Diabetes Prevents the Normal Responses of the Ovary to Fsh

Garris²

2004

Pathobiology

Both diabetes (db/db) and obese (ob/ob) 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 db/db and ob/ob mutation expression when modified by /KsJ (severe DOS expression) or /6 (modified DOS expression) background strain influences as compared to littermate control (+/?) indices. Both db/db and ob/ob mutations induced dramatic increases in body weights, blood glucose and serum insulin concentrations relative to +/? 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 db/db and ob/ob mutants relative to /6 background strain influences or +/? 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 B-cell lipodeposition was markedly enhanced in ob/ob and db/db mutants expressed on either the -/KsJ or -/6 background. In both ob/ob and db/db models, B-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 B-cell atrophy, characterized by insulin degranulation, cellular hypertrophy and hypercytolipidemia associated with tissue involution, in both ob/ob and db/db mutants. Dramatic alterations in tissue norephinephrine (NE) and alpha-1-receptor populations in ob/ob and db/db 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 ob/ob or db/db 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.

Section: Introductionmentioning

confidence: 99%

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

Garris²

2004

Pathobiology

“…Characterized by ovarian follicular atresia (4), inhibition of follicular recruitment (4), depressed ovarian steroid hormone production (1,3,5), refractory responsiveness to gonadotropin stimulation (6), and failure of corpus luteum formation (4,7,8), the maturation of the reproductive tract is developmentally and structurally impaired as compared with littermate controls (ϩ/?). Uterine structural parameters influenced by the expression of the db/db mutation include a marked depression in uterine epithelial cellular integrity (1,7), depressed responsivity to ovarian steroid hormone therapy (7,9,10), suppressed mitotic indexes (3), and premature tissue involution (2), accompanied by an enhanced cytoplasmic lipid inclusion volume (4).…”

mentioning

confidence: 99%

Diabetes-Induced, Progressive Endometrial Involution Characterization of Periluminal Epithelial Lipoatrophy

2003

Diabetes

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.

“…5, 6, Table 1) suggest that that the pronounced pituitary vasoand cyto-lipidemia compromises cellular structural and functional mechanisms modulating normal hypothalamicpituitary axis regulatory interactions in db/db mutants (Garris et al 2004). Subsequently, under continuing hyperphagic-hypercaloric conditions (Garris 2004a), the systemic hyperglycemic-hyperinsulinemic-hypertriglyceridemic state promotes progressive hypophyseal hypercytolipidemia, with the resultant hypophyseal lipo-metabolic disruptions further compromising pituitary-gonadal axis integration (Bray and York 1978;Foreman et al 1993;Garris 1989Garris , 2004a. The coincident increase in ovarian follicular atresia rates (Garris 2004b;Garris and Garris 2003b;Garris et al 1985c), cytoadiposity (Garris and Garris 2003b), and uteroovarian involution Garris 2003a, b, 2004b, c) correlate with the noted suppression of ovarian steroid production (Garris and Garris 2003b;Garris et al 1985c) and the depressed gonadotropin secretion rates and follicular sensitivity (Foreman et al 1993, Johnson andSidman 1979) in this hypogonadal model.…”

Section: Discussionmentioning

confidence: 99%

“…The db/db-induced hypercytolipidemia also suppresses functional utero-ovarian development Garris 2003a,b, 2004b), resulting in a hypogonadal, acyclic, and infertile metabolic (X) syndrome model (Garris 2004a;Garris and Garris 2002). The systemic and cellular compromises related to non-homeostatic glucose and lipid metabolic indices (Garris and Garris 2004b,c) suppress gonadal steroid production (Garris and Garris 2003b) and depress gonadal steroid stimulation of the female reproductive neuroendocrine axis (Coirini et al 1980;Dudley et al 1981;Garris et al 1984Garris et al , 2004Garris 1985a;Garris and Coleman 1985) and result in the disruption of normal hypothalamic influences on pituitary gonadotropin secretion in several DOS models Jeanrenaud 1979, 1980;Bestetti et al 1985;Bray and York 1978;Coirini et al 1980;Dudley et al 1981;Foreman et al 1993;Garris et al 2004;Garris 2004a;Spindler-Vomachka and Johnson 1985). Although hypothalamic gonadotropin-releasing hormone (GnRH) and pituitary gonadotropin concentrations have been reported to be comparable in control and db/db mutants (Batt et al 1982;Johnson and Sidman 1979;Spindler-Vomachka and Johnson 1985), altered hypophyseal responsivity to GnRH stimulation has been suspected of being associated with the systemic metabolic and hypogonadal compromise that typifies Type II diabetes (NIDDM) models (Batt et al 1982;Bray and York 1978;Garris et al 1982aGarris et al ,b, 2004Garris 2004a;Garris and Michael 1988;Spindler-Vomachka and Johnson 1985).…”

Section: Introductionmentioning

confidence: 96%

Structural, metabolic and endocrine analysis of the diabetes (db/db) hypogonadal syndrome: relationship to hypophyseal hypercytolipidemia

Novikova

et al. 2005

Cell Tissue Res

Expression of the diabetes (db/db) mutation in C57BL/KsJ mice results in functional suppression of the female pituitary-gonadal axis accompanied by premature utero-ovarian cytolipoatrophy. Cellular gluco- and lipo-metabolic disturbances promoted by the db/db systemic hyperglycemic-hyperinsulinemic state suppress pituitary gonadotropin release in response to gonadotropin-releasing hormone and gonadal steroid stimulation and results in a hypogonadal-infertility syndrome. Adult female C57BL/KsJ control (+/+ and +/? genotypes) and db/db littermates were monitored for associations in systemic and cellular alterations in luteinizing hormone (LH), follicle-stimulating hormone (FSH), gonadal steroid (binding) levels, and pituitary glucometabolic indices associated with db/db-enhanced lipid imbibition and cytostructural disruption. Obesity, hyperglycemia, and hyperinsulinemia characterized all db/db mutants relative to controls. Serum and pituitary progesterone and estradiol concentrations were suppressed in db/db mutants, in association with serum LH and FSH levels, but not with pituitary LH and FSH concentrations, which were comparable between groups. Pituitary insulin receptor binding and glucose utilization rates were suppressed in db/db groups relative to +/? indices. Structural and cytochemical analysis of anterior (AP), intermediate (IL), and neuro-(NP) hypophyseal lobes demonstrated prominent hypercytolipidemia in db/db mutants relative to controls. Prominent cytolipidemia was localized within well-granulated basophilic gonadotrophs and within IL and NP pituicytes. Vasolipidemia and interstitial cytoadiposity were prominent throughout all db/db pituitary lobes. Thus, disturbances associated with pituitary hypercytolipidemia are functional components of the expressed diabetes-associated hypogonadal syndrome in db/db mutants. Progressive alterations in hypophyseal cytoarchitecture are correlated with suppression of pituitary metabolic and endocrine indices, alterations that contribute to functional disruption of the pituitary-hypogonadal axis in C57BL/KsJ-db/db mice.