ПРОФИЛАКТИКА САХАРНОГО ДИАБЕТА I ТИПА

ÎÃËßÄ
Â.Â. Ïîëòîðàê1
Í.È. Ãîðáåíêî1
Å.À. Ñàêàëî2
Óêðàèíñêèé íàó÷íîèññëåäîâàòåëüñêèé èíñòèòóò
ôàðìàêîòåðàïèè ýíäîêðèííûõ
çàáîëåâàíèé, Õàðüêîâ
1
ÏÐÎÔÈËÀÊÒÈÊÀ ÑÀÕÀÐÍÎÃÎ
ÄÈÀÁÅÒÀ ² ÒÈÏÀ:
ÏÀÒÎÔÈÇÈÎËÎÃÈ×ÅÑÊÎÅ
ÎÁÎÑÍÎÂÀÍÈÅ, ÑÒÐÀÒÅÃÈß
È ÊËÈÍÈ×ÅÑÊÀß ÐÅÀËÈÇÀÖÈß
Ïðåäñòàâèòåëüñòâî êîìïàíèè
«Íîâî Íîðäèñê» â Óêðàèíå, Êèåâ
2
Êëþ÷åâûå ñëîâà: ñàõàðíûé
äèàáåò I òèïà, èììóíîïàòîãåíåç,
èììóíîïðîôèëàêòèêà.
Ðåçþìå. Â ñòàòüå ïðîàíàëèçèðîâàíû äàííûå ëèòåðàòóðû î âîçìîæíîñòÿõ èììóíîïðîôèëàêòèêè è èììóíîòåðàïèè ïðè ñàõàðíîì äèàáåòå I òèïà,
öåëüþ êîòîðûõ ÿâëÿåòñÿ ïðåäîòâðàòèòü èëè ïðèîñòàíîâèòü àóòîèììóííîå ðàçðóøåíèå β-êëåòîê ïîäæåëóäî÷íîé æåëåçû. Îïèñàíû ñîâðåìåííûå
ïðåäñòàâëåíèÿ î ïàòîôèçèîëîãè÷åñêîì îáîñíîâàíèè òàêîãî òåðàïåâòè÷åñêîãî ïîäõîäà.
Ñàõàðíûé äèàáåò I òèïà — àóòîèììóííîå çàáîëåâàíèå, õàðàêòåðèçóþùååñÿ ïîñòåïåííûì ðàçðóøåíèåì β-êëåòîê ïîäæåëóäî÷íîé æåëåçû ñ ïîñëåäóþùèì ðàçâèòèåì àáñîëþòíîé íåäîñòàòî÷íîñòè
èíñóëèíà. Â ðàçâèòèè ýòîãî çàáîëåâàíèÿ âûäåëÿþò
ñëåäóþùèå ñòàäèè (Verge C., Eisenbarth W., 1996):
1-ÿ ñòàäèÿ — ãåíåòè÷åñêàÿ ïðåäðàñïîëîæåííîñòü
ê ñàõàðíîìó äèàáåòó I òèïà àññîöèèðîâàíà ñ àêòèâíîñòüþ îïðåäåëåííûõ àëëåëåé ãåíîâ ãèñòîñîâìåñòèìîñòè âòîðîãî êëàññà — DR-3 / DR4, ðàñïîëîæåííûõ íà êîðîòêîì ïëå÷å 6-é õðîìîñîìû, è â ìåíüøåé ñòåïåíè — ñ ïîëèìîðôèçìîì èíñóëèíîâîãî
ãåíà íà êîðîòêîì ïëå÷å 11-é õðîìîñîìû;
2-ÿ ñòàäèÿ — íà÷àëî àóòîàãðåññèè (ïîÿâëåíèå â
êðîâè àóòîàíòèòåë ê îñòðîâêîâîêëåòî÷íûì àíòèãåíàì);
3-ÿ ñòàäèÿ — ïðîãðåññèâíîå óìåíüøåíèå êîëè÷åñòâà β-êëåòîê è ñíèæåíèå ñåêðåöèè èíñóëèíà, ÷òî
äèàãíîñòèðóåòñÿ âî âðåìÿ âíóòðèâåííîãî òåñòà òîëåðàíòíîñòè ê ãëþêîçå çàäîëãî äî ìàíèôåñòàöèè
ñàõàðíîãî äèàáåòà;
4-ÿ ñòàäèÿ — ÿâíûé ñàõàðíûé äèàáåò. Êëèíè÷åñêàÿ ìàíèôåñòàöèÿ çàáîëåâàíèÿ ïðîèñõîäèò, êîãäà
êîëè÷åñòâî ôóíêöèîíèðóþùèõ β-êëåòîê ñîñòàâëÿåò ìåíåå 20% èñõîäíîãî óðîâíÿ.
Ïîíÿòíî, ÷òî â êëèíè÷åñêîé ïðàêòèêå äèàãíîç
ñàõàðíîãî äèàáåòà I òèïà ìîæåò áûòü óñòàíîâëåí
ëèøü íà ïîñëåäíåé ñòàäèè áîëåçíè, êîãäà ðàçðóøåíî áîëåå 80% β-êëåòîê è íåäîñòàòî÷íîñòü èíñóëèíà ñòàíîâèòñÿ ÿâíîé. Èìåííî ñ ýòîãî âðåìåíè áîëüíîìó íàçíà÷àþò çàìåñòèòåëüíóþ òåðàïèþ èíñóëèíîì, ââåäåíèå êîòîðîãî ñòàíîâèòñÿ àáñîëþòíî íåîáõîäèìûì íà ïðîòÿæåíèè âñåé æèçíè áîëüíîãî.
Ìíîãî÷èñëåííûå ïîïûòêè çàùèòèòü β-êëåòêè îò
ðàçðóøåíèÿ è òåì ñàìûì ïðåäîòâðàòèòü ðàçâèòèå
ñàìîãî çàáîëåâàíèÿ äî íåäàâíåãî âðåìåíè áûëè
ìàëîóñïåøíûìè (Åôèìîâ À.Ñ., Ïîëòîðàê Â.Â.,
1989; Áàëàáîëêèí Ì.È., 1997). Îäíàêî äîñòèæåíèÿ
ïîñëåäíèõ ëåò â äèàáåòîëîãèè è èììóíîëîãèè ñïîñîáñòâîâàëè ñîçäàíèþ íîâûõ òåõíîëîãèé è ïîäõîäîâ, ïîçâîëÿþùèõ (âî âñÿêîì ñëó÷àå â ýêñïåðèìåíòàëüíûõ óñëîâèÿõ) ïðàêòè÷åñêè ïîëíîñòüþ ïîäàâèòü ðåàêöèè àóòîàãðåññèè è ñîõðàíèòü ôóíêöèîíèðóþùèé ïóë β-êëåòîê. Ðàññìîòðåíèå äàííîãî
àñïåêòà ïðîáëåìû ÿâëÿåòñÿ öåëüþ íàñòîÿùåãî îáçîðà.
Ìíîãî÷èñëåííûå èññëåäîâàíèÿ, ïðîâåäåííûå
â ïîñëåäíèå ãîäû, ñïîñîáñòâîâàëè áîëåå ãëóáîêîìó ïîíèìàíèþ ïðîöåññîâ, ïðîèñõîäÿùèõ â îðãàíèçìå ÷åëîâåêà ïðè àóòîèììóííîé ïàòîëîãèè, â
òîì ÷èñëå ïðè ñàõàðíîì äèàáåòå I òèïà.  ÷àñòíîñòè, óñòàíîâëåíî, ÷òî àóòîèììóííûå ðåàêöèè íà
àíòèãåíû β-êëåòîê âûçûâàþò öåëûé ðÿä ñîáûòèé,
êîòîðûå âåäóò ê íàêîïëåíèþ ñâîáîäíûõ ðàäèêàëîâ êèñëîðîäà è îêñèäà àçîòà (NO). ×ðåçìåðíîå èõ
íàêîïëåíèå ÿâëÿåòñÿ îñíîâíîé ïðè÷èíîé ðàçðóøåíèÿ β-êëåòîê (Mandrup-Poulsen T., 1996; Corbett J. et al., 1997). Ýòîìó ñîáûòèþ ïðåäøåñòâóåò
àêòèâàöèÿ ñïåöèôè÷åñêèõ àíòèãåíðåàêòèâíûõ
Ò-õåëïåðîâ, öèòîêèíû êîòîðûõ (èíòåðëåéêèí-2
(ÈË-2), ôàêòîð íåêðîçà îïóõîëåé-áåòà, èíòåðôåðîí-ãàììà) ñîâìåñòíî ñ ìîíîêèíàìè ìàêðîôàãîâ
(èíòåðëåéêèí-1 (ÈË-1), ôàêòîð íåêðîçà îïóõîëåéàëüôà) ïðèâîäÿò ê ðàçâèòèþ âîñïàëèòåëüíîé ðåàêöèè, àêòèâàöèè ñïåöèôè÷åñêèõ Ò-êèëëåðîâ è
âêëþ÷åíèþ íåñïåöèôè÷åñêèõ ìåõàíèçìîâ ðàçðóøåíèÿ β-êëåòîê.
Îñîáîå âíèìàíèå óäåëÿåòñÿ NO â êà÷åñòâå ýôôåêòîðíîé ìîëåêóëû, îñóùåñòâëÿþùåé ðàçðóøåíèå è ãèáåëü ïàíêðåàòè÷åñêèõ β-êëåòîê (MandrupPoulsen T., 1996; Corbett J. et al., 1997). Íà ìîäåëè
îñòðîâêîâ êðûñ áûëî ïîêàçàíî, ÷òî NO, íèòðîçè-
ÓÊÐÀ¯ÍÑÜÊÈÉ ÌÅÄÈ×ÍÈÉ ×ÀÑÎÏÈÑ – ¹ 2 (22) – III/IV 2001
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ÎÃËßÄ
ëèðóÿ Fe-S-ãðóïïû â ìèòîõîíäðèàëüíûõ äûõàòåëüíûõ ôåðìåíòàõ, ïðèâîäèò ê èõ èíàêòèâàöèè. Èñêëþ÷èòåëüíàÿ ÷óâñòâèòåëüíîñòü ê îáðàçîâàíèþ æåëåçî-íèòðîçèëüíûõ êîìïëåêñîâ àêòèâíûõ ãðóïï
êëþ÷åâîãî ôåðìåíòà öèêëà Êðåáñà àêîíèòàçû îáóñëîâëèâàåò íàðóøåíèå ìèòîõîíäðèàëüíîãî îêèñëåíèÿ ãëþêîçû è ãåíåðàöèè ÀÒÔ ñ ïîñëåäóþùåé ãèáåëüþ êëåòêè â ðåçóëüòàòå ýíåðãåòè÷åñêîãî ãîëîäà.
Ñâîáîäíûå ðàäèêàëû, â ÷àñòíîñòè NO, òàêæå âûçûâàþò ðàçðûâ íèòè ÄÍÊ (Fehsel K. et al., 1993).
Àêòèâàöèÿ ïîëè (ÀÄÔ-ðèáîçî)-ïîëèìåðàçû (ÏÀÐÏ)
äëÿ âîññòàíîâëåíèÿ ýòèõ ðàçðûâîâ ñíèæàåò ñîäåðæàíèå â êëåòêå íèêîòèíàìèäàäåíèíäèíóêëåîòèäà
(ÍÀÄ) è òàêæå âåäåò ê åå ñìåðòè. Óñèëåííîå îáðàçîâàíèå ñâîáîäíîãî ðàäèêàëà NO ÿâëÿåòñÿ ðåçóëüòàòîì ýêñïðåññèè èíäóöèáåëüíîé NO-ñèíòàçû
(iNOS) ïîä âëèÿíèåì ÈË-1. L-àðãèíèí ïðè âîçäåéñòâèè iNOS ïðåâðàùàåòñÿ â L-öèòðóëëèí è NO (Corbett J. et al., 1997).
 ñîîòâåòñòâèè ñ ñîâðåìåííîé êîíöåïöèåé ñïåöèôè÷åñêàÿ äåñòðóêöèÿ ïàíêðåàòè÷åñêèõ β-êëåòîê
ìîæåò áûòü ñâÿçàíà ñ èíäóöèðîâàííûì öèòîêèíàìè ñèíòåçîì NO è àïîïòîçîì (çàïðîãðàììèðîâàííîé ñìåðòüþ) èìåííî β-êëåòîê, íî íå äðóãèõ ýíäîêðèííûõ êëåòîê ïàíêðåàòè÷åñêèõ îñòðîâêîâ (Mandrup-Poulsen T., 1996; Corbett J. et al., 1997). Òàê,
îáðàáîòêà êðûñèíûõ îñòðîâêîâ ÈË-1 ïðèâîäèëà ê
ýêñïðåññèè iNOS â èíñóëèíñîäåðæàùèõ êëåòêàõ, à
èíñóëèííåñåêðåòèðóþùèå ýëåìåíòû íå ýêñïðåññèðîâàëè äàííûé àãåíò (Corbett J., McDaniel M., 1995).
Ïðè ýòîì äëÿ ñòèìóëÿöèè ýêñïðåññèè iNOS β-êëåòêàìè êðûñ áûëî äîñòàòî÷íî îäíîãî ÈË-1.  òî æå
âðåìÿ äëÿ ñòèìóëÿöèè ýêñïðåññèè iNOS β-êëåòêàìè íåòó÷íûõ (NOD) ìûøåé è ÷åëîâåêà ñ ñàõàðíûì
äèàáåòîì òðåáîâàëàñü êîìáèíàöèÿ ÈË-1 è èíòåðôåðîíà-ãàììà (Corbett J. et àl., 1997).
Ñëåäóåò ïîä÷åðêíóòü, ÷òî ÈË-1 ñàìîñòîÿòåëüíî
íå ïîâðåæäàåò ïàíêðåàòè÷åñêèå îñòðîâêè ÷åëîâåêà
(Eizirik D.L., Welsh N., 1993). Èíäóêöèÿ ñèíòåçà NO
è äèñôóíêöèÿ β-êëåòîê â ïàíêðåàòè÷åñêèõ îñòðîâêàõ ÷åëîâåêà íàáëþäàëàñü ïîñëå èõ ýêñïîçèöèè ñî
ñìåñüþ öèòîêèíîâ (ÈË-1-áåòà + ôàêòîð íåêðîçà
îïóõîëåé-àëüôà + èíòåðôåðîí-ãàììà) (CetkovicCvrije M., Eizink D.L., 1994). Âûøåîòìå÷åííàÿ êîìáèíàöèÿ öèòîêèíîâ áûëà òàêæå íåîáõîäèìà äëÿ
èíäóêöèè ðàçðûâîâ ÄÍÊ è àïîïòîçà ÷åëîâå÷åñêèõ
β-êëåòîê, êóëüòèâèðóåìûõ áîëåå 9 äíåé (Delaney C.A. et al., 1997). Ýòî ñâèäåòåëüñòâóåò î âàæíîñòè, íàðÿäó ñ âèäîâûìè îñîáåííîñòÿìè, è ðåàêöèè
ñàìèõ êëåòîê-ìèøåíåé ïðè àóòîàãðåññèè (MandrupPoulsen T., 1996).
 îòëè÷èå îò ïàíêðåàòè÷åñêèõ îñòðîâêîâ ãðûçóíîâ, ãäå NO èãðàåò ãëàâíóþ ðîëü â ðåàëèçàöèè ïîâðåæäàþùèõ ýôôåêòîâ öèòîêèíîâ, âûçûâàåìàÿ
öèòîêèíàìè äèñôóíêöèÿ β-êëåòîê è îáðàçîâàíèå
NO ìîãóò áûòü äèññîöèèðîâàííûìè â ïàíêðåàòè÷åñêèõ îñòðîâêàõ ÷åëîâåêà. Òàê, õîòÿ êîìáèíàöèÿ
öèòîêèíîâ (ÈË-1-áåòà + ôàêòîð íåêðîçà îïóõîëåéàëüôà + èíòåðôåðîí-ãàììà) ñóùåñòâåííî ïîâûøà84
ëà îáðàçîâàíèå NO â ïàíêðàòè÷åñêèõ îñòðîâêàõ ÷åëîâåêà (Corbet J., Sweetland M. et al., 1993), èíãèáèòîðû ñèíòåçà NO íå ïðåäóïðåæäàëè ñóïðåññèâíîå
äåéñòâèå öèòîêèíîâ íà ñèíòåç èíñóëèíà. Ýòè æå
èíãèáèòîðû íå ïðåïÿòñòâîâàëè òàêæå ñíèæåíèþ
ñîäåðæàíèÿ ÄÍÊ è èíñóëèíà â êóëüòóðå äèñïåðãèðîâàííûõ êëåòîê ïàíêðåàòè÷åñêèõ îñòðîâêîâ ÷åëîâåêà, íåñìîòðÿ íà ñóïðåññèþ iNOS è ïðåäóïðåæäåíèå îáðàçîâàíèÿ NO. Ìåõàíèçìû, áëàãîäàðÿ êîòîðûì êîìáèíàöèÿ öèòîêèíîâ óõóäøàåò ôóíêöèþ
β-êëåòîê, ïîäëåæàò äàëüíåéøåìó èçó÷åíèþ. Ïî
êðàéíåé ìåðå ýòîò ïîâðåæäàþùèé ýôôåêò îáóñëîâëåí íè èíãèáèðîâàíèåì îáìåíà ãëþêîçû, íè ñíèæåíèåì óðîâíÿ ÍÀÄ+. Îäèí èç âîçìîæíûõ ìåõàíèçìîâ, ñ ïîìîùüþ êîòîðîãî NO âûçûâàåò äèñôóíêöèþ è ñìåðòü β-êëåòîê ÷åëîâåêà, ÿâëÿåòñÿ ðàçðûâ
öåïè ÄÍÊ (Fehsel K. et al., 1993).
Îáíàðóæåíà è áîëåå íèçêàÿ ÷óâñòâèòåëüíîñòü
β-êëåòîê ÷åëîâåêà ê ïîâðåæäàþùåìó äåéñòâèþ ðàçëè÷íûõ äîíîðîâ NO (Eizirik D.L., 1996). Âñå ñêàçàííîå âûøå îáîñíîâûâàåò îñòîðîæíîñòü ïðè ýêñòðàïîëÿöèè äàííûõ, ïîëó÷åííûõ íà ìîäåëÿõ ñàõàðíîãî äèàáåòà ó æèâîòíûõ íà ñèòóàöèþ, êîòîðàÿ ìîæåò
èìåòü ìåñòî ïðè ðàçâèòèè ñàõàðíîãî äèàáåòà I òèïà
ó ÷åëîâåêà.  òî æå âðåìÿ èõ çíà÷åíèå äëÿ ðàçðàáîòêè îáîñíîâàííîé ïåðñïåêòèâíîé ñòðàòåãèè ïðåâåíòèâíîé òåðàïèè íà äîêëèíè÷åñêîé ñòàäèè áîëåçíè
íåñîìíåííî. Ýòî êàñàåòñÿ òàêòèêè ïðåäóïðåæäåíèÿ
ñàõàðíîãî äèàáåòà I òèïà, êîòîðàÿ îñíîâàíà íà óñòàíîâëåííîé ðîëè öèòîêèíîâ â ôîðìèðîâàíèè èììóííûõ ïîâðåæäåíèé. Òåðàïèÿ ñàõàðíîãî äèàáåòà
ìîæåò áûòü íàïðàâëåíà íà èíãèáèðîâàíèå òðàíñêðèïöèè öèòîêèíîâîãî ãåíà, èíäóêöèþ öèòîêèíîâîãî àíòàãîíèçìà, òîðìîæåíèå öèòîêèíîâîãî
ýôôåêòà, à òàêæå íà çàùèòó β-êëåòîê áåëêàìè òåïëîâîãî øîêà, óãíåòåíèå iNOS è äð. (Mandrup-Poulsen T., 1996). Íåêîòîðûå èç ýòèõ íàïðàâëåíèé, íàïðèìåð òîðìîæåíèå ñèíòåçà NO ñèíòåòè÷åñêèìè
àíàëîãàìè àðãèíèíà èëè íèêîòèíàìèäîì, áëèçêè
ê êëèíè÷åñêîé àïðîáàöèè èëè óæå ïðîõîäÿò åå.
Àóòîèììóííûé ïðîöåññ, ïðèâîäÿùèé ê ñàõàðíîìó äèàáåòó I òèïà, ðàçâèâàåòñÿ, êàê ïðàâèëî, íà
ïðîòÿæåíèè íåñêîëüêèõ ëåò. Íà÷àëó êëèíè÷åñêèõ
ïðîÿâëåíèé çàáîëåâàíèÿ ïðåäøåñòâóåò äëèòåëüíûé
ïåðèîä áåññèìïòîìíîé àóòîàãðåññèè (Verge C.F.,
1996; Bingley P.J., 1997). Äèàãíîñòèêà ïîñëåäíåé ñòàëà âîçìîæíîé áëàãîäàðÿ íàëè÷èþ ìåòîäîëîãèè
îïðåäåëåíèÿ àíòèòåë ê êëåòêàì ïàíêðåàòè÷åñêèõ
îñòðîâêîâ è ê èõ îòäåëüíûì ìîëåêóëàì — öèòîïëàçìàòè÷åñêèì àíòèãåíàì (IÑÀ), ê ïðîèíñóëèíó,
èíñóëèíó (IÀÀ), äåêàðáîêñèëàçå ãëóòàìèíîâîé êèñëîòû (GAD) è òðàíñìåìáðàííîìó áåëêó òèðîçèíôîñôàòàçå-2 (IÀ-2) (Leslie R.D.G. et al., 1999). Îäèí
èç óêàçàííûõ âèäîâ àíòèòåë ìîæåò îáíàðóæèâàòüñÿ ïî÷òè ó 90% ïàöèåíòîâ. Èíòåíñèâíîñòü, ïðîäîëæèòåëüíîñòü è ãåòåðîãåííîñòü èììóííûõ ðåàêöèé
îòëè÷àþòñÿ ó ðàçíûõ ëþäåé è çàâèñÿò îò äëèòåëüíîñòè ñàõàðíîãî äèàáåòà. Îäíîâðåìåííî â êðîâè
ìîãóò îïðåäåëÿòüñÿ àêòèâèðîâàííûå Ò-ëèìôîöè-
ÓÊÐÀ¯ÍÑÜÊÈÉ ÌÅÄÈ×ÍÈÉ ×ÀÑÎÏÈÑ – ¹ 2 (22) – III/IV 2001
ÎÃËßÄ
òû, êîòîðûå ðàñïîçíàþòñÿ ïî óâåëè÷åíèþ ýêñïðåññèè HLA-DR (Atkinson M., Maclaren N., 1994). Ðèñê
ðàçâèòèÿ ñàõàðíîãî äèàáåòà I òèïà ïîâûøàåòñÿ ìíîãîêðàòíî ïðè îäíîâðåìåííîì îïðåäåëåíèè àóòîàíòèòåë ê íåñêîëüêèì àíòèãåíàì (Kulmala P. et al.,
1998). Òàê, ðèñê ðàçâèòèÿ çàáîëåâàíèÿ ó ðîäñòâåííèêîâ 1-é ñòåïåíè ðîäñòâà áîëüíûõ ñàõàðíûì äèàáåòîì ñ íàëè÷èåì îäíîãî, äâóõ èëè òðåõ òèïîâ àóòîàíòèòåë ñîñòàâëÿë 2, 25 è 70% ñîîòâåòñòâåííî â îäíîì èññëåäîâàíèè (Verge C.F., Gianani R. et al., 1996)
è 15, 44 è 100% — â äðóãîì (Kulmala P., Savola K. et al.,
1998). Âåðîÿòíåå âñåãî íàëè÷èå ðàçíûõ àóòîàíòèòåë
ñâèäåòåëüñòâóåò î âûðàæåííîñòè èììóííûõ íàðóøåíèé, ÷åì è îïðåäåëÿåòñÿ ïîâûøåíèå ðèñêà äàëüíåéøåãî ïðîãðåññèðîâàíèÿ ïàòîëîãè÷åñêîãî ïðîöåññà.
Ôîðìèðîâàíèå èììóííîãî îòâåòà ãåíåòè÷åñêè
äåòåðìèíèðîâàíî (Hawa M. et al., 1997). Ñëåäîâàòåëüíî, èäåíòèôèêàöèÿ ïðîäèàáåòè÷åñêèõ ãåíîâ
ìîæåò áûòü î÷åíü öåííîé äëÿ âûÿâëåíèÿ ëèö, ïðåäðàñïîëîæåííûõ ê çàáîëåâàíèþ (Thai A.C., Eisenburth G.S., 1993). Ãåíåòè÷åñêèå ìàðêåðû âêëþ÷àþò
HLA-àëëåëè ðèñêà (HLA DQ, DR è êëàññ 1) (Honeyman M.C. et al., 1995). Èçó÷àþòñÿ òàêæå è íåñâÿçàííûå ñ HLA ãåíû, îïðåäåëÿþùèå ÷óâñòâèòåëüíîñòü
ê ñàõàðíîìó äèàáåòó (Wicker L.S. et àl., 1995; Morahan G. et al., 1996).
Íà äîêëèíè÷åñêîé ñòàäèè ðàçâèòèÿ áîëåçíè ìîãóò íàáëþäàòüñÿ àóòîèììóííûå ðåàêöèè ðàçëè÷íîé
âûðàæåííîñòè, ïðîäîëæèòåëüíîñòü ðåãèñòðàöèè
êîòîðûõ ìîæåò äëèòüñÿ äåñÿòêè ëåò. Âîçìîæíî, ñóùåñòâóþò îïðåäåëåííûå ìåõàíèçìû çàùèòû êëåòîê, âêëþ÷àþùèå èõ óñòîé÷èâîñòü è ðåãåíåðàöèþ.
 íàñòîÿùåå âðåìÿ èçâåñòíî íåñêîëüêî çàùèòíûõ
ñèñòåì β-êëåòîê. Îíè âêëþ÷àþò àíòèîêñèäàíòíûå
ôåðìåíòû (êàòàëàçà è ñóïåðîêñèääèñìóòàçà), âîññòàíîâëåííûé ãëóòàòèîí, ñòðåññîðíûé áåëîê òåïëîâîãî øîêà (hsp 70) è ãåìîêñèãåíàçó, èñõîäÿ èç ÷åãî
âîçìîæåí íîâûé ïîäõîä ê çàùèòå β-êëåòîê, äîïîëíÿþùèé ñïîñîáû ìîäèôèêàöèè àíòèãåííîñòè
β-êëåòîê è èììóííîãî îòâåòà ó ëèö ñ âûñîêèì ðèñêîì ðàçâèòèÿ çàáîëåâàíèÿ, à èìåííî — óâåëè÷åíèå
èõ çàùèòíîãî ïîòåíöèàëà (Eizirik D.L., 1996).
Íà îñíîâàíèè ïîëó÷åííûõ ôàêòîâ ñëîæèëîñü
ïðåäñòàâëåíèå î âîçìîæíîñòè ïðåäóïðåæäåíèÿ ðàçâèòèÿ ñàõàðíîãî äèàáåòà I òèïà ó ëèö ñ íàëè÷èåì
ãåíåòè÷åñêèõ è èììóííûõ ìàðêåðîâ áîëåçíè íà åå
äîêëèíè÷åñêîé ñòàäèè (Eisenburth G.S. et al., 1993).
Ïðåäóïðåæäåíèå ñàõàðíîãî äèàáåòà I òèïà îáåñïå÷èâàåòñÿ:
à) èñêëþ÷åíèåì ôàêòîðîâ îêðóæàþùåé ñðåäû,
êîòîðûå âûçûâàþò ðàçâèòèå ïàòîëîãè÷åñêîãî ïðîöåññà (ïåðâè÷íàÿ ïðîôèëàêòèêà);
á) ïðåðûâàíèåì àóòîèììóííîé ðåàêöèè, íàïðàâëåííîé ïðîòèâ ïàíêðåàòè÷åñêèõ β-êëåòîê (âòîðè÷íàÿ ïðîôèëàêòèêà).
Ñëåäóåò îòìåòèòü, ÷òî äî íàñòîÿùåãî âðåìåíè
åùå îêîí÷àòåëüíî íå âûÿâëåíû âñå ôàêòîðû, êîòîðûå ñïîñîáíû èíäóöèðîâàòü ïàòîëîãè÷åñêèé ïðî-
öåññ ó ãåíåòè÷åñêè ïðåäðàñïîëîæåííûõ ê ñàõàðíîìó äèàáåòó ëèö. Ê äèàáåòîãåííûì ôàêòîðàì îòíîñÿò âèðóñû, òîêñèíû è íåêîòîðûå ïèùåâûå ïðîäóêòû (Dahlquist G., 1995; 1999; Haverkas N.W., 1997).
Åñòü îòäåëüíûå ñîîáùåíèÿ î ïðåäóïðåæäåíèè ðàçâèòèÿ ñàõàðíîãî äèàáåòà ñ ïîìîùüþ èñêëþ÷åíèÿ èç
ðàöèîíà äåòåé ñ âûñîêèì ðèñêîì çàáîëåâàíèÿ êîðîâüåãî ìîëîêà â ïåðâûå 6–8 ìåñ èõ æèçíè.
Ñòðàòåãèÿ âòîðè÷íîé ïðîôèëàêòèêè âêëþ÷àåò
íåñêîëüêî ïîäõîäîâ, ñðåäè êîòîðûõ íàèáîëüøóþ
ðàñïðîñòðàíåííîñòü ïîëó÷èëî ïðèìåíåíèå íèêîòèíàìèäà è èíñóëèíà (Leslie R.D.G.et al., 1999).
Êëèíè÷åñêîå ïðèìåíåíèå íèêîòèíàìèäà îñíîâàíî â ïåðâóþ î÷åðåäü íà ýêñïåðèìåíòàëüíûõ íàáëþäåíèÿõ, â êîòîðûõ ñ ïîìîùüþ ýòîãî âåùåñòâà
ïðåäóïðåæäàëè ðàçðóøåíèå β-êëåòîê, âûçâàííîãî
in vivo èëè in vitro òîêñèíàìè è öèòîêèíàìè. Òàê,
íèêîòèíàìèä ïðåïÿòñòâîâàë ðàçâèòèþ àëëîêñàíîâîãî èëè ñòðåïòîçîòîöèíîâîãî äèàáåòà (Íèêóëèíà M., Ïîëòîðàê Â., 1997; Poltorack V. et al., 1999).
Áîëåå òîãî, îáðàáîòêà ìûøåé NOD íà ïðåäèàáåòè÷åñêîé ñòàäèè íèêîòèíàìèäîì ïðåïÿòñòâîâàëà èëè
ñóùåñòâåííî çàäåðæèâàëà ìàíèôåñòàöèþ ñïîíòàííîãî ñàõàðíîãî äèàáåòà (Yamada K. et àl., 1982; Nomikos I.N. et àl., 1986). Ïðè ýòîì îòìå÷åíî íåêîòîðîå óìåíüøåíèå îñòðîâêîâîé èíôèëüòðàöèè ìîíîíóêëåàðíûìè êëåòêàìè (Yamada K. et àl., 1982). Ó
ñêëîííûõ ê ñàõàðíîìó äèàáåòó êðûñ ÂÂ çàùèòíûé
ýôôåêò íèêîòèíàìèäà áûë ìåíåå âûðàæåí è â íåñêîëüêèõ ýêñïåðèìåíòàõ íå ïîäòâåðäèëñÿ (Kolb H.,
Schmidt M., 1989). Ïðè èñïîëüçîâàíèè íèêîòèíàìèäà â ñðåäíåòåðàïåâòè÷åñêèõ äîçàõ ñîõðàíÿëèñü
îñòàâøèåñÿ β-êëåòêè ó ÷àñòè÷íî ïàíêðåàòýêòîìèðîâàííûõ êðûñ è óñèëèâàëàñü èõ ðåãåíåðàöèÿ. Îí
òàêæå ñòèìóëèðîâàë ðîñò êóëüòóðû êëåòîê ïàíêðåàòè÷åñêèõ îñòðîâêîâ ïëîäà ÷åëîâåêà (Akerblom H.K.,
Knip M., 1997). Ïðèìåíåíèå íèêîòèíàìèäà in vitro
â êîíöåíòðàöèè 2 è 5 ììîëü/ë ïðåïÿòñòâîâàëî íåêðîçó äèñïåðãèðîâàííûõ ïàíêðåàòè÷åñêèõ β-êëåòîê êðûñ, îáóñëîâëåííîìó ñòðåïòîçîòîöèíîì èëè
ïåðåêèñüþ âîäîðîäà. Âìåñòå ñ òåì, íèêîòèíàìèä íå
ïðåïÿòñòâîâàë àïîïòîçó β-êëåòîê ïðè âîçäåéñòâèè
íà íèõ ÈË-1-áåòà, èíòåðôåðîíà-ãàììà è ôàêòîðà
íåêðîçà îïóõîëåé-àëüôà (Hoorens A., Pipeleers D.,
1999).  òî æå âðåìÿ íà ìîäåëè èçîëèðîâàííûõ ïàíêðåàòè÷åñêèõ îñòðîâêîâ âûñîêèå äîçû íèêîòèíàìèäà (>10 ììîëü) ïðîÿâëÿëè ñâîé çàùèòíûé ýôôåêò ïðè öèòîêèí-èíäóöèðóåìîé ãèáåëè β-êëåòîê
(Andersen H.U. et àl., 1994).
Âìåñòå ñ òåì, â õîäå äðóãèõ èññëåäîâàíèé âûÿâëåíî, ÷òî äëèòåëüíàÿ ýêñïîçèöèÿ ïàíêðåàòè÷åñêèõ
îñòðîâêîâ êðûñ ñ òàêèìè æå êîíöåíòðàöèÿìè íèêîòèíàìèäà ïðèâîäèëà ê ïîâðåæäåíèþ èõ ôóíêöèè
(Reddy S. et àl., 1995). Íàïðîòèâ, β-êëåòêè ÷åëîâåêà
îêàçàëèñü áîëåå ðåçèñòåíòíûìè, ÷åì òàêîâûå êðûñ,
ê èíäóöèðóåìîìó âûñîêîé äîçîé (20 ììîëü/ë) íèêîòèíàìèäà àïîïòîçó: ïîñëå 10-äíåâíîé èíêóáàöèè
ïðèçíàêè ïîñëåäíåãî îáíàðóæåíû òîëüêî ó êðûñ
(Hoorens A. et àl., 1999).
ÓÊÐÀ¯ÍÑÜÊÈÉ ÌÅÄÈ×ÍÈÉ ×ÀÑÎÏÈÑ – ¹ 2 (22) – III/IV 2001
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ÎÃËßÄ
Èññëåäîâàíèÿ in vitro ïîçâîëèëè âûñêàçàòü ìíåíèå î âîçìîæíîì ìåõàíèçìå ïðîòåêòîðíîãî ýôôåêòà íèêîòèíàìèäà, êîòîðûé âêëþ÷àåò àíòèîêñèäàíòíîå äåéñòâèå, èíãèáèðîâàíèå àêòèâíîñòè ÏÀÐÏ è
ïðÿìîå âîññòàíîâëåíèå óðîâíÿ ÍÀÄ+ (Gale E.A.,
1996). Óñòàíîâëåíî, ÷òî â êëåòêàõ ïàíêðåàòè÷åñêèõ
îñòðîâêîâ ãðûçóíîâ íèêîòèíàìèä âûçûâàåò óãíåòåíèå àêòèâíîñòè ÏÀÐÏ è îäíîâðåìåííî ñîõðàíÿåò âíóòðèêëåòî÷íûé ïóë ÍÀÄ+ (Uchigata Y. et àl.,
1982; Heller B. et al., 1995). Ýêñïîçèöèÿ ïàíêðåàòè÷åñêèõ îñòðîâêîâûõ êëåòîê ê ñòðåïòîçîòîöèíó, àëëîêñàíó èëè ïåðåêèñè âîäîðîäà ïðèâîäèò ê áûñòðîìó ïîÿâëåíèþ ìíîæåñòâåííûõ ðàçðûâîâ öåïè
ÄÍÊ ñ ïîñëåäóþùåé èçáûòî÷íîé àêòèâàöèåé
ÏÀÐÏ.  ðåçóëüòàòå ýòîãî ïðîèñõîäèò êðèòè÷åñêîå
óìåíüøåíèå âíóòðèêëåòî÷íîãî ïóëà ÍÀÄ+ (ÍÀÄ+
ÿâëÿåòñÿ ñóáñòðàòîì äëÿ ÏÀÐÏ ïðè ñèíòåçå áîëüøèõ ïîëèìåðîâ, ñîñòîÿùèõ èç ÀÄÔ-ñóáúåäèíèö).
 êîíå÷íîì ñ÷åòå ýòî îáóñëîâëèâàåò ýíåðãåòè÷åñêóþ ñìåðòü: íàðóøåíèå ôóíêöèè ìåìáðàíû è ëèçèñ êëåòêè. Ñîõðàíåíèå ñîäåðæàíèÿ êëåòî÷íîãî
ÍÀÄ+, êàê ïîëàãàþò, ïðåäóïðåæäàåò ëèçèñ êëåòêè.
Ïðè èññëåäîâàíèè ìåõàíèçìà âûçâàííîé ðàäèêàëàìè êèñëîðîäà è îêñèäà àçîòà ãèáåëè êëåòêè îáíàðóæåíî íàêîïëåíèå ýíäîãåííûõ ÀÄÔ-ðèáîçàïîëèìåðîâ âáëèçè ÿäåð âñåõ îñòðîâêîâûõ êëåòîê â
òå÷åíèå íåñêîëüêèõ ìèíóò ñ îäíîâðåìåííûì èñòîùåíèåì ÍÀÄ+.  β-êëåòêàõ, ýêñïîíèðîâàííûõ ñ
íèêîòèíàìèäîì, íå íàáëþäàëîñü ïîòåðè ÍÀÄ+ è
îíè áûëè ñïîñîáíû âûæèâàòü ïðè âûøåóêàçàííîì
ëåòàëüíîì âîçäåéñòâèè. Óñòàíîâëåíà òàêæå ïîëíàÿ
ðåçèñòåíòíîñòü ê äèàáåòîãåííîìó äåéñòâèþ ñòðåïòîçîòîöèíà (íîðìîãëèêåìèÿ, ñîõðàíåíèå èíñóëèíà â ïàíêðåàòè÷åñêèõ îñòðîâêàõ) ìûøåé ëèíèè
129SV ñ ðàçîðâàííûì ãåíîì ÏÀÐÏ è îòñóòñòâèåì â
ðåçóëüòàòå ýòîãî ÏÀÐÏ-ôåðìåíòíîé àêòèâíîñòè
(ÏÀÐÏ -/-) (Kolb H., Burkart V., 1999).  êëåòêàõ ïàíêðåàòè÷åñêèõ îñòðîâêîâ ÷åëîâåêà ìåõàíèçì ìåíåå
ÿñåí, òàê êàê óðîâåíü ÍÀÄ íå òàê ëåãêî ïîâðåæäàåòñÿ, êàê â êëåòêàõ ãðûçóíîâ (Kolb H., 1997). Ñóùåñòâóåò
îáîñíîâàííîå ïðåäïîëîæåíèå, ÷òî ãëàâíîé ìîëåêóëîé-êàíäèäàòîì äëÿ ïðîÿâëåíèÿ ôàðìàêîëîãè÷åñêîãî äåéñòâèÿ íèêîòèíàìèäà ó ÷åëîâåêà (β-êëåòêè, ëåéêîöèòû èëè ýíäîòåëèàëüíûå êëåòêè) ÿâëÿåòñÿ ñåìåéñòâî ÀÄÔ-ðèáîçèëèðóþùèõ ôåðìåíòîâ. Ïðè ýòîì
íàèâûñøåé ÷óâñòâèòåëüíîñòüþ ê èíäóöèðóåìîìó
íèêîòèíàìèäîì èíãèáèðîâàíèþ èõ àêòèâíîñòè îáëàäàåò ÏÀÐÏ è â ñóùåñòâåííî ìåíüøåé ñòåïåíè (ìîíî)ÀÄÔ-ðèáîçèëòðàíñôåðàçà (ÀÄÔÐÒ). Òîðìîæåíèå ÏÀÐÏ ïðèâîäèò ê ïîäàâëåíèþ êàê ýêñïðåññèè
ãåíîâ (iNOS, ÈË-1, àäãåçèâíûõ ìîëåêóë-ICAM-1),
òàê è íåêðîçà êëåòîê, ñ îäíîé ñòîðîíû, è ñòèìóëÿöèè àïîïòîçà, ñ äðóãîé. Òîðìîæåíèå æå ÀÄÔÐÒ ïîâûøàåò ôóíêöèîíàëüíóþ àêòèâíîñòü èììóííûõ
êëåòîê (Kolb H., Burkart V., 1999).
Ñðåäè ìåõàíèçìîâ äåéñòâèÿ íèêîòèíàìèäà ïðè
ñàõàðíîì äèàáåòå I òèïà ìîæíî íàçâàòü ñëåäóþùèå:
1. Ïîâûøåíèå ñîäåðæàíèÿ ÍÀÄ+ â β-êëåòêàõ çà
ñ÷åò èíãèáèöèè ïîëè(ÀÄÔ-ðèáîçî-ïîëèìåðàçû.
86
2. Âîññòàíîâëåíèå ÈË-1-èíäóöèðîâàííîé èíãèáèöèè ñåêðåöèè èíñóëèíà.
3. Ñíèæåíèå òîêñè÷íîñòè NO.
4. Ñóïðåññèÿ ýêñïðåññèè HLA-àíòèãåíîâ íà
êëåòêàõ îñòðîâêîâ.
5. Àíòèîêñèäàíòíûé ýôôåêò.
6. Èíäóêöèÿ äèôôåðåíöèðîâêè ñòâîëîâûõ
β-êëåòîê.
Ñóùåñòâåííûì ïîëîæèòåëüíûì ìîìåíòîì ïðè
èñïîëüçîâàíèè íèêîòèíàìèäà ÿâëÿåòñÿ åãî áåçîïàñíîñòü äëÿ îðãàíèçìà ÷åëîâåêà â òåðàïåâòè÷åñêèõ
äîçàõ è äîçàõ, íåçíà÷èòåëüíî ïðåâûøàþùèõ òåðàïåâòè÷åñêèå (Mandrup-Poulsen T. et àl., 1993;
Elliott R.B., Pilcher C.C. et al., 1996). Åñòü ñâåäåíèÿ î
ïðèìåíåíèè íèêîòèíàìèäà â äîçàõ, ïðåâûøàþùèõ
â 10–200 ðàç ðåêîìåíäîâàííûå, â êà÷åñòâå âèòàìèííîãî ïðåïàðàòà.  òî æå âðåìÿ, åñòü ñîîáùåíèÿ, ÷òî
íèêîòèíàìèä ïðè ïðèìåíåíèè â î÷åíü âûñîêèõ
äîçàõ çàäåðæèâàë ðîñò êðûñ, à â äîçå âûøå 300 ìã/êã
ïîòåíöèðîâàë îïóõîëåâûé ðîñò îñòðîâêîâûõ êëåòîê
(Yamagami Y. et al., 1985). Ñëåäóåò îòìåòèòü íàëè÷èå
ïîáî÷íûõ ýôôåêòîâ ïðè èñïîëüçîâàíèè íèêîòèíàìèäà íà ïðîòÿæåíèè 6–40 ìåñ ó çíà÷èòåëüíîãî
÷èñëà áëèæàéøèõ ðîäñòâåííèêîâ áåç ñàõàðíîãî äèàáåòà è ó çäîðîâûõ äåòåé (Elliott R.B. et àl., 1996). Ïðè
ëå÷åíèè íèêîòèíàìèäîì íà ïðîòÿæåíèè 1,5–12 ìåñ
28 áîëüíûõ ñ íåäàâíî äèàãíîñòèðîâàííûì ñàõàðíûì äèàáåòîì I òèïà (ñóòî÷íàÿ äîçà 1–3 ã) íå áûëî
çàôèêñèðîâàíî ïîáî÷íûõ ýôôåêòîâ (Vague P. et àl.,
1989).
Îñîáîãî âíèìàíèÿ çàñëóæèâàåò ñïîñîáíîñòü
íèêîòèíàìèäà ñîõðàíÿòü îñòàòî÷íóþ ôóíêöèþ
β-êëåòîê ó áîëüíûõ ñ âïåðâûå âûÿâëåííûì ñàõàðíûì äèàáåòîì I òèïà (Gale E.A., 1996; Kolb H.,
Burkart V., 1999; Ïîëòîðàê Â.Â., Ãîðáåíêî Í.È., 1999).
Îáíàäåæèâàþùèìè ïðåäñòàâëÿþòñÿ è äàííûå îá
ýôôåêòèâíîñòè íèêîòèíàìèäà ó çäîðîâûõ ðîäñòâåííèêîâ 1-é ñòåïåíè ðîäñòâà áîëüíûõ ñàõàðíûì
äèàáåòîì I òèïà (Kolb H., Schmidt M., 1989).
Èíòåðåñíûå ðåçóëüòàòû ïîëó÷åíû â õîäå èññëåäîâàíèÿ, â êîòîðîì íèêîòèíàìèä ïðèìåíÿëè â âûñîêîé äîçå ó 14 ñèáñîâ ñ óìåíüøåííîé ñåêðåöèåé
èíñóëèíà.  êîíòðîëüíóþ ãðóïïó áûëè âêëþ÷åíû
8 ëèö ñ âûñîêèì ðèñêîì ðàçâèòèÿ ñàõàðíîãî äèàáåòà (Elliott R.B., Chase H.P., 1991).  òå÷åíèå ïåðâîãî
ãîäà íàáëþäåíèÿ ñàõàðíûé äèàáåò ðàçâèëñÿ ó 4 ÷åëîâåê èç êîíòðîëüíîé ãðóïïû è íè ó îäíîãî èç 14,
ïðèíèìàâøèõ íèêîòèíàìèä. ×åðåç äâà ãîäà ñàõàðíûé äèàáåò áûë äèàãíîñòèðîâàí ó 7 ëèö êîíòðîëüíîé ãðóïïû. ×åðåç äâà ñ ïîëîâèíîé ãîäà ñàõàðíûé äèàáåò áûë äèàãíîñòèðîâàí ó âñåõ 8 ÷åëîâåê,
âõîäÿùèõ â êîíòðîëüíóþ ãðóïïó, òîãäà êàê â ãðóïïå íàáëþäåíèÿ — òîëüêî ó 5 èç 14. Êðóïíîå ðàíäîìèçèðîâàííîå èññëåäîâàíèå ñ ó÷àñòèåì øêîëüíèêîâ, ó êîòîðûõ ñóùåñòâóåò ðèñê ðàçâèòèÿ ñàõàðíîãî
äèàáåòà I òèïà (ICA-ïîëîæèòåëüíûå), áûëî ïðîâåäåíî â Íîâîé Çåëàíäèè.  ãðóïïó ñðàâíåíèÿ âõîäèëè 48 335 äåòåé â âîçðàñòå 5–7 ëåò.  ýòîé ãðóïïå
ñàõàðíûé äèàáåò ðàçâèëñÿ ó 59 äåòåé (åæåãîäíàÿ ÷à-
ÓÊÐÀ¯ÍÑÜÊÈÉ ÌÅÄÈ×ÍÈÉ ×ÀÑÎÏÈÑ – ¹ 2 (22) – III/IV 2001
ÎÃËßÄ
ñòîòà âîçíèêíîâåíèÿ áîëåçíè ñîñòàâëÿåò 21 íà
100 000 íàñåëåíèÿ). Èç ÷èñëà îáñëåäîâàííûõ áûëà
âûäåëåíà ãðóïïà äåòåé, â êðîâè êîòîðûõ îïðåäåëÿëèñü àóòîàíòèòåëà ê îñòðîâêîâîé òêàíè (òèòð >20
JDF åäèíèö). Îíè ïîëó÷àëè íèêîòèíàìèä, è ïðè
ýòîì çàáîëåâàåìîñòü ñàõàðíûì äèàáåòîì áûëà çíà÷èòåëüíî ñíèæåíà (äî 7,3 ñëó÷àÿ íà 100 000 íàñåëåíèÿ â ãîä).
Âìåñòå ñ òåì, ìíîãîöåíòðîâîå èññëåäîâàíèå ýôôåêòèâíîñòè ïðèìåíåíèÿ íèêîòèíàìèäà ó ëèö ñ
ðèñêîì ðàçâèòèÿ ñàõàðíîãî äèàáåòà I òèïà, ïðîâåäåííîå â Ãåðìàíèè (DENIS), áûëî ïðåêðàùåíî â
1997 ã. èç-çà îòñóòñòâèÿ ñóùåñòâåííîãî ñíèæåíèÿ
ðèñêà ðàçâèòèÿ ñàõàðíîãî äèàáåòà â ãðóïïå, ïîëó÷àâøåé íèêîòèíàìèä, ïî ñðàâíåíèþ ñ ãðóïïîé ïëàöåáî (Lampeter E.F. et al., 1998). Îäíàêî ñëåäóåò îáðàòèòü âíèìàíèå íà âêëþ÷åíèå â èññëåäîâàíèå ëèö
ñ âûñîêèì ðèñêîì ðàçâèòèÿ ñàõàðíîãî äèàáåòà è
ïðåäïîëàãàåìûì áûñòðûì ïðîãðåññèðîâàíèåì çàáîëåâàíèÿ (ICA-ïîëîæèòåëüíûå, 3–12-ëåòíèå ñèáëèíãè áîëüíûõ ñ ñàõàðíûì äèàáåòîì I òèïà).
Ðåøèòü âîïðîñ îá ýôôåêòèâíîñòè íèêîòèíàìèäà äëÿ ïðîôèëàêòèêè ñàõàðíîãî äèàáåòà ìîæíî
òîëüêî íà îñíîâàíèè âñåñòîðîííèõ èññëåäîâàíèé,
êîòîðûå â íàñòîÿùåå âðåìÿ ïðîâîäÿò ïî ïðîãðàììå ENDIT (European Nicotinamide Diabetes Intervention Trials). Öåëüþ ïðîãðàììû ÿâëÿåòñÿ ñêðèíèíã
40 000 ðîäñòâåííèêîâ 1-é ñòåïåíè ðîäñòâà áîëüíûõ
ñàõàðíûì äèàáåòîì, èç ÷èñëà êîòîðûõ ïëàíèðóåòñÿ
îòîáðàòü 422 ÷åëîâåêà ñ âûñîêîé ñòåïåíüþ ðèñêà.
Ïîëîâèíå èç íèõ áóäåò íàçíà÷åíà òåðàïèÿ íèêîòèíàìèäîì (1,3 ã/ì â äåíü ïåðîðàëüíî).  ðåàëèçàöèè
ïðîãðàììû ó÷àñòâóþò 20 íàöèîíàëüíûõ ãðóïï: îñíîâíûå ó÷àñòíèêè — Êàíàäà, Ôèíëÿíäèÿ, Ïîëüøà,
Àíãëèÿ, Äàíèÿ, Øâåöèÿ è Íîðâåãèÿ. Îêîí÷àòåëüíûé ñòàòèñòè÷åñêèé àíàëèç ðåçóëüòàòîâ áóäåò çàâåðøåí â 2002 ãîäó.
 ïîñëåäíèå ãîäû ïîëó÷èëî ñâîå ðàçâèòèå è èíîå
íàïðàâëåíèå ïðîôèëàêòèêè ñàõàðíîãî äèàáåòà
I òèïà. Îíî îñíîâàíî íà èíäóêöèè èììóííîé òîëåðàíòíîñòè ïðè ïåðîðàëüíîì ïðèìåíåíèè íåêîòîðûõ àíòèãåíîâ β-êëåòîê, â ÷àñòíîñòè èíñóëèíà
èëè äåêàðáîêñèëàçû ãëþòàìèíîâîé êèñëîòû.
Ïåðâîíà÷àëüíûå èññëåäîâàíèÿ íà êðûñàõ ÂÂ
(Gotfredsen C.F. et al., 1985) è ìûøàõ NOD (Atkinson M., 1990) âûÿâèëè, ÷òî ïàðåíòåðàëüíî ââåäåííûé èíñóëèí ïîäàâëÿåò ôóíêöèþ îñòðîâêîâ, ýêñïðåññèþ àíòèãåíîâ è ïðåäóïðåæäàåò èíñóëèò è ñàõàðíûé äèàáåò. Òàêîé ïðîòåêòîðíûé ýôôåêò
èíñóëèíà îáóñëîâëåí åãî òîðìîçÿùèì âëèÿíèåì íà
ôóíêöèþ β-êëåòîê è êàê ñëåäñòâèå — ñíèæåíèåì
ýêñïðåññèè àóòîàíòèãåíîâ íà ìåìáðàíå êëåòîê.
Ïðîôèëàêòèêà ðàçâèòèÿ ñàõàðíîãî äèàáåòà ìîæåò áûòü äîñòèãíóòà è ïðè ââåäåíèè èíñóëèíà ïåðîðàëüíî, ÷òî äîñòîâåðíî áûëî óñòàíîâëåíî â ýêñïåðèìåíòàõ íà æèâîòíûõ (Von Herrath M.G. et al.,
1996). Ïîñêîëüêó â äàííîì ñëó÷àå èíñóëèí ïîäâåðãàåòñÿ ýíçèìàòè÷åñêîìó ïåðåâàðèâàíèþ â ïèùåâàðèòåëüíîì òðàêòå, åãî ïðîòåêòîðíûé ýôôåêò íå
ìîæåò áûòü ñâÿçàí ñ ãîðìîíàëüíûì âëèÿíèåì íà
ôóíêöèþ β-êëåòîê.  ñïåöèàëüíî ïðîâåäåííûõ èññëåäîâàíèÿõ áûëî óñòàíîâëåíî, ÷òî â ýòîì ñëó÷àå
èíñóëèí âûçûâàåò òàê íàçûâàåìóþ ïåðîðàëüíóþ
òîëåðàíòíîñòü, ñâÿçàííóþ ñ óíè÷òîæåíèåì àóòîðåàêòèâíûõ êëîíîâ, èíäóêöèåé àíåðãèè è ïîÿâëåíèåì àíòèãåí-ñïåöèôè÷åñêèõ êëåòîê, àêòèâíî ñóïðåññèðóþùèõ ýôôåêòîðíûå êëåòêè (Eisenbarth G.S.,
1997, Ìàëûæåâ Â.À., 1998).
 íàñòîÿùåå âðåìÿ äîêàçàíî, ÷òî èíñóëèí è ïðîèíñóëèí ÿâëÿþòñÿ îñíîâíûìè ñïåöèôè÷åñêèìè
àóòîàíòèãåíàìè β-êëåòîê (Eisenbarth G.S., 1997). Ó
ìûøåé NOD âíóòðè ïàíêðåàòè÷åñêèõ îñòðîâêîâ
îáíàðóæèâàåòñÿ áîëüøîå êîëè÷åñòâî Ò-êëåòîê,
âñòóïàþùèõ â ðåàêöèþ ñ èíñóëèíîâûì ïåïòèäîì
Â: 9–23, êîòîðûå îáëàäàþò ñâîéñòâîì ïàññèâíî ïåðåíîñèòü çàáîëåâàíèå è ðàçðóøàòü β-êëåòêè îñòðîâêîâ (Wegmann D. et al., 1994). Îáíàðóæåíî, ÷òî ïàðåíòåðàëüíîå èëè èíòðàíàçàëüíîå ââåäåíèå äàííîãî
ïåïòèäà ïðèâîäèò ê ïðåäóïðåæäåíèþ ðàçâèòèÿ ñàõàðíîãî äèàáåòà â ýêñïåðèìåíòå (Danniel D., Wegmann D., 1996; French M.B. et al., 1996).
Íà ïðåäèàáåòè÷åñêîé ñòàäèè ðàçâèòèÿ áîëåçíè
ó ÷åëîâåêà àíòèèíñóëèíîâûå àóòîàíòèòåëà ñèíòåçèðóþòñÿ îäíèìè èç ïåðâûõ, è îíè ñóùåñòâåííî
êîððåëèðóþò ñ íà÷àëîì ðàçâèòèÿ ñàõàðíîãî äèàáåòà. Ïàðàëëåëüíî â ïåðèôåðè÷åñêîé êðîâè áîëüíûõ
ñ íåäàâíî âûÿâëåííûì ñàõàðíûì äèàáåòîì I òèïà
ìîãóò îïðåäåëÿòüñÿ Ò-ëèìôîöèòû, ñïåöèôè÷åñêè
ðàñïîçíàþùèå ïåïòèä Â: 9–23 (Eisenbarth G.S.,
1997).
Ïîñêîëüêó èíñóëèí ÿâëÿåòñÿ ïðàêòè÷åñêè åäèíñòâåííûì ñïåöèôè÷åñêèì àíòèãåíîì β-êëåòîê, åãî
èñïîëüçîâàíèå äëÿ ìîäóëÿöèè èììóííûõ ðåàêöèé
èëè èíäóöèðîâàíèÿ òîëåðàíòíîñòè ÿâëÿåòñÿ âåñüìà îïðàâäàííûì (Eisenbarth G.S., 1997). Âïåðâûå
ýòîò ãîðìîí äëÿ ïðîôèëàêòèêè ñàõàðíîãî äèàáåòà
I òèïà áûë èñïîëüçîâàí â Äæîñëèíñêîì öåíòðå
(ÑØÀ). Èíñóëèí ââîäèëè ïîäêîæíî â íèçêèõ äîçàõ 2 ðàçà â äåíü äëèòåëüíîå âðåìÿ è êàæäûå 9 ìåñ
êîðîòêèì êóðñîì (5 äíåé) — âíóòðèâåííî. Èññëåäóåìàÿ ãðóïïà ñîñòîÿëà èç 5 äåòåé ñ âûñîêèì ðèñêîì ðàçâèòèÿ ñàõàðíîãî äèàáåòà è íàëè÷èåì â êðîâè àóòîàíòèòåë ê îñòðîâêîâûì êëåòêàì, õîòÿ è ñ
íîðìàëüíûìè òåñòàìè òîëåðàíòíîñòè ê ãëþêîçå. Â
òå÷åíèå 5-ëåòíåãî íàáëþäåíèÿ ó äâóõ ëèö, ïîëó÷àâøèõ ïðîôèëàêòè÷åñêè èíñóëèí, ðàçâèëñÿ ñàõàðíûé
äèàáåò: ó îäíîãî — ïîñëå 2 ëåò, à ó äðóãîãî — ïîñëå
4 ëåò èíñóëèíîâîé òåðàïèè. Ó âñåõ 7 äåòåé êîíòðîëüíîé ãðóïïû ñ òàêèìè æå êëèíè÷åñêèìè õàðàêòåðèñòèêàìè, íî íå ïîëó÷àâøèõ ëå÷åíèÿ, ñàõàðíûé
äèàáåò ðàçâèëñÿ â òå÷åíèå 2,5 ãîäà (Jackson R., 1994).
Ïîäîáíûå ðåçóëüòàòû áûëè ïîëó÷åíû ïðè ïàðåíòåðàëüíîì èñïîëüçîâàíèè èíñóëèíà è â äðóãèõ èññëåäîâàíèÿõ (Eisenbarth G.S., 1997; Fuchtenbusch M.
et al., 1998).
Âî âñåõ ïåðå÷èñëåííûõ ñëó÷àÿõ ââåäåíèå èíñóëèíà â íèçêèõ äîçàõ íå áûëî äîñòàòî÷íûì äëÿ èíãèáèöèè ôóíêöèîíàëüíîé àêòèâíîñòè β-êëåòîê
ÓÊÐÀ¯ÍÑÜÊÈÉ ÌÅÄÈ×ÍÈÉ ×ÀÑÎÏÈÑ – ¹ 2 (22) – III/IV 2001
87
ÎÃËßÄ
ïàöèåíòîâ. Ïîëîæèòåëüíûé ýôôåêò, âåðîÿòíåå âñåãî, îáóñëîâëåí ìåõàíèçìàìè ïåðèôåðè÷åñêîé òîëåðàíòíîñòè íà ââîäèìûé àíòèãåí. Ïîäîáíàÿ íåâîñïðèèì÷èâîñòü ê ïîñëåäíåìó ìîæåò áûòü äîñòèãíóòà áîëåå óäîáíûì ïóòåì ïîñòóïëåíèÿ àíòèãåíà â
îðãàíèçì, à èìåííî ñ ïèùåé (Weiner H., 1994).
Ïî äàííûì H. Weiner (1994), àíòèãåí â íèçêîé
äîçå, ïîïàäàÿ â ïèùåâàðèòåëüíûé òðàêò, âçàèìîäåéñòâóåò ñ ëèìôîèäíîé òêàíüþ êèøå÷íèêà è àêòèâèçèðóåò ðåãóëÿòîðíûå Òh-2 êëåòêè, êîòîðûå
ïðîäóöèðóþò ñâîéñòâåííûå èì öèòîêèíû, â òîì
÷èñëå è òðàíñôîðìèðóþùèé ðîñò ôàêòîð-áåòà. Ïîñëåäíèé îáëàäàåò ñâîéñòâîì èíãèáèðîâàòü ïðîëèôåðàöèþ è àêòèâíîñòü âñåõ êëåòîê èììóííîãî îòâåòà.  ñèëó ýòîãî ïðè ìèãðàöèè àêòèâèðîâàííûõ
Òh-2 êëåòîê â îðãàí-ìèøåíü (ïàíêðåàòè÷åñêèå îñòðîâêè) ïðîèñõîäèò ïîëíîå ïîäàâëåíèå ðåàêöèè
àóòîàãðåññèè.
Ó ìûøåé NOD (ìîäåëü àóòîèììóííîãî ñàõàðíîãî äèàáåòà ó ëþäåé) ïåðîðàëüíîå ââåäåíèå ñâèíîãî èíñóëèíà íà ïðîòÿæåíèè 1 ãîäà ñïîñîáñòâîâàëî ïðåäîòâðàùåíèþ ðàçâèòèÿ áîëåçíè èëè áîëåå
ïîçäíåìó íà÷àëó åå ðàçâèòèÿ. Ïðè ýòîì îòìå÷åíî
óìåíüøåíèå êîëè÷åñòâà ïðîâîñïàëèòåëüíûõ è ïîâûøåíèå àêòèâíîñòè ïðîòèâîâîñïàëèòåëüíûõ öèòîêèíîâ. Áîëåå òîãî, ïåðåíîñ êëåòîê îò æèâîòíûõ,
êîòîðûì ïåðîðàëüíî ââîäèëè èíñóëèí, äðóãèì ñèíãåííûì æèâîòíûì òàêæå ïðèâîäèëî ê çàùèòå
β-êëåòîê îò ðàçðóøåíèÿ (Weiner et al., 1994; Simone E., Wegmann D., 1999).
 1996 ã. â ÑØÀ íà÷àòî ïëàöåáî-êîíòðîëèðóåìîå êëèíè÷åñêîå èññëåäîâàíèå DPT-1 (Diabetes
Prevention Trial-1) ïî èçó÷åíèþ ýôôåêòèâíîñòè ïåðîðàëüíîãî ïðèåìà ïðîñòîãî èíñóëèíà â ôîðìå êàïñóë (7,5 ìã â äåíü) â êà÷åñòâå ïðîòåêòîðíîãî ñðåäñòâà ó ëèö ñî ñðåäíåé ñòåïåíüþ ðèñêà ðàçâèòèÿ ñàõàðíîãî äèàáåòà I òèïà (The DTP-1 Study Group,
1997). Â ýòîì øèðîêîìàñøòàáíîì ïðîåêòå ïðåäïîëàãàåòñÿ ñêðèíèíã 60 000 ðîäñòâåííèêîâ 1-é ñòåïåíè ðîäñòâà äëÿ âûÿâëåíèÿ ëèö ñ äîêàçàííîé ïðîäðîìàëüíîé àóòîèììóííîé äåñòðóêöèåé β-êëåòîê.
Ïëàíèðóåòñÿ òàêæå ñðàâíèòü ðåçóëüòàòèâíîñòü ïðåâåíòèâíîé èíñóëèíîâîé òåðàïèè ïðè ïåðîðàëüíîì
è ïàðåíòåðàëüíîì ââåäåíèè ãîðìîíà.
Ñëåäóåò îòìåòèòü òðóäîåìêîñòü íàñòîÿùåãî èññëåäîâàíèÿ: ñêðèíèíã 60 000 ðîäñòâåííèêîâ ïðè
åæåãîäíîì îáñëåäîâàíèè 15 000 ÷åëîâåê ðàññ÷èòàí
íà 4 ãîäà. Ïðîåêò âêëþ÷àåò, ïîìèìî îïðåäåëåíèÿ
IÑÀ, è âíóòðèâåííûé òåñò òîëåðàíòíîñòè ê óãëåâîäàì ñ îöåíêîé ôàçíîé ñåêðåöèè èíñóëèíà. Çàâåðøåíèå ýòîãî ìíîãîöåíòðîâîãî èññëåäîâàíèÿ,
ðàññ÷èòàííîãî íà 7 ëåò, ïîçâîëèò ñäåëàòü êîððåêòíûé âûâîä îòíîñèòåëüíî ïðàêòè÷åñêîé öåííîñòè
èíñóëèíîâîé ïðîôèëàêòè÷åñêîé òåðàïèè ó ëèö ñ
âûñîêèì ðèñêîì ðàçâèòèÿ ñàõàðíîãî äèàáåòà
I òèïà.
Äâîéíîå ñëåïîå ïëàöåáî-êîíòðîëèðóåìîå èññëåäîâàíèå ïî èçó÷åíèþ èíòðàíàçàëüíîãî ââåäåíèÿ
èíñóëèíà ëèöàì ñ âûñîêèì ðèñêîì ðàçâèòèÿ ñàõàð88
íîãî äèàáåòà I òèïà ïðîâîäèòñÿ â Ìåëüáóðíå. Çàñëóæèâàåò âíèìàíèÿ è ôèíñêèé ïðîåêò ïî èçó÷åíèþ ïðîôèëàêòè÷åñêîãî äåéñòâèÿ èíñóëèíà, ââîäèìîãî èíòðàíàçàëüíî (The Diabetes Prediction and
Prevention Project, DIPP). Ïðèîáðåòàåìàÿ ïðè ýòîì
òîëåðàíòíîñòü ôîðìèðóåòñÿ àíàëîãè÷íî ïåðîðàëüíîé. Îñîáåííîñòüþ ïðîåêòà ÿâëÿåòñÿ ó÷àñòèå â èññëåäîâàíèÿõ äåòåé ñ ìîìåíòà ðîæäåíèÿ, ó êîòîðûõ
âûÿâëåíû ãåíåòè÷åñêèå è èììóíîëîãè÷åñêèå ìàðêåðû ðèñêà ðàçâèòèÿ ñàõàðíîãî äèàáåòà. Êðîâü äëÿ
èññëåäîâàíèÿ â ýòîì ñëó÷àå ïîëó÷àþò íåïîñðåäñòâåííî â ðîäàõ èç ïóïî÷íîãî êàíàòèêà. Äëÿ íàáëþäåíèÿ îòáèðàþò äåòåé, ó êîòîðûõ ìàðêåðû ðèñêà
îïðåäåëÿþòñÿ íåïîñðåäñòâåííî ïðè ðîæäåíèè èëè
ïðîÿâëÿþòñÿ â òå÷åíèå ïåðâîãî ãîäà æèçíè. Äîçà
èíòðàíàçàëüíîãî èíñóëèíà ñîñòàâëÿåò 1 åäèíèöó íà
êèëîãðàìì ìàññû òåëà ðåáåíêà (Akerblom H.K.,
Knip M., 1997).
Ñëåäóåò ïîä÷åðêíóòü, ÷òî èäåíòèôèêàöèÿ 1À-2
è GAD, ïîìèìî èíñóëèíà, â êà÷åñòâå àíòèãåíîâ ïðè
ñàõàðíîì äèàáåòå ïîâûøàåò íå òîëüêî øàíñ âûÿâëåíèÿ ïðåäðàñïîëîæåííîñòè ê áîëåçíè, íî è ðàñøèðÿåò òåðàïåâòè÷åñêèå âîçìîæíîñòè åå ïðåäóïðåæäåíèÿ (Leslie R.D.G. et al., 1999). Òàê, ïðîòåêòîðíûå ñâîéñòâà â îòíîøåíèè àóòîèììóííîãî
ñàõàðíîãî äèàáåòà ó ìûøåé NOD îïèñàíû ïðè èíòðàòèìè÷åñêîì, èíòðàïåðèòîíåàëüíîì, ïåðîðàëüíîì èëè èíòðàíàçàëüíîì ââåäåíèè GAD èëè
GAD-ïåïòèäîâ (Elliot R.B., 1994; Ma S.W. et al., 1997;
Bellmann K. et al., 1998; Tisch R., 1998). Ìåõàíèçì ïðîòåêòîðíîãî ýôôåêòà ýòîãî àíòèãåíà íå âûÿñíåí, íî
ïîñêîëüêó ïðîôèëàêòèêà ñàõàðíîãî äèàáåòà ó ìûøåé, äîñòèãíóòàÿ ïåðîðàëüíûì ââåäåíèåì GAD,
ìîãëà áûòü àäàïòèâíî ïåðåíåñåíà ëèìôîöèòàìè ê
êîíòðîëüíûì ìûøàì NOD, ïðåäïîëàãàåòñÿ àêòèâèçàöèÿ ðåãóëÿòîðíûõ Ò-êëåòîê ïóòåì ñâÿçûâàíèÿ
ýòèì àíòèãåíîì Ò-êëåòî÷íîãî ðåöåïòîðà (Elliott R.B.
et al., 1994; Tian J. et al., 1996).
Ïîñêîëüêó GAD ìîæíî ïðîèçâîäèòü â áîëüøèõ
êîëè÷åñòâàõ ñ ïîìîùüþ ãåííîé ðåêîìáèíàíòíîé
òåõíîëîãèè, òî âåñüìà ðåàëüíûì â áëèæàéøåå âðåìÿ ÿâëÿåòñÿ èññëåäîâàíèå åãî ïðîòåêòîðíîãî äåéñòâèÿ â îòíîøåíèè àóòîèììóííîãî ïðîöåññà ïðè
ïåðîðàëüíîì ïðèåìå ó ëèö ñ ïðèçíàêàìè ïðîãðåññèðîâàíèÿ ìàíèôåñòíîãî ñàõàðíîãî äèàáåòà I òèïà
(Zimmet P.Z., 1999).
Íåñîìíåííî, ÷òî àíòèãåíñïåöèôè÷åñêàÿ òåðàïèÿ äëÿ ïðåäóïðåæäåíèÿ ñàõàðíîãî äèàáåòà ÿâëÿåòñÿ î÷åíü ïðèâëåêàòåëüíîé, íî ê íåé íóæíî îòíîñèòüñÿ ñ îñòîðîæíîñòüþ. Òàê, â íåêîòîðûõ èññëåäîâàíèÿõ íà æèâîòíûõ ìîäåëÿõ áûëî âûÿâëåíî, ÷òî
ïåðîðàëüíàÿ àíòèãåííàÿ òåðàïèÿ, íàîáîðîò, ìîæåò
âûçûâàòü èëè óñêîðÿòü ðàçâèòèå áîëåçíè (Bellmann K. et al., 1998). Êðîìå òîãî, ïîñêîëüêó àóòîèììóíèòåò ê GAD òàêæå îáóñëîâëåí íåâðîëîãè÷åñêèì çàáîëåâàíèåì, à èìåííî — ñèíäðîìîì StiffMan, íå èñêëþ÷åíî ðàçâèòèå ïîñëåäíåãî ïðè
ïðîâåäåíèè äàííîãî âèäà ïðîòåêòîðíîé àíòèäèàáåòè÷åñêîé òåðàïèè (Daw K. et al., 1996).
ÓÊÐÀ¯ÍÑÜÊÈÉ ÌÅÄÈ×ÍÈÉ ×ÀÑÎÏÈÑ – ¹ 2 (22) – III/IV 2001
ÎÃËßÄ
Çàñëóæèâàþò âíèìàíèÿ è ïîïûòêè èçìåíèòü
òå÷åíèå àóòîèììóííîé äåñòðóêöèè β-êëåòîê ñ ïîìîùüþ ÁÖÆ-âàêöèíàöèè. Ðåçóëüòàòû ðÿäà èññëåäîâàíèé, ïðîâåäåííûõ íà ìûøàõ NOD, ñâèäåòåëüñòâóþò, ÷òî äàæå îäíîêðàòíàÿ èíúåêöèÿ ïîëíîãî
àäúþâàíòà Ôðåéíäà èëè ÁÖÆ-âàêöèíû â ðàííåì
âîçðàñòå ïðåäóïðåæäàëà ðàçâèòèå ñàõàðíîãî äèàáåòà ó ýòèõ æèâîòíûõ ïóòåì íåñïåöèôè÷åñêîé ñòèìóëÿöèè åñòåñòâåííîé ðåçèñòåíòíîñòè. Íåäàâíî
îáíàðóæåíî, ÷òî ïîëíûé àäúþâàíò Ôðåéíäà è
ÁÖÆ-âàêöèíà èçìåíÿþò ðàçâèòèå ñàõàðíîãî äèàáåòà ó ìûøåé NOD (Shehadeh N. et al., 1994). Áîëåå
òîãî, â îòêðûòîì êëèíè÷åñêîì èññëåäîâàíèè
17 áîëüíûõ ñ âïåðâûå äèàãíîñòèðîâàííûì ñàõàðíûì äèàáåòîì I òèïà âíóòðèêîæíîå ââåäåíèå 0,1 ìë
ÁÖÆ-âàêöèíû (1ìã/ìë) ñîïðîâîæäàëîñü êëèíè÷åñêîé ðåìèññèåé ÷àùå, ÷åì ó ïàöèåíòîâ êîíòðîëüíîé ãðóïïû. Íà ýòîì îñíîâàíèè áûëî íà÷àòî
íåñêîëüêî êðóïíîìàñøòàáíûõ ïëàöåáî-êîíòðîëèðóåìûõ èññëåäîâàíèé ñ öåëüþ ïåðâè÷íîãî ïðåäóïðåæäåíèÿ ñàõàðíîãî äèàáåòà ó çäîðîâûõ äåòåé.
Âìåñòå ñ òåì, ðåçóëüòàòû ïðîâåäåííûõ â Øâåöèè
íàáëþäåíèé íå ïîäòâåðäèëè ïîëîæèòåëüíîãî ýôôåêòà ÁÖÆ-âàêöèíàöèè â îòíîøåíèè çàáîëåâàåìîñòè ñàõàðíûì äèàáåòîì ó äåòåé (Dahlquist G., Gothefors L., 1995).
Çàñëóæèâàåò âíèìàíèÿ è ñòðàòåãèÿ ïðåäóïðåæäåíèÿ àóòîèììóííîé ïàòîëîãèè, îñíîâàííàÿ íà
«ëèìôîöèòàðíîé âàêöèíàöèè». Ê íàñòîÿùåìó âðåìåíè ïîëó÷åíû äîêàçàòåëüñòâà òîãî, ÷òî âàêöèíàöèÿ îñëàáëåííûìè àóòîðåàêòèâíûìè ëèìôîöèòàìè ïðåäóïðåæäàåò íåêîòîðûå àóòîèììóííûå çàáîëåâàíèÿ ó æèâîòíûõ (Lider O. et al., 1987). Áîëåå òîãî,
ïîÿâèëèñü ïåðâûå ñîîáùåíèÿ îá óñïåøíîì îïûòå
èñïîëüçîâàíèÿ òàêîé áåçîïàñíîé òåðàïèè ó íåáîëüøîãî ÷èñëà áîëüíûõ ñ ìíîæåñòâåííûì ñêëåðîçîì
è ðåâìàòîèäíûì àðòðèòîì. Èññëåäîâàíèÿ íà ìûøàõ NÎD âûÿâèëè òîðìîæåíèå èëè ïðåäóïðåæäåíèå ðàçâèòèÿ ñàõàðíîãî äèàáåòà ó æèâîòíûõ ñ ïðåäèàáåòîì âàêöèíàöèåé îñëàáëåííûìè ëèìôîöèòàìè îò íåäèàáåòè÷åñêèõ ìûøåé NOD/B10 (Gearon C.
et al., 1997). Ïîëó÷åííûå ðåçóëüòàòû äàþò âîçìîæíîñòü èñïîëüçîâàòü âàêöèíû èç îñëàáëåííûõ àóòîëîãè÷íûõ ëèìôîöèòîâ ïåðèôåðè÷åñêîé êðîâè â
êà÷åñòâå ýôôåêòèâíîãî ñðåäñòâà âòîðè÷íîé ïðîôèëàêòèêè ñàõàðíîãî äèàáåòà I òèïà, à èìåííî, ó ðîäñòâåííèêîâ 1-é ñòåïåíè ðîäñòâà áîëüíûõ ñàõàðíûì
äèàáåòîì I òèïà ñ âûñîêèì ðèñêîì ðàçâèòèÿ çàáîëåâàíèÿ.
Íåñìîòðÿ íà ìíîãî÷èñëåííûå èññëåäîâàíèÿ,
ìåõàíèçì, îïðåäåëÿþùèé ýôôåêòèâíîñòü ëèìôîöèòàðíîé âàêöèíàöèè íà ýêñïåðèìåíòàëüíûõ ìîäåëÿõ àóòîèììóííîãî çàáîëåâàíèÿ, îñòàåòñÿ íåÿñíûì. Ïðåäïîëàãàåòñÿ, ÷òî èíäóêöèÿ èììóííîãî
îòâåòà íà âàêöèíó, ñîñòîÿùóþ èç àóòîðåàêòèâíûõ
Ò-êëåòîê, àêòèâèðóåò àíòèèäèîòèïè÷åñêóþ ãðóïïó ðåãóëÿòîðíûõ ëèìôîöèòîâ, ñïîñîáíóþ ïîäàâëÿòü èëè ýëèìèíèðîâàòü êëåòêè, èíôèëüòðèðóþùèå îðãàíû-ìèøåíè, ÷òî â êîíå÷íîì ñ÷åòå ñïî-
ñîáñòâóåò ïîäàâëåíèþ àóòîàãðåññèè (Lider O. et al.,
1987).
 ïîñëåäíèå ãîäû ïîÿâèëèñü ñîîáùåíèÿ î âîçìîæíîì ïðîòåêòîðíîì äåéñòâèè ìåòèëîâîãî ýôèðà ÿíòàðíîé êèñëîòû îòíîñèòåëüíî β-öèòîòîêñè÷åñêîãî ýôôåêòà ÈË-1 è ñòðåïòîçîòîöèíà. Ýòîò
ôàêò îáóñëîâëåí ñïîñîáíîñòüþ ÿíòàðíîé êèñëîòû
ìåòàáîëèçèðîâàòüñÿ â öèêëå Êðåáñà ñ ïîñëåäóþùèì
âîññòàíîâëåíèåì óðîâíÿ ÀÒÔ, êîòîðûé áûë ñíèæåí â ðåçóëüòàòå àóòîèììóííîãî è òîêñè÷åñêîãî
âìåøàòåëüñòâà (Valverde I. et al., 1997).
 Óêðàèíñêîì ÍÈÈ ôàðìàêîòåðàïèè ýíäîêðèííûõ çàáîëåâàíèé áûëî ñèíòåçèðîâàíî îðèãèíàëüíîå ïðîèçâîäíîå ÿíòàðíîé êèñëîòû — ôåíñóêöèíàë, êîòîðûé, êàê ñâèäåòåëüñòâóþò ðåçóëüòàòû
èññëåäîâàíèé, ïðåäîòâðàùàåò ðàçâèòèå àáñîëþòíîé
èíñóëèíîâîé íåäîñòàòî÷íîñòè ïîñëå èíäóêöèè
ñòðåïòîçîòîöèíîâîãî è äèòèçîíîâîãî ñàõàðíîãî
äèàáåòà. Ïðîòåêòîðíûå ñâîéñòâà ôåíñóêöèíàëà
ïðîÿâëÿëèñü â óëó÷øåíèè ìåòàáîëèçìà ãëþêîçû,
ñòèìóëÿöèè ðåãåíåðàòèâíûõ ïðîöåññîâ â ïàíêðåàòè÷åñêèõ îñòðîâêàõ, ñîõðàíåíèè ôóíêöèîíàëüíîé
àêòèâíîñòè β-êëåòîê è àêòèâèçàöèè àíòèîêñèäàíòíîé ñèñòåìû çàùèòû (Poltorack V., et al., 1995; Gorbenko N. et al., 1997; 1999). Âûñîêàÿ ýôôåêòèâíîñòü
ôåíñóêöèíàëà â ñî÷åòàíèè ñ íèçêîé òîêñè÷íîñòüþ
ïîçâîëÿþò ðàññìàòðèâàòü ýòîò ïðåïàðàò â êà÷åñòâå
ïåðñïåêòèâíîãî ôàðìàêîëîãè÷åñêîãî àãåíòà äëÿ
ïåðâè÷íîé ïðîôèëàêòèêè ñàõàðíîãî äèàáåòà I òèïà.
Òàêèì îáðàçîì, íà ñîâðåìåííîì ýòàïå ôóíäàìåíòàëüíîé è ïðèêëàäíîé äèàáåòîëîãèè ïîëó÷åíû
íîâûå äàííûå î ïàòîãåíåçå ñàõàðíîãî äèàáåòà ² òèïà
è íàìåòèëèñü ïóòè ê ðåøåíèþ çàäà÷è — ïðåâåíòèâíîãî ëå÷åíèÿ äàííîãî çàáîëåâàíèÿ. Îáøèðíûé ìàòåðèàë, ïðåäñòàâëåííûé â äàííîì îáçîðå, ñâèäåòåëüñòâóåò î íåîáû÷àéíîé ñëîæíîñòè äàííîé ïðîáëåìû. Ýòî âûòåêàåò èç ïîëèãåííîãî è ìóëüòèôàêòîðèàëüíîãî ãåíåçà ñàìîãî çàáîëåâàíèÿ è âñå åùå
íåðåøåííîé çàäà÷è èñêóññòâåííîãî ñîçäàíèÿ èììóííîé òîëåðàíòíîñòè íà îïðåäåëåííûå àíòèãåíû,
âêëþ÷àÿ è òå, êîòîðûå ÿâëÿþòñÿ èíäóêòîðàìè ôîðìèðîâàíèÿ àóòîàãðåññèè ê β-êëåòêàì.
ËÈÒÅÐÀÒÓÐÀ
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ÏÐÎÔ²ËÀÊÒÈÊÀ ÖÓÊÐÎÂÎÃΠIJÀÁÅÒÓ
² ÒÈÏÓ: ÏÀÒÎԲDzÎËÎò×ÍÅ
ÎÁÃÐÓÍÒÓÂÀÍÍß, ÑÒÐÀÒÅòß
ÒÀ Ê˲Ͳ×ÍÀ ÐÅÀ˲ÇÀÖ²ß
Â.Â. Ïîëòîðàê, Í.². Ãîðáåíêî, Î.À. Ñàêàëî
Ðåçþìå. Ó ñòàòò³ ïðîàíàë³çîâàí³ äàí³ ë³òåðàòóðè
ùîäî ìîæëèâîñòåé ³ìóíîïðîô³ëàêòèêè òà ³ìóíîòåðàﳿ õâîðèõ íà öóêðîâèé ä³àáåò ² òèïó, ìåòîþ ÿêèõ
º ïåðåøêîäèòè àáî çóïèíèòè àóòî³ìóííå ðóéíóâàííÿ β-êë³òèí ï³äøëóíêîâî¿ çàëîçè. Îïèñàí³ ñó÷àñí³
óÿâëåííÿ ùîäî ïàòîô³ç³îëîã³÷íîãî îáãðóíòóâàííÿ
òàêîãî òåðàïåâòè÷íîãî ï³äõîäó.
Êëþ÷îâ³ ñëîâà: öóêðîâèé äèàáåò ² òèïó, ³ìóíîïàòîãåíåç, ³ìóíîïðîô³ëàêòèêà.
PROPHYLAXIS OF TYPE ² DIABETES
MELLITUS: PATHOPHYSIOLOGICAL
SUBSTANTIATION, STRATEGY
AND CLINICAL REALIZATION
V.V. Poltorack, N.I. Gorbenko, E.A. Sakalo
Summary. This article contains the analyses of literature data about the possibilities of immune prophylaxis
and immune therapy of patients with type 1 diabetes mellitus, the main aim of which is to prevent or to stop the
autoimmune destruction of pancreatic beta-cells. The
authors describe the modern state of pathophysiological
ground for this therapeutical approach.
Key words: type I diabetes mellitus, immune pathogenesis, immune prophylaxis.
Àäðåñ äëÿ ïåðåïèñêè:
Ïîëòîðàê Âèêòîðèÿ Âèòàëüåâíà
61002, Õàðüêîâ, óë. Àðòåìà, 10
Óêðàèíñêèé íàó÷íî-èññëåäîâàòåëüñêèé èíñòèòóò
ôàðìàêîòåðàïèè ýíäîêðèííûõ çàáîëåâàíèé
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