Insulin Receptor Substrate 2 Is Required for Testicular Development

Abstract

Insulin receptor substrate (IRS) proteins are key mediators of insulin and insulin-like growth factor (IGF) signalling. In mice, deletion of Irs1 is associated with profound growth retardation and increased longevity whereas Irs2-deficiency causes diabetes and female infertility. Clinical studies suggest that diabetes and obesity diminish male fertility. However, the role of IRS proteins in male reproduction is unknown. We observed that testis weight is reduced by 45% in Irs2-deficient mice as compared with control males. The weight of these organs in Irs1 −/− males was similar to controls; however, since Irs1-deficient mice are 50% smaller, testis weight:body weight was increased in this model. Neonatal Irs2 −/− mice also exhibited reduced testicular size, suggesting that impairments in this model occur during development. Histological examination of testicular cross sections from Irs2 −/− mice revealed normal cellular associations without obvious abnormalities in the seminiferous epithelium. Reduced testicular weight was associated with fewer Sertoli cells, spermatogonia, spermatocytes, elongated spermatids, and epididymal spermatozoa. However, Leydig cell number and the concentration of serum testosterone were equivalent between Irs2-deficient and control males. Testicular weight was reduced similarly in non-diabetic and diabetic Irs2 −/− mice, indicating that hyperglycemia does not compound the effects of Irs2 deletion on impaired testis development. Expression of Irs1, Irs3, and Irs4 was comparable between experimental groups. Collectively, our results demonstrate that IRS2 plays a critical role in testicular development, potentially by mediating IGF1 signalling during embryonic and early postnatal development.

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

“…Our results showed decreased testicular weights (26%) in all diabetic mice. 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).…”

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

“…Finally, KO studies focused on insulin superfamily members (Baker et al 1996, Burnicka-Turek et al 2012, their receptors (Nef et al 2003) or on intermediaries of insulin signaling pathway (Griffeth et al 2013), provided further data supporting the importance of insulin signaling pathway on the male reproductive function, namely on testicular aspects and sperm characteristics (Baker et al 1996, Burnicka-Turek et al 2012, Griffeth et al 2013 as well as on male sex determination during development (Nef et al 2003) are present.…”

The Effects of the Wild African Potato (Hypoxis hemerocallidea) Supplementation on Streptozotocin-Induced Diabetic Wistar Rats Reproductive Function

“…Testosterone is responsible for regulating and maintaining growth and proper functioning of the reproductive organs [42,43]. Testicular size has been directly linked to spermatogenesis and sperm quality [44,45]. In this study it was observed that there was a significant decrease in body weights after the 6 week period in the diabetic control group when compared to the normal control group as well as when compared to their initial weights.…”