SURGICAL CURES FOR DIABETES UCSF Diabetes Update March 12, 2009 Andrew M. Posselt, MD, PhD Transplant Surgery, UCSF
Surgical Treatment Options Whole Organ Pancreas Transplant Type 1 and 2 Pancreatic Islet Transplant Type 1 Bariatric Surgery Type 2
Pancreas Transplants Worldwide Number of Transplants 2000 1800 1600 1400 1200 1000 800 600 400 200 0 pre 78 Total: n = 23,043 Non USA: n = 5,916 USA: n = 17,127 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 1//05
Expansion of Selection Criteria Simultaneous pancreas-kidney transplant (SPK) Pancreas transplant after successful kidney transplant (PAK) Solitary pancreas transplant in the preuremic diabetic (PTA)
5-Year Pancreas/Kidney Graft Function USA DD Primary Pancreas Transplants, 1/1/1988 12/31/2006 80 70 60 50 40 30 20 10 0 % PAK PTA SPK Px SPK Kd 1988/89 1990/91 1992/93 1994/95 1996/97 1998/99 2000/01 2002/03 2004/05 2006/07 4/07
Pancreas Transplant for Type II DM Limited experience Works well in carefully selected pts. Combined with kidney transplant only Younger pts (< 45), BMI < 30 Insulin requirement usually not an issue
Effect on Secondary Complications Potential benefit is to halt the progression of complications of diabetes Patients present often with far advanced disease Difficult to demonstrate an impact on disease progression
Quality of Life More positive perception of health Less pain Greater ability to function socially Patients with failed grafts often return for retransplantation
Why transplant islets? Safer, simpler procedure than pancreas transplant Better control than insulin therapy
John D. Pirsch, Jon S. Odorico & Hans W. Sollinger
Pancreatic Islet Transplantation
Islet Processing GMP Facility
Islet Processing Head 62 grams Tail 15 grams
Fluoroscopy Islet Infusion Recovery
Edmonton Protocol - Steroid-free regimen - Short cold ischemia time - High quality islet preps - Immediate transplant - Usually 2 txps (>10,000 IE/kg) Shapiro AMJ et al., NEJM 2000;343:230-8
Graft Survival (Insulin Independence) Islet Transplant Registry Edmonton 87%
Insulin-independent islet allograft survival Edmonton/Miami/Minnesota (+ UCSF) n= 118 1-yr insulin independence: 82 %
Insulin independence after 1:1 transplant % Insulin Independent 100 80 60 40 20 0 0 25 50 75 100 125 Days Posttransplant
Glucose control after islet transplant Pre-transplant Post-transplant Blood Glucose (mg/dl) 450 400 350 300 250 200 150 100 50 Blood Glucose (mg/dl) 450 400 350 300 250 200 150 100 50 0 Fasting Before Lunch Before Dinner Bedtime 0 0 Fasting 1 Before 2 Lunch 3 4Before 5Dinner 6 Bedtime 7 8
Hypoglycemia Score HYPO Score 3500 3000 2500 2000 1500 1000 500 0 Pre Tx 1 year post 2nd Tx Controls Ryan E et al., Diabetes 2004
The Vanishing Islet Allo ^ Ryan EA Diabetes 54:2060-2069, 2005
5-year Graft Survival Rates in Islet and Pancreas Recipients Islet Pancreas % Insulin Independence 100 50 0 Kaplan-Meier Estimates (n=20) 50% 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr 6 Yr Years Post Transplant % 100 90 80 70 60 50 40 30 20 10 0 1988/89 1990/91 1992/93 1994/95 1996/97 1998/99 2000/01 PAK PTA SPK Px SPK Kd 50%! 2002/03
Decay in Islet Function Over Time Challenges and Opportunities Rejection? Autoimmunity? Inadequate site? Drug toxicity? No precursor cells? Biopsies Measurement of antibodies Different site? Different Immunosuppression?
New Immunosuppressive Agents LEA29Y (Belatacept) Efalizumab (Raptiva) Vincenti, AJT 2002
Graft Function with Raptiva Pt 1 Pt 2 Pt 3 Pt 4 Pt 5 Infusions 2/7/07 3/17/08 6/21/07 6/29/07 8/14/07 12/4/07 2/25/09 C Peptide at 1 mo Yes Yes Yes Yes Yes Insulin Independent >30d Yes Yes Yes Yes Yes Currently Insulin Independent Yes Yes Yes Yes +/- Duration of Independence > 5 mos (> 18 mos) > 14 mos > 14 mos > 12 mos 8 mos HbA1c Decr. > 2.5% Yes Yes Yes Yes Yes 2 patients treated with belatacept: both are insulin independent after single islet transplants
HbA1c after Islet Transplant 9 8 HbA1c (%) 7 6 5 Pretxp 3 Months 6 Months 4 3 Pt 2 Pt 3 Pt 4
Metabolic Testing - MMTT Pt. 3 MMT Glucose 600 Glucose (mg/dl) 500 400 300 200 100 0-0.16-0.08 0 0.25 0.5 1 1.5 2 Time (hrs) pretx d90 d180 Pt. 3 MMT C Peptide 10 C peptide (ng/ml) 8 6 4 2 pretx d90 d180 0-0.16-0.08 0 0.25 0.5 1 1.5 2 Time (hrs)
Renal Function Serum Cr (mg/dl) 1.4 1.2 1 0.8 0.6 0.4 0.2 0 PreTxp 30 90 180 270 365 Time since Txp (d) Pt-1 Pt-2 Pt-3 Pt-4 Pt-5
Broad Indications for Beta Cell Replacement: Solid Organ Pancreas or Islets Pancreas (but not islets) Patients with large body habitus (>180lb) or large insulin requirements Patients with life-threatening diabetes and good cardiac reserve Patients receiving a simultaneous kidney with good cardiac reserve Islets (but not pancreas) Low BMI patients or patients with low insulin requirements who do not want invasive procedure Patients with life-threatening diabetes and high cardiac risks
The next steps New Agents New source Single donor Multicenter trials 2002 2005 2006 2008 20--? //
Ongoing Clinical Islet Transplant Trials at UCSF C Clinical i Clinical Islet Transplantation Consortium CIT 03 Islet alone +DSG CIT 07 Islet alone ctrl. CIT 06 Islet after kidney JDRF Trial: Islet Transplantation using a calcineurin-free immunosuppressive regimen based on Belatacept Other UCSF Trials: - IAK in HIV+ patients - SIK in diabetic children receiving live donor kidney txps
Diabetes in the United States, 1980 2005 The number of Americans with diabetes increased from 5.6 to 15.8 million 24,000,000 w/ DM in 2007! 300,000,000 pop., 100,000,000 BMI>30
Obesity and Type II Diabetes Insulin resistance β-cell hypertrophy/hypermetabolism β-cell death Lean Obese Diabetic Insulin Glucagon, SS, PP Pick, Diabetes 47, 1998
Medical Therapies for Type 2 Diabetes Mellitus Usually address only glycemic control 30% effective in reducing HbA1c < 6%) Oral Agents: α-glucosidase inhibitors biguanides (metformin) meglitinides thiazolidinediones sulfonylureas Injectable Agents: Glucagon-like peptide-1 (GLP-1) analogues Exenatide (Byetta ) Liraglutide - longer t1/2; phase 3 trials Dipeptidyl peptidase-iv (DPP-IV) inhibitors Prevent breakdown of endogenous GLP- Sitagliptin (Januvia ) Vildagliptin (Galvus )
R-Y Gastric Bypass Gastric Banding BPD/DS 75% 22% 3% Sleeve Gastrectomy
Weight Loss Effects of Bariatric Surgery on Mortality in Swedish Obese Subjects Sjöström et al. NEJM. 2007; 357 (8):741-52
Improvement/Resolution of Diabetes % Resolution/Improvement Diabetes 100 90 80 70 60 50 40 30 20 10 0 48% Band n=205 84% RYGBP n=989 98% BPD/DS n=288 P value <0.01 <0.01 NS vs. RYGBP, DS vs. Band vs. RYGBP Bariatric Surgery A Systematic Review and Meta-analysis. Buchwald H. et al. JAMA. 2004; 292(14):1724-37
Improvement/Resolution of Diabetes 35 DM II pre-op 30 25 DM II 1 year FU 34% 34% 38% Imp./Resolved % Diabetic 20 15 10 71% Imp./Resolved P=0.01 21% 5 0 10% Lap Gastric Bypass Lap Band Rabl C, Palazzo F, Rogers S, Posselt A, Cello J, Campos GM Laparoscopic Gastric Bypass is as Safe as Laparoscopic Gastric Banding and Provides Superior Weight Loss Outcomes. Obesity Surgery. 2008
Bariatric Surgery and T2DM Lap Band is superior to Non-Surgical Treatment Lap GBP is superior to Lap Banding BPD/DS effective but has significant SE s
Mechanisms for Diabetes Resolution after RYGBP - Calorie restriction and negative energy balance - Weight loss - Reduced carbohydrate intake (dumping) - Changes in adipocytokines - Altered synthesis of intestinal and pancreatic peptides that regulate glucose metabolism
GLUCOSE METABOLISM - INCRETINS GLP-1 (glucagon-like peptide-1) L cells in the distal portion of small bowel Promotes insulin production Suppresses glucagon secretion Reduces glucose production Decreases gastric emptying (satiety) GIP (Glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide) K cells in duodenum and proximal small bowel Promotes insulin secretion In Type 2 DM: insulin secretory response to hyperglycemia is reduced In Euglycemia: stimulates Glucagon and does not No effect on gastric emptying
Glucose Levels During a Meal Test before and 2 weeks after Bypass or Calorie Restriction - Glucose excursions normalize sooner after RYGBP - No change in CR group Campos GM, Rabl C, Havel P, et al. NIH-NCRR Grant Number KL2 RR024130
Insulin Excursions During a Meal Test before and 2 weeks after Bypass or Calorie Restriction - Insulin secretion greater after RYGBP - No change in CR group Campos GM, Rabl C, Havel P, et al. NIH-NCRR Grant Number KL2 RR024130
GLP-1 Excursions During a Meal Test before and 2 weeks after Bypass or Calorie Restriction - GLP-1 secretion greater after RYGBP - No change in CR group Campos GM, Rabl C, Havel P, et al. NIH-NCRR Grant Number KL2 RR024130
GIP Excursions During a Meal Test before and 2 weeks after Bypass or Calorie Restriction - GIP secretion unchanged after RYGBP - GIP secretion increased in CR group Campos GM, Rabl C, Havel P, et al. NIH-NCRR Grant Number KL2 RR024130
Peripheral Glucose Uptake by Euglycemic Hyperinsulinemic Clamp after RYGBP 12 10 P=0.018 8 mg/kg/min 6 4 P=0.93 2 0 1 2 3 Pre-op 15 days 6 months Campos GM, Rabl C, Havel P, et al. NIH-NCRR Grant Number KL2 RR024130
RYGBP, DM2 and Gut Hormones At 6 Months after RYGBP: - Altered pattern of gut (GLP-1, GIP) and pancreatic hormone (insulin, glucagon) secretion during meal - Improved peripheral glucose uptake, decreased fasting glucose GLP-1 GIP GLP-1 GIP Rubino, Ann Surg 236, 2002
Mechanisms for Weight loss and Diabetes Resolution after RYGBP or DS #1: Reduced Caloric Intake #2: Appetite + Ghrelin (stomach) + Insulin (pancreas) - Leptin (adipose tissue) - CCK (duodenum) Glucose Metabolism + Insulin (pancreas) - Glucagon (pancreas) + GLP-1 (distal small bowel) - GIP (proximal small bowel)
Islet Isolation Team: Courtney Cusack Pavel Koudria Jiena Lang Mike Lee Andrew Posselt Greg Szot Clinical Team: Lynda Frassetto Kristina Johnson Bob Kerlin Umesh Masharani Joan McElroy Debbie Ramos Tara Rojas Mehdi Tavakol Michael Worden Andrew Posselt Peter Stock Jeff Bluestone The GCRC Staff