Insulin arginine

H. Schmidt, T.D. Warner, K. Ishii, H. Sheng, and F. Murad, Insulin-secretion from pancreatic B-cells caused by L-arginine derived nitrogen-oxides. Science 255, 721—723 (1992). 

A comprehensive, randomized, placebo-controlled trial of infused bolus L-arg and its enantiomer (D-arg) included healthy subjects, non-insulin dependent diabetics, hypertensive subjects, and normotensives with primary hypercholesterolemia [147]. A blood-pressure drop and an acute inhibition of ADP-induced aggregation in platelet-rich plasma were observed in all subjects after L-arg administration (<5 g). Both responses to L-arg infusion closely correlated in magnitude, were weaker in noninsulin dependent diabetics and hypercholesterolemics, and declined with increasing age. Notably, D-arg did not elicit any of the L-arg effects, which were reduced by some 70% when superimposed upon ongoing, nonselective NOS inhibition with infused L-N-monomethyl-arginine (L-NMMA). Since D-arg is not a NOS substrate, and L-NMMA is a substrate-competitive NOS inhibitor, the L-arg effects observed in this study were theorized to reflect a rise in vascular NO production by eNOS. In contrast, the inhibition of platelet aggregation observed in vitro after a 5 min L-arg infusion (160 mg total dose) into healthy subjects and patients with angiographic... 

In rats, infusion of the insulin secretagogues arginine and glucose induced a calciuria proportional to serum insulin levels. Suppression of insulin secretion by mannoheptulose or streptozotocin prevented the calciuria. Parathyroidectomy did not affect arginine-induced hypercalciuria in the rat, so insulin is not inhibiting parathyroid hormone secretion or activity. 

The importance of insulin as a mediator of the hypercalciuric effect of arginine infusion was also evident from studies conducted in chronically diabetic rats, where diabetes was induced by strepto-zotocin (23). Animals were injected with streptozotocin prior to arginine infusion 100 mg/kg i.p. was given on the seventh day before, followed by 25 mg/kg six days before the arginine infusion and renal clearance studies. In contrast to non-diabetic controls, diabetic animals did not increase their urinary calcium excreted (per ml glomerular filtrate) in response to the arginine infusion, nor did the arginine stimulate insulin secretion. 

The above experiments strongly suggest to us that a linear relationship exists between serum or plasma insulin levels over a wide physiological range, and urinary calcium excretion. The calciuric response to arginine or glucose infusion does not occur if insulin secretion is prevented, as evidenced by the data obtained from animals made acutely insulinopenic by mannoheptulose, or more chronically diabetic by streptozotocin. 

As anticipated, arginine infusion caused a large (221 percent) increase in calcium excretion in sham-operated animals. Parathyroidectomy had no effect on the calciuric response to arginine uri-ary calcium increases in PTX control and arginine-infused animals were 299 and 302 percent respectively. These results persisted when data were corrected for differences in GFR. The data illustrate that neither PTH activity nor secretion is involved in insulin impairment of renal calcium transport. 

Chromatographic or electrophoretic analysis of conventional insulins generally yields three major fractions or bands a, b and c). Fraction a contains high molecular mass material which can be removed from the product by additional recrystallization steps. The major components of fraction b are proinsulin and insulin dimers, while insulin, as well as slightly modified forms of insulin (e.g. arginine-insulin and desamido-insulin), are found in fraction c. 

The porcine insulin is first subjected to digestion with chymotrypsin-free trypsin at pH 7.5 for in excess of 45 min. This results in the selective cleavage of the peptide bond linking arginine 22... 

Jansson, L., and Sandler, S. (1991). The nitric oxide synthase II inhibitor N -nitro-L-arginine stimulates pancreatic islet insulin release in vitro, but not in the perfused pancrease. Endocrinology (Baltimore) 128, 3081-3085. 

Panagiotidis, G., Aim, P., and Lundquist, 1. (1992). Inhibition of islet nitric oxide synthase increases arginine-induced insulin release. Eur. J. Pharmacol. 229, 277-278. 

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