Novel -209A/G MT2A Polymorphism in Old Patients with Type 2 Diabetes and Atherosclerosis: Relationship with Inflammation (IL-6) and Zinc

Abstract

Vascular complications, including ischaemic cardiomyopathy, are the major causes of death in old diabetic patients. Chronic inflammation due to high IL-6 production occurs in type 2 diabetes (NIDDM) and atherosclerosis. High levels of IL-6 are associated with hyperglycaemia, dyslipidemia and provoke insulin resistance. In ageing and inflammation, IL-6 affects Metallothionein (MT) homeostasis, which in turn is involved in zinc turnover. Zinc deficiency is an usual event in ageing, inflammation, type 2 diabetes and atherosclerosis. No genetic study exists on MT polymorphisms in NIDDM-atherosclerotic patients. The aim of the present study is to screen a single nucleotide polymorphism in the promoter region of the MT2A gene in relation to inflammation (IL-6) and plasma zinc in NIDDM-atherosclerotic patients. The -209 A/G MT2A polymorphism is associated with chronic inflammation (higher plasma levels of IL-6), hyperglycaemia, enhanced HbA1c and more marked zinc deficiency in AA than AG genotype carrying patients. Analysing patients and controls subdivided in AA and AG genotypes, significant interactions existed between disease status and genotypes for glucose and zinc. AA patients are more at risk of developing NIDDM in association with atherosclerosis (p=0.0015 odds ratio=2.617) and its complications, such as ischaemic cardiomyopathy (p=0.0050 odds ratio=12.6). In conclusion, high levels of IL-6 unmask the phenotypes (higher insulin resistance and zinc deficiency) in relation to the genotypes with subsequent risk of developing ischaemic cardiomyopathy in NIDDM-atherosclerotic patients carrying AA genotype. Hence, the novel -209A/G MT2A polymorphism may be a further useful tool for the prevention, diagnosis and therapy of these combined pathologies in the elderly.

Zinc and the aging brain

“…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). Similarly a mutation in the MT2A promoter is associated with low plasma zinc, higher blood glucose levels, and risk of atherosclerosis and ischemic cardiomyopathy among DM patients (Giacconi et al 2005). The above data suggests that individuals with IL6 and MT mutations may have higher optimal zinc intake requirements.…”

“…Zinc supplementation can also improve glycemic control in patients with diabetes mellitus (DM) (Jayawardena et al 2012) and may benefit a large portion of the aging population (Maylor et al 2006). However several polymorphisms that affect zinc homeostasis have been identified, future research is needed to understand how these mutations may alter dietary zinc requirements and the efficacy of zinc supplementation to prevent or treat major chronic diseases that affect the aging population (Giacconi et al 2005;Xu et al 2012).…”

Zinc–gene interaction related to inflammatory/immune response in ageing

“…On the other side, feeding the body with the adequate requirement of zinc can result in a proper antiinflammatory response which may be pivotal to reach longevity severe infections and atherosclerosis. The main results of the project confirmed a strong contribution of MT genetic variants in regulating zinc homeostasis and perhaps its dietary requirements as well as their relevance in longevity and in some age-related pathologies [34,57,95,98]. Moreover, it has been confirmed that IL-6 -174 polymorphisms can be used to identify old subjects with higher risk to develop zinc deficiency [98,108].…”

“…The recent discovery of novel polymorphisms of MT2A and MT1A supports this assumption. Indeed, old subjects carrying AA genotype for MT2A polymorphism display low zinc ion bioavailability, chronic inflammation by high IL-6 and altered lipid assessments, with subsequent elevated risk for atherosclerosis and diabetes type II [57]. By contrast, polymorphism corresponding to A/C (Asparagin/ Threonin) transition at +647 nt position in the MT1A coding region is the most involved in the women longevity [34].…”

“…In this context, some polymorphisms of MT (isoform I and II) have to be included in the network, taking into account that MTs homeostasis is also involved in the longevity of worm Caenorhabditis elegans [11]. Recent data from our laboratory show for the first time that a polymorphisms of MTs is involved in longevity [34], whereas MT2A polymorphism is involved in atherosclerosis worsening [57]. Moreover, the addition of some intermediate phenotypes (i.e.…”