Frontiers in Clinical Drug Research-Diabetes and Obesity

Volume: 3

Pharmacological Relevance of Novel Biomarkers Associated with Diabetes-mellitus Related Infertility

Author(s): Luis Rato, Marco G. Alves, Branca M. Silva and Pedro F. Oliveira

Pp: 114-194 (81)

DOI: 10.2174/9781681082479116030006

* (Excluding Mailing and Handling)

Abstract

Metabolic diseases are major public health problems both in developed and developing countries. Factors associated with lifestyle including physical inactivity and excessive consumption of high-energy diets are the primary causes for the increasing incidence of these pathologies. In parallel, an unprecedented decrease of fertility rates is also being witnessed. Male reproductive health is very sensitive to the insults induced by alterations in the metabolic status and the number of men suffering from metabolic diseases (such as diabetes mellitus and obesity) is dramatically high, being expected to increase even further in the next decades.

Diabetes mellitus is associated with a decrease in male reproductive potential and known to promote several sexual disorders, such as erectile dysfunction or retrograde ejaculation. Still, the “hidden effects” of this pathology on testicular physiology may lead to even more serious consequences for male fertility. Diabetes mellitus induces shifts in testicular metabolism, particularly in glucose metabolism, which is vital for the normal occurrence of spermatogenesis. So the maintenance of testicular glucose metabolism homeodynamics is of particular relevance; otherwise spermatogenesis may be arrested. For many years this issue was overlooked, but compelling evidence shows that spermatogenesis only occurs under a tight metabolic control. Thus, this subject is becoming a hot topic and will be on the spotlight in the next years. On the other hand, metabolic alterations induce pressure in biological systems whose responses are mediated by epigenetic modifications, particularly in sperm. These modifications are stable and can be passed to the subsequent generations, enhancing the transmission of phenotypes. Hence, the metabolic mechanisms responsible for the alterations in male reproductive health and subfertility/infertility in diabetic individuals deserve special attention.

p> This chapter will present cutting-edge information on the effects of diabetes mellitus in the testicular physiology and metabolism. It will be also discussed how this metabolic disease contributes to stable epigenetic changes that may alter not only male gametes’ function but also contribute to a potential transgenerational amplification of the current diabetes-related deleterious effects. Finally we will address the concept that testicular metabolism can be a potential pharmacologic target to counteract subfertility/infertility promoted by diabetes mellitus.


Keywords: Anti-diabetic drugs, Diabetes mellitus, Glucose metabolism, Highenergy diets, Hormonal control, Male infertility, Metabolic diseases, Metabolic reprogramming, Natural products, Oxidative stress, Reactive oxygen species, Sertoli cells, Sperm parameters, Spermatogenesis, Spermatozoa, Testicular biomarkers, Testicular metabolism, Therapeutic target, Transgenerational effects.

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      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740549785 and j.to_date >= 1740549785 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 9742) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740549785 and j.to_date >= 1740549785 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 9742) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740549785 and j.to_date >= 1740549785 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 9742)
      560μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1549
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 2185 and `b`.`banner_from_date` <= 1740549785 and `b`.`banner_to_date` >= 1740549785 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.13msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 2185
      • 3: 1740549785
      • 4: 1740549785
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='92817b065603c502b3815a4244a0051e'
      200μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Keywords
    19Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        V9Ck1OGLBqwJ6BQTBECJIHddMJb790inejbeDuj7
        uc_cart_id
        92817b065603c502b3815a4244a0051e
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/9742" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/9742
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:16 [ "x-https" => array:1 [ 0 => "1" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] "priority" => array:1 [ 0 => "u=0, i" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate, br, zstd" ] "sec-fetch-dest" => array:1 [ 0 => "document" ] "sec-fetch-user" => array:1 [ 0 => "?1" ] "sec-fetch-mode" => array:1 [ 0 => "navigate" ] "sec-fetch-site" => array:1 [ 0 => "none" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "sec-ch-ua-platform" => array:1 [ 0 => ""Windows"" ] "sec-ch-ua-mobile" => array:1 [ 0 => "?0" ] "sec-ch-ua" => array:1 [ 0 => ""HeadlessChrome";v="129", "Not=A?Brand";v="8", "Chromium";v="129"" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] ]
        request_cookies
        []
        
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Wed, 26 Feb 2025 06:03:05 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6Ik9RcXFiWE9LOHdpYnREQzFXempUWVE9PSIsInZhbHVlIjoiZnNucFFvMkhwQUdpQXpMRTNJVUpkeHRYd3hEcVF5RUNtSnRHS3V5Qm11M3MwYjBxNEdsZmVSTW5nR1FUYTR0bkFkSkZzSlU4dFAyQ2tKV0NYZFJNckF6SE41cTYzM1pjSkt2d2JpTlFTZkNISWh2WkpENzE4b2ZMZHUrNGN0UjIiLCJtYWMiOiJkMTg4MWIyOGIyNTc5YmVkNDNmNmExYTMzZDRlODM3NjgxYTdlMzFkYjlhMGE3NTk1NWNmY2RkMzk3ODhlMWQxIiwidGFnIjoiIn0%3D; expires=Fri, 28 Feb 2025 18:03:05 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6Ik9RcXFiWE9LOHdpYnREQzFXempUWVE9PSIsInZhbHVlIjoiZnNucFFvMkhwQUdpQXpMRTNJVUpkeHRYd3hEcVF5RUNtSnRHS3V5Qm11M3MwYjBxNEdsZmVSTW5nR1FUYTR0bkFkSkZzS" 1 => "alphaeurekaselectnet_session=eyJpdiI6ImZMUFNBcFpWOExVVTR2UXZvZnFvNVE9PSIsInZhbHVlIjoiNUlVc2k2bnRPMXhZdkNRV21OQ1lTbFdzQ2FQU3MvTTNNWUVnSkxYOVhYakR2ZnVZVFVzTVVpSllwMVBDaFBNVS81UUQ4RXFqYnhZbzFyMkV0Y2xITVdTOGVkWFBNUkZhQk5iQnBMSTcwdUMvYUgvMGZrU1IxYm53dENyT3RxUDgiLCJtYWMiOiI2ZjZhMDM0OGU3ZWQ4YjRiNDY5MThmNjM1NGY4NTQ0Mzg0Zjg4OWM0MTk5NzFlNDIwNmRlYjg5NDljZTdiNzUyIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6ImZMUFNBcFpWOExVVTR2UXZvZnFvNVE9PSIsInZhbHVlIjoiNUlVc2k2bnRPMXhZdkNRV21OQ1lTbFdzQ2FQU3MvTTNNWUVnSkxYOVhYakR2ZnVZVFVzTVVpSll" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6Ik9RcXFiWE9LOHdpYnREQzFXempUWVE9PSIsInZhbHVlIjoiZnNucFFvMkhwQUdpQXpMRTNJVUpkeHRYd3hEcVF5RUNtSnRHS3V5Qm11M3MwYjBxNEdsZmVSTW5nR1FUYTR0bkFkSkZzSlU4dFAyQ2tKV0NYZFJNckF6SE41cTYzM1pjSkt2d2JpTlFTZkNISWh2WkpENzE4b2ZMZHUrNGN0UjIiLCJtYWMiOiJkMTg4MWIyOGIyNTc5YmVkNDNmNmExYTMzZDRlODM3NjgxYTdlMzFkYjlhMGE3NTk1NWNmY2RkMzk3ODhlMWQxIiwidGFnIjoiIn0%3D; expires=Fri, 28-Feb-2025 18:03:05 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6Ik9RcXFiWE9LOHdpYnREQzFXempUWVE9PSIsInZhbHVlIjoiZnNucFFvMkhwQUdpQXpMRTNJVUpkeHRYd3hEcVF5RUNtSnRHS3V5Qm11M3MwYjBxNEdsZmVSTW5nR1FUYTR0bkFkSkZzS" 1 => "alphaeurekaselectnet_session=eyJpdiI6ImZMUFNBcFpWOExVVTR2UXZvZnFvNVE9PSIsInZhbHVlIjoiNUlVc2k2bnRPMXhZdkNRV21OQ1lTbFdzQ2FQU3MvTTNNWUVnSkxYOVhYakR2ZnVZVFVzTVVpSllwMVBDaFBNVS81UUQ4RXFqYnhZbzFyMkV0Y2xITVdTOGVkWFBNUkZhQk5iQnBMSTcwdUMvYUgvMGZrU1IxYm53dENyT3RxUDgiLCJtYWMiOiI2ZjZhMDM0OGU3ZWQ4YjRiNDY5MThmNjM1NGY4NTQ0Mzg0Zjg4OWM0MTk5NzFlNDIwNmRlYjg5NDljZTdiNzUyIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6ImZMUFNBcFpWOExVVTR2UXZvZnFvNVE9PSIsInZhbHVlIjoiNUlVc2k2bnRPMXhZdkNRV21OQ1lTbFdzQ2FQU3MvTTNNWUVnSkxYOVhYakR2ZnVZVFVzTVVpSll" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "V9Ck1OGLBqwJ6BQTBECJIHddMJb790inejbeDuj7" "uc_cart_id" => "92817b065603c502b3815a4244a0051e" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/9742" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-26 06:03:05GET/chapter/97421121921