Transcript The Effect of Exenatide on Insulin Requirement, Weight and

The effect of Exenatide Therapy on
inflammation, insulin requirement and
weight in Obese Type 2 diabetes
Mellitus patients on Insulin
Shahid Mukhtar Banday MBBS
Mentors
DR PARESH DANDONA
MBBS., Ph.D., F.R.C.P, F.A.C.P, F.A.C.C
DR AJAY CHOUDHARY
MBBS. MRCP
• Diabetes Mellitus along with its complications
costs 174 billion Dollars(Economic Costs of Diabetes
in the U.S. in 2007 Diabetes Care March 2008 )
• GLP1 mimetic/analogues/DPP4 inhibitors –
 New and effective adjunctive treatment strategy to
manage Type 2 Diabetes Mellitus
STIMULATES
INSULIN RELEASE
GLP1
INCRETIN
INHIBITS
GLUCAGON
RELEASE
DPP-4
DPP-4 INHIBITORS
BLOCKS DPP4 ENZYME TO
DECREASE GLUCOSE
LOWERING
BLOOD
SUGAR
Insulinotropic effect,8,9
INSULIN RELEASE IN PRESENCE OF HYPERGLYCEMIA
insulin biosynthesis and gene expression5,10
GLP1
•L cells of jejunum/ileum
ANIMAL
STUDIES
The transcription of glucokinase and the GLUT 2
transporter genes .11
GLUCAGONOSTIC EFFECT:VIA8,18,19
•GLP1 R ON ALPHA CELLS
•INSULIN
•SOMATOSTATIN
GLP-1 receptor activation directly stimulates beta-cell
replication and neogenesis14-16
(RODENT STUDIES)
INHIBITS BETA CELL APOPTOSIS
animal models of obesity and hyperglycemia.17
Exenatide exhibits actions that are
similar to those of GLP-1
EXENATIDE
Synthetic
exendin-4
Stimulation of insulin secretion only
when blood glucose concentrations are
elevated
Suppression of postprandial glucagon
secretion. BUT DOES Not impair normal
glucagon response to hypoglycemia
 Restoration of First-phase of insulin
response
Slowing of gastric emptying and
promotes satiety(5, 6)
Obesity
•Pro inflimmatory
•High oxidative
state ⁴⁸⁻⁵⁶
Insulin
Resistance
IL6 /CRP/TNF
ALPHA ⁵⁷
Diabetes
Mellitus
Insulin
IV
DIET
INDUCED
WEIGHT
LOSS
•TNF ALPHA
• IL6
•CRP52,76-81
•OXIDATIVE STRESS
•INFLAMMATORY
MEDIATORS49,52,82
CALORIE
RESTRICTION
NFkB
•Glucose
and mixed
meal63-65
Total
cellular
IB
Two cardinal indices of
inflammation at the cellular level
RATIONALE
• Obesity and Diabetes
 States of increased inflammation
 Exenatide is expected to lead to decreased inflammation by
virtue of better glycemic control and weight loss.
• Exenatide results in better control of T2 Diabetes Mellitus
• Long term use of exenatide reduces insulin requirement.
AIMS
• Exenatide has anti inflammatory effect
 Single dose of Exenatide causes anti inflammatory effect
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Effect of exenatide over 12 weeks v/s placebo on
HbA1c
Fasting blood glucose
Body weight
Total Insulin Requirement
Single-center, randomized, placebocontrol, single blinded (patient)
prospective study.
N=24 subjects
Type2DM
On insulin
PLACEBO
N=12
EXENATIDE
N=12
Inclusion criteria
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Males or females 20-75 years of age inclusive.
Type 2 diabetes
On insulin therapy
HbA1c 7.5% and ≤ 10.0%
BMI ≥ 30 kg/m2
Subjects on statins, ACE inhibitors, metformin
and will be allowed as long as they are on stable
doses of these compounds and the dosage in not
changed during the study.
Exclusion criteria
• Coronary event or procedure (myocardial infarction,
unstable angina, coronary artery bypass surgery or
coronary angioplasty) in the previous four weeks
• Pregnancy
• Hepatic disease (abnormal LFT’s)
• Use of DPP4 inhibitors.
• Renal impairment (serum creatinine > 1.5)
• Participation in any other concurrent clinical trial
• Any other life-threatening, non-cardiac disease
• Uncontrolled hypertension (BP > 160/100 mm of Hg)
• Use of an investigational agent or therapeutic regimen
within 30 days of study
• Dietitian/Certified Diabetes Educator meeting on Day 0
• Dietary recommendations - American Diabetes Association
guidelines
• They were randomized to receive either
• Exenatide 10micg or Placebo 30 min before breakfast and
dinner for 12wk.
• The dose of Exenatide was started at
5micg twice daily for 1 wk to ensure tolerability.
24 obese Type 2 diabetes
HbA1c(7.5 --9%)
 All patients were on Insulin
 Stable doses of antidiabetic
medications
 Stable weight over prior 4
weeks
 All were on 1 -2g of
Metformin
 Statins/ACEI DOSES
were not changed
during the study
 No patient was on
Thiazolidinediones,
Antioxidants,NSAIDS .
 14/24:sulfonylureas glyburide/ glipizide 5–10
mg/d).
 10/24: long acting insulin(glargine/detemir)
 12/24:long acting + pre meal bolus
 2/24: Novolog 70/30 BID
0 day
3wk
6 wk
12 wk
12 WEEK study
0hr
exenitide
5micg
2hr
placebo
4hr
6hr
Single dose study
Insulin
titration
wk3
wk6
•Target fasting blood glucose
100
•2 hour post prandial 160
• Mono Nuclear Cells collection- Na EDTAwashed Hanks salt solution- yeild 95%
• Reactive Oxygen Species
generation:measured by chemiluminiscence
• Nuclear NFkB and Oct-1 DNA-binding activity
was measured by EMSA (electrophoretic
mobility shift assay)
• Nuclear extracts -salt extraction method from
MNC
Quantification of JNK-1,
TLR-2, TLR-4, TNF alpha
Real Time-PCR.
•The mRNA expression of
JNK-1, TLR-2, TLR-4,
TNFalpha,SOCS-3, IL-1B, and
IL-10
Statistical analysis
Statistical analysis was conducted using Sigma Stat software
(SPSS Inc., Chicago, IL)
• All data are represented as mean ± SE.Baseline measurements were
normalized to 100%, and changes from baseline were calculated as
percent change from baseline.
• Statistical analysis was carried out using one way repeated
measures ANOVA (RMANOVA) with Holm-Sidak post hoc test.
• Two-factor RMANOVA followed by Dunnett’s post hoc was
used for multiple comparisons between different treatments.
• Paired t test and Student’s t test were used where appropriate.
• Multivariate analysis of changes in inflammatory mediators
from baseline with changes in free fatty acids (FFA), insulin,
glucose, percent HbA1c, body mass index, Systolic and diastolic
blood pressure was performed using multiple linear regression.
Placebo
Baseline
Exenatide
At 12 Wk
Baseline
At 12 Wk
Age (Yrs)
54±4
56±3
Weight (lbs.)
231±13
234±18
251±18
251± 20
BMI(Kg/m2)
39.1±1.6
39.1±1.7
39.8 ±2.0
39.2±1.8
HbA1c(%)
8.5±0.3
8.0±0.3
8.6±0.4
7.4±0.5
Â
Diabetes
duration (Yr)
12±2
Fasting glucose
(mg/dl)
128 ±13
139± 33
139±17
110± 9
Â
Fasting
insulin(uU/ml)
13.1±3.1
13.9±5.9
12.7±2.8
16.4±3.2
Â
FFA (mM)
0.64±0.08
0.61±0.09
0.69±0.07
0.50±0.03
Â
SBP (mmHg)
128± 5
130±6
134± 6
127± 5
DBP (mmHg)
78±2
76±4
82±2
77±3
Insulin Dose (U)
82± 13
88 ±13
105± 30
105± 31
12±2
• Data represented as mean ± Standard
Error(SE)
• Â - P value <0.05(paired t test compared with
baseline)
 Fasting blood glucose fell from 139 ±17 to 110 ±9
mg/dl(P<0.05)
HbA1c from 8.6% ± 0.4% to 7.4%±0.5%(P<0.05)
•Data are presented as mean +/- SE; n =12 each. * and
**, P < 0.05 by RMANOVA (compared with baseline) in exenatide and placebo groups, respectively; # P
< 0.05 by two-way RMANOVA compared with control groups.
Insulin increased (P <0.05 ) in the Exenatide group whereas it did not
change significantly in the placebo group
•Data are presented as mean ±SE; n =12 each. * and
**, P # 0.05 by RMANOVA (compared with baseline) in exenatide and placebo groups,
respectively; # P < 0.05 by two-way RMANOVA compared with control groups.
 Percent change in FFA(C) after placebo and exenatide 10 mic g twice daily
for 12 wk
 Percentage change in FFA (D) after a single dose of 5 mic g exenatide or
placebo in type 2 diabetic subjects.
 Percentage FFA decreased by 21.5% from baseline (P<0.05)with exenatide
•Data are presented as mean +/- SE; n =12 each. * and
**, P # 0.05 by RMANOVA (compared with baseline) in exenatide and placebo groups, respectively; # P < 0.05 by
two-way RMANOVA compared with control groups.
 Percent change in ROS generation by MNC after
(A) Placebo and exenatide 10 micg bid for 12 wk
(B) Single dose of placebo or exenatide (5 micg) and after 6 h
Time (weeks)
Time (hours)
Change in NFkB/Oct-1 DNA-binding activity (B and C)
Data are presented as mean +/-SE; n = 12 each. *, P < 0.05 by RMANOVA (compared with baseline); #,
P <0.05 by two-way RMANOVA
compared with control groups..
Change of mRNA expression of TNFalpha (D and E)
 IL-1B (F and G) from baseline (100%) after placebo and exenatide 10 micg
twice-daily treatment for 12 wk and after 6 h of a single dose of placebo or
exenatide (5 micg) in type 2 diabetic subjects.
• Percent change in JNK-1 (B), TLR-2 (C), and SOCS-3 (D) proteins in MNC
after placebo and exenatide 10 micg twice-daily treatment for 12 wk (W)
in type 2 diabetic subjects.
Data are presented as mean +/-SE; n =12 each. *, P <0.05 by RMANOVA (compared with baseline); #, P
<0.05 by two-way RMANOVA compared with control
Discussion
• Data shows clearly that exenatide suppresses
several indices of inflammation when given over
a period of 12wk.
• They include ROS generation by MNC,
 Intranuclear NFkB binding,
 Expression of TNF alpha, JNK-1, TLR-2, IL-1B, and SOCS-3
in MNC
 There was Fall in the plasma concentrations of MCP1,SAA, IL-6, and MMP-9
 All these changes were independent of weight loss
• Effect more impressive as all patients were on
insulin which has its own anti-inflammatory
effect
• An explanation for the lack of exenatide induced
weight loss could be the short duration of our
study in subjects on relatively large doses of
insulin.
• HbA1c was also reduced significantly from 8.6 to
7.4%, and the reduction in calorie loss from
glycosuria could have neutralized the effect of
exenatide on weight loss.
• Potent but transient Rapid Anti inflammatory
effect: single injection of 5micg exenatide:
peak effect at 2hrs : coincides with time of
peak plasma concentration.
• Possible mechanisms for the anti
inflammatory/antioxidant effects of exenatide
include the
 suppression of FFA ₤
enhancement of the anti inflammatory action
of insulin ₤
Suppression of Glucagon(not studied)
Limitations of study
• Small sample size
• Diet recommendations were made at baseline
and dietary history was not collected at the
end of the study.
• Likely that subjects did not make any substantial dietary changes during the course of the
study.
Conclusion
Exenatide when administered for 12 wk
comprehensive ROS suppressive and anti
inflammatory effect in presence of insulin
Single dose of 5micg: rapid but transient anti
inflammatory effect.
Future studies
• Whether exenatide might be used in acute
inflammatory settings in the intensive care
unit or following heart attacks and strokes,
where a rapid anti-inflammatory effect is
required and such drugs may be of potential
use.
• THANK YOU
Acknowledgement
• Faculty Diabetic Research Center of WNY
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