Emerging Roles of Metallothioneins in Beta Cell Pathophysiology: Beyond and above Metal Homeostasis and Antioxidant Response

Abstract

Metallothioneins (MTs) are low molecular weight, cysteine-rich, metal-binding proteins whose precise biological roles have not been fully characterized. Existing evidence implicated MTs in heavy metal detoxification, metal ion homeostasis and antioxidant defense. MTs were thus categorized as protective effectors that contribute to cellular homeostasis and survival. This view has, however, been challenged by emerging evidence in different medical fields revealing novel pathophysiological roles of MTs, including inflammatory bowel disease, neurodegenerative disorders, carcinogenesis and diabetes. In the present focused review, we discuss the evidence for the role of MTs in pancreatic beta-cell biology and insulin secretion. We highlight the pattern of specific isoforms of MT gene expression in rodents and human beta-cells. We then discuss the mechanisms involved in the regulation of MTs in islets under physiological and pathological conditions, particularly type 2 diabetes, and analyze the evidence revealing adaptive and negative roles of MTs in beta-cells and the potential mechanisms involved. Finally, we underscore the unsettled questions in the field and propose some future research directions.

The Bioinorganic Chemistry of Mammalian Metallothioneins

“…In our opinion, statements that try to relate the protein to general observations of redox changes are superficial without identifying targets and should address changes in metal metabolism and resolving the ambiguity of whether the induced protein restricts metal ions or makes them available as would be the case in an antioxidant function when the protein thiols are oxidized. We will discuss general pathways that underlie many diseases and not discuss in detail noncommunicable diseases such as cancer, diabetes, and neurodegeneration, for which a lot of work regarding a positive or negative effect of MTs and a role of MT3 in the brain has been published as apparent from the cited reviews. ,− With specific reference to the healthy, diseased, or injured brain, MT3 is mainly in neurons, while MT1/2 are mainly in astrocytes . Various forms of stress, inflammation, hypoxia, bacterial and viral infections, and aspects of cell fate (cell cycle/proliferation, differentiation/development, cell death/apoptosis) and cell adhesion/migration are such general processes linked to pathways of MT induction.…”

Transcriptional Remodeling of the Stromal and Endothelial Microenvironment in MGUS to Multiple Myeloma Progression

“…Interestingly, EC from MGUS were characterized by overexpression of Slpi, Mt1, Mt2 , and Hspa5 , genes related to protein folding, endoplasmic reticulum stress and metal ion homeostasis, suggesting a stress state of EC at the onset of the disease ( Table S2; Figure 3B; Figure S5A-B ). Metallothioneins (Mts) are metal-binding proteins that play a role in several processes, including metal homeostasis, detoxification, and cell proliferation 16 . Although their connection to myeloma is less well characterized, several studies have demonstrated that metallothioneins play an essential role in tumor angiogenesis 17 .…”

Pancreas–Liver–Adipose Axis: Target of Environmental Cadmium Exposure Linked to Metabolic Diseases

“…The mRNA level of Mt1 is relatively higher than Mt2. In human β-cells, MT1E, MT1F, MT1X, and MT2A participate in differentiation, maturation, and other significant biological roles [ 107 , 108 , 109 ]. The MTs are the first line of defense in β-cell, when their thiols are oxidized, releasing Zn.…”

“…MT gene expression in β-cells is also regulated by glucose [ 108 , 111 , 112 , 113 , 114 ]. Langerhans islets exposure to H 2 O 2 , IL-1β, TNF-α, and IFNγ markedly increases Mt1a mRNA levels [ 109 , 115 ]. Interestingly, Mt1a upregulation parallels oxidative stress-responsive genes, such as Cat, Gst, and Sod2 [ 116 , 117 ].…”