Apoptosis in Type 2 Diabetes: Can It Be Prevented? Hippo Pathway Prospects

Abstract

Diabetes mellitus is a heterogeneous disease of complex etiology and pathogenesis. Hyperglycemia leads to many serious complications, but also directly initiates the process of β cell apoptosis. A potential strategy for the preservation of pancreatic β cells in diabetes may be to inhibit the implementation of pro-apoptotic pathways or to enhance the action of pancreatic protective factors. The Hippo signaling pathway is proposed and selected as a target to manipulate the activity of its core proteins in therapy-basic research. MST1 and LATS2, as major upstream signaling kinases of the Hippo pathway, are considered as target candidates for pharmacologically induced tissue regeneration and inhibition of apoptosis. Manipulating the activity of components of the Hippo pathway offers a wide range of possibilities, and thus is a potential tool in the treatment of diabetes and the regeneration of β cells. Therefore, it is important to fully understand the processes involved in apoptosis in diabetic states and completely characterize the role of this pathway in diabetes. Therapy consisting of slowing down or stopping the mechanisms of apoptosis may be an important direction of diabetes treatment in the future.

Proteomics and Phosphoproteomics of Circulating Extracellular Vesicles Provide New Insights into Diabetes Pathobiology

“…Of note, a group of CMGC kinases (i.e., CDK1, GSK3B, MAPK1, MAPK14, CDK2, CDK5, and CDK14), as well as a mixed group of CAMK and AGC kinases (including two PKC isoforms, CHECK1, PRKACA, CAMK2A, and CSNK2A1), appear to have key non-redundant activities on specific substrates ( Figure 5 ). Interestingly, upstream activation of STK4 (a major signaling kinase of the Hippo pathway [ 30 ]) appears to be the single kinase responsible for the increased phosphorylation of MYLK, one of the kinases that were central to the upregulated phosphoprotein network in T2DM ( Figure 4 E), as compared to the NGT group. Additional information on the differentially expressed phosphosites and pathways enrichment analysis results on those sets are provided in Supplementary Tables S12–S17 .…”

“…The kinase-substrate heatmap also uncovered that STK4 (a major signaling kinase of the Hippo pathway [ 30 ]) appears to be the kinase responsible for the increased phosphorylation of MYLK, a myosin light chain kinase that is involved in Ca 2+ signaling, myofibroblast contraction, microvascular endothelial barrier dysfunction, gastric motility, and insulin secretion [ 57 , 60 , 61 , 62 ]. Supporting our finding, altered contractility of the gastric smooth muscles has been found impaired in people with obesity and diabetes [ 60 ].…”

Investigation of the relationship between NFKB1 polymorphisms and telomere length and apoptosis in patients with type-2 diabetes

“…There are two distinct pathways for apoptosis 33 : the internal pathway 34 mediated by the Bcl2 protein family and caspases and the external pathway associated with Fas or TNF death receptors (TNFR) 35,36 . The internal pathway, which is mediated by the Bcl2 family of proteins and is linked to the mitochondria [36][37][38] . The release of cytochrome c by mitochondria into the cytoplasm is an important step of mitochondrial apoptosis.…”

“…The release of cytochrome c by mitochondria into the cytoplasm is an important step of mitochondrial apoptosis. The following activation phase of initiator caspase-9 is important, causing cleavage of executive caspases-3/7 36,39 . Proteins in the Bcl-2 family are involved in mitochondrial integrity 36,40,41 .…”

“…The following activation phase of initiator caspase-9 is important, causing cleavage of executive caspases-3/7 36,39 . Proteins in the Bcl-2 family are involved in mitochondrial integrity 36,40,41 . In the present study, we examined the mRNA expressions of caspase-3, caspase-9, Bax and Bcl2 apoptotisis genes and found that while the expression of the Bcl2 gene expression was lower in the T2DM group, caspase-3, Bax and caspase-9 genes were all higher in T2DM patients when compared to healthy individuals.…”