Showing papers by "Garth J. S. Cooper published in 1992"

Amylin and insulin in rat soleus muscle: dose responses for cosecreted noncompetitive antagonists.

Abstract: Increasing concentrations of amylin progressively depressed the maximal insulin-stimulated radioglucose incorporation into soleus muscle glycogen, but did not substantively change the EC50 (range 0.78 to 1.52 nM); these findings show noncompetitive, insurmountable antagonism of insulin action by amylin. The results from 36 combinations of different insulin and amylin concentrations were used to construct a response surface that can be used to predict the response for any combination of insulin and amylin concentration. The predicted response to a constant ratio of insulin and amylin concentration is a bell-shaped curve. The experimentally determined response to increasing amounts of an amylin-insulin mixture (molar ratio of 0.14:1, within the range measured for pancreatic secretion and plasma levels) gave a bell-shaped response rather than the sigmoidal response seen with insulin alone. The amylin dose-response relation in the soleus system provides a useful bioassay for amylin agonists. The dose response for highly purified, synthetic human amylin obtained by measuring amylin concentrations by radioimmunoassay in the incubation medium gave an EC50 of 456 pM (+/- 0.18 log units). Human amylin had a potency greater than or equal to that of human insulin in this highly insulin-sensitive preparation.

Treatment of diabetes mellitus with amylin agonists

Abstract: Novel methods for treating diabetes mellitus and hyperglycemia are described which comprise administering to a diabetic or hypoglycemic subject an amount of an amylin agonist effective to induce amylin activity in said subject. Various amylin agonist compounds, and therapeutic methods utilizing such compounds, are also disclosed.

Treatment of insulin resistance

Abstract: Compounds and methods for blocking the effects of diabetes-associated peptide, or "amylin", a hormone found in the amyloid masses of Type 2 diabetics This putative hormone has been discovered to function both to inhibit insulin secretion and to inhibit glycogen synthesis Regulation is accomplished by blocking the binding of amylin or amylin agonists, including calcitonin gene related peptide (CGRP], or biologically active sub-peptides thereof Inhibitors include substituted peptides or sub-peptides of amylin or CGRP, cross-linked amylin and amylin agonists, synthetic amylin, anti-amylin receptor antibodies and anti-idiotype antibodies, and antibodies directed to amylin and amylin agonist active sites Other antagonists include organic compounds which can be screened and assayed for anti-amylin effects by disclosed methods

Amylin activity assays

Abstract: Methods are disclosed for use in identifying or assaying compounds which can inhibit or simulate the ability of amylin to cause hyperlactemia and/or hyperglycemia in in vivo biological models. Methods are also disclosed for use in evaluating the potency of compounds known or suspected to simulate either or both of these actions of amylin. The figure shows the plasma glucose response of rats infused with somatostatin plus amylin (open circle), with a peptide control (open square), or with phentolamine (open triangle).