This document discusses the pathophysiology of type 2 diabetes and new therapies based on incretin hormones. It describes how both insulin resistance and relative insulin deficiency contribute to diabetes due to impaired beta cell function. Incretin hormones like GLP-1 enhance insulin secretion and reduce glucagon levels, but are broken down quickly. New therapies include incretin mimetics like exenatide that are resistant to breakdown and have the added benefit of weight loss. DPP-IV inhibitors allow the body's own GLP-1 to remain active for longer by preventing its breakdown, and are weight neutral oral therapies like sitagliptin and vildagliptin that have few side effects. These new incretin based therapies improve

1. Incretin Based Therapy of
Type 2 Diabetes Mellitus
BY
Prof. ADEL A EL-SAYED MD
Prof. of Internal Medicine
Sohag Faculty of Medicine
SOHAG
EGYPT

2. Pathophysiology of Type 2
Diabetes
• Insulin resistance.
• Beta cell dysfunction.

3. Pathophysiology of Type 2 Diabetes
Insulin Resistance
• Insulin Resistance starts very early in the
course of the disease.
• insulin resistance alone will not produce
diabetes. If beta-cell function is normal,
one can compensate for insulin resistance
by increasing insulin secretion.

4. Pathophysiology of Type 2 Diabetes
Beta cell defect
• all type 2 patients have at least a relative defect in both
beta-cell function and mass.
• Function: in the (UKPDS), newly diagnosed people with
diabetes had, on average, only about 50% of normal
beta-cell function.[Diabetes. 1995;44:1249-1258 , Diab Res
Clin Pract. 1998;40(suppl):S21-S25.]
• Mass: Autopsy studies comparing the volume of beta
cells in nondiabetic individuals with that of people with
diabetes found a 41% decrease in beta-cell mass among
people with type 2 diabetes

5. Pathophysiology of Type 2 Diabetes
Beta cell defect
IV glucose infusion to a nondiabetic
individual results in a biphasic insulin
response:
- Immediate first-phase insulin response
in the first few minutes.
- Second-phase response, more
prolonged.

6. Pathophysiology of Type 2 Diabetes
Beta cell defect
• This first-phase insulin response is absent
in type 2 diabetic patients contributing to
the excessive and prolonged glucose rise
after a meal in those with diabetes
Diabetologia. 2004;47(suppl 1):A279.
• Infusing insulin can only partially
improve this condition.

7. Pathophysiology of Type 2 Diabetes
Other Factors
• Historically, hyperglycemia in diabetes has
been viewed as a failure of insulin-
mediated glucose disposal into muscle
and adipose tissue.
• This looks to be an over simplification of a
more complicated issue.

8. Pathophysiology of Type 2 Diabetes
Other Factors
• Two other factors:
- Glucagon.
- Gastric emptying.

9. Pathophysiology of Type 2 Diabetes
The Glucagon Factor
• In response to a carbohydrate-containing meal,
individuals without diabetes not only increase
insulin secretion but also simultaneously
decrease pancreatic alpha-cell glucagon
secretion.
• The decrease in glucagon is associated with a
decrease in hepatic glucose production, and
along with the insulin response, results in a very
modest increase in postprandial glucose.
N Engl J Med. 1971;285:443-449.

10. Pathophysiology of Type 2 Diabetes
The Glucagon Factor
• In contrast, the glucagon secretion in type 2 diabetics is
not decreased, and may even be paradoxically
increased.
• These insulin and glucagon abnormalities produce an
excessive postprandial glucose excursion.
• more than 35 years ago, Roger Unger presciently stated,
"One wonders if the development of a pharmacologic
means of suppressing glucagon to appropriate levels
would increase the effectiveness of available treatments
for diabetes”.
N Engl J Med. 1971;285:443-449.

12. Pathophysiology of Type 2 Diabetes
The Gastric Emptying Factor
• Many factors can affect the rate of gastric
emptying.
• studies suggest that all other factors being
equal, most people with type 1 and type 2
diabetes have accelerated gastric
emptying compared to those without
diabetes.
Gastroenterology. 1990;98:A378.

13. Pathophysiology of Type 2 Diabetes
One last observation
• In 1930 La Barre described a greater effect of oral rather
parenteral glucose in increasing insulin secretion.
• In 1986 Nauck demonstrated that a glucose infusion
graded to achieve plasma glucose levels identical o
those achieved with oral glucose led to a insulin
response that was only one quarter as great.
J Clin Endocrinol Metab. 1986;63:492-498.
• Incretin hormones were discovered during researchers
trials to find out interpretation to this phenomenon which
has been called the incretin effect.

14. 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).

15. What are incretins?
Gastric Inhibitory Polypeptide
(GIP)
• Secreted by the K cells of the proximal
gut. However, type 2 diabetes patients are
resistant to its action (high blood level),
making it a less attractive therapeutic
target.

16. What are incretins?
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) .

17. 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.

18. Actions of GLP-1
• In animal studies it increases beta-cell
mass by:
- Decreasing beta cell apoptosis.
- Stimulating the growth of new beta
cells. Diabetes Care. 2003;26:2929-2940.
???... Long term benefit in reversing the
progressive insulin deficiency.

19. Actions of GLP-1
• Important, as glucose levels approach the
normal range, the GLP-1 effects on insulin
stimulation and glucagon inhibition
declined (glucose dependence - reduction
of hypoglycemia. - therapeutic advantage)
Diabetologia. 1993;36:741-744

21. Actions of GLP-1
The Problem
• Unfortunately, GLP-1 is rapidly broken
down by the DPP-IV enzyme (very short
half-life in plasma - requires continuous IV
infusion).

22. The solution
Two options:
• Incretin mimetics are glucagon-like
peptide-1 (GLP-1) agonists.
• Dipeptidyl peptidase-IV (DPP-IV)
antagonists inhibit the breakdown of
GLP-1.

23. Incretin mimetics
Exenatide
• The first incretin-related therapy available
for patients with type 2 diabetes.
• Naturally occurring peptide from the saliva
of the Gila Monster.
• Has an approximate 50% amino acid
homology with GLP-1.
• Binds to GLP-1 receptors and behaves as
GLP-1.

25. Incretin mimetics
Exenatide
• Resistant to DPP-IV inactivation. Following
injection, it is measurably present in
plasma for up to 10 hours. Suitable for
twice a day administration by
subcutaneous injection.
Regul Pept. 2004;117:77-88.
Am J Health Syst Pharm. 2005;62:173-181.

27. Clinical Trials of Exenatide
• Three pivotal randomized, double-blind,
placebo-controlled, multicenter clinical trials
were conducted to support the approval of
exenatide (the AMIGO studies).
• patients with type 2 diabetes who had not
achieved adequate glycemic control despite
treatment with metformin, a sulfonylurea, or the
combination of metformin and a sulfonylurea.
• Patients were randomized to two well matched
groups to receive either placebo or exenatide (5
and 10 (mcg) twice daily by subcutaneous
injection).

29. Weight Loss With Exenatide
After adding exenatide:
• the group that was on metformin alone lost about 3 kg of
body weight at 30 weeks,
• while the sulfonylurea group experienced a 1.5- to 2-kg
weight reduction.
• Patients receiving metformin and a sulfonylurea in
combination along with exenatide lost an average of 2
kg.
• Weight loss of up to 10 kg has been documented, but it
varies from person to person.
• recently published findings have shown progressive
weight loss continuing for 82 weeks. Patients
convenience
Diabetes Care. 2004;27:2628-2635, 2005;28:1092-1100,
2005;28:1083-1091. Diabetes, Obesity and Metabolism. 2006;
8(4):436; ISSN: 4.

30. Nausea With Exenatide
• was seen uniformly across the clinical
trials, although most episodes were mild-
to-moderate in intensity and generally
intermittent.
• more frequent at the initiation of treatment
and decreased over the course of several
weeks.

31. Incretin mimetics
Recent Advances
• Liraglutide: Another GLP-1 analog with
longer half-life, similar to exenatide with
once-daily injection. Diabetes Care. 2007;30:1608-
1610
• Long acting exenatide: Highly effective
with once weekly injection. Diabetes Care.
2007;30:1487-1493

32. 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, rather than injectable.
• Weight neutral.
• associated with a low incidence of hypoglycemia
or gastrointestinal side effects. Diabetes Care.
2004;27:2874-2880.
• Preliminary long-term studies suggest a durable
effect on glycemia and improvement in some
parameters of beta-cell function.
(www.glucagon.com).

34. Dipeptidyl Peptidase-IV Antagonists
Sitagliptin and Vildagliptin
• Sitagliptin and vildagliptin are the first agents in
this class to have received FDA approval.
• Incidence of adverse reactions was reported to
be very low in a pooled safety data from 5141
patients. ADA meeting, Chicago, June 2007.
• They are indicated as monotherapy and in
combination with metformin, thiazolidinediones
and insulin.
• They look to be at least weight neutral.

35. Dipeptidyl Peptidase-IV Antagonists
Recent Advances
• During the last ADA meeting in Chicago, Illiois,
22-26 June 2007, fifty-five presentations
addressed 12 different DPP-IV inhibitors and “…
more will be seen during the coming months…”
• Some members seem particularly interesting as
saxagliptin (? potent) and alogliptin (long
acting… ? Better affecting fasting glucose).

36. 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.

37. Summary
• 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 that appears to be
prolonged based on initial studies.

38. Summary
• DPP-IV inhibitors raise GLP-1 levels 2- to 3-fold.
• They appear to be weight neutral and have a
remarkable low incidence of adverse reactions.
• Sitagliptin ad vildagliptin are the first of the DPP-
IV inhibitors to receive FDA approval.
• these promising new therapies should be
undertaken in combination not only with existing
oral antidiabetes medications as indicated, but
also with other proven cardiovascular risk-
reduction strategies, including lifestyle reduction
and pharmacologic therapy, as needed.

40. THANK YOU