PHYSIOLOGICAL AND GENETIC-CHARACTERIZATION OF THE GLY40SER MUTATION IN THE GLUCAGON RECEPTOR GENE IN THE SARDINIAN POPULATION

A Gly40Ser amino acid substitution in the glucagon receptor gene has b een associated with non-insulin-dependent diabetes mellitus (NIDDM), b ut the questions raised about its physiological implications have not been resolved. The aim of this study was to determine the frequency of the Gly40Ser mutation in different regions of Sardinia and to investi gate the physiological implications of the mutation in glucose and ins ulin homeostasis. We studied a population of 691 subjects, selected on the basis of their Sardinian origin. Only heterozygous subjects were found, 21 of 574 (3.6%) in NIDDM patients and 5 of 117 in non-diabetic subjects (4.2%). In northern Sardinia 3.4% of the NIDDM patients were carriers of the Gly40Ser substitution, 1.4% in central Sardinia, whil e 7.6% carried the substitution in the Southern part. No significant d ifferences were found between hypertensive and normotensive subjects w ith respect to the presence of Gly40Ser. Ten subjects with Gly40Ser we re carefully matched for diabetic state, BMI, age, sex, and geographic al origin with 10 patients with Gly40, and a glucagon infusion test wa s performed using 1, 3, 9 and 27 ng glucagon kg(-1). min(-1) for 30 mi n. Blood for determination of glucose, glucagon, and insulin concentra tions was drawn at 15-min intervals from the Controlateral arm. Plasma glucagon increased dose-dependently during the infusion with no signi ficant difference between the two groups. Carriers of Gly40Ser had a s ignificantly lower (p < 0.02) increase in plasma glucose concentration in response to glucagon infusion compared to Gly40 homozygous subject s at all times, while the plasma insulin increase was not significantl y different at any time. In conclusion, our results indicate that the Gly40Ser variation is not associated with NIDDM in the Sardinian popul ation, and that its frequency varies in different parts of Sardinia. M oreover in vivo Gly40Ser plays a physiological role in the glucose hom eostasis under glucagon control both in NIDDM and non-diabetic subject s. This latter result suggests that this amino acid substitution in th e glucagon receptor may lead to a decreased blood glucose concentratio n because of the reduced stimulation of liver glucose output via the g lucagon receptor.