AGING, INSULIN RESISTANCE AND MITOCHONDRIAL FUNCTION. Kitt Falk Petersen, M.D. Yale University School of Medicine

Transcription

1 AGING, INSULIN RESISTANCE AND MITOCHONDRIAL FUNCTION Kitt Falk Petersen, M.D. Yale University School of Medicine

2 % of Population Prevalence of Diabetes and Glucose Intolerance Age Impaire d Glucose Tole rance Undiagnose d Diabe te Diagnosed Diabetes Harris. Diabetes Care 1993;16:

3 Subject Characteristics Young (n=13) Elderly (n=15) P-value Age (years) 27±2 71±4 < Body Weight (kg) 71±4 70±3 NS Body Mass Index (kg/m 2 ) 24±1 25±1 NS Body Fat (%) 28±3 29±2 NS Fat Mass (kg) 20±2 20±2 NS Lean Body Mass (kg) 54±5 49±3 NS Fasting Glucose (mg/dl) 90±3 94±3 NS Fasting Insulin (µu/ml) 9±1 10±1 NS Petersen et al, Science 300:1140, 2003

4 Oral Glucose Tolerance Test - Glucose Glucose (m g/dl) 180 Young Elde rly Tim e (minute s

5 Oral Glucose Tolerance Test - Insulin Insulin ( m U/mL) 80 * * Young Elderly * * Time (minutes)

6 Rates of Insulin Stimulated Whole Body Glucose Uptake 40 P= µmol / (kg LBM-min) Petersen et al, Science 300:1140, 2003 Young Elderly

7 1 H spectrum of the soleus muscle of a lean subject EMCL IMCL Diabetologia 1999;42: ppm

8 1 H MRS Spectrum of Liver H 2 O Coil Voxel Lipid (ppm)

9 Intramyocellular and Hepatic Triglyceride Content Intramyocellular Triglyceride (%) Hepatic Triglyceride (%) P < P < Young Elderly Young Elderly Petersen et al, Science 300:1140, 2003

10 Muscle Insulin IRS-1 serine/threonine phosphorylation IRS-1 tyrosine phosphorylation serine/threonine kinase cascade glucose GLUT 4 AKT PI PI 33 kinase H + fatty acyl CoA diacylglycerol npkc H + plasma glucose plasma fatty acid Shulman JCI 2000, Savage, Petersen et al. Physiological Reviews 2007

11 Liver Insulin IRS-2 tyrosine phosphorylation GLYCOGEN PI 3 kinase TAG serine/threonine kinase cascade GS DAG PKCe plasma glucose plasma fatty acid JBC :8546, JCI ;171 PNAS :7522, JBC :32345, Cell Metabolism :55

12 Increased Fatty Acid Delivery and/or Decreased Fatty Acid Oxidation? CO 2 H + H + ADP ATP TCA?? H + Petersen et al, Science 300:1140, 2003

13 µmol/(kg fat mass-min) µmol/(kg fat mass-min) Rates of Whole Body Glycerol Turnover Basal Clamp P=NS P=NS Young Elderly Young Elderly Petersen et al, Science 300:1140, 2003

14 Potential Role of Mitochondial Dysfuntion

15 31 P NMR measurement of ATP synthase flux P i ATP P i ATP saturation ppm Petersen et al, Science 300:1140, 2003

16 13 C NMR measurement of TCA cycle Acetate 13 C2 Acetyl CoA 13 Citrate TCA Cycle Flux KG Glu 13 C4 Glu 13 C2 on the 2 nd turn

17 Mitochondrial Oxidative-Phosphorylation Activity (nmol/g/min) 120 TCA Flux Rates P<0.006 (mmol/g/min) 9.00 ATP Synthesis Rates P< Young Elderly 0.00 Young Elderly Petersen et al, Science 300:1140, 2003

18 Mitochondrial Oxidative-Phosphorylation Activity is Reduced in the Elderly CO 2 DAG s H + H + ADP ATP TCA H + DAG s mitochondrial oxidativephosphorylation activity Petersen et al, Science 300:1140, 2003

19 The Road to Insulin Resistance CO 2 H + H + ADP ATP TCA Defects in Adipocyte Fatty Acid Metabolism Caloric Intake H + Acquired (aging) or Inherited (IR Offspring) Defects in Mitochondrial Metabolism

20 Effects of Aging on Neuronal and Astroglial Mitochondrial Metabolism

21 Glutamatergic neuron The 2 compartments model: [1-13 C]Glucose infusion Plasma Glucose Glucose Gln Gln TCA cycle Glu Glu TCA cycle Astroglia Post-synaptic neuron Courtesy of R. de Graaf

22 Glutamatergic neuron The 2 compartments model: [2-13 C]Acetate infusion Glucose Acetate Plasma Gln Gln TCA cycle Glu Glu TCA cycle Astroglia Post-synaptic neuron Courtesy of R. de Graaf

23 13 C MRS Studies of Brain Metabolism N=8 young: 27 3 years N=7 elderly: 76 3 years 1 H 1 H Neuronal TCA Activity: [1-13 C]glucose 13 C Boumezbeur et al. J Cerebral Blood Flow & Metab., 2009

24 Neuronal TCA Cycle Flux P = 0.01 (µmol per gram per min) % 0.2 Young Elderly Boumezbeur et al. J Cerebral Blood Flow & Metab. 1-11, 2009

25 Astrocyte TCA Cycle Flux P < 0.01 (µmol per gram per min) % 0.10 Young Elderly Boumezbeur et al. J Cerebral Blood Flow & Metab. 1-11, 2009

26 Brain Composition and Atrophy with Aging Young White Matter Gray Matter 45 ± 1 40 ± 1 CSF 15 ± 1 Elderly White Matter Gray Matter 42 ± 2 40 ± 2 White Matter Grey Matter CSF CSF 18 ± 2 Boumezbeur et al. J Cerebral Blood Flow & Metab. 1-11, 2009

27 Can Overexpression of Catalase in the Mitochondria Prevent Age-Associated Muscle Insulin Resistance?

28 lesion/10kb MCAT mice are protected from age-associated mtdna damage in skeletal muscle 0.3 Mitochondrial DNA P< 0.05 P< WT MCAT WT MCAT Young Old Lee et al. Cell Metabolism 12, , 2010

29 (pmol/g mito protein/sec) MCAT mice are protected from age-associated reduction in mitochondrial activity (μmol/g tissue/min) In Vitro State III oxygen consumption ** 600 * In Vivo Muscle ATP synthesis by 31 P MRS * * WT MCAT WT MCAT Young Old 0 WT WT MCAT Young Old Lee et al. Cell Metabolism 12, , 2010

30 MCAT mice are protected from age-associated muscle insulin resistance Rates of Glucose Uptake (mg/[kg/min]) 60 P< 0.01 P= WT MCAT WT MCAT Young Old Lee et al. Cell Metabolism 12, , 2010

31 The Metabolic Syndrome Type 2 diabetes Atherosclerosis Hypertension Hypertriglyceridemia Decreased fibrinolytic activity Insulin Resistance or Abdominal Obesity? Impaired glucose tolerance Decreased HDL Inflammation Hyperuricemia Polycystic ovarian syndrome

32 Hypothesis Insulin resistance in muscle promotes the development of atherogenic dyslipidemia and NAFLD by changing the pattern of energy deposition.

33 Subjects Young (N=12) Elderly (N=12) P-value Age (years) 26±2 73±2 < Body Mass Index (kg/m 2 ) 23±1 24±1 NS Body Fat (%) 24±2 26±2 NS Fat Mass (kg) 14±3 18±1 NS Lean Body Mass (kg) 43±7 51±4 NS Systolic Blood Pressure (mmhg) 111±2 129±4 0.03

34 Plasma Concentrations Young Elderly P-value Insulin Sensitivity Index 6.7 ± ± Fasting Glucose (mg/dl) 84 ± 2 96 ± 2 < Fasting Insulin (µu/ml) 7 ± 1 11 ± Fasting Triglyceride (mg/dl) 66 ± ± Total Cholesterol 147 ± ± HDL (mg/dl) 46 ± 4 57 ± Flannery, Diabetes, 2012

35 Protocol 6am 12pm 6pm 12am 6am 1 H MRS Meals* D 2 O De Novo Lipogenesis *Liquid Meals: 125% of daily total energy requirements (+ 25% additional sucrose) % 64 carbohydrate, % 28 fat, & % 8 protein

36 Plasma Glucose Concentration (mmol/l) Plasma Glucose Concentrations 10 Meal Meal 10am 1pm * P < MRS am 2pm 6pm 10pm 2am 6am

37 Plasma Insulin Concentrations (pmol/l) Plasma Insulin Concentrations Meal 10am Meal 1pm MRS 10am 2pm 6pm 10pm 2am 6am

38 Plasma C-peptide Concentration (pmol/l) Plasma C-Peptide Concentrations Meal 10am Meal 1pm 6 4 MRS am 2pm 6pm 10pm 2am 6am

39 Plasma Triglyceride Concentrations (mmol/l) Plasma Triglyceride Concentrations 2.50 Meal 10am Meal 1pm MRS am 2pm 6pm 10pm 2am 6am

40 Plasma Fatty Acid Concentrations (mmol/l) Non-Esterified Fatty Acid Concentrations Meal 10am Meal 1pm MRS 10am 2pm 6pm 10pm 2am 6am

41 Change in Muscle Glycogen Concentrations (mmol/l) Change in Muscle Glycogen Content 25 P= Flannery, Diabetes, 2012 Young Older

42 Change in Liver Glycogen Content (mmol/l) Change in Hepatic Glycogen Content P=0.85 Flannery, Diabetes, Young Older

43 De novo lipogenesis (%) De Novo Lipogenesis Flannery, Diabetes, 2012 Young P= Older

44 Triglyceride Glycogen De novo lipogenesis Glucose NAFLD Glycogen Glycogen Young (IS) Elderly (IR)

45 Collaborators Tiago Alves Douglas Befroy Kevin Behar Fawzi Boumezbeur Sylvie Dufour Clare Flannery Rina Garcia Anne Impellizeri Silvio Inzucchi Yanna Kosover Martin Krssak Vincent Lebon Graeme Mason Gianluca Perseghin Rasmus Rabøl Varman Samuel Jun Shen Irina Smolgovsky Shin Yonemitsu Xian-Man Zhang Howard Hughes Medical Institute Gerald I. Shulman Yale-Diabetes Endocrine Research Center Gary W. Cline (Stable Isotope Core) Yale-Magnetic Resonance Center Douglas Rothman Yale-Center for Clinical Investigation Gina Solomon Catherine Parmelee Mikhail Smolgovsky ADA Distinguished Clinical Scientist Award, NIH R01 AG-23686, R01 NS , R24 DK