Abstract
ABSTRACTPatients with metabolic syndrome, which is defined as obesity, dyslipidemia, hypertension and impaired glucose tolerance (IGT), can develop the same macro- and microvascular complications as patients with type 2 diabetes, including peripheral neuropathy. In type 2 diabetes, glycemic control has little effect on the development and progression of peripheral neuropathy, suggesting that other metabolic syndrome components may contribute to the presence of neuropathy. A parallel phenomenon is observed in patients with prediabetes and metabolic syndrome, where improvement in weight and dyslipidemia more closely correlates with restoration of nerve function than improvement in glycemic status. The goal of the current study was to develop a murine model that resembles the human condition. We examined longitudinal parameters of metabolic syndrome and neuropathy development in six mouse strains/genotypes (BKS-wt, BKS-Leprdb/+, B6-wt, B6-Leprdb/+, BTBR-wt, and BTBR-Lepob/+) fed a 54% high-fat diet (HFD; from lard). All mice fed a HFD developed large-fiber neuropathy and IGT. Changes appeared early and consistently in B6-wt mice, and paralleled the onset of neuropathy. At 36 weeks, B6-wt mice displayed all components of the metabolic syndrome, including obesity, IGT, hyperinsulinemia, dyslipidemia and oxidized low density lipoproteins (oxLDLs). Dietary reversal, whereby B6-wt mice fed a HFD from 4-20 weeks of age were switched to standard chow for 4 weeks, completely normalized neuropathy, promoted weight loss, improved insulin sensitivity, and restored LDL cholesterol and oxLDL by 50% compared with levels in HFD control mice. This dietary reversal model provides the basis for mechanistic studies investigating peripheral nerve damage in the setting of metabolic syndrome, and ultimately the development of mechanism-based therapies for neuropathy.
Highlights
The number of individuals with prediabetes and type 2 diabetes mellitus (T2DM) is increasing in parallel with the rise in obesity
Between 12 and 36 weeks, high-fat diet (HFD)-fed B6-wt and B6-Leprdb/+ mice were significantly heavier than mice fed a standard diet (Fig. 1A); on the BKS background, the Leprdb/+ mutation was required for HFD-induced obesity (Fig. 1B)
Area under the curve analyses (Fig. 1D-F) of longitudinal glucose tolerance testing (Fig. S1) revealed that HFD-fed mice exhibited varying degrees of impaired glucose tolerance between 12 and 24 weeks, all responses improved by 36 weeks
Summary
The number of individuals with prediabetes and type 2 diabetes mellitus (T2DM) is increasing in parallel with the rise in obesity. Received 4 November 2016; Accepted 30 March 2017 the United States, 35% of adults, and 17% of children and young adults, are obese and at risk of developing prediabetes (Ogden et al, 2014). Prediabetes is characterized by impaired glucose tolerance, and often develops into T2DM. Both prediabetes and T2DM are components of the metabolic syndrome, whose other risk factors include obesity, dyslipidemia and hypertension. Prediabetic patients largely develop the same macro- and microvascular complications as patients with T2DM, including neuropathy (Callaghan et al, 2012b,b). 10% of patients with prediabetes convert to T2DM (Tabák et al, 2012) with progression of existing, as well as new onset, complications. It is estimated that one-third of the 80 million Americans with prediabetes have neuropathy (Cortez et al, 2014), while the prevalence in the 30 million Americans with T2DM reaches 60% (Callaghan et al, 2015)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
