Abstract
Glucagon is a crucial hormone in glucose homeostasis and hence has great potential for application to research which seeks to understand its role in normal and diabetic states. Furthermore, antagonists of glucagon, acting at the glucagon receptor, have numerous applications for studying glucagons role in various physiological functions, and as a potential drug for the treatment of diabetes and diabetic syndromes. In this paper we will discuss research done over the last decade or so which has led to development of 1) the first pure glucagon receptor antagonists which have no partial agonist activity even at high concentrations and under conditions where the cAMP signal is greatly enhanced; 2) systematic studies of glucagon structure-function which have greatly extended our knowledge of those amino acids in glucagon which are most responsible for high affinity binding; 3) residues most important for agonist and for antagonist biological activities; 4) the first highly truncated analogues of glucagon which possess high affinity for the glucagon receptor and are antagonists; 5) cyclic analogues of glucagon which provide insight in the role of α-helix and β-turn structures in the binding affinity of glucagon to its receptor; 6) the first glucagon analogues with subnanomolar binding at the glucagon receptor; and 7) insights into those stereostructural properties which are different in agonist and antagonist analogues. We also discuss conformational studies which have been performed on glucagon and its agonist and antagonist analogues using various biophysical methods including NMR, X-ray crystallography and circular dichroism spectroscopy. Finally we briefly discuss the uses of glucagon analogues, especially glucagon antagonists, in examining the mechanisms and roles of glucagon in normal and diabetic states, and some aspects of the molecular biology of the glucagon receptor.
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