Potassium Loss Promotes Impairments in Insulin Sensitivity in Rats

Abstract

Clinical observations have associated potassium (K+) wasting with metabolic syndrome and insulin resistance. Chronic alkali ingestion can lead to K+ wasting. The alkali sodium bicarbonate (NaHCO3) is now used commonly in chronic kidney disease (CKD) patients to slow renal functional decline, even in patients without metabolic acidosis. Whether chronic ingestion of alkali like NaHCO3 promotes K+ wasting and loss of insulin sensitivity in CKD remains unknown. We hypothesized that chronic NaHCO3 treatment leads to K+ wasting and impairs insulin sensitivity in a rat model of CKD. To test our hypothesis, 12 male, 12 week old Sprague Dawley (SD) rats underwent a 2/3 nephrectomy and were given 4 weeks to recover prior to being placed on either 0.1M NaHCO3 (n=6) or maintained on tap water (n=6) for 4 weeks. After 4 weeks, rats were given hydrochlorothiazide (HCTZ, 10 mg/kg/day) in the drinking water to promote additional K+ wasting in combination with NaHCO3 or tap water for another 4 weeks. Animals underwent insulin tolerance tests (ITT; 0.75 U/kg insulin i.v.) at 4 and 8 week time points. At the conclusion of the protocol, rats were sacrificed, a terminal blood gas measurement taken, and the remaining remnant kidney harvested. Following 4 weeks of NaHCO3 or tap water there was no difference in the blood glucose response to insulin or in the magnitude of the fall in blood glucose (inverse area under the curve (AUC)) in response to insulin. However, following HCTZ treatment, NaHCO3 treated rats were less sensitive to insulin compared to tap water treated rats (Two-way ANOVA, PRxGroup=0.0005, PTime<0.0001, PInteraction=0.17) and had a smaller AUC (NaHCO3 + HCTZ 1688 ± 815 vs tap water + HCTZ 4002 ± 774; unpaired t-test, p=0.06). To determine if K+ depletion could account for the loss of insulin sensitivity, we placed animals on a low K+ diet for 1 week to deplete total body K+ and then determined insulin sensitivity. 6 naïve male, 10 week old SD rats underwent a baseline ITT and an ITT after 1 week of low K+ diet (0K). There was a significant decrease in plasma K+ (baseline 3.55 ± 0.21 vs 0K 2.71 ± 0.29; paired t-test, p=0.01) and a significant effect of diet and time on the blood glucose response to insulin following dietary K+ restriction (RM Two-way ANOVA, PDiet=0.0004, PTime<0.0001, PInteraction=0.70, PSubjects=0.04). At baseline, fasted blood glucose was 144 ± 9.27 mg/dL and fell to its lowest point of 100 ± 7.05 mg/dL at 60 minutes (min), gradually recovering to 132 ± 4.95 mg/dL by end of study (120 min). In contrast, after 1 week of dietary K+ restriction, fasted blood glucose was 151 ± 5.13 mg/dL and fell to its lowest point of 112 ± 6.15 mg/dL by 40 min and recovered to 142 ± 5.30 mg/dL at 80 min, a level that was sustained until the end of the study. In conjunction with a thiazide, chronic NaHCO3 treatment results in reduced insulin sensitivity in rats. K+ depletion with dietary K+ restriction also results in loss of insulin sensitivity in rats. These data strongly implicate K+ wasting as the cause of reduced insulin sensitivity. These findings suggest that K+ wasting may be a cause of insulin resistance and underscore the importance of access to dietary K+, even for patients with CKD. CKD patients treated with NaHCO3 may be at increased risk due to the K+ wasting effects of alkali, particularly those without prior metabolic acidosis.