Hyperglycemia promotes microvillus membrane expression of DMT1 in intestinal epithelial cells in a PKCα‐dependent manner

Abstract

Excessive iron increases the incidence of diabetes and worsens diabetic complications. Reciprocally, diabetes induces iron loading, partially attributable to elevated intestinal iron export according to a recent report. Herein, we show that iron uptake and the mRNA expression of iron importer divalent metal transporter 1 (DMT1) were significantly increased in the duodenum of streptozotocin‐induced diabetic mice. Immunofluorescence staining of human intestinal biopsies revealed increased brush border membrane (BBM) and decreased cytoplasmic DMT1 expression in patients with diabetes, suggesting translocation of DMT1. This pattern of DMT1 regulation was corroborated by immunoblotting results in diabetic mice showing that BBM DMT1 expression was increased by 210%, in contrast to a 60% increase in total DMT1. PKC mediates many diabetic complications, and PKCα activity was increased in diabetic mouse intestine. Intriguingly, diabetic mice with PKCα deficiency did not show increases in iron uptake and BBM DMT1 expression. High‐glucose treatment increased plasma membrane DMT1 expression via the activation of PKCα in cultured IECs. Inhibition of PKCv potentiated the ubiquitination and degradation of DMT1 protein. We further showed that high glucose suppressed membrane DMT1 internalization. These findings demonstrate that PKCα promotes microvillus membrane DMT1 expression and intestinal iron uptake, contributing to diabetic iron loading.—Zhao, L., Bartnikas, T., Chu, X., Klein, J., Yun, C., Srinivasan, S., He, P. Hyperglycemia promotes microvillus membrane expression of DMT1 in intestinal epithelial cells in a PKCα‐dependent manner. FASEB J. 33, 3549–3561 (2019). http://www.fasebj.org

The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System

“…Zhao et al have found out that hyperglycemia in a PKCα-dependent manner inhibits the ubiquitination, internalization and degradation of the divalent metal transporter 1 (DMT1) present on the microvillar membranes of IECs. Subsequently, intestinal iron uptake is enhanced and accumulated iron ions aggravate diabetes-related complications and increase mortality (82,83).…”

Crosstalk Between Oxidative Stress and Endoplasmic Reticulum (ER) Stress in Endothelial Dysfunction and Aberrant Angiogenesis Associated With Diabetes: A Focus on the Protective Roles of Heme Oxygenase (HO)-1

“…Liu et al (2012) observed that the selective inhibition of PKC-β, improved left ventricular function and structure in a diabetes animal model of streptozotocin-injected rats. More recently, it was reported that the activation of PKC-α in the intestine of streptozotocin-induced diabetic mice contributed to the enhanced uptake of iron leading to iron loading that contributes to diabetic complications (Zhao et al, 2018). Furthermore, the inhibition of PKC-ζ was shown recently to improve insulin sensitivity and uptake of glucose in rat adipocytes rendered insulin-resistant by incubating them in high glucose and high insulin concentrations (Lu et al, 2018).…”

“Porcine Digestible Peptides (Pdp) in Weanling Diets Improves Gut Barrier Function, Immune Response and Nutrient Transport in Nursery Pigs” 

“…The divalent metal transporter (SCL11A2/DMT1) is located on the apical surface of the enterocyte and is involved in the intestinal Fe uptake [19]. SLC11A2/DMT1 gene expression is upregulated in circumstances of low Fe intake [27] and hyperglycemia conditions [59]. We have no evidence of differences in the Fe content or glycemic levels among experimental diets; therefore, the reason why the SDP-PDP treatment increased the expression of SLC11A2/DMT1 should be researched further.…”