Alterations in Hypothalamic KiSS-1 System in Experimental Diabetes: Early Changes and Functional Consequences

Abstract

Using long-term streptozotocin (STZ)-treated male rats, we recently proposed that defective function of hypothalamic KiSS-1 system is mechanistically relevant for central hypogonadotropism of uncontrolled diabetes. However, the temporal pattern of such defects and its potential contribution to disturbed gonadotropin secretion in the diabetic female remain so far unexplored. To cover these issues, expression analyses and hormonal tests were conducted in diabetic male (1 wk after STZ; short term) and female (4 wk after STZ; long term) rats. Short-term diabetic males had lower basal testosterone levels and decreased gonadotropin responses to orchidectomy (ORX), which associated with significantly attenuated post-ORX rises of hypothalamic KiSS-1 mRNA. Yet kisspeptin administration to diabetic males was able to acutely elicit supramaximal LH and testosterone responses and normalize post-ORX gonadotropin secretion. Long-term diabetic females showed persistent anestrus and significantly decreased basal gonadotropin levels as well as blunted LH responses to ovariectomy; changes that were linked to lowering of basal and postovariectomy expression of hypothalamic KiSS-1 mRNA. Moreover, despite prevailing gonadotropin suppression, LH responses to acute kisspeptin administration were fully preserved, and even enhanced after its repeated injection, in diabetic females. In sum, our present findings further define the temporal course and mechanistic relevance of altered hypothalamic KiSS-1 system in the hypogonadotropic state of uncontrolled diabetes. Furthermore, our data provide the basis for the potential therapeutic intervention of the KiSS-1 system as adjuvant in the management of disturbed gonadotropin secretion of type 1 diabetes in the female. The time-course and functional consequences of disturbances of the hypothalamic Kisspeptin-1-system in a rat model of uncontrolled diabetes are reviewed, with findings of potential physiopathologic and therapeutic implications for impaired fertility in type 1 diabetes.