Diabetes and Exercise: Why Exercise Works When Insulin Does Not. Laurie J. Goodyear Metabolism Section Joslin Diabetes Center Harvard Medical School

Transcription

1 Diabetes and Exercise: Why Exercise Works When Insulin Does Not Laurie J. Goodyear Metabolism Section Joslin Diabetes Center Harvard Medical School

2 Type 2 Diabetes is Reaching Epidemic Levels A major factor leading to increased rates of type 2 diabetes is inactivity. hysical exercise is critical in the prevention of type 2 diabetes.

3 Diabetes and Exercise: Why Exercise Works When Insulin Does Not Background on Diabetes Skeletal Muscle Glucose Transport Studies in Human Subjects The Exercise ill

4 Basic hysiology: Glucose concentrations in the blood rise after a meal. Insulin is released from the pancreas, binding to insulin receptors on tissues throughout the body, resulting in glucose entering the tissues. Muscle Liver ancreas Fat

5 Type 1 Diabetes (juvenile-onset or insulin-dependent) ancreas loses its ability to produce and secrete insulin. This is almost always caused by autoimmune attack and destruction of the β cells. Muscle Liver ancreas Fat

6 Type 2 diabetes (adult-onset or non-insulin dependent) Insulin is produced by the pancreas and levels in the blood are often normal or even high, but the tissues don t respond - insulin resistance. Muscle Liver Fat ancreas

7 Diabetes Complications Leading cause of blindness Leading cause of kidney failure Leading cause of amputations Major cause of heart attacks Major cause of strokes

8 Diabetes is Reaching Epidemic Levels 2000 = = % % % % Zimmet et al WHO Data % World 2000 = 151 million 2010 = 221 million 2020 = 300 million %

9 Type 2 Diabetes is Reaching Epidemic Levels Cumulative incidence (%) Incidence of Diabetes (D)( Risk reduction 31% by metformin lacebo 58% by lifestyle Metformin Years from randomization Lifestyle

10 Diabetes and Exercise: Why Exercise Works When Insulin Does Not Background on Diabetes Skeletal Muscle Glucose Transport Studies in Human Subjects The Exercise ill

11 Effect of Exercise on Blood Glucose Concentrations in a Subject with Type 2 Diabetes glucose (mm) basal Exercise at 70% VO 2 max (minutes)

12 Type 2 Diabetes Blood Vessel Glucose Exercise Muscle

13 Blood Vessel Glucose Insulin Muscle

14 Type 2 Diabetes Blood Vessel Glucose X Insulin Muscle

15 Skeletal Muscle Glucose Uptake Type 2 Diabetes Exercise + Insulin What is the molecular basis for the ability of exercise to increase glucose uptake in skeletal muscle of patients with Type 2 diabetes?

16 Methods to Study Exercise and Muscle Contraction Muscle contraction system for cultured myotubes Treadmill running exercise (acute and chronic studies) Contraction by direct electrical stimulation Contraction by sciatic and peroneal nerve stimulation Wheel running exercise (chronic studies) Human exercise with biopsies

17 Glucose Transport System in Skeletal Muscle glucose glucose transport is the rate limiting step in glucose utilization facilitated diffusion glucose transporter proteins GLUT1, GLUT4 expressed in skeletal muscle GLYCOGEN GLYCOLYSIS exercise, insulin most potent physiological stimuli

18 Under Basal Conditions GLUT4 is rimarily Intracellular surface membrane GLUT4-containing vesicle

19 Exercise Regulation of Glucose Transport Exercise GLUT4-containing vesicle

20 Exercise Regulation of Glucose Transport Glucose Exercise GLUT4 Translocation

21 Insulin Regulation of Glucose Transport Insulin Receptor Glucose Exercise GLUT4 Translocation

22 Insulin Stimulates GLUT4 Translocation in Skeletal Muscle In vivo imaging of GLUT4-GF t=0 t=30 Mouse quadriceps muscle Bar = 20 µm (Lauritzen HMM, Diabetes, 2006)

23 Contraction Stimulates GLUT4 Translocation in Skeletal Muscle In vivo imaging of GLUT4-GF t=0 t=15 Mouse quadriceps muscle Bar = 20 µm

24 Are there distinct mechanisms for insulinand exercise-stimulated glucose transport? Insulin Receptor Glucose Exercise GLUT4 Translocation

25 Contraction + Insulin have Additive Effects on Glucose Transport in Skeletal Muscle Glucose Transport Arbitrary units basal maximal contraction maximal insulin contraction + insulin

26 Exercise and Insulin Regulate Glucose Transport via Distinct Signaling Mechanisms Insulin Receptor Glucose Exercise GLUT4 Translocation

27 What are the signaling mechanisms that mediate glucose transport in skeletal muscle? Insulin Receptor Glucose Exercise?? GLUT4 Translocation

28 Insulin Regulation of Glucose Transport Insulin Receptor Glucose Exercise IRS-1 p85-p110 I 3-Kinase Akt GLUT4 Translocation

29 Exercise and Insulin Regulate Glucose Transport via Distinct Signaling Mechanisms Insulin Receptor Glucose Exercise IRS-1 p85-p110 I 3-Kinase Akt GLUT4 Translocation

30 Exercise and Insulin Regulate Glucose Transport via Distinct Signaling Mechanisms Insulin Receptor Glucose Exercise IRS-1 p85-p110 I 3-Kinase Akt GLUT4 Translocation?

31 Exercise and Insulin Regulate Glucose Transport via Distinct Signaling Mechanisms Insulin Receptor Glucose Exercise IRS-1 p85-p110 I 3-Kinase Akt GLUT4 Translocation AMK

32 5 AM-Activated rotein Kinase (AMK) β α γ α1, α2 (α2 predominant in skeletal muscle) β1, β2 γ1, γ2, γ3 A member of metabolite-sensing protein kinase family Activated under conditions of low energy state, exercise roposed to regulate numerous metabolic and transcriptional processes in multiple cell types

33 5 AM-Activated rotein Kinase (AMK) Activating T-loop phosphorylation site α AM γ β

34 5 AM-Activated rotein Kinase (AMK) LKB1 α AM

35 What is the evidence that AMK mediates exercise-stimulated glucose transport? Insulin Receptor Glucose Exercise IRS-1 p85-p110 I 3-Kinase Akt GLUT4 Translocation AMK

36 ACIAR and the Regulation of Glucose Transport in Skeletal Muscle Glucose Insulin Receptor AICAR IRS-1 p85-p110 I 3-Kinase Akt GLUT4 Translocation AMK

37 NH2 C O C C H2N N CH N O H OH H OH H H CH2 O O O O - - NH2 C O C C N N CH N O H OH H OH H H CH2 O O O O - - HC ZM AM AICAR (5-aminoimidazole-4-carboxamide-riboside) AICAR ZM α β γ AMKK AMK Activity Adenosine kinase

38 AICAR + Insulin have Additive Effects on Glucose Transport in Skeletal Muscle Glucose Transport Arbitrary units basal maximal AICAR maximal insulin AICAR + insulin

39 AICAR + Contraction do not have Additive Effects on Glucose Transport Glucose Transport Arbitrary units basal maximal AICAR maximal contraction AICAR + contraction

40 ACIAR and Insulin Regulate Glucose Transport via Distinct Signaling Mechanisms Glucose Insulin Receptor AICAR Exercise IRS-1 p85-p110 I 3-Kinase Akt GLUT4 Translocation AMK

41 Summary Skeletal Muscle Glucose Transport Exercise and insulin increase glucose transport in skel etal muscle, resulting in glucose clearance from the bloo d. Exercise and insulin increase glucose transport throug h the translocation of GLUT4 transporters to the cell surfa ce and transverse tubules in skeletal muscle. There are distinct proximal signaling mechanisms for e xercise- and insulin-stimulated GLUT4 translocation. AICAR increases AMK activity and can increase gluco se transport in skeletal muscle.

42 Diabetes and Exercise: Why Exercise Works When Insulin Does Not Background on Diabetes Skeletal Muscle Glucose Transport Studies in Human Subjects The Exercise ill

43 What is the physiological relevance of these findings for patients with type 2 diabetes?

44 Skeletal Muscle from atients with Type 2 Diabetes Exercise + Insulin Does exercise bypass defects in insulin action in skeletal muscle by utilizing alternative signaling mechanisms leading to increased GLUT4 translocation?

45 Skeletal Muscle Biopsy from Human Subjects

46 Are there defects in insulin- and exercisestimulated GLUT4 translocation in patients with type 2 diabetes? Insulin Receptor Glucose Exercise GLUT4 Translocation

47 Insulin-stimulated GLUT4 Translocation is Impaired in atients with Type 2 Diabetes 100 Arbitrary units Basal Insulin Basal Insulin Controls Type 2 DM

48 Exercise Causes Normal GLUT4 Translocation in Subjects with Type 2 Diabetes 100 Arbitrary units Basal Exercise Controls Basal Exercise Type 2 DM

49 Exercise and Insulin Regulate Glucose Transport via Distinct Signaling Mechanisms Insulin Receptor Glucose Exercise IRS-1 p85-p110 I 3-Kinase Akt GLUT4 Translocation

50 ACIAR and Insulin Regulate Glucose Transport via Distinct Signaling Mechanisms Insulin Receptor Glucose Exercise IRS-1 p85-p110 I 3-Kinase Akt GLUT4 Translocation AMK

51 Exercise Increases AMKα2 Activity In Controls and Subjects with Type 2 Diabetes 2.0 * (pmol/mg/min) * * * * * Type 2 DM Controls 0.0 Exercise 70% VO 2max Rest minutes

52 Exercise Can Bypass Defects in Insulin Signaling and GLUT4 Translocation in eople with Type 2 Diabetes Insulin Receptor Glucose Exercise IRS-1 p85-p110 I 3-Kinase Akt GLUT4 Translocation AMK

53 Can we make a drug to activate AMK leading to increased glucose transport in skeletal muscle? Insulin Receptor Glucose Drug? IRS-1 p85-p110 I 3-Kinase Akt GLUT4 Translocation AMK

54 Can we make a drug to activate AMK leading to increased glucose transport in skeletal muscle? Insulin Receptor Glucose Metformin IRS-1 p85-p110 I 3-Kinase Akt GLUT4 Translocation AMK

55 Metformin - Single most prescribed oral antidiabetic drug in the U.S. - Cellular mechanism of action is unclear * Suppresses hepatic glucose production * Increases muscle glucose uptake * Inhibits Complex 1 of Respiratory Chain (Owen, Biochem J, 2000 and El-Mir, JBC, 2000)

56 AICAR and Metformin Share Metabolic Effects AICAR Metformin Inhibit Hepatic Glucose roduction Stimulate Muscle Glucose Uptake Increase Lactic Acid roduction

57 Does the mechanism of Metformin action involve the regulation of AMK? Insulin Receptor Glucose Metformin? IRS-1 p85-p110 I 3-Kinase Akt GLUT4 Translocation AMK

58 Effect of Metformin on AMK Activity (rat epitrochlearis muscles) (pmol/mg/min) * 0.0 Control Metformin 3hr

59 Effects of 4 and 10 Weeks of Metformin Treatment on AMKα2 Activity (human vastus lateralis muscle) 0.80 * (pmol/mg/min) * 0.00 Basal 4 Weeks 10 Weeks

60 Activation of AMK Increases Skeletal Muscle Glucose Transport Insulin Receptor Glucose IRS-1 p85-p110 I 3-Kinase Akt GLUT4 Translocation AMK

61 Summary Studies in Human Subjects Exercise and insulin increase GLUT4 translocation in h uman skeletal muscle. Insulin signaling and GLUT4 translocation are impaired in patients with type 2 diabetes. Exercise-stimulated AMK activation and GLUT4 transl ocation are normal in patients with type 2 diabetes. Activation of AMK can increase glucose transport in s keletal muscle, making AMK a drug target for treatment of type 2 diabetes. Metformin, the most widely used diabetes drug, works t hrough stimulation of AMK.

62 Multiple Signals Mediate Exercise-Stimulated Glucose Transport Exercise Ca2 + AM/AT ROS mechanical LKB1 GLUT4 Translocation calmodulin CaMKs SNARK? AMK NRG akcs CBD TBC1D1 RAB GA domain CBD AS160 RAB GA domain

63 Diabetes and Exercise: Why Exercise Works When Insulin Does Not Background on Diabetes Skeletal Muscle Glucose Transport Studies in Human Subjects The Exercise ill

64 News Headlines, August 2008 It s the exercise pill: the pill that helps you burn off calories just by sitting on the couch. It s America s dream. Couch Mouse to Mr. Mighty by ills Alone ill may boost endurance without exercise

65 The Exercise ill: AICAR

66 Volume October 23, 2008 Number : The Exercise ill Too Good to Be True? Laurie J. Goodyear, h.d.

67 Effects of AICAR Treatment and Chronic AMK Activation Acute Effects: Blood Vessel Increase glucose uptake (Hayashi, Winder, others, 1998) Lower blood glucose levels (Shulman, others, 1999) Glucose AICAR Chronic Effects: Increase exercise endurance (Witters, 2007) (Evans, 2008) Increase in muscle glycogen (Winder, Holloszy, others, 1999) Increase in GLUT4, mitochondrial enzymes (Winder, Holloszy, others, 1999)

68 The Exercise ill Too Good to Be True? AICAR has a short half-life after intravenous infusion and poor bioavailability after oral ingestion. AICAR treatment causes lactic acidosis in humans. AMK activation in the hypothalamus can stimulate appetite. Activating mutations of AMK cause heart conduction abnormalities in humans (WW syndrome).

69 Benefits of Regular hysical Exercise ulmonary function Increase lung capacity Improve sleep Decrease depression, anxiety Decrease Alzheimer's Decrease stroke Decrease appetite Increase blood volume Improve cardiac function Improve pancreatic function Improve lipid profile Improve liver function Lower blood pressure Reduce fat stores revention of Diabetes Increase glucose tolerance Increase insulin sensitivity Increase muscle glucose uptake Increase mitochondrial function Increase bone density Increase muscle strength Increase flexibility Decrease Rates of Cancer Colon, breast, endometrial

70 Joslin Diabetes Center Longwood Medical Area, Boston

71 Ho-Jin Koh Nobuharu Fujii Hans Lauritzen Jeff An Fritz Kramer Eric Taylor Carol Witczak Jonas Treebak Taro Toyoda Haiyan Yu Carrie Sharoff Michelle Jung Kanokwan Vichaiwong Jan Willem Middelbeek Niels Jessen Sarah Lessard Julie Ripley Michael Hirshman Hiroyasu Esumi (NCCRCR Institute East) Jianxin Xie (Cell Signaling) Jørgen Wojtaszewski Eric Richter (U. Copenhagen) Funding Support: NIH (NIAMS, NIDDK) American hysiological Society American Diabetes Association