Genomics of type I diabetes mellitus and its late complications

In ethnic Russians, MHC (HLA) was shown to be the major locus determining the predisposition to type 1 diabetes mellitus (T1DM). To map the regions linked to T1DM, families with concordant or discordant sib pairs were selected from the Russian population of Moscow. With these families, linkage to T1DM was demonstrated for CTLA4 (IDDM12, 2q32.1-q33), which codes for a T-cell surface antigen, and PDCD2 (IDDM8, 6q25-q27), which is homologous to the mouse programmed cell death activator gene. With polymorphic microsatellites, regions 3q21-q25 (IDDM9) and 10p12.2 (IDDM10) were also linked to T1DM. Case/control and family studies of the polymorphic markers from region 11p13 revealed a new T1DM-associated locus in the vicinity of the catalase gene (CAT); linkage to this locus was not reported earlier for other populations. Diabetic polyneuropathy (DPN) proved to be associated with single-nucleotide polymorphisms Ala(-9)Val (SOD2), Arg213Gly (SOD3), and T(-262)C (CAT) and with a polymorphic microsatellite of the NOS2 promoter. Hence oxidative stress, which results from hyperglycemia, increased mitochondrial production of superoxide radicals, and insufficient activities of antioxidative enzymes, was assumed to play an important part in DPN development in T1DM. Diabetic nephropathy (DN) showed no association with the antioxidative enzyme genes. However, the association was observed for the insertion/deletion (I/D) polymorphism of ACE and the ecNOS34a/4b polymorphism of NOS3, two genes involved in controlling vascular tonicity, and for the I/D polymorphism of APOB and the epsilon 2/epsilon 3/epsilon 4 polymorphism of APOE, two genes involved in lipid transport. In addition, polymorphic microsatellites of chromosome 3q21-q25 proved to be closely associated with DN. The tightest association was established for D3S1550, carriers of allele 12 or genotype 12/14 having high risk of DN (OR = 4.85 and 6.25, respectively). Region 3q21-q25 was assumed to contain a major gene determining DN development, while the other DN-associated genes mostly affect the progression of DN.     

长链非编码RNA与糖尿病及其并发症

长链非编码RNA起初被认定是基因转录"噪音",随着DNA元件百科全书的研究进展发现,lnc RNA能以RNA的形式在表观遗传、转录以及转录后水平调控基因的表达,参与多种重要的生命调控过程,与人类疾病的发生发展和预防都有着紧密联系。文章介绍lnc RNA的功能和特点,结合对lnc RNA的研究思路,并在已有研究的基础上综述lnc RNA与糖尿病及其并发症的关系,这些研究进展将为进一步理解糖尿病及其发生发展的分子医学基础提供依据。     

The potential of adipokines as biomarkers and therapeutic agents for vascular complications in type 2 diabetes mellitus

Over the past decades, there has been a major increase in type 2 diabetes (T2D) prevalence in most regions of the world. Diabetic patients are more prone to cardiovascular complications. Accumulating evidence suggests that adipose tissue is not simply an energy storage tissue but it also functions as a secretory tissue producing a variety of bioactive substances, also referred to as adipokines. The balance between pro-inflammatory adipokines and protective adipokines is disturbed in type 2 diabetes, this can be regarded as adipose tissue dysfunction which partly promote the pathogenesis of diabetes complications. In this review, we not only discuss the favorable adipokines like adiponectin, omentin, C1q tumor necrosis factor-related proteins, but also unfavorable ones like resisitin and visfatin, in the aim of finding potential biomarkers recommended for the clinical use in the diagnosis, prognosis and follow up of patients with T2D at high risk of developing cardiovascular diseases as well as leading to new therapeutic approaches.     

Polymorphisms of chemokine and chemokine receptor genes in Type 1 diabetes mellitus and its complications

Cytokines and chemokines have been implicated in the pathogenesis of Type 1 diabetes mellitus (T1DM) and its microvascular complications. Recently, genetic variants of monocyte chemotactic protein-1 (MCP-1), CC-chemokine receptor 2 (CCR2), CC-chemokine receptor 5 (CCR5) genes have been identified. The aim was to investigate whether genetic variants of the MCP-1 G(-2518)A, CCR2B 64I, CCR5 G(59029)A, and CCR5 Delta32 are associated with T1DM and its microvascular complications. Two hundred and sixty patients with T1DM with and without diabetic microvascular complications, and 104 normal controls were recruited for this study. Genotypes of the MCP-1 G(-2518)A, CCR2B 64I, CCR5 G(59029)A, and CCR5 delta32 were performed by polymerase chain reaction followed by digestion with appropriate restriction endonucleases. Frequencies of the MCP-1 A(-2518) allele (74.6% vs. 63.5%, p < 0.003) and A/A genotype (54.5% vs. 34.6%, p < 0.001, Pc = 0.002) were significantly higher in patients with T1DM compared with normal controls. CCR5 G(59029) was slightly increased in the patients with microvascular complications compared with the uncomplicated (21.4% vs. 10%, p < 0.03, Pc = ns). The frequency of haplotype G/G/W was slightly increased in the patients with diabetic complications compared to the uncomplicated (39.6% vs. 28.8%, p < 0.02, Pc = ns). These results suggest that polymorphisms of the MCP-1, CCR2 and CCR5 genes may be associated with T1DM and its complications.     

Role of the Na/Ca exchanger on the development of diabetes mellitus and its chronic complications

Diabetes mellitus (DM) is a serious metabolic disorder with micro- and macrovascular complications that results in significant morbidity and mortality. It is well established that cytosolic Ca²⁺ play an important role in controlling insulin secretion in pancreatic β-cells. The Na⁺/Ca²⁺ exchanger (NCX), an ion transport protein, is expressed in the plasma membrane of virtually all animal cells. NCX is a reversible carrier that can mediate the transport of Ca²⁺ across the plasma membrane in both directions. Therefore, great efforts have been made to identify NCX associated with DM. NCX is expressed in several tissues, and acts in the protection against intracellular calcium overload; in the regulation of insulin secretion by beta cells, and in improving vascular endothelium-dependent relaxation. All these mechanisms are associated with DM pathogenesis and its chronic complications. Therefore, NCX is a candidate protein for the development of these disorders. Only a few studies investigated NCX in relation to chronic complications of diabetes, with inconclusive results.     

Targeting AMPK signaling pathway by natural products for treatment of diabetes mellitus and its complications

Diabetes affects a large population of the world. Lifestyle, obesity, dietary habits, and genetic factors contribute to this metabolic disease. A target pathway to control diabetes is the 5′-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. AMPK is a heterotrimeric protein with α, β, and γ subunits. In several studies, AMPK activation enhanced glucose uptake into cells and inhibited intracellular glucose production. Impairment of AMPK activity is present in diabetes, according to some studies. Drugs used in the treatment of diabetes, such as metformin, are also known to act through regulation of AMPK. Thus, drugs that activate and regulate AMPK are potential candidates for the treatment of diabetes. In addition, many patients encounter important adverse effects, like hypoglycemia, while using allopathic drugs. As a result, the investigation of plant-derived natural drugs that lack adverse side effects and treat diabetes is necessary. Natural products like berberine, quercetin, resveratrol, and so forth have shown significant potential in regulating and activating the AMPK pathway which can lead to manage diabetes mellitus and its complications.     

The pathogenesis of diabetes mellitus. Possible usefulness of spontaneous hyperglycemic syndromes in animals.

Systematic studies of the patterns of anatomic distribution, pathways of probable spread, and prognosis of the malignant lymphomas have been greatly aided by the development of new histopathologic classifications and the introduction of more sophisticated and precise diagnostic techniques, such as lymphangiography and laparotomy with splenectomy and retroperitoneal node biopsy. Concomitantly, megavoltage radiotherapy apparatus has made total-lymphoid radiotherapy feasible and practical, and the availability of a widening spectrum of chemotherapeutic agents has ushered in a new era of combination chemotherapy. Collectively, these diagnostic and therapeutic advances have already begun to yield a dramatic improvement in the prognosis of Hodgkin''s disease and the other malignant lymphomas.     

The potential role of albumin glycation by ribose in diabetes mellitus

<正>Human serum albumin (HSA) is one of the most abundant plasma proteins and accounts for 50%–60%of total plasma proteins. HSA has various physiological and biochemical properties, undergoing different structural and conformational changes, which involves transport and ligand-binding characteristics, enzyme activities, and antioxidant properties(Rabbani and Ahn, 2019).     

The complex role of Wnt ligands in type 2 diabetes mellitus and related complications

Type 2 diabetes mellitus (T2DM) is one of the major chronic diseases, whose prevalence is increasing dramatically worldwide and can lead to a range of serious complications. Wnt ligands (Wnts) and their activating Wnt signalling pathways are closely involved in the regulation of various processes that are important for the occurrence and progression of T2DM and related complications. However, our understanding of their roles in these diseases is quite rudimentary due to the numerous family members of Wnts and conflicting effects via activating the canonical and/or non-canonical Wnt signalling pathways. In this review, we summarize the current findings on the expression pattern and exact role of each human Wnt in T2DM and related complications, including Wnt1, Wnt2, Wnt2b, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, Wnt8a, Wnt8b, Wnt9a, Wnt9b, Wnt10a, Wnt10b, Wnt11 and Wnt16. Moreover, the role of main antagonists (sFRPs and WIF-1) and coreceptor (LRP6) of Wnts in T2DM and related complications and main challenges in designing Wnt-based therapeutic approaches for these diseases are discussed. We hope a deep understanding of the mechanistic links between Wnt signalling pathways and diabetic-related diseases will ultimately result in a better management of these diseases.     

1533例2型糖尿病患者合并症与并发症的调查分析

目的:了解上海地区门诊糖尿病患者的各种慢性合并症与并发症及其相关危险因素.方法:调查我院门诊糖尿病患者1533例,记录慢性合并症、并发症及各种相关危险因素并进行相关的统计分析.结果:上海地区糖尿病患者的各种慢性合并症与并发症的发生率由高到低依次为周围血管病变67.0%,高血压63.2%,血脂紊乱45.1%,家族糖尿病34.8%,高尿酸血症29.O%,视网膜病变28.0%,脂肪肝27.1%,糖尿病肾病21.1%.女性患者高尿酸血症、脂肪肝、家族糖尿病史发生率高于男性,各种慢性合并症与并发症多随年龄与病程的增加而升高.结论:上海地区门诊糖尿病患者各种慢性合并症与并发症的发病率较高,定期监测并联合控制血糖、血压、血脂水平是防治各种慢性合并症与并发症的关键.     

The role of ncRNAs-mediated pyroptosis in diabetes and its vascular complications

Over the past decade, the prevalence of diabetes has increased significantly worldwide, leading to an increase in vascular complications of diabetes (VCD), such as diabetic cardiomyopathy (DCM), diabetic nephropathy (DN), and diabetic retinopathy (DR). Noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long Noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), play a key role in cellular processes, including the pathophysiology of diabetes and VCD via pyroptosis. ncRNAs (e.g., miR-17, lnc-MEG3, and lnc-KCNQ1OT1) can regulate pyroptosis in pancreatic β cells. Some ncRNAs are involved in VCD progression. For example, miR-21, lnc-KCNQ1OT1, lnc-GAS5, and lnc-MALAT1 were reported in DN and DCM, and lnc-MIAT was identified in DCM and DR. Herein, this review aimed to summarize recent research findings related to ncRNAs-mediated pyroptosis at the onset and progression of diabetes and VCD.     

Biophotonics methods for functional monitoring of complications of diabetes mellitus

The prevalence of diabetes complications is a significant public health problem with a considerable economic cost. Thus, the timely diagnosis of complications and prevention of their development will contribute to increasing the length and quality of patient life, and reducing the economic costs of their treatment. This article aims to review the current state‐of‐the‐art biophotonics technologies used to identify the complications of diabetes mellitus and assess the quality of their treatment. Additionally, these technologies assess the structural and functional properties of biological tissues, and they include capillaroscopy, laser Doppler flowmetry and hyperspectral imaging, laser speckle contrast imaging, diffuse reflectance spectroscopy and imaging, fluorescence spectroscopy and imaging, optical coherence tomography, optoacoustic imaging and confocal microscopy. Recent advances in the field of optical noninvasive diagnosis suggest a wider introduction of biophotonics technologies into clinical practice and, in particular, in diabetes care units.     

The use of taurine analogues to investigate taurine functions and their potential therapeutic applications

Summary.  Despite the multitude of evidence for the beneficial effects of taurine supplementation in a variety of disease, the underlying modifying action of taurine with respect to either molecular or biochemical mechanisms is almost totally unknown. We have assessed the development of taurine analogues, particularly where there has been substitution at the suphonate or amine group. Such substitutions allow the investigator to probe the relationship between structure and function of the taurine molecule. In addition such studies should help to ascertain taurine's point of interaction with the effector molecule. These results will prepare the way for the development of the second generation of taurine analogues. Received January 2, 2002 Accepted January 28, 2002 Published online August 30, 2002 Acknowledgements This research has been funded by the COST Chemistry programmes COST D8 “Chemistry of Metals in Medicine” and D-13 “New Molecules for Human Health Care”. All of the authors are members of the Working Group D13/0011/00 “Investigation of mechanisms underlying the pharmacological actions of taurine upon cell apoptosis and calcium homeostasis”. Authors' address: Dr. R.J. Ward, Unite de Biochimie, Catholic Universite de Louvain, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium, E-mail: ward@bioc.ucl.ac.be     

Monitoring the occurrence of diabetes mellitus and its major complications: the combined use of different administrative databases

Background

The high glucose levels typically occurring among adults with type 2 diabetes contribute to blood vessel injury and complications such as blindness, kidney failure, heart disease, and stroke. Higher physical activity levels are associated with improved glycemic control, as measured by hemoglobin A1C. A 1% absolute increase in A1C is associated with an 18% increased risk for heart disease or stroke. Among Canadians with type 2 diabetes, we postulate that declines in walking associated with colder temperatures and inclement weather may contribute to annual post-winter increases in A1C levels.

Methods

During this prospective cohort study being conducted in Montreal, Quebec, Canada, 100 men and 100 women with type 2 diabetes will undergo four assessments (once per season) over a one-year period of observation. These assessments include (1) use of a pedometer with a concealed viewing window for a two-week period to measure walking (2) a study centre visit during which venous blood is sampled for A1C, anthropometrics are assessed, and questionnaires are completed for measurement of other factors that may influence walking and/or A1C (e.g. food frequency, depressive symptomology, medications). The relationship between spring-fall A1C difference and winter-summer difference in steps/day will be examined through multivariate linear regression models adjusted for possible confounding. Interpretation of findings by researchers in conjunction with potential knowledge "users" (e.g. health professionals, patient groups) will guide knowledge translation efforts.

Discussion

Although we cannot alter weather patterns to favour active lifestyles, we can design treatment strategies that take seasonal and weather-related variations into account. For example, demonstration of seasonal variation of A1C levels among Canadian men and women with T2D and greater understanding of its determinants could lead to (1) targeting physical activity levels to remain at or exceed peak values achieved during more favourable weather conditions. Strategies may include shifting to indoor activities or adapting to less favourable conditions (e.g. appropriate outdoor garments, more frequent but shorter duration periods of activity) (2) increasing dose/number of glucose-lowering medications during the winter and reducing these during the summer, in anticipation of seasonal variations (3) examining the impact of bright light therapy on activity and A1C among T2D patients with an increase in depressive symptomology when sunlight hours decline.     

COX-2与糖尿病并发症关系研究进展

糖尿病是一种慢性、低度炎症性疾病。多种因素刺激下,环氧化酶COX-2在胰岛及多种组织中高水平表达。它通过与炎症因子和炎症介质,如一氧化氮、核因子-κB、前列腺素E等相互作用,对相应组织产生作用,从而促进了糖尿病并发症的发生和发展。对COX-2的研究可进一步揭示糖尿病并发症发生的分子机制,为预防和治疗糖尿病并发症提供新的思路。     

Diabetes mellitus and its complications in a Hungarian population

The aim of this study was to examine the disease characteristics and complications of diabetes mellitus in patients in a Hungarian rural community. Data relating to age, sex, date of onset of diabetes, fasting blood glucose values and all diseases associated with diabetics were retrieved from the medical records of patients. Almost six percent (5.7%) of the population has diabetes mellitus. The percentage of Type I diabetic patients in this population was 5.8 percent. The prevalence of diabetes was slightly but not significantly higher in females than in males. The mean age of the diabetic population was 52.1 +/- 11.3 for male and 53.47 +/- 15.7 for the female patients. The peak age of onset of diabetes mellitus was in the sixth decade of life. The mean fasting blood sugar value was 10.64 +/- 0.6 and 10.57 +/- 0.5 mmol L(-1), in male and female diabetic patients (n = 103), respectively. Diabetic patients presented with many signs and symptoms in the general practice setting. The findings of this study showed that diabetics present with many disease conditions and signs and symptoms in the general practice setting. Many of these conditions are known to be associated with diabetes while others are not. As a result of the adverse effects of diabetes mellitus on the cardiovascular system and on body metabolism as a whole, the damage and morbidity caused by diabetes mellitus may have been underestimated. The results of this study have shed light on the unrecognised complications of diabetes mellitus.