t0901317 and Diabetes-Mellitus--Type-1

Diabetes triggers peripheral nerve alterations at a structural and functional level, collectively referred to as diabetic peripheral neuropathy (DPN). This work highlights the role of the liver X receptor (LXR) signaling pathway and the cross talk with the reactive oxygen species (ROS)-producing enzyme NADPH oxidase-4 (Nox4) in the pathogenesis of DPN. Using type 1 diabetic (T1DM) mouse models together with cultured Schwann cells (SCs) and skin biopsies from patients with type 2 diabetes (T2DM), we revealed the implication of LXR and Nox4 in the pathophysiology of DPN. T1DM animals exhibit neurophysiological defects and sensorimotor abnormalities paralleled by defective peripheral myelin gene expression. These alterations were concomitant with a significant reduction in LXR expression and increase in Nox4 expression and activity in SCs and peripheral nerves, which were further verified in skin biopsies of patients with T2DM. Moreover, targeted activation of LXR or specific inhibition of Nox4 in vivo and in vitro to attenuate diabetes-induced ROS production in SCs and peripheral nerves reverses functional alteration of the peripheral nerves and restores the homeostatic profiles of MPZ and PMP22. Taken together, our findings are the first to identify novel, key mediators in the pathogenesis of DPN and suggest that targeting LXR/Nox4 axis is a promising therapeutic approach.

Topics: Aged; Aged, 80 and over; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Humans; Hydrocarbons, Fluorinated; Liver X Receptors; Male; Mice; Myelin Proteins; NADPH Oxidase 4; Pyrazoles; Pyrazolones; Pyridines; Pyridones; Reactive Oxygen Species; Schwann Cells; Signal Transduction; Sulfonamides

Activation of liver X receptors (LXRs) can improve glucose tolerance in insulin-independent diabetes, however, whether similar effects can be achieved in insulin-dependent diabetes remains unclear. Here, we evaluated the anti-diabetic activity of T0901317, a potent agonist of LXRs, in diabetic mice induced by streptozotocin, and our data demonstrate that T0901317 is most effective when combined with cold treatment of animals. Treatment with T0901317 improved glucose tolerance of diabetic mice, which was associated with repressed expression of key genes involved in hepatic gluconeogenesis such as Pepck and G6p. Combined treatment by T0901317 and cold exposure reduced transcription of gluconeogenic genes to similar levels. Intriguingly, combined treatment greatly increased expression of Ucp1, Cidea, Dio2, and Elvol3 predominantly in the inguinal white adipose tissue, consequently leading to browning of this fat pad, and resulting in further improvement of glucose tolerance which was associated with increased protein levels of UCP1 and GLUT4. Collectively, these results suggest that browning of white adipose tissue via cold exposure in combination with activation of liver X receptors is an alternative and effective strategy to manage insulin-dependent diabetes.

Topics: Adipose Tissue, White; Animals; Cold Temperature; Combined Modality Therapy; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Gene Expression Regulation; Glucose Tolerance Test; Hydrocarbons, Fluorinated; Hypoglycemic Agents; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Orphan Nuclear Receptors; Streptozocin; Sulfonamides