Role of Incretin
in the management of diabetes

Outline
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Core defect in Type 2 DM
What is Incretin?
Evidences
Safety
DPP4 Inhibitor
GLP 1

Defect in Type 2 DM
One Hormone Theory
Insulin Deficiency
Two Hormone Theory
Insulin Deficiency
Glucagon Excess
Three Hormone Theory
Insulin Deficiency,Glucagon Excess
Decreased Incretin
effect

Multiple Defects Underlie the
Pathophysiology of Type 2 Diabetes
Impaired
Incretin Effect
Insulin
Resistance
Relative Insulin
Deficiency
Prediabetes and
Type 2 Diabetes
Kendall DM, Cuddihy, RM, Bergenstal RM. Provided by David M. Kendall. MD.

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.

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.

Major Pathophysiologic Defects in Type 2 Diabetes1,2
Islet-cell
dysfunction
Glucagon
(alpha cell)
Pancreas
Hepatic
glucose
output
Insulin
(beta cell)
Insulin
resistance
Glucose uptake
Hyperglycemia
Liver
Muscle
Adipose
tissue
Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed.
Lippincott Williams & Wilkins; 2005:145–168.
1. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781. 2. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.

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.

Pathophysiology of Type 2 Diabetes
Another 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 of 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.

The incretin hormones play a crucial role
in a healthy insulin response
Insulin response
15
180
5
90
60
120
Time (min)
180
0
Oral glucose load (50 g)
Insulin (mU/L)
10
0
–10 –5
80
270
Plasma glucose (mg/dL)
Plasma glucose (mmol/L)
Plasma glucose
60
40
Incretin
effect
20
0
–10 –5
60
120
Time (min)
180
IV glucose infusion
• Insulin response is greater following oral glucose than IV glucose, despite
similar plasma glucose concentration
Nauck et al. Diabetologia 1986;29:46–52, healthy volunteers (n=8)

History of Incretins
• Concept proposed in 1906 by Moore; secretin proposed as
gut hormone that enhanced postprandial insulin release
• Term incretin introduced 1932 by LaBerre
• Berson and Yalow developed RIA for insulin in 1960s, after
which several groups found plasma insulin levels were
higher after PO than IV glucose when BG was the same
• Term entero-insular axis coined by Unger (1969)
• GIP isolated by Brown in 1969 (Gastric Inhibitory Peptide)
• GLP-1 (7-36) discovered in 1988 (Göke)
• Term incretins (glucoincretins, insulinotrophic hormones)
today refer to hormones/peptides that reduce glucose
excursions into blood after a meal via various mechanisms

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).
INCRETIN= INtestinal+seCRETion of INsulin

GLP-1 and GIP Are Incretin Hormones
GLP-1
GIP
 Is released from L cells in ileum and
colon1,2
 Is released from K cells in duodenum1,2
 Stimulates insulin response from
beta cells in a glucose-dependent
manner1
 Stimulates insulin response from
beta cells in a glucose-dependent
manner1
 Inhibits gastric emptying1,2
 Has minimal effects on gastric
emptying2
 Reduces food intake and
body weight2
 Has no significant effects on satiety or
body weight2
 Inhibits glucagon secretion from
alpha cells in a glucose-dependent
manner1
 Does not appear to inhibit glucagon
secretion from alpha cells1,2
1. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.
2. Drucker DJ. Diabetes Care. 2003;26:2929–2940.

The two primary incretin hormones are Glucagon-like
Polypeptide -1 (GLP-1) and Gastric Inhibitory Polypeptide (GIP)
GLP-1
GIP
30 amino acid peptide1
42 amino acid peptide2
Synthesised and released by L
cells of ileum and colon2
Synthesised and released from K
cells of jejunum and duodenum2
Sites of action1:
Pancreatic β-cells and α-cells
GI tract
CNS
Lungs
Heart
Sites of action2:
Pancreatic β-cells
Adipocytes
• Circulating GIP and GLP-1 levels are regulated by multiple factors2
– Low in the basal fasting state; they rise rapidly following a meal from neuronal,
neuroendocrine, and direct nutrient stimulation of intestinal cells
1Wei
Y, et al. FEBS Lett 1995;358:219–224; 2Drucker DJ. Diabetes Care 2003;26:2929–2940.

Incretin Physiology in Type 2
Diabetes Mellitus
GLP-1 & GIP Secretion in
Type 2 Diabetes Mellitus

Decreased Postprandial Levels of the Incretin Hormone
GLP-1 in Patients With Type 2 Diabetes
*
*
*
*
*
*
*
(10-15)
Meal
Meal
Started Finished
*P<0.05, Type 2 diabetes vs NGT.
Reprinted with permission from Toft-Nielsen MB et al. J Clin Endocrinol Metab. 2001;86:3717–3723. Copyright © 2001, The
Endocrine Society.

Glucose-Dependent Insulinotropic Polypeptide (GIP) Response During OGTT

Gastric Inhibitory Polypeptide (GIP) Insulinotrophic
polypeptide
•
Type 2 diabetes patients are resistant to its action (high
blood level), making it a less attractive therapeutic target.
•
In contrast to GLP-1 levels, plasma GIP is increased in patients
with T2DM during an OGTT, while the plasma insulin response is
diminished. This suggests resistance to the stimulator effect of GIP
on insulin secretion and, in fact, this has been demon-strated by
Holst et al.
•
Jones IR, Owens DR, Luzio S, et al. The glucose dependent insulinotropic
polypeptide response to oral glucose and mixed meals is increased in patients with
type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1989;32(9):668-677.
•
Holst JJ, et al. Role of incretin hormones in the regulation of insulin secretion in
diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab 2004;287:
199-206.

Summary of Pharmacologic Incretin Actions
on Different Target Tissues
Heart
Brain
Neuroprotection
Appetite
Stomach
Gastric
Emptying
Cardioprotection
Cardiac Output
GLP-1
_
Liver
GI Tract
Insulin Secretion
β-Cell Neogenesis
+
Glucose
Production
Drucker DJ. Cell Metab. 2006;3:153-165.
Muscle
β-Cell Apoptosis
Glucose
Uptake
Glucagon Secretion

EVIDENCE?
GLP-1 modes of action in humans
Upon ingestion of food…
• Stimulates glucose-dependent
insulin secretion
• Suppresses glucagon secretion
• Slows gastric emptying
GLP-1 is secreted
from the L-cells
in the intestine
• Reduces food intake
• Improves insulin sensitivity
Long term effects
demonstrated in animals…
This in turn…
Drucker DJ. Curr Pharm Des 2001; 7:1399-1412
Drucker DJ. Mol Endocrinol 2003; 17:161-171
• Increases beta-cell mass and
maintains beta-cell efficiency

GLP-1 effects are glucose-dependent
in type 2 diabetes
Placebo (PBO)
GLP-1
*
10
5
0
-30 0
*
*
*
300
* *
*
Insulin (pmol/L)
Glucose (mmol/L)
15
PBO
GLP-1
PBO
GLP-1
200
100
60 120 180 240
Time (min)
Mean (SE); N = 10; *P < 0.05.
Nauck MA, et al. Diabetologia 1993;36:741–744.
* *
0
-30 0
* *
*
* *
*
60 120 180 240
Time (min)
Glucagon (pmol/L)
PBO
GLP-1
20
10
0
-30 0
*
* * *
60 120 180 240
Time (min)

Effect of GLP-1 (7-36)amide SC on
Gastric Emptying
Subcutaneous injection of GLP-1 reduces the
postmeal plasma glucose concentration,
stimulates insulin secretion, and delays gastric
emptying of a liquid meal.

Exenatide Increases Gastric Half-Emptying Time (T50) for Solid Meal (Tc-Labeled Eggs)
Exenatide
causes a
doseresponse
inhibition of
gastric
emptying of a
solid meal.

GLP-1 Regulates Central Feeding Behavior
Intracerebrov
entricular
injection of
GLP-1
causes a
doseresponse
decrease in
food intake in
rats. As
shown in the
insert in the
upper right,
GLP-1
receptors are
abundant in
the
paraventricu
ar nucleus of
the
hypothalamu
s and the
central
nucleus of
the
amygdala.

Change in Body Weight Over 24 Weeks:
Sitagliptin Monotherapy Studies
In a 24-week study, sitagliptin was shown to
have no effect on body weight in patients with
T2DM.

Sitagliptin + Pioglitazone Are Weight Neutral Compared to Pioglitazone Alone in T2DM

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).

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.

What Is DPP-4?
• A serine protease widely distributed throughout the body
• Cleaves N-terminal amino acids of a number of biologically
active peptides, including the incretins GLP-1 and gastric
inhibitory peptide (GIP), resulting in inactivation
• Its effects on GLP-1 and GIP have been shown to affect
incretin activity
• Inactivates GLP-1 >50% in ~1 to 2 minutes
Ahrën B. Curr Enzyme Inhib. 2005;1:65-73.

DPP-4

Inhibition of DPP-4 Increases Active GLP-1

GLP-1 and GIP Are Degraded by the DPP-4 Enzyme
Meal
Intestinal
GIP and
GLP-1
release
GIP-(1–42)
GLP-1(7–36)
Intact
DPP-4
Enzyme
Rapid Inactivation
Half-life*
GLP-1 ~ 2 minutes
GIP ~ 5 minutes
GIP and GLP-1
Actions
Deacon CF et al. Diabetes. 1995;44:1126–1131.
*Meier JJ et al. Diabetes. 2004;53:654–662.
GIP-(3–42)
GLP-1(9–36)
Metabolites

Native GLP-1 is rapidly degraded by
dipeptidyl peptidase 4 (DPP-4)
Human ileum,
GLP-1 producing
L-cells
Capillaries, DPP-4
(Di-Peptidyl
Peptidase-4)
Double immunohistochemical staining for DPP-4 (red) and GLP-1 (green) in the
human ileum
Adapted from: Hansen et al. Endocrinology 1999;140:5356–63

DPP-4 Inhibitors Enhance Incretin and
Insulin Secretion
Food intake
DPP-4 inhibitor
DPP-4
Beta-cells
Increases and prolongs GLP-1
and GIP effects on beta-cells:
Insulin release
Stomach
Net effect:
Pancreas
GI tract
Incretins
Blood glucose
Increases and prolongs
GLP-1 effect on alpha-cells:
Glucagon secretion
Alpha-cells
Intestine
Adapted from: Barnett A. Int J Clin Pract 2006;60:1454-70
Drucker DJ, Nauck MA. Nature 2006;368:1696-705
Idris I, Donnelly R. Diabetes Obes Metab 2007;9:153-65

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.

Plasma Levels of Bioactive Intact GLP-1 (9-36)amide After Sitagliptin Administration in T2DM

Sitagliptin Reduces Glucose AUC
After a Glucose Load

Sitagliptin Once Daily Improves Both Fasting and Postmeal Glucose Concentration
Part 3
Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2
diabetes. Diabetes Care. 2006;29(12):2632-2637. Aschner P, Kipnes MS, Lunceford JK, et al; Sitagliptin Study
021 Group

Sitagliptin Monotherapy and
Coadministration With Metformin
Sitagliptin monotherapy and metformin monotherapy produce similar reductions in A1C in patients with
T2DM and, when given in combination, provide an additive effect to reduce A1C.

Sitagliptin: Proportion of Patients
Achieving A1C Goals
Sitagliptin monotherapy and metformin monotherapy
allow a similar percentage of participants with T2DM
to achieve an A1C <7.0% and have an additive effect
to reduce A1C to <7.0%.

Sitagliptin: Active-Comparator
(Glipizide) Add-on to Metformin
The addition of sitagliptin to metformin produces a
similar decrease in A1C as the addition of glipizide to
metformin over a 1-year period.

Sitagliptin: Effect on Baseline A1C
The addition of sitagliptin to metformin produces a similar decrease in A1C, irrespective of the starting
baseline A1C, as does the addition of glipizide to metformin over a 1-year period.

Clinical Adverse Events in ActiveComparator Add-on to Metformin Study
Sitagliptin has an excellent safety profile and is associated with significantly fewer drug-related adverse
events than glipizide.
Patients With Adverse Events, n (%)
Sitagliptin 100 mg
(n=588)
Glipizide
(n=584)
One or more AEs
419
(71.3)
444 (76.0)
Drug-related AEs
85
(14.5)
177 (30.3)
Serious AEs (SAEs)
43
( 7.3)
44
( 7.5)
Serious drug-related AEs
0
( 0.0)
2
( 0.3)
Died
1
( 0.2)
2
( 0.3)
16
( 2.7)
21
( 3.6)
Discontinued due to drug-related AEs
8
( 1.4)
8
( 1.4)
Discontinued due to SAEs
6
( 1.0)
7
( 1.2)
Discontinued due to serious drug-related AEs
0
( 0.0)
0
( 0.0)
Discontinued due to AEs
Stein P. ADA 66th Scientific Sessions; June 9-14, 2006; Washington DC. Late-breaking abstracts.

Sitagliptin and Measures of -Cell Function
Compared to placebo, sitagliptin therapy for 24 weeks reduced the proinsulin/insulin ratio and increased
HOMA-beta, suggesting a beneficial effect on beta-cell function

Sitagliptin: B-Cell Response to Glucose
During the
frequently
sampled meal
tolerance test
(MTT)
performed
before and after
18 weeks,
sitagliptin
significantly
augmented
insulin
secretion
compared to
the placebotreated group.

Sitagliptin Studies: Summary1
As monotherapy,
sitagliptin was as
effective in reducing
A1C as metformin
and pioglitazone
and was completely
additive in
decreasing A1C
when given to
metformintreated patients with
T2DM.

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.

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.

Conclusion
As there is no proven link between
use of incretin therapies and
pancreatic cancer
Diabetes UK does not advocate any
change in its management. In particular,
patients should NOT stop their
medication unless advised to by
their doctor.
At the same time vigilance is required of
patients on such therapies for any side
effects suggestive of pancreatic disease.
It also reminds clinicians and people
with diabetes to be aware that
incretin therapies are contraindicated in
people with previous pancreatitis.

At this time,
patients should
continue to take
their medicine as
directed until
they talk to their
health care
professional, and
health care
professionals
should continue to
follow the
prescribing
recommendations
in the drug
labels.

The mean age of included
individuals was 52 years, and
57.45% were male. Cases were
significantly more likely than
controls to have
hypertriglyceridemia (12.92% vs
8.35%), alcohol use (3.23% vs
0.24%), gallstones (9.06% vs
1.34), tobacco abuse (16.39% vs
5.52%), obesity (19.62% vs
9.77%), biliary and pancreatic
cancer (2.84% vs 0%), cystic
fibrosis (0.79% vs 0%), and any
neoplasm (29.94% vs 18.05%).
After adjusting for available
confounders and metformin
hydrochloride use, current use
of GLP-1–based therapies
within 30 days (adjusted
odds ratio, 2.24 [95% CI,
1.36-3.68]) and recent use
past 30 days and less than 2
years (2.01 [1.37-3.18]) were
associated with significantly
increased odds of acute
pancreatitis relative to the
odds in nonusers.

Considerations for
Healthcare Professionals:
•Be aware of the possibility
for and monitor for the
emergence of the signs and
symptoms of pancreatitis
such as nausea, vomiting,
anorexia, and persistent
severe abdominal pain,
sometimes radiating to the
back.
•Discontinue sitagliptin or
sitagliptin/metformin if
pancreatitis is suspected.
•Understand that if
pancreatitis is suspected in a
patient, supportive medical
care should be instituted. The
patient should be monitored
closely with appropriate
laboratory studies such as
serum and urine amylase,
amylase/creatinine clearance
ratio, electrolytes, serum
calcium, glucose, and lipase.
•Inform patients of the signs
and symptoms of acute
pancreatitis so they are aware
of and able to notify their
healthcare professional if
they experience any unusual
Advice:
Health care person should honestly discuss with patient about risk of
acute pancreatitis

The three
organizations firmly
believe that people
taking these
medications, or
those who may
consider taking
them, should be
informed of all that
is currently known
about their potential
risks and
advantages in order
to make the best
possible decisions
about their treatment
and care, in
consultation with
their health care
providers. At this
time, there is
insufficient
information to
modify current
treatment
recommendations.

Old Antidiabetes
drugs
Incretin

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