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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.

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Amit. World Journal of Pharmacy and Pharmaceutical Sciences

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

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Amit. World Journal of Pharmacy and Pharmaceutical Sciences

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

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*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)

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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. Metformin Glucagon 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

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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

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Amit. World Journal of Pharmacy and Pharmaceutical Sciences

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

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Amit. World Journal of Pharmacy and Pharmaceutical Sciences

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

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Amit. World Journal of Pharmacy and Pharmaceutical Sciences

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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