Frontiers in Clinical Drug Research-Diabetes and Obesity

Volume: 4

Through the Perspective of Histology - The Alzheimer’s Disease Promotion by Obesity and Glucose Metabolism: Type 3 Diabetes

Author(s): Cigdem Elmas and Cemile Merve Seymen

Pp: 135-198 (64)

DOI: 10.2174/9781681084459119040007

* (Excluding Mailing and Handling)

Abstract

Since the 1990s The World Health Organisation (WHO) has stated that “… obesity should now be regarded as one of the greatest neglected public health problems of our time…” and defined the global epidemic of being overweight and obese as “globesity”. A positive energy balance, which consists of an imbalance between energy intake and calorie expenditure is the main cause of obesity, however, genetic, environmental, socioeconomical, behavioral and psychological factors may also be the inducing factors when it comes to obesity. The excess of adiposity has an enhancing effect on the development of hypertension, cardiovascular diseases and type 2 diabetes mellitus (T2DM) as a result of the resistance to insulin-mediated glucose disposal. T2DM which represents a common disease associated with obesity and often aging is characterized by high blood glucose levels, impaired insulin production and peripheral insulin resistance. Homeostatic degradation of glucose affects the cerebral functions directly or indirectly because glucose is a significant metabolic substrate for all cells and also for the cells of the brain. Insulin has a key effect on the regulation of energy metabolism of neurons and neuronal recovery, which acts as a growth factor on all cells including neurons in the central nervous system. Therefore, simply put, impairment in neuronal homeostasis which occurs as a result of insulin deficiency. These are considered to be a risk factor for Alzheimer’s disease (AD) development. Indeed, many studies have shown that glucose intolerance and impairment of insulin secretion are associated with a higher risk to develop dementia or AD. It is worth remembering that AD is associated with brain insulin resistance and deficiency, whereas T2DM is associated with peripheral insulin resistance. In short, it can be said that T2DM causes AD-type neurodegeneration in the brain. T2DM and AD share several molecular processes that underlie the degenerative developments. Dysregulated glucose metabolism, abnormalities in insulin signaling, the formation of advanced glycation end products, oxidative stress, the activation of inflammatory pathways and abnormal protein processing are the common characteristics of T2DM and AD. The misfolding of proteins plays an important role in both diseases, so as the aggregation of amyloid peptides. AD is characterized by the deposition of amyloid within neurons and amyloid plaques. Also in AD, the formation of amyloid fibers could be the product of ubiquitin-mediated protein degradation defects induced by a dysfunction of the proteasome. According to one study which was conducted on T2DM rats, T2DM-dependent decreases in p62 (a known cargo molecule that transports polyubiquitinated tau to proteosomal and autophagic degradation systems) transcription which is a primary mechanism underlying increased AD-like pathology. In some studies, brain amyloid deposition occurs as a result of increased blood-brain barrier permeability in case of diabetes conditions. In the recent years, according to some members of the diabetes community, AD is seen as a neuroendocrine disorder and the term “Type 3 Diabetes” defines the insulin deficiency and resistance in the brain of those with AD. In the context of these information, in this chapter, we propose a study about “Type 3 Diabetes” with the underlying mechanisms through the perspective of histology.


Keywords: Advanced Glycation Products, Alzheimer’s Disease, Amyloid Beta Deposition, Calcium Dysregulation, Ceramides, Endoplasmic Reticulum Stress, Glucose Metabolism, Inflammatory Response, Insulin, Insulin Degrading Enzyme, Insulin Resistance, Mitochondrial Dysfunction, Neurofibrillary Tangles, Neuronal Homeostasis, Neurodegeneration, Obesity, Oxidative Stress, Tau Hyperphosphorylation, The Apolipoprotein E, Toll-Like Receptors, Type 2 Diabetes Mellitus, Type 3 Diabetes, Ubiquitin Proteosome System.

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      • 13. app/Models/UserAccess/UserAccess.php:1266
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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 <= 59424481 and j.to_ip >=59424481 )) and ((j.from_date <= 1740551471 and j.to_date >= 1740551471 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 12850) 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 <= 59424481 and j.to_ip >=59424481 )) and ((j.from_date <= 1740551471 and j.to_date >= 1740551471 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 12850) 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 <= 59424481 and j.to_ip >=59424481 )) and ((j.from_date <= 1740551471 and j.to_date >= 1740551471 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 12850)
      550μsalphaeurekaselec_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` = 2247 and `b`.`banner_from_date` <= 1740551471 and `b`.`banner_to_date` >= 1740551471 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.07msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 2247
      • 3: 1740551471
      • 4: 1740551471
      • 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='6d5a7c7fba4b8397dfae8ef2dc44309c'
      240μsalphaeurekaselec_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
    23Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        1VbvfeHbEzd1ywADHcdAZxQ883nQhFaHw0oqVqNB
        uc_cart_id
        6d5a7c7fba4b8397dfae8ef2dc44309c
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/12850" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/12850
        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:17 [ "x-https" => array:1 [ 0 => "1" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] "priority" => array:1 [ 0 => "u=0, i" ] "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6ImNPRzNSVWprdHJ6Q0d6dWJBaEhuWHc9PSIsInZhbHVlIjoiR1owaXBKcWZsWjA3eTVWWTJ3VnZYZzU5TnJuWHlTWTNjSDAxTnpBb2lkUT0iLCJtYWMiOiJiOGViZDI4MmE5NTY3NDYyNWZkYzkyYWFkYzI2Y2UzZWYxODNjMDcwNzgxOWFjYWI1M2IzMGJhYTA3ZjI5YmZlIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6ImNPRzNSVWprdHJ6Q0d6dWJBaEhuWHc9PSIsInZhbHVlIjoiR1owaXBKcWZsWjA3eTVWWTJ3VnZYZzU5TnJuWHlTWTNjSDAxTnpBb2lkUT0iLCJtYWMiOiJiOGViZDI4MmE5NTY3" ] "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
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        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 06:31:11 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6InQxRW8wVXJTdll2cGd2cVRSOUFtRkE9PSIsInZhbHVlIjoiRzhjaEowZVRpNkFGaGYwTTYvblFURVlWREovdlFKc2ZQd1RMTEJRMk5qVUJBTndjU2xDakN3dGtXMXZFbVZsNFFUZ0p1eGEzSnFCRlFwZmw3V21YSUluTmgrSmFCTWZFZHhkQWhiblJKazl3Q2phYWU0ZnR0QlpwR0pqVnlOUmIiLCJtYWMiOiI4MmExZmFhYzM2YWI4MGU5ZDRmODE4NDBkNmJiM2I5ZGRhMzcyMzVmNjVmODQ0MmIzYmRmNzJmNDUwOTQwNjIzIiwidGFnIjoiIn0%3D; expires=Fri, 28 Feb 2025 18:31:11 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6InQxRW8wVXJTdll2cGd2cVRSOUFtRkE9PSIsInZhbHVlIjoiRzhjaEowZVRpNkFGaGYwTTYvblFURVlWREovdlFKc2ZQd1RMTEJRMk5qVUJBTndjU2xDakN3dGtXMXZFbVZsNFFUZ0p1e" 1 => "alphaeurekaselectnet_session=eyJpdiI6IlA4Y2xEd0hUVjYzSGtZZ2FFUVpzZFE9PSIsInZhbHVlIjoiSXgwMCtxTEhQdGJZRnc3VjBvZFgwcnpIMWdyaXJXb1J1NTFma0w4Y01EdEFoR1hsbGtXanVZc1AxYVRtUlk1UkxMSUUvbnpOTytvM0FsOVUybjBzQ1FNZjRiQzY0VHRzVUpkK0txdW1Pak96QjhKNFhlWlZWbWVJT1NPNFNqWGciLCJtYWMiOiIxMDMxMTIzNjkyOTExZDk5ZTZkYjM2YzUwMTliZTg0ZTdjYWQyNDFjNzBmMzdiM2NmMjNiMGY2MDVkNTIxNzVjIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IlA4Y2xEd0hUVjYzSGtZZ2FFUVpzZFE9PSIsInZhbHVlIjoiSXgwMCtxTEhQdGJZRnc3VjBvZFgwcnpIMWdyaXJXb1J1NTFma0w4Y01EdEFoR1hsbGtXanVZc1A" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6InQxRW8wVXJTdll2cGd2cVRSOUFtRkE9PSIsInZhbHVlIjoiRzhjaEowZVRpNkFGaGYwTTYvblFURVlWREovdlFKc2ZQd1RMTEJRMk5qVUJBTndjU2xDakN3dGtXMXZFbVZsNFFUZ0p1eGEzSnFCRlFwZmw3V21YSUluTmgrSmFCTWZFZHhkQWhiblJKazl3Q2phYWU0ZnR0QlpwR0pqVnlOUmIiLCJtYWMiOiI4MmExZmFhYzM2YWI4MGU5ZDRmODE4NDBkNmJiM2I5ZGRhMzcyMzVmNjVmODQ0MmIzYmRmNzJmNDUwOTQwNjIzIiwidGFnIjoiIn0%3D; expires=Fri, 28-Feb-2025 18:31:11 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6InQxRW8wVXJTdll2cGd2cVRSOUFtRkE9PSIsInZhbHVlIjoiRzhjaEowZVRpNkFGaGYwTTYvblFURVlWREovdlFKc2ZQd1RMTEJRMk5qVUJBTndjU2xDakN3dGtXMXZFbVZsNFFUZ0p1e" 1 => "alphaeurekaselectnet_session=eyJpdiI6IlA4Y2xEd0hUVjYzSGtZZ2FFUVpzZFE9PSIsInZhbHVlIjoiSXgwMCtxTEhQdGJZRnc3VjBvZFgwcnpIMWdyaXJXb1J1NTFma0w4Y01EdEFoR1hsbGtXanVZc1AxYVRtUlk1UkxMSUUvbnpOTytvM0FsOVUybjBzQ1FNZjRiQzY0VHRzVUpkK0txdW1Pak96QjhKNFhlWlZWbWVJT1NPNFNqWGciLCJtYWMiOiIxMDMxMTIzNjkyOTExZDk5ZTZkYjM2YzUwMTliZTg0ZTdjYWQyNDFjNzBmMzdiM2NmMjNiMGY2MDVkNTIxNzVjIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IlA4Y2xEd0hUVjYzSGtZZ2FFUVpzZFE9PSIsInZhbHVlIjoiSXgwMCtxTEhQdGJZRnc3VjBvZFgwcnpIMWdyaXJXb1J1NTFma0w4Y01EdEFoR1hsbGtXanVZc1A" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "1VbvfeHbEzd1ywADHcdAZxQ883nQhFaHw0oqVqNB" "uc_cart_id" => "6d5a7c7fba4b8397dfae8ef2dc44309c" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/12850" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-26 06:31:11GET/chapter/128501121925