Addis Ababa University school of medicine departement of physiology

1. Recent advances management of
Diabetes Mellitus-Targeting to
Gastrointestinal tract
Addis Ababa University
Physiology Department
Kiflay M

2. Presentation outline
• Definition of DM
• Incretins
• Incretin based therapy
• Bariatric surgery
• Summary
• Reference

3. • Definition of Diabetes Mellitus (DM)
 DM is a metabolic disorder of multiple etiology characterized by
chronic hyperglycemia with disturbances of carbohydrate, fat, and
protein metabolism resulting from defects of insulin secretion, insulin
action, or a combination of both.

4. • Types of Diabetes Mellitus
- Type 1 diabetes: due to a virtually complete lack of endogenous
pancreatic insulin production;
- Type 2 diabetes: the rising blood glucose results from a
combination of genetic predisposition, unhealthy diet, physical
inactivity, and increasing weight with a central distribution
resulting in complex pathophysiological processes.

5. What are incretins?
• Hormones produced by the gastrointestinal tract in response to incoming
nutrients, and have important actions that contribute to glucose homeostasis.
• Two hormones:
- Gastric inhibitory polypeptide (GIP)
- Glucagon-like peptide-1 (GLP-1)
• GIP is not effective in stimulating insulin
• GLP 1 is effective- hence GLP1 signalling system – successful drug target

6.  Insulin from beta cells
(GLP-1 and GIP)
 Glucagon from
alpha cells
(GLP-1)
Release of gut
hormones—
Incretins
Pancreas2,3
Glucose Dependent
Active
GLP-1 & GIP
DPP-4
enzyme
Inactive
GIP
Inactive
GLP-1
Glucose Dependent
↓ Blood
glucose
GI tract ↓Glucose
production
by liver
Food ingestion
↑Glucose
uptake by
peripheral
tissue
Beta cells
Alpha cells
Incretins: Role in Glucose Homeostasis
6

7. Gastric Inhibitory Polypeptide (GIP)
• Is a 42-amino-acid hormone that is produced by enteroendocrine K-
cells and released into the circulation in response to nutrient
stimulation.
• However, type 2 diabetes patients are resistant to its action (high
blood level), making it a less attractive therapeutic target.

8. Glucagon-like peptide-1 (GLP-1)
• A 30-amino acid peptide secreted in response to the oral ingestion of
nutrients by L cells, primarily in the ileum and colon.
• There are GLP-1 receptors in islet cells and in the central nervous
system, among other places.
• GLP-1 is metabolized by the enzyme dipeptidyl peptidase-IV (DPP-IV)
.

9. Actions of GLP-1
• It enhances glucose-dependent insulin secretion.
• Inhibits glucagon secretion and therefore hepatic glucose production.
• Slows gastric emptying.
• Increases satiety resulting in less food intake.
• Appears to stimulate insulin gene transcription and insulin synthesis.

10. Pancreas
Stomach
Brain
Liver
Intestine
Satiety
Gastric
emptying
Glucose production
Glucose dependent
insulin secretion
Insulin synthesis
Glucose dependant
Glucagon secretion
β

GLP-1: an incretin hormone with multiple direct effects on
human physiology.
Physiological Effects of GLP-1
10

11. Con…
• Unfortunately, GLP-1 is rapidly broken down by the DPP-IV enzyme
(very short half-life in plasma - requires continuous IV infusion).
Two options:
• Incretin mimetics are glucagon-like peptide-1 (GLP-1) agonists.
• Dipeptidyl peptidase-IV (DPP-IV) antagonists inhibit the breakdown of
GLP-1.

12. Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003
GLP-1 secretion is impaired in Type 2 diabetes
Natural GLP-1 has extremely short half-life
Add GLP-1 analogues
with longer half-life:
 Exenatide
 Liraglutide
 Lixisenitide
Injectables
Block DPP- 4, enzyme
that degrades GLP-1:
 Sitagliptin
 Saxogliptin
 Vildagliptin
 Linagliptin
Oral agents
Incretin Based Therapies
12

13. GLP1 receptor agonists
• Short acting- exenatide and lixisenatide
• Lower postprandial glucose levels and insulin concentrations via
retardation of gastric emptying
• Long acting- albiglutide, dulaglutide
• Lower blood glucose levels through stimulation of insulin secretion
and reduction of glucagon levels

14. Mechanism of action
• Activation of the GLP-1 receptor
• GLP1 receptors are expressed on beta cells, cells in the peripheral and
central nervous system, the heart and vasculature, kidney, lung, and GI
mucosa
• Binding of agonists to the GLP-1 receptor activates the cAMP-PKA pathway
and several GEFs (guanine nucleotide exchange factors)
• The end result of these actions is increased insulin biosynthesis and
exocytosis in a glucose-dependent manner

16. Pharmacokinetics
• Exenatide –
• S.C twice daily
• Rapidly absorbed, reaches peak concentrations in ~2 hours
• Little metabolism in circulation
• Clearance is glomerular filtration

17. Con…
• Liraglutide
• S.C once daily
• Peak in 8-12 hrs.
• elimination t1/2 is 12-14 hours
• clearance is primarily through the metabolic pathways of large plasma
proteins

19. Dipeptidyl Peptidase-IV Antagonists
• The concept is to allow the endogenous GLP-1 to remain in circulation for a
longer period.
• DPP-IV inhibitors are oral
• Weight neutral
• Associated with a low incidence of hypoglycemia or gastrointestinal side effects.
• A durable effect on glycaemia and improvement in some parameters of beta-cell
function.

21. Metformin
Metabolic actions
• Reduction of excessive Hepatic Glucose Output
• Stimulation of insulin-mediated muscle glucose uptake -glycogen
synthesis is increased
• Inhibition of lipolysis and of FFA availability

22. Metformin
Cellular actions
• Increased insulin binding
• Stimulation of insulin receptor tyrosine kinase activity
• Enhanced glucose transport (GLUT 4)
• Increased glycogen synthase

24. bariatric surgery
 Originally developed to treat morbid obesity (“bariatric surgery”)
 When performed to manage diabetes, bariatric or weight-loss surgery is known
as “metabolic surgery.”
 The term covers Roux-en-Y “gastric bypass” surgeries, which reduce your
stomach to a small pouch and plug it into the middle of the small intestine
 it provides an important option for treating type 2 diabetes in severely obese
patients
- often normalising blood glucose levels, within days in some procedures
- reducing or avoiding the need for medications

25. • Pancreatic hormone function markedly greater in Gastric bypass than
medical therapy.
• But not different between sleeve gastrostomy and medical therapy.
• Insulin sensitivity is higher in gastric bypass compared by gastrostomy,
despite equivalent weight loss.

27. Summary
• Insulin resistance and relative insulin secretory defect are key
elements of the pathogenesis of type 2 diabetes.
• GLP-1 deficiency is another key component in diabetic
pathophysiology contributing to:
- insulin secretory deficit.
- excess of plasma glucagon.
- postprandial hyperglycemia.

28. Con…
• Incretin mimetics offer a new approach in the management of type 2
diabetes.
• Exenatide is the first agent in this class and is administered via
injection twice a day.
• In addition to improving glycemic control, exenatide has the unique
benefit of causing weight loss
• DPP-IV inhibitors raise GLP-1 levels 2- to 3-fold.
• Sitagliptin ad vildagliptin are the first of the DPP-IV inhibitors

29. Reference
kif reference.docx