It has been controversial that the sodium glucose cotransporter-2 inhibitor (SGLT2i) have a protective effect for muscle atrophy. We previously reported that muscle atrophy in Db/Db mice were improved by luseogliflozin via upregulation of foxo1 expression. Here we show that systemic or local lipidome were altered in Db/Db mice, which were modified by luseogliflozin. Additionally, we investigated the underling molecular mechanisms between altered lipidome and gene expressions in the atrophic soleus muscle. Eight-week-old mice were fed a standard diet or the standard diet with added luseogliflozin (0.01% w/w in chow) for 8 weeks. The mice were divided into the following three genotype/dietary groups: Db/m mice without (w/o) SGLT2i, Db/Db w/o SGLT2i, and Db/Db with SGLT2i. Concentration of stearate acids in blood in Db/Db mice with SGLT2i decreased compared to that without. The expression of scd1 or foxo1 increased in Db/Db mice w/o SGLT2i and decreased in Db/Db mice with SGLT2i. Stearate acids in blood increased in Db/Db mice, which increased stearate acids in skeletal muscle. Increased stearate acid concentration in skeletal muscle stimulates the expression of scd1, on the other hand, the administration of luseogliflozin decreased stearate acids in blood and skeletal muscle, which decreased the expression of scd1 in skeletal muscle. Disclosure R. Bamba: Research Support; Spouse/Partner; Taisho Pharmaceutical Co., Ltd.
Background: More than 25% of middle-aged people living with diabetes mellitus (DM) have myocardial dysfunction including early onset diastolic dysfunction (DD), harbingers for symptomatic heart failure and frequent hospitalizations. This DD which is more prevalent in females than in males is associated with increased systemic inflammation, coronary microvascular dysfunction, myocardial fibrosis/stiffness and ischemia. Here we show using the db/db mouse model of DM that the diverse pathobiologies associated with DD are originating from accumulation of the glycolysis by-product, methylglyoxal (MG) arising from inflammation-induced downregulation of the MG-degrading enzyme glyoxalase-1 (Glo1). Methods/Results: At six month of age, female db/db mice developed degree I-II DD, with increases in E:e’ ratio, and isovolumetric relaxation time. Speckle tracking analyses also indicated increased global longitudinal and circumferential strains. Histopathological analyses of ex vivo hearts showed increased amounts of the inflammation-induced protein vascular adhesion protein-1 (VAP-1), reduced level of Glo1, increased MG and the MG-adduct, MG-H1, microvascular leakage, micro-ischemia and fibrosis. Time to decay of myocytes evoked Ca2+ transient was also increased. Administration of a single injection of an engineered adeno-associated virus that uses the promoter of an inflammation-induced protein, endothelin-1 (AAV2/9-Endo-Glo1) to express Glo1 in hearts of three months db/db mice, attenuate coronary microvascular leakage, ischemia, fibrosis and myocardial and myocyte dysfunction, establishing a cause-effect relationship between MG accumulation and myocardial dysfunction in db/db mice. Conclusions: These new data implicates accumulation of MG as a contributing cause of myocardial dysfunction type 2 DM. They also show that an AAV driven by the promoter of an inflammation-induced protein to express Glo1 in hearts of db/db mice can successfully attenuate DD. Disclosure K. Bidasee: None.
Введение. Согласно данным литературы Аппарат лазерной диагностики «ЛАЗМА СТ» не был ранее использован для доклинических исследований тканевых нарушений на мелких лабораторных животных. Цель исследования – изучение возможности использования аппарата лазерной диагностики «ЛАЗМА СТ» на мелких лабораторных животных – мутантных мышах линии С57BL/KsJYLeprdb/+ (db/db) – в качестве новой тест системы, для оценки тканевых изменений при сахарном диабете 2 типа (СД 2). Методика. Патологические изменения у мышей с СД изучали на генетической модели СД 2 у мутантных мышей С57BL/KsJYLeprdb/+ (db/db) (n=40); для контроля использовали группу фенотипически здоровых гетерозиготных мышей той же линии (db/+m) (n=16). Общее количество животных составляло 56 голов. Исследование проводили на аппарате лазерной диагностики «ЛАЗМА СТ», который адаптирован приспособлением, ограничивающим подвижность мышей во время измерений. Аппарат «ЛАЗМА СТ» позволяет осуществлять одновременный неинвазивный контроль состояния микроциркуляци крови и лимфы, а также определять уровень активности митохондриальных окислительных коферментов в тканях. Дополнительно измеряли уровень глюкозы в крови фотометрическим методом на приборе Accu-Chek (Швейцария). Результаты. Использование аппарата ЛАЗМА СТ позволило в реальном времени неинвазивно изучить в динамике нарушения микроциркуляции (крови и лимфы) и окислительного метаболизма (НАДН и ФАД) при СД 2, сопоставить их с нарушениями глюкозы в крови, а также прогнозировать тяжесть выявленных нарушений в условиях компенсации, субкомпенсации и декомпенсации. Аппарат ЛАЗМА СТ позволил одновременно выявить начавшиеся нарушения липидного и белкового обмена (пигменты-липофусцин и порфирин), которые свидетельствуют о тяжести прогноза заболевания. Выводы. Аппарат ЛАЗМА СТ, адаптированный для применения у мышей с генетической моделью СД 2 типа, представляет собой новую неинвазивную, информативную и безопасную тест-систему, позволяющую в динамике контролировать и прогнозировать тяжесть нарушений микроциркуляции и тканевых окислительно-восстановительных коферментов – НАДН и – ФАД. The aim of this study was to evaluate a possibility of using the LAZMA ST laser diagnostic apparatus in small laboratory animals, C57BL/KsJYLeprdb/+ (db/db) mutant mice, as a new test system for assessing changes in tissues in type 2 diabetes mellitus (DM2). Methods. Pathological changes were studied on a genetic model of DM2 in C57BL/KsJYLeprdb/+ (db/db) mutant mice (n=40). Phenotypically healthy heterozygous mice of the same strain (db/+m) (n=16) were used as a control group. The study was performed with a LAZMA ST laser diagnostic apparatus that was adapted for mice with a device limiting their mobility during measurements. LAZMA ST allows simultaneous noninvasive monitoring of blood and lymph microcirculation along with measurements of tissue activity of mitochondrial oxidative coenzymes. Additionally, blood glucose was measured photometrically with an Accu-Chek (Switzerland) glucometer. Results. The use of LAZMA ST allowed noninvasive, real-time evaluation of disorders in blood and lymph microcirculation and oxidative metabolism (NADH and FAD) in DM2, comparing them with glycemic disorders, and also predicting severity of these disorders in the conditions of DM2 compensation, subcompensation and decompensation. The LAZMA ST device provided simultaneous detection of the onset of lipid and protein metabolic disorders (lipofuscin and porphyrin pigments) to predict severity of the disease. Conclusion. The LAZMA ST device adapted for using in a murine genetic model of DM2 is a new, noninvasive, informative, and safe test system that allows to monitor and predict the dynamics of severity of disorders in microcirculation and tissue redox coenzymes, NADH and FAD.
In this study, we evaluated the antidiabetic effect of a submerged culture of Ceriporia lacerata mycelium (CL01) on hematological indices, as well as protein and mRNA expression of the insulin-signaling pathway, in db/db mice. After CL01 was administrated for 4 weeks, blood glucose levels decreased consistently, and plasma insulin and c-peptide levels each decreased by roughly 55.8%, 40% of those in the negative control (p<0.05). With regard to HOMA-IR, an insulin resistance index, insulin resistance of the CL01-fed group improved over that of the negative control group by about 62% (p<0.05). In addition, we demonstrated that the protein expression levels of pIR, pAkt, pAMPK, and GLUT4 and the mRNA expression levels of Akt2, IRS1, and GLUT4 in the muscle cells of db/db mice increased in the CL01-fed group compared to the corresponding levels in the control group. These results demonstrate that CL01 affects glucose metabolism, upregulates protein and gene expression in the insulin-signaling pathway, and decreases blood glucose levels effectively by improving insulin sensitivity. More than 90% of those who suffer from type 2 diabetes are more likely to suffer from hyperinsulinemia, hypertension, obesity, and other comorbidities because of insulin resistance. Therefore, it is possible that CL01 intake could be used as a fundamental treatment for type 2 diabetes by lowering insulin resistance, and these results may prove be useful as basic evidence for further research into the mechanisms of a cure for type 2 diabetes.