Expression of skin Glyoxalase-I, advanced glycation end products (AGEs) and receptor (RAGE) in patients with long-term type 1 diabetes and diabetic neuropathy.

Ahmed T. Alahmar^1,2, Ioannis N. Petropoulos^2,3, Maryam Ferdousi², Wendy Jones²,  Hassan Fadavi², Shazli Azmi²,   Uazman Alam²,  Omar Asghar², Aisha Meskiri², Ahmad Kheyami², Georgios  Ponirakis^2,3, Andrew  Marshall⁴, Andrew J.M. Boulton^2,5, Mitra Tavakoli², Maria Jeziorska², Rayaz A. Malik ^2,5

¹College of Pharmacy, University of Babylon, Iraq, ²Institute of Human Development, Centre for Endocrinology and Diabetes, University of Manchester, UK, ³Research division, Weill Cornell Medical College, Doha, Qatar, ⁴Department of Neurophysiology and ⁵Manchester Diabetes Centre, Central Manchester NHS Foundation Trust, Manchester, UK.

ABSTRACT

Background: Certain group of diabetic patients have been shown to remain free of diabetic complications despite having had diabetes for longer periods. Advanced glycation end products (AGEs), their receptor (RAGE) and Glyoxalase-I (GLO-I) have been implicated in the development of diabetic neuropathy. Objective: To assess the effect of long-term type 1 diabetes mellitus on skin distribution and expression of AGEs, RAGE and GLO-I and to correlate these expressions with measures of small and large nerve fibre damage. Methods: Sixty-seven patients with type 1 diabetes mellitus of shorter (<15 years, n=20), intermediate (15-40 years, n=25) and longer (>40 years, n=22) duration and 34 non-diabetic controls underwent diabetic neuropathy assessment: Neuropathy disability score (NDS), quantitative sensory testing (QST) including vibration pressure and thermal thresholds, nerve conduction studies (NCS), deep breathing heart rate variability (DB-HRV), corneal confocal microscopy (CCM) and intra-epidermal nerve fibre density (IENFD) and AGEs, RAGE and GLO-I expression in foot skin biopsies. Results: Compared to controls, type 1 diabetes mellitus patients showed progressively increased skin expression of AGEs, RAGE but progressively lower GLO-I expression with increasing duration of diabetes. Thus patients with longer-duration diabetes demonstrated significantly higher skin AGEs and RAGE but lower GLO-I expression than both shorter and intermediate-duration diabetic groups. In patients with longer-duration diabetes who developed diabetic neuropathy, the skin expression of AGEs and RAGE were significantly higher but GLO-I were significantly lower than those who did not develop diabetic neuropathy. These expressions also correlated with IENFD, CCM and NCS measures. Conclusion: Patients with type 1 diabetes mellitus showed progressively increased skin expression of AGEs, RAGE but progressively lower GLO-I expression with increasing duration of diabetes. Patients with longer-duration diabetes who developed diabetic neuropathy have significantly higher skin AGEs and RAGE and decreased GLO-I expression suggesting a potential role for these macromolecules as aetiological, marker of the disease as well as therapeutic target for diabetic neuropathy.

Keywords: Advanced glycation end products, diabetes mellitus, type 1, diabetic neuropathy, receptor for advanced glycation end products, GLO-I protein, human.

Correspondence: Ahmed T Alahmar, MBChB, MSc, College of Pharmacy, University of Babylon, Iraq. Tel: +9647808180900, Email: ahmed.t.alahmar@gmail.com

Brunei Int Med J. 2017; 13 (6): 180-193