Glucagon-Like Peptide 1, Insulin, Sensory Neurons, and Diabetic Neuropathy

Abstract

Like insulin, glucagon-like peptide 1 (GLP-1) may have direct trophic actions on the nervous system, but its potential role in supporting diabetic sensory neurons is uncertain. We identified wide expression of GLP-1 receptors on dorsal root ganglia sensory neurons of diabetic and nondiabetic mice. Exendin-4, a GLP-1 agonist, increased neurite outgrowth of adult sensory neurons in vitro. To determine the effects ofexendin-4 in comparison with continuous low- or high-dose insulin in vivo, we evaluated parallel cohorts of type 1 (streptozotocin-induced) and type 2 (db/db) mice of 2 months' diabetes duration with established neuropathy during an additional month of treatment. High-dose insulin alone reversed hyperglycemia in type 1 diabetic mice, partly reversed thermal sensory loss, improved epidermal innervation but failed to reverse electrophysiological abnormalities. Exendin-4 improved both sensory electrophysiology and behavioral sensory loss. Low-dose insulin was ineffective. In type 2 diabetes, hyperglycemia was uncorrected, and neither insulin nor exendin-4 reversed sensory electrophysiology, sensory behavior, or loss of epidermal axons. However, exendin-4 alone improved motor electrophysiology. Receptor for advanced glycosylated end products and nuclear factor-κB neuronal expression were not significantly altered by diabetes or treatment. Taken together, these results suggest that although GLP-1 agonists and insulin alone are insufficient to reverse all features of diabetic neuropathy, in combination, they might benefit some aspects of established diabetic neuropathy.

Neurotrophic and neuroprotective properties of exendin-4 in adult rat dorsal root ganglion neurons: involvement of insulin and RhoA

“…2b). Consistently, GLP-1R immunoreactivity spread throughout the cytoplasm of neurons in DRG sections in the previous (Himeno et al 2011;Kan et al 2012) and present studies (Fig. 1).…”

“…To minimize the effects of known and unknown neurotrophic molecules that were in the serum, we maintained DRG neurons in nominally serum-free medium in the presence [insulin(+)] or absence of insulin [insulin(−)]. In agreement with previous studies (Himeno et al 2011;Kan et al 2012), the treatment with Ex-4 enhanced neurite outgrowth from DRG neurons in a dose-dependent manner. After 2 days in culture, 10 and 100 nM of Ex-4 significantly increased the average number of neurite-bearing cells under the insulin(−) condition and the average neurite length under both insulin(+) and insulin(−) conditions (Figs.…”

“…Exendin (Ex)-4, a 39-amino-acid peptide, shows bioactivities that are almost identical to GLP-1 and a substantially longer plasma half-life because of its resistance to DPP-IV. Ex-4 has been shown to restore the neurological abnormalities of streptozotocin (STZ)-induced diabetic mice and rats without lowering blood glucose levels (Himeno et al 2011;Jolivalt et al 2011;Liu et al 2011;Kan et al 2012). These findings provide further evidence of the direct actions of Ex-4 on the peripheral nervous system; however, the underlying mechanisms remain unclear.…”

“…These findings imply the potential efficacy of Ex-4 and other GLP-1R agonists on the acceleration of functional repair after axonal injury (Yamamoto et al 2013). Although other studies have already demonstrated the neurite outgrowth-promoting activities of Ex-4 in adult rodent DRG neurons (Himeno et al 2011;Kan et al 2012), they have not determined the underlying mechanisms. In the present study, the treatment of DRG neurons with 100 nM Ex-4 under insulin-deprived conditions significantly upregulated the number of viable neurons and neurite-bearing cells to the extent of those in the control group under insulin-supplemented conditions.…”

Effects of Epalrestat as Aldose Reductase Inhibitor (ARI), Sitagliptin as Incretin-Based Therapy (IBT), or Combined Epalrestat and Sitagliptin on Cardiac Vagal Neuropathy (CVN) in Patients with Type 2 Diabetic Mellitus

“…In such fibers, PN is due to decreased activities of Na+/ K+-ATPase, myoinositol, diacylglycerol, and protein kinase C via attenuation of cAMP levels [12][13] by the polyol pathway [9][10][12][13], Wnt pathway [35][36] or other causes [3,[14][15][16][17][18][20][21][37][38][39][40]. Both GLP-1 receptors were detected in DRG [18] and in Schwann cells [38], and GIP receptors were detected in Purkinje cells [39] and have a neurite outgrowth of the nerve fibers via a promoter of nerve growth factor [14,16], as well as a significant role in increasing the activity of Na+/K+-ATPase [38] by phosphorylation through signalregulated kinase levels [38] and by the Wnt pathway [36] via cyclic AMP in the fibers, which protects the structure and function of the nerve fibers [13,16,19].…”