title: Estrogenic restoration of functional pancreatic islet cytoarchitecture in diabetes (db/db) mutant C57BL/KsJ mice: relationship to estradiol localization, systemic glycemia, and persistent hyperinsulinemia.
abstract: The diabetes (db/db) genotype mutation induces a hyperglycemic-hyperinsulinemic endometabolic state in C57BL/KsJ mice, manifesting a type 2 NIDDM diabetes-obesity syndrome (DOS) in this hyperphagic, leptin receptor (lf) defective model. The severity of the DOS induced by the single gene, homozygous-recessive mutation may be therapeutically moderated by gonadal steroids and pre-steroidal metabolites. The current studies define the estradiol (E2)-modulated phenotypic, systemic, cytochemical, and cellular metabolic responses to db/db mutation expression as compared to littermate control (+/?) indices. The db/db mutation induced dramatic age- and DOS severity-related increases in body weights, blood glucose, and serum insulin concentrations relative to +/? indices between 4-week-old (i.e., initial onset stage of DOS phenotype) and 16-week-old (i.e., chronic stage of DOS) groups. Chronic, low-dose (0.1 microg/3.5 days) E2 treatment (E2-HRx) significantly reduced the obesity mass and blood glucose levels of db/db mutants relative to oil-HRx groups. Similarly, E2-HRx maintained pancreatic glucose utilization rates and pancreatic tissue weights in db/db mutants to near +/? indices. Concurrent amelioration of db/db-enhanced pancreatic lipogenesis and islet hypercytolipidemia occurred following E2-HRx. Pancreatic islet lipo-deposition was markedly reduced in db/db mutants following E2-HRx, and the restoration of islet size and cellular insulin concentrations correlated with beta-cell cytoplasmic regranulation of insulin secretory vesicles. In chronic E2-HRx db/db groups, autoradiographic localization of (3)H-E2 was demonstrated in the nuclear compartments of regranulated, nonhypertrophic islet cell populations, including insulin-containing beta-cells. In chronic E2-HRx db/db mutants, beta-cell insulin granulation was prominent in mildly hypertrophic pancreatic islets, with cytodistribution patterns and concentrations comparable to normal +/? indices. In contrast, E2-HRx maintained the systemic hyperinsulinemia characteristic of oil-HRx db/db mutants. The results of these studies indicate that the severity of the type 2 NIDDM endometabolic syndrome induced by the db/db genotypic mutation may be influenced by E2-HRx, including reduction of the islet hypercytolipidemia and hypertrophic atrophy which are indicators of impending pancreatic involution in this mutant model. The hypercytolipidemia-induced demise of beta-cell cytoarchitecture was reduced by E2-HRx, including the reestablishment of islet beta-cell cytogranulation. These data suggest that the severity of genomic db/db-mutation expression may be modified by E2-HRx, with the gonadal steroid probably acting as a nuclear-specific stimulatory transcriptional modulator of cellular glucometabolic cascades in the absence of leptin-directed homeostatic influences.
authors.affiliation: Division of Cell Biology and Biophysics, Schools of Biological Sciences and Medicine, University of Missouri-Kansas City, 5007 Rockhill Road, Kansas City, MO 64110, USA. garrisd@umkc.edu
authors.forename: David R
authors.initials: DR
authors.lastname: Garris
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Garris
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000032:analysis; D000818:Animals; D001284:Atrophy / Q000517:prevention & control; D001345:Autoradiography; D001786:Blood Glucose; D001835:Body Weight / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005808:Genes, Recessive; D006651:Histocytochemistry; D006720:Homozygote; D006943:Hyperglycemia / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D006946:Hyperinsulinism / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D006949:Hyperlipidemias / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D007279:Injections, Subcutaneous; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D009765:Obesity / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D009929:Organ Size / Q000235:genetics; D011863:Radioimmunoassay; D013997:Time Factors; D014316:Tritium
chemical_list: D001786:Blood Glucose; D007328:Insulin; D014316:Tritium; D004958:Estradiol; D000103:Acetyl-CoA Carboxylase