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Lipid Disorders and Their Management in Type 1 Diabetes Mellitus Robert H. Eckel, M.D. University of Colorado at Denver

Lipid Disorders and Their Management in Type 1 Diabetes Mellitus Robert H. Eckel, M.D. University of Colorado at Denver and Health Sciences Center Lipid Disorders and Their Management in Type 1 Diabetes Mellitus Lipid and lipoprotein metabolism in type 1 diabetes

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Lipid Disorders and Their Management in Type 1 Diabetes Mellitus Robert H. Eckel, M.D. University of Colorado at Denver

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  1. Lipid Disorders and Their Management in Type 1 Diabetes MellitusRobert H. Eckel, M.D.University of Colorado at Denver and Health Sciences Center

  2. Lipid Disorders and Their Management in Type 1 Diabetes Mellitus • Lipid and lipoprotein metabolism in type 1 diabetes • Relationship between lipids and lipoproteins and complications of type 1 diabetes • Management of lipid and lipoprotein disorders in type 1 diabetes

  3. Lipid Disorders and Their Management in Type 1 Diabetes Mellitus • Lipid and lipoprotein metabolism in type 1 diabetes • Relationship between lipids and lipoproteins and complications of type 1 diabetes • Management of lipid and lipoprotein disorders in type 1 diabetes

  4. Patients with Type 1 Diabetes in DCCT p Conventional Intensive Purnell, J.Q. et al Diabetes 44: 1220, 1995

  5. Lipid Levels Adjusted for Age and Waist/Hip Ratio in Male Type 1 Diabetic and Control Subjects: CACTI * p < 0.001 for all Wadwa P et al, Diabetes Care, In Press

  6. Lipid Levels Adjusted for Age and Waist/Hip Ratio in Female Type 1 and Control Subjects: CACTI * p < 0.01 for all Wadwa P et al, Diabetes Care, In Press

  7. Lipid and Lipoprotein Abnormalities in Type 1 Diabetes • Hypertriglyceridemia (VLDL, IDL, remnants, apo B) •  HDL cholesterol • Lipoprotein composition •  TG •  cholesterol/lecithin •  Lp(a) (renal disease) • Glycation/oxidation

  8. Cholesterol Metabolism in Type 1 Diabetes Miettinen TA et al, Diabetes Care 27:56, 2004

  9. Fractional Escape Rates of LDL and Albumin in Type 1 Diabetes and Controls Konnerup K et al, Atherosclerosis 170:163, 2003

  10. TG TG CE TG TG TG TG FC FC Extracellular Intracellular Apo A-1 Synthesis (liver, intestine) HDL2 Phospholipid (PL) Recycling CE rich HDL Free Cholesterol (FC) Synthesis FC SR-B1 mediated selective uptake of CE CE CE CE Lipid poor apo A1 FC FC Transfer of CE ABCA1 LDL FC + LCAT CE CE CE CE FC FC HDL3 CE CE FC CE Recyling from Lipoproteins FC Lipolysis Uptake by liver and other tissue Chol Ester (CE) Droplet FC Transfer of FC and PL Apo B VLDL

  11. HDL in Type 1 Diabetes HDL cholesterol is typically normal or increased in type 1 diabetes!

  12. * *p<0.001 * A-I/A-II Apolipoprotein Ratios in Men and Women with Type 1 Diabetes Men Women Eckel, RH et al. Diabetes 30:134-135, 1981

  13. Factors Related to Lipid and Lipoprotein Levels in Diabetes • Glycemia • Obesity • Diet (Quantity and Composition) • Route of insulin administration • Genetic hyperlipidemia • Drugs • Alcohol and cigarette smoking • Nephropathy (Proteinuria and CRF)

  14. Lipid Disorders and Their Management in Type 1 Diabetes Mellitus • Lipid and lipoprotein metabolism in type 1 diabetes • Relationship between lipids and lipoproteins and complications of type 1 diabetes • Management of lipid and lipoprotein disorders in type 1 diabetes

  15. Renal Disease, Lipids and Diabetes Mellitus • Microalbuminuria • Often indicates or predicts lipoprotein abnormalities • Gross proteinuria •  LDL,  HDL,  VLDL,  Lp(a) • CRF •  VLDL,  HDL,  Lp(a)

  16. Difference Plot for Lipoproteins: Type 1 Diabetics with Micro- vs Normoalbuminuria Sibley, S.D. et al, Diabetes Care 22:1167, 1999

  17. Difference Plot for Lipoproteins: Type 1 Diabetics with Macro- vs Normoalbuminuria Sibley, S.D. et al, Diabetes Care 22:1167, 1999

  18. Incidence of CHD in Type 1 Diabetes: Effect of Nephropathy Tuomilehto, J. et al, Diabetologia 41:786, 1998

  19. Incidence of Stroke in Type 1 Diabetes: Effect of Nephropathy Tuomilehto,J. et al, Diabetologia 41:786, 1998

  20. Don’t forget about lipids and lipoproteins in type 1 diabetes and their to retinopathy and nephropathy!

  21. What about lipid and lipoprotein metabolism and neuropathy in type 1 diabetes?

  22. Is LPL in the sciatic nerveaffected by diabetes?

  23. Male Sprague Dawley Rats STZ injection SQ (55 mg/Kg) Vehicle Sample nerve at different time points and measure LPL activity and mRNA and MNCV

  24. Plasma Glucose 30 20 Glucose (mM) 10 0 STZ Vehicle Ferreira LDMC-B et al, Endo 143:1213, 2002

  25. 1 0 Motor Nerve Conduction Velocity Measurement *, P<0.001 0 * 8 0 6 0 MNCV (m/sec) 4 0 2 0 0 Control STZ n=4 n=5 Ferreira LDMC-B et al, Endo 143:1213, 2002

  26. STZ 6 4 LPL 2 0 0 5 10 15 20 25 30 35 Days Sciatic Nerve LPL Activity * vs control, p<0.05 Vehicle (nmoles FFA/min/g) * * * * * Ferreira LDMC-B et al, Endo 143:1213, 2002

  27. Plasma Glucose vs Sciatic LPL Activity r=0.623 p<0.001 6 LPL activity (nmoles FFA/min/g) 4 2 0 0 10 20 30 Glucose (mM) Ferreira LDMC-B et al, Endo 143:1213, 2002

  28. Plasma Glucose 30 20 Glucose (mM) 10 0 Vehicle STZ + Ins STZ Ferreira LDMC-B et al, Endo 143:1213, 2002

  29. LPL Activity After Insulin Treatment * vs STZ, p<0.05 10 * LPL (nmoles FFA/min/g) * 5 0 STZ STZ + Ins Vehicle Ferreira LDMC-B et al, Endo 143:1213, 2002

  30. 7 * 6 5 LPL activity (nmoles FFA/min/g) 4 # * # * 3 2 1 0 Veh STZ Insulin Phloridzin # p<0.05 vs Insulin * p<0.05 vs Vehicle Is It Glucotoxicity or Insulin Deficiency?

  31. “With an excess of fat diabetes begins and from an excess of fat diabetics die . . .” EP Joslin, 1927

  32. Cumulative Coronary Artery Disease Mortality in Type 1 Diabetes Krolewski, A.S. et al, Am J Card 59:750, 1987

  33. Atherosclerosis and Type 1 Diabetes •  mortality • 9x in men, 14x in women • Associated with • age • duration of disease • nephropathy • hypertension • lipid abnormalities

  34.  Atherosclerosis in Type 1 Diabetes • Is it simply glucose? • AGES • Oxidative stress • Endothelial dysfunction? • Precursor • Associated pathophysiology • Hypertension? • Nephropathy • Genetics? • Metabolic syndrome? • Inflammation and pro-thrombotic state included

  35. Intensive Insulin Treatment and BMI: DCCT Purnell, J.Q. et al, JAMA 280:142, 1998

  36. Lipid Levels at Follow-up By Quartile of Weight Gain in Intensively Treated Individuals: DCCT Purnell, J.Q. et al, JAMA 280:142, 1998

  37. Lipoprotein Cholesterol Distribution after Intensive Insulinization : Effect of Change in BMI Purnell, J.Q. et al, JAMA 280:145, 1998

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