Disclosures Post-transplant metabolic syndrome Robert H. Lustig, - PDF document

Disclosures Post-transplant metabolic syndrome Robert H. Lustig, M.D., M.S.L. Division of Endocrinology, Department of Pediatrics Institute for Health Policy Studies University of California, San Francisco Adjunct Faculty, UC Hastings College of the Law BIOLUMEN BIO Te Technologies Chief Science Officer, Eat REAL UCSF Transplant Symposium, Sept. 21, 2018 NAFLD and Metabolic Syndrome are congruent (if not the same) Adults: Marchesini et al. Hepatology 37:917, 2003 Children: Schwimmer et al. Circulation 118:277, 2008 1

Metabolic Syndrome: where all the money goes (75% of all healthcare dollars) Diabetes* Hypertension Lipid abnormalities Cardiovascular disease Non-alcoholic fatty liver disease* Polycystic ovarian disease Chronic renal failure* Cancer Dementia *transplantable Thoefner et al, Tranplant Rev 32:69, 2018 The standard model of metabolic syndrome But what is Metabolic Syndrome? Cytokines And what is Post-Transplant Metabolic Syndrome (PTMS)? Is it substantially different? 2

The standard model of metabolic syndrome The standard model of metabolic syndrome Cytokines Cytokines It’s about obesity — It’s about obesity — or is it? or is it? Basu et al. PLoS One 8:e58783, 2013 Basu et al. PLoS One 8:e58783, 2013 3

It’s about obesity — It’s about obesity — or is it? or is it? Basu et al. PLoS One 8:e58783, 2013 Basu et al. PLoS One 8:e58783, 2013 Secular trend in diabetes among Obesity is the problem (?) U.S. adults, 1988-2012 • Obesity is increasing worldwide by 2.78% per year 1975-2015 Lancet Oct 10, 2017 http://dx.doi.org/10.1016/S0140-6736(14)60460-8 • Diabetes is increasing worldwide by 4.07% per year • 1980-2014 Lancet Apr 6, 2016 • http://dx.doi.org/10.1016/S0140-6736(16)00618-8 Menke et al. JAMA 314:1021, 2015, doi:10.1001/jama.2015.10029 4

Secular trend in diabetes among Secular trend in diabetes among U.S. adults, 1988-2012 U.S. adults, 1988-2012 25% increase in obese 25% increase in obese 25% increase in nl wt Menke et al. JAMA 314:1021, 2015, doi:10.1001/jama.2015.10029 Menke et al. JAMA 314:1021, 2015, doi:10.1001/jama.2015.10029 Familial Partial Lipodystrophy: Dunningan or Type 2 Comparison between lipodystrophy and obesity •X-linked or autosomal dominant obesity LD •Absence of limb fat • Fat mass  Easily visible veins • Leptin  Defined musculature •Minimal visceral fat • Adiponectin •Normal or excess facial fat • Inflam. Cytokines •Cushingoid facies (moon facies) +++ ± • Metabolic Syndrome •Dorsocervical fat pad •Acanthosis nigricans •Metabolic Syndrome Peters et al. Nature Genet 18:292, 1998 Asterholm et al. Drug Disc Today Dis Models 4:17, 2007 5

Obesity and lipodystrophy share insulin resistance Comparison between lipodystrophy and obesity Obesity Lipodystrophy obesity LD • Fat mass • Leptin Insulin • Adiponectin Resistance • Inflam. Cytokines +++ ± • Metabolic Syndrome So the metabolic syndrome can arise from too much, or too little fat i.e. it ’ s not the fat that counts Asterholm et al. Drug Disc Today Dis Models 4:17, 2007 Chehab, Endocrinol 149:925, 2008 OGTT in ‘healthy’ volunteers from ~1970 till 2014 OGTT in ‘healthy’ volunteers from ~1970 till 2014 IGT‐’pre‐diabetic’ So in 40‐50 years our need for insulin increased 2‐4 fold: e.g. did we became 2‐4 fold more insulin resistant? 6

“Exclusive” view of obesity and “Exclusive” view of obesity and metabolic dysfunction metabolic dysfunction 240 million adults in U.S. 240 million adults in U.S. 168 million 168 million Normal weight (70%) Normal weight (70%) 72 million 72 million Obese (30%) Obese (30%) Obese and sick (80% of 30%) Total: 57 million sick “Inclusive” view of obesity and “Inclusive” view of obesity and metabolic dysfunction metabolic dysfunction 240 million adults in U.S. 240 million adults in U.S. 168 million 168 million Normal weight (70%) Normal weight (70%) 72 million 72 million Obese (30%) Obese (30%) Normal weight, Obese and sick (80% of 30%) Metabolic dysfunction (40% of 70%) 57 million 67 million Total: 124 million sick 7

Relation between visceral and subcutaneous obesity: Visceral fat can be due to chronic stress (thin on the outside, fat on the inside) STRESS Br own NE NPY Y2R Adipocyte White  -ADR  -ADR Adipocyte Y2R Angiogenesis thermogenesis Lipid Lipolysis, storage proliferation Pre-adipocyte Proliferation, Burn fat, Adipocyte Gro w fat, differentiation L o se we ight gain we ight Zukowska, Science 2008 Thomas et al. Obesity doi: 10.1038/oby.2011.142, 2011 Intrahepatic fat explains metabolic perturbation better than visceral fat MRI Fat Fraction Maps Hepatic Insulin Sensitivity VLDL Index Secretion Rate Insulin Stimulated Glucose Disposal Contribution Rate Of Free Fatty Acids Insulin To VLDL Obese Stimulated Palmitate Low Liver Fat = 2.6% Suppression Rate Fabbrini et al. Proc Natl Acad Sci 106:15430, 2009 8

MRI Fat Fraction Maps MRI Fat Fraction Maps Obese Obese Obese Low Liver Fat = 2.6% Low Liver Fat = 2.6% High Liver Fat = 24% MRI Fat Fraction Maps MRI Fat Fraction Maps Thin Obese Obese Obese Obese High Liver Fat = 23% High Liver Fat = 24% High Liver Fat = 24% Low Liver Fat = 2.6% Low Liver Fat = 2.6% 9

MRI Fat Fraction Maps Nature 487:27-29, Feb 1, 2012 Thin Obese Obese New York Times, April 17, 2011 High Liver Fat = 23% Low Liver Fat = 2.6% High Liver Fat = 24% Sugar is toxic unrelated to calories Strategy • Isocaloric fructose restriction x 9 days in children who are habitual sugar consumers • No change in weight Lustig et al. Obesity 24:453, 2016 • Substitute complex carbs for sugar • Maintain baseline macronutrient composition of the the diet Gugliucci et al. Atherosclerosis 253:171, 2016 • Study in PCRC at Day 0 and Day 10 • Assess changes in organ fat, de novo lipogenesis, and metabolic health Schwarz et al. Gastroenterology 153:743, 2017 10

Fasting Labs DNL is the Conversion of Dietary Day 0 Day 10 β - coefficient p value Carbohydrates into Lipids (Adjusted Change) [95% CI] Heart rate (bpm) 83.1 ± 10.7 80.1 ± 11.3 ‐2.8 [‐6.5, +0.9] 0.13 122.6 ± 10.5 121.1 ± 9.9 Systolic BP (mmHg) ‐ 1.39 [‐4.9, +2.1] 0.43 *) 68.8 ± 8.9 63.7 ± 7.5 ‐ 4.9 [‐8.1, ‐1.8] 0.003 Diastolic BP *) *) *) *) * *) Fasting lactate 1.2 ± 0.4 0.9 ± 0.3 ‐0.3 [‐0.5, ‐0.2] <0.001 *) *) * *) *) (mmol/L) *) *) *) *) *) *) *) *) *) 160.0 ± 34.5 129.0 ± 34.5 ‐31.2 [‐41.9, ‐20.5] <0.001 Lactate AUC (mM/120 min) Sugar Into Fat (lipids) HOMA‐IR ¥ 7.9 ± 4.8 5.2 ± 2.6 ‐2.7 [‐3.8, ‐1.5] <0.001 AST (U/L) * 27.4 ± 14.1 23.8 ± 8.9 0.02 28.9 ± 22.8 26.7 ± 19.6 ALT (U/L) ¥ ‐2.2 [‐4.7, +0.3] 0.09 Fructose Palmitate 1.4 ± 0.9 1.0 ± 0.5 ‐0.4 [‐0.6, ‐0.2] 0.002 *) Fasting TG (mM) * * * *) Fasting LDL‐C (mM) 2.4 ± 0.6 2.1 ± 0.6 ‐0.3 [‐0.4, ‐0.1] <0.001 Acetate 1.2 ± 0.2 1.0 ± 0.2 <0.001 Fasting HDL‐C (mM) ‐0.1 [‐0.2, ‐0.1] New Tracer Method using MIDA: Hellerstein and Neese, AJP 1999 0.6 ± 0.2 0.7 ± 0.2 +0.1 [+0.1, +0.2] <0.001 Fasting FFA (mM) Oral glucose tolerance test DNL AUC Pre and Post Fructose Restriction before and after isocaloric fructose restriction 160 140 120 100 80 60 40 20 0 Day 0 Day 10 Endocrine Society, March 5, 2015 Lustig et al. Obesity Society Nov. 4, 2015 11

Changes in liver, visceral, and subcutaneous fat De novo (n = 37) Lipogenesis DNL Glycerol-P TG* Malonyl Fatty Ac CoA* VLDL* CoA Acid* De novo De novo Lipogenesis Lipogenesis DNL DNL Glycerol-P Glycerol-P TG* TG* Malonyl Fatty Malonyl Fatty Ac CoA* Ac CoA* VLDL* VLDL* CoA Acid* CoA Acid* 9 days 9 days fructose fructose restriction restriction LIVER DNL FAT VLDL * Visceral fat 12

De novo Sugar and disease Lipogenesis DNL Glycerol-P TG* Improved • Causation Malonyl Fatty Ac CoA* VLDL* CoA Acid* Insulin – Diabetes kinetics – Heart Disease 9 days – Fatty Liver Disease fructose restriction – Tooth Decay LIVER DNL FAT • Correlation – Cancer VLDL * – Dementia Visceral fat A different model of insulin resistance A different model of insulin resistance Fructose Fructose Alcohol Alcohol Cytokines Cytokines Hepatic insulin Hepatic insulin resistance resistance Fatty liver Fatty liver Sensitivity Sensitivity 13

A different model of insulin resistance Actually 3 metabolic syndromes • SQ fat — the ”bucket” hypothesis Fructose Alcohol Hepatic insulin Cytokines • Visceral fat — the “stress” hypothesis resistance Fatty liver • Liver fat — the “mainlining” hypothesis Sensitivity Toward a unifying hypothesis of metabolic syndrome But what about FRUCTOSE FRUCTOSE post-transplant metabolic syndrome (PTMS)? Endoplasmic Cell Mitochondria NH 2 Reticulum death UPR Cellular/ ROS metabolic dysfunction Acetyl-CoA ROS If you do a liver transplant, ATP ROS ROS shouldn’t the metabolic syndrome get better? ROS Acyl-CoA Lipid ROS droplet PKC  Fat deposition JNK1 pSer-IRS-1 Peroxisome Insulin resistance Insulin Receptor Bremer et al., Pediatrics 129:557. 2012 14