IMPAIRED DEVELOPMENT OF PANCREATIC BETA-CELL MASS IS A PRIMARY EVENT DURING THE PROGRESSION TO DIABETES IN THE GK RAT

In the endocrine pancreas of the GK rat, a genetic model of non-insuli n-dependent diabetes mellitus (NIDDM), it is not clear whether the his topathological changes reported up to now are related to the pathogene sis of hyperglycaemia or whether they occur secondarily to metabolic a lterations. Using GK rats from the Paris colony, our study chronicles for the first time the pathophysiologic changes that occur in the GK p ancreas from the late fetal period (day 21.5) until adult age (18 week s): As compared to Wistar controls, GK fetuses exhibited higher plasma glucose level, lower plasma insulin level and normal plasma glucagon level. Their pancreatic insulin content and the relative volume and th e total mass of their beta cells were sharply decreased, representing only 23, 38 and 23% of control values, respectively. During the period from 4 days to 14 days after birth, GK neonates exhibited normal basa l plasma glucose and glucagon levels despite decreased plasma insulin level. Their pancreatic insulin content represented only 31-40% of val ues found in the age-related control pancreases and their total beta-c ell mass was only 35% on day 4, 30% on day 7 and 37% on day 14. The ad ult diabetic GK rats exhibited higher basal plasma glucose and insulin levels while their basal plasma glucagon level remained normal. Their pancreatic insulin content and the total beta-cell mass remained decr eased, representing only 32% and 47% of control values, respectively. Moreover, the adult GK pancreases exhibited noticeable alteration in t he architecture of the large islet subpopulation which displayed consi derable fibrosis with clusters of beta cells widely separated from eac h other by strands of connective tissue. Concerning the development of alpha cells in the GK rats, their relative volume was found to be nor mal during fetal and early neonatal periods. It was found to be modera tely decreased (representing 64-67% of corresponding control values) i n 14-day-old neonates and adult GK rats. Our findings demonstrate that in the GK rat, the deficit of total beta-cell mass as observed in the adult animal is related to impaired beta-cell development. The restri ction of the beta-cell mass must be considered as a primary and crucia l event in the sequence leading to overt diabetes in this NIDDM model.