The plasma concentration of the reactive carbonyl, methylglyoxal (MGO), is elevated in diabetes. Increased accumulation of MGO may contribute to insulin resistance at peripheral sites of glucose uptake. A deficiency in podocyte insulin signalling impairs podocyte function resulting in kidney disease. Glyoxalase-1 (GLO-1) is an enzyme considered to detoxify MGO. Hence, we examined the effects of inhibiting GLO-1 on podocyte insulin signalling and renal function under diabetic conditions.
Human podocytes were exposed to a GLO-1 inhibitor under normal and diabetic-like conditions. Insulin sensitivity and glucose uptake were assessed using pAKT/AKT and membranous GLUT4 protein expression. Male db/db mice (reminiscent of human type 2 diabetes) and db/H control mice were administered with a GLO-1 inhibitor on alternate days from weeks 6 to 9 of life (50mg/kg body weight) and renal function and glycaemic control were assessed.
Human podocytes exposed to an inhibitor of GLO-1 showed reduced insulin signalling with lower pAKT/AKT ratios and GLUT4 membrane translocation. In the db/db mouse, serum cystatin C was elevated at 9 weeks, and this was exacerbated with GLO-1 inhibition. However, peripheral insulin sensitivity was not affected by GLO-1 inhibition. Decreased insulin signalling and expression of GLUT4 in human podocytes exposed to an inhibitor of GLO-1 were consistent with the degree of renal dysfunction in mice.
Alterations to the glyoxalase system in diabetes may contribute to renal impairment by adversely affecting podocyte insulin sensitivity.