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Non-Coding RNA in Type 2 Diabetes Cardio-Renal Complications and SGLT2 Inhibitor Response
Elena Rykova1,2, Elena Shmakova3,4, Igor Damarov1
1Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (IC&G SB RAS), Lavrentjev Prospect 10, 630090 Novosibirsk, Russia.
Abstract:
Type 2 diabetes mellitus (T2DM) is characterized by an uncontrolled increase in blood glucose levels and insulin resistance in cells of various tissues. Vascular complications in T2DM have an inflammatory nature. Drugs with different mechanisms of action have been developed and used to treat T2DM, initially aimed at controlling blood glucose levels. Among them, sodium-glucose cotransporter 2 inhibitors (SGLT2-i) were developed as specific inhibitors of glucose reabsorption in the kidneys, but along with lowering blood glucose levels, they demonstrated multiple (including non-glycemic) positive effects in the treatment of T2DM related to their beneficial effects on the immune system. SGLT2 inhibitors can reduce the risk of diabetic cardiomyopathy (DCM) and chronic kidney disease (CKD) development in patients with and without diabetes. SGLT2-is improve cardio-renal complications through a number of signaling pathways, including those dependent on the involvement of non-coding RNAs (ncRNAs) and their targets. The best-studied classes of ncRNAs are microRNAs, which are short (less than 200 bases) RNAs (miRNAs), long non-coding RNAs (lncRNAs) (more than 200 bases), and circular RNAs (circRNAs). The regulatory effect of ncRNAs has broad physiological significance, and changes in the ncRNAs' expression are associated with the pathogenesis of different diseases, including T2DM. RNA-seq allows the construction of networks of interactions of lncRNA/circRNA-miRNA-mRNA called competitive endogenous RNA (ceRNA) networks, to identify clinically significant molecular markers, to improve the mechanistic understanding of pathogenesis, and to contribute to the development of new diagnostics and therapies. Our review summarizes the role of non-coding RNA in the action of SGLT2 inhibitors in cardio-renal complications in T2DM. We focus on methods of detection, genetics, and the effects of non-coding RNA. Specific attention is given to the role of non-coding RNAs in the inflammatory reactions of innate immune cells in relation to the SGLT2 inhibitors.
Insights
Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) offer benefits beyond blood glucose control in type 2 diabetes mellitus (T2DM). This review explores how non-coding RNAs mediate SGLT2-i
Area of Science:
- Biochemistry
- Molecular Biology
- Immunology
Background:
- Type 2 diabetes mellitus (T2DM) involves hyperglycemia and insulin resistance, leading to inflammatory vascular complications.
- Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) lower blood glucose and exhibit beneficial non-glycemic effects, including immune system modulation.
- SGLT2 inhibitors show promise in reducing diabetic cardiomyopathy (DCM) and chronic kidney disease (CKD) risks, potentially via non-coding RNA pathways.
Purpose of the Study:
- To review the role of non-coding RNAs (ncRNAs) in mediating the cardio-renal benefits of SGLT2 inhibitors in T2DM.
- To explore the detection, genetics, and functional effects of ncRNAs in T2DM.
- To highlight the involvement of ncRNAs in innate immune cell inflammatory responses influenced by SGLT2 inhibitors.
Main Methods:
- Literature review focusing on ncRNAs (miRNAs, lncRNAs, circRNAs) and SGLT2 inhibitor mechanisms.
- Analysis of RNA-sequencing data for constructing competitive endogenous RNA (ceRNA) networks.
- Examination of ncRNA expression changes in T2DM pathogenesis and SGLT2 inhibitor action.
Main Results:
- ncRNAs, including miRNAs, lncRNAs, and circRNAs, play a significant regulatory role in T2DM pathogenesis.
- SGLT2 inhibitors exert cardio-renal protective effects through signaling pathways involving ncRNAs.
- ncRNAs are implicated in the inflammatory responses of innate immune cells modulated by SGLT2 inhibitors.
Conclusions:
- Non-coding RNAs are critical mediators of SGLT2 inhibitor efficacy in managing cardio-renal complications in T2DM.
- Understanding ncRNA-mediated ceRNA networks can lead to novel diagnostic markers and therapeutic strategies for T2DM.
- Targeting ncRNAs offers a promising avenue for enhancing the immune-modulatory and protective effects of SGLT2 inhibitors.
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