The metabolic memory. Antonio Ceriello

Transcription

1 The metabolic memory Antonio Ceriello :

2 DCCT/EDIC - Long-term Microvascular Risk Reduction in Type 1 Diabetes A1C 12% 10% Intensive Retinopathy progression (incidence) Conventional % risk reduction P < % % P<0.001 P<0.001 P= DCCT End of randomized treatment EDIC Year 1 EDIC Year Years in EDIC DCCT/EDIC Research Group. JAMA. 2002;287:

3 EDIC Results: Nephropathy Microalbuminuria No. at Risk Conventional Intensive At DCCT closeout, cumulative incidences of microalbuminuria were 22% in the intensive cohort and 34% in the conventional cohort Writing Team for the DCCT/ EDIC Research Group. JAMA. 2003;290:

4 Where we are 30 years later In individuals with type 1 diabetes, intensive diabetes treatment yields durable renal benefits that persist for at least 18 years after its application. Lancet Diabetes Endocrinol 2014; 2: DCCT INT and the attendant 6.5 years of lower HbA1c had long-term salutary effects on the development and progression of atherosclerosis and cardiovascular disease during the subsequent follow-up during EDIC. Diabetes Care 2014;37: The persistent effects of prior intensive therapy on neuropathy measures through 14 years of EDIC largely mirror those observed for other diabetes complications. Diabetes Care 2014;37:31-38 Intensive control delays the onset and slows the progression of DR. Furthermore, the early effects of metabolic control continue to accrue over many years despite subsequent comparable glycemic control (metabolic memory). Diabetes Care 2014;37:17-23 After a mean of 27 years' follow-up of patients with type 1 diabetes, 6.5 years of initial intensive diabetes therapy was associated with a lower all-cause mortality rate when compared with conventional therapy. JAMA 2015;313:45-53

5 10-Year follow-up of intensive glucose control in type 2 diabetes Early HbA1c control including insulin treatment is key in preventing microvascular disease and long term macrovascular complications No treatment Early HbA control 1c including insulin treatment is key in preventing microvascular disease and long term macrovascular complications. Holman R,R. et al, UKPDS year follow up. NEJM 2008

6 R.R.Holman et al. N Engl J Med 2008;359: The benefits of early tight control: UKPDS 10-year posttrial follow-up

7 The Metabolic Memory Evidence for a long-term persistence of hyperglycemia-induced damage DCC/EDIC Research Group N Engl J Med, 2005

8 The Metabolic Memory UKPDS VADT Holman R et al. N Engl J Med ;359: Del Prato S, Diabetologia 2009; 52:

9 The Metabolic Memory The role of oxidative stress

10 Hyperglycemia Mitochondria O 2 - Polyol Pathway AGE Formation Hexosamine Flux PKC NAD(P)H oxidase NF-kB inos enos NO Adhesion molecules Proinflammatory Cytokines O 2 - DNA damage Peroxynitrite Nitrotyrosine PARP NAD + Ceriello A, Diabetes Care 2003 GAPDH Endothelial disfunction Diabetic Complications

11 The Metabolic Memory: the role of oxidative stress Ihnat M et al, Diabetologia 2007

12 Effects of high glucose for three weeks or for two weeks plus one week of normal glucose in HUVECs

13 Effects of various antioxidant treatments on the hyperglycemia-induced Memory

14 Previous studies have shown that in type 1 diabetic patients even when glycemia is normalized endothelial dysfunction still persists 1. Huvers FC, De Leeuw PW, Houben AJ, et al. Endothelium-dependent vasodilatation, plasma markers of endothelial function, and adrenergic vasoconstrictor responses in type 1 diabetes under nearnormoglycemic conditions. Diabetes. 1999;48: Dogra G, Rich L, Stanton K, Watts GF. Endothelium-dependent and independent vasodilation studies at normoglycaemia in type I diabetes mellitus with and without microalbuminuria. Diabetologia. 2001;44:

15 Controls Protocol Protocol Protocol A B C Sex 6M 6F 7M 5F 5M 7M 7M 5F Age (years) 22.3± ± ± ±1.4 Duration of the disease (years) 7.1± ± ±2.5 BMI (Kg/m2) 23.8± ± ± ±2.3 Fasting glucose (mmol/l) 4.3± ±2.3* 8.1±3.2* 7.8±2.4* HbA1c (%) 8.3± ± ±0.5 Resting systolic blood pressure (mm 119.1± ± ± ±1.5 Hg) Resting diastolic blood pressure (mm 80.4± ± ± ±3.7 Hg) Total cholesterol (mmol/l) 4.8± ± ± ±0.6 Triglycerides (mmol/l) 1.1± ± ± ±0.4 HDL-C (mmol/l) 1.4± ± ± ±0.2 LDL-C (mmol/l) 2.6± ± ± ±0.6 FMD (%) 10.8± ±0.5* 5.6±0.7* 5.6±0.8* Nitrotyrosine (μmol/l) 0.35± ±0.2* 0.71±0.4* 0.72±0.3* Ceriello A. et al. Diabetes Care 2007 * p< vs controls

16 A: 12 h 12 h Insulin and/ or 5% glucose Vitamin C 3mg/min B: C: 12 h 12 h Vitamin C 3mg/min Insulin and/ or 5% glucose 12 h 12 h Insulin and/ or 5% glucose Vitamin C 3mg/min

17 mmol/l % µmol/l % FMD Nitrotyrosine time time Glucose Insulin and Vit. C 24 h Vit. C 24 h + Insulin 12 h Insulin 24 + Vit. C 12 h 3.5 time

18 Patients Without Complications Subgroup 1: Patients enrolled within 1 month from the diagnosis. Subgroup 2: Patients had years of diagnosis and included in these subgroup because the mean HbA1c over the last 5 years was 7%. Subgroup 3: Patients had years of diagnosis and included in these subgroup because the mean HbA1c over the last 5 years was 7%. Ceriello A. et al. J Clin Endocrinol Metab 2009

19 Baseline characteristics of controls and subgroups of type 1 diabetic patients Controls Subgroup 1 Subgroup2 Subgroup3 Sex 12M 8F 11M 9F 12M 9M 12M 12F Age years 23.4± ± ± ±4.5 BMI Kg/m2 23.5± ± ± ±3.3 Fasting glucose mmol/l 4.2± ±2.3* 7.1±1.7* 8.5±2.2* HbA1c % at the time of the 8.3± ±0. 2** 8.9±0. 7 study Mean HbA1c %of the last 5 6.4±0. 3*** 8.7±0. 6 years (range of the last 5 years) ( ) ( ) Resting systolic blood pressure 114.3± ± ± ±2.0 mm Hg Resting diastolic blood 78.1± ± ± ±2.7 pressure mm Hg Total cholesterol mmol/l 4.3± ± ± ±0.3 Triglycerides mmol/l 1.2± ± ± ±0.5 HDL-C mmol/l 1.4± ± ± ±0.4 LDL-C mmol/l 2.3± ± ± ±0.9 FMD % 10.8± ±0.9* 6.2±1.14* 4.1±0.8*β Nitrotyrosine μmol/l 0.35± ±0.07* 0.75±0.04* 0.94±0.07*β 8-iso-PGF2a (pg/ml) 32.6± ±4.2* 63.4±3.8* 83.4±5.3*β sicam-1a (ng/ml) 124.2± ±12.5* 165.5±12.8* 190.9±18.4*β svicam-1 (ng/ml) ± ±12.3* ±22.4* ±28.4*β IL-6 (pg/ml) ± ±11.1* ±12.5* ±18.3*β IL-18 (pg/ml) 73.7± ±17.5* 125.5±17.8* 164.4±16.2*β Data are expressed as mean±sd * p< vs controls ** p< vs sub1 and 3 *** p< vs sub3 β p< 0.05 vs sub1 and 2

20 Study design Treatment A hyperglycemia normoglycemia normoglycemia + Vit C Treatment B hyperglycemia hyperglycemia + Vit C normoglycemia + Vit C Treatment C hyperglycemia normoglycemia + Vit C normoglycemia + Vit C Treatment D hyperglycemia Hyperglicemichyperinsulinemic clamp Hyperglicemichyperinsulinemic clamp + Vit C Time (h)

21 Glycemia mmol/l FMD % Glycemia mmol/l Treatment D Treatment C Treatment B Treatment A FMD % Glycemia mmol/l FMD % Glycemia mmol/l FMD % Sub 1 Sub

22 Glycation and Carboxymethyllysine Levels in Skin Collagen Predict the Risk of Future 10-Year Progression of Diabetic Retinopathy and Nephropathy in the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications Participants With Type 1 Diabetes S. Genuth, W. Sun, P. Cleary, D. R. Sell, W. Dahms, J. Malone, W. Sivitz, and V.M. Monnier, for the DCCT Skin Collagen Ancillary Study Group Diabetes, Vol. 54, November 2005

23 Distribution of skin collagens by retinopathy progression status. Distribution of skin collagens by nephropathy progression status

24 Hyperglycemia Mitochondria Polyol Pathway Hexosamine Flux O 2 - AGEs PKC NAD(P)H oxidase NF-kB inos enos NO Adhesion molecules Proinflammatory Cytokines O 2 - DNA damage Peroxynitrite Nitrotyrosine PARP NAD + Ceriello A, Diabetes Care 2003 GAPDH Endothelial disfunction Diabetic Complications

25 Schematic representation of the interplay between AGE and RAGE and high glucose in promoting mitochondrial superoxide production in the diabetic kidney AGEs binding to RAGE induce cytosolic H2O2 production. Cytosolic H2O2 facilitates induction of mpt, promoting a deficiency in complex I of the mitochondrial respiratory chain. Hyperglycemia provides increased mitochondrial NADH availability for OXPHOS, which, when coupled with a deficient complex I activity, amplifies mitochondrial superoxide generation. Both the AGE-RAGE interaction and hyperglycemia synergistically coordinate overproduction of mitochondrial superoxide and promote diabetic kidney disease. M. T. Coughlan et al. J Am Soc Nephrol 20: , 2009

26 Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation M. Rosca, T. Mustata, M. Kinter, A. Ozdemir, T. Kern, L. Szweda, M. Brownlee,V. Monnier, M. Weiss. Am J Physiol Renal Physiol 289: F420 F430, 2005

27 Cortical renal mitochondria isolated from 12 mo diabetic animals (squares) form higher levels of superoxide than their age-matched controls (circles)

28 Defining metabolic memory Antonio Ceriello, Michael A. Ihnat and Jessica E. Thorpe The "Metabolic Memory": Is More Than Just Tight Glucose Control Necessary to Prevent Diabetic Complications? Epidemiological and prospective data support a long-term influence of early metabolic control on clinical outcomes...early glycaemic environment is remembered in the target organs (i.e., eye, kidney, heart, extremities) J Clin. Endocrinol. Metab : The concept of a metabolic memory is of diabetic vascular stresses persisting after glucose normalization

29 The vicious circle of the Metabolic Memory (glycated) A. Ceriello et al. J Clin Endocrinol Metab, 2009;94:410-5

30 Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia A. El-Osta, D. Brasacchio, D. Yao, A. Pocai, P.L. Jones, R.G. Roeder, M.E. Cooper and M. Brownlee JEM Vol. 205, September 29, 2008

31 Abstract We show that transient hyperglycemia induces long-lasting activating epigenetic changes in the promoter of the nuclear factor kb (NF- kb) subunit p65 in aortic endothelial cells both in vitro and in nondiabetic mice, which cause increased p65 gene expression. Hyperglycemia- induced epigenetic changes and increased p65 expression are prevented by reducing mitochondrial superoxide production or superoxide-induced-oxoaldehydes.

32 Persistent increases in Set7-mediated histone methylation and p65 gene expression in nondiabetic mice WT mice were exposed to 20 mm glucose for 6 h using a hyperinsulinemic hyperglycemic clamp. Aortas were removed at the indicated times, and aortic endothelial cells were isolated by LCM. (a) cchip of NF- B p65 promoter by H3K4m1 antibody ( n = 2). (b) (b) NF- B p65 subunit mrna levels ( n = 3).

33 Evaluating the role of epigenetic histone modifications in the metabolic memory of type 1 diabetes We assessed whether epigenetic histone posttranslational modifications are associated with the prolonged beneficial effects (metabolic memory) of intensive versus conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term Epidemiology of Diabetes Interventions and Complications (EDIC) study. Monocytes from case subjects had statistically greater numbers of promoter regions with enrichment in H3K9Ac (active chromatin mark) compared with control subjects (P = ). Among the patients in the two groups combined, monocyte H3K9Ac was significantly associated with the mean HbA1c level during the DCCT and EDIC (each P < 2.2E-16). Of note, the top 38 case hyperacetylated promoters (P < 0.05) included >15 genes related to the nuclear factor-κb inflammatory pathway and were enriched in genes related to diabetes complications. These results suggest an association between HbA1c level and H3K9Ac, and a possible epigenetic explanation for metabolic memory in humans. Miao F. et al Diabetes 2014;63:

34 The take-home message is that good glucose control should be started as early as possible to delay or prevent serious diabetes-related complications said Alan D. Cherrington, PhD, president, American Diabetes Association. ADA S. Diego 2005

35 GRACIAS THANK YOU GRAZIE