Biomedical subjects

David R Garris

Publications and source records attributed to David R Garris.

23 records · Page 2Linked to original sources

PubMed2003

Diabetes (db/db) mutation-induced ovarian involution: progressive hypercytolipidemia.

Ovarian atrophy and reproductive tract incompetence are recognized consequences of the progressive expression of the overt, diabetes-obesity syndrome (DOS) in C57BL/KsJ (db/db) mutant mice. The present studies evaluated the progressive changes in ovarian cytoarchitecture, endocrine expression, and reproductive tract cytolipidemic parameters that promote reproductive failure and ovarian involution during the pre-onset, initial, progressive, and chronic expression stages of the DOS. Paired littermate control (normal: +/?) and diabetic (mutant: db/db) C57BL/KsJ females were selected for analysis of ovarian parameters at 2 weeks (pre-onset expression of DOS), 4 weeks (initial DOS expression), 8 weeks (progressive DOS: hyper-glycemic/lipidemic), and 16 weeks (overt/chronic DOS expression) of age. All 4- to 16-week-old (db/db) groups were obese, hyperglycemic, and hyperinsulinemic as compared with age-matched (+/?) controls. Prior to phenotypic expression of the DOS (2 week groups), ovarian interstitial cytolipidemia characterized the perifollicular and cortical regions of db/db tissue samples relative to +/? indices, while comparable body weight, blood glucose, as well as serum insulin and ovarian steroid hormone concentrations characterized both the +/? and db/db groups. Overt DOS expression in the 4-week-old db/db groups was characterized by body obesity, systemic hyperglycemia-hyperinsulinemia, and extensive hypercytolipidemia of ovarian folliculothecal compartments, as well as enhanced tissue lipase activities. By 8 weeks of age, progressive hypercytolipidemia characterized interstitial, thecal, and follicular granulosa cell layers of db/db tissue samples concurrent with suppressed ovarian steroid hormone production, enhanced lipid sequestration, and exacerbation of systemic hyper-glycemia/insulinemia. By 16 weeks of age, the chronic-DOS was characterized by extensive ovarian follicular involution, cortical perivascular hyperlipidemic infiltration, thecal cell atrophy, and follicular granulosa lipid imbibition. These data indicate that db/db mutation-induced ovarian structural and functional involution is a direct reflection of the cellular metabolic shift towards lipogenesis, indicated by the progressive cytoarchitectural transformation into adipocyte-like entities. The cytological indications of cellular metabolic compromise, which precede the phenotypic expression of the DOS indices, suggests that correction of these abnormal shifts in ovarian endocrine and cellular metabolism may restore, delay, or prevent the further compromise of ovarian function by db/db mutation expression.

Age Factors↗

PubMed2003

Diabetes-induced, progressive endometrial involution characterization of periluminal epithelial lipoatrophy.

The present studies detail the cytopathological alterations in uterine epithelial, basal lamina, and stromal endometrial subregions, and associated endocrine parameters that occur during the progressive exacerbation of the diabetes syndrome in this species of mouse. These alterations result in a cellular lipoatrophic condition that compromises uterine tissue integrity and promotes reproductive involution. Uterine tissue samples were obtained from litter-matched control (+/?) and diabetic (db/db) C57BL/KsJ mice at four designated stages of the progressive expression of the diabetes mutation. In db/db mice between the ages of 4 and 12 weeks, the uterine epithelial cellular architecture exhibited progressive deterioration, characterized by cytoplasmic lipid imbibition (accumulation), organelle disintegration, apical membrane ciliary regression, and peristromal lamina separation from basal membrane surfaces, as compared with control indexes. The cytoplasmic volume occupied by lipid inclusions dominated the epithelial cells in diabetic mice, presenting dense basal pole lipid vacuoles, with perinuclear-intracytoplasmic migration of the inclusions promoting an apical cytoplasmic lipid condensation of increasing volume 8-12 weeks after mutation expression. These cytoplasmic lipid accumulations occurred under altered metabolic and endocrine conditions characterized by hyperglycemic, hyperinsulinemic, hypertriglyceridemic, and enhanced noradrenergic indexes, which were exacerbated between 4- and 12-week stages. These structural changes were accompanied by enhanced adrenergic counterregulatory metabolic responses as well as elevated lipoprotein and triacylglycerol lipase activities. These data indicate that diabetes-associated uterine involution is characterized by a progressive cellular and peristromal lipoatrophy of epithelial cell cytology and metabolic parameters, promoting stromal separation and ultimate endometrial involution.

Animals↗

PubMed2002

Lipoatrophic diabetes-associated utero-ovarian dysfunction: influence of cellular lipid deposition on norepinephrine indices.

OBJECTIVE: Elucidation of the intracellular lipoatrophic diabetic state and the concomitant alterations in norepinephrine (NE) parameters characterizing female reproductive failure. METHODS: Quantitation of intrinsic NE levels in utero-ovarian and pancreatic tissue samples of C57BL/KsJ (+/?) control and (db/db) diabetic littermate mice was by high performance liquid chromatography (HPLC) and compared with the microspectrofluorometric histofluorescent (HF) localization of cellular and parenchymal NE. RESULTS: Diabetes-associated elevations in HPLC-detectable tissue NE concentrations occurred in all pancreatic and reproductive tract tissue samples as compared to control-matched samples, whereas concurrent HF analysis revealed suppressed perivascular and parenchymal NE depositions in diabetic mice. CONCLUSIONS: These data suggest that progressive hypertriglyceridemia/lipidemia may suppress the effectiveness of intrinsic elevations in tissue NE concentrations from effectively counterregulating the deleterious effects of the hyperglycemic, type-2 diabetic condition.

Animals↗

PubMedDate not supplied

Cytolipotoxicity-induced involution of the female reproductive tract following expression of obese (ob/ob) and diabetes (db/db) genotype mutations: progressive, hyperlipidemic transformation into adipocytic tissues.

Both diabetes (db/db) and obese (ob/ob) single gene mutations induce a progressive, hyperglycemic-hyperinsulinemic endometabolic environment which promotes hypercytolipidemic, utero-ovarian involution in C57BL/KsJ mice. The progressive expression of the induced diabetes-obesity syndrome (DOS) results in female reproductive sterility and eventual organoatrophy. In order to define the intra-cytoplasmic alterations induced by the progressive cytolipidemia on cellular vitality, utero-ovarian tissue samples were collected from both control (+/?) and littermate-matched ob/ob or db/db C57BL/KsJ mice at either 4 weeks (initial-onset DOS phase), 8 weeks (progressive, overt DOS phase), or 16 weeks (chronic-DOS phase) of age for cytolipid distribution analysis. All db/db and ob/ob mutant groups exhibited phenotypic obesity and systemic hyperglycemia-hyperinsulinemia relative to age-matched littermate +/? groups. In all db/db and ob/ob age groups, a progressive hypercytolipidemia was noted relative to +/? groups. When analyzed for lipid channeling, a progressive perinuclear mapping pattern of cytolipid distribution was noted. The primary locus of initial db/db and ob/ob cytolipid deposition was localized to the baso-polar regions in endometrial epithelia samples, or to the interstitium-thecal layer border of ovarian follicular compartments, during the initial-onset DOS phase. Progressively, intra-cytoplasmic lipid mobilization promoted a consistent perinuclear channeling of lipid vacuoles, ultimately isolating nuclear loci from the peripherally displaced cytoplasmic organelles within uterine epithelial layers. In db/db and ob/ob ovarian tissue samples, a progressive, gradient-related lipid infiltration of interstitial, thecal and, ultimately, granulosa cell layers promoted an enhanced rate of follicular-lipidemic atresia relative to +/? groups. In each tissue layer, the cytolipidemia promoted a dramatic perinuclear lipid-isolation barrier from intra-cytoplasmic organelle domains. With age-related exacerbation of the DOS syndrome, cytoplasmic nuclear-organelle displacement and lipoisolation resulted in cellular atresia, promoting the eventual utero-ovarian organoatrophy which characterized the chronic-DOS phase in db/db and ob/ob C57BL/KsJ mutants. These results indicate that the cytoinvolution associated with reproductive tract atrophy in these genetically mutant, diabetic-obese models is promoted by the disruption of the normal cytoarchitecture of utero-ovarian tissue layers induced by the progressive lipid sequestration, accumulation and ultimate isolation-induced disruption of intra-cellular organelle compartmentalization.

Adipose Tissue↗

PubMedDate not supplied

Ovarian follicular lipoapoptosis: structural, cytochemical and metabolic basis of reproductive tract atrophy following expression of the hypogonadal diabetes (db/db) syndrome.

The diabetes (db/db) mutation (i.e., leptin membrane receptor defect) promotes a progressive, hypercytolipidemia within ovarian follicular granulosa, thecal and interstitial layers of C57BL/KsJ mice which manifests an infertile, acyclic hypogonadal syndrome. The current studies focus on the structural, cytochemical and gluco-/lipo-metabolic changes which induce cellular lipoapoptosis and the resulting cytostructural disruption of db/db follicular populations, relative to littermate control indices, following the expression of progressive ovarian hypercytolipidemia. Control (normal: +/+ and +/?) and diabetes (db/db) genotype groups were prepared for high resolution light microscopic (HRLM) analysis of cytolipidemia and nuclear apoptosis (TUNEL-labeled 3'-DNA fragmentation) indices and compared to the transmission electron (TEM) microscopic analysis of ovarian follicular samples collected from 8-16-week-old groups. Compared to controls, the db/db mutation induced a dramatic increase in cytolipid vacuole volume and density within all ovarian follicular layers. TEM analysis revealed that the lipid vacuoles initially aggregated along the inner membrane compartments of affected thecal and granulosa cells in response to the interstitial and vaso-lipidemic-hyperglycemic conditions which characterized the ovarian microenvironment of db/db follicles. Progressive cytoplasmic movement of lipid pools into the perinuclear compartment of affected granulosa cells induced nuclear isolation from cytoplasmic organelles that were displaced towards peripheral intracellular compartments. Cytochemical analysis of lipid vacuole accumulations indicated attraction towards, and incorporation within, the nuclear envelope of hyperlipidemic cells. Co-localization of nuclear apoptotic 3'-DNA fragments within identified hyperlipidemic granulosa cells was coincident with the cytochemical and ultrastructural identification of lipid penetration through the nuclear envelope in db/db mutants. These results are the first cytochemical evidence that the lipometabolic disturbances in db/db mutants, which promote hypercytolipidemia-induced premature ovarian involution, are coincident with lipoapoptosis-induced nuclear dissolution within follicular granulosa layers. The lipidemia-induced alterations in cellular and nuclear architecture suggests that the disturbances in glucose and lipid metabolic cascade activities in diabetes (db/db) mutants disrupts follicular cytointegrity, culminating in nuclear disregulation (as indicated by lipoapoptosis) which results in premature reproductive tract organo-involution and manifest reproductive sterility.

Adipocytes↗