Sodium-retaining effect of insulin in diabetes

Abstract

Insulin has long been hypothesized to cause sodium retention, potentially of enough magnitude to contribute to hypertension in obesity, metabolic syndrome, and Type II diabetes. There is an abundance of supportive evidence from correlational analyses in humans, acute insulin infusion studies in humans and animals, and chronic insulin infusion studies in rats. However, the absence of hypertension in human insulinoma patients, and negative results for sodium-retaining or blood pressure effects of chronic insulin infusion in a whole series of dog studies, strongly refute the insulin hypothesis. We recently questioned whether the euglycemic, hyperinsulinemia model used for most insulin infusion studies, including the previous chronic dog studies, was the most appropriate model to test the renal actions of insulin in obesity, metabolic syndrome, and Type II diabetes. In those circumstances, hyperinsulinemia coexists with hyperglycemia. Therefore, we tested the sodium-retaining effect of insulin in chronically instrumented, alloxan-treated diabetic dogs. We used 24 h/day intravenous insulin infusion to regulate plasma insulin concentration. Induction of diabetes (∼400 mg/dl) caused sustained natriuresis and diuresis. However, if we clamped insulin at baseline, control levels, i.e., prevented it from decreasing, then the sustained natriuresis and diuresis were completely reversed, despite the same level of hyperglycemia. We also found that 24 h/day intrarenal insulin infusion had the same effect in diabetic dogs but had no sodium-retaining action in normal dogs. This new evidence that insulin has a sodium-retaining effect during hyperglycemia may have implications for maintaining sodium balance in uncontrolled Type II diabetes.

Fig. 1.

Mean arterial pressure (top) and urinary sodium excretion (bottom) in chronically instrumented rats during 3 control days (C) and 5 days of insulin+glucose infusion (I). Redrawn from Brands et al. (18).

Fig. 2.

Insulin infusion dose (top) and blood glucose (bottom) in chronically instrumented, alloxan (Allox)-treated dogs during 3 control days (C), 6 days of Type I diabetes (D), and 3 recovery days (R). Redrawn from Manhiani et al. (61).

Fig. 3.

Insulin infusion dose (top) and blood glucose (bottom) in chronically instrumented, Allox-treated dogs during 3 control days (C), 6 days of glucose-infusion-induced diabetes (D), and 3 recovery days (R). Redrawn from Manhiani et al. (61).

Fig. 4.

Urinary sodium excretion in chronically instrumented, Allox-treated dogs during 3 control days (C), 6 days of diabetes (D) induced either by lowering the insulin infusion dose (top) or by infusing glucose intravenously (bottom), and 3 days of recovery (R). Redrawn from Manhiani et al. (61).

Fig. 5.

Urinary sodium excretion in chronically instrumented, Allox-treated dogs during 4 control days (C), 6 days of diabetes with (IR, bottom) or without (D, top) intra-renal insulin infusion, and 4 recovery days (R). Redrawn from Manhiani et al. (62).

Fig. 6.

Urine volume in chronically instrumented, Allox-treated dogs during 4 control days (C), 6 days of diabetes with (IR, bottom) or without (D, top) intrarenal insulin infusion, and 4 recovery days (R). Redrawn from Manhiani et al. (62).

Fig. 7.

Urinary sodium excretion in normal dogs during 4 control days (C), 6 days of intrarenal infusion of glucose+insulin (GI), and 5 recovery days (R). Redrawn from Manhiani et al. (62).

Fig. 8.

Hypothesis for physiological regulation of sodium balance in uncontrolled Type II diabetes. The natriuretic effect of hyperglycemia and glycosuria is counterbalanced in part by epithelial sodium channel (ENaC)-mediated sodium reabsorption, which is stimulated by additive effects of aldosterone and combined actions of hyperinsulinemia and hyperglycemia. UNaV, urinary sodium excretion; MR, mineralocorticoid receptor.