The insulin sensitiser metformin regulates chicken Sertoli and germ cell populations

Abstract

Metformin, an insulin sensitiser from the biguanide family of molecules, is used for the treatment of insulin resistance in type 2 diabetes individuals. It increases peripheral glucose uptake and may reduce food intake. Based on the tight link between metabolism and fertility, we investigated the role of metformin on testicular function using in vitro culture of Sertoli cells and seminiferous tubules, complemented by in vivo data obtained following metformin administration to prepubertal chickens. In vitro, metformin treatment reduced Sertoli cell proliferation without inducing apoptosis and morphological changes. The metabolism of Sertoli cells was affected because lactate secretion by Sertoli cells increased approximately twofold and intracellular free ATP was negatively impacted. Two important pathways regulating proliferation and metabolism in Sertoli cells were assayed. Metformin exposure was not associated with an increased phosphorylation of AKT or ERK. There was a 90% reduction in the proportion of proliferating germ cells after a 96-h exposure of seminiferous tubule cultures to metformin. In vivo, 6-week-old chickens treated with metformin for 3 weeks exhibited reduced testicular weight and a 50% decrease in testosterone levels. The expression of a marker of undifferentiated germ cells was unchanged in contrast to the decrease in expression of 'protamine', a marker of differentiated germ cells. In conclusion, these results suggest that metformin affects the testicular energy content and the proliferative ability of Sertoli and germ cells.

Impact of 5'-amp-activated Protein Kinase on Male Gonad and Spermatozoa Functions

“…In chicken (7–10 weeks old), metformin induced a decrease in testis weight, in the proliferative activity of Sertoli cells and in germ cells population, but not in spermatogonia population. Metformin also decreased testosterone levels in chicken Sertoli cells (Faure et al, 2016). These data suggest that the AMPK pathway is involved in the nutritional modulation of the male gonad and spermatozoa production.…”

“…In rat Leydig cells, the use of the AMPK activator resveratrol decreased testosterone secretion through a reduction in cholesterol transport into the mitochondria and decreased conversion of progesterone into androstenedione (Svechnikov et al, 2009). In chicken testis, the AMPKα1/2 subunit is found in seminiferous tubules and in Leydig cells, AMPKβ1/2 and AMPKγ1 subunits in seminiferous tubules as well, and AMPKγ3 in Leydig cells (Faure et al, 2016). In chicken (7–10 weeks old), metformin induced a decrease in testis weight, in the proliferative activity of Sertoli cells and in germ cells population, but not in spermatogonia population.…”

Metformin in Reproductive Biology

“…In birds, metformin (1 mM) treatment increased viability, mobility and acrosomal response of chicken sperm ( 72 ). During chicken seminiferous tubule culture, 48 h of metformin treatment (5 mM) induced a decrease in the rate of proliferative germ cells number ( 73 ). This effect was opposite to that observed in equines.…”

Metformin use during pregnancy: Is it really safe?

“…18 Further, metformin reduced testicular weight and testosterone production in prepubertal chickens. 19 Metformin treatment during pregnancy caused changes in the sexual behavior of and reduced the sperm count in the male offspring of female Wistar rats. 20 It must be acknowledged that there is still a lot of debate as to whether animal models do predict the effects of endocrine disruptors in humans.…”

“…Metformin can upregulate a number of genes associated with an endocrine‐disrupting profile, including those for the androgen receptor, 3β‐hydroxysteroid dehydrogenase (HSD) and 17β‐HSD in the male gonads . Further, metformin reduced testicular weight and testosterone production in prepubertal chickens . Metformin treatment during pregnancy caused changes in the sexual behavior of and reduced the sperm count in the male offspring of female Wistar rats .…”