Homeostasis of β₂-microglobulin in diabetics and non-diabetics with modest cadmium intoxication

Beta-2-microglobulin (β₂M) is released into plasma from nucleated cells, filtered by glomeruli, and degraded by proximal tubular cells (PTCs). Normally, < 1% of filtered β₂M is excreted in urine. Intoxication of PTCs by cadmium (Cd) reduces degradation and increases excretion of β₂M (TD_β2M and E_β2M). Diabetes may exacerbate these effects or produce them independently. Herein, we normalized fluxes to creatinine clearance (C_cr) to quantify amounts of β₂M excreted and degraded per volume of filtrate (E_β2M/C_cr and TD_β2M/C_cr). We then performed a case-control study of diabetics (DM, n = 65) and non-diabetics (CTRL, n = 72) with modest Cd exposure. β₂M influx (I_β2M, equated with β₂M filtration rate), serum β₂M ([β₂M]_s), and TD_β2M/C_cr were higher in DM. Fractional tubular degradation of filtered β₂M (FrTD_β2M) emerged as the least confounded descriptor of PT β₂M processing, and low values of FrTD_β2M were seen in a subset of diabetics with minimal Cd intoxication. FrTD_β2M varied inversely with E_Cd/C_cr in DM and directly with estimated GFR (eGFR) in DM and CTRL. In both groups, E_β2M/C_cr was inversely related to eGFR and FrTD_β2M, but at any value of FrTD_β2M, E_β2M/C_cr varied by a large multiple. We conclude that in subjects with modest Cd intoxication, I_β2M was variable in DM and CTRL and higher in DM; FrTD_β2M was related inversely to E_Cd/C_cr in DM and directly to eGFR in DM and CTRL; and E_β2M/C_cr varied inversely with eGFR and FrTD_β2M in both groups. E_β2M/C_crdid not depict FrTD_β2M precisely. We recommend FrTD_β2M as an indicator of proximal tubular dysfunction.