Inhibitory karboksylazy acetylokoenzymu A
Karboksylaza acetylo-CoA katalizuje nieodwracalną karboksylację malonylo-CoA podczas biosyntezy kwasów tłuszczowych. Krążące wolne kwasy tłuszczowe i zwiększone stężenie wewnątrzkomórkowych lipotoksycznych metabolitów kwasów tłuszczowych (FACoA, DAG i ceramidy) wywołują insulinooporność w wątrobie oraz mięśniach szkieletowych i hamują wydzielanie insuliny.2 Nie zaskakuje więc wykazanie, że inhibitor karboksylazy acetylo-CoA, NDI-630, zwiększa insulinowrażliwość, zmniejsza stężenie wolnych kwasów tłuszczowych i glukozy w osoczu oraz koryguje zaburzenia lipidowe w zwierzęcych modelach otyłości i cukrzycy typu 2.139
Inne doustne leki przeciwcukrzycowe
Różne inne doustne leki przeciwcukrzycowe są obiecujące, jeżeli chodzi o poprawę glikemii w cukrzycy typu 2, w tym leki wiążące kwasy żółciowe,140 aktywatory farnezoidowego receptora X kwasów żółciowych,141 aktywatory kinazy aktywowanej przez monofosforan adenozyny (AMPK),142-144 modulatory mikroflory jelitowej,145 aktywatory syntazy glikogenu,146 inhibitory fosforylazy glikogenu147 oraz ranolazyna.148 Ranolazyna została zarejestrowana przez FDA jako lek przeciwdławicowy, który działa przez hamowanie późnego prądu sodowego w miocytach serca. Nie jest jasne, w jaki sposób wiąże się to ze zmniejszeniem stężenia HbA1C obserwowanym u chorych na cukrzycę typu 2, chociaż wykazano, że w większych dawkach niż stosowane klinicznie ranolazyna zmniejsza wydzielanie glukagonu przez komórki α trzustki przez hamowanie kanałów sodowych.149,150
W badaniach przedklinicznych wykazano, że aktywacja deacetylazy białkowej SIRT1 za pomocą SRT3025 sprzyjała redukcji masy ciała, hamowała glukoneogenezę i lipogenezę w wątrobie oraz zwiększała wrażliwość na insulinę.151 Nie wiadomo, czy podobne efekty będą obserwowane u ludzi. Ostatnio w próbie klinicznej sponsorowanej przez NIH wykazano, że kwas obetycholowy jest skuteczny w leczeniu niealkoholowej stłuszczeniowej choroby wątroby (NAFLD), a u chorych na cukrzycę typu 2 i NAFLD lek ten zwiększał wrażliwość tkanek na insulinę. Wywołało to zainteresowanie możliwością zastosowania kwasu obetycholowego w leczeniu chorych na cukrzycę typu 2.
Leki przeciwko otyłości
Obecna epidemia cukrzycy jest napędzana przez epidemię otyłości, czyli stanu przeładowania tkanek tłuszczem. Nagromadzenie lipotoksycznych metabolitów w komórkach β hamuje wydzielanie insuliny, natomiast zwiększone stężenie FACoA, DAG i ceramidów w wątrobie i mięśniach wywołuje insulinooporność.2,119 Ostatnio FDA zarejestrowała preparaty Qsymia (połączenie fenterminy i topiramatu o przedłużonym uwalnianiu) oraz Belviq (lorkaseryna) jako leki zmniejszające masę ciała u osób otyłych. Lorkaseryna jest selektywnym agonistą receptora 5-hydroksytryptaminy (serotoniny) typu C (5-HTC), który zmniejsza spożycie pokarmów przez wpływ na układ proopiomelanokortyny. Fentermina jest sympatykomimetykiem o działaniu hamującym łaknienie, natomiast topiramat jest modulatorem receptora kwasu γ-aminomasłowego, chociaż mechanizm jego działania sprzyjającego redukcji masy ciała jest słabo poznany.
W badaniu Behavioral Modification and Lorcaserin for Obesity and Overweight Management in Diabetes Meillitus (BLOOM-DM)152 lorkaseryna spowodowała zmniejszenie masy ciała o około 5%, a średniego stężenia HbA1C o około 1,0%, mimo że zużycie leków przeciwcukrzycowych się zmniejszyło. W 2-letnim badaniu SEQUEL153 kombinacja fenterminy i topiramatu zmniejszyła masę ciała o około 10%, a w podgrupie otyłych chorych na cukrzycę typu 2 spowodowała większy spadek wartości HbA1C w porównaniu z placebo i wiązała się z rzadszą potrzebą intensyfikacji leczenia przeciwcukrzycowego. W grupie pacjentów bez cukrzycy leczonych fenterminą i topiramatem zaobserwowano istotnie rzadszą progresję do cukrzycy typu 2 (0,9 vs 3,7%; p <0,001).153
Obecnie nie jest jasne, czy lorkaseryna lub połączenie fenterminy z topiramatem wywierają działanie przeciwcukrzycowe wykraczające poza efekt redukcji masy ciała. Mimo to te leki zmniejszające masę ciała skutecznie poprawiają kontrolę glikemii u otyłych chorych na cukrzycę typu 2.
Wnioski
Na cukrzycę typu 2 składa się wiele zaburzeń patofizjologicznych. Dalsze prace nad nowymi lekami mają zasadnicze znaczenie, ponieważ epidemia cukrzycy trwa i w ciągu najbliższych kilku dziesięcioleci prawdopodobnie się nasili. Opracowano i nadal opracowuje się obiecujące leki, z których część to nowe odmiany już dostępnych klas leków (agoniści receptora GLP-1, inhibitory DPP-4, inhibitory SGLT-2, metformina, tiazolidynediony/modulatory mTOT oraz leki wiążące kwasy żółciowe), niektóre są lekami przeciwko otyłości, dla których uzyskano obiecujące wyniki w odniesieniu do cukrzycy typu 2 (fentermina/topiramat oraz lorkaseryna), a inne są unikatowymi klasami, które w przyszłości znajdą ostatecznie zastosowanie w leczeniu cukrzycy lub też nie (inhibitory PDHK, inhibitory PTP-1B, analogi FGF-21, inhibitory 11-β-HSD-1, inhibitory DGAT-1, antagoniści receptora glukagonu, aktywatory glukokinazy, inhibitory fruktozo-1,6-bisfosfatazy, inhibitory karboksylazy acetylo-CoA, leki przeciwzapalne, aktywatory AMPK oraz modulatory mikroflory jelitowej). Czas ujawni prawdziwy potencjał każdego z tych kandydatów, ale nie ulega wątpliwości, że w farmakoterapii cukrzycy istnieje wiele nowych możliwości.
Copyright 2014 American Diabetes Association. From Diabetes Spectrum, Vol. 27, No. 2, 2014, p. 100. Novel agents for the treatment of type 2 diabetes. Reprinted with permission from The American Diabetes Association.
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