PHENOTYPIC ALTERATIONS IN INSULIN-DEFICIENT MUTANT MICE

Two mouse insulin genes, Ins1 and Ins2, were disrupted and lacZ was in serted at the Ins2 locus by gene targeting. Double nullizygous insulin -deficient pups were growth-retarded. They did not show any glycosuria at birth but soon after suckling developed diabetes mellitus with ket oacidosis and liver steatosis and died within 48 h. Interestingly, ins ulin deficiency did not preclude pancreas organogenesis and the appear ance of the various cell types of the endocrine pancreas, The presence of lacZ expressing beta cells and glucagon-positive alpha cells, was demonstrated by cytochemistry and immunocytochemistry. Reverse transcr iption-coupled PCR analysis showed that somatostatin and pancreatic po lypeptide mRNAs were present, although at reduced levels, accounting f or the presence also of delta and pancreatic polypeptide cells, respec tively. Morphometric analysis revealed enlarged islets of Langherans i n the pancreas from insulin-deficient pups, suggesting that insulin mi ght function as a negative regulator of islet cell growth. Whether ins ulin controls the growth of specific islet cell types and the molecula r basis for this action remain to be elucidated.