Estrogenic Stimulation of Hypothalamic-Limbic System Metabolism in Ageing Diabetic C57BL/KsJ Mice

Abstract

The therapeutic influences of estrogen treatment on age- and diabetes-related declines in regional brain glucose utilization (RBGU) rates were evaluated in 8- to 20-week-old female C57BL/KsJ normal (+/?) and diabetic (db/db) mice. Following either oil vehicle (oil: 0.1 ml) or estradiol (E: 1 µg/3.5 days) treatments starting at 3 weeks of age, RBGU rates were subsequently determined at 8, 12, 16 and 20 weeks of age. A gradual decline in the basal rate of brain glucose utilization was observed in all control (oil- and E-treated) groups between 8 and 20 weeks. Expression of the hyperglycemic-obese diabetes syndrome in db/db mice resulted in a significant reduction in RBGU rates between 8 and 20 weeks relative to control values. In estrogen-sensitive hypothalamic, septal and amygdaloid regions, E therapy modulated RBGU rates in db/db mice relative to oil-treated diabetics, but did not significantly alter utilization rates in +/? mice. In cortical samples, E therapy had no significant influence on glucose utilization rates in either control or diabetic groups. A noticeable pattern of maturation-associated decline in CNS glucose utilization rates in all brain regions resulted in comparable regional metabolic indices being exhibited by all groups at 20 weeks of age, with the exception of the diabetes-associated exacerbation of RBGU rates in the oil-treated db/db group. These data demonstrate that the normal development-related decline in regional brain carbohydrate metabolism is accelerated by the diabetes syndrome, and that E therapy can modulate the syndrome-associated suppression of glucose utilization in steroid-sensitive CNS loci. These data suggest that the depressive influences of the diabetes syndrome on brain carbohydrate utilization rates may be therapeutically modified in recognized CNS regions possessing steroid-sequestering, metabolically responsive neurons.

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

“…The results of the present studies extend previous reports of reproductive tract atrophy, utero-ovarian cellular degeneration, and depressed ovarian steroidogenesis resulting from the chronic diabetes syndrome in various genetic and experimentally induced hyperglycemic models (1,2,5,8,13,15,21) by identifying the progressive nature of the hypercytolipidemia that characterizes this metabolic mutation. The evaluation of the progressive imbibition and accumulation of cytoplasmic lipid stores observed in the current studies correlates with the temporal expression of the hyperglycemic-hyperinsulinemic state and the enhanced tissue triglyceride levels present in endometrial samples of db/db groups relative to controls.…”

“…The progressive triglyceride accumulation and intracellular lipid distribution pattern, as well as the metabolic consequences of endometrial hypercytolipidemia associated with the chronic expression of the diabetes-obesity syndrome mutation in C57BL/KsJ mice, potentiates the expressed reproductive dysfunction and tissue atrophy in this model (1,5,12,13,15). The results of the present studies extend previous reports of reproductive tract atrophy, utero-ovarian cellular degeneration, and depressed ovarian steroidogenesis resulting from the chronic diabetes syndrome in various genetic and experimentally induced hyperglycemic models (1,2,5,8,13,15,21) by identifying the progressive nature of the hypercytolipidemia that characterizes this metabolic mutation.…”

“…Research has indicated that the acute (initial) expression of the mutation-induced cellular alterations continue to expand through chronic expression periods, culminating in tissue and organ involution, depressed metabolic activity (1,3,8,9), inhibition of adrenergic counterregulatory influences (11)(12)(13)(14)(15)(16), and, ultimately, reproductive tract atrophy. The severity of these cellular changes mimic the enhanced blood glucose and triglyceride concentrations that continue to increase across successive time periods (7,17,18).…”

Lipoatrophic Diabetes-Associated Utero-Ovarian Dysfunction: Influence of Cellular Lipid Deposition on Norepinephrine Indices

“…However, the ability to visibly localize the chemically identified amines by microscopic spectrofluorescence was impaired by the imbalance in cellular metabolism and pronounced tissue and cellular lipid accumulation [1, 2, 7]. The results support and extend previous observations that alterations in the intracellular uptake, production and deposition of triglycerides as intracellular lipids in hyperglycemic diabetics have deleterious consequences on cellular metabolism, vitality and function within the tissue framework [1, 2, 19]. The observed alterations in NE concentrations and localization suggest that the (db/db) mutation induces an intracellular, metabolic environment in the peripheral tissues of diabetics, modified by the enhanced cellular lipidemia, which interferes with the normal regulatory response to amine-influenced cellular homeostasis.…”

“…Recent studies suggest that the development-related increases in tissue NE levels in C57BL/KsJ (+ /?) mice are enhanced in hyperglycemic (db/db) mutants [13, 14], and that changes in noradrenergic-influenced cellular metabolism may be causally associated with the atrophic alterations in cellular structural and metabolic indices in this species [19]. To date, however, no combined histofluorescent and chemical evaluation of utero-ovarian tissue NE concentrations or localization during the initial onset of the diabetes syndrome has been reported.…”