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The Meta-Analysis of Glucose and Insulin related traits Consortium (MAGIC) recently identified 16 loci robustly associated with fasting glucose, some of which were also associated with type 2 diabetes. The purpose of our study was to explore the role of these variants in South Asian populations of Punjabi ancestry, originating predominantly from th...
Citations
... [11][12][13] Numerous genome-wide association studies have further implicated GLIS3 as a risk locus for the development of both Type 1 and Type 2 diabetes. [14][15][16][17][18][19][20][21] Previous studies have shown that oxidative stress resulting from chronically elevated glucose concentrations decreased the expression or DNA binding activities of Pdx1 and MafA within pancreatic β cells but little is known about the effects of glucotoxicity on Glis3 expression and function. [22][23][24][25][26] In this report, Glis3 transcription was shown to be dramatically decreased in INS1 (832/13) cells maintained under conditions of chronically elevated glucose. ...
Chronically elevated levels of glucose are deleterious to pancreatic β cells and contribute to β cell dysfunction, which is characterized by decreased insulin production and a loss of β cell identity. The Krüppel-like transcription factor, Glis3 has previously been shown to positively regulate insulin transcription and mutations within the Glis3 locus have been associated with the development of several pathologies including type 2 diabetes mellitus. In this report, we show that Glis3 is significantly downregulated at the transcriptional level in INS1 832/13 cells within hours of being subjected to high glucose concentrations and that diminished expression of Glis3 is at least partly attributable to increased oxidative stress. CRISPR/Cas9-mediated knockdown of Glis3 indicated that the transcription factor was required to maintain normal levels of both insulin and MafA expression and reduced Glis3 expression was concomitant with an upregulation of β cell disallowed genes. We provide evidence that Glis3 acts similarly to a pioneer factor at the insulin promoter where it permissively remodels the chromatin to allow access to a transcriptional regulatory complex including Pdx1 and MafA. Finally, evidence is presented that Glis3 can positively regulate MafA transcription through its pancreas-specific promoter and that MafA reciprocally regulates Glis3 expression. Collectively, these results suggest that decreased Glis3 expression in β cells exposed to chronic hyperglycemia may contribute significantly to reduced insulin transcription and a loss of β cell identity.
... Multiple SNPs have been identified in human ADCY5 and are linked to various disorders such as diabetes 25 , obesity 26 and central nervous system disorders 27 (Fig. 4a). Many of the SNPs are in regions known to be involved in modulation of AC activity, including six in the coiled-coil domain (Fig. 4b), six in C 1b (Fig. 4c) and ten in the catalytic domains (Fig. 4d). ...
The nine different membrane-anchored adenylyl cyclase isoforms (AC1–9) in mammals are stimulated by the heterotrimeric G protein, Gαs, but their response to Gβγ regulation is isoform specific. In the present study, we report cryo-electron microscope structures of ligand-free AC5 in complex with Gβγ and a dimeric form of AC5 that could be involved in its regulation. Gβγ binds to a coiled-coil domain that links the AC transmembrane region to its catalytic core as well as to a region (C1b) that is known to be a hub for isoform-specific regulation. We confirmed the Gβγ interaction with both purified proteins and cell-based assays. Gain-of-function mutations in AC5 associated with human familial dyskinesia are located at the interface of AC5 with Gβγ and show reduced conditional activation by Gβγ, emphasizing the importance of the observed interaction for motor function in humans. We propose a molecular mechanism wherein Gβγ either prevents dimerization of AC5 or allosterically modulates the coiled-coil domain, and hence the catalytic core. As our mechanistic understanding of how individual AC isoforms are uniquely regulated is limited, studies such as this may provide new avenues for isoform-specific drug development.
... Multiple single nucleotide polymorphisms (SNPs) have been identified in human ADCY5 and are linked to various disorders such as diabetes 25 , obesity 26 , and central nervous system disorders 27 (Fig. 4A). Many of the SNPs are in regions known to be involved in modulation of AC activity, including six in the coiled-coil domain (Fig. 4B), six in C1b (Fig. 4C), and ten in the catalytic domains (Fig. 4D). ...
The nine different membrane-anchored adenylyl cyclase isoforms (AC1-9) in mammals are stimulated by the heterotrimeric G protein Gα s , but their response to Gβγ regulation is isoform-specific. For example, AC5 is conditionally activated by Gβγ. Here, we report cryo-EM structures of ligand-free AC5 in complex with Gβγ and of a dimeric form of AC5 that could be involved in its regulation. Gβγ binds to a coiled-coil domain that links the AC transmembrane region to its catalytic core as well as to a region (C1b) that is known to be a hub for isoform-specific regulation. We confirmed the Gβγ interaction with both purified proteins and cell-based assays. The interface with Gβγ involves AC5 residues that are subject to gain-of-function mutations in humans with familial dyskinesia, indicating that the observed interaction is important for motor function. A molecular mechanism wherein Gβγ either prevents dimerization of AC5 or allosterically modulates the coiled-coil domain, and hence the catalytic core, is proposed. Because our mechanistic understanding of how individual AC isoforms are uniquely regulated is limited, studies such as this may provide new avenues for isoform-specific drug development.
... Alterations in SLC30A8, such as the single nucleotide polymorphism (SNP) rs11558471, have been studied particularly in the population with type 2 diabetes [8][9][10]. This SNP has been shown to have a positive association with the regulation of glucose homeostasis [8,11] and necessary to evaluate the influence of this SNP on other cardiometabolic markers, especially in postmenopausal women, who are more susceptible to metabolic changes and no study assessment these aspects this population. Therefore, this study aimed to identify the presence of the polymorphic allele rs11558471 in the SLC30A8 gene and analyze its relationship with cardiometabolic markers in postmenopausal women. ...
... Extensive genome-wide association studies have shown that genetic variables can modulate the metabolism and signaling pathways in an individual, which can trigger various diseases [23]. Thus, associations of variations in the ZnT8-coding gene, such as SNP rs11558471, with glycemic response have been reported [8][9][10][11], but those with variables of lipid metabolism have not been demonstrated yet. ...
Postmenopausal women have more risk factors for metabolic syndrome, and genetic alterations in SLC30A8 (zinc transporter 8 [ZnT8]) are directly related to these factors. Our aim was to assess the relationship of the single nucleotide polymorphism (SNP) rs11558471 in the SLC30A8/ZnT8 gene with cardiometabolic markers in postmenopausal women. This cross-sectional study included 53 postmenopausal women divided into two groups according to the SNP genotype (AG + GG [n = 25] and AA [n = 28]). Anthropometric, dietary, and biochemical (glycemic, lipidic, hepatic, renal, and hormonal markers) variables were evaluated and compared between groups. No differences in glycemic, hepatic, renal, and hormonal markers were found between groups. However, the group with the polymorphic allele (AG + GG) had a better lipid profile than non-carriers (total cholesterol, p = 0.041; low-density lipoprotein cholesterol [LDL-c], p = 0.035; non-high-density lipoprotein cholesterol [non-HDL-c], p = 0.043). Logistic regression showed that the group with polymorphic allele had lower chances of increasing levels of LDL-c (odds ratio [OR] = 0.225, p = 0.012) and non-HDL-c (OR = 0.316, p = 0.045). After adjusting for age, body mass index, physical activity, and use of diabetes and dyslipidemia drugs, only LDL-c remained associated (OR = 0.218; p = 0.017). The variant allele of SNP rs11558471 in the SLC30A8 gene was associated with better LDL-c levels, which helps reduce the risks for cardiovascular diseases in postmenopausal women.
... In addition, ADCY5 has been reported in numerous types of tumors, such as glioma (19), prostate cancer (20) and lung cancer (21), and is involved in neovascularization and inflammatory infiltration (22). However, there are few reports on CRC, and the present findings suggested a new direction. ...
Type 2 diabetes mellitus (T2DM) has an increased risk of cancer. In the present study, the relationship between T2DM and 13 types of cancer was analyzed and key methylation genes were searched. First, DNA methylation and mRNA expression were obtained data for T2DM and 13 types of cancer from The Cancer Genome Atlas and Gene Expression Omnibus. The t-test was used to screen the differentially methylated expression overlapping genes (DE-MGs) in T2DM and cancer on both methylation and expression levels. DE-MGs are weighted based on the methylation and projected into the human protein interaction network. The correlation between T2DM and each type of cancer was analyzed, and key genes were identified. The results showed that 293 DE-MGs were related to T2DM and 3307 were related to cancer. The network found that T2DM is more related to colorectal cancer (CRC) compare with the other 12 types of cancer. A total of 5 from 8 candidate genes were associated with CRC. A total of 28 clinical patients were used to validate these 5 genes. A CRC tissue sample was collected from each patient, as well as a paracancerous sample that served as a control. A total of 56 tissue samples were divided into 4 groups: control group, T2DM group, CRC group and T2DM with CRC group (combination group). Compared with the control group, the methylation level of adenylate cyclase 5 (ADCY5), neuregulin 1 and ELAV-like RNA-binding protein 4 in the combination group was significantly upregulated, and the mRNA level was significantly downregulated. Furthermore, based on the methylation level of ADCY5, the correlation coefficient between the combination group and the T2DM group was greater than that of the CRC group. In conclusion, T2DM is most likely to be associated with CRC among 13 common types of cancer based on methylation characteristics. An upregulated methylation of ADCY5 in T2DM may have a higher risk of CRC.
... Today, the West has launched a campaign of Dismantling (Genocide) of Global Hindutva (DGH), an open call for genocide of Hindus by creating the Hinduphobia 16 . A blatant call for genocide of Hindus all over the globe by an international event with over 70 co-sponsors from over 50 universities that began on 11 September 2021 (9)(10)(11) was unprecedented after the propaganda against Jewish communities in Europe and USA resulting in Holocaust, with the opening of the official anti-Semitic campaign on 1 April 1933 17 . The Holocaust was the state-sponsored persecution and murder of European Jews by Nazi Germany and its collaborators. ...
... Previous studies reported that environmental factors can alter epigenetic features and change the future behavior of target cells and may play a role in susceptibility to MetS as well as other chronic diseases [14][15][16]. In humans this non genetic influences to change the pattern of gene expression are heritable across more than one generation and such transgenerational tradition of epigenetic states may contribute to the hereditary risk of various metabolic disorders [17][18][19][20][21]. DNA methylation is one of the most extensively studied epigenetic mechanisms and plays an important role in the process of development and differentiation [22]. ...
... Most risk-alleles appear to exert similar directions and magnitudes effects in European and South Asian populations (17,18), but it is important to consider whether this applies universally, and whether the frequency of such risk-alleles varies between populations. One global study reported decreasing frequencies of type II diabetes risk-alleles with increasing geographical distance from Africa toward East Asia, suggesting a diabetesprotective consequence of migration (19). ...
The British Raj has cast a deep and deadly impact on the Indian Continent physically and mentally which continues to haunt the Indian Continent and its peoples wherever they maybe. The thrifty gene hypothesis, proposed back in 1962 by Dr. James Van Gundia Neel, describes how people protected during periods of famine in past by having metabolisms efficient enough to allow survival on small amounts of food. Those who survived were wired to be able to use minimal amounts of energy, and store the rest as fat for the next famine. Famines were administrative disasters in colonial India which the British government never really acknowledged. India has rapidly become a “diabetes capital” of the world, despite maintaining high rates of under-nutrition. Indians develop diabetes at younger age and at lower body weights than other populations. The drastic reduction in stature in India is greater than that observed in most other global regions indicates nutritional stress operating across many generations due to regular famines induced by the undermining of agricultural security during the colonial period. Thus, colonial imperialism not only destroyed Hindutva and continues to destroy through the Socioreligious Order of the Liberal Evangelical Western Democracy (SO LEWD), but caused tremendous damage to the genetics and physical health of Indians.
Winston Churchill in 1942 said that that passion for empire did not, however, entail the duty of protecting the lives of the King's distant subjects, especially Indians, a beastly people with a beastly religion. Churchill repeatedly denied all food exports to India, in spite of the fact that about 2.4 million Indians served in British units during the Second World War .
... [169,[176][177][178] G-allele is associated with increased risk of type 2 diabetes mellitus in most but not all ethnic groups, and especially in elderly patients. [169,177,178,182,184,185,188,190,192,202,208,209,[211][212][213][214][215][216][217][218][219] G allele is associated with increased pancreatic islet MTNR1B expression and decreased beta cell glucose sensitivity. [169,186,191,195,220,221] G-allele is associated with decreased early phase insulin secretion after glucose load. ...
he pineal hormone melatonin has attracted great scientific interest since its discovery in 1958. Despite the enormous number of basic and clinical studies the exact role of melatonin in respect to human physiology remains elusive. In humans, two high-affinity receptors for melatonin, MT1 and MT2, belonging to the family of G protein-coupled receptors (GPCRs) have been cloned and identified. The two receptor types activate Gi proteins and MT2 couples additionally to Gq proteins to modulate intracellular events. The individual effects of MT1 and MT2 receptor activation in a variety of cells are complemented by their ability to form homo- and heterodimers, the functional relevance of which is yet to be confirmed. Recently, several melatonin receptor genetic polymorphisms were discovered and implicated in pathology—for instance in type 2 diabetes, autoimmune disease, and cancer. The circadian patterns of melatonin secretion, its pleiotropic effects depending on cell type and condition, and the already demonstrated cross-talks of melatonin receptors with other signal transduction pathways further contribute to the perplexity of research on the role of the pineal hormone in humans. In this review we try to summarize the current knowledge on the membrane melatonin receptor activated cell signaling in physiology and pathology and their relevance to certain disease conditions including cancer.
... This variant is overlapping an islet enhancer region in humans [19], where it removes a CpG site, exhibiting differential DNA methylation by genotype, in addition to being associated with DNA methylation at the surrounding CpG sites [21]. In line with this function, rs11708067 in ADCY5 has been associated with increased risk of T2DM [22,23], lower conversion of proinsulin to insulin [24], and reduced HOMA-B [17] in adults. It is also associated with high plasma glucose concentrations in adults [17,18,24], neonates [25], and children [25,26], as well as with lower birth weight [27]. ...
Background and purposeNeonates at the highest and lowest percentiles of birth weight present an increased risk of developing metabolic diseases in adult life. While environmental events in utero may play an important role in this association, some genetic variants are associated both with birth weight and type 2 diabetes mellitus (T2DM), suggesting a genetic link between intrauterine growth and metabolism in adult life. Variants rs11708067 in ADCY5 and rs7754840 in CDKAL1 are associated with low birth weight, risk of T2DM, and lower insulin secretion in adults. We aimed to investigate whether, besides birth weight, these polymorphisms were related to insulin secretion at birth.MethodsA cohort of 218 healthy term newborns from uncomplicated pregnancies were evaluated for anthropometric and biochemical variables. Cord blood insulin and C-peptide were analyzed by ELISA. Genotyping of rs11708067 in ADCY5 and rs7754840 in CDKAL1 was performed.ResultsNewborns carrying the A allele of ADCY5 rs11708067 had lower cord blood insulin and C-peptide, even after adjusting by maternal glycemia, HbA1c, and pregestational BMI. Lower birth weight was found for AA-AG genotypes compared to GG, but no differences were seen in adjusted birth weight or z-score. Variant rs7754840 in CDKAL1 was not associated with birth weight, neonatal insulin, or C-peptide for any genotype or genetic model.Conclusions
The variant rs11708067 in ADCY5 is associated with lower neonatal insulin and C-peptide concentrations. Our results suggest that the genetic influence on insulin secretion may be evident from birth, even in healthy newborns, independently of maternal glycemia and BMI.
... Adcy5 −/− mice exhibit decreased bodyweight on standard and high-fat diet, with improved glucose tolerance and increased insulin sensitivity [43,44]. Numerous studies linked Adcy5 gene polymorphisms to altered glucose metabolism, diabetes, and obesity [45,46]. Adcy5 is activated by the G-protein Gαs, PKC, and Raf kinase, while be inhibited by Gαi and Ca 2+ [17,40]. ...
Obesity is closely associated with low-bone-mass disorder. Discoidin domain receptor 2 (DDR2) plays essential roles in skeletal metabolism, and is probably involved in fat metabolism. To test the potential role of DDR2 in fat and fat-bone crosstalk, Ddr2 conditional knockout mice (Ddr2Adipo) were generated in which Ddr2 gene is exclusively deleted in adipocytes by Adipoq Cre. We found that Ddr2Adipo mice are protected from fat gain on high-fat diet, with significantly decreased adipocyte size. Ddr2Adipo mice exhibit significantly increased bone mass and mechanical properties, with enhanced osteoblastogenesis and osteoclastogenesis. Marrow adipocyte is diminished in the bone marrow of Ddr2Adipo mice, due to activation of lipolysis. Fatty acid in the bone marrow was reduced in Ddr2Adipo mice. RNA-Seq analysis identified adenylate cyclase 5 (Adcy5) as downstream molecule of Ddr2. Mechanically, adipocytic Ddr2 modulates Adcy5-cAMP-PKA signaling, and Ddr2 deficiency stimulates lipolysis and supplies fatty acid for oxidation in osteoblasts, leading to the enhanced osteoblast differentiation and bone mass. Treatment of Adcy5 specific inhibitor abolishes the increased bone mass gain in Ddr2Adipo mice. These observations establish, for the first time, that Ddr2 plays an essential role in the crosstalk between fat and bone. Targeting adipocytic Ddr2 may be a potential strategy for treating obesity and pathological bone loss simultaneously.
... 15 Studies based in the USA and Europe have shown significant ethnic disparities in the overall distribution of diabetes, with non-white people having a higher prevalence. [16][17][18][19] Asian people had a high prevalence of cardiometabolic diseases such as type 2 diabetes and hypertension compared with other ethnic groups even at lower body mass index (BMI). 16 The distribution of diabetes according to HCV infection status across different ethnic groups in Canada remains unknown. ...
Introduction
Increasing evidence indicates that chronic hepatitis C virus (HCV) infection is associated with higher risk of diabetes. Previous studies showed ethnic disparities in the disease burden of diabetes, with increased risk in Asian population. We described the incidence of type 2 diabetes related to HCV infection and assessed the concurrent impact of HCV infection and ethnicity on the risk of diabetes.
Research design and methods
In British Columbia Hepatitis Testers Cohort, individuals were followed from HCV diagnosis to the earliest of (1) incident type 2 diabetes, (2) death or (3) end of the study (December 31, 2015). Study population included 847 021 people. Diabetes incidence rates in people with and without HCV were computed. Propensity scores (PS) analysis was used to assess the impact of HCV infection on newly acquired diabetes. PS-matched dataset included 117 184 people. We used Fine and Gray multivariable subdistributional hazards models to assess the effect of HCV and ethnicity on diabetes while adjusting for confounders and competing risks.
Results
Diabetes incidence rates were higher among people with HCV infection than those without. The highest diabetes incidence rate was in South Asians with HCV (14.7/1000 person-years, 95% CI 12.87 to 16.78). Compared with Others, South Asians with and without HCV and East Asians with HCV had a greater risk of diabetes. In the multivariable stratified analysis, HCV infection was associated with increased diabetes risk in all subgroups: East Asians, adjusted HR (aHR) 3.07 (95% CI 2.43 to 3.88); South Asians, aHR 2.62 (95% CI 2.10 to 3.26); and Others, aHR 2.28 (95% CI 2.15 to 2.42).
Conclusions
In a large population-based linked administrative health data, HCV infection was associated with higher diabetes risk, with a greater relative impact in East Asians. South Asians had the highest risk of diabetes. These findings highlight the need for care and screening for HCV-related chronic diseases such as type 2 diabetes among people affected by HCV.
