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 (TDβ2M and Eβ2M). Diabetes may exacerbate these effects or produce them independently. Herein, we normalized fluxes to creatinine clearance (Ccr) to quantify amounts of β₂M excreted and degraded per volume of filtrate (Eβ2M/Ccr and TDβ2M/Ccr). We then performed a case-control study of diabetics (DM, n = 65) and non-diabetics (CTRL, n = 72) with modest Cd exposure. β₂M influx (Iβ2M, equated with β₂M filtration rate), serum β₂M ([β₂M]s), and TDβ2M/Ccr were higher in DM. Fractional tubular degradation of filtered β₂M (FrTDβ2M) emerged as the least confounded descriptor of PT β₂M processing, and low values of FrTDβ2M were seen in a subset of diabetics with minimal Cd intoxication. FrTDβ2M varied inversely with ECd/Ccr in DM and directly with estimated GFR (eGFR) in DM and CTRL. In both groups, Eβ2M/Ccr was inversely related to eGFR and FrTDβ2M, but at any value of FrTDβ2M, Eβ2M/Ccr varied by a large multiple. We conclude that in subjects with modest Cd intoxication, Iβ2M was variable in DM and CTRL and higher in DM; FrTDβ2M was related inversely to ECd/Ccr in DM and directly to eGFR in DM and CTRL; and Eβ2M/Ccr varied inversely with eGFR and FrTDβ2M in both groups. Eβ2M/Ccr did not depict FrTDβ2M precisely. We recommend FrTDβ2M as an indicator of proximal tubular dysfunction.