Transcript Presentation: The Metabolic Effects of Surgery and Type II Diabetes

Treatment for Morbid
Obesity and Type II
Diabetes
Your Title Here
T2DM Projected Global Incidence
50,800
Projected 2012
US diabetic Population
22.7 MM
OUS diabetic Population 226.5 MM
15,120
22,700
IFEGS
29,400
¹ Wild et al Diabetes Care 27:1047–1053, 2004
2 |
Japan
Indonesia
4,780
China
India
Pakistan
Turkey
Bangladesh
Brazil
Egypt
US
2012
7,620
6,370
Philippines
8,670
4,260 4,320
7,250
2000
13,600
Diabetes Mortality and Cost
• Diabetes is the sixth leading cause of death in the USA.
• 2002: 71,000 Americans died from diabetes, but another 186,000 died
from diabetes related conditions.
• Diabetes increases the risk for heart disease six fold and multiplies the
risk of stroke by four.
• Diabetes is the most costly disease in America, consuming one out of
every 7 dollars*
• $137.7 billion per year with $92 billion spent on medical care and the
remainder on lost wages, lost productivity
• The annual cost of diabetes medical care was $10,683 per diabetic
patient in 2002
http://www.diabetes.org/diabetes-statistics/cost
Diabesity, Dr. Katherine Kaufman, former ADA president, Bantam Books, 2005
3 |
Diabetes Related Comorbidities
In a single year in the United States……
• 82,000 amputations are performed because of diabetes
• 12,000-24,000 people lose their eyesight from diabetes
• 41,000 people begin treatment for end stage renal disease
http://www.diabetes.org/diabetes-statistics
4 |
Objectives
• Review current medical therapy for treating diabetes
• Introduce surgical therapy to treat diabetes
• Examine the physiologic basis for diabetes surgical
intervention
– Enteroinsular axis
– Adipoinsular axis
• Introduction to novel surgical options
5 |
T2DM & THE METABOLIC EFFECTS OF BARIATRIC SURGERY
A Novel Language for Surgeons
6 |
Glucose
• Major immediate fuel
source
• Normal serum value
80-100mg/dl
• Stored in muscle and
liver as glycogen
Carbon
Hydrogen
Aerobic respiration
Glucose + Oxygen = Carbon Dioxide + Water + Energy
C6H12O6+ 6O2=6CO2+6H2O+Energy
7 |
Oxygen
Pancreas
The pancreas resides posterior to the stomach
and liver. It secretes pancreatic juice containing
digestive enzymes as well as several important
hormones, including insulin and glucagon
• Beta cells produce insulin
• Stimulates liver and muscle cells to store
glucose in glycogen
• Stimulates adipocytes to form fats from fatty
acids and glycerol
• Stimulates liver and muscle cells to make
proteins from amino acids
• Inhibits gluconeogenesis
• Alpha cells produce glucagon
• Stimulates liver and muscle cells to
breakdown glycogen
• Stimulates gluconeogenesis
8 |
Glucagon and Insulin
Raises
Blood
Sugar
High
Blood
Sugar
Promotes
Insulin
Release
Stimulates
breakdown of
glycogen
Liver
Glycogen
Glucagon
Glucose
Stimulates
formation of
glygogen
Pancreas
Insulin
Stimulates
glucose uptake
in tissue
Lowers
Blood
Sugar
9 |
Promotes
Glucagon
Release
Low
Blood
Sugar
Types of Diabetes
•Type I Diabetes
– 5-10% of all cases
– Autoimmune destruction of the pancreatic beta cells
– Most common in children and young adults
•Type II Diabetes (Previously NIDDM)
– 80-90% of all cases
– 80% of all patients are overweight (mean T2DM BMI in
US=30)
– Hyperinsulinemia with insulin resistance
– Ultimate beta cell failure
10 |
HbA1c
Measure of the degree to which hemoglobin is glycosylated
within erythryocytes
Represents average levels of serum glucose over prior 2-3
months
Definitions
– Normal = 5-6%
– Good glycemic control = 7-8%
– Fair glycemic control = 8-9%
– Poor or uncontrolled = >9%
11 |
Insulin Resistance
A condition in which normal amounts of insulin
produce an inadequate response in liver, muscle and
fat cells
– Elevated free fatty acids secondary to hydrolysis
of stored triglycerides in adipose tissue
– Elevated serum glucose secondary to inadequate
uptake in muscle and inadequate storage in liver
– Elevated serum levels of insulin
12 |
HOMA
Homeostasis model assessment
Correlates well with more rigorous hyperglycemic,
hyperinsulinemic clamp*
Requires fasting plasma insulin and glucose
HOMA IR = (glucose) mM x (insulin) pM
22.5 x 6
* Bonora E. et.al. Diab Care 2000
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Resolution, Remission or Cure
It is generally accepted that effective medical or
surgical diabetes therapy results in remission of
the disease and not cure
This generally means that the patient is off all
hypoglycemic medications and/or insulin and
that they have normal fasting plasma glucose,
normal post prandial glucose excursions and
normal HbA1c
14 |
T2DM & THE METABOLIC EFFECTS OF BARIATRIC SURGERY
Medical Therapy
15 |
Diabetes Disease State
HbA1c (%)
Classification
6
7
Controlled
8
Good
9
Uncontrolled
Poor
Maintain Treatment Change Treatment
Phase I
Diet, and physical activity
Oral Pharmaceuticals
Treatment
Phase II
Oral and Insulin
Phase III
Insulin Only
Hypertension
Cardiovascular
Nephropathy
Amputation
Blindness
Comorbidities
% of Diab
Pop
16 |
42.3
21.1
15.4
21.1
Phase IV
Treatment Map - Type 2 Diabetes
Typical Decision Tree For
The Treatment Of Type 2
Diabetes
Elderly patient
Monotherapy with an
aplpha-glucosidase
inhibitor, meglitinide, PPAR
agonist or sulfonylurea
HbA1c
declines
HbA1c not
controlled
Add metformin in patients
unless liver or renal
impairment is present
HbA1c not
controlled
Replace sulfonylurea or
other secretagogue with
insulin; maintain on
metformin, if appropriate
HbA1c
declines
Type 2 diabetes
confirmed
Diet modification
and exercise
HbA1c
controlled;
maintain diet and
exercise
HbA1c not
controlled
Nonelderly
patient
Obese
patient
Non-obese
patient
Metformin
monotherapy
Sulfonylurea
monotherapy
HbA1c not
controlled
HbA1c not
controlled
Add sulfonylurea or, less
often, PPAR agonist,
meglitinide, or, rarely
acarbose
HbA1c not
controlled
Combination
insulin and oral ag
Add
Metformin
HbA1c
declines
HbA1c
declines
HbA1c not
controlled
Add PPAR
agonists
HbA1c
declines
Decision Resources; 2007
17 |
Meglitides
Sulfonylureas
And nonsulfonylurea
secretagogues
Pharmacologic Options
TZDs
Increase insulin
secretion
Biguanides
Glitazones
Thaizolidinediones
(TZDs)
Increase glucose
uptake
Decrease
Hepatic glucose
production
Liver
Increased Glucose
Production
Decrease
Lipolysis
Adipose Tissue
Increased Liposysis
Increased
FFA
Skeletal Muscle
Decreased
Glucose Uptake
Insulin
Resistance
Glucotoxcity
Alpha-glucosidase
Inhibitors
Delay intestinal
Carbohydrate
absorbtion
Small Intestine
Carbohydrate
Absorption
Pancreatic Beta Cell
Decreased insulin
Secretion
Defective
Insulin
Secretion
Hyperglycemia
GLP-1 Agonists +/DPP-IV Inhibitors
Inzucchi S. JAMA 2002
18 |
Hypoglycemic Drugs
Class
Effect
Drug name (Brand Name)
HbA1c
Effect
Side Effects
Increase insulin secretion
chlorpropamide( Diabinese); Gliclazide
(Diamicron); glimepiride (Amaryl);
glipizide (Glucotrol); glyburide
(Diabeta); glynase (Micronase);
tolazamide (Tolinase); tolbutamide
(Orinase)
0.82.0%
Weight gain;
hypoglycemia
Meglitides
Increase insulin
production of short
duration
repaglinide (Prandin); nateglinide
(Starlix)
0.52.0%
Weight gain;
hypoglycemia
Biguanides
Decrease hepatic glucose
carbohydrate absorption;
increase insulin sensitivity
metformin (Glucophage)
1.52.0%
GI distress;
lactic acidosis,
B12 absorption
Thaizolidinedion
e(TZDs)
Increase insulin sensitivity
rosiglitazone (Avandia); pioglitazone
(Actos)
0.51.5%
Heart Failure,
weight gain
Delay intestinal
carbohydrate absorption
acarbose (Precose); miglitol (Glyset)
0.7-1.0
Abdominal
pain, diarrhea
Injected to replace or
supplement natural insulin
insulin aspart (Novolog, NovoRapid);
lispro (Humalog); glulisine (Apidra)
glargine (Lantus); detemir (Levemir)
Human rDNA insulin (Humulin, Iletin,
Novolin, Velosulin, Actrapid, Insultard,
Lente)
Weight Gain;
hypoglycemia
Analogous GLP-1
exanatide( Byetta)
Nausea
Extends activity GLP-1
sitagliptin phosphate (Januvia)
Sulfonylureas
α-glucosidase
Inhibitors
Insulin
GLP-1 mimic
DPP- IV inhibitor
19 |
UK Prospective Diabetes Study
(UKPDS)
–20 year trial
–Recruited 5,102 T2DM patients
–21 clinical centers
– England
– Northern Ireland
– Scotland
–Major results presented in 1998 in 5
publications
www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/
20 |
Association of glyaecemia with macrovascular and microvascular
complications of type 2 diabetes
(UKPDS 35)
– Methods
– Prospective, observational study
– 3642 patients included in analyses of risk
– Primary outcome = any endpoint or death related
to NIDDM
– Secondary outcomes = MI, stroke, amputation,
microvascular
UKPDS 35. BMJ 2000; 321: 405-12
21 |
Any Diabetes Related Endpoint
Hazard ratio
5
p<0.0001
1
21% decrease per 1% decrement in HbA1c
0.5
0 5
6
7
8
9
10
11
Updated mean HbA1cUKPDS 35. BMJ 2000; 321: 405-12
22 |
Diabetes Related Deaths
Hazard ratio
5
p<0.0001
1
21% decrease per 1% decrement in HbA1c
0.5
0 5
6
7
8
9
10
11
Updated mean HbA1cUKPDS 35. BMJ 2000; 321: 405-12
23 |
All Cause Mortality
Hazard ratio
5
p<0.0001
1
14% decrease per 1% decrement in HbA1c
0.5
0 5
6
7
8
9
10
11
Updated mean HbA1cUKPDS 35. BMJ 2000; 321: 405-12
24 |
Association of glyaecemia with macrovascular and microvascular
complications of type 2 diabetes
(UKPDS 35)
– Conclusions
– The risk of diabetic complications is strongly
associated with previous glyacemia
– Any reduction in HbA(1c) is likely to reduce the
risk of complications
– The lowest risk appears to be in those patients
whose HbA(1c) values are <6%
UKPDS 35. BMJ 2000; 321: 405-12
25 |
Effect of intensive blood glucose control with Metformin on
complications in overweight patients with type 2 diabetes
(UKPDS 34)
Methods
– Randomized controlled trial (median duration 10.7 years)
– N=753 patients
– Diet alone (n=411)
– Intensive blood-glucose control policy with Metformin (n=342)
– Primary outcome = any diabetes-related clinical endpoint,
diabetes-related death, and all cause mortality
– Results
– Risk reduction associated with Metformin
– 32% for any diabetes-related endpoint
– 42% for any diabetes-related death
– 36% for all cause mortality
– Median HbA(1c)
– 7.4 % Metformin
– 8.0 % Conventional
UKPDS 34. Lancet. 1998 Sep 12; 352(9131):854-65.
26 |
Intensive blood glucose control with sulphonylureas or insulin
compared with conventional treatment and risk of complications in
patients with type 2 diabetes
(UKPDS 33)
– Methods
– Randomized controlled trial (10 years)
– N= 3867 patients
– Intensive policy with sulfonylurea or insulin
– Intensive policy with diet (conventional)
– Primary outcome = any diabetes-related clinical endpoint, diabetes-related
death, and all cause mortality
– Results
– Risk reduction associated with sulfonylurea or insulin
– 12% for any diabetes-related endpoint
– 10% for any diabetes-related death
– 6% for all cause mortality
– Weight gain
– Statistically greater in intensive group (2.9kg) than in conventional group
(p<0.001) and in insulin patients (4.0kg) versus sulfonylurea group (1.7kg)
– HbA(1c)
– 7% intensive control with sulfonylurea or insulin (no difference between
agents)
– 7.9% conventional group
UKPDS 33. Lancet. 1998 Sep 12; 352(9131): 837-53.
27 |
Glycemic control with diet, sulfonylurea, metformin or insulin in
patients with type 2 diabetes mellitus: progressive requirement for
multiple therapies
(UKPDS 49)
– Methods
– Randomized controlled trial (10 years)
– Diet alone
– Insulin
– Metformin
– Sulfonylurea
– Outcome measures
– FPG
– HbA(1c)
– Percentage of patients who achieve target levels below 7% HbA(1c
or FPG < 140mg/dl
– Results
– Proportion of patients achieving FPG target (< 140mg.dl) after 9 years
– 8% diet, 42% insulin, 24% sulfonylurea
– Proportion of patients achieving HbA(1c) target (< 7%) after 9 years
– 9% diet, 28% insulin, 24% sulfonylurea
UKPDS 49. JAMA. 1999 Jun 2; 281(21): 2005-12.
28 |
Conventional vs Intensive Therapy
Steno 2 Trial, NEJM, 2003
29 |
Efficacy & safety of incretin therapy in T2DM:
Systematic review and meta-analysis
– 29 randomized controlled trials evaluated
– Select outcomes – GLP-1 versus placebo
– Lowered HbA1c -0.97% (DPP4 inhibitors -0.74%)
– Lowered body weight 1.4kg (4.8 kg versus insulin)
– Higher incidence of nausea/vomiting (risk ratio 2.9/3.2)
R Amori, J Lau, A Pittas, JAMA 2007
30 |
Effects of exenatide (exendin-4) on glycemic control and weight
over 30 weeks in metformin-treated patients with type 2 diabetes
– Methods
–
–
–
–
Triple blind, placebo controlled 30 week study
366 patients at 83 US sites
Intent to treat population = BMI 34; HbA1c 8.2
5mcg enexatide x 4 weeks then 5 or 10mcg x 26 weeks
– Results at week 30:
– HbA1c change: -0.78 (10mcg), -0.40 (5mcg), +0.08 (placebo)
– % achieving HbA1c < 7%: 46% (10mcg), 32%(5mcg), 13% (placebo)
– Weight change: -2.8kg (10mcg), -1.6kg (5mcg) v placebo
DeFronzo RA. et.al. Diabetes Care, 2005
31 |
Exenatide versus insulin glargine in patients with suboptimally
controlled type II diabetes: a randomized trial
– Methods
– 551 patients suboptimally controlled with metformin or
sulfonylurea (HbA(1c) 7-10%)
– 10 mcg exenatide or single daily dose insulin
– 82 outpatient centers in 13 countries
– 26 week, open label, randomized controlled trial
– Results
– At 26 weeks, both agents reduced HbA(1c) by mean 1.11%
– Exenatide mean A(1c) 8.2% ; Insulin mean A(1c) 8.3%
– 21% insulin group and 9% exenatide group achieved FPG
<100mg/dl
– Weight data:
– Exenatide = - 2.3kg
– Insulin = + 1.8kg
Heine RJ. Ann Int Med, 2005
32 |
Medical Therapy
Conclusions
“Diabetes processes of care and
intermediate outcomes have
improved nationally in the past
decade. But…1 in 5 persons still
has poor glycemic control”
Improvements in diabetes processes of care and intermediate outcomes:
United States, 1988-2002. Ann Int Med 2006;144(7):465-473
33 |
T2DM & THE METABOLIC EFFECTS OF BARIATRIC SURGERY
Current Surgical Therapy
34 |
Bariatric Surgery Procedures
35 |
An old concept…..
Surgery, Gynecology & Obstetrics; February 1955
36 |
….with renewed interest
1995
2006
2004
37 |
Worldwide Interest in “Metabolic” Surgery
38 |
Diabetes Surgery Symposium – Rome, Italy
(March 29-31, 2007)
– International
multidisciplinary
voting panel of
experts
– Surgeons (1/3
of the panel)
– Endocrinologi
sts
– Basic
Scientists
39 |
Major points of consensus
– Anatomic modification of various regions of the GI tract
likely contribute to the amelioration of T2DM trough
distinct physiological mechanisms.
– Gastrointestinal bypass procedures can improve diabetes
by mechanisms beyond changes in food intake and body
weight.
– Gastrointestinal surgery may be appropriate for the
treatment of T2DM in patients who are appropriate
surgical candidates with BMI of 30 to 35 who are
inadequately controlled by lifestyle and medical therapy
– Collaboration among endocrinologists, surgeons and
basic investigators should be encouraged to facilitate the
understanding of GI mechanisms of metabolic regulation
and to allow use of these mechanisms for improved
treatment of T2DM.
Diabetes Surgery Symposium – Rome, Italy
(March 29-31, 2007)
– Major points of consensus
– Gastrointestinal surgery may be appropriate for the treatment
of T2DM in patients who are appropriate surgical candidates
with BMI of 30 to 35 who are inadequately controlled by
lifestyle and medical therapy
– Collaboration among endocrinologists, surgeons and basic
investigators should be encouraged to facilitate the
understanding of GI mechanisms of metabolic regulation and
to allow use of these mechanisms for improved treatment of
T2DM.
40 |
Bariatric Surgery Efficacy
Procedure
% EWL
T2DM
(Resolved)
Gastric Banding
47% (n=1848)
48%
Gastroplasty
68% (n=506)
68%
Gastric Bypass
62% (n=4204)
84%
BPD
70% (n=2480)
98%
Buchwald H. JAMA, 2004
41 |
Bariatric Surgery Efficacy
42 |
Author
Procedure
Resolution
Pories et al 1995
Gastric Bypass
89%
Torquati et al 2005
Gastric Bypass
74%
Schauer et al 2003
Gastric Bypass
82%
Sugerman et al 2003
Gastric Bypass
86%
Dixon et al 2003
Lap Band
64%
Gagner (unpublished)
Sleeve Gastrectomy
65%
Bariatric Surgery is Effective,
But Not Equal
Benefit
Diabetes Resolution Rate
Excess Weight Loss
100%
Switch
Roux-en-Y
50%
Banding
10%
0.001
Risk
0.01
0.1
1
10
30 Day Mortality
Adapted from Buckwald H, et al, Bariatric surgery, a systematic review and metaanalysis, JAMA. 2004;292:1724-1737 and Maggard M, et al, Meta-Analysis:
Surgical Treatment of Obesity, Ann Intern Med. 2005;142:547-559.
43 |
Effect on Beta Cell Function and
Metabolic Markers
-cell preservation
Metabolic Syndrome
Sjostrom, L, et.al.; N Engl J Med; 2004; 3551; 26: 2683-2693
44 |
Effects on Weight Loss and Mortality
24%
Sjostrom, L, et.al.; N Engl J Med. 2007;357:741-52
45 |
Diabetes Treatment Has Risk
Mortality
1000
N
5730
1544
8866
3099
3099
Study
Duration
(months)
91
46 |
Patients
Ref
96
2.2
Newly treated oral
hypoglycmics
Evans Diabetologia. 2006;49:930
36
8.7
Glibenclamide and
metformin
Monami Diabetes Metab Res
Rev. 2006; 22:477-82.
60
3.5
Newly treated
sulphonylureas and/or
biguanides
Johnson Diabetes Care. 2002
Dec;25(12):2244-8
2.6
Metformin only
Gulliford Diabetes Metab Res
Rev. 2004;20:239-45
4.4
Glibenclamide +/insulin metformin
Monami Diabetes Metab Res
Rev. 2007 Mar 23; [Epub]
378
58
Annualized
Mortality
Rate (%)
435
45.6
3.5
Hypertensive diabetic
outpatients
Mannucci Diabetes Metab Res
Rev. 2006;22:172-5.
1200
48
2.0
< 5yr diagonosis (2yr
avg)
Bo Diabetes Metab Res Rev.
2006;22:172-5.
471
57
4.1
Diabetic Outpatients
Salles Diabetes Care.
2004;27:1299-305
Effect of Laparoscopic Gastric Bypass on T2DM
– Methods
– 1160 LGB
– 240 (21%) IGT or T2DM
– 5 year follow-up on 191 (80%)
– Results
– Mean excess weight loss = 60%
– FPG and HbA(1c) returned to normal levels in 83% and
improved in 17%
– Significant reduction in oral agents (80%) and insulin (79%)
– Shortest duration (<5 years), mildest disease (diet
controlled) and greatest EWL did best
Schauer P. et.al. Ann Surg 2003
47 |
Laparoscopic Gastric Bypass and Insulin
Resistance
Loss of insulin resistance after gastric bypass surgery: a time
course study
– Methods
– 71 gastric bypass patients (mean BMI 45)
– 3 groups of analysis = diabetics (n=31), IGT (n=11), normal
(n=29)
– n=26 IVGTT the morning of and 6 days after open GBP (Fobi
pouch)
– n=71 HOMA (homeostasis model assessment) 6 days, 3,6,9,12
months
– Results (12 months)
– None of the IGT have become diabetic
– 28/31 left hospital 6 days after surgery without medications
Wickremesekra K. et.al. Obes Surg 2005
48 |
Laparoscopic Gastric Bypass and Insulin
Resistance
Fasting insulin (pM) over time
Fasting glucose (mM) over time
160
P<0.001
140
10
120
100
Diabetes
9
p<0.171
8
Diabetic
IGT
Normal
80
60
40
7
6
Diabetic
IGT
Normal
5
4
3
2
20
1
0
0
Pre-op
6d
3m
6m
9m
12m
Pre-op
6d
3m
6M
9M
12M
Adapted from Wickremesekra K. et.al. Obes Surg 2005
49 |
Laparoscopic Gastric Bypass and Insulin
Resistance
12
Liquids
Very low calorie dietCD
HOMA - IR
10
8
Diabetic
IGT
Normal
6
4
2
0
pre-op
6d
3m
6m
9m
12m
Adapted from Wickremesekra K. et.al. Obes Surg 2005
50 |
Oral Glucose Tolerance Test
10%
Not
Good
Weight
Loss
Good
Not
Good
One
Year
Good
Gastric
Banding
Gastric
Bypass
Gastric
Banding
Gastric
Bypass
F Pattou, et al
51 |
Gastric Banding & T2DM
Lap-Band® vs. Intensive Medical Management
– Methods
– Randomized, controlled trial
– n=80 patients (BMI 30-35) Randomized to
– VLCD, pharmacologic or lifestyle change x 24
months
– Lap-Band®
– Results
– Weight Change
– 87.2% excess weight loss (surgical)
– 21 % excess weight loss (nonsurgical)
– Metabolic Syndrome (in 38% each group at start)
– 24% nonsurgical group with residual
– 3% surgical group with residual (p<0.002
Dixon et.al. Ann Int Med, 2006
52 |
T2DM & THE METABOLIC EFFECTS OF BARIATRIC SURGERY
The Physiologic Basis for
Surgery
53 |
Hormones in the GI Track
Intake
Grehlin
Usage
Processing
Stomach
GLP-1
GIP
CCK
PYY
Insulin
Glucose
Storage
Liver
Bowel
Leptin
Adiponectin
Resitin
Fat
54 |
The Entero-insular Axis
Enteral glucose ingestion yields a greater
insulin release than does parenteral glucose
infusion *
Secreted gut hormones effect insulin
production, secretion and usage = “incretins” /
“anti-incretins”
Select “known” peptides with various effects
* Elrick H. J Clin Endocrinol Metab. 1964
55 |
Gut Hormone Discovery
1967 – Gastric Bypass
Rehfeld J, 2004
56 |
Glucagon Like Protein – 1
GLP-1 “Enteroglucagon”
– Secreted by ileal “L-cells” in (rapid) response to a mea
– Actions
– Potent stimulator of insulin / supresses glucagon
– Slows gastric emptying
– Reduces appetite
– Increases beta cell mass
– Increased after gastric bypass (??)
Wynne K. J Clin Endo Met, 2004
57 |
Peptide YY
– Secreted from entire GI tract – “L” cells
– Mainly distal (ileum, colon and rectum)
– Food intake stimulates its release – fasting reduces it
– Effects
– May ameliorate insulin resistance (in mice)
– Delays pancreatic/gastric secretions/gastric
emptying/intestinal transit
– No known alterations in obesity relative to normal weight
individuals
– Dose response has been demonstrated (taste eversion to
reduced intake)
Bloom SR. et.al. Nature 2006
58 |
GIP
GIP – Gastric Inhibitory Peptide / Glucose
Dependant Insulinotrophic Peptide
– Secreted by duodenal “k-cells”
– Actions
– Potent stimulator of insulin
– Inhibits gastric acid
– Reduced insulinotrophic effects in T2DM
and obesity
– No known effect of food intake but
knockout mice are resistant to obesity
59 |
Foregut Theory
– Exclusion of the
duodenum results in
inhibition of a
“putative”signal that is
responsible for insulin
resistance and/or
abnormal glycemic
control (T2DM)
Rubino et.al, Ann Surg, 2006
60 |
Incretins and Anti-Incretins
Rubino et.al, Ann Surg, 2002
61 |
Animate Model Results -Foregut Theory
– Primary procedure
– Group 1 = Duodenal-jejunal exclusion
– Group 2 = Gastrojejunostomy
– Secondary procedure
– Group 1 = Duodenal-jejunal exclusion converted to
restored anatomy
– Group 2 = Gastrojejunostomy converted to duodenal
exclusion
Controls
– Pair-fed
– Sham operated
– Untreated
Rubino et.al, Ann Surg, 2006
62 |
Oral Glucose Tolerance Test
OGTT GK rats
GK DJB
GK Sham
GK GJ
Glucose levels (mg/dl)
600
500
400
300
200
100
Time (min)
0
0
50
100
150
200
Rubino et.al, Ann Surg, 2006
63 |
Effect of Duodenum
Duodenal Exclusion vs Inclusion in food passage
OGTT
AUC
69000
64000
59000
Duodenal Pass.
Duod. Exclus
54000
49000
44000
Duodenal Pass.
Duod. Exclus
Rubino et.al, Ann Surg, 2006
64 |
The Hindgut Theory
– The more rapid delivery
of undigested nutrients
to the distal bowel
upregulates the
production of L-cell
derivatives like GLP-1
Mason E. Obes Surg 2005 15, 459-461
Rubino et.al, Ann Surg, 2006
65 |
Animate Model and Hindgut Theory
– Non-obese, Diabetic (GK):
– Ileal transposition (IT) (n=5)
– sham operated rats (intestinal
transection/re-anatomosis) (n=5)
– non-operated rats (n=5)
– Non-diabetic (SD):
– Ileal transposition (n=4)
– Non-operated rats (n=3)
– Oral glucose tolerance test, insulin tolerance test,
GLP-1
Patriti et.al. Obes Surg, 2005
66 |
Animate Model Results – Hindgut Theory
– No differences in food intake, weight gain within groups pre
and post op
– Oral glucose tolerance test (GK rats) (No differences in SD rats)
300
250
*
200
*
Control
Sham
IT
150
100
50
* p<0.03
0
Day 0
Day 10
Day 30
Day 40
Patriti et.al. Obes Surg, 2005
67 |
Animate Model Results – Hindgut Theory
– ITT – No differences within groups on any measure
– Mean GLP-1 secretion 0-15 minutes post glucose infusion (GK
rats)
40
35
30
*
25
IT
Control
Sharm
20
15
10
5
* p=0.05
0
Day 45
Patriti et.al. Obes Surg, 2005
68 |
Hindgut Conclusions
– Conclusions
– IT is effective in inducing improved
glycemic control independent of
weight and food intake
– The potential mechanism of action
may be insulin independent (i.e.
enhanced glucose uptake,
utilization…)
– In this study, GLP-1 does not appear
to the mediator of this effect
Patriti et.al. Obes Surg, 2005
69 |
The Adipo-insular Axis
Possible mechanisms of action
Free fatty acids and insulin resistance
–
–
–
–
–
–
Impaired insulin signaling (muscle) / glucose transport
Increased oxidative stress (reactive oxygen species)
Inhibition of insulin suppression of glycogenolysis in liver
Direct endothelial damage
Impairment of beta cell function
Alterations in blood pressure
Fat-derived peptides – “Adipokines”
– TNF-alpha – impairs insulin signaling pathways / suppresses adipocyte
differentiation
– Leptin – enhances insulin action / anorexigenic
– Resistin – Known to be elevated in obesity / IR – unknown action
– Adiponectin - enhances insulin action / glucose clearance / fatty acid
oxidation
– IL-1/ IL-6 – Hyperinflamatory response
Gabriely I. Diabetes 2002
Nielsen S. J Clin Invest, 2004
70 |
T2DM & THE METABOLIC EFFECTS OF BARIATRIC SURGERY
Novel Surgical Options
71 |
Novel Procedures
Novel procedures are experimental and require further study
under Good Clinical Practice – International Commission on
Harmonization guidelines.
Investigation of these procedures should be done under IRB
protocol and with input from key opinion leaders in the field.
72 |
Obesity and Diabetes Prevalence
14
India Urban
Diabetes Rate (%)
12
Greece
10
Italy
India (total)
8
Kuwait
Bahrain
Saudi Arabia
USA
Turkey
Japan
6
4
Australia
Peru
Korea
Germany Hungary
England
Finland
Netherlands
France
Switzerland
China
Laos
2
0
0
5
10
15
20
25
30
35
40
Obesity Rate (%)
Adapted from htttp://www.irdes.fr/ecosante/OCDE/814010.html & http://www.who.int/bmi.index.jsp
73 |
Bariatric Surgery and Diabetes Resolution
Author
Interventio
n
Resoluti
on
Non-resolution associated
with….
Pories et.al.
1995
Gastric
Bypass
89%
Older patients; long standing disease
Torquati et al
2005
Gastric
Bypass
74%
Waist Circumference; insulin usage
Schauer et.al.
2003
Gastric
Bypass
82%
Long standing disease; disease
severity; insulin usage
Sugerman et
al 2003
Gastric
Bypass
86%
Older patients; greater weight
Dixon et.al
2003
Lap Band
64%
Less weight loss; long standing
disease
Gagner
(unpublished)
Sleeve
Gastrectomy
65%
Higher initial weight
74 |
Medium
Low
Efficacy
High
Diabetes Surgical Interventions (DSI)
Low
Medium
Technical Complexity
75 |
High
Omentectomy
– Physiologic Basis =
Adipoinsular Axis
– Highlights
– Straightforward MIS procedure
– Conflicting efficacy data
76 |
A pilot study of long term effects of a novel obesity treatment:
omentectomy in connection with adjustable gastric banding
(AGB)
– Methods
– Randomized, controlled trial (n=50)
– AGB (n=25) v AGB plus omentectomy (n=25)
– Follow-up x 2 years with metabolic profiles at 0 and
24 months
– Results
– No significant differences between groups
preoperatively
– No significant weight loss differences between
groups
– OGTT, Insulin sensitivity, fasting plasma glc and
insulin 2-3x greater in omentectomized patients (p
from 0.009 to 0.04)
– No adverse events
Thorne A. et.al. Int J Obes, 2002
77 |
Ileal Transposition +/- Sleeve Gastrectomy
– Physiologic Basis =
Enteroinsular Axis
– Highlights
– Moderate MIS procedure
– 3 GI anastomosis
– Scant worldwide experience
78 |
Duodenal Jejunal Bypass
– Physiologic Basis = Enteroinsular
Axis
– Highlights
– Moderate MIS procedure
– Preserves gastric reservoir
function
– Exciting preliminary data
– Increasing interest worldwide
79 |
Metabolic Surgery
Severity of Diabetes
High
Interposition with
Gastrectomy
Switch
Roux en Y
Mid
Duodenal
Exclusion
Gastrectomy
II or Oment
Banding
Low
25
30
New Market Development
80 |
BMI
35
40
45
50
Current Market Development
Metabolic Surgery
Medical therapy is always advancing…but will likely continue to
underserve considerable numbers of T2DM patients
Current surgical therapy is highly effective…but is more often thought of
in terms of its weight loss rather than its metabolic outcomes…and is
designed for higher BMI populations
Our current knowledge of these concepts as well the role of
gastrointestinal physiology provides rationale for expansion and
augmentation of “metabolic” surgical interventions in carefully
controlled research trials only
81 |
Acknowledgements
Content and images provided by
– Michael Tarnoff MD, FACS, Boston MA
– Francesco Rubino MD, Rome Italy
– Covidien, North Haven, CT
– Scott Cunningham (Research & Development)
– Dean Geraci (Global Market Development)
82 |
Discussions
83 |