A genetic link between type 2 diabetes and prostate cancer

Epidemiological studies suggest that men with type 2 diabetes are less likely than non-diabetic men to develop prostate cancer. The cause of this association is not known. Recent genetic studies have highlighted a potential genetic link between the two diseases. Two studies have identified a version (allele) of a variant in the HNF1B (also known as TCF2) gene that predisposes to type 2 diabetes, and one of them showed that the same allele protects men from prostate cancer. Other, separate, studies have identified different variants in the JAZF1 gene, one associated with type 2 diabetes, another associated with prostate cancer. These findings are unlikely to completely explain the epidemiological association between the two diseases but they provide new insight into a possible direct causal link, rather than one that is confounded or biased in some way.     

Insulin resistance--a common link between type 2 diabetes and cardiovascular disease

Evidence suggests that diabetes and cardiovascular disease (CVD) may share an underlying cause(s), a theory known as the 'common soil' hypothesis. Insulin resistance is central both to the progression from normal glucose tolerance to type 2 diabetes and to a constellation of cardiovascular risk factors known as the metabolic syndrome. These risk factors include visceral obesity and dyslipidaemia characterized by low levels of high-density lipoprotein cholesterol, hypertriglyceridaemia and raised small dense low-density lipoprotein particle levels. Changes in adipose tissue mass and metabolism may link insulin resistance and visceral obesity, a condition that is common in type 2 diabetes. Furthermore, weight reduction, increased physical activity, metformin and acarbose have been shown to reduce the development of type 2 diabetes in genetically predisposed subjects and may decrease the high cardiovascular risk of patients with diabetes. Some fatty acid derivatives can affect energy metabolism by activating peroxisome proliferator-activated receptors (PPARs), nuclear receptors that play a key role in energy homeostasis. These receptors represent an ideal therapeutic target for reducing cardiovascular risk, because they are involved in the regulation of both insulin action and lipid metabolism. In addition to lifestyle changes, PPARgamma agonists such as thiazolidinediones are frequently beneficial and have been shown to ameliorate insulin resistance, while activation of PPARalpha (e.g. by fibrates) can lead to improvements in free fatty acid oxidation and lipid profile, and a reduction in cardiovascular events. The development of agents with both PPARalpha and PPARgamma activity promises added benefits with amelioration of insulin resistance, delayed progression to and of type 2 diabetes and a reduction of CVD.     

Chemerin: a potential endocrine link between obesity and type 2 diabetes

Obesity and type 2 diabetes have reached epidemic levels and account for a substantial portion of the annual health expenditures of developed nations. While there is an abundance of epidemiological evidence demonstrating that obesity is a primary risk factor for developing type 2 diabetes, the mechanism(s) underlying this linkage are not completely understood. Given the enormous impact of these disorders on global health, considerable research effort has been devoted to elucidate the pathophysiological relationship between these two disorders. Two factors believed to contribute to the causal link between obesity and type 2 diabetes are chronic inflammation and altered secretion of adipose-derived signaling molecules (adipokines). Independent lines of investigation have implicated the novel adipokine chemerin as a regulator of adipogenesis, inflammation, and glucose metabolism through interactions with the cognate cell surface receptor chemokine-like receptor 1. Increased levels of chemerin that occur with obesity are hypothesized to be a causal factor in the development of type 2 diabetes as a consequence of dysregulation of the key physiological processes regulated by this adipokine. This review summarizes current research on the biological roles of chemerin and chemokine-like receptor 1, and highlights key questions to guide future research on the role of this adipokine in mediating obesity and the development of type 2 diabetes.     

Inflammation as a link between obesity,metabolic syndrome and type 2 diabetes

It is recognized that a chronic low-grade inflammation and an activation of the immune system are involved in the pathogenesis of obesity-related insulin resistance and type 2 diabetes. Systemic inflammatory markers are risk factors for the development of type 2 diabetes and its macrovascular complications. Adipose tissue, liver, muscle and pancreas are themselves sites of inflammation in presence of obesity. An infiltration of macrophages and other immune cells is observed in these tissues associated with a cell population shift from an anti-inflammatory to a pro-inflammatory profile. These cells are crucial for the production of pro-inflammatory cytokines, which act in an autocrine and paracrine manner to interfere with insulin signaling in peripheral tissues or induce β-cell dysfunction and subsequent insulin deficiency. Particularly, the pro-inflammatory interleukin-1β is implicated in the pathogenesis of type 2 diabetes through the activation of the NLRP3 inflammasome. The objectives of this review are to expose recent data supporting the role of the immune system in the pathogenesis of insulin resistance and type 2 diabetes and to examine various mechanisms underlying this relationship. If type 2 diabetes is an inflammatory disease, anti-inflammatory therapies could have a place in prevention and treatment of type 2 diabetes.     

Endothelial perturbation: a link between non-dipping and retinopathy in type 2 diabetes?

Reduced diurnal blood pressure (BP) variation (“non-dipping”) is associated with both micro- and macrovascular complications in patients with type 2 diabetes. The relation between endothelial perturbation and diurnal BP variation in diabetic subjects has not previously been studied. Seventy-six subjects, stratified to 4 gender-, age-, and duration-matched groups of 19 subjects each, were studied (group A: non-diabetic subjects; group B to D, type 2 diabetic subjects; group B: no retinopathy; group C: minimal background retinopathy; group D: diabetic maculopathy). All subjects underwent a 24-hour ambulatory BP monitoring. von Willebrand factor (vWF), fibrinogen, E-selectin, and intercellular adhesion molecule-1 were measured in plasma. Systolic night/day BP ratio increased gradually in groups A to D: 85.2 ± 5%, 85.7 ± 7%, 88.5 ± 6%, and 90.5 ± 7%, respectively, P < .05. Among diabetic patients, non-dippers had significantly higher plasma levels of vWF and fibrinogen than dippers (median/interquartile range 1.7/1.4 to 2.1 vs. 1.2/0.9 to 1.5 U/mL, P < .01 and 3.6/3.6 to 3.7 vs. 2.9/2.5 to 3.6 g/L, P = .01). Non-dipping is associated with elevated plasma levels of proteins related to endothelial cell activation as well as with retinopathy in subjects with type 2 diabetes. This finding suggests a possible mechanism linking non-dipping with microvascular complications in these subjects.     

Environmental and genetical aspects of the link between pregnancy, birth size, and type 2 diabetes

Exposure of the fetus to the intrauterine milieu can have profound effects on the health of the offspring in adulthood. These observations are highly reproducible in many populations worldwide although the mechanisms behind them remain elusive. The 'thrifty phenotype' hypothesis proposes that poor fetal nutrition leads to programming of metabolism and an adult phenotype that is adapted to poor but not plentiful nutrition. Results of a series of studies demonstrate the powerful influence of the mother's metabolic state on whether the emerging adult develops obesity and hyperinsulinemia. Importantly, these attributes can be passed on to the next generation non-genetically and can be reversed and prevented. Such hypothesis has been expanded on by the "Developmental Origins of Health and Disease" (DOHaD) hypothesis which describes the origin of adult disease in terms of fetal developmental 'plasticity' or the ability of the fetus to respond to poor in-utero conditions. A wealth of epidemiological evidence has provided a convincing link between a sub-optimal gestational environment and an increased propensity to develop adult onset metabolic disease. In this paper the factors that participate in the programming of the fetus and infants that lead to endocrine dysfunction in postnatal life are reviewed.     

The link between metabolic abnormalities and endothelial dysfunction in type 2 diabetes: an update

Despite abundant clinical evidence linking metabolic abnormalities to diabetic vasculopathy, the molecular basis of individual susceptibility to diabetic vascular complications is still largely undetermined. Endothelial dysfunction in diabetes-associated vascular complications is considered an early stage of vasculopathy and has attracted considerable research interests. Type 2 diabetes is characterized by metabolic abnormalities, such as hyperglycemia, excess liberation of free fatty acids (FFA), insulin resistance and hyperinsulinemia. These abnormalities exert pathological impact on endothelial function by attenuating endothelium-mediated vasomotor function, enhancing endothelial apoptosis, stimulating endothelium activation/endothelium–monocyte adhesion, promoting an atherogenic response and suppressing barrier function. There are multiple signaling pathways contributing to the adverse effects of glucotoxicity on endothelial function. Insulin maintains the normal balance for release of several factors with vasoactive properties. Abnormal insulin signaling in the endothelium does not affect the whole-body glucose metabolism, but impairs endothelial response to insulin and accelerates atherosclerosis. Excessive level of FFA is implicated in the pathogenesis of insulin resistance. FFA induces endothelial oxidative stress, apoptosis and inflammatory response, and inhibits insulin signaling. Although hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia independently contribute to endothelial dysfunction via various distinct mechanisms, the mutual interactions may synergistically accelerate their adverse effects. Oxidative stress and inflammation are predicted to be among the first alterations which may trigger other downstream mediators in diabetes associated with endothelial dysfunction. These mechanisms may provide insights into potential therapeutic targets that can delay or reverse diabetic vasculopathy.     

Systemic exposure to Pseudomonal bacteria: a potential link between type 1 diabetes and chronic inflammation

Bacterial endotoxins have been associated with chronic inflammation and the development and progression of diabetic nephropathy. We hypothesized that subjects with high serum lipopolysaccharide activity also carry remains of bacterial DNA in their system. Serum-derived bacterial DNA clones were isolated and identified from 10 healthy controls and 14 patients with type 1 diabetes (T1D) using universal primers targeted to bacterial 16S rDNA. A total of 240 clones representing 35 unique bacterial species were isolated and identified. A significant proportion of the isolated bacteria could be assigned to our living environment. Proteobacteria was by far the most prevalent phylum among the samples. Notably, the patients had significantly higher frequencies of Stenotrophomonas maltophilia clones in their sera compared to the healthy controls. Real-time PCR analysis of S. maltophilia and Pseudomonas aeruginosa flagellin gene copy number in the human leukocyte DNA fraction revealed that the overall Pseudomonal bacterial load was higher in older patients with T1D. Serum IgA- and IgG-antibody levels against Pseudomonal bacteria Delftia acidovorans, P. aeruginosa, and S. maltophilia were also determined in 200 healthy controls and 200 patients with T1D. The patients had significantly higher serum levels of IgA antibodies against all three Pseudomonal bacteria. Additionally, the IgA antibodies against Pseudomonal bacteria correlated significantly with serum C-reactive protein. These findings indicate that recurrent or chronic Pseudomonal exposure may increase susceptibility to chronic inflammation in patients with T1D.     

Platelets microparticles as a link between micro- and macro-angiopathy in young patients with type 1 diabetes

The development of vasculopathies in diabetes involves multifactorial processes. Increased levels of platelets-derived microparticles (PMPs) have been reported in diseases associated with thrombotic risk, but few data are available in diabetes. We explored the level of PMPs in young patients with type 1 diabetes in relation to inflammation, glycemic control, micro-vascular complications and carotid intima media thickness (CIMT). Eighty children and adolescents with type 1 diabetes were divided into two groups according to the presence of micro-vascular complications and compared with 40 healthy controls. Patients were subjected to medical history, clinical examination and assessment of high-sensitivity C-reactive protein (hs-CRP), HbA1c, urinary albumin creatinine ratio (UACR), flow cytometric analysis for PMPs using anti-CD41b and CIMT. PMP levels were significantly increased in all patients with type 1 diabetes (2.92?±?1.3%) whether with micro-vascular complications (3.46?±?1.11%) or those without complications (2.37?±?1.28%) compared with healthy controls (1.28?±?0.64%; p?<?0.001). CIMT was significantly elevated in all patients, and the highest levels were among those with micro-vascular complications (p?<?0.001). Significant positive correlations were found between PMPs and body mass index, HbA1c, serum creatinine, total cholesterol, UACR, hs-CRP and CIMT (p?<?0.05). Multiple linear regression analysis showed that HbA1c, UACR, hs-CRP and CIMT were independently related to PMPs levels in type 1 diabetes. According to Receiver operating characteristic curve analysis, the cutoff value of PMPs at 2.48% could differentiate patients with and without micro-vascular complications with a sensitivity of 80% and specificity of 73.3%. PMPs are elevated in patients with type 1 diabetes and can be considered as an early marker of micro-vascular complications and subclinical atherosclerosis.     

MicroRNAs 103 and 107 link type 2 diabetes and post-menopausal breast cancer

Type 2 diabetes mellitus (T2DM) increases the incidence of post-menopausal breast cancer (PMBC). This study is intended to determine whether microRNA-103/107 (miR-103/107) should be regarded as a potential molecular link between T2DM and PMBC. Samples of serum from 90 patients with T2DM and/or PMBC were collected. Samples of serum from 20 non-diabetic post-menopausal women were used as the control. The body mass index (BMI) of patients with T2DM and PMBC was lower than the BMI of patients with only T2DM or PMBC (p?<?0.05). The expression of miR-103/107 was higher in the serum of T2DM patients compared with that in control samples (2.80?±?0.46/36.29?±?3.41 vs 0.88?±?0.25/8.59?±?1.91, p?<?0.05). The expression of miR-103/107 in the serum of PMBC patients was higher than that in T2DM patients (5.06?±?0.92/49.59?±?6.99 vs 2.80?±?0.46/36.29?±?3.41, p?<?0.05) but lower than that in patients diagnosed with both T2DM and PMBC (7.67?±?0.87/63.24?±?8.58, p?<?0.05). miR-103/107 was positively correlated with the homeostasis model assessment-insulin resistance (HOMA-IR) index (r?=?0.71, 0.685, p?<?0.01). The expression of miR-103/107 was an independent factor of the HOMA-IR index (β?=?0.638, 0.073, p?=?0.02, 0.01). There were higher levels of estradiol (E2) in patients with T2DM and/or PMBC than that in the control group. High expression of miR-103/107 results in insulin resistance and is associated with overweight or obese patients with T2DM and PMBC through elevated levels of E2. miR-103/107 may be a potential molecular link between T2DM and PMBC.     

IGRP与1型糖尿病的关系

1型糖尿病是由T细胞介导的自身免疫性疾病.许多研究表明,抗原特异性的CD4~+和CD8~+T细胞在1型糖尿病的发病过程中起重要作用.胰岛细胞特异性葡萄糖-6-磷酸酶催化亚基相关蛋白(IGRP)作为1型糖尿病的主要自身抗原之一,是葡萄糖-6-磷酸酶蛋白家族中的一员,在人和非肥胖糖尿病鼠胰腺中均有表达.它在胰岛β细胞的代谢过程中起重要作用,但是确切机制仍不清楚.IGRP的研究将有助于探索1型糖尿病诊断和治疗的新方法.     

PAI-1基因多态性与2型糖尿病的相关性

目的分析2型糖尿病患者（T2DM）纤溶酶原激活物抑制物（PAI）-1基因型及分布频率,探讨PAI-1基因多态性与T2DM的关系。方法观察组为34例T2DM患者,对照组为39例健康体检正常者,采用等位基因特异性引物PCR扩增技术检测各组人群PAI-1基因多态性,两组人群血浆PAI-1含量检测采用美国USCNLIFE原装人PAI-1 ELISA试剂盒,酶标仪450nm波长下测定吸光度（OD值）,两次平行测定取均值计算样品PAI．1水平。结果观察组与对照组相比PAI-1基因型频率及等位基因频率均有显著性差异（r=24．127,P〈0．001;X^2=7．312,P〈0．05）。观察组4G等位基因频率明显高于对照组,有显著性差异（X^2=6．280,P〈0．05）。观察组血浆PAI-1水平明显高于对照组（t=10．7,P〈0．01）,观察组内比较4G／4G者血浆PAI-1含量明显高于4G／5G和5G／5G者,有显著性差异（F=21．02,P〈0．001）。结论PAI-1基因多态性与T2DM间存在一定的关联性,其中4C等位基因可能是T2DM发病的危险因子。     

IGRP与1型糖尿病的关系

Type 1 diabetes is a T cell-mediated autoimmune disease. Many studies have suggested that both CD4~+ and CD8~+ T cells are involved in the pathogenesis of type 1 diabetes. Islet-specific glucose-6-phosphatase catalytic subunit related peptide (IGRP) ,which is recognized as a major autoantigen for autoim-mune type 1 diabetes, is a member of the glucose-6-phosphatsse family. IGRP is expressed in the pancreas of both human and NOD mice and is thought to have a role in islet β cell metabolism. However,its exact func-tion has not yet been defined. The research of IGRP will help to explore new methods of the diagnosis and treatment of type 1 diabetes.     

IGRP与1型糖尿病的关系

Type 1 diabetes is a T cell-mediated autoimmune disease. Many studies have suggested that both CD4~+ and CD8~+ T cells are involved in the pathogenesis of type 1 diabetes. Islet-specific glucose-6-phosphatase catalytic subunit related peptide (IGRP) ,which is recognized as a major autoantigen for autoim-mune type 1 diabetes, is a member of the glucose-6-phosphatsse family. IGRP is expressed in the pancreas of both human and NOD mice and is thought to have a role in islet β cell metabolism. However,its exact func-tion has not yet been defined. The research of IGRP will help to explore new methods of the diagnosis and treatment of type 1 diabetes.     

Link between obesity and type 2 diabetes

The relationship between obesity and diabetes is of such interdependence that the term 'diabesity' has been coined. The passage from obesity to diabetes is made by a progressive defect in insulin secretion coupled with a progressive rise in insulin resistance. Both insulin resistance and defective insulin secretion appear very prematurely in obese patients, and both worsen similarly towards diabetes. Thus, the classic 'hyperbolic relationship' between insulin resistance and insulin secretion and the 'glucose allostasis concept' remain prevailing concepts in this particular field of knowledge. An increase in overall fatness, preferentially of visceral as well as ectopic fat depots, is specifically associated with insulin resistance. The accumulation of intramyocellular lipids may be due to reduced lipid oxidation capacity. The ability to lose weight is related to the capacity to oxidize fat. Thus, a relative defect in fat oxidation capacity is responsible for energy economy and hampered weight loss.     

Assessment of the association between glycemic variability and diabetes-related complications in type 1 and type 2 diabetes

Chronic hyperglycemia is the main risk factor for the development of diabetes-related complications in both type 1 and type 2 diabetes, but it is thought that frequent or large glucose fluctuations may contribute independently to diabetes-related complications.     

磺脲受体1基因多态性与2型糖尿病相关性家系研究

依据传递不平衡法(TDT)对上海地区55个2型糖尿病家系进行磺脲受体1(SUR1)基因多态性分析及临床表型联系分析,未发现SUR1基因的多态性和突变与上海地区2型糖尿病连锁的证据,但其对胰岛素、C肽水平有一定影响。