Carbamylation is a competitor of glycation for protein modification in vivo

Diabetes Metab. 2018 Mar;44(2):160-167. doi: 10.1016/j.diabet.2017.05.006. Epub 2017 Jul 8.

Abstract

Aim: Chronic kidney disease (CKD) and diabetes mellitus are two diseases that accelerate protein molecular ageing through carbamylation and glycation reactions, characterized by the binding of urea-derived isocyanic acid and of sugars on proteins, respectively. These two reactions target the same protein amino groups and, thus, compete with each other. Such competition may arise especially in diabetic patients with nephropathy. This study aimed to evaluate their potential competitive effects in vitro and under conditions reproducing CKD and/or diabetes in vivo.

Methods: Albumin was incubated in vitro with glucose, urea or cyanate. Carbamylation in vivo was enhanced in normal and diabetic (db/db) mice by either subtotal nephrectomy or cyanate consumption. Homocitrulline, carbamylated haemoglobin and furosine were measured by LC-MS/MS, fructosamine by colorimetric assay and HbA1c by immunological assay.

Results: Reciprocal inhibition between carbamylation and glycation was observed during albumin incubations in vitro. Besides, 5 weeks after induction of CKD in vivo, plasma homocitrulline concentrations were similar in both diabetic and non-diabetic mice, whereas fructosamine and HbA1c were decreased (-23% and -42%, respectively) in diabetic mice with CKD compared with only diabetic ones. Fructosamine and HbA1c were also decreased in cyanate-spiked water-drinking mice compared with plain water-drinking diabetic mice.

Conclusion: Carbamylation competes with glycation in vivo, especially under conditions of high glycation. Thus, the classic markers of glycaemic control should be interpreted with caution in diabetic patients with CKD because of this competitive effect.

Keywords: Carbamylation; Chronic kidney disease; Competition; Diabetes mellitus; Glycation; HbA(1c).

MeSH terms

  • Albumins / chemistry
  • Albumins / metabolism
  • Animals
  • Blood Glucose / chemistry
  • Blood Glucose / metabolism*
  • Blood Proteins / chemistry*
  • Blood Proteins / metabolism*
  • Carbamates / chemistry
  • Carbamates / metabolism*
  • Cyanates
  • Diabetes Mellitus, Experimental / metabolism*
  • Fructosamine / metabolism
  • Glycosylation
  • Male
  • Mice
  • Mice, Inbred NOD
  • Renal Insufficiency, Chronic / metabolism*
  • Urea / metabolism

Substances

  • Albumins
  • Blood Glucose
  • Blood Proteins
  • Carbamates
  • Cyanates
  • Fructosamine
  • Urea
  • carbamic acid
  • isocyanic acid