Obesity and the Metabolic Syndrome Underlie Type 2 Diabetic Neuropathy

Transcription

1 Obesity and the Metabolic Syndrome Underlie Type 2 Diabetic Neuropathy Eva L. Feldman M.D. Ph.D. Russell N. DeJong Professor of Neurology University of Michigan Ann Arbor, Michigan USA Funding: National Institutes of Health (NIDDK, NINDS), American Diabetes Association, Juvenile Diabetes Foundation, Taubman Foundation and the ALS Association

2 Diabetic Neuropathy Group at University of Michigan 2

3 Peripheral Neuropathy: Clinical Challenges and Opportunities Overview of basic nerve anatomy and clinical neuropathy ( Diabetic neuropathy: Introduction to diabetes and clinical studies Disease mechanisms Experimental models to test ideas and develop therapies The role of diet, exercise and metabolic control in the treatment of diabetic neuropathy 3

4 Peripheral Nervous System Large myelinated fibers Unmyelinated Small fibers myelinated fiber 4

5 Unmyelinated Axons: Most Abundant Axon in the PNS 5

6 Symptoms and Signs: Relate to Fiber Type Involved Symptom Exam Function Dx Test Large Myelinated Fibers Numbness Tingling Poor balance Reflexes, proprioception vibration Pressure, balance NCV Testing Sural nerve Biopsy Small Myelinated & Unmyelinated Fibers Pain: Burning, electric shocks Stabbing pain Thermal, pin-prick sensation Nociception; protective sensation Historically invisible Nerve Biopsy, Skin Biopsy 6

7 Axonal Loss of all Fiber Types in Neuropathy Mild Normal Severe Moderate 7

8 Axons Degenerate in Neuropathy: Human Sural Nerve Biopsy 8

9 Neuropathy: Distal to Proximal Axonal Loss 9

10 Peripheral Neuropathy: Clinical Challenges and Opportunities Overview of basic nerve anatomy and clinical neuropathy ( Diabetic neuropathy: Introduction to diabetes and clinical studies Disease mechanisms Experimental models to test ideas and develop therapies The role of diet, exercise and metabolic control in the treatment of diabetic neuropathy 10

11 Neuropathy The most common cause of neuropathy in the Western world, China and India is type 2 diabetes World Health Organization: 346 million people worldwide have diabetes and 50% have diabetic neuropathy The number is accelerating at an alarming rate DIABETIC NEUROPATHY IS A SERIOUS WORLDWIDE EPIDEMIC 11

12 Diabetic Neuropathy 12

13 Diabetes Epidemic in the U.S.A People (millions) Diagnosed cases Projected diagnosed cases 0 Year Data for from the National Health Interview Survey, NCHS, CDC. Projected data for from Boyle JP, et al, Diabetes Care 24: ,

14 Prevalence of Obesity* Among U.S. Adults in 1991 <10 % % >15 % N/A (*Approximately 30 pounds overweight) National Center for Chronic Disease Prevention and Health Promotion website. Available at: Accessed 9/11/03. 14

15 Prevalence of Obesity* Among U.S. Adults in % % >25 % (*Approximately 30 pounds overweight) American Diabetes Association and National Center for Disease Control 15

16 Prevalence of Obesity* Among U.S. Adults in % >25 % (*Approximately 30 pounds overweight) American Diabetes Association and National Center for Disease Control 16

17 Prevalence of Obesity* Among U.S. Adults in % >25 % (*Approximately 30 pounds overweight) American Diabetes Association and National Center for Disease Control 17

18 Diabetes and Diabetic Neuropathy in USA & China USA: In 2010, 25.8 million Americans had diabetes (8.3% of population) Center for Disease Control, 2012 CHINA: In 2008, 92.4 million Chinese had diabetes (9.7% of Chinese) Zhao et al. Curr Cardiol Rep 14: , % of Type 2 diabetics develop Diabetic Neuropathy Callaghan et al. Lancet Neurology, 2012

19 Glucose Control Impacts Neuropathy In Patients with Type 1 Diabetes Trial Pts Years Effect Dahl-Jorgensen 45 2 Yes Holman et al 74 2 Yes DCCT 1,441 5 Yes Reichard et al Yes Linn et al 49 5 Yes Callaghan et al., Cochrane Reviews,

20 Glucose Control Alone Does NOT Impact Neuropathy in Type 2 Diabetics Trial Pts Years Effect UKPDS 3, No* Azad et al No Gaede et al No Duckworth et al 1, No Ismail-Beigi et al 10, No Callaghan et al., Cochrane Reviews,

21 Results from Patients with Type 2 Diabetes - STENO 2 Gæde, P. et. al. N Engl J Med 2003;348:

22 Type 2 Diabetes: UKPDS 3867 patients received intensive therapy (sulfonylurea, insulin or metformin) or conventional therapy (diet) 7.0% versus 7.9% over at least a 10 year period Using bioesthiometer as a measure of neuropathy, there is no effect at year 10 on intensive control Lancet 352: ,

23 Diabetic Neuropathy in Type 2 Patients MFD Sural nerve biopsies of 427 patients Patients can be classified into 2 groups based on myelinated fiber density loss over 52 weeks TRIGLYCERIDES Wiggin et al, Diabetes, 2009

24 Gene Expression Patterns in Sural Nerves in Diabetic Neuropathy 532 differentially regulated genes Key regulated pathways: Lipid metabolism and inflammation (Hur et al. Brain 2011) Lipid metabolism NGFR Axonogenesis LEP PPARG KRT19 APOE THX JUN SERPINE1 Immune response STMN1 Inflammatory response

25 What Does Impact Neuropathy in Patients with Type 2 Diabetes? Metabolic Syndrome: HIGH LIPIDS HYPERLIPIDEMIA, HYPERTENSION, HYPERTENSION OBESITY AND CONTRIBUTE TO OBESITY DIABETIC NEUROPATHY IN ABNORMAL GLUCOSE TYPE 2 DIABETES 25

26 Peripheral Neuropathy: Clinical Challenges and Opportunities Overview of basic nerve anatomy and clinical neuropathy ( Diabetic neuropathy: Introduction to diabetes and clinical studies Disease mechanisms Experimental models to test ideas and develop therapies The role of diet, exercise and metabolic control in the treatment of diabetic neuropathy 26

27 The Metabolic Syndrome Underlies Diabetic Neuropathy in Type 2 Diabetes HOW? Components of the Metabolic Syndrome lead to systemic & nervous system OXIDATIVE STRESS and CELL INJURY and INFLAMMATION May

28 Cellular stress and insulin resistance Acute injury Hyperglycemia Dyslipidemia OXIDATIVE STRESS Mitochondrial injury & energy failure Diabetic Neuropathy INFLAMMATION

29 Mitochondria are the Sites of Energy Production in Cells (ATP) 29

30 Mitochondria: Life Energy production ATP produced via electron transport chain (oxidative phosphorylation) in the mitochondria Glucose/Lipids ATP(Energy) Life Science 281(28): by Green et al. 30

31 se/lipids Mitochondria: and Injury Injury Mitochondria Matrix swelling & abnormal fission ROS ATP(Energy) Toxins Leak ROS Activation of death enzyme cascade

32 Diabetes Results in Sick Sick and Small Neuronal Mitochondria

33 Diabetes Results in Sick Sick and Small Axonal Mitochondria

34 Reactive Oxygen Species (ROS) Mediate Cellular and Organ Injury

35 s and Glucose Oxidative Stress Leads to Energy Failure, Injury and Neuropathy

36 Peripheral Neuropathy: Clinical Challenges and Opportunities erview of basic nerve anatomy and clinical ropathy ( betic neuropathy: Introduction to diabetes d clinical studies Disease mechanisms perimental models to test ideas and develop rapies e role of diet, exercise and metabolic trol in the treatment of diabetic

37 Diabetic Peripheral Neuropathy

38 Unmyelinated Axons: Measured via Skin Biopsy

39 The Skin Biopsy Technique

40 The Skin Biopsy Technique

41 The Skin Biopsy Technique HEALED SITE: 2 months

42 The Skin Biopsy Technique

43 The Skin Biopsy Technique

44 The Skin Biopsy Technique

45 Normal Cutaneous Innervation Assessed with Skin Biopsy

46 U of M & U of Utah Clinical Trial to Reverse Neuropathy in Type 2 DM ients with pre-diabetes or type 2 diabetes and early ropathy with pain rvention: 30 minutes/day exercise and the goal of ng 7% of their body weight ary outcome: reversal of neuropathy using skin psies to measure nerve fiber density; secondary comes include mitochondrial markers and serum asures of oxidative stress ults: Diet and exercise leading to weight loss and

47 Intraepidermal Nerve Fiber Density Improves with Diet and Exercise rs/mm *

48 Mitochondria Size and Number are Restored by Improved Fitness in Type 2 Patients with Neuropathy

49 Ongoing Study of Obese Patients at the University of Michigan Neuropathy No Diabetes (28) N (%) Pre-diabetes (15) Diabetes (15) N (%) N (%) Definite 4 (14%) 4 (27%) 3 (20%) Probable 5 (18%) 6 (40%) 3 (20%) Possible or probable 12 (43%) 7 (47%) 5 (33%) Definite small fiber 0 (0%) 1 (7%) 0 (0%)

50 In Conclusion pe 2 diabetes and diabetic neuropathy resent a world-wide epidemic betic neuropathy in type 2 patients is diated by the metabolic syndrome: perlipidemia, hypertension, obesity are as portant as hyperglycemia; underlying thogenesis is inflammation, oxidative stress d insulin resistance tabolic control via diet and exercise

51 University of Michigan Ann Arbor, Michigan

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54 Logistic regression of Metabolic Factors for Definite neuropathy Metabolic parameter Unadjusted OR (95%CI) Adjusted OR (95%CI) Age 1.10 (1.02, 1.19) 1.10 (1.00, 1.20) Female 0.57 (0.17, 1.85) 1.18 (0.15, 9.08) SBP 1.54 (1.00, 2.35) 1.34 (0.70, 2.57) (unit=10) DBP 0.93 (0.45, 1.94) (unit=10) Diabetes 1.85 (0.38, 8.91) 0.80 (0.10, 6.28) Pre-diabetes 4.93 (1.23, 19.86) 3.01 (0.44, 20.53) GTT (0.92, 1.15) (unit=10) GTT (1.00, 1.07) Waist_cm 1.08 (0.85, 1.37) (unit=10) BMI 1.09 (1.00, 1.18) 1.09 (0.97, 1.21)