-1
SGLT-2 inhibitors
Block the re-uptake of glucose in the renal
tubules, promoting loss of glucose in the urine
e. g. Canagliflozin, Dapagliflozin
Amylin (Islet Amyloid Polypeptide (IAPP))
analogues
e. g. Pramlintide functions as a synergistic partner
to insulin, with which it is cosecreted from pancreatic
beta cells in response to meals.
PPAR agonists
e. g. Saroglitazar Agonist action
at PPARα lowers high blood triglycerides, and
agonist action on PPARγ improves insulin
resistance and consequently lowers blood sugar
Thiazolidinediones
e. g. Rosiglitazone, Pioglitazone activate
PPARs (peroxisome proliferator-activated
receptors), a group of nuclear receptors,
with greatest specificity
for PPARγ (gamma)
Insulin shots
Meglitinides
e. g. Repaglinide, Nateglinideare secretagogues
that stimulate rapid insulin production by the
pancreas andreduce both post-prandial blood
glucose and HbA1c by0.5–2%.
Straight line: Orally acting
Curved line: Injectables

Amylin analogues
Amylin is a peptide neurohormone that is synthesized and released by beta cells of the
pancreas with insulin. Patients without active beta cells are deficient in both insulin and
amylin. Secretion of amylin, like GLP-1, is stimulated by the presence of food in the gut. The
physiological effects of amylin are also akin to those of GLP-1 but it is not an incretin
hormone. Amylin is similar to the incretins, but one exception is there; amylin does not cause
insulin secretion, but it does all of the other things that the incretins do to prevent the shoot in
glucose level after food is taken.[21]
Amylin represses glucagon secretion, holdups gastric-
emptying, and acts centrally in the area postrema of the hindbrain to induce feeling of
fullness (satiety). Amylin slows the entry of glucose into the circulation while insulin
stimulates cellular uptake of glucose to reduce glucose concentrations.[22, 23]
By augmenting
endogenous amylin, pramlintide (drug available on a prescription) aids in the cellular
absorption and regulation of blood glucose by delaying gastric emptying, promoting feeling
of stuffed stomach via hypothalamic receptors (not GLP-1 receptor), and inhibiting
inappropriate secretion of glucagon.
DISCUSSION AND CONCLUSION
Increased occurrence of type 2 diabetes mellitus and obesity has elevated the medical need
for new agents to treat these metabolic ailments. Resistance to the hormones insulin and
leptin are characteristic of both type 2 diabetes and obesity. Drugs that can mitigate this
resistance should be effective in treating these two.[24]
Type 2 diabetes mellitus is estimated
to affect more than 5% of the adult population in Western societies (figures for children
population also alarming), and its occurrence is expected to further boost considerably in the
future, in particular owing to the remarkable increase in obesity. Hyperglycaemia, the
prominent and easiest diagnostic symptom, is associated with flawed insulin production and
peripheral insulin resistance, and leads to the development of a range of signature
complications of diabetes mellitus. Incretin based pharmacognosy is youngest among
USFDA approved, which mimic the activity of natural glucoregulatory peptides.[17]
Various
implication and ways of bringing these incretin in use for other metabolic disorders are being
studied. A latest paper published in Science Translational Medicine has shown that an under
trial diabetes drug that targets two members of the incretin family of hormone receptors may
have superior metabolic effects than approved diabetes drugs such as exenatide (Byetta;
Amylin) and Liraglutide.[25]
Incretins are gut hormones that potentiate insulin secretion post
meal. The two best-studied incretins so far, GIP and GLP-1 exert their insulinotropic actions

through G-protein-coupled receptors highly expressed on islet β cells. These two incretins are
really incredible, because they are addressing not only diabetes mellitus but may also show
exhibit potential as antiobesity molecule in various ongoing studies in various laboratories.
This later effect may be due to the fact that GLP-1 and GIP receptors are also widely
expressed in nonislet cells and also exert indirect metabolic events. Two ways have been
identified to use these incretins. Inhibition of DPP - IV, the enzyme which causes for N-
terminal cleavage and inactivation of GIP and GLP-1. A second class of incretin-based
therapies is comprised of injectable GLP-1R.[26]
The glucagon-like peptide 1 receptor is a
human gene, resting on chromosome 6. A member of the glucagon receptor family of G
protein-coupled receptors is expressed by this gene.[27-29]
The insulinotropic properties of GIP and GLP-1 were came to fore more than 25 years ago;
however, new dimensions of incretin hormones will continue mesmerize and happify
scientists, as our understanding of underlying mechanism of diabetes grows,
pharmacotherapy will further be explored3
. GLP - 1 receptor agonist are also being used in
treatment of obesity in some part of world (off label use).[30-32]
Pharmacotherapy using DPP-4
inhibitors has few side effects and does not affect wait. Animal studies support their use in
prediabetes. GLP-1 receptor agonist effects are also apparent in non-diabetic obese
individuals.[33-34]
A paper published in International Journal of Obesity (Nature) in 2013
reviews around 130 references and reported various conclusions drawn by earlier researches
on feeding behavior apropos to incretins namely GIP and GLP-1. It says Results from studies
in both experimental animals and humans have indicated that GLP-1 has a key role in
satiation signaling. In the periphery, satiation-inducing effects of GLP-1 are most probably
mediated by vagal afferents originating in the intestine in combination with other mechanism
that may involve circumventricular organs, and peripheral GLP-1 appears to activate CNS
nuclei that are involved in satiation, including the PVN, the central nucleus of the amygdala
and possibly the nucleus accumbens. Intrinsic to the CNS, a GLP-1 pathway arising in the
NTS (nucleus of the solitary tract) is also involved in satiation. ICV (intracerebroventricular)
administration of GLP-1 receptors in the CNS reduces food intake. Circulating levels of
GLP-1, including responses to meals, are decreased in obese individuals. Weight loss
associated with diet and exercise or bariatric surgery is associated with increased GLP- 1
levels, and it has been suggested that elevated satiation signaling mediated by GLP-1 may
contribute to weight loss in both the settings.[35]
In another study it has been found that
weight loss induced by GLP-1 analogues is dose dependent and progressive. Liraglutide has

shown to cause a mean weight loss of around 6.0 kg (more than thirty five percent of the
subjects achieving more than or equal to ten percent reduction) of weight. Longer acting
version of Exenatide has been found to improve bodyweight with an average weight
reduction of around 3 kg.[36-37]
The most recent update about upcoming antiobesity molecule
based on incretin is Liraglutide. USFDA may give its final nod to this molecule (Saxenda®
)
which is already in market as anti diabetic drug by Novo Nordisk.[38,39]
US FDA panel
endorsed on September 09, 2014 Liraglutide as obesity treatment but not given final nod for
launching into market. It is suggested and reported that incretin based molecule should not
be used for shedding extra pounds of fats, especially not in nondiabetic patients, until it
emerges as foolproof antiobesity molecule associated with no potential cardiovascular risks
and other major side effects in long run, but still few GLP-1 agonists are being consumed by
people for decreasing wait. Other antiobesity options, still in infancy, are superabsorbent
hydrogel, temporary controllable gastric pseudobezoars (pseudobezoar is an indigestible
material administered intentionally into the digestive system).[40, 41]
In summary, incretin therapy appears to offer an effective choice to the currently available
hypoglycaemic agents and it potential to serve diabetics for a long time with an added
advantage of weight reduction. Weight regain remains a major limitation among patients
whoa e on antiobesity medication. Though simultaneous options are there, indeed they are
warranted for effective output of pharmacotherapy, like lifestyle modification and surgical
interventions, but most subjects suffer from wait gain after certain period of time or after
finishing prescribed medicament regimen. Here incretins may play a crucial role and may fill
the gap, as none of the incretin analogues are in practice (recommended by regulatory bodies)
for antiobesity effect around the world. Chances might be there for approval of specifically
designed incretins for treatment of obesity in years to come. Incretin-based analogues may be
effective in preventing progression of prediabetes and GLP-1 agonists if modified properly
may have potential for use in the treatment of obesity. As per Dr. Daniel Drucker, a senior
instigator at Lunenfeld Tanenbaum Research Institute (LTRI), Mount Sinai Hospital,
Toronto; and a pioneer in diabetes and obesity research from view point of incretins (chiefly
GLP – 1) “since enhanced gut hormone action may be beneficial in diabetes, obesity and
inflammatory bowel disorders, these analogues have real potential to lead to new and better
treatments for diseases that afflict millions of people worldwide”. It will not be an hyperbole
to expect whopping sale of a molecule based on incretin approach, which can address both
obesity and diabetes without major side effects because WHO report says that over 347

million people in the world are afflicted with diabetes type 2 and number for obese people is
also disturbing. Problem with obesity treatment is that they are adjunct to a reduced-calorie
diet and increased physical activity (with shunning away from sedentary life style), if patient
wants to see some significant wait loss. Very rightly told by Larry Page, co-founder of
Google, “If the past is any indicator of our future success, today’s big bets won’t seem so
wild in a few years’ time”.
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