MicroRNA 375 modulates hyperglycemia-induced enteric glial cell apoptosis and Diabetes-induced gastrointestinal dysfunction by targeting Pdk1 and repressing PI3K/Akt pathway

Abstract

Diabetic neuropathy can damage systemic nervous system, including alteration of enteric nervous system and subsequent gastrointestinal dysfunction. The effect of diabetes on enteric glia cell (EGC) is not clear. We investigated the effect of diabetes and hyperglycemia on EGC, and the role of microRNA375 in modulating EGC survival in vivo and in vitro. Streptozotocin-induced diabetic mice were intraperitoneally injected with microRNA375 inhibitor or its negative control. EGC was transfected with microRNA375 inhibitor or its mimic. Diabetes mice with gastrointestinal dysfunction showed increased apoptosis of EGC (no difference in cell numbers) and gene expression of micorRNA375 in the myenteric plexus. Hyperglycemia triggered apoptosis of EGC in vitro with decreased expression of Pdk1 and p-Akt, but increased expression of micorRNA375. MicorRNA375 mimic induced apoptosis of EGC in vitro with repressed Pdk1and p-Akt. MicorRNA375 inhibitor could both prevent hyperglycemia-induced apoptosis of EGC in vitro and diabetes-induced gastrointestinal dysfunction in vivo. Our results suggest that diabetes-induced gastrointestinal dysfunction is related to increased apoptosis of EGC in the myenteric plexus. Hyperglycemia can increase the expression of microRNA375 and damage EGC survival through PI3K/Akt pathway. MicroRNA375 specific inhibition can prevent hyperglycemia induced EGC damage and diabetes-induced gastrointestinal dysfunction.

Astrocyte Clocks and Glucose Homeostasis

“…While most of the research focused on the enteric neurons, less attention was directed towards the enteric glial cells (EGCs). Glucose enters the body via the gastrointestinal (GI) tract, and conversely, diabetes-induced GI dysfunction is related to increased apoptosis of EGC in the myenteric plexus ( 211 ). On the other hand, the gut clock synchronized by food intake ( 27 , 212 ) regulates the expression of brush border disaccharidases and glucose absorption to the habitual feeding period ( 168 ).…”

PI3Kinases in Diabetes Mellitus and Its Related Complications

“…Similarly, diabetes can reduce the number of enteric nerves, and restoration of PI3K signaling can lead to regeneration of lost enteric neurons [59], which may alleviate gastrointestinal symptoms in diabetic patients. More recently, sustaining PI3K signaling has been shown to improve gastrointestinal function in diabetes, also by facilitating survival of other cells connected with nerve fibers, such as enteric glia [60].…”

Dysbiosis-Associated Enteric Glial Cell Immune-Activation and Redox Imbalance Modulate Tight Junction Protein Expression in Gulf War Illness Pathology

“…Furthermore, it has been observed that metabolic diseases e.g., diabetes and obesity also present with increased ratio of Firmicutes to Bacteriodetes (Conlon and Bird, 2014; Johnson et al, 2017). Studies concerning the mechanisms of these gastrointestinal diseases have found that change of EGC phenotype from homeostatic to pathogenic is a characteristic of these diseases (Cabarrocas et al, 2003; Linan-Rico et al, 2016; Chen et al, 2018). A study by Wang et al reported a significantly increased expression of glial fibrillary acidic protein (GFAP), Tyrosine receptor kinase B and Substance P in the colon of IBS patients with a correlated increase in intestinal inflammation (Wang et al, 2016).…”