Cytochemical Analysis of Pancreatic Islet Hypercytolipidemia following Diabetes <i>(db/db)</i> and Obese <i>(ob/ob)</i> Mutation Expression: Influence of Genomic Background

Both diabetes <i>(db/db)</i> and obese <i>(ob/ob)</i> genotype mutations induce a hyperglycemic-hyperinsulinemic endometabolic state in C57BL mice, manifesting a type II NIDDM diabetes-obesity syndrome (DOS) in these leptin ligand/receptor-deficient models. The severity of the DOS induced by these single gene, homozygous-recessive mutations may be moderated by the background genome on which the mutation is expressed. The current studies define the phenotypic, systemic, cytochemical and cellular metabolic responses to <i>db/db</i> and <i>ob/ob</i> mutation expression when modified by /KsJ (severe DOS expression) or /6 (modified DOS expression) background strain influences as compared to littermate control (<i>+/?</i>) indices. Both <i>db/db</i> and <i>ob/ob</i> mutations induced dramatic increases in body weights, blood glucose and serum insulin concentrations relative to <i>+/?</i> indices when expressed on either the C57BL/KsJ (-/KsJ) or C57BL/6 (-/6) backgrounds. However, the -/KsJ background enhanced the severity of expression of these DOS indices relative to the -/6 strain. Similarly, the -/KsJ genome suppressed cellular glucose uptake rates, pancreatic tissue weights and insulin concentrations in both <i>db/db</i> and <i>ob/ob</i> mutants relative to /6 background strain influences or <i>+/?</i> indices. Concurrent enhancement of tissue and cellular lipogenic metabolism and islet cytolipid depositions were exaggerated when the mutations were expressed on the -/KsJ background relative to the -/6 genome. Pancreatic islet <i>B</i>-cell lipodeposition was markedly enhanced in <i>ob/ob</i> and <i>db/db</i> mutants expressed on either the -/KsJ or -/6 background. In both <i>ob/ob</i> and <i>db/db </i>models, <i>B</i>-cell insulin granulation was prominent in mildly hypertrophic pancreatic islets when the mutations were expressed on the -/6 background. In contrast, the severity of the DOS state expressed on the -/KsJ background resulted in pronounced <i>B</i>-cell atrophy, characterized by insulin degranulation, cellular hypertrophy and hypercytolipidemia associated with tissue involution, in both <i>ob/ob</i> and <i>db/db</i> mutants. Dramatic alterations in tissue norephinephrine (NE) and alpha-1-receptor populations in <i>ob/ob</i> and <i>db/db</i> mutants were exaggerated by the -/KsJ genome as compared to -/6 or control indices. The influences of the -/KsJ genome on the progressive expression of tissue NE counter-regulatory responses to enhanced cytolipidemic indices were inversely related, with cytochemical lipodeposition occurring under conditions of diminished adrenergic responses to the DOS indices. The results of these studies indicate that the severity of the type-II diabetes endometabolic syndrome induced by the <i>ob/ob</i> or <i>db/db</i> genotypic mutations is modified by the existing genome on which the mutations are expressed. These data suggest that the severity of genomic mutation expression may by modified depending on the capability of the background genome to counter-regulate the systemic, cellular or metabolic consequences of these mutations.