Directed overexpression of insulin in Leydig cells causes a progressive loss of germ cells

Institute of Human Genetics, University of Göttingen, Heinrich-Düker-Weg 12, D-37073 Göttingen, Germany.
Molecular and Cellular Endocrinology (Impact Factor: 4.41). 08/2008; 295(1-2):79-86. DOI: 10.1016/j.mce.2008.07.007
Source: PubMed


The primary goal of this study was to determine the 5'region of the Insl3 gene that specifically targets the expression of human insulin to Leydig cells, and to explore whether the testicular proinsulin is efficiently processed to insulin that is able to rescue the diabetes in different mouse models of diabetes. We show here that the sequence between nucleotides -690 and +4 of mouse Insl3 promoter is sufficient to direct the Leydig cell-specific expression of the human insulin transgene (Insl3-hIns). We also found that the 3'untranslated region (3'UTR) of Insl3 was effective in enhancing transgene expression of the insulin in vivo. Expression analysis revealed that the temporal expression pattern of the hIns transgene in Leydig cells of transgenic testes is roughly the same as that of the endogenous Insl3. Despite the Leydig cells translate human proinsulin and secrete a significant level of free C-peptide into the serum, the Leydig cell-derived insulin is not able to overcome the diabetes in different mouse models of diabetes, suggesting a lack of glucose sensing mechanisms in the Leydig cells. A consequence of overexpression of the human proinsulin in Leydig cells was the decrease of fertility of transgenic males at older ages. Germ cells in transgenic males were able to initiate and complete spermatogenesis. However, there was a progressive and age-dependent degeneration of the germ cells that lead to male infertility with increasing age.

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Available from: Detlef Boehm, Dec 06, 2014
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    • "Furthermore poor semen quality has also been reported in DM1 men, including decreased sperm motility and concentration, abnormal morphology, and increased seminal plasma abnormalities [10, 11]. In addition, diabetic men may have decreased serum testosterone due to impaired Leydig cell function in line with SCOS [12]. The reason for this was not conclusively investigated. "
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    ABSTRACT: The aim was to report an unusual case of insulinoma presenting with long-standing depression and primary testicular failure. We describe a 34-year-old male with clinical, laboratory, and radiologic data consistent with islet cell tumor and seminiferous tubule failure primary hypogonadism. The literature is reviewed relative to the component of this syndrome, and a possible association is discussed. The subject was investigated for a long-standing history of depression requiring medical attention because of mental confusion and slurred speech and was found to have an insulinoma. He was diagnosed with primary gonadal failure and physical examination showed no evidence of dysmorphic features. Chromosomal analysis revealed normal 46 XY and testicular biopsy showed Sertoli cell only syndrome (SCOS). Biochemistry revealed endogenous hyperinsulinism and histology confirmed an islet cell tumor. He remained euglycemic postoperatively and on followup. From this report, we emphasize drawing clinicians' attention to the possibility of an association between insulinoma and primary testicular failure and suggest consideration of this diagnosis in patients with hypergonadotropic hypogonadism who may present with infertility.
    Full-text · Article · Dec 2013 · Case Reports in Endocrinology

  • No preview · Article · Jan 2009 · Annales UMCS Pharmacia
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    ABSTRACT: BACKGROUND Insulin-like factor 3 (INSL3) is a neohormone that has evolved to address specific mammalian traits, in particular, the first phase of testicular descent towards the scrotum during mid-gestation. METHODS A thorough literature search was made in PubMed using the terms INSL3, as well as the older synonyms RLF and Ley-IL. RESULTS INSL3 is a major secretory product of the testicular Leydig cells in the fetus and in adult men, and in rodent models, reduction in fetal INSL3 expression is an early marker of the testicular dysgenesis syndrome. In women, it is produced in lower amounts by ovarian theca and luteal cells, and circulating levels are increased in women with polycystic ovarian syndrome. During pregnancy, there is evidence for an interaction regulating the feto-placental unit. The presence of INSL3 in amniocentesis samples taken at 12-14 weeks gestation is absolutely specific for male gender, and levels are predictive of subsequent pre-eclampsia and/or birthweight. INSL3 is also involved in adult traits, such as spermatogenesis and bone metabolism. In adult men, INSL3 is constitutively expressed and secreted into the bloodstream at a constant level, reflecting the number and/or functional capacity of the Leydig cells. In complete contrast, testosterone is highly variable within individuals, is acutely responsive to fluctuations in the hypothalamic-pituitary-gonadal axis and appears to have marginal diagnostic value. INSL3 declines consistently with age in adult men. CONCLUSIONS INSL3 promises to become an important new diagnostic tool to characterize those men with late-onset hypogonadism and to add clinical diagnostic value at amniocentesis.
    No preview · Article · Apr 2009 · Human Reproduction Update
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