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Diabetic peripheral neuropathy and serum cholesterol– is lower necessarily better?

22nd June 2019, Dr Chee L Khoo

Distal polyneuropathy (DPN) is one of the more severe complications of diabetes. The exact pathologic metabolic process of DPN is still uncertain but it is more common in patients with type 2 diabetes (T2DM) than in patients with type 1 diabetes (T1DM) even after adjusting for glucose levels. Thus, in addition to hyperglycaemia, other factors could be involved in the development of DPN such as obesity, hypertension, dyslipidaemia and renal impairment. While high cholesterol may be implicated in the development of the neuropathy, cholesterol is required by axons, neuritic tips and Schwann cells in the repair process. Lowering cholesterol levels logically should reduce further deterioration of DPN but does it? Will aggressive reduction of cholesterol levels affect the healing and repair of the damaged nerve structures?

The evidence as to whether high or low cholesterol is beneficial in DPN is conflicting. There are studies which show that lowering cholesterol and LDL-cholesterol levels slows the progression of DPN (1,2). Yet, there are also studies which shows that intake of statins and a decrease of serum cholesterol level are associated with neuropathic symptoms, microvascular damage, and an accelerated deterioration of peripheral nerve fibres (3-7).

Magnetic resonance neurography (MRN) is a non-invasive method that allows for an exact qualitative and quantitative analysis of nerve damage in different neuropathies. In a recent first, MRN was used to investigate the association between serum cholesterol levels and peripheral nerve lesions in patients with T2DM with and without DPN (8). 100 participants with T2DM with or without DPN underwent MRN to assess the cross-sectional area of the sciatic nerve and to calculate the volume and extent of the lipid-equivalent nerve lesions present.  Electrophysiological examinations were conducted to measure the nerve conduction velocity, compound motor action potentials and sensory nerve action potential of the tibial, peroneal, and sural nerves.

They found that low levels of total serum cholesterol and LDL-C were associated with a higher load of lipid-equivalent nerve lesions (LEL) and with impaired nerve conduction and an increasing severity of a patient’s clinical symptoms. LELs occurred independently from other risk factors, such as elevated HbA1c levels, renal function outcomes, patient’s age, BMI, or disease duration. In other words, lowering serum cholesterol levels in patients with T2D and DPN is associated with a higher amount of nerve lesions and declining nerve conduction velocities and amplitudes.

It is thought that perhaps lowering serum cholesterol levels impairs peripheral nerve regeneration because cholesterol cannot be produced in axons and therefore has to be supplied to neurite tips and adjacent Schwann cells of regenerating axons by either axonal transport or external supply via HDL-C and LDL-C (8-11).

Reducing serum cholesterol and LDL-cholesterol levels have other cardiovascular benefits. While the jury is still out on whether lowering or maintaining cholesterol and LDL-cholesterol levels is beneficial for DPN, we should be vigilant about deterioration of neuropathic symptoms when we reduce cholesterol and/or LDL-cholesterol in our patients with diabetes and DPN.

Access the abstract here.

Reference:

  1. Perez-Matos MC, Morales-Alvarez MC, Mendivil CO. Lipids: a suitable therapeutic target in diabetic neuropathy? J Diabetes Res. 2017;2017:6943851. doi:10.1155/2017/6943851
  2. Román-Pintos LM, Villegas-Rivera G, Rodríguez-Carrizalez AD, Miranda-Díaz AG, Cardona-Muñoz EG. Diabetic polyneuropathy in type 2 diabetes mellitus: inflammation, oxidative stress, and mitochondrial function. J Diabetes Res. 2016;2016:3425617. doi:10.1155/2016/3425617
  3. Gaist D, Jeppesen U, Andersen M, García Rodríguez LA, Hallas J, Sindrup SH. Statins and risk of polyneuropathy: a case-control study. Neurology. 2002;58(9):1333-1337. Doi:10.1212/WNL.58.9.1333
  4. Novak P, Pimentel DA, Sundar B, Moonis M, Qin L, Novak V. Association of statins with sensory and autonomic ganglionopathy. Front Aging Neurosci. 2015;7:191. doi:10.3389/fnagi.2015.00191
  5. Hermans MP, Ahn SA, Rousseau MF. The mixed benefit of low lipoprotein(a) in type 2 diabetes. Lipids Health Dis. 2017;16(1):171. doi:10.1186/s12944-017-0564-9
  6. Koslik HJ,Meskimen AH, Golomb BA. Physicians’ experiences as patients with statin side effects: a case series. Drug Saf Case Rep. 2017;4(1):3. doi:10.1007/s40800-017-0045-0
  7. Andersen ST, Witte DR, Dalsgaard E-M, et al. Risk factors for incident diabetic polyneuropathy in a cohort with screen-detected type 2 diabetes followed for 13 years: ADDITION-Denmark. Diabetes Care. 2018;41(5): 1068-1075. doi:10.2337/dc17-2062
  8. Johann M. E. Jende, MD; Jan B. Groener, MD; Christian Rother, et al. Association of Serum Cholesterol Levels With Peripheral Nerve Damage in Patients With Type 2 Diabetes. JAMA Network Open. 2019;2(5):e194798. doi:10.1001/jamanetworkopen.2019.4798
  9. de Chaves EI, Rusiñol AE, Vance DE, Campenot RB, Vance JE. Role of lipoproteins in the delivery of lipids to axons during axonal regeneration. J Biol Chem. 1997;272(49):30766-30773. doi:10.1074/jbc.272.49.30766
  10. Vance JE, Campenot RB, Vance DE. The synthesis and transport of lipids for axonal growth and nerve regeneration. Biochim Biophys Acta. 2000;1486(1):84-96. doi:10.1016/S1388-1981(00)00050-0
  11. Tuck E, Cavalli V. Roles of membrane trafficking in nerve repair and regeneration. Commun Integr Biol. 2010;3 (3):209-214. doi:10.4161/cib.3.3.11555
  12. Saher G, Quintes S, Nave K-A. Cholesterol: a novel regulatory role in myelin formation. Neuroscientist. 2011;17 (1):79-93. doi:10.1177/1073858410373835

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