GLYOXALASE-1 INHIBITION LEADS TO DIABETIC KIDNEY DISEASE ASSOCIATED WITH PODOCYTE INSULIN RESISTANCE — ASN Events

GLYOXALASE-1 INHIBITION LEADS TO DIABETIC KIDNEY DISEASE ASSOCIATED WITH PODOCYTE INSULIN RESISTANCE (#93)

Linda A Gallo 1 , Brooke E Harcourt 1 , Amelia K Fotheringham 1 , Domenica A McCarthy 1 , Sally A Penfold 2 , Josephine M Forbes 1 3
  1. Mater Research Institute, University of Queensland, Woolloongabba, QLD, Australia
  2. Baker IDI, Melbourne, VIC, Australia
  3. Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia

Background:

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.

 

Methods:

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.

 

Results:

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.

 

Conclusions:

Alterations to the glyoxalase system in diabetes may contribute to renal impairment by adversely affecting podocyte insulin sensitivity.

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