Mechanisms by which variants in the TCF7L2 gene increase the risk of developing Type 2 diabetes

Type 2 diabetes mellitus (T2DM) is a heterogeneous disease with a multifactorial aetiology comprising of genetic and environmental factors. The common variant most highly associated with T2DM known to date is a SNP rs7903146 in the TCF7L2 gene. However, the role TCF7L2 plays in the development of T2DM was unclear. Clinical, animal and in vitro studies have revealed an association of the risk T-allele of rs7903146 with impaired β cell function including glucose- and incretin-stimulated insulin secretion and β cell survival. The aim of this thesis is to elucidate the function of TCF7L2 in the β cells and explain the mechanisms by which genetic variants in TCF7L2 confer the increased risk of developing T2DM. TCF7L2 is a transcription factor of the WNT signalling pathway. Risk genotype carriers of rs7903146 displayed higher TCF7L2 mRNA expression in islets of Langerhans, reduced insulin content and perturbed glucose stimulated insulin secretion. We have identified a large number of target genes (study I) and target networks (study II) of TCF7L2 that regulate β cell survival, proinsulin expression and insulin maturation. The expression of many of these TCF7L2 target genes, including T2DM associated genes/loci, correlated with TCF7L2 mRNA expression in CC, but not in CT/TT genotype carriers in human pancreatic islets. These data indicate that TCF7L2 has a central role in insulin synthesis and secretion, as well as in the regulation of other T2DM associated genes. We provided a possible explanation for the large impact TCF7L2 has on the risk of T2DM. The molecular link between the T-risk allele and the diabetogenic action of TCF7L2 in β cells is still unclear. In vitro and animal experiments have indicated that the 92kb around rs7903146 locus is an enhancer region, and that the T-allele has a higher activity compared to the C-allele. In study III, we identified a protein (HMGB1) that binds the rs7903146 locus, which potentially influence this enhancer activity. At last, we have also investigated the function of different TCF7L2 splice variants and their influence on β cell function using Antisense Oligo Nucleotides (study IV). These results indicated that exon 4 of TCF7L2 has an inhibitory function, influencing both insulin synthesis and β cell survival

TCF7L2 is a master regulator of insulin production and processing

Genome-wide association studies have revealed >60 loci associated with type 2 diabetes (T2D), but the underlying causal variants and functional mechanisms remain largely elusive. Although variants in TCF7L2 confer the strongest risk of T2D among common variants by presumed effects on islet function, the molecular mechanisms are not yet well understood. Using RNA-sequencing, we have identified a TCF7L2-regulated transcriptional network responsible for its effect on insulin secretion in rodent and human pancreatic islets. ISL1 is a primary target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1, PCSK2 and SLC30A8, thereby providing evidence for a coordinated regulation of insulin production and processing. The risk T-allele of rs7903146 was associated with increased TCF7L2 expression, and decreased insulin content and secretion. Using gene expression profiles of 66 human pancreatic islets donors', we also show that the identified TCF7L2-ISL1 transcriptional network is regulated in a genotype-dependent manner. Taken together, these results demonstrate that not only synthesis of proinsulin is regulated by TCF7L2 but also processing and possibly clearance of proinsulin and insulin. These multiple targets in key pathways may explain why TCF7L2 has emerged as the gene showing one of the strongest associations with T2

N-1-methylnicotinamide is a signalling molecule produced in skeletal muscle coordinating energy metabolism

Obesity is a major health problem, and although caloric restriction and exercise are successful strategies to lose adipose tissue in obese individuals, a simultaneous decrease in skeletal muscle mass, negatively effects metabolism and muscle function. To deeper understand molecular events occurring in muscle during weight-loss, we measured the expressional change in human skeletal muscle following a combination of severe caloric restriction and exercise over 4 days in 15 Swedish men. Key metabolic genes were regulated after the intervention, indicating a shift from carbohydrate to fat metabolism. Nicotinamide N-methyltransferase (NNMT) was the most consistently upregulated gene following the energy-deficit exercise. Circulating levels of N-1-methylnicotinamide (MNA), the product of NNMT activity, were doubled after the intervention. The fasting-fed state was an important determinant of plasma MNA levels, peaking at similar to 18 h of fasting and being lowest similar to 3 h after a meal. In culture, MNA was secreted by isolated human myotubes and stimulated lipolysis directly, with no effect on glucagon or insulin secretion. We propose that MNA is a novel myokine that enhances the utilization of energy stores in response to low muscle energy availability. Future research should focus on applying MNA as a biomarker to identify individuals with metabolic disturbances at an early stage.Peer reviewe

Staphylococcus aureus Phenol-Soluble Modulins α1–α3 Act as Novel Toll-Like Receptor (TLR) 4 Antagonists to Inhibit HMGB1/TLR4/NF-κB Signaling Pathway

Phenol-soluble modulins (PSMs) have recently emerged as key virulence determinants, particularly in highly aggressive Staphylococcus aureus isolates. These peptides contribute to the pathogenesis of S. aureus infections, participating in multiple inflammatory responses. Here, we report a new role for S. aureus PSMs in high mobility group box-1 protein (HMGB1) induced inflammation by modulating toll-like receptor (TLR) 4 pathway. Direct ligation of TLR4 with S. aureus PSMα1–α3 and PSMβ1–β2 was identified by surface plasmon resonance. Remarkably, the binding affinity of TLR4 with HMGB1 was attenuated by PSMα1–α3. Further study revealed that PSMα1–α3 directly inhibited HMGB1-induced NF-κB activation and proinflammatory cytokines production in vitro using HEK-Blue hTLR4 cells and THP-1 cells. To analyze the molecular interactions between PSMs and TLR4, blast similarity search was performed and identified that PSMα1 and PSMβ2 were ideal templates for homology modeling. The three-dimensional structures of PSMα2, PSMα4, PSMβ1, and δ-toxin were successfully generated with MODELLER, and further refined using CHARMm. PSMs docking into TLR4 were done using ZDOCK, indicating that PSMα1–α3 compete with HMGB1 for interacting with the surrounding residues (336–477) of TLR4 domain. Our study reveals that S. aureus PSMα1–α3 can act as novel TLR4 antagonists, which account at least in part for the staphylococcal immune evasion. Modulation of this process will lead to new therapeutic strategies against S. aureus infections

Quercetin Prevents Intestinal Stem Cell Aging via Scavenging ROS and Inhibiting Insulin Signaling in <i>Drosophila</i>

Adult stem cells, a class of cells that possess self-renewal and differentiation capabilities, modulate tissue regeneration, repair, and homeostasis maintenance. These cells undergo functional degeneration during aging, resulting in decreased tissue regeneration ability and increased disease incidence. Thus, it is essential to provide effective therapeutic solutions to preventing the aging-related functional decline of stem cells. Quercetin (Que) is a popular natural polyphenolic flavonoid found in various plant species. It exhibits many beneficial effects against aging and aging-related diseases; however, its efficacy against adult stem cell aging remains largely unclear. Drosophila possesses a mammalian-like intestinal system with a well-studied intestinal stem cell (ISC) lineage, making it an attractive model for adult stem cell research. Here, we show that Que supplementation could effectively prevent the hyperproliferation of ISCs, maintain intestinal homeostasis, and prolong the lifespan in aged Drosophila. In addition, we found that Que could accelerate recovery of the damaged gut and improve the tolerance of Drosophila to stressful stimuli. Furthermore, results demonstrated that Que prevents the age-associated functional decline of ISCs via scavenging reactive oxygen species (ROS) and inhibiting the insulin signaling pathway. Overall, our findings suggest that Que plays a significant role in delaying adult stem cell aging

Knowledge and practices regarding diabetic retinopathy among diabetic patients registered in a chronic disease management system in eastern China.

PurposeTo investigate the knowledge and practices regarding diabetic retinopathy (DR) among diabetic patients included in a community-based primary health system (CBPHS) in China.MethodsDiabetic patients aged 18 years and above registered in the CBPHS in Yueqing city, Zhejiang province were recruited. Information obtained by questionnaire included: demographic and socioeconomic status, knowledge about DR, and ocular and medical history. The primary outcome was whether the participant knew that DM can affect the eyes, defined according to the question: "Do you know diabetes mellitus (DM) can affect eyes? (yes or no)". A knowledge score was calculated based on the responses to seven questions, with 1 point awarded for a correct response and 0 points for an incorrect or uncertain answer.ResultsA total of 1972 diabetic patients were included in the study with an average age of 65.2±10.8 years, 45.7% were male. One thousand two hundred and nineteen patients (61.8%) knew that DM can affect the eyes. Significant differences in age, education, income status, insurance covering eye care, fasting blood glucose, duration of DM, history of hypertension existed between subjects who knew and those who did not know that DM can affect the eyes (PConclusionsThe knowledge toward DR among DM patients were still low within the chronic disease management system in eastern China. Routine ophthalmic screening, health care promotions, and educational programs should be emphasized and implemented for better DR prevention and management

Radiotherapy of the Primary Disease for Synchronous Metastatic Cancer: A Systematic Review

In the case of synchronous metastatic disease, the local treatment of primary tumors by radiotherapy has long been reserved for palliative indications. The emergence of the concept of oligometastatic and oligopersistent diseases, the advent of new systemic therapies enabling longer overall survival with an enhanced quality of life, a better understanding of the biologic history of metastatic spread, and technical advances in radiation therapy are revolutionizing the management of patients with de novo metastatic cancer. The prognosis of these patients has been markedly improved and many studies have investigated the survival benefits from the local treatment of various primary tumors in cases of advanced disease at the time of diagnosis or in the case of oligopersistence. This article provides an update on the place of irradiation of the primary tumor in cancer with synchronous metastases, and discusses its interest through published or ongoing trials

High-FOM Temperature Sensing Based on Hg-EIT-Like Liquid Metamaterial Unit

High-performance temperature sensing is a key technique in modern Internet of Things. However, it is hard to attain a high precision while achieving a compact size for wireless sensing. Recently, metamaterials have been proposed to design a microwave, wireless temperature sensor, but precision is still an unsolved problem. By combining the high-quality factor (Q-factor) feature of a EIT-like metamaterial unit and the large temperature-sensing sensitivity performance of liquid metals, this paper designs and experimentally investigates an Hg-EIT-like metamaterial unit block for high figure-of-merit (FOM) temperature-sensing applications. A measured FOM of about 0.68 is realized, which is larger than most of the reported metamaterial-inspired temperature sensors

Role of TCF7L2 risk variant and dietary fibre intake on incident type 2 diabetes.

AIMS/HYPOTHESIS: The T allele of transcription factor 7-like 2 gene variant, TCF7L2 rs7903146, increases the risk of type 2 diabetes by 40-50%. As TCF7L2 rs7903146 has been associated with diminished incretin effect we investigated whether interaction between dietary intake of carbohydrate, fat, protein or fibre and this variant affects the risk of type 2 diabetes. METHODS: A cohort of 24,799 non-diabetic individuals from the Malmö Diet and Cancer Study (MDCS), with dietary data obtained by a modified diet history method, were followed up for 12 years, with 1,649 recordings of incident type 2 diabetes made. Risk of type 2 diabetes in strata of diet quintiles was analysed prospectively adjusting for potential confounders. Cross-sectional analyses were performed on baseline fasting glucose and HbA(1c) levels in a subset of 5,216 randomly selected individuals from the MDCS. RESULTS: The elevated risk of type 2 diabetes with rs7903146 (OR 1.44, 95% CI 1.33, 1.56, p = 4.6 × 10(-19)) increased with higher intake of dietary fibre (OR 1.24, 95% CI 1.04, 1.47 to OR 1.56, 95% CI 1.31, 1.86 from the lowest to highest quintile; p (interaction) = 0.049). High intake of dietary fibre was inversely associated with diabetes incidence only among CC genotype carriers (OR 0.74, 95% CI 0.58, 0.94 per quintile, p = 0.025). The T allele was associated with 0.027% elevated HbA(1c) (p = 0.02) and this effect increased with higher intake of fibre (from -0.021% to 0.079% for the lowest to the highest quintile, p (interaction) = 0.02). Each quintile of higher fibre intake was associated with lower HbA(1c) levels among CC and CT but not among TT genotype carriers (-0.036%, p = 6.5 × 10(-7); -0.023%, p = 0.009; and 0.012%, p = 0.52, respectively). CONCLUSIONS/INTERPRETATION: Our study suggests that dietary fibre intake may modify the association between TCF7L2 rs7903146 and incidence of type 2 diabetes, and that higher fibre intake may associate with protection from type 2 diabetes only among non-risk allele carriers