Homeostasis of β<sub>2</sub>-microglobulin in diabetics and non-diabetics with modest cadmium intoxication

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