Slide 1: Metabolic Surgery for Type 2 Diabetes - Window into Pathophysiology
Metabolic Surgery for Type 2 Diabetes - Window into Pathophysiology- Prof. Francesco Rubino, MD Chair of Bariatric and Metabolic Surgery King's College London London, UK September 15, 2014
Slide 2: Disclosure Slide
DISCLOSURE SLIDE • NGM Biopharmaceuticals (SAB Member) • Fractyl Laboratories (Advisor/Consultant) THE TRUTH ABOUT METABOLIC SURGERY
Slide 3: Surgery and Physiology
Surgery and Physiology Surgical manipulations of anatomy have played a major role in advancing knowledge about physiology and disease Surgery has helped advance understanding the functioning of: • Central nervous system • Pituitary gland • Adrenals • Pancreas
Slide 4: Bariatric Surgery and Metabolic Disease
Bariatric Surgery and Metabolic Disease “criteria ex juvantibus” making an inference about disease causation from observations on the response of the disease to a treatment
Slide 5: Surgical Treatment of Type 2 Diabetes: Clinical Outcomes
Surgical Treatment of Type 2 Diabetes: Clinical Outcomes
Slide 6: Blood Glucose Levels after RYGB
Preoperative BMI: 30 Female, 42yo, BMI 31 On Insulin and Multiple OHAs Hyperglycemia (BG>180mg/dl) Normal blood sugar (BG btwn 70-180) Hypoglycemia (BG<70mg/dl) Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 2 Weeks after RYGB Blood Glucose Levels Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 3 Months after RYGB B
Slide 7: An Instructive Case
An Instructive Case: Female, 42yo; BMI: 31 T2DM; Dyslipidemia, Hypertension Diabetes No Diabetes
Slide 8: JAMA, June 2014
Original Investigation Association of Bariatric Surgery With Long-term Remission of Type 2 Diabetes and With Microvascular and Macrovascular Complications JAMA, June 2014 Lars Sjéstrém, MD, PhD; Markku Peltonen, PhD; Peter Jacobson, MD, PhD; Sofie Ahlin, MD, PhD; Johanna Andersson-Assarsson, PhD; As
Slide 9: BMJ Oct 22, 2013 meta-analysis
BMJ Oct 22, 2013 • 11 studies, 796 patients, BMI 27-53 • Surgery superior to med Rx – Wt. loss, HbA1c, T2DM remission, TG, HDL, remission of metabolic syndrome, QOL, medication reduction • No CV events or death after surgery • Anemia (15%), Reoperation (4-8%)
Slide 10: BMI < 35 vs. BMI ≥ 35
BMI < 35 vs. BMI ≥ 35 Change in HbA1c
Slide 11: JAMA, June 2014
Original Investigation Association of Bariatric Surgery With Long-term Remission of Type 2 Diabetes and With Microvascular and Macrovascular Complications JAMA, June 2014 Lars Sjéstrém, MD, PhD; Markku Peltonen, PhD; Peter Jacobson, MD, PhD; Sofie Ahlin, MD, PhD; Johanna Andersson-Assarsson, PhD; As
Slide 12: STAMPEDE Trial: QoL Changes
STAMPEDE Trial: QoL Changes • Gastric Bypass: 5/8 domains improved • Sleeve Gastrectomy: 2/8 domains improved • Intensive Med Rx: 0/8 domains improved Schauer et al. NEJM 2014
Slide 13: JAMA, June 2014
Original Investigation Association of Bariatric Surgery With Long-term Remission of Type 2 Diabetes and With Microvascular and Macrovascular Complications JAMA, June 2014 Lars Sjéstrém, MD, PhD: Markku Peltonen, PhD: Peter Jacobson, MD, PhD: Sofie Ahlin, MD, PhD: Johanna Andersson-Assarsson, PhD: As
Slide 14: Bariatric Surgery Associated With Reduced Long-Term All-Cause Mortality
Bariatric Surgery Associated With Reduced Long-Term, All- Cause Mortality Compared With Non-Operated Controls Mortality Study Procedure F/U Reduction MacDonald, 1997 RYGB 9 yr 88% Flum, 2004 RYGB 4.4 yr 33% Christou, 2004 RYGB 5 yr 89% Sowemimo, 2007 RYGB 4.4 yr 63% Dixon, 2007 LAGB 12 yr 72% Adams,
Slide 15: Is there something special in the mechanism of action of bariatric surgery?
Is there something special in the mechanism of action of bariatric surgery ?
Slide 16: Gastrectomy and RYGB procedures
BI Gastrectomy BII-Gastrectomy RY-Gastrectomy RYGB
Slide 17: Early reports of diabetes and operation
1162 Tur Lancer,] DR. 0. LEYTON: DIABETES AND OPERATION. Ca DIABETES AND OPERATION. A NOTE ON THE EFFECT OF GASTRO-JEJUNOSTOMY UPON A CASE OF MILD DIABETES MELLITUS WITH A LOW RENAL ‘TITRESHOLD. By O. LEYTON, M.D. Cams., F.R.C.P. Lonpb., PUYSICIAN TO THK LONDON HOSPITAL. How can we account for the a
Slide 18: Reports of Diabetes Remission after Bariatric Surgery Procedures
Reports of Diabetes Remission after Bariatric Surgery Procedures • Jejuno-ileal bypass – Ahmad et al; Diabetes Care 1978 – Ackerman NB. Surg Gynecol Obstet. 1981 • Verical banded gastroplasty – Neve HJ et al; Obesity Surg 1993 • Biliopancreatic diversion – Scopinaro et al; WJS 1998 • Gastric Bypass
Slide 19: Surgical control of diabetes reported since 1925, yet remained unknown
Despite surgical control of diabetes was reported since 1925, the effect (and opportunity) remained unknown to the scientific community through the XX century - Segmentation of medical specialties in XX-century medicine - Diabetes considered invariably chronic and progressive disease > things that c
Slide 20: First Protocol for a Randomized Clinical Study of Diabetes Surgery
1999 First Protocol for a Randomized Clinical Study of Diabetes Surgery Submitted to IRB (Mount Sinai Medical Center, New York) RCT comparing Gastric Bypass Surgery vs Intensive Medical Therapy in patients with BMI 30-35 The IRB does not approve
Slide 21: GK-Rat
GK-Rat Lean, type 2 diabetes Hyperinsulinism Insulin resistance (Nature Genetics 1996)
Slide 22: January 2004: First experimental evidence of weight-independent effect
January 2004 First experimental evidence that diabetes resolution is a weight-independent, direct effect of GI surgery Rationale for DIABETES SURGERY
Slide 23: Gastrointestinal Bypass Improves Glucose Homeostasis in Rodents
Gastrointestinal Bypass Improves Glucose Homeostasis in Rodents by Weight Independent Mechanisms DJB Obese mice Troy et al, Cell Metabolism, Sept 2008 GK-Rat (Lean) Stretptoz. Diabetes Rubino et al, Ann Surg 2004 Breen et al, Nature Med 2011 Rubino et al, Ann Surg 2006 Pacheco et al, Am J Surg 2007
Slide 24: Mechanisms of Action of GI Surgery 2004-2014
Mechanisms of Action of GI Surgery 2004-2014
Slide 25: How Does Surgery work?
Gastric pouch Stomach Duodenum How Does Intestines Surgery work?
Slide 26: Mechanisms of Surgical Control of Diabetes
Mechanisms of Surgical Control of Diabetes Gut Hormones Bile Acids -intestinal glucose re- programming (Science 2013) -intestinal gluco- neogenesis -others Microbiota Nutrient Sensing
Slide 27: Glucose-lowering effect of DJB in absence of insulin
Glucose-lowering effect of DJB in absence of insulin Breen et al. Non-obese type 1 diabetic mice Nature Medicine 2012
Slide 28: Comparison of surgical procedures and their features
Courtesy of Dr Ileal Endo- Gastric Sleeve Lee Kaplan RYGB DJB BPD Inter- luminal Band Gastrex position Sleeve Gastric Restriction ± Gastrectomy Altered gastric function ? Gastric exclusion Duodenal exclusion Enhanced distal nutrient delivery Malabsorption Part
Slide 29: Evidence for anti-diabetic effects of proximal intestinal bypass
Evidence for anti-diabetic effects of proximal intestinal bypass
Slide 30: Gastric Banding, RY Gastric Bypass, Sleeve Gastrectomy, BPD
Gastric Banding RY Gastric Bypass Sleeve Gastrectomy BPD All improve Diabetes, although with different potency and likely distinct mechanisms RCTs and clinical series suggest Gradient BPD > RYGB > Sleeve > Banding
Slide 31: Lower Intestinal vs. Upper Intestinal Hypothesis
Lower Intestinal vs. Upper Intestinal Hypothesis? Rubino F, et al Annals of Surgery 2006
Slide 32: Duodenal (Jejunal) Exclusion and Gastro-jejunal Anastomosis
Duodenal (Jejunal) Gastro-jejunal Exclusion Anastomosis (enhanced distal delivery of nutrients) Rubino F, et al., Ann Surg 2006; 244:741
Slide 33: G-J Anastomosis alone does not improve diabetes in rats
G-J Anastomosis alone does not Improve Diabetes in Rats OGTT GK rats GK DJB GK Sham GK GJ 600 Glucose levels (mg/dl) 500 400 300 200 100 0 Time (min) 0 50 100 150 200 Rubino et al; Annals of Surgery Nov 2006
Slide 34: Adding Duodenal Exclusion to GJ improves diabetes in rats
Adding Doudenal Exclusion to GJ improves diabetes in rats OGTT AUC 69000 64000 59000 Duodenal Pass. Duod. Exclus 54000 49000 44000 Duodenal Pass. Duod. Exclus P<0.05 Rubino et al; Annals of Surgery Nov 2006
Slide 35: Restoration of Duodenal Passage after DJB worsens glucose tolerance
Restoration of Duodenal Passage after DJB worsens glucose tolerance AUC OGTT X 2 Rubino et al; Annals of Surgery Nov 2006
Slide 36: Duodenal (Jejunal) Exclusion vs Gastro-jejunal Anastomosis
Gastro-jejunal Duodenal (Jejunal) Gastro-jejunal Anastamosis Exclusion Anastomosis Improves DM in rats No Effect on DM in rats Rubino F, et al., Ann Surg 244:741
Slide 37: Duodenal Jejunal Exclusion has distinct anti-diabetic effects
Duodenal Jejunal Exclusion has distinct anti- diabetic effects Rubino et al. Ann Rev Med 2010
Slide 38: ELS Improves IP Glucose Tolerance
ELS Improves IP Glucose Tolerance (Kaplan et al) 0.0 -0.5 % Change HbA1c -1.0 -0.8 -0.76 -1.5 -1.3 -2.0 -2.5 EndoBarrier -3.0 Sham -2.9 -3.5
Slide 39: GLP-1 not the principal mediator of diabetes remission
rapid rise and fall of Effects of SG not abolished in injection of GLP1-R postprandial GLP-1 GLP-1R KO mice Antagonist does not DOES (Wilson-Perez et al; Diabetes 2013) NOT reverse improvement SG 60 of diabetes in humans 50 * who had RYGB 40 (Jimenez et al; Diabetes 30 20 Care 2013) 10 0 (N=12) 0 15
Slide 40: Bypass of the Proximal Intestine: How Does it Work?
Bypass of the Proximal Intestine : How Does it Work? Other endocrine mechanisms? Paracrine mechanisms ? Changes in gut microbiota ? Alterations in bile acid metabolism? Changes in nutrient sensing mechanisms? Anti-incretins? Others?
Slide 41: Is Type 2 Diabetes an Operable Intestinal Disease?
Is Type 2 Diabetes an Operable Intestinal Disease? A provocative yet reasonable hypothesis Frecesco Romeo so TYPE 2 BLABETES: 15 IT AN INTESTINAL DISEASE? — The Ln
Slide 42: The incretin effect
The incretin effect I.V. pr. OS Glucose (mmol/l) Glucose 10 • 70% of post-glucose insulin secretion is due to the incretin effect 5 • The incretin effect is due to gut hormones; 1000 Insulin (pmol/l) Incretin 500 Time (min)
Slide 43: Glucose Lowering Mechanisms in the Postprandial State
Glucose Lowering Mechanisms in the Postprandial State Nutrients Passage in the GI Tract Induces: - Suppression of ghrelin - Increase in GLP-1/GIP - Suppression of Glucagon - Increase in Insulin - Reduction of hepatic glucose production (nutrient sensing) (Lam et al, Nature) - Increased intestinal gl
Slide 44: Anti-incretin Theory
Anti-incretin Theory (Ann Surg 2002; Ann Surg 2004; Diabetes Care 2009; Nature Rev Endo 2010; Diabetes July 2014)
Slide 45: The Anti-Incretin Theory
The Anti-Incretin Theory Foodborne stimuli may cause exaggerated/untimely activation of anti-incretin mechanisms, which may act as a diabetogenic factor
Slide 46: Anti-incretin Theory may Explain Benefits and Complications of RYGB
Anti-incretin Theory may Explain Benefits and Complications of RYGB
Slide 47: Glucose Excursions after Alterations of GI Anatomy
Glucose Excursions after Alterations of GI Anatomy Suggest Disruption of Physiologic Incretin/Anti-Incretin Balance Glucose (mg/dl) 200 180 GB OW 160 140 120 Post-RYGB 100 80 60 0 20 40 60 80 100 120 Time (min) Post-gastrectomy
Slide 48: Predictions
Predictions Excess anti-incretin results in IR and/or beta-cell Dysfunction/depletion >> gut factors from subjects with IR or diabetes should be able to induce IR in normal cells/subjects
Slide 49: Jejunal Proteins Impair Insulin Signaling and Determine Insulin Resistance
Jejunal Proteins Secreted by db/db Mice or Insulin- Resistant Humans Impair the Insulin Signaling and Determine Insulin Resistance S. Salinari, C. Debard , A. Bertuzzi , C. Durand, P. Zimmet, H. Vidal, G. Mingrone PLOS ONE 2013 Normal Mice Soleus Muscle Insulin Resistance L-cells skeletal muscle I
Slide 50: Predictions
Predictions incretin/anti-incretin balance ensures control of beta-cell proliferation/growth Uncoupling or net reduction of anti-incretin mechanisms by disruption of GI anatomy can cause beta-cell proliferation
Slide 51: Beta-Cell Proliferation after RYGB/DJB
Beta-Cell Proliferation after RYGB/DJB Suggests Disruption of Physiologic Regulation of Beta-Cell Growth Glucose (mg/dl) RYGB vs Sham Operation in non diabetic anumals (pigs) GB RYGB > Increased in β-cell OW mass, Increased islet number increased number of extraislet β-cells Lindqvist et al; Diabete
Slide 52: Diabetes, July 2014, in press
Diabetes, July 2014, in press
Slide 53: Upcoming Diabetes and Metabolic Surgery event, London, September 2015
LONDON, UK SEPTEMBER 2015 the most important event in Diabetes and Metabolic Surgery More to come…
Slide 54: Acknowledgements
Acknowledgements Strasbourg’s Lab (2000-2007) Antonello Forgione International Collaborations Stefano Sereno David Cummings, Seattle (USA) Weill Cornell NYC Lab (2007-2012) Lee Kaplan, (Boston, USA) Rajesh Patel Phil Schauer, (Cleveland USA) Alpana Shukla Geltrude Mingrone, (Rome, Italy) M. Moreira