Triglyceride, nonesterified fatty acids, and prediabetic neuropathy: role for oxidative–nitrosative stress

• Published in: Free radical biology & medicine Vol. 52; no. 8; pp. 1255 - 1263
• Main Authors: Lupachyk, Sergey, Watcho, Pierre, Hasanova, Nailia, Julius, Ulrich, Obrosova, Irina G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.04.2012
• Subjects: Acipimox; Animals; antioxidants; behavior change; blood serum; Cells, Cultured; Dyslipidemia; Fatty Acids, Nonesterified - metabolism; free fatty acids; Free radicals; glucose; glucose tolerance; homeostasis; Human Schwann cells; humans; hypercholesterolemia; hyperglycemia; hyperinsulinemia; hypertriglyceridemia; insulin; insulin resistance; Insulin signaling; Male; metabolic syndrome; NAD(P)H oxidase; nerve tissue; niacin; Nitrosation; Nitrotyrosine; obesity; Oxidative Stress; Oxidative–nitrosative stress; peripheral nervous system diseases; Peripheral Nervous System Diseases - metabolism; Prediabetic neuropathy; Prediabetic State - metabolism; Rats; Rats, Zucker; Schwann cells; Superoxide; triacylglycerols; Triglycerides - metabolism; Zucker fatty (fa/fa) rat; Free radicals; IRS-1; Human Schwann cells; Dyslipidemia; IRβ; SNCV; Superoxide; Acipimox; NAD(P)H oxidase; MNCV; HDL; LDL; NEFA; VLDL; ROS; Prediabetic neuropathy; HSC; Zucker fatty (fa/fa) rat; Nitrotyrosine; Oxidative–nitrosative stress; Insulin signaling
• ISSN: 0891-5849; 1873-4596; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2012.01.029

Peripheral neuropathy develops in human subjects with prediabetes and metabolic syndrome before overt hyperglycemia. The contributions of impaired glucose tolerance and insulin signaling, hypertriglyceridemia and/or increased nonesterified fatty acids (NEFA), and hypercholesterolemia to this condition remain unknown. Niacin and its derivatives alleviate dyslipidemia with a minor effect on glucose homeostasis. This study evaluated the roles of impaired glucose tolerance versus dyslipidemia in prediabetic neuropathy using Zucker fatty (fa/fa) rats and the niacin derivative acipimox, as well as the interplay of hypertriglyceridemia, increased NEFA, and oxidative–nitrosative stress. Sixteen-week-old Zucker fatty rats with impaired glucose tolerance, obesity, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and increased NEFA displayed sensory nerve conduction velocity deficit, thermal and mechanical hypoalgesia, and tactile allodynia. Acipimox (100mgkg−1day−1, 4weeks) reduced serum insulin, NEFA, and triglyceride concentrations without affecting glucose tolerance and hypercholesterolemia. It alleviated sensory nerve conduction velocity deficit and changes in behavioral measures of sensory function and corrected oxidative–nitrosative stress, but not impaired insulin signaling, in peripheral nerve. Elevated NEFA increased total and mitochondrial superoxide production and NAD(P)H oxidase activity in cultured human Schwann cells. In conclusion, hypertriglyceridemia and/or increased NEFA concentrations cause prediabetic neuropathy through oxidative–nitrosative stress. Lipid-lowering agents and antioxidants may find a use in the management of this condition. ► Nonesterified fatty acids (NEFA) increase mitochondrial superoxide and NAD(P)H oxidase activity in human Schwann cells. ► Acipimox reduces triglycerides/NEFA and alleviates neuropathy in Zucker fatty rats. ► Hypertriglyceridemia and NEFA, but not glucose intolerance, cause prediabetic neuropathy. ► Lipid-lowering agents and antioxidants may find a use in the management of this condition.