Effects of intensive insulin therapy alone and with added pioglitazone on renal salt/water balance and fluid compartment shifts in type 2 diabetes

Objective: To evaluate the effects of intensive insulin therapy alone or with added pioglitazone on renal salt/water balance and body fluid compartment shifts in type 2 diabetes. Methods: A total of 25 insulin-treated, obese patients with type 2 diabetes were randomized to pioglitazone 45 mg (n = 12) or placebo (n = 13) and treated intensively for 12-16 weeks to achieve equivalent glycaemic control. We measured total body water (TBW) and extracellular/intracellular fluid by bioimpedance analysis; plasma/RBC volume with I131albumin; sodium handling by fractional excretion of sodium/lithium (FeNa/FeLi) and other renal/hormonal parameters. Results: Intensification of insulin therapy and the addition of pioglitazone significantly improved glycaemia (HbA1C 7.8-7.2% and 7.6-7.1%) and increased body weight (1.7 and 4.9 kg) respectively. TBW increased 1.7 l with insulin alone (65% intracellular) and 1.6 l with added pioglitazone (75% extracellular) (p = 0.06 and 0.09 respectively). Plasma volume increased 0.2 +/- 0.1 l with insulin alone (p = 0.05) and 0.4 +/- 0.1 l with added pioglitazone (p < 0.05). Extravascular, extracellular (interstitial) fluid increased significantly and more with added pioglitazone (0.8 +/- 0.2 l, p < 0.01) than with insulin alone (0.4 +/- 0.2 l, p = ns). At steady-state, FeLi (marker of proximal-tubular sodium delivery to the distal nephron) increased significantly with added pioglitazone (12.4 +/- 1.3 to 18.0 +/- 3.2%) vs. no significant change with insulin alone (15.4 +/- 1.2 to 14.5 +/- 2.3%). There were no significant changes in the other parameters. Conclusion: In intensively insulin-treated obese type 2 diabetic patients, at equivalent glycaemic control, the addition of pioglitazone causes greater weight gain, but a similar increase in body water that is mainly extracellular and interstitial compared with intracellular increase with insulin therapy alone. Pioglitazone also increases the filtered load of sodium reabsorbed at the distal nephron with no net change in FeNa.