Nephrectomy decreases amylin and pramlintide clearance in rats.

Amylin is a 37 amino acid hormone, co-secreted with insulin from the pancreatic beta-cell in response to nutrient stimuli. Because the human amylin analog, pramlintide, is being tested in patients with diabetes mellitus, a known risk factor for nephropathy, we examined the role of the kidney on amylin and pramlintide metabolism and action in functionally nephrectomized rats. Nephrectomy markedly altered amylin metabolism: it increased incremental area under the plasma amylin concentration curve 3.6-fold (P<0.001) and increased the elimination half-life from 17+/-1 to 26+/-2 minutes (P < 0.01) after subcutaneous injection of 100 microg amylin. Nephrectomy decreased plasma amylin clearance from 20.3+/-1.1 to 7.9+/-0.4 mL/min (P < 0.0001). Thus, at these doses in the rat, the kidney is important for metabolizing amylin and pramlintide.

Effects of rat amylin on renal function in the rat.

Amylin is a peptide secreted from the pancreatic beta-cell along with insulin in response to nutrient stimuli. Amylin has been reported to delay gastric emptying, inhibit glucagon secretion and gastric acid secretion, increase plasma lactate, plasma glucose and plasma renin activity, and decrease plasma calcium. Receptors for amylin have been found in the rat nucleus accumbens and the kidney. In the present experiments, amylin was administered to anesthetized rats by continuous intravenous infusions at varied rates. Amylin significantly increased urine flow at an infusion rate resulting in a plasma concentration of approximately 52 pM, and at a concentration of approximately 193 pM, it increased sodium excretion, glomerular filtration rate and renal plasma flow. Renal calcium and potassium excretion were significantly elevated at plasma amylin concentrations of approximately 52 pM and 193 pM, respectively. Higher concentrations of plasma amylin decreased plasma calcium and potassium and blunted urinary excretion of these electrolytes. Thus, of the renal responses tested, diuresis and natriuresis appeared to be the most sensitive to infused amylin. These renal effects occurred only at plasma concentrations above the normal range, but within the range of concentrations reported in insulin resistant rats.

Lactate production from the rat hindlimb is increased after glucose administration and is suppressed by a selective amylin antagonist: evidence for action of endogenous amylin in skeletal muscle.

By serially measuring blood flow and venous-arterial lactate differences across the hindlimb of the fasted anesthetized rat, we examined (1) whether exogenous amylin increased muscle lactate production in vivo, (2) whether glucose administration increased muscle lactate production, and (3), by using the selective amylin antagonist AC187 to block endogenous peptide, whether amylin secreted in response to glucose could mediate muscle lactate production. Abdominal aortic flow was unchanged by any treatment. Hindlimb lactate production was increased by both 100 micrograms s.c. amylin (4.0 +/- 0.4 cf 2.6 +/- 0.3 mumol/min after saline, P < 0.05) and by infusion of 2mmol D-glucose (3.0 +/- 0.2 cf 2.3 +/- 0.2 mumole/hr after saline, P < 0.03). The increase in hindlimb lactate production was prevented by infusion of AC187 (mean post-treatment venoarterial delta-lactate 140 +/- 11 microM; n.s. vs saline-treated delta-lactate 154 +/- 10 microM; P < 0.05 vs glucose-treated delta-lactate 201 +/- 14 microM). These findings are consistent with endogenous amylin secreted in response to a glucose challenge having acted at skeletal muscle to release lactate.