Correction of Metabolic Acidosis Ameliorates Insulin, Branched-Chain Amino Acid and Lipid Abnormalities in Uremia through a 1,25 Vitamin D₃ Associated Mechanism

Abstract 1974 Poster Session II, Sunday, 5/2 (poster 167)

Metabolic acidosis affects both 1,25 vitamin D₃[(OH)₂D₃] and insulin metabolism. I have previously shown that 1,25(OH)₂D₃ is important in modulation of both insulin sensitivity and secretion in uremia (Kidney Int 53:1353-57, 1998). Insulin resistance has been associated with branched-chain amino acid and lipid abnormalities in uremia. The effect of metabolic acidosis on 1,25(OH)₂D₃, insulin, branched-chain amino acid and lipid metabolism was examined in patients with uremia in the present study. Eight patients (18±1 y) on maintenance hemodialysis with metabolic acidosis were studied before and after 2 weeks of oral sodium bicarbonate(NaHCO₃)(3 mEq/kg/day) to correct acidosis. To control for the effect of additional sodium, they were also studied after 2 weeks of equivalent amounts of oral sodium chloride(NaCl)(3 mEq/kg/day). The order of the treatment periods was randomized so that 4 patients were treated with NaHCO₃ first before crossing over to NaCl and vice versa in the other 4 patients. Controls consisted of 7 healthy volunteers (19±1 y). Before treatment, patients had low venous pH(7.27±0.01), low serum HCO3(16±2 mEq/dl), low serum 1,25(OH)₂D₃(13±1 ρg/ml) and high serum PTH(733±80 pg/ml) levels compared with controls (p<0.01 in all cases). Oral NaHCO₃ led to significant increases in venous pH(7.37±0.01), serum HCO₃(24±2 mEq/dl) and serum 1,25(OH)₂D₃(20±3 ρg/ml) (p<0.01 in all cases) but no change in serum PTH(728±78 ρg/ml). Serum 1,25(OH)₂D₃ increased from about 33% to 50% of control values (40±3 pg/ml). Insulin sensitivity was measured by the hyperinsulinemic euglycemic clamp technique and insulin secretion was measured by the hyperglycemic clamp technique. Patients had low insulin sensitivity(insulin resistance) and low insulin secretion(hypoinsulinemia) whilst acidotic. Oral NaHCO₃ led to significant increases both in insulin sensitivity(p<0.01) and insulin secretion(p<0.01). Serum branched-chain amino acids (leucine and valine) were low in patients whilst acidotic (p<0.01 compared with controls in both cases) and increased(p<0.01 in both cases) after NaHCO₃. Serum triglycerides were elevated and high density lipoprotein (HDL) cholesterol was low but total cholesterol was normal in patients whilst acidotic. There was a significant decrease in serum triglycerides (p<0.01) but no change in HDL cholesterol and total cholesterol after NaHCO₃ treatment. There were no changes in any of the metabolic parameters (including insulin sensitivity, insulin secretion, branched-chain amino acids and lipids) after oral NaCl treatment compared with baseline acidotic values. Thus treatment of acidosis ameliorated insulin resistance and hypoinsulinemia as well as abnormalities in branched-chain amino acids and triglycerides in patients with uremia on hemodialysis. This was accompanied by an increase in serum 1,25(OH)₂D₃ but no change in serum PTH. Thus metabolic acidosis may play a role in the pathogenesis of insulin, branched-chain amino acid and lipid abnormalities in uremia through a 1,25(OH)₂D₃ associated mechanism.