Аннотация
Уже на ранних стадиях тяжелого сахарного диабета 1-го типа (СД1), для которого характерны сильно выраженный инсулиновый дефицит, острая гипергликемия и гиперфагия, возникают нарушения инкретинового и адипокинового статуса и эндокринные дисфункции, меняется гипоталамическая регуляция. Это во многом обусловлено дефицитом инсулина в мозге, вследствие чего применение интраназально вводимого инсулина (ИВИ), компенсирующего его недостаток, способно предотвратить ряд негативных последствий СД1. Поскольку при СД1 также отмечается дефицит С-пептида проинсулина, способного усиливать эффекты инсулина, то представляется перспективным использовать совместное введение ИВИ с интраназально вводимым С-пептидом (ИСП). Целью работы было изучить влияние 7-дневного лечения крыс с непродолжительным СД1, вызванным высокой дозой стрептозотоцина (65 мг/кг), с помощью ИВИ (20 мкг/крысу/день), в том числе совместно с ИСП (36 мкг/крысу/день), на уровни гормонов и инкретинов в крови и на экспрессию гипоталамических генов, кодирующих факторы пищевого поведения, рецепторы инсулина, лептина, серотонина и дофамина, а также регуляторы митохондриальной динамики и апоптоза. Лечение ИВИ и его комбинацией с ИСП нормализовали повышенные при СД1 уровни глюкагоноподобного пептида-1 (ГПП-1) и грелина и увеличивали сниженные при СД1 уровни лютеинизирующего и тиреотропного гормонов, тиреоидных гормонов, не влияя на уровень тестостерона. Одним из механизмов этого было повышение в гипоталамусе экспрессии анорексигенных генов, кодирующих меланокортиновый рецептор 4-го типа и про-опиомеланокортин, снижение генной экспрессии орексигенного нейропептида Y и нормализация экспрессии генов, ответственных за митохондриальную динамику (Mfn-1, Mfn-2, Drp-1), апоптоз (Bcl-2) и аутофагию (Beclin-1). Монотерапия с ИВИ была менее эффективной, в то время как монотерапия ИСП практически не влияла на оцениваемые показатели. Таким образом, лечение комбинацией ИВИ с ИСП и, в меньшей степени, одним ИВИ нормализует уровни ГПП-1 и грелина, восстанавливает уровень лютеинизирующего гормона и гормональные показатели тиреоидной системы у самцов крыс с краткосрочным тяжелым СД1, что обусловлено, в том числе, нормализацией гипоталамической сигнализации.
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