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

Abstract

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.

Influences of diabetes (db/db), obese (ob/ob) and dystrophic (dy/dy) genotype mutations on hind limb bone maturation: a morphometric, radiological and cytochemical indices analysis

“…In both the db/db and ob/ob groups, expression of the genotype mutations resulted in a severe hypercaloric, endometabolic compromise of systemic and interstitial support of homeostatic cytometabolic cascades [16,18]. The progressive lipogenic shunting of interstitium‐derived nutrient sources in affected cell types, including osteocytes as defined in the current studies, culminates in liponuclear structural disruption and chromatin dissolution within the nuclear compartment [24,25] as demonstrated by pronounced DNA fragmentation and diminished transcriptional expression of glucometabolic regulatory enzyme cascade components [16–18,26]. In ob/ob genotype mutants, the lipo‐osteopaenic aberrations in bone maturation indices are similar to recognized hypophysoprivia chronica‐induced osteodysplasia, in which the similar hypopituitary (gonadal) endometabolic compromise of osteogenesis results in afflicted patient symptoms which mimic the premature lipoapoptotic disturbances that suppress hypophyseal hormone synthesis/secretion cascades in these genotype mutants [37].…”

“…These single-gene mutations promote systemic and cellular hypercaloric, dysregulated glucometabolic type 2 diabetes-obesity syndromes in C57BL/KsJ mice [15][16][17][18][19] in a duration-dependent manner, similar to conditions observed in both progressive youth and adult maturity [20][21][22][23] onset diabetes states. The resulting phenotypic [15][16][17], endometabolic [16][17][18] and osteomaturation [19] aberrations are related to mutationinduced leptin membrane receptor protein/ligand misexpressions [19,20], generating hyperphagic experimental models which experience progressive body mass expansion, hyperglycaemia, hyperinsulinaemia, hypertriglyceridaemia and premature cytolipoinvolution accompanied by systemic hyperglucocorticoidismassociated skeletal osteopaenia [16][17][18][23][24][25][26][27]. By contrast, expression of the dystrophic (dy/dy) genotype mutation results in the suppression of skeletal maturation associated with fibrous osteodysplasia and laminopathic osteomalformation under dyslipidaemic (i.e.…”

The Protective Effect of Granulocyte Colony-Stimulating Factor on Endometrium and Ovary in a Rat Model of Diabetes Mellitus

“…The pathophysiological mechanisms of endometrial damage in DM remain unclear. Garris et al [28] observed a significant enhancement of the tissue metabolism and the premature involution of the female reproductive tract due to induced cellular toxicity in endometrial epithelial and stromal layers. Enhanced oxidative stress and changes in antioxidant capacity are considered to play an important role in the pathogenesis of DM [29].…”

Hypercytolipidemia-Induced Nuclear Lipoapoptosis: Cytochemical Analysis and Integrated Review of Hypogonadal, Diabetes-Obesity Syndrome-Induced Female Reproductive Axis Disruption

“…7,20,21,34,44 Subsequently, under continuing hyperphagic-hypercaloric conditions, 7,9,38,44,54 the systemic hyperglycemichyperinsulinemic-hypertriglyceridemic state promotes progressive hypercytolipidemia, 9 with the resultant systemic and tissue disruptions compromising the functional integrity of the pituitary-gonadal axis. 3,7,18,20,21,34,44 The correlated hypermetabolic stimulation of systemic and tissue triglyceride concentrations, progressive cytolipidemia as well as the persistent stimulation of lipid enzyme cascade shifts towards pronounced non-oxidative lipogenic activities 7,15,21,32,66 indicate that the denoted systemic endometabolic aberrations precede, and continually exacerbate, the resulting hypercytolipidemia associated with the demonstrated cytoatrophy and chronic organo-involution consequences of db/db mutation expression. The co-incident increase in ovarian follicular atresia rates, 10,21,52 cytoadiposity 2,20,21,34 and utero-ovarian involution 4,7,10,20,21,44 correlate with the noted suppression of ovarian steroid production 7,44 and gonadotropin secretion rates 1,3,11 in this hypogonadal model.…”