Cukrzyca typu 2 – Patofizjologia i mechanizm

Cukrzyca typu 2
Patofizjologia i mechanizm

Cukrzyca typu 2 (T2DM) jest złożonym zaburzeniem metabolicznym, w którym kluczową rolę odgrywają insulinooporność tkanek obwodowych (mięśnie, wątroba, tkanka tłuszczowa) oraz dysfunkcja komórek β trzustki. Insulinooporność, występująca nawet 10-20 lat przed klinicznym rozpoznaniem, prowadzi do zmniejszonego wychwytu glukozy i nadmiernej produkcji glukozy w wątrobie, co skutkuje hiperglikemią na czczo i poposiłkową. Na poziomie molekularnym defekty w fosforylacji receptorów insulinowych i białek IRS, a także akumulacja metabolitów lipidowych (DAG, ceramidy) zaburzają sygnalizację insulinową i ekspresję GLUT4. Dysfunkcja komórek β objawia się początkowo kompensacyjną hiperinsulinemią, a następnie ich apoptozą, dedyferencjacją i transróżnicowaniem, co prowadzi do względnego niedoboru insuliny i progresji hiperglikemii. Dodatkowo, nieprawidłowe wydzielanie glukagonu przez komórki α, zaburzenia osi inkretynowej (m.in. GLP-1) oraz przewlekły stan zapalny o niskim stopniu nasilają patogenezę choroby. Dysfunkcja mitochondrialna i stres retikulum endoplazmatycznego również przyczyniają się do uszkodzenia komórek β, a zmiany epigenetyczne (metylacja DNA, modyfikacje histonów) wpływają na ekspresję genów związanych z metabolizmem glukozy i funkcją komórek β.

Patogeneza cukrzycy typu 2

Insulinooporność jako kluczowy mechanizm
Molekularne mechanizmy insulinooporności
Rola ektopowej akumulacji tłuszczu
Dysfunkcja komórek β trzustki
Zaburzenia wydzielania glukagonu
Rola czynników zapalnych i adipokin
Rola mikrobioty jelitowej
Defekt inkretynowy

Współzależności i mechanizmy kompensacyjne

Metylacja DNA i epigenetyka

Podsumowanie patogenezy cukrzycy typu 2

Implikacje kliniczne
Kolejne rozdziały

Patogeneza cukrzycy typu 2

Cukrzyca typu 2 (T2DM) jest złożonym zaburzeniem metabolicznym charakteryzującym się hiperglikemią wynikającą z kombinacji dwóch podstawowych czynników: zaburzeń wydzielania insuliny przez komórki β trzustki oraz niezdolności tkanek wrażliwych na insulinę do prawidłowej odpowiedzi na jej działanie¹². Oba te defekty muszą współistnieć, aby doszło do rozwoju pełnoobjawowej cukrzycy typu 2³. Wady w mechanizmach zaangażowanych w te procesy prowadzą do zaburzeń metabolicznych odpowiedzialnych za rozwój choroby¹.

Insulinooporność jako kluczowy mechanizm

Insulinooporność stanowi centralny element patogenetyczny cukrzycy typu 2 i definiowana jest jako zmniejszona odpowiedź tkanek docelowych na fizjologiczne stężenia insuliny⁴. Insulinooporność występuje na 10-20 lat przed klinicznym rozpoznaniem choroby i jest jej najlepszym predyktorem⁵. W stanie insulinooporności komórki mięśni, wątroby i tkanki tłuszczowej nie reagują prawidłowo na insulinę, co prowadzi do zmniejszonego wychwytu glukozy i nasilenia produkcji glukozy w wątrobie⁶⁷.

W wątrobie insulina w warunkach prawidłowych hamuje produkcję glukozy. Jednakże w stanie insulinooporności wątroba nieprawidłowo uwalnia glukozę do krwi, przyczyniając się do hiperglikemii na czczo⁸⁹. W mięśniach szkieletowych insulinooporność prowadzi do zmniejszonego wychwytu glukozy po posiłkach, co skutkuje hiperglikemią poposiłkową¹⁰. Insulinooporność mięśni szkieletowych jest uważana za jeden z najistotniejszych pozatrzustkowych czynników w rozwoju cukrzycy typu 2¹¹.

Molekularne mechanizmy insulinooporności

Na poziomie molekularnym insulinooporność związana jest z defektami w szlakach sygnałowych, prowadzącymi do zmniejszonej fosforylacji tyrozyny receptora insulinowego i białek IRS (insulin receptor substrate)¹². Skutkuje to zmniejszeniem ekspresji transportera glukozy GLUT4 na powierzchni komórek, ograniczając wychwyt glukozy¹².

Najbardziej prawdopodobną hipotezą wyjaśniającą molekularne mechanizmy insulinooporności jest udział metabolitów lipidowych, takich jak diacyloglicerol (DAG), kwas lizofosfatydowy (LPA), ceramidy i acylokarnityny¹³¹⁴. Akumulacja DAG w komórkach mięśniowych upośledza sygnalizację insulinową poprzez aktywację kinazy białkowej C (PKC), która fosforyluje białko IRS-1 w pozycji Ser1101, blokując insulino-zależną fosforylację IRS-1¹³.

Ceramidy również odgrywają ważną rolę w patogenezie insulinooporności. Hamowanie syntezy ceramidów przy użyciu miriocyny, inhibitora seryno-palmitylotransferazy, zapobiegało insulinooporności i zmniejszało zawartość ceramidów u myszy karmionych dietą wysokotłuszczową¹³. Dokładny mechanizm, w jaki ceramidy indukują insulinooporność, nie został w pełni wyjaśniony, ale proponowane mechanizmy obejmują upośledzenie translokacji kinazy AKT poprzez aktywację atypowej PKC oraz aktywację fosfatazy PP2A¹³.

Rola ektopowej akumulacji tłuszczu

Ektopowa akumulacja lipidów w tkankach obwodowych, szczególnie w wątrobie i mięśniach szkieletowych, może prowadzić do nasilenia insulinooporności, nawet przy braku otyłości trzewnej¹⁵. Liczne badania wykazały, że akumulacja lipidów w wątrobie i mięśniach szkieletowych spowodowana krótkotrwałym karmieniem dietą wysokotłuszczową lub infuzją lipidów/heparyny indukuje insulinooporność u szczurów¹⁵.

W kontekście insulinooporności, wykazano, że cykl glukoza-kwasy tłuszczowe powinien zwiększać poziom glukozo-6-fosforanu i syntezę glikogenu poprzez działanie kwasów tłuszczowych, a glikoliza powinna być hamowana. Jednakże ekspozycja na wysokie stężenia kwasów tłuszczowych w osoczu powodowała insulinooporność i zmniejszała stężenie glukozo-6-fosforanu w mięśniach zdrowych osób¹⁵.

Dysfunkcja komórek β trzustki

Dysfunkcja komórek β trzustki stanowi drugi kluczowy element patogenezy cukrzycy typu 2 i objawia się niedostatecznym wydzielaniem insuliny w odpowiedzi na insulinooporność i hiperglikemię¹⁶¹⁷. W początkowym okresie rozwoju cukrzycy typu 2, komórki β kompensują insulinooporność poprzez zwiększenie wydzielania insuliny (hiperinsulinemia), co pozwala utrzymać normoglikemię¹⁸. Z czasem jednak komórki β nie są w stanie podtrzymać tej nadmiernej produkcji insuliny, co prowadzi do ich dysfunkcji i apoptozy¹⁹.

Tradycyjnie dysfunkcję komórek β przypisywano utracie masy komórek β z powodu ich wyczerpania w stanie przedłużonej hiperglikemii i zwiększonego wydzielania insuliny, a także apoptozy komórek β spowodowanej glukotoksycznością i lipotoksycznością¹¹. Jednakże coraz więcej dowodów sugeruje, że dysfunkcja komórek β w cukrzycy typu 2 może wynikać z bardziej złożonych mechanizmów i interakcji¹⁶.

Dedyferencjacja i transróżnicowanie komórek β

Jednym z proponowanych mechanizmów jest dedyferencjacja komórek β, proces definiowany jako utrata czynników transkrypcyjnych charakterystycznych dla komórek β¹¹. Taka utrata tożsamości komórki β może być wynikiem glukotoksyczności¹¹. Udowodniono, że dedyferencjacja jest istotnym mechanizmem dysfunkcji i utraty komórek β podczas progresji cukrzycy typu 2²⁰²¹.

Innym mechanizmem jest transróżnicowanie komórek β, czyli proces przekształcania jednego w pełni zróżnicowanego typu komórek w inny¹¹. Część zdedyferencjowanych komórek wykazuje fenotyp podobny do komórek egzokrynnych, co wiąże się z głęboką dysfunkcją²¹.

Glukotoksyczność i lipotoksyczność

Przewlekła hiperglikemia może prowadzić do glukotoksyczności, która sprzyja rozwojowi i progresji cukrzycy typu 2. Podwyższone poziomy NADH i reaktywnych form tlenu (ROS), które występują w przewlekłej hiperglikemii, są związane z dysfunkcją komórek β¹¹. Nadmiar wolnych kwasów tłuszczowych (FFA) i hiperglikemia prowadzą do dysfunkcji komórek β poprzez indukcję stresu retikulum endoplazmatycznego (ER) i aktywację apoptotycznych szlaków odpowiedzi na nieprawidłowo sfałdowane białka (UPR)¹⁶¹⁷.

Nadmierne FFA hamują wydzielanie insuliny i upośledzają funkcję komórek β (lipotoksyczność), podczas gdy przewlekła hiperglikemia (glukotoksyczność) również przyczynia się do dysfunkcji komórek β¹⁸. Gdy cukrzyca typu 2 staje się jawna klinicznie, osoba chora traci około połowy swoich komórek β⁸.

Dysfunkcja mitochondriów i stres oksydacyjny

Dysfunkcja mitochondriów jest kolejnym czynnikiem, który może prowadzić do dysfunkcji komórek β w cukrzycy typu 2. Zaobserwowano, że mitochondria u osób z cukrzycą typu 2 są mniejsze, sfragmentowane i obrzęknięte¹¹. Istnieje coraz więcej dowodów łączących dysfunkcję mitochondrialną z rozwojem cukrzycy typu 2, insulinoopornością związaną z wiekiem i powikłaniami cukrzycy¹⁶.

Generowanie reaktywnych form tlenu (ROS) jest ściśle związane z relacją między dysfunkcją mitochondrialną a insulinoopornością¹⁶¹⁷. Utrzymujący się i znaczny wzrost stężenia ROS przyczynia się istotnie do patogenezy cukrzycy typu 2 i insulinooporności¹⁷. Nadmierne wytwarzanie ROS przez mitochondria przyczynia się do przyspieszenia progresji cukrzycy typu 2¹⁶.

Zaburzenia wydzielania glukagonu

W patogenezie cukrzycy typu 2 istotną rolę odgrywa również nieprawidłowe wydzielanie glukagonu przez komórki α trzustki, szczególnie w okresie poposiłkowym⁶. Wiąże się to z utratą tonicznych hamujących sygnałów, które w warunkach prawidłowych wywierane są przez wysokie lokalne stężenia insuliny na komórki α²².

Nieprawidłowo zwiększona funkcja komórek α istotnie przyczynia się do hiperglikemii i odzwierciedla utratę tonicznych ograniczeń normalnie wywieranych przez wysokie lokalne stężenia insuliny na komórki α, prawdopodobnie w wyniku niewydolności komórek β i insulinooporności komórek α, ale zasugerowano również dodatkowe mechanizmy, takie jak udział hormonów inkretynowych w tej odpowiedzi²².

Utrata odwrotnej zależności między insuliną a glukagonem u pacjentów z cukrzycą typu 2 może być wtórna do zaobserwowanej zmniejszonej masy pulsów insuliny i sugeruje, że zmiany w interakcji między komórkami β i α mogą leżeć u podstaw hiperglukagonemii²².

Rola czynników zapalnych i adipokin

Coraz więcej danych wskazuje na rolę dysregulacji adipokin, przewlekłego stanu zapalnego o niskim stopniu i nieprawidłowości mikrobioty jelitowej w patogenezie cukrzycy typu 2¹². Tkanka tłuszczowa działa jak narząd endokrynny, uwalniając hormony zwane adipokinami, które obejmują adipokiny prohiperglikemiczne i antyhiperglikemiczne (leptynę i adiponektynę)¹².

Poziomy adiponektyny są zmniejszone w otyłości, co przyczynia się do insulinooporności, podczas gdy cytokiny prozapalne wydzielane w odpowiedzi na nadmiar substancji odżywczych, takich jak wolne kwasy tłuszczowe i glukoza, prowadzą zarówno do insulinooporności, jak i dysfunkcji komórek β¹²²³.

Cukrzyca typu 2 jest obecnie uważana za zaburzenie zapalne wywołane zaburzeniami metabolizmu²⁴²⁵. Mechanizmy komórkowe, takie jak aktywacja receptorów Toll-podobnych, stres retikulum endoplazmatycznego i aktywacja inflamasomu, są związane z nadmiarem składników odżywczych, łącząc patogenezę i progresję cukrzycy typu 2 ze stanem zapalnym²⁴.

Coraz więcej dowodów sugeruje obecność środowiska zapalnego w wyspach trzustkowych w cukrzycy typu 2, takich jak zwiększone poziomy cytokin, chemokin i infiltracja komórek odpornościowych²⁶. Krytyczną rolę IL-1β w zapaleniu wysp potwierdzono niedawno poprzez analizę globalnej ekspresji genów w wyspach trzustkowych ludzi, która wykazała związek grupy współwyrażanych modułów wzbogaconych o geny związane z IL-1β z cukrzycą typu 2 i insulinoopornością²⁶.

Rola mikrobioty jelitowej

Mikrobiota jelitowa może przyczyniać się do rozwoju cukrzycy typu 2 poprzez wiele mechanizmów molekularnych¹¹. Mikrobiom jelitowy wydaje się odgrywać rolę w zaburzeniach hormonalnych i metabolicznych obserwowanych w cukrzycy typu 2⁶.

Obecnie nie ma jednoznacznej odpowiedzi, czy zmiany w mikroorganizmach jelitowych u pacjentów z cukrzycą typu 2 są przyczyną czy skutkiem cukrzycy. Jednak jest pewne, że zmiany w mikrobiocie jelitowej odgrywają ważną rolę w progresji cukrzycy typu 2²⁷.

Defekt inkretynowy

Postuluje się, że zarówno upośledzenie wydzielania insuliny, jak i nadmierne wydzielanie glukagonu w cukrzycy typu 2 są wtórne do defektu inkretynowego, definiowanego przede wszystkim jako nieadekwatne uwalnianie lub odpowiedź na hormony inkretynowe pochodzące z przewodu pokarmowego po spożyciu posiłku⁶.

GLP-1 (glukagonopodobny peptyd-1) jest jednym z głównych hormonów inkretynowych i odgrywa ważną rolę w regulacji glikemii. Mechanizm, w jaki GLP-1 zmniejsza wydzielanie glukagonu, jest przedmiotem debaty; doniesienia dotyczące ekspresji receptorów GLP-1 w komórkach α wahały się od braku, przez bardzo niskie, do obecności w 20% komórek α²².

Współzależności i mechanizmy kompensacyjne

Cukrzyca typu 2 charakteryzuje się złożonymi współzależnościami między różnymi mechanizmami patogenetycznymi. Początkowo, w odpowiedzi na insulinooporność tkanek obwodowych, komórki β trzustki zwiększają wydzielanie insuliny, co pozwala utrzymać normoglikemię¹⁰. Ten mechanizm kompensacyjny może utrzymywać się przez wiele lat, zanim dojdzie do jawnej cukrzycy²⁸.

Wraz z upływem czasu, gdy insulinooporność się pogłębia, komórki β „męczą się”, co prowadzi do zmniejszonego wydzielania insuliny (względny niedobór insuliny)²⁸. Początkowo występuje hiperglikemia poposiłkowa, a następnie hiperglikemia na czczo, co ostatecznie prowadzi do rozpoznania cukrzycy typu 2²⁹.

Przewlekła hiperglikemia (glukotoksyczność) jest bezpośrednio toksyczna dla komórek β, co dodatkowo pogarsza ich funkcję³⁰. Z kolei lipotoksyczność, wynikająca z nadmiaru wolnych kwasów tłuszczowych, hamuje funkcję transportera glukozy GLUT2 na komórkach β, zmniejszając import glukozy i dalsze upośledzając wydzielanie insuliny³¹.

Metylacja DNA i epigenetyka

Badania wykazały, że czynniki środowiskowe ryzyka cukrzycy typu 2 regulują, poprzez modyfikacje epigenetyczne, ekspresję genetycznych czynników ryzyka cukrzycy typu 2, które kontrolują określone wewnątrzkomórkowe szlaki sygnałowe zaangażowane w początek i rozwój cukrzycy typu 2³².

Proces wyciszania genów przez metylację DNA jest niezbędny dla kluczowych procesów biologicznych, takich jak różnicowanie komórkowe, impriniting genomowy, inaktywacja chromosomu X i wyciszanie retrotranspozonów³³. Zaproponowano dwa mechanizmy wyjaśniające, w jaki sposób metylacja DNA wycisza ekspresję genów. Pierwszy mechanizm zakłada, że metylacja zapobiega wiązaniu czynników transkrypcyjnych do cytozyny w głównym rowku DNA. Drugi mechanizm sugeruje, że metylacja rekrutuje białka zawierające domenę wiążącą metylo-CpG do 5mC, co z kolei rekrutuje pewne modyfikatory histonów, takie jak deacetylazy histonów, które zmieniają stan chromatyny w sposób prowadzący do kompaktowej struktury chromatyny³³.

Rolę metylacji DNA zbadano dalej w innym badaniu z wykorzystaniem wysp trzustkowych od dawców z cukrzycą typu 2 i bez cukrzycy typu 2. Wyniki wskazują, że wydzielanie insuliny stymulowane glukozą (GSIS), mRNA insuliny i zawartość insuliny były zmniejszone w wyspach trzustkowych pacjentów z cukrzycą typu 2 w porównaniu z dawcami bez cukrzycy typu 2³³.

Ekspresja mRNA insuliny była ujemnie skorelowana ze stopniem metylacji w trzech z tych miejsc CpG (−234, −180 i +63). Badanie wykazało również, że zwiększona metylacja CpG4 może przyczyniać się do zwiększonego ryzyka cukrzycy typu 2 u mężczyzn³⁴.

Podsumowanie patogenezy cukrzycy typu 2

Cukrzyca typu 2 jest heterogennym i progresywnym zaburzeniem, które reprezentuje serię stanów metabolicznych związanych z hiperglikemią, spowodowanych defektami w wydzielaniu insuliny i/lub działaniu insuliny, wynikającymi ze złożonej sieci stanów patologicznych¹⁶¹⁷.

Główne mechanizmy patofizjologiczne w rozwoju cukrzycy typu 2 to defekt produkcji insuliny i insulinooporność w tkankach organizmu¹¹. Defekty w syntezie insuliny mogą być przypisane śmierci komórek β lub dysfunkcji komórek β, która może być wynikiem kilku różnych mechanizmów, takich jak dedyferencjacja komórek β, transróżnicowanie, indukcja genów zakazanych, wpływ stresu oksydacyjnego lub stresu ER, a także dysfunkcja mitochondrialna¹¹.

Chociaż względny wkład insulinooporności i niewydolności komórek β w rozwój cukrzycy typu 2 może się różnić w różnych grupach etnicznych, to właśnie postępująca niewydolność komórek β nałożona na istniejącą insulinooporność stanowi kluczowy defekt patofizjologiczny odpowiedzialny za rozwój jawnej cukrzycy¹⁰.

Mechanizm patogenetyczny	Kluczowe procesy	Konsekwencje metaboliczne
Insulinooporność	Zmniejszona wrażliwość komórek mięśniowych, wątroby i tkanki tłuszczowej na insulinę Defekty w szlakach sygnałowych receptora insulinowego Ektopowa akumulacja lipidów i metabolitów (DAG, ceramidy)	Zwiększona produkcja glukozy w wątrobie Zmniejszony wychwyt glukozy w tkankach obwodowych Hiperglikemia na czczo
Dysfunkcja komórek β	Zmniejszona sekrecja insuliny Dedyferencjacja i transróżnicowanie komórek β Apoptoza komórek β Glukotoksyczność i lipotoksyczność Stres retikulum endoplazmatycznego Dysfunkcja mitochondrialna	Nieadekwatne wydzielanie insuliny w stosunku do hiperglikemii Utrata pierwszej fazy wydzielania insuliny Hiperglikemia poposiłkowa Progresywny spadek masy komórek β
Zaburzenia wydzielania glukagonu	Utrata tonicznych hamujących sygnałów z komórek β Insulinooporność komórek α Zaburzenia osi inkretynowej	Hiperglukagonemia Zwiększona produkcja glukozy w wątrobie Nasilenie hiperglikemii
Stan zapalny	Dysregulacja adipokin Przewlekły stan zapalny o niskim stopniu Aktywacja inflamasomu NLRP3 Produkcja cytokin prozapalnych	Nasilenie insulinooporności Dysfunkcja komórek β Zaburzenia sygnalizacji insulinowej
Zmiany epigenetyczne	Metylacja DNA Modyfikacje histonów Zmiany w ekspresji genów regulujących metabolizm glukozy	Zmieniona ekspresja genów związanych z insuliną Zaburzenia funkcji komórek β Predyspozycja do rozwoju cukrzycy typu 2
Mikrobiota jelitowa	Zmiany składu mikrobioty jelitowej Zaburzenia w produkcji hormonów jelitowych Wpływ na metabolizm kwasów żółciowych	Zmieniona produkcja hormonów inkretynowych Zaburzenia homeostazy glukozy Nasilenie stanu zapalnego

Implikacje kliniczne

Zrozumienie złożonej patogenezy cukrzycy typu 2 ma istotne implikacje kliniczne. Leczenie cukrzycy typu 2 powinno być ukierunkowane na różne mechanizmy patogenetyczne³⁵. Przykładowo, metformina obniża poziom glukozy we krwi głównie poprzez zmniejszenie ilości glukozy produkowanej przez wątrobe³⁵, podczas gdy inhibitory DPP-4 pomagają poprawić A1C bez powodowania hipoglikemii, interferując w procesie rozkładu GLP-1 i GIP, co pozwala tym hormonom pozostać aktywnymi w organizmie dłużej³⁵.

Bardziej kompleksowe zrozumienie mechanizmów patogenetycznych cukrzycy typu 2 pozwala na opracowanie bardziej spersonalizowanych strategii terapeutycznych, ukierunkowanych na specyficzne defekty u poszczególnych pacjentów³⁶. Umożliwia to również wcześniejszą identyfikację osób zagrożonych rozwojem cukrzycy typu 2 i wdrożenie interwencji mających na celu zapobieganie lub opóźnienie jej wystąpienia³⁷.

Warto podkreślić, że cukrzyca typu 2 jest częścią szerszego spektrum zaburzeń metabolicznych, obejmujących otyłość, dyslipidemię, nadciśnienie tętnicze i niealkoholową stłuszczeniową chorobę wątroby³⁸. Podejście terapeutyczne powinno zatem uwzględniać nie tylko kontrolę hiperglikemii, ale także modyfikację innych czynników ryzyka sercowo-naczyniowego³⁸.

Podsumowując, cukrzyca typu 2 jest heterogenną chorobą metaboliczną wynikającą ze współdziałania wielu mechanizmów patogenetycznych. Insulinooporność i dysfunkcja komórek β trzustki stanowią centralne elementy jej patofizjologii, ale coraz więcej danych wskazuje na udział innych czynników, takich jak zaburzenia wydzielania glukagonu, stan zapalny, dysregulacja adipokin, zmiany w mikrobiocie jelitowej oraz modyfikacje epigenetyczne. Lepsze zrozumienie tych złożonych mechanizmów może prowadzić do opracowania nowych, bardziej skutecznych strategii terapeutycznych ukierunkowanych na podstawowe defekty w cukrzycy typu 2.

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Materiały źródłowe

#1 Pathophysiology of Type 2 Diabetes Mellitus
https://pmc.ncbi.nlm.nih.gov/articles/PMC7503727/
Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic -cells and the inability of insulin-sensitive tissues to respond appropriately to insulin. […] Defects in any of the mechanisms involved in these processes can lead to a metabolic imbalance responsible for the development of the disease. This review analyzes the key aspects of T2DM, as well as the molecular mechanisms and pathways implicated in insulin metabolism leading to T2DM and insulin resistance. […] The organs involved in T2DM development include the pancreas (-cells and -cells), liver, skeletal muscle, kidneys, brain, small intestine, and adipose tissue. […] Evolving data suggest a role for adipokine dysregulation, inflammation, and abnormalities in gut microbiota, immune dysregulation, and inflammation have emerged as important pathophysiological factors.
#2 Pathophysiology of Type 2 Diabetes Mellitus
https://www.mdpi.com/1422-0067/21/17/6275
Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic Î²-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin. […] Defects in any of the mechanisms involved in these processes can lead to a metabolic imbalance responsible for the development of the disease. This review analyzes the key aspects of T2DM, as well as the molecular mechanisms and pathways implicated in insulin metabolism leading to T2DM and insulin resistance. […] The organs involved in T2DM development include the pancreas (Î²-cells and Î±-cells), liver, skeletal muscle, kidneys, brain, small intestine, and adipose tissue. […] Evolving data suggest a role for adipokine dysregulation, inflammation, and abnormalities in gut microbiota, immune dysregulation, and inflammation have emerged as important pathophysiological factors.
#3 Type 2 Diabetes Mellitus: Background, Pathophysiology, Etiology
https://emedicine.medscape.com/article/117853-overview
For type 2 diabetes mellitus to occur, both insulin resistance and inadequate insulin secretion must exist. For example, all overweight individuals have insulin resistance, but diabetes develops only in those who cannot increase insulin secretion sufficiently to compensate for their insulin resistance. Their insulin concentrations may be high, yet inappropriately low for the level of glycemia. […] With prolonged diabetes, atrophy of the pancreas may occur. […] Beta-cell dysfunction is a major factor across the spectrum of prediabetes to diabetes. […] A study of obese adolescents by Bacha et al confirms what is increasingly being stressed in adults as well: Beta-cell dysfunction develops early in the pathologic process and does not necessarily follow the stage of insulin resistance. […] Insulin resistance is associated with increased lipid accumulation in liver and smooth muscle, but not with increased myocardial lipid accumulation.
#4 Insulin Resistance: From Mechanisms to Therapeutic Strategies
https://www.e-dmj.org/journal/view.php?number=2614
Insulin resistance is the pivotal pathogenic component of many metabolic diseases, including type 2 diabetes mellitus, and is defined as a state of reduced responsiveness of insulin-targeting tissues to physiological levels of insulin. […] Although the underlying mechanism of insulin resistance is not fully understood, several credible theories have been proposed. […] This review summarizes the function of insulin in glucose metabolism in metabolic tissues, such as liver, skeletal muscle, and adipose tissue, and describes several putative mechanisms of insulin resistance, including the ectopic accumulation of lipids in liver and skeletal muscle. […] Insulin resistance is physiologically defined as an inability of some type of tissues to respond to normal insulin levels, and thus, higher than normal levels of insulin are required to maintain the normal functions of insulin.
#5
https://www.jci.org/articles/view/10583
It is estimated that by the year 2020 there will be approximately 250 million people affected by type 2 diabetes mellitus worldwide. […] Although the primary factors causing this disease are unknown, it is clear that insulin resistance plays a major role in its development. Evidence for this comes from (a) the presence of insulin resistance 10-20 years before the onset of the disease; (b) cross-sectional studies demonstrating that insulin resistance is a consistent finding in patients with type 2 diabetes; and (c) prospective studies demonstrating that insulin resistance is the best predictor of whether or not an individual will later become diabetic. […] These studies demonstrate that under hyperglycemic, hyperinsulinemic conditions, muscle glycogen synthesis is the major pathway for glucose metabolism in both normal and diabetic individuals, and that defective muscle glycogen synthesis plays a major role in causing insulin resistance in patients with type 2 diabetes.
#6 Pathogenesis of Type 2 Diabetes Mellitus – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK279115/
Numerous distinct pathophysiologic abnormalities have been associated with type 2 diabetes mellitus (T2DM). It is well established that decreased peripheral glucose uptake (mainly muscle) combined with augmented endogenous glucose production are characteristic features of insulin resistance. Increased lipolysis, elevated free fatty acid levels, along with accumulation of intermediary lipid metabolites contributes to further increase glucose output, reduce peripheral glucose utilization, and impair beta-cell function. Adipocyte insulin resistance and inflammation have been identified as important contributors to the development of T2DM. […] The presence of non-alcoholic fatty liver disease [NAFLD] is now considered an integral part of the insulin resistant state. The traditional concepts of glucotoxicity and lipotoxicity, which covers the process of beta cell deterioration in response to chronic elevations of glucose and lipids, has been expanded to encompass all nutrients [nutri-toxicity]. The delayed transport of insulin across the microvascular system is also partially responsible for the development of tissue insulin resistance.
#6 Pathogenesis of Type 2 Diabetes Mellitus – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK279115/
Compensatory insulin secretion by the pancreatic beta cells may initially maintain normal plasma glucose levels, but beta cell function is already abnormal at this stage, and progressively worsens over time. Concomitantly, there is inappropriate release of glucagon from the pancreatic alpha-cells, particularly in the post-prandial period. It has been postulated that both impaired insulin and excessive glucagon secretion in T2DM are secondary to an incretin defect, defined primarily as inadequate release or response to the gastrointestinal incretin hormones upon meal ingestion. […] To a certain extent, the gut microbiome appears to play a role in the hormonal and metabolic disturbances seen in T2DM. Moreover, hypothalamic insulin resistance (central nervous system) also impairs the ability of circulating insulin to suppress glucose production, and renal tubular glucose reabsorption capacity may be enhanced, despite hyperglycemia. These pathophysiologic abnormalities should be considered for the treatment of hyperglycemia in patients with T2DM.
#7 Type 2 Diabetes Mellitus: Background, Pathophysiology, Etiology
https://emedicine.medscape.com/article/117853-overview
Type 2 diabetes mellitus consists of an array of dysfunctions characterized by hyperglycemia and resulting from the combination of resistance to insulin action, inadequate insulin secretion, and excessive or inappropriate glucagon secretion. […] Type 2 diabetes is characterized by a combination of peripheral insulin resistance and inadequate insulin secretion by pancreatic beta cells. Insulin resistance, which has been attributed to elevated levels of free fatty acids and proinflammatory cytokines in plasma, leads to decreased glucose transport into muscle cells, elevated hepatic glucose production, and increased breakdown of fat. […] A role for excess glucagon cannot be underestimated; indeed, type 2 diabetes is an islet paracrinopathy in which the reciprocal relationship between the glucagon-secreting alpha cell and the insulin-secreting beta cell is lost, leading to hyperglucagonemia and hence the consequent hyperglycemia.
#8 Type 2 diabetes – Wikipedia
https://en.wikipedia.org/wiki/Type_2_diabetes
Type 2 diabetes is due to insufficient insulin production from beta cells in the setting of insulin resistance. Insulin resistance, which is the inability of cells to respond adequately to normal levels of insulin, occurs primarily within the muscles, liver, and fat tissue. In the liver, insulin normally suppresses glucose release. However, in the setting of insulin resistance, the liver inappropriately releases glucose into the blood. The proportion of insulin resistance versus beta cell dysfunction differs among individuals, with some having primarily insulin resistance and only a minor defect in insulin secretion and others with slight insulin resistance and primarily a lack of insulin secretion. […] Other potentially important mechanisms associated with type 2 diabetes and insulin resistance include: increased breakdown of lipids within fat cells, resistance to and lack of incretin, high glucagon levels in the blood, increased retention of salt and water by the kidneys, and inappropriate regulation of metabolism by the central nervous system. However, not all people with insulin resistance develop diabetes since an impairment of insulin secretion by pancreatic beta cells is also required.
#8 Type 2 diabetes – Wikipedia
https://en.wikipedia.org/wiki/Type_2_diabetes
In the early stages of insulin resistance, the mass of beta cells expands, increasing the output of insulin to compensate for the insulin insensitivity, so that the disposition index remains constant. But when type 2 diabetes has become manifest, the person will have lost about half of their beta cells. […] The causes of the aging-related insulin resistance seen in obesity and in type 2 diabetes are uncertain. Effects of intracellular lipid metabolism and ATP production in liver and muscle cells may contribute to insulin resistance.
#9 Pathogenesis of Type 2 Diabetes – Histopathology.guru
https://www.histopathology.guru/pathogenesis-of-type-2-diabetes/
Caused by a combination of peripheral resistance to insulin action and an inadequate secretory response by the pancreatic cells. […] Type 2 diabetes is complex disease involving an interplay of genetic, environmental factors and proinflammatory state. […] Two important metabolic defects that characterise type 2 diabetes are decreased response of peripheral tissues, especially skeletal muscles, adipose tissue and liver to insulin and inadequate insulin secretion in the face of insulin resistance and hyperglycemia (cell dysfunction). […] In the early stages, there is compensatory cell hyperfunction and hyperinsulinemia but later cells cannot adapt and lead to chronic hyperglycemia leading to complications. […] Insulin resistance results in failure to inhibit endogenous glucose production in the liver which contributes to high fasting blood glucose levels.
#10 Pathogenesis of Type 2, Part 2: International Textbook of Diabetes Mellitus
https://www.diabetesincontrol.com/international-textbook-of-diabetes-mellitus-excerpt-131-pathogenesis-of-type-2-diabetes-mellitus-part-2/
The natural history of T2DM has been well described in multiple populations and is reviewed in references. Individuals destined to develop T2DM inherit a set of genes from their parents that make their tissues resistant to insulin and the insulin resistance is aggravated by weight gain and physical inactivity. Hepatic insulin resistance is manifested by an overproduction of glucose during the basal state despite the presence of fasting hyperinsulinemia and an impaired suppression of hepatic glucose production (HGP) in response to insulin, as occurs following a meal. Muscle insulin resistance is manifest by impaired glucose uptake following ingestion of a carbohydrate meal and results in postprandial hyperglycemia. The origin of the insulin resistance can be traced to the genetic background. However, the epidemic of diabetes that has enveloped Westernized countries primarily results from the epidemic of obesity and physical inactivity. Both obesity and decreased physical activity are insulin-resistant states and, when added to the genetic burden of the insulin resistance, place a major stress on the pancreatic cells to augment their secretion of insulin to offset the defect in insulin action. Initially the cells augment their secretion of insulin to offset the insulin resistance and glucose tolerance remains normal. However, with time the cells begin to fail and initially the postprandial plasma glucose levels and subsequently the fasting plasma glucose concentration rise, leading to the onset of overt diabetes. Collectively, the insulin resistance in muscle and liver and -cell failure have been referred to as the Triumvirate. The resultant hyperglycemia and poor metabolic control may cause a further decline in insulin sensitivity, but it is the progressive -cell failure that determines the rate of disease progression.
#10 Pathogenesis of Type 2, Part 2: International Textbook of Diabetes Mellitus
https://www.diabetesincontrol.com/international-textbook-of-diabetes-mellitus-excerpt-131-pathogenesis-of-type-2-diabetes-mellitus-part-2/
Although the relative contributions of insulin resistance and -cell failure to the development of T2DM may vary amongst different ethnic groups, progressive -cell failure superimposed upon a background of insulin resistance represent the core pathophysiologic defects responsible for the development of overt diabetes.
#11 Type 2 Diabetes Mellitus: New Pathogenetic Mechanisms, Treatment and the Most Important Complications
https://www.mdpi.com/1422-0067/26/3/1094
The balance between insulin and glucagon is especially important since it determines the relative degree of phosphorylation of downstream enzymes in the regulatory signaling pathways. […] IR of skeletal muscles is regarded as one of the most essential extra-pancreatic factors in the development of T2DM. […] In the liver, insulin partakes in regulating glucose production and utilization, and it affects lipid metabolism via different downstream pathways that regulate multiple metabolic processes, such as glycogen synthesis, gluconeogenesis, glycolysis, and lipid synthesis. […] The regulation of hepatic glucose output is achieved via the combined action of glucagon and insulin; glucagon promotes the synthesis of glucose, while insulin inhibits it if serum glucose is elevated. […] However, in the state of IR, the levels of circulating insulin are not sufficient to exert an appropriate insulin response in hepatic cells.
#11 Type 2 Diabetes Mellitus: New Pathogenetic Mechanisms, Treatment and the Most Important Complications
https://www.mdpi.com/1422-0067/26/3/1094
Traditionally, the dysfunction of Î²-cells has been attributed to the loss of Î²-cell mass due to Î²-cell exhaustion in a state of prolonged elevations in glucose metabolism and insulin secretion, as well as Î²-cells apoptosis caused by glucotoxicity and lipotoxicity. However, it is suggested that the impaired function of Î²-cells may be a result of more complex mechanisms and interactions. […] One of the proposed mechanisms is the dedifferentiation of Î²-cells, a process defined as the loss of Î²-cell-defining transcription factors. Such loss of identity of a Î²-cell can occur as a result of glucotoxicity. […] Another mechanism is the transdifferentiation of Î²-cells, which is a process of converting one terminally differentiated cell type into another. […] Chronic hyperglycemia can result in glucotoxicity which promotes the development and progression of T2DM. Elevated levels of NADH and reactive oxygen species (ROS), which are present in chronic hyperglycemia, have been associated with the dysfunction of Î²-cell.
#11 Type 2 Diabetes Mellitus: New Pathogenetic Mechanisms, Treatment and the Most Important Complications
https://www.mdpi.com/1422-0067/26/3/1094
Mitochondrial dysfunction is another factor that can lead to Î²-cell dysfunction, as seen in T2DM, and it has been observed that mitochondria in humans with T2DM are smaller, fragmented, and swollen. […] The state of hyperglycemia and increased insulin production can lead to endoplasmic reticulum (ER) stress, which can result in unfolded protein response (UPR) in Î²-cells. […] Systemic inflammation and hyperglycemia, which are present in T2DM, can lead to alterations in prostaglandin signaling. […] IR means a decline in a target cellâs metabolic response to insulin or, at a systemic level, a decreased blood glucose-lowering effect of insulin. […] The action of insulin is regulated by different hormones, including growth factors and insulin-like growth factor 1 (IGF-1) in the fed state and glucagon, glucocorticoids, and catecholamines in the state of fasting.
#11 Type 2 Diabetes Mellitus: New Pathogenetic Mechanisms, Treatment and the Most Important Complications
https://www.mdpi.com/1422-0067/26/3/1094
Gut microbiota can contribute to the development of T2DM through multiple molecular mechanisms. […] Evidence suggests that the distribution of fat mass is an important factor in overall metabolic health, which studies defined as an increased gluteofemoral and leg fat mass, together with high insulin sensitivity and high insulin secretion. […] The main pathomechanisms in which T2DM is developed are the defect of insulin production and IR in body tissues. Defective insulin synthesis may be attributed to the death of Î²-cells or Î²-cells dysfunction, which may be a result of several different mechanisms such as Î²-cells dedifferentiation, transdifferentiation, the induction of disallowed genes, the impact of oxidative or ER stress, as well as mitochondrial dysfunction.
#12 Pathogenesis of Type 2 Diabetes – Histopathology.guru
https://www.histopathology.guru/pathogenesis-of-type-2-diabetes/
Defects in signaling pathways leading to decreased tyrosine phosphorylation of insulin receptor and IRS proteins. […] This leads to decreased levels of GLUT 4 levels on the surface of the cell. […] Adipose tissue acts as endocrine organ releasing hormones called adipokines which include pro hyperglycemic adipokines and anti hyperglycemic adipokines (Leptin and Adiponectin). […] Adiponectin levels are decreased in obesity this contributes to insulin resistance. […] Proinflammatory cytokines are secreted in response to excess nutrients such as Free fatty acids and glucose. […] Along with insulin resistance B cell dysfunction is also required for the development of Type 2 diabetes. […] Mechanisms that promote cell dysfunction are excess FFA attenuate insulin release and compromise the cell function (Lipotoxicity) and chronic hyperglycemia (Glucotoxicity).
#13 Insulin Resistance: From Mechanisms to Therapeutic Strategies
https://www.e-dmj.org/journal/view.php?number=2614
The most plausible hypothesis of the mechanism whereby ectopic lipid accumulation induces insulin resistance is that several lipid metabolites, including diacylglycerol (DAG), lysophosphatidic acid (LPA), ceramides, and acylcarnitines, are involved in the pathogenesis of insulin resistance in liver and skeletal muscle. […] The accumulation of intramyocellular DAG impairs insulin signaling and muscle glucose uptake by activating PKC (muscle-type nPKC), which elicits the phosphorylation of IRS-1 at Ser1101 and blocks the insulin-stimulated phosphorylation of IRS-1. […] Inhibition of ceramide synthesis using myriocin, an inhibitor of serine palmitoyltransferase, prevented insulin resistance and attenuated ceramide contents in fat-fed mice. […] The underlying molecular mechanism whereby ceramide induces insulin resistance has not been clearly demonstrated. […] However, some candidate mechanisms have been proposed, namely, the impairment of AKT translocation through the activation of atypical PKC, and the activation of PP2A.
#14 Insulin Resistance: From Mechanisms to Therapeutic Strategies
https://e-dmj.org/journal/view.php?number=2614
Since skeletal muscle is a quantitatively central tissue for insulin-stimulated glucose disposal, and liver and adipose tissue are qualitatively the critical sites for glucose-induced insulin signaling, these tissues are considered central to the understanding of the mechanisms responsible for insulin resistance. […] In T2DM patients, insulin cannot regulate hepatic glycogen synthesis or glucose production, and increased hepatic gluconeogenesis is the primary cause of fasting hyperglycemia in T2DM. […] Defective suppression of hepatic gluconeogenesis in insulin resistance is largely associated with lipolysis defects in adipose tissue and the de-suppression of FOXO1 transcription factor in liver. […] The most plausible hypothesis of the mechanism whereby ectopic lipid accumulation induces insulin resistance is that several lipid metabolites, including diacylglycerol (DAG), lysophosphatidic acid (LPA), ceramides, and acylcarnitines, are involved in the pathogenesis of insulin resistance in liver and skeletal muscle.
#15 Insulin Resistance: From Mechanisms to Therapeutic Strategies
https://www.e-dmj.org/journal/view.php?number=2614
The glucose-fatty acid cycle shows that glucose-6-phosphate and glycogen synthesis levels should be increased by fatty acid and that glycolysis should be inhibited. […] However, exposure to high plasma fatty acid concentrations caused insulin resistance and reduced glucose-6-phosphate concentrations in the muscle of healthy individuals. […] Many theories have been proposed for the mechanism responsible for the development of insulin resistance due to excess lipid availability. […] Ectopic lipid accumulation in peripheral tissues, especially in liver and skeletal muscle, can lead to more severe insulin resistance, even in the absence of visceral adiposity. […] Numerous studies have shown that lipid accumulation in liver and skeletal muscle caused by short-term HFD feeding or lipid/heparin infusions induce insulin resistance in rats.
#16 Pathophysiology of Type 2 Diabetes Mellitus
https://pmc.ncbi.nlm.nih.gov/articles/PMC7503727/
In the case of -cell dysfunction, insulin secretion is reduced, limiting the body’s capacity to maintain physiological glucose levels. On the other hand, IR contributes to increased glucose production in the liver and decreased glucose uptake both in the muscle, liver and adipose tissue. […] However, when both -cell dysfunction and IR are present, hyperglycaemia is amplified leading to the progression of T2DM. […] -cell dysfunction has been traditionally associated with -cell death. However, recent evidence suggests that the dysfunction of -cells in T2DM might be due to a more complex network of interactions between the environment and different molecular pathways implicated in cell biology. […] An excess of FFAs and hyperglycemia lead to -cell dysfunction by inducing ER stress through the activation of the apoptotic unfolded protein response (UPR) pathways.
#16 Pathophysiology of Type 2 Diabetes Mellitus
https://pmc.ncbi.nlm.nih.gov/articles/PMC7503727/
Insulin secretion has to be finely regulated to precisely meet metabolic demand. For that reason, proper islet integrity must be conserved in order to allow -cells to respond to metabolic needs. […] Defects in the synthesis of any insulin precursors, or insulin itself, as well as disruption of the secretion mechanism, can lead to insulin secretory dysfunction, the primary driver of -cell failure, and a foundation of T2DM. […] There is increasing evidence associating mitochondrial dysfunction with T2DM development, age-related IR and T2DM complications. […] The generation of ROS is highly implicated in the relationship between mitochondrial dysfunction and insulin resistance. […] Excessive ROS generation by mitochondria contributes to accelerated T2DM progression. […] In summary, T2DM is a heterogeneous and progressive disorder that represents a series of metabolic conditions associated with hyperglycemia and caused by defects in insulin secretion and/or insulin action due to a complex network of pathological conditions.
#17 Pathophysiology of Type 2 Diabetes Mellitus
https://www.mdpi.com/1422-0067/21/17/6275
Regarding the pathophysiology of the disease, a malfunctioning of the feedback loops between insulin action and insulin secretion results in abnormally high glucose levels in blood. […] In the case of Î²-cell dysfunction, insulin secretion is reduced, limiting the bodyâs capacity to maintain physiological glucose levels. On the other hand, IR contributes to increased glucose production in the liver and decreased glucose uptake both in the muscle, liver and adipose tissue. […] However, when both Î²-cell dysfunction and IR are present, hyperglycaemia is amplified leading to the progression of T2DM. […] Insulin release is primarily triggered by a response to high glucose concentrations. […] An excess of FFAs and hyperglycemia lead to Î²-cell dysfunction by inducing ER stress through the activation of the apoptotic unfolded protein response (UPR) pathways.
#17 Pathophysiology of Type 2 Diabetes Mellitus
https://www.mdpi.com/1422-0067/21/17/6275
The sustained and marked increase in steady-state levels of ROS contributes significantly to the pathogenesis of T2DM and IR. […] The generation of ROS links mitochondrial dysfunction and IR. […] The accumulation of ROS in the mitochondria is one proposed mechanism linking mitochondrial dysfunction to IR. […] In summary, T2DM is a heterogeneous and progressive disorder that represents a series of metabolic conditions associated with hyperglycemia and caused by defects in insulin secretion and/or insulin action due to a complex network of pathological conditions.
#18 Pathogenesis and complications of Type 2 Diabetes – Histopathology.guru
https://www.histopathology.guru/pathogenesis-and-complications-of-type-2-diabetes/
In the early stages, there is compensatory cell hyperfunction and hyperinsulinemia but later cells cannot adapt and lead to chronic hyperglycemia leading to complications. […] Insulin resistance results in failure to inhibit endogenous glucose production in the liver which contributes to high fasting blood glucose levels. […] Defects in signaling pathways leading to decreased tyrosine phosphorylation of insulin receptor and IRS proteins lead to decreased levels of GLUT 4 levels on the surface of the cell. […] Adipose tissue acts as an endocrine organ releasing hormones called adipokines which include pro hyperglycemic adipokines and anti hyperglycemic adipokines (Leptin and Adiponectin). […] Along with insulin resistance, B cell dysfunction is also required for the development of Type 2 diabetes. […] Mechanisms that promote cell dysfunction are excess FFA attenuating insulin release and compromising the cell function (Lipotoxicity), chronic hyperglycemia (Glucotoxicity), an abnormal incretin effect, amyloid deposition in the islets, and polymorphisms in genes that control insulin secretion.
#19 Type 2 Diabetes pathogenesis and treatments | DMSO
https://www.dovepress.com/a-review-of-current-trends-with-type-2-diabetes-epidemiology-aetiology-peer-reviewed-fulltext-article-DMSO
The consensus in the literature is that T2D clinical manifestation is provoked by peripheral tissue insulin resistance, which is in turn, usually induced by obesity. Obesity is characterised by elevated levels of cytokines and fatty acids, and it is thought that elevated levels of both provoke insulin resistance. […] Following the induction of insulin resistance, islet beta-cells can maintain normoglycaemia and metabolic homeostasis by increasing their secretion of insulin and/or by increasing their number. […] However, over time islet beta-cells are seemingly unable to compensate for the insulin resistance and their ability to secrete insulin decreases and many islet beta-cells undergo apoptosis, which is thought to be a result of a variety of stressors, such as increased insulin demand, oxidative, endoplasmic reticulum, dyslipidemic, amyloidal, and inflammatory stress.
#20
https://insight.jci.org/articles/view/143791
Islet cell dedifferentiation is a pathologic mechanism of long-standing progression of type 2 diabetes. […] Dedifferentiation has been implicated in cell dysfunction and loss in rodent diabetes. However, the pathophysiological significance in humans remains unclear. […] Our work reveals the involvement of dedifferentiation in cell dysfunction and loss during the course of diabetes progression. […] The pathogenesis of cell failure integrates both functional and quantitative (cell number) defects. […] Our study using surgically resected pancreatic specimens, taken into consideration with clinical information, demonstrated that islet plasticity in diverse disease conditions, which leads to dedifferentiation, is a pathologic basis of cell failure over the entire course of type 2 diabetes.
#21
https://insight.jci.org/articles/view/143791
First, the clinical relevance of dedifferentiation to long-standing progression of diabetes was demonstrated. […] Finally, a subset of dedifferentiated cells exhibited an exocrine-like phenotype, in association with profound dysfunction. […] Loss of maturity through dedifferentiation provides a pathophysiologic link between dysfunction and reduced cell numbers. […] Our observations highlight islet cell dedifferentiation as a mechanism underlying diabetes progression.
#22 The role of glucagon on type 2 diabetes at a glance | Diabetology & Metabolic Syndrome | Full Text
https://dmsjournal.biomedcentral.com/articles/10.1186/1758-5996-6-91
Although the pathogenesis of T2D is classically focused on insulin resistance and beta-cell dysfunction, the inappropriately increased alpha-cell function and consequent hyperglucagonemia has long been recognised as a contributor to hyperglycemia in diabetic patients, by stimulating hepatic glucose production. […] The loss of the inverse relationship between these two hormones in T2D patients might be secondary to the observed diminished mass of insulin pulses, and suggests that alterations in the cross-talk between beta- and alpha-cells may underlie hyperglucagonemia. […] Unger and Orci have recently introduced the term paracrinopathy to designate the loss of tonic restraint normally exerted by a high local concentration of insulin on alpha-cells; beta-cell destruction and beta-cell failure to secrete the first phase of insulin associated with alpha-cells insulin resistance would be the main mechanistic factors in type 1 and type 2 diabetes, respectively. […] In summary, the relevance of dysfunctional glucagon secretion to the pathogenesis of diabetes has been widely recognized and, for that reason, targeting glucagon and not only insulin secretion abnormalities in the treatment of T2D has gained increased interest.
#22 The role of glucagon on type 2 diabetes at a glance | Diabetology & Metabolic Syndrome | Full Text
https://dmsjournal.biomedcentral.com/articles/10.1186/1758-5996-6-91
The opposite effects of insulin and glucagon in fuel homeostasis, the paracrine/endocrine inhibitory effects of insulin on glucagon secretion and the hyperglucagonemia in the pathogenesis of type 2 diabetes (T2D) have long been recognized. […] Inappropriately increased alpha-cell function importantly contributes to hyperglycemia and reflects the loss of tonic restraint normally exerted by high local concentrations of insulin on alpha-cells, possibly as a result of beta-cell failure and alpha-cell insulin resistance, but additional mechanisms, such as the participation of incretin hormones in this response, have also been suggested. […] The mechanism by which GLP-1 decreases glucagon secretion is a matter of debate; reports regarding the expression of GLP-1 receptors in alpha-cells have ranged from absent, to very low and to present in 20% of the alpha-cells.
#23 Pathogenesis DM | PPT
https://www.slideshare.net/slideshow/pathogenesis-dm/227127343
Pathogenesis of Type 2 DM A complex multifactorial disease which involves interactions of genetics, environmental risk factors and inflammation with no autoimmune basis. Genetic factors; More than a dozen diabetogenic genes identified (both parents diabetic; 50% risk to the child). Environmental factors; Sedentary life style, dietary habits and obesity. Insulin resistance; Decreased ability of peripheral tissues to respond to insulin. Beta cell dysfunction; Manifested as inadequate insulin secretion in the face of insulin resistance and hyperglycemia. […] Type 2 DM: Insulin Resistance Insulin resistance is influenced by; Genetic defects of Insulin receptor. Genetic defects of Insulin signaling pathway (inactivating mutations). Obesity. […] Type 2 DM: Genetic Factors. […] Obesity and Insulin Resistance Role of free fatty acids (FFAs); In obese, increased intracellular TGs in muscle and liver and products of FFAs metabolism are potent inhibitors of insulin signaling pathways. Role of Adipokines Released by adipose tissue into systemic circulation (like; leptin, adiponectin, and resistin), changes in their levels associated with insulin resistance as for example; Adiponectin levels reduced in states of obesity causing insulin resistance where as its normal levels contributes to insulin sensitivity in peripheral tissues where as; Resistin levels increased in obesity which contributes to insulin resistance. Inflammation Pro-inflammatory cytokines secreted in response to FFAs results in both insulin resistance and beta cell dysfunction.
#24 Type 2 diabetes mellitus: From a metabolic disorder to an inflammatory condition
https://www.wjgnet.com/1948-9358/full/v6/i4/598.htm
Diabetes mellitus is increasing at an alarming rate and has become a global challenge. Insulin resistance in target tissues and a relative deficiency of insulin secretion from pancreatic -cells are the major features of type 2 diabetes (T2D). Chronic low-grade inflammation in T2D has given an impetus to the field of immuno-metabolism linking inflammation to insulin resistance and -cell dysfunction. […] Numerous cellular factors trigger inflammatory signalling cascades, and as a result T2D is at the moment considered an inflammatory disorder triggered by disordered metabolism. Cellular mechanisms like activation of Toll-like receptors, Endoplasmic Reticulum stress, and inflammasome activation are related to the nutrient excess linking pathogenesis and progression of T2D with inflammation.
#25 Type 2 diabetes mellitus: From a metabolic disorder to an inflammatory condition
https://www.wjgnet.com/1948-9358/full/v6/i4/598.htm
The pathogenesis and progression of T2D is ascribed to four mechanisms; increased advanced glycation end product (AGE) formation, increased polyol pathway flux, activation of protein kinase C (PKC) isoforms, and increased hexosamine pathway flux. […] Downstream to oxidative stress, activation of inflammatory pathways has emerged as an imperative link between T2D and inflammation. […] T2D at the moment is considered an inflammatory disorder triggered by disordered metabolism. […] The role of inflammation in insulin resistance is traced by the integration of metabolism and innate immunity via nutrient-sensing pathways mutual to pathogen-sensing pathways. […] The mechanisms in development of inflammation-induced insulin resistance are different for JNK and IKK. […] The production of inflammatory molecules further activates JNK and NF-B pathways promoting a vicious loop of insulin resistance by feed-forward mechanism.
#26 Type 2 diabetes mellitus: From a metabolic disorder to an inflammatory condition
https://www.wjgnet.com/1948-9358/full/v6/i4/598.htm
Increasing evidence suggests the presence of an inflammatory milieu in pancreatic islets in T2D, such as increased cytokine levels, chemokine levels and immune cell infiltration. […] The critical role of IL-1 in islet inflammation was recently confirmed by analysing global gene expression in pancreatic islets of humans that showed an association of a group of co-expressed modules enriched for IL-1 related genes with T2D and insulin resistance. […] The NLRP3 inflammasome is a general metabolic alarmin stimulated by different endogenous and exogenous stimuli. NLRP3 inflammasome activation is augmented in T2D patients. […] Dysregulation of lipid metabolism, paving the way to aberrant lipid accumulation, as well as formation of oxidized LDL and cholesterol, triggers NLRP3 activation.
#27 Mechanism underlying the effects of exercise against type 2 diabetes: A review on research progress
https://www.wjgnet.com/1948-9358/full/v15/i8/1704.htm
Exercise, particularly aerobic exercise and a combination of aerobic and resistance exercises, enhance the vasodilation function. […] Currently, no definite conclusion has been reached on whether alterations in the intestinal microorganisms in patients with T2D are the cause or the consequence of diabetes. However, it is affirmative that changes in the gut microbiota play an important role in the progression of T2D. […] The understanding of the multifaceted mechanisms through which exercise combats diabetes and its complications is essential for developing effective treatment strategies tailored to individual requirements, emphasizing lifestyle modifications, in addition to medication, as pillars of diabetic care.
#28 Pathogenesis of Diabetes mellitus DM), Type II | Calgary Guide
https://calgaryguide.ucalgary.ca/pathogenesis-of-diabetes-mellitus-dm-type-ii/dm-ii-pathogenesis/
Endocrinology Diabetes Mellitus: pathogenesis and clinical findings Pathogenesis of Diabetes Mellitus (DM), Type II Pathogenesis of Diabetes mellitus DM), Type II […] Over many years, as insulin resistance worsens, Beta-cells tire out, ? insulin secretion(relative insulin deficiency) […] Insulin resistance(liver, muscle, adipose tissue become less responsive to insulin, and thus less able to use glucose as a fuel source) […] Initially, beta-cells of the pancreas work overtime to ? Insulin secretion […] Adipokines […] Inflammatory mediators […] Unhealthy Lifestyle: i.e. over-eating, obesity, inactivity […] Free fatty acids (FFAs) […] Genetic Susceptibility: Polygenetic or monogenetic factors (i.e. maturity-onset diabetes of the young (MODY)) can predispose insulin resistance
#29 Diabetes mellitus – Knowledge @ AMBOSS
https://www.amboss.com/us/knowledge/diabetes-mellitus/
Type 2 diabetes mellitus (T2DM), which is much more common, has a strong genetic component as well as a significant association with obesity and a sedentary lifestyle. T2DM is characterized by insulin resistance and impaired insulin secretion due to pancreatic -cell dysfunction, resulting in relative insulin deficiency. […] Insulin resistance, progressive destruction of pancreatic -cells. […] Peripheral insulin resistance […] Central obesity increased plasma levels of free fatty acids impaired insulin-dependent glucose uptake into hepatocytes, myocytes, and adipocytes. […] Pancreatic cell dysfunction: accumulation of pro-amylin (islet amyloid polypeptide) in the pancreas; decreased endogenous insulin production. […] Initially, insulin resistance is compensated by increased insulin and amylin secretion. Over the course of the disease, insulin resistance progresses, while insulin secretion capacity declines. After a period of impaired glucose tolerance with isolated postprandial hyperglycemia, diabetes manifests with fasting hyperglycemia.
#30 Pathogenesis of Diabetes mellitus DM), Type II | Calgary Guide
https://calgaryguide.ucalgary.ca/pathogenesis-of-diabetes-mellitus-dm-type-ii/dm-ii-pathogenesis/
Medications: i.e. corticosteroids, anti-psychotics, highly-active anti-retrovirals, progestin-only oral contraceptives […] Intraperitoneal cavity accumulates visceral fat (aka. abdominal fat), which is an endocrine organ that secretes: Hyperglycemia […] Glucotoxicity: hyperglycemia is directly toxic to Beta-cells […] Over many more years: Beta-cells deteriorate until they finally stop producing insulin, (absolute insulin deficit) […] Note: adipokines are inflammatory mediators released from adipose tissue (e.g. TNFalpha). The more adipose tissue a patient has, the more adipokines are released. […] Note: There is a HUGE genetic basis for Type II DM: high concordance rate between family members (90% for monozygotic twins), and if a first-degree relative is affected, the risk for other family members is 5-10x above baseline.
#31 Pathogenesis of Diabetes mellitus DM), Type II | Calgary Guide
https://calgaryguide.ucalgary.ca/pathogenesis-of-diabetes-mellitus-dm-type-ii/dm-ii-pathogenesis/
Lipotoxicity: FFAs inhibit function of GLUT2 on Beta-cells, ? glucose import […] Beta-cells do not recognize high blood glucose ? ? insulin secretion […] Aging: Beta-cell mass declines with aging, so those predisposed to insulin resistance may develop Type II DM as they age. […] Directly destroy or damage Beta cells, enough to expose its antigens to bodys immune system […] Foreign antigens structurally mimic Beta-cell antigens (molecular mimicry) immune system attacks both these foreign -and self-antigens.
#32 The role of DNA methylation in the pathogenesis of type 2 diabetes mellitus | Clinical Epigenetics | Full Text
https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-020-00896-4
Despite the high prevalence of DM, the exact mechanisms underlying the development of GDM, T1DM, and T2DM are not fully understood. Therefore, a greater understanding of the aetiology of DM is necessary to develop improved prevention and diagnostic tools and treatments for associated complications. […] Recent studies have found that T2DM environmental risk factors regulate, through epigenetic modifications, the expression of T2DM genetic risk factors that control the particular intracellular signalling pathways involved in the onset and development of T2DM. […] The following section focuses on what is known regarding the role of DNA methylation in the development and pathogenesis of T2DM, although the exact mechanisms underlying the involvement of DNA methylation in T2DM pathogenesis remain unclear.
#33 The role of DNA methylation in the pathogenesis of type 2 diabetes mellitus | Clinical Epigenetics | Full Text
https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-020-00896-4
The process of gene silencing by DNA methylation is required for critical biological processes, such as cellular differentiation, genomic imprinting, X chromosome inactivation, and retrotransposon silencing. […] To date, two mechanisms have been proposed on how DNA methylation silences gene expression. The first mechanism posits that methylation prevents the binding of transcription factors to cytosine in the major DNA groove. The second mechanism suggests that methylation recruits proteins containing the methyl-CpG-binding domain to the 5mC, which in turn recruits certain histone modifiers, such as histone deacetylases, that change the chromatin state in a way that leads to a compact chromatin structure. […] The role of DNA methylation was further examined in another study using human islets from T2DM and non-T2DM donors. The findings indicate that the glucose-stimulated insulin secretion (GSIS), insulin mRNA, and insulin content were reduced in the pancreatic islets of T2DM in comparison with the non-T2DM donors.
#34 The role of DNA methylation in the pathogenesis of type 2 diabetes mellitus | Clinical Epigenetics | Full Text
https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-020-00896-4
Furthermore, insulin mRNA expression was found to negatively correlate with the degree of methylation in three of these CpG sites (234, 180, and +63). […] The study concluded that the increased CpG4 DNA methylation may contribute to the increased T2DM risk in males. […] The findings of this study suggest that DNMT1 caused PTPRD DNA hypermethylation and silenced insulin signalling in patients with T2DM. […] The authors concluded that DNA methylation biomarkers in blood might be used as surrogate biomarkers when the target tissue is inaccessible. […] In conclusion, although T2DM is a considerably complex disease, the above-mentioned studies provide some insights into the significant role played by epigenetics and DNA methylation in particular in the pathogenesis of T2DM, including insulin production, cell secretion, and resistance.
#35 What Are My Options for Type 2 Diabetes Medications? | ADA
https://diabetes.org/health-wellness/medication/oral-other-injectable-diabetes-medications
Metformin lowers blood glucose levels primarily by decreasing the amount of glucose produced by the liver. […] DPP-4 inhibitors help improve A1C (a measure of average blood glucose levels over two to three months) without causing hypoglycemia (low blood glucose). […] By interfering in the process that breaks down GLP-1 and GIP, DPP-4 inhibitors allow these hormones to remain active in the body longer, lowering blood glucose levels only when they are elevated. […] Use of GLP-1 and dual GLP-1/GIP receptor agonists is another strategy to help use these hormones to improve blood glucose management in people with type 2 diabetes. […] SGLT2 inhibitors block this action, causing excess glucose to be eliminated in the urine. […] By increasing the amount of glucose excreted in the urine, people can see improved blood glucose, some weight loss, and small decreases in blood pressure.
#36
https://consensus.app/questions/diagram-of-diabetes-type-2/
Deteriorating -cell function and insulin resistance contribute to the progression of type 2 diabetes, with a steeper rate of increasing fasting glucose, higher BMI, blood pressure, and triglycerides, and lower HDL cholesterol being key predictors. […] Type 2 diabetes is caused by genetic and environmental factors, and long-term glycemic control requires progressive, stepwise combination treatment with oral agents and insulin. […] Type 2 diabetes is caused by multiple factors, including obesity, and is managed through diet, exercise, and combination drug treatments. […] Understanding the diverse aetiologies of type 2 diabetes is crucial for better patient management and understanding its impact on progression rates, treatment response, and complications. […] Multiple antidiabetic agents are needed to effectively manage type 2 diabetes, with a focus on enhancing insulin sensitivity and preventing microvascular complications.
#37 About Insulin Resistance and Type 2 Diabetes | Diabetes | CDC
https://www.cdc.gov/diabetes/about/insulin-resistance-type-2-diabetes.html
Insulin resistance leads to prediabetes and type 2 diabetes. […] Insulin resistance sets the stage for prediabetes and type 2 diabetes. […] If you have insulin resistance, there’s good news. You can reverse it by making your cells more sensitive to insulin.
#38 Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-024-01951-9
Type 2 diabetes (T2D) is a disease characterized by heterogeneously progressive loss of islet cell insulin secretion usually occurring after the presence of insulin resistance (IR) and it is one component of metabolic syndrome (MS), and we named it metabolic dysfunction syndrome (MDS). The pathogenesis of T2D is not fully understood, with IR and cell dysfunction playing central roles in its pathophysiology. Dyslipidemia, hyperglycemia, along with other metabolic disorders, results in IR and/or islet cell dysfunction via some shared pathways, such as inflammation, endoplasmic reticulum stress (ERS), oxidative stress, and ectopic lipid deposition. […] T2D is often accompanied by other components of MDS, such as preobesity/obesity, metabolic dysfunction associated steatotic liver disease, dyslipidemia, which usually occurs before it, and they are considered as the upstream diseases of T2D. It is more appropriate to call diabetic complications as MDS-related target organ damage (TOD), since their development involves not only hyperglycemia but also other metabolic disorders of MDS, promoting an up-to-date management philosophy.
#38 Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-024-01951-9
T2D, usually accompanied by other manifestations of MDS, is a complex metabolic disease with multiple underlying mechanisms not fully understood, while IR and cell dysfunction are two core pathophysiological mechanisms. Inflammation, ectopic lipid deposition, endoplasmic reticulum stress (ERS), and oxidative stress are involved in the onset and progression of T2D and TOD by impairing insulin sensitivity and/or cell dysfunction, reciprocal with metabolic disorders. […] The realization of T2D as downstream disease of MDS suggests that metabolic complications or MDS-related TOD may be more reasonable instead of so-called chronic diabetic complications. This updated philosophy is crucial for the management of T2D, emphasizing that TOD is not only caused by hyperglycemia. […] Islet cell dysfunction plays a key role in the progression of T2D, which includes impaired insulin synthesis and secretion, and a reduced mass of cells. It occurs before the diagnosis of T2D, by when the cells have been lost approximately 50% compared with that of nondiabetic individuals.