Cell and Tissue Research

, Volume 319, Issue 2, pp 231–242

Estrogenic restoration of functional pancreatic islet cytoarchitecture in diabetes (db/db) mutant C57BL/KsJ mice: relationship to estradiol localization, systemic glycemia, and persistent hyperinsulinemia

Regular Article

DOI: 10.1007/s00441-004-1019-y

Cite this article as:
Garris, D.R. & Garris, B.L. Cell Tissue Res (2005) 319: 231. doi:10.1007/s00441-004-1019-y


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 (0.1μg/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 β-cell cytoplasmic regranulation of insulin secretory vesicles. In chronic E2-HRx db/db groups, autoradiographic localization of 3H-E2 was demonstrated in the nuclear compartments of regranulated, nonhypertrophic islet cell populations, including insulin-containing β-cells. In chronic E2-HRx db/db mutants, β-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 β-cell cytoarchitecture was reduced by E2-HRx, including the reestablishment of islet β-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.


Cellular glucose utilizationDiabetes (db/db) mutationEstradiol autoradiographyHypercytolipidemiaHyperinsulinemia-hyperglycemiaPancreatic islet hypertrophic atrophyMouse (C57BL/KsJ)

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Division of Cell Biology and Biophysics, Schools of Biological Sciences and MedicineUniversity of Missouri–Kansas CityKansas CityUSA