Targeting the Zinc Transporter ZIP7 in the Treatment of Insulin Resistance and Type 2 Diabetes

Abstract

Type 2 diabetes mellitus (T2DM) is a disease associated with dysfunctional metabolic processes that lead to abnormally high levels of blood glucose. Preceding the development of T2DM is insulin resistance (IR), a disorder associated with suppressed or delayed responses to insulin. The effects of this response are predominately mediated through aberrant cell signalling processes and compromised glucose uptake into peripheral tissue including adipose, liver and skeletal muscle. Moreover, a major factor considered to be the cause of IR is endoplasmic reticulum (ER) stress. This subcellular organelle plays a pivotal role in protein folding and processes that increase ER stress, leads to maladaptive responses that result in cell death. Recently, zinc and the proteins that transport this metal ion have been implicated in the ER stress response. Specifically, the ER-specific zinc transporter ZIP7, coined the “gate-keeper” of zinc release from the ER into the cytosol, was shown to be essential for maintaining ER homeostasis in intestinal epithelium and myeloid leukaemia cells. Moreover, ZIP7 controls essential cell signalling pathways similar to insulin and activates glucose uptake in skeletal muscle. Accordingly, ZIP7 may be essential for the control of ER localized zinc and mechanisms that disrupt this process may lead to ER-stress and contribute to IR. Accordingly, understanding the mechanisms of ZIP7 action in the context of IR may provide opportunities to develop novel therapeutic options to target this transporter in the treatment of IR and subsequent T2DM.

Zinc transporter SLC39A7 relieves zinc deficiency to suppress alternative macrophage activation and impairment of phagocytosis

“…To compensate for the Zn 2+ deficiency, SLC39A7 is upregulated in patients with asthma than healthy controls as previously reported [16]. Recent data shows that SLC39A7 is implicated in glucose metabolism and glycemic control in skeletal muscle cells [13,14]. SLC39A7 has essential role in B cell development, SLC39A7 was required for BCR signaling [15].…”

“…Deletion of the SLC39A7 gene in mesenchymal stem cells leads to the accumulation of zinc in the ER, triggering overexpression of the UPR gene and endoplasmic reticulum stress [12]. Recent data shows that SLC39A7 is implicated in glucose metabolism and glycemic control in skeletal muscle cells [13,14]. For immune cells, SLC39A7 is essential for B cell development and BCR signaling [15].…”

Zinc status in infants and children with cholestatic liver diseases and its effect on growth

“…Recently, zinc and the proteins that transfer zinc ion have been implicated in the endoplasmic reticulum stress response. Specifically, the endoplasmic reticulum-specific zinc transporter ZIP7, named the gatekeeper of zinc release from the endoplasmic reticulum into the cytosol, was found to be essential for maintaining endoplasmic reticulum homeostasis in intestinal epithelium cells (Adulcikas et al, 2019).…”

Ernährung bei Diabetes mellitus Typ 2

“…Dabei werden Zink sowie dessen Transportproteine, wie ZIP7, in Verbindung mit oxidativem Stress gebracht. Eine gestörte Funktion von ZIP7 führt zu einem beeinträchtigten Zinkfluss und Stress des endoplasmatischen Retikulums (ER-Stress), was wiederum eine Insulinresistenz begünstigen könnte [3]. Studien zeigten eine Verbindung zwischen einer unzureichenden Zinkaufnahme und dem Risiko für T2DM sowie erhöhten Blutglukosewerten [8].…”

“…Es gibt Hinweise, dass ein schlecht eingestellter T2DM mit einer Unterversorgung an Mikronährstoffen einhergehen könnte, was wiederum mit diabetischen Folgeerkrankungen in Verbindung gebracht wird [2]. Zudem nehmen Mikronährstoffe verschiedenste Aufgaben hinsichtlich der Glukosehomöostase ein und können an unterschiedlicher Stelle im komplexen Krankheitsgeschehen beteiligt sein [3] [4]. Des Weiteren ist die Mehrzahl der Menschen mit T2DM übergewichtig, während Adipositas wiederum oftmals mit einer Mangelernährung einhergeht und weitere Komorbiditäten fördert.…”