Altered expression of uncoupling protein 2 in GLP-1-producing cells after chronic high glucose exposure: implications for the pathogenesis of diabetes mellitus

Abstract

Glucagon-like peptide-1 (GLP-1) is a gut L-cell hormone that enhances glucose-stimulated insulin secretion. Several approaches that prevent GLP-1 degradation or activate the GLP-1 receptor are being used to treat type 2 diabetes mellitus (T2DM) patients. In T2DM, GLP-1 secretion has been suggested to be impaired, and this defect appears to be a consequence rather than a cause of impaired glucose homeostasis. However, although defective GLP-1 secretion has been correlated with insulin resistance, little is known about the direct effects of chronic high glucose concentrations, which are typical in diabetes patients, on GLP-1-secreting cell function. In the present study, we demonstrate that glucotoxicity directly affects GLP-1 secretion in GLUTag cells chronically exposed to high glucose. Our results indicate that this abnormality is associated with a decrease in ATP production due to the elevated expression of mitochondrial uncoupling protein 2 (UCP2). Furthermore, UCP2 inhibition using small interfering RNA (siRNA) and the application of glibenclamide, an ATP-sensitive potassium (KATP(+)) channel blocker, reverse the GLP-1 secretion defect induced by chronic high-glucose treatment. These results show that glucotoxicity diminishes the secretory responsiveness of GLP-1-secreting cells to acute glucose stimulation. We conclude that the loss of the incretin effect, as observed in T2DM patients, could at least partially depend on hyperglycemia, which is typical in diabetes patients. Such an understanding may not only provide new insight into diabetes complications but also ultimately contribute to the identification of novel molecular targets within intestinal L-cells for controlling and improving endogenous GLP-1 secretion.

Ghrelin gene products rescue cultured adult rat hippocampal neural stem cells from high glucose insult

“…We also investigated the effects of these peptides on UCP2 expression in hippocampal NSCs exposed to HG. In agreement with previous studies demonstrating increased UCP2 activity in response to hyperglycemia (Koziel et al 2015, Urbano et al 2016, we found that UCP2 protein levels were significantly increased by HG. Enhanced activity of UCP2 in hyperglycemic condition is known to lessen the reduction level of mitochondrial respiratory chain complexes and result in the attenuation of mitochondrial ROS production (Koziel et al 2015).…”

“…It has been reported that HG exposure induces significant upregulation of UCP2 (Koziel et al 2015, Urbano et al 2016). Similar to these findings, we found that HG exposure significantly increased UCP2 expression in a time-dependent manner ( Fig.…”

Impaired glucagon suppression and reduced insulin sensitivity in subjects with prediabetes undergoing atorvastatin therapy

“…For Western blot analysis, cell lysates were analyzed as previously described (38). Proteins of interest were detected with the following specific antibodies: antiphospho-IRS-1 (Tyr612) and anti-total IRS-1 (Santa Cruz Biotechnology); anti-phospho-AKT (Ser473) and anti-total AKT (Cell Signaling Technology); anti β-Actin (Sigma-Aldrich).…”

Metabolic Regulation of Methionine Restriction in Diabetes

“…UCP1 is a potential target for the treatment of patients with diabetes and improves the whole metabolism . In addition, the altered expression of UCP2 is implicated in the pathogenesis of diabetes, and the activation of UCP2 in diabetic mitochondria seems to be a response to the diabetes process that leads to more efficient cleaving of ROS . Of interest, the upregulation of UCPs has been observed in several MR models, indicating a potential mechanism in MR‐mediated mitochondrial respiratory chain.…”