Ferroportin (Q248H) mutations in African families with dietary iron overload

BACKGROUND: Dietary iron overload found in sub-Saharan Africa might be caused by an interaction between dietary iron and an iron-loading gene. Caucasian people with ferroportin gene mutations have iron overload histologically similar to that found in African patients with iron overload. Ferroportin is also implicated in the hypoferremic response to inflammation. The prevalence of the ferroportin Q248H mutation, unique to African people, and its association with dietary iron overload, mean cell volume (MCV) and C-reactive protein (CRP) were examined in 19 southern African families. METHODS: Polymerase chain reaction (PCR) and restriction enzyme digestion were used to identify the Q248H mutation. Statistical analysis was carried out to correlate the presence of the mutation with markers of iron overload and inflammation. RESULTS: We identified three (1.4%) Q248H homozygotes and 53 (24.1%) heterozygotes in the families examined in the present study. There was no increased prevalence of the mutation in index subjects or their families. Logistic regression showed significantly higher serum ferritin concentrations with the mutation. The mean cell volume (MCV) was significantly lower, and the serum CRP significantly higher in subjects who carried the mutation. CONCLUSIONS: The present study of 19 families with African iron overload failed to show evidence that the ferroportin (Q248H) mutation is responsible for the condition. Logistic regression, correcting for factors influencing iron status, did show increased ferritin levels in individuals with the mutation. The strong association with low MCV suggests the possibility that the ferroportin (Q248H) mutation might interfere with iron supply, whereas the elevated serum CRP might indicate that the ferroportin mutation influences the inflammatory response in African populations.     

Ferroportin (SLC40A1) Q248H mutation is associated with lower circulating serum hepcidin levels in Rwandese HIV-positive women

The Q248H mutation in the gene SLC40A1 which encodes for the cellular iron exporter ferroportin is relatively common in Africa. This mutation has been associated with resistance to hepcidin and therefore we hypothesized that iron-related parameters and the prevalence of opportunistic infections in HIV might be influenced by the Q248H mutation. We conducted a cross-sectional study among 200 HIV-positive women in the Butare University Teaching Hospital in Rwanda. Polymerase chain reaction (PCR) and restriction enzyme digestion were used to identify the Q248H mutation. Physical examination was carried out and WHO HIV disease stage classification, complete blood count, CD4 count, indirect measures of iron status, serum hepcidin, and C-reactive protein concentrations were determined. The prevalence of ferroportin Q248H mutation was 6%. Subjects with ferroportin Q248H mutation had significantly higher values for serum ferritin (P = 0.001) and significantly lower values for serum hepcidin (P = 0.001) and transferrin (P = 0.01). Among the 12 HIV + Q248H heterozygotes, 8 suffered from at least one opportunistic infection. There was significantly higher prevalence of pulmonary TB (P = 0.01) and Pneumocystis jiroveci pneumonia (P = 0.02) in subjects with ferroportin Q248H mutation. Low hepcidin levels were found in ferroportin Q248H heterozygotes with HIV infection, notwithstanding the absence of anemia and the higher prevalence of some opportunistic infections. Hepcidin seems to be regulated in a different way in Q248H heterozygotes than is known thus far.     

Ferroportin Q248h, dietary iron, and serum ferritin in community African-Americans with low to high alcohol consumption

Background: Alcohol consumption is associated with increased iron stores. In sub‐Saharan Africa, high dietary ionic iron and the ferroportin Q248H allele have also been implicated in iron accumulation. We examined the associations of ferroportin Q248H, alcohol and dietary iron with serum ferritin, aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT) concentrations in African‐Americans. Methods: Inner‐city African‐Americans (103 men, 40 women) were recruited from the community according to reported ingestion of >4 alcoholic drinks/d or <2/wk. Typical daily heme iron, nonheme iron and alcohol were estimated using University of Hawaii’s multiethnic dietary questionnaire. Based on dietary questionnaire estimates we established categories of < versus ≥56 g alcohol/d, equivalent to 4 alcoholic drinks/d assuming 14 g alcohol per drink. Results: Among 143 participants, 77% drank <56 g alcohol/d and 23%≥56 g/d as estimated by the questionnaire. The prevalence of ferroportin Q248H was 23.3% with alcohol >56 g/d versus 7.5% with lower amounts (p = 0.014). Among subjects with no history of HIV disease, serum ferritin concentration had positive relationships with male gender (p = 0.041), alcohol consumption (p = 0.021) and ALT concentration (p = 0.0001) but not with dietary iron intake or ferroportin Q248H. Serum AST and ALT concentrations had significant positive associations with male gender and hepatitis C seropositivity but not with alcohol or dietary iron intake or ferroportin Q248H. Conclusions: Our findings suggest a higher prevalence of ferroportin Q248H with greater alcohol consumption, and this higher prevalence raises the possibility that the allele might ameliorate the toxicity of alcohol. Our results suggest that alcohol but not dietary iron contributes to higher body iron stores in African‐Americans. Studies with larger numbers of participants are needed to further clarify the relationship of ferroportin Q248H with the toxicity of alcohol consumption.     

高尿酸血症与2型糖尿病

正2010年国际糖尿病联盟(IDF)成员国统计数字显示,6.4%的成人为糖尿病患者,即2.85亿人,预计这一数字在2030年将达到超过4.4亿人~([1]),其中约85%至95%的患者为2型糖尿病患者。而中国人群糖尿病的患病率为9.7%,糖尿病前期的患病率为15.5%~([2])。近年来,全球高尿酸血症的患病率正逐年上升。美国1988—1994年间高尿酸血症的患病率为18.2%;2007—2008年间已经增长到21.4%~([3])。在我国,高尿酸血症的患病率差异很     

Genes and type 2 diabetes mellitus

In 2007, five whole genome-wide association studies were published on the genetics of type 2 diabetes mellitus (T2DM), followed by the discovery of 11 genes consistently associated with T2DM. This breakthrough provided the first glimpses of a complete picture of the disease’s genetic complexity. Currently, we are only beginning to understand how DNA methylation, histone acetylation, and deacetylation may introduce epigenetic changes throughout one’s lifetime. Such changes may influence age-related modifications in gene-expression that contribute to age-related diseases. In the future, the possibility of whole-genome DNA methylation studies may elucidate the extent of these epigenetic effects. This article reviews genes that have recently been determined to be associated with T2DM.     

Dyslipidemia in type 2 diabetes mellitus

Cardiovascular disease is a significant cause of morbidity and mortality in patients with diabetes mellitus (DM). DM is now recognized as a risk equivalent for coronary heart disease. The lipid profile in patients with type 2 DM is characterized by elevated triglycerides, low levels of high-density lipoprotein cholesterol, and small dense low-density lipoprotein cholesterol (LDLC) particles and is believed to be a key factor promoting atherosclerosis in these patients. Both primary and secondary prevention studies have provided ample evidence that aggressive statin therapy reduces cardiovascular end points in patients with DM. In all persons with DM, current treatment guidelines recommend reduction of LDLC to less than 100 mg/dL, regardless of baseline lipid levels. Lowering LDLC to less than 70 mg/dL may provide even greater benefits, particularly in very high risk patients with DM and coronary heart disease.     

自噬与2型糖尿病

自噬是机体处于物质与能量代谢障碍时主要防御机制之一,在维持胰岛β细胞结构功能、改善IR等方面有重要作用。某些治疗T2DM药物也参与自噬途径调节。本文就近年关于自噬对T2DM影响的相关研究进行综述。     

糖皮质激素与2型糖尿病

糖皮质激素与2型糖尿病的发生、发展密切相关,但其诱导2型糖尿病发生的具体机制尚不明确.研究认为,糖皮质激素可能通过对胰岛β细胞增殖和发育、分泌功能的作用,以及对胰岛素信号转导通路、糖、脂代谢、葡萄糖转运和吸收等方面的影响,参与2型糖尿病的发生.11β-羟类固醇脱氢酶、糖皮质激素受体、热休克蛋白等通过影响糖皮质激素的作用,成为治疗2型糖尿病的新靶点.     

高尿酸血症与2型糖尿病

大量研究已证实高尿酸血症(HUA)与2型糖尿病(T2DM)密切相关,HUA患者中T2DM发生率显著高于尿酸正常者,而T2DM患者相对于非糖尿病者更容易发展为HUA.HUA可能通过引起慢性炎性反应和胰岛素抵抗参与T2DM的发生、发展,而T2DM中HUA发生率高可能与氧化应激和高胰岛素血症有关.另外,HUA与糖尿病并发症之间也存在紧密联系.     

铁调素与2型糖尿病

铁过度累积可加重胰岛素抵抗,对2型糖尿病的发生、发展具有推动作用.铁代谢调节机制中涉及铁调素,它是铁代谢的核心调节剂,能抑制铁的吸收和释放.有研究发现,2型糖尿病患者血清铁调素水平较正常人升高,但关于铁调素参与2型糖尿病的机制目前研究甚少.通过对铁调素与2型糖尿病关系的研究发现,在2型糖尿病患者中铁调素与铁蛋白呈正相关.铁调素与糖代谢有关,其可能通过对铁代谢的调节在2型糖尿病中发挥一定作用,从而为2型糖尿病的防治提供新思路.     

血管紧张素Ⅱ、炎性反应和2型糖尿病

以往临床研究发现高血压病患者发生2型糖尿病的风险增加,阻断肾素-血管紧张素系统(RAS)对于预防2型糖尿病的发生具有一定的保护作用.近期研究还表明,RAS可能直接参与了糖尿病发生发展过程.炎性反应是肥胖、2型糖尿病等代谢性疾病的重要分子基础.血管紧张素介导的氧化应激、炎性反应水平以及游离脂肪酸的增加在局部和全身都对机体产生重要的影响.     

Sleep,circadian rhythms,and type 2 diabetes mellitus

Over the last 60 years we have seen a significant rise in metabolic disease, especially type 2 diabetes. In the same period, the emergence of electricity and artificial lighting has allowed our behavioural cycles to be independent of external patterns of sunlight. This has led to a corresponding increase in sleep deprivation, estimated to be about 1 hour per night, as well as circadian misalignment (living against the clock). Evidence from experimental animals as well as controlled human subjects have shown that sleep deprivation and circadian misalignment can both directly drive metabolic dysfunction, causing diabetes. However, the precise mechanism by which these processes contribute to insulin resistance remains poorly understood. In this article, we will review the new literature in the field and propose a model attempting to reconcile the experimental observations made. We believe our model will serve as a useful point of reference to understand how metabolic dysfunction can emerge from sleep or circadian rhythm disruptions, providing new directions for research and therapy.     

Evaluation of the burden of type 2 diabetes mellitus in population of Puducherry,South India

AimsTo find out the prevalence of undiagnosed diabetes mellitus and the correlates among the adult population of Puducherry, South India.MethodsIn this population based cross-sectional study in the rural and urban field practice area of Mahatma Gandhi Medical College and Research Institute, Puducherry, by simple random sampling 1013 adults of 30 years and above, not on anti-diabetics drugs were included. Main outcome measures were the prevalence and correlates of undiagnosed diabetes mellitus among the adult population. Pre-designed and pre-tested questionnaire was used to elicit the information on family and individual socio-demographic variables. Height, weight, waist and hip circumference, blood pressure were measured and venous blood was collected to measure fasting blood glucose and blood cholesterol.ResultsOverall, 10.3% study subjects were diagnosed as diabetic. In univariate analysis age, dilatory habit, tobacco addiction, body mass index, waist hip ratio, hypertension, and total blood cholesterol were found statistically significant. In multivariate logistic regression (LR method) analysis age, residence, education, dietary habit, tobacco addiction, body mass index, waist hip ratio and total blood cholesterol were statistically significant.ConclusionsIn our study adults having increased age, urban residence, illiterate, non-vegetarian diet, tobacco addiction, obese and high total blood cholesterol were important correlates.     

Factor V Leiden mutation and type 1 diabetes mellitus.

Diabetes mellitus is considered to cause a tendency for arterial thrombosis. Recent studies addressed the association between venous and arterial disease. Resistance to activated protein C is one of the most common causes of venous thrombosis and linked to a single point mutation in the factor V gene, designated as factor V Leiden mutation. There is little information regarding the status of factor V Leiden mutation in type 1 diabetes. The aim of this study is to evaluate association among activated protein C sensitivity ratio, factor V Leiden mutation, and type 1 diabetes taking into account metabolic control, lipids and diabetic complications. The study population consisted of 47 healthy subjects (27.9 +/- 1.2 years) and 48 type 1 diabetic patients (27.9 +/- 1.1 years). Activated protein C sensitivity ratio was measured by activated partial thromboplastin time based assay. The presence of factor V Leiden mutation was determined by amplifying the fragments encompassing gene mutation by PCR. Mean normalized activated protein C sensitivity ratio values and prevalence of heterozygous factor V Leiden mutation were not significantly different between groups (1.08 +/- 0.03 and 6.3% in healthy subjects; 1.01 +/- 0.03 and 6.4% in type 1 diabetic patients, respectively). The activated protein C sensitivity ratio and factor V Leiden mutation were not found to be linked with metabolic control parameters, lipids and diabetic complications in type 1 diabetic patients. There was no association among factor V Leiden mutation, activated protein C sensitivity ratio and type 1 diabetes, metabolic control parameters as well as complications of diabetes. Although the propensity to thrombosis is increased in individuals with type 1 diabetes, activated protein C sensitivity ratio and factor V Leiden mutation do not appear to be significant determinants.     

解偶联蛋白2与2型糖尿病关系研究进展

2型糖尿病作为严重影响人类健康的慢性病、多发病,已经成为全球共同关注的健康及社会问题,其发病机制是目前研究的热点.最近,越来越多的研究者关注解偶联蛋白2(UCP2)与2型糖尿病的相关性,并且发现UCP2参与和影响2型糖尿病的发生、发展过程中的多个环节.