+647 A/C and +1245 MT1A polymorphisms in the susceptibility of diabetes mellitus and cardiovascular complications

Giacconi, Robertina; Bonfigli, Anna Rita; Testa, Roberto; Sirolla, C.; Cipriano, Catia; Marra, Maurizio; Muti, Elisa; Malavolta, Marco; Costarelli, Laura; Piacenza, Francesco; Tesei, Silvia; Mocchegiani, Eugenio

doi:10.1016/j.ymgme.2007.12.006

Cited by 76 publications

(58 citation statements)

References 42 publications

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“…A mutation in the IL6 promoter upregulates its expression leading to increased MT, low plasma zinc, impaired innate immunity (Mocchegiani et al 2007), and increased risk of AD (Licastro et al 2003). A mutation in the coding region of MT1A is associated with increased expression of IL6 and MT, higher risk of DM2, and shorter lifespan (Cipriano et al 2006;Giacconi et al 2008). Furthermore, this mutation may directly interfere with the functions of zinc in cellular signal transduction because it attenuates the release of zinc in response to nitric oxide (Cipriano et al 2006).…”

Section: Zinc and Insulin Signaling In Diabetes Mellitus And Dementiamentioning

confidence: 99%

Zinc and the aging brain

Nuttall

Oteiza

2013

Genes Nutr

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Alterations in trace element homeostasis could be involved in the pathology of dementia, and in particular of Alzheimer's disease (AD). Zinc is a structural or functional component of many proteins, being involved in numerous and relevant physiological functions. Zinc homeostasis is affected in the elderly, and current evidence points to alterations in the cellular and systemic distribution of zinc in AD. Although the association of zinc and other metals with AD pathology remains unclear, therapeutic approaches designed to restore trace element homeostasis are being tested in clinical trials. Not only could zinc supplementation potentially benefit individuals with AD, but zinc supplementation also improves glycemic control in the elderly suffering from diabetes mellitus. However, the findings that select genetic polymorphisms may alter an individual's zinc intake requirements should be taken into consideration when planning zinc supplementation. This review will focus on current knowledge regarding pathological and protective mechanisms involving brain zinc in AD to highlight areas where future research may enable development of new and improved therapies.

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Section: Zinc and Insulin Signaling In Diabetes Mellitus And Dementiamentioning

confidence: 99%

Zinc and the aging brain

Nuttall

Oteiza

2013

Genes Nutr

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“…Polymorphisms have also been found in MT-1 and MT-2 [Giacconi et al 2008[Giacconi et al , 2005Yang et al 2008]. A polymorphism in MT-1A for example, was associated with type 2 diabetes in patients with cardiovascular complications [Giacconi et al 2008]. Less zinc was released from stimulated blood leucocytes in these patients, suggesting loss of zinc bioavailability.…”

Section: Gene Polymorphisms: Potential Gene-environment Interactionsmentioning

confidence: 99%

Adverse Effects of Low Level Heavy Metal Exposure on Male Reproductive Function

Wirth

Mijal

2010

Systems Biology in Reproductive Medicine

245

164

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Lead, cadmium, mercury, and arsenic, often referred to as ''heavy metals'', are toxic for wildlife, experimental animals, and humans. While experimental animal and human occupational studies with high exposure levels generally support an adverse role for these metals in human reproductive outcomes, information on the effects of low, environmentally-realistic exposure levels of these metals on male reproductive outcomes is limited. We review the literature on effects of exposure to low levels of these metals on measures of male fertility (semen quality and reproductive hormone levels) and provide supporting evidence from experimental and occupational studies. Potentially modifying effects of genetic polymorphisms on these associations are discussed. A brief review of the literature on the effects of three trace metals, copper, manganese, and molybdenum, that are required for human health, yet may also cause adverse reproductive effects, follows. Overall, there were few studies examining the effects of exposure to low levels of these metals on male reproductive health. For all metals, there were several well-designed studies with sufficient populations appropriately adjusted for potential confounders and many of these reported harmful effects. However, many studies lacked sufficient numbers of participants to be able to detect differences in outcomes between exposed and non-exposed individuals, did not clearly identify the source and characteristics of the participants, and did not control for other exposures that could alter or contribute to the outcomes. The evidence for the effects of low exposure was strongest for cadmium, lead, and mercury and less certain for arsenic. The potential modifying effects of genetic polymorphisms has not been fully explored. Additional studies on the reproductive effects of these toxic ubiquitous metals on male reproduction are required to expand the knowledge base and to resolve inconsistencies.

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“…Importantly, diabetes patients with polymorphisms in the MT gene are more susceptible to the development of various diabetic complications (10,34). We considered that MT protection from diabetes-induced pathological changes might be attributed to its antioxidant function, theorizing that it might reduce nitrosative damage, based on our previously published data showing that diabetic MT-TG mice had significantly less 3-NT accumulation in the heart at 2-4 wk of diabetes (4).…”

Section: Discussionmentioning

confidence: 99%

Metallothionein prevents diabetes-induced cardiac pathological changes, likely via the inhibition of succinyl-CoA:3-ketoacid coenzyme A transferase-1 nitration at Trp³⁷⁴

Cong

Zhao

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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L. Metallothionein prevents diabetes-induced cardiac pathological changes, likely via the inhibition of succinyl-CoA:3-ketoacid coenzyme A transferase-1 nitration at Trp 374 . Am J Physiol Endocrinol Metab 304: E826 -E835, 2013. First published February 26, 2013 doi:10.1152/ajpendo.00570.2012.-We previously demonstrated that metallothionein (MT)-mediated protection from diabetesinduced pathological changes in cardiac tissues is related to suppression of superoxide generation and protein nitration. The present study investigated which diabetes-nitrated protein(s) mediate the development of these pathological changes by identifying the panel of nitrated proteins present in diabetic hearts of wild-type (WT) mice and not in those of cardiac-specific MT-overexpressing transgenic (MT-TG) mice. At 2, 4, 8, and 16 wk after streptozotocin induction of diabetes, histopathological examination of the WT and MT-TG diabetic hearts revealed cardiac structure derangement and remodeling, significantly increased superoxide generation, and 3-nitrotyrosine accumulation. A nitrated protein of 58 kDa, succinyl-CoA:3-ketoacid CoA transferase-1 (SCOT), was identified by mass spectrometry. Although total SCOT expression was not significantly different between the two types of mice, the diabetic WT hearts showed significantly increased nitration content and dramatically decreased catalyzing activity of SCOT. Although SCOT nitration sites were identified at diabetes; cardiac pathological changes; metallothionein; SCOT; 3-nitrotyrosine DIABETES HAS BECOME one of the most prolific public health issues worldwide (25). Mechanistic studies have revealed that oxidative and nitrosative stress are major causes of diabetes and its complications (4, 13). Overproduced superoxide has been shown in diabetic individuals to interact with nitric oxide, forming the peroxynitrite (ONOO Ϫ ) free radical that mediates biomacromolecule nitration and can ultimately lead to organ dysfunction. The covalent product of tyrosine nitration, 3-nitrotyrosine (3-NT), serves as an index of peroxynitrite-induced protein damage and is used in clinic as a convenient quantitative biomarker of cardiovascular risk (measured in free and protein-bound forms in human plasma) (23). Moreover, overproduction of superoxide and associated peroxynitrite has been implicated in the development of diabetic cardiomyopathy (4, 20, 28). Therefore, a promising approach to prevent the development of diabetic complications will include the prevention of oxidative and nitrosative stress (2).The well-established and widely used animal model of type 1 diabetes induced by streptozotocin (STZ) has several nitrated molecules in the cardiac tissue. The majority of these nitrated molecules are mitochondrial proteins with known functions in cellular energy metabolism and oxygen oxidation (26,27,29). However, whether the nitration of these mitochondrial proteins contributes to the development of diabetic cardiomyopathy remains largely unknown.The cysteine-rich protein metallothionein (MT) is a ubiquito...

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+647 A/C and +1245 MT1A polymorphisms in the susceptibility of diabetes mellitus and cardiovascular complications

Cited by 76 publications

References 42 publications

Zinc and the aging brain

Zinc and the aging brain

Adverse Effects of Low Level Heavy Metal Exposure on Male Reproductive Function

Metallothionein prevents diabetes-induced cardiac pathological changes, likely via the inhibition of succinyl-CoA:3-ketoacid coenzyme A transferase-1 nitration at Trp³⁷⁴

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+647 A/C and +1245 MT1A polymorphisms in the susceptibility of diabetes mellitus and cardiovascular complications

Cited by 76 publications

References 42 publications

Zinc and the aging brain

Zinc and the aging brain

Adverse Effects of Low Level Heavy Metal Exposure on Male Reproductive Function

Metallothionein prevents diabetes-induced cardiac pathological changes, likely via the inhibition of succinyl-CoA:3-ketoacid coenzyme A transferase-1 nitration at Trp374

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Product

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Metallothionein prevents diabetes-induced cardiac pathological changes, likely via the inhibition of succinyl-CoA:3-ketoacid coenzyme A transferase-1 nitration at Trp³⁷⁴