Compensatory responses in mice carrying a null mutation for Ins1 or Ins2

Intrauterine growth retardation and postnatal acute diabetes result from in sulin deficiency in double homozygous null mutants for Ins1 and Ins2 (Duvil lie B, et al,, Proc Natl Acad Sci USA 94:5137-5140, 1997), The characteriza tion of single homozygous null mutants for Ins1 or Ins2 is described here. Neither kind of mutant mice was diabetic. Immunocytochemical analysis of th e islets showed normal distribution of the endocrine cells producing insuli n, glucagon, somatostatin, or pancreatic polypeptide, Analysis of the expre ssion of the functional insulin gene in Ins1(-/-) or Ins2(-/-) mice reveale d a dramatic increase of Ins1 transcripts in Ins2(-/-) mutants. This compen satory response was quantitatively reflected by total pancreatic insulin co ntent similar for both types of mutants and wild-type mice. Moreover, both mutants had normal plasma insulin levels and normal glucose tolerance tests . The determination of beta -cell mass by morphometry indicated beta -cell hyperplasia in the mutant mice, The beta -cell mass in Ins2(-/-) mice was i ncreased almost threefold, which accounts for the increase of Ins1 transcri pts in Ins2(-/-) mutants. This study thus contributes to evaluate the poten tial of increasing the beta -cell mass to compensate for low insulin produc tion.