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Diabetes. 2015 Sep;64(9):3294-304. doi: 10.2337/db15-0133. Epub 2015 May 15.

The Metabolic Syndrome and Microvascular Complications in a Murine Model of Type 2 Diabetes.

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Department of Neurology, University of Michigan, Ann Arbor, MI Department of Basic Sciences, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND.
Department of Neurology, University of Michigan, Ann Arbor, MI.
Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.
Department of Neurology, University of Michigan, Ann Arbor, MI


To define the components of the metabolic syndrome that contribute to diabetic polyneuropathy (DPN) in type 2 diabetes mellitus (T2DM), we treated the BKS db/db mouse, an established murine model of T2DM and the metabolic syndrome, with the thiazolidinedione class drug pioglitazone. Pioglitazone treatment of BKS db/db mice produced a significant weight gain, restored glycemic control, and normalized measures of serum oxidative stress and triglycerides but had no effect on LDLs or total cholesterol. Moreover, although pioglitazone treatment normalized renal function, it had no effect on measures of large myelinated nerve fibers, specifically sural or sciatic nerve conduction velocities, but significantly improved measures of small unmyelinated nerve fiber architecture and function. Analyses of gene expression arrays of large myelinated sciatic nerves from pioglitazone-treated animals revealed an unanticipated increase in genes related to adipogenesis, adipokine signaling, and lipoprotein signaling, which likely contributed to the blunted therapeutic response. Similar analyses of dorsal root ganglion neurons revealed a salutary effect of pioglitazone on pathways related to defense and cytokine production. These data suggest differential susceptibility of small and large nerve fibers to specific metabolic impairments associated with T2DM and provide the basis for discussion of new treatment paradigms for individuals with T2DM and DPN.

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