INCRETIN BASED

THERAPY IN
MANAGEMENT OF
DIABETES
DR.VISHALEE M
2ND YEAR DNB, INTERNAL MEDICINE
INTRODUCTION:
• Incretins are gut hormones that potentiate insulin secretion after meal ingestion in a glucose-
dependent manner.
• The two best studied incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-
like peptide-1 (GLP-1), exert their insulinotropic actions through distinct G-protein-coupled
receptors highly expressed on islet b cells.
• The GLP-1 and GIP receptors are also widely expressed in non islet cells and also exert indirect
metabolic actions ; hence, there is considerable interest in identifying extra pancreatic actions of
incretin hormones.
• Two strategies encompassing potentiation of incretin receptor signaling have been pursued for the
treatment of type 2 diabetes.
Inhibition of dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for N-terminal cleavage and
inactivation of GIP and GLP-1, has been achieved through the use of orally available medications
with high selectivity for the catalytic subunit of DPP-4.
• A second class of incretin-based therapies is comprised of injectable GLP-1R agonists that
exhibit structural homology to human GLP-1 or to nonmammalian GLP-1R agonists
• GLP-1 is synthesized in and secreted from enteroendocrine L cells found throughout the small
and large intestine, after posttranslational processing of proglucagon by prohormone convertase
1/3 (PC1/3).
GLP-1 is also produced in the central nervous system (CNS), predominantly in the brainstem, from
where it transported throughout the brain to elicit metabolic, cardiovascular,
and neuroprotective actions
• The constant basal secretion of GLP-1 from enteroendocrine cells is rapidly augmented by
the ingestion of luminal nutrients, including carbohydrates, fats, and proteins
• GLP-1 secretion is stimulated by nutrient intake, specifically carbohydrates and fats, while
proteins appear to be less effective.
• In general, GLP-1 can be detected at low concentrations during fasting.
During a postprandial state, a 2- to 3-fold increase in GLP-1 concentrations can be observed within
minutes.
• Postprandial time to peak GLP-1 concentration depends on the contents of the meal.
• Oral glucose administration during an oral glucose tolerance test (OGTT) can cause a peak at
approximately 20 minutes, while a standard mixed meal takes closer to 60 to 90 minutes.
• Once in circulation, GLP-1 travels and binds to the GLP-1 receptor (GLP-1R) on pancreatic β-
cells, where it augments insulin secretion and lowers blood glucose.
GLP-1 is a strong inhibitor of glucagon secretion; however, this effect depends on glucose
concentration and does not pose a risk of hypoglycemia.
Only 10% to 15% of endogenously released GLP-1 reaches systemic circulation, potentially because
of dipeptidyl peptidase 4 (DPP-4), which cleaves active GLP-1 at the N-terminal dipeptide.
• This observation has given rise to a class of drugs known as DPP-4 inhibitors, which increase
active GLP-1 and insulin secretion. The half-life of GLP-1 has been estimated at approximately 1
to 3 minutes.
• GIP is a 42-amino-acid peptide hormone synthesized and secreted from enteroendocrine K cells.
• Unlike L cells, K cells are found primarily in proximal regions of the small intestine, such as the
duodenum and proximal jejunum.
• While GIP is also secreted in response to a meal, fat was found to be a more potent GIP
secretagogue than glucose, even when matched for calories.
• Once in systemic circulation, GIP causes insulinotropic effects by binding to the gastric inhibitory
polypeptide receptor (GIPR) on β-cells.
• Unlike GLP-1’s inhibition of glucagon, GIP has been shown to increase glucagon secretion.
• GIPRs are also located on α-cells. As with GLP-1, GIP can be found in small concentrations
during fasting.
• However, unlike the 2- to 3-fold increase in GLP-1 typically observed after a meal, GIP
concentrations may increase by a factor of 10.
• DPP-4 will degrade GIP by cleaving the first 2 amino acids (tyrosine and alanine) at the N
terminus.
• This turns active GIP (1-42) into inactive GIP (3-42) with little to no insulinotropic effect.
• After a meal, approximately 55% of the total GIP is in the active form, with the kidneys
constituting the major site of elimination
• Consequently, the half-life of active GIP is 5 to 7 minutes.
 Incretins

Glucose-dependent
Glucagon-like peptide-1
insulinotropic polypeptide
(GLP-1)
(GIP)

Produced by Proglucagon gene of

enteroendocrine K cells – enteroendocrine L cells –
duodenum, jejunum ileum, colon
Incretin effect: There is a much greater release of insulin in response to oral glucose
administration as compared to administering the same amount of glucose by intravenous infusion.

• This “incretin” effect results from the release of incretin peptides from the GI track following the
ingestion of food, stimulates additional insulin release, beyond that produced by the direct effect
of plasma glucose on pancreatic beta cells.

• Patients with Type 2 diabetes have a markedly decreased incretin effect. This results in both a
delayed and reduced insulin release after oral glucose administration.
• While early studies indicated that postprandial GLP-1 levels were decreased in patients with type
2 diabetes, more recent studies suggest that the decrease in incretin effect is probably the result
of global β-cell dysfunction linked to chronic hyperglycemia, rather than a primary defect in
GLP-1 or GIP action.
 DPP-4 inhibitors GLP-1 agonist therapy
• Increases endogenous GLP-1 Exert all the effects of DPP-4 agents
• Stimulate glucose-dependent insulin secretion • Slow gastric emptying
from B cells • Decrease food intake
• Lower glucagon secretion
• Overall effect -- lowers hepatic glucose output • Weight loss

• Weight neutral  Exenatide

 Liraglutide
 Sitagliptin
 Albiglutide
 Saxagliptin
 Dulaglutide
 Linagliptin
 Lixisenatide
 Alogliptin
 Semaglutide
 Vildagliptin
 Tirzepatide
GLP-1 agonists
Pharmacokinetics:
 Absorption: GLP-1 Receptor Agonists (RAs) like Exenatide, Liraglutide, and Semaglutide are
administered subcutaneously, ensuring rapid absorption and achieving peak concentrations within
hours.

 Distribution: Post-absorption, GLP-1 RAs (eg, Exenatide, Liraglutide, and Semaglutide) exhibit a
low volume of distribution, predominantly remaining in the bloodstream.

• These agents selectively target GLP-1 receptors in various tissues involved in glucose regulation,
with specific affinity for pancreatic cells and other metabolic control sites.
 Metabolism: Exenatide undergoes primary metabolism in the kidneys and liver through
hydrolysis, yielding smaller, inactive peptides subsequently excreted renally.

• Liraglutide follows a similar pathway involving proteolytic cleavage in various tissues, akin to the
metabolism of large proteins.

• Enzymes like Dipeptidyl Peptidase-4 (DPP-4) and Neutral Endopeptidase (NEP) are likely
involved, resulting in smaller, biologically inactive fragments subsequently eliminated.

• Semaglutide, a polypeptide, undergoes metabolic breakdown into individual amino acids

facilitated by serum and tissue proteases.
 Excretion: Renal elimination primarily governs the clearance of GLP-1 RAs, including Exenatide,
Liraglutide, and Semaglutide.

• The kidneys play a pivotal role in removing these compounds from the body. The rate of renal
excretion impacts the duration of action and dosing frequency.

• Semaglutide, with its extended-release (ER) profile, exhibits a significantly prolonged half-life
compared to short-acting formulations.

 Adverse effects: nausea, vomiting, and diarrhea that could lead to an acute kidney injury due to
volume contraction.

• Dizziness, mild tachycardia, infections, headaches, and dyspepsia may also occur.

• Increases satiety, and transient, mild nausea may occur if they attempt to eat while feeling full.
• Minor episodes of hypoglycemia
 Contraindications:

• hypersensitivity and pregnancy

• severe GI diseases such as gastroparesis and inflammatory bowel disease

• with a personal or family history significant for multiple endocrine neoplasia 2A (MEN 2A),
multiple endocrine neoplasia 2B (MEN 2B), or medullary thyroid cancer.
DPP-4 inhibitors
Mechanism of action:

• By inhibiting the DPP-4 enzyme, DPP-4 inhibitors increase the levels of GLP-1 and GIP,
which in turn increase beta-cell insulin secretion in the pancreas, thereby reducing
postprandial and fasting hyperglycemia.
Adverse effects:

• upper respiratory tract infection, nasopharyngitis, headache, urinary tract infection,

arthralgia.

• hypersensitivity reactions such as anaphylaxis and angioedema

Contraindications:

• type 1 diabetes and diabetic ketoacidosis.

• pancreatitis
THANK YOU