Insulin Rescues Impaired Spermatogenesis via the Hypothalamic-Pituitary-Gonadal Axis in Akita Diabetic Mice and Restores Male Fertility

Abstract

The mechanism responsible for poor reproductive outcomes in type 1 diabetic males is not well understood. In light of new evidence that the Sertoli cells of the testis secrete insulin, it is currently unclear whether diabetic subfertility is the result of deficiency of pancreatic insulin, testicular insulin, or both. In this study, the Akita mouse diabetic model, which expresses a mutant, nonfunctional form of ins2 in testes and pancreas, was used to distinguish between systemic and local effects of insulin deficiency on the process of spermatogenesis and fertility. We determined that Akita homozygous male mice are infertile and have reduced testis size and abnormal morphology. Spermatogonial germ cells are still present but are unable to mature into spermatocytes and spermatids. Exogenous insulin treatment regenerates testes and restores fertility, but this plasma insulin cannot pass through the blood-testis barrier. We conclude that insulin does not rescue fertility through direct interaction with the testis; instead, it restores function of the hypothalamic-pituitary-gonadal axis and, thus, normalizes hormone levels of luteinizing hormone and testosterone. Although we show that the Sertoli cells of the testis secrete insulin protein, this insulin does not appear to be critical for fertility.

Effects of concomitant diabetes mellitus and hyperthyroidism on testicular and epididymal histoarchitecture and steroidogenesis in male animals

“…Similarly, in adult IRS2 (Insulin Receptor Substrate 2) deficient mice (8-12 weeks of age), reduced testicular weight (45%) was reported (Griffeth et al, 2013). Furthermore, reduced testicular weights were also observed in Akita homozygous mice at the age of 9 weeks (Schoeller et al, 2012).…”

“…Similarly, reduced levels of testosterone and luteinizing hormone (LH), along with normal follicle-stimulating hormone (FSH), have been reported earlier in Akita homozygous mice (mutant at ins2 gene) in comparison to wild-type animals (Schoeller et al, 2012). Insulin is known to affect the hypothalamic-pituitary axis, which can alter serum levels of hormones important in spermatogenesis (Bucholtz et al, 2000).…”

Nutritional modifications in male infertility: a systematic review covering 2 decades

“…Data suggests that low-fat milk intake may be associated with increased levels of circulating insulin growth factor 1 (IGF-1) and insulin. 70 Results from animal studies indicate that insulin has the potential to rescue spermatogenesis in type 1 diabetic mice 74 as well as increase sperm motility and sperm concentration in rats. 9 Furthermore, it has been demonstrated that IGF-1 protects equine Leydig cells from undergoing apoptosis in vitro.…”

Antidiabetic therapies and male reproductive function: where do we stand?

“…In fact, this degenerative disease was described to affect not only sperm quality and function R S Tavares and others R14 (Bartak et al 1975, Padron et al 1984, Handelsman et al 1985, Vignon et al 1991, Baccetti et al 2002, Soudamani et al 2005, Amaral et al 2006, Scarano et al 2006, Agbaje et al 2007, Delfino et al 2007, Shrilatha & Muralidhara 2007a, Rama Raju et al 2012, Roessner et al 2012, Schoeller et al 2012a, Mangoli et al 2013 but also the hypothalamus-pituitary-gonadal axis (HPG) (Benitez & Perez Diaz 1985, Seethalakshmi et al 1987, Sudha et al 2000, Baccetti et al 2002, Lopez-Alvarenga et al 2002, Ballester et al 2004, Kim & Moley 2008, Schoeller et al 2012b, the testicular function and spermatogenesis (Cameron et al 1985, Gondos & Bevier 1995, Sanguinetti et al 1995, Sainio-Pollanen et al 1997, Ballester et al 2004, Arikawe et al 2006, Amaral et al 2009, Kianifard et al 2012, Schoeller et al 2012b, Wankeu-Nya et al 2013, Kyathanahalli et al 2014, Tavares et al 2016, the accessory organs (epididymis, prostate and seminal vesicles) (Murray et al 1981, Fukumoto et al 1993, Ikeda et al 2000, Saito et ...…”

“…Studies in diabetic individuals or in diabetic conditions, provided important insights concerning the importance of insulin (its absence or excess) to the male reproductive system, with several studies reporting that the reproductive changes found in diabetic individuals could be reverted or attenuated by insulin treatment (Seethalakshmi et al 1987, Gondos & Bevier 1995, Ikeda et al 2000, Yamanaka et al 2003, Kim & Moley 2008, Singh et al 2009, Yonezawa et al 2009, Schoeller et al 2012a.…”