scholarly journals Requirement of the ATM/p53 Tumor Suppressor Pathway for Glucose Homeostasis

2010 ◽  
Vol 30 (24) ◽  
pp. 5787-5794 ◽  
Author(s):  
Heather L. Armata ◽  
Diane Golebiowski ◽  
Dae Young Jung ◽  
Hwi Jin Ko ◽  
Jason K. Kim ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Tumor Suppressor ◽  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
Germ Line ◽  
Neuronal Degeneration ◽  
Phosphorylation Site ◽  
P53 Tumor Suppressor ◽  
Increased Risk ◽  
Risk Of Cancer

ABSTRACT Ataxia telangiectasia (A-T) patients can develop multiple clinical pathologies, including neuronal degeneration, an elevated risk of cancer, telangiectasias, and growth retardation. Patients with A-T can also exhibit an increased risk of insulin resistance and type 2 diabetes. The ATM protein kinase, the product of the gene mutated in A-T patients (Atm), has been implicated in metabolic disease, which is characterized by insulin resistance and increased cholesterol and lipid levels, blood pressure, and atherosclerosis. ATM phosphorylates the p53 tumor suppressor on a site (Ser15) that regulates transcription activity. To test whether the ATM pathway that regulates insulin resistance is mediated by p53 phosphorylation, we examined insulin sensitivity in mice with a germ line mutation that replaces the p53 phosphorylation site with alanine. The loss of p53 Ser18 (murine Ser15) led to increased metabolic stress, including severe defects in glucose homeostasis. The mice developed glucose intolerance and insulin resistance. The insulin resistance correlated with the loss of antioxidant gene expression and decreased insulin signaling. N-Acetyl cysteine (NAC) treatment restored insulin signaling in late-passage primary fibroblasts. The addition of an antioxidant in the diet rendered the p53 Ser18-deficient mice glucose tolerant. This analysis demonstrates that p53 phosphorylation on an ATM site is an important mechanism in the physiological regulation of glucose homeostasis.

Neuroradiology Manifestations of Li-Fraumeni Syndrome: Epidemiology, Genetics, Imaging Findings, and Management

Neurographics ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 228-235
Author(s):  
S. Naganawa ◽  
T. Donohue ◽  
A. Capizzano ◽  
Y. Ota ◽  
J. Kim ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Soft Tissue Sarcomas ◽  
Suppressor Gene ◽  
Imaging Findings ◽  
Li Fraumeni Syndrome ◽  
Increased Risk ◽  
Li Fraumeni ◽  
Risk Of Cancer

Li-Fraumeni syndrome is a familial cancer predisposition syndrome associated with germline mutation of the tumor suppressor gene 53, which encodes the tumor suppressor p53 protein. Affected patients are predisposed to an increased risk of cancer development, including soft-tissue sarcomas, breast cancer, brain tumors, and adrenocortical carcinoma, among other malignancies. The tumor suppressor gene TP53 plays an important, complex role in regulating the cell cycle, collaborating with transcription factors and other proteins. The disruption of appropriate cell cycle regulation by mutated TP53 is considered to be the cause of tumorigenesis in Li-Fraumeni syndrome. Appropriate surveillance, predominantly by using MR imaging, is used for early malignancy screening in an effort to improve the survival rate among individuals who are affected. Patients with Li-Fraumeni syndrome are also at increased risk for neoplasm development after radiation exposure, and, therefore, avoiding unnecessary radiation in both the diagnostic and therapeutic settings is paramount. Here, we review the epidemiology, genetics, imaging findings, and the current standard surveillance protocol for Li-Fraumeni syndrome from the National Comprehensive Cancer Network as well as potential treatment options.Learning Objective: Describe the cause of second primary malignancy among patients with Li-Fraumeni syndrome.

scholarly journals Deregulation of PP2A-Akt Interaction Contributes to Sucrose Non-Fermenting Related Kinase (SNRK) Deficiency Induced Insulin Resistance in Adipose Tissue (P21-071-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Jie Li ◽  
Ran An ◽  
Simin Liu ◽  
Haiyan Xu
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Knockout Model ◽  
Potential Substrate

Abstract Objectives Sucrose Non-Fermenting Related Kinase (SNRK), a serine/threonine kinase, is a novel member of the AMPK/SNF1 family. We previously reported that adipose specific SNRK deficiency induced systemic inflammation and insulin resistance. In this study, we aimed to dissect the role of SNRK in white versus brown adipose tissue in insulin signaling and glucose homeostasis. Methods The SNRKloxp/loxp mice were mated with adiponectin-Cre (A-Cre) transgenic mice to generate the adipose tissue specific knockout model (SNRK−/−, A-Cre), and with UCP1-Cre (U-Cre) mice to generate the brown adipose tissue (BAT) specific knockout model (SNRK−/−, U-Cre). RNA sequencing and phosphoproteomics analysis were applied to identify the signaling pathways affected by SNRK deficiency and the potential substrate of SNRK. Results SNRK deletion exclusively in BAT is sufficient to impair insulin signaling and glucose uptake without inducing local and systemic inflammation. Phosphoproteomic study identified PPP2R5D as the potential substrate of SNRK that regulates insulin signaling through controlling PP2A activity. Dephosphorylated PPP2R5D promotes constitutive assembly of PP2A-Akt complex in SNRK deficient primary brown adipocytes and BAT, therefore reduces insulin stimulated Akt phosphorylation and subsequent glucose uptake. RNA sequencing data provided further evidence to show that the PI3K/AKT signaling pathway is suppressed by SNRK deletion in primary brown adipocytes. Conclusions Insulin resistance in BAT alone is not sufficient to impact whole body glucose homeostasis, indicating that the role of SNRK in WAT and inflammation might be critical for observed systemic insulin resistance in SNRK−/−, A-Cre mice. Funding Sources National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK103699).

Ataxia-Telangiectasia genes and breast cancer risk in a French family study

2005 ◽  
Vol 72 (S1) ◽  
pp. 73-80 ◽  
Author(s):  
Nadine Andrieu ◽  
Eve Cavaciuti ◽  
Anthony Laugé ◽  
Katia Ossian ◽  
Nicolas Janin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ataxia Telangiectasia ◽  
Screening Program ◽  
Neuronal Degeneration ◽  
Carrier Status ◽  
X Rays ◽  
Increased Risk ◽  
Exogenous Factors ◽  
Atm Protein ◽  
Risk Of Cancer

Ataxia-telangiectasia (AT) is a rare autosomal recessive early childhood disorder, characterized by progressive neuronal degeneration, immunological deficiency, radiosensitivity and an increased risk of cancer caused in most cases by mutations in the AT-mutated gene (ATM). Epidemiological studies on AT families have shown that AT heterozygous women have an increased risk of developing breast cancer (BC). The ATM protein plays a central role in the recognition and repair of DNA double-strand breaks and the subsequent activation of cell-cycle checkpoints. Whilst AT is a rare disease, 0·5–1% of the general population are estimated to be AT mutation carriers, thus any increases in the risks of cancer associated with ATM carrier status are of public health relevance. The main results of our published studies on the risk of BC in 34 French AT families according to heterozygote status, type of ATM mutation and exogenous factors are summarized here. The risk of BC was higher in ATM heterozygous (HetATM) women and did not differ significantly according to the type of ATM mutation (missense vs truncating) carried by the AT family members but appeared associated with the position of some truncating mutations in certain binding domains of the ATM protein. The effect of exogenous factors, such as reproductive life factors and exposure to ionizing radiation, on the risk of BC according to ATM heterozygote status was assessed. There was no evidence for interaction (except for age at first full-term pregnancy). These findings does not appear to justify a separate screening program from that already available to other women with a first-degree relative affected by BC, as their risks have similar amplitude. Chest X-rays did not appear to be a risk factor for BC in our study population. More powerful studies, using data sets pooled from international sources are being set up to confirm these observations.

Long-term melatonin administration improves glucose homeostasis and insulin resistance state in high-fat-diet fed rats

2013 ◽  
Vol 8 (10) ◽  
pp. 958-967
Author(s):  
Xue-Dong Wan ◽  
San-Qiang Li ◽  
Shou-Min Xi ◽  
Jian-Fei Wang ◽  
Yan-Chun Guo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Reactive Oxygen Species ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Metabolic Profiles ◽  
Oxygen Species ◽  
High Fat

AbstractEmerging evidence support an important role of reactive oxygen species in various forms of insulin resistance. It is identified that melatonin has antioxidant properties and prevents toxic effects of reactive oxygen species. In this study, we sought to assess the involvement of melatonin in the progression of insulin resistance in response to a high-fat diet (HFD) and to investigate the underlying mechanisms. Male rats were fed with a control diet, a high-fat diet, or a high-fat diet supplemented with melatonin (5 mg kg−1, i.p.) for 10 weeks. Glucose homeostasis, insulin sensitivity, antioxidative potency, and metabolic profiles in the rats were evaluated. Our results showed that a HFD led to increasing body mass, adipose tissue weight, plasma insulin, total cholesterol (TC), triglycerides (TG), free fatty acids (FFA), and decreased HDL-cholesterol (HDL-C) in rats. There was also a significant increase in the level of malondialdehyde (MDA) and decrease in superoxide dismutase (SOD) activity, oxidative stress markers both in the plasma and liver. An enhanced hepatic phosphoenolpyruvate carboxy-kinase (PEPCK) activity and RNA expression were observed. Impaired insulin signaling was evidenced by reducing insulin receptor substrate 2 (IRS2) tyrosine phosphorylation and protein kinase B (PKB) serine phosphorylation in response to insulin. Overactivation of stress-activated protein kinases JNK was also observed in the liver of HFD rats. However, simultaneous administration of melatonin to HFD rats significantly reduced oxidative stress in the system and liver, markedly improved impaired glucose homeostasis, insulin sensitivity, antioxidative potency, metabolic profiles and all the aforesaid adverse changes in HFD rats. Our results demonstrated that anti-oxidative property of melatonin is sufficient to ameliorate the insulin resistance condition, leading to the improvement of glucose homeostasis and the restoration of hepatic insulin signaling in a rat model of HFD-induced insulin resistance.

scholarly journals Is Nitric oxide the missing link in glucose homeostasis? A study on correlation of Nitric oxide and Insulin Resistance in Obstructive Sleep Apnoea

2019 ◽  
Vol 10 (2) ◽  
pp. 820-825
Author(s):  
Ramya K ◽  
Gowri Sethu ◽  
Dhanasekar T
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Glucose Homeostasis ◽  
Reciprocal Relationship ◽  
Control Group ◽  
Group I ◽  
Obstructive Sleep ◽  
Increased Risk

Nitric oxide is associated with glucose homeostasis. An independent relationship between Nitric oxide and insulin resistance in Prediabetic and Obstructive sleep apnea patients without pre-existing diabetes mellitus are equivocally linked to increased risk of type II diabetes. A reciprocal relationship seems to exist between nitric oxide and insulin resistance. Aim of this present study is to determine relationship between nitric oxide and glucose parameters in control, prediabetic and Obstructive sleep apnea. A cross sectional study was performed in 150. They were divided into, group I (control), group II (prediabetics) and group III (OSA). Fasting blood sugar (FBS), fasting insulin, HbA1c and nitric oxide were measured in these subjects and insulin resistance calculated by HOMA-IR. Data was analyzed statistically using Pearson’s correlation coefficient analysis, the significant value being P<0.05. Negative correlation was observed between the NO and insulin resistance in prediabetic (r=-0.627, P =<0.001) and OSA (r= -0.416, P=0.003) respectively. Nitric oxide is significantly inversely associated with insulin resistance in Prediabetic and Obstructive sleep apnea.

Germ-Line Genetic Variations in TP53 and Risk for Pediatric Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1890-1890
Author(s):  
Toralf Bernig ◽  
Laurie Burdette ◽  
Thomas Lehrnbecher ◽  
Ulrike B. Graubner ◽  
Monique L. den Boer ◽  
...  
Keyword(s):  
At Risk ◽  
Genetic Variation ◽  
Acute Lymphoblastic Leukemia ◽  
Tumor Suppressor ◽  
Germ Line ◽  
Lymphoblastic Leukemia ◽  
Risk Haplotype ◽  
Childhood All ◽  
Increased Risk ◽  
The Common

Abstract The tumor suppressor p53 plays an essential role in the prevention of tumor development by its ability to respond to stress signals, resulting in the inhibition of cell growth, via cell-cycle arrest or induction of apoptosis. p53 also contributes to the repair of genotoxic DNA damages and is involved in cellular senescence. Previous studies have shown that both germ-line and somatic mutations in the TP53 gene, which encodes p53, can occur in a wide spectrum of cancers, including acute lymphoblastic leukemia, ALL. Recently, we characterized the common germ-line genetic variation across TP53 by extensive re-sequence analysis (http://snp500cancer.nci.nih.gov). Patients and Methods: We conducted a genetic association study in childhood ALL to investigate the possible contribution of common single nucleotide polymorphisms, SNPs, and the common haplotypes on which they reside. For TP53, we analyzed haplotype-tagging SNPs, which are estimated to capture greater than 95% of common haplotypes across the gene (IVS2+38C, Ex4+119 (R72P), IVS4-91, Ex6-34 (R213R), IVS6+62, IVS6-36 and 1846bp 3′ of STP). Cases of ALL (n = 513) were drawn from anonymized samples from the German co-operative therapy study (COALL-06-97) and 751 healthy anonymized blood donor controls collected from regional blood banks in Germany. Genotype analysis was performed by validated Taqman assays posted on the SNP500cancer website. Haplotypes were deduced by maximization-estimation analysis of unphased genotypes using PHASEv2.0.1 (http://www.stat.washington.edu/stephens/software.html). Results: The single locus analysis revealed an increased risk for ALL for four of the seven SNPs individually: C allele at IVS2+38C (304/982 in patients vs. 399/1476 in controls, OR 1.21 95% CI 1.01 – 1.45), G allele at IVS4-91 (150/988 vs. 168/1456, OR 1.37 95% CI 1.08 – 1.75), A allele at Ex6-34 (R213R) (164/996 vs. 178/1450, OR 1.41 95% CI 1.11 – 1.78) and T allele at 1846bp 3′ of STP (185/990 vs. 203/1420, OR 1.38 95% CI 1.10 – 1.72). Individuals homozygous AA at IVS6+62 (16/350 vs. 9/556, OR 2.82, 95% CI 1.16 – 6.99) or TT at 1846bp 3′ of STP (24/334 vs. 15/522 OR 2.50, 955 CI 1.24 – 5.09) showed further risk for disease. The non-synonymous coding SNP at Ex4+119 (R72P) did not show any association with ALL. The distribution of the inferred haplotypes differed significantly between cases and controls (global haplotype test p = 0.02). Children carrying the haplotype CCGAAGT have an increased risk for ALL (138/611 vs. 155/972, OR 1.42, 95% CI 1.09 −1.83) in reference to the most common haplotype GGAAGGC. Conclusions: Our data suggest that susceptibility to pediatric ALL could be associated with at least one copy of an “at risk” haplotype. The study results imply that germ-line genetic variation in TP53, a key tumor suppressor gene, could contribute to susceptibility to childhood ALL. Additional studies are required to confirm our findings and to characterize the functional elements in the at-risk haplotypes.

scholarly journals The Circadian Clock, Shift Work, and Tissue-Specific Insulin Resistance

Endocrinology ◽  
2020 ◽  
Vol 161 (12) ◽  
Author(s):  
Johanneke E Oosterman ◽  
Suzan Wopereis ◽  
Andries Kalsbeek
Keyword(s):  
Insulin Resistance ◽  
Eating Behavior ◽  
Shift Work ◽  
Glucose Homeostasis ◽  
Biological Clock ◽  
The Body ◽  
Health Concern ◽  
Phenotypic Flexibility ◽  
Increased Risk ◽  
Eating Out

Abstract Obesity and type 2 diabetes (T2D) have become a global health concern. The prevalence of obesity and T2D is significantly higher in shift workers compared to people working regular hours. An accepted hypothesis is that the increased risk for metabolic health problems arises from aberrantly timed eating behavior, that is, eating out of synchrony with the biological clock. The biological clock is part of the internal circadian timing system, which controls not only the sleep/wake and feeding/fasting cycle, but also many metabolic processes in the body, including the timing of our eating behavior, and processes involved in glucose homeostasis. Rodent studies have shown that eating out of phase with the endogenous clock results in desynchronization between rhythms of the central and peripheral clock systems and between rhythms of different tissue clocks (eg, liver and muscle clock). Glucose homeostasis is a complex process that involves multiple organs. In the healthiest situation, functional rhythms of these organs are synchronized. We hypothesize that desynchronization between different metabolically active organs contributes to alterations in glucose homeostasis. Here we summarize the most recent information on desynchronization between organs due to shift work and shifted food intake patterns and introduce the concept of phenotypic flexibility, a validated test to assess the contribution of each organ to insulin resistance (IR) in humans. We propose this test as a way to provide further insight into the possible desynchronization between tissue clocks. Because different types of IR benefit from different therapeutic approaches, we also describe different chronotherapeutic strategies to promote synchrony within and between metabolically active organs.

scholarly journals Exploring mechanistic links between extracellular branched-chain amino acids and muscle insulin resistance: an in vitro approach

2020 ◽  
Vol 319 (6) ◽  
pp. C1151-C1157
Author(s):  
Hannah Crossland ◽  
Kenneth Smith ◽  
Iskandar Idris ◽  
Bethan E. Phillips ◽  
Philip J. Atherton ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Amino Acids ◽  
Insulin Signaling ◽  
Prolonged Exposure ◽  
Glycogen Synthesis ◽  
Branched Chain Amino Acids ◽  
Increased Risk ◽  
Impaired Insulin ◽  
Branched Chain

Branched-chain amino acids (BCAAs) are essential for critical metabolic processes; however, recent studies have associated elevated plasma BCAA levels with increased risk of insulin resistance. Using skeletal muscle cells, we aimed to determine whether continued exposure of high extracellular BCAA would result in impaired insulin signaling and whether the compound sodium phenylbutyrate (PB), which induces BCAA metabolism, would lower extracellular BCAA, thereby alleviating their potentially inhibitory effects on insulin-mediated signaling. Prolonged exposure of elevated BCAA to cells resulted in impaired insulin receptor substrate 1/AKT signaling and insulin-stimulated glycogen synthesis. PB significantly reduced media BCAA and branched-chain keto acid concentrations and increased phosphorylation of AKT [+2.0 ± 0.1-fold; P < 0.001 versus without (−)PB] and AS160 (+3.2 ± 0.2-fold; P < 0.001 versus −PB); however, insulin-stimulated glycogen synthesis was further reduced upon PB treatment. Continued exposure of high BCAA resulted in impaired intracellular insulin signaling and glycogen synthesis, and while forcing BCAA catabolism using PB resulted in increases in proteins important for regulating glucose uptake, PB did not prevent the impairments in glycogen synthesis with BCAA exposure.

scholarly journals Insulin Resistance and Cancer Risk: An Overview of the Pathogenetic Mechanisms

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Biagio Arcidiacono ◽  
Stefania Iiritano ◽  
Aurora Nocera ◽  
Katiuscia Possidente ◽  
Maria T. Nevolo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cellular Proliferation ◽  
Inflammatory Cells ◽  
Sex Hormone Binding Globulin ◽  
Diabetic Patients ◽  
Insulin Resistant ◽  
Increased Risk ◽  
Igf I ◽  
Risk Of Cancer

Insulin resistance is common in individuals with obesity or type 2 diabetes (T2D), in which circulating insulin levels are frequently increased. Recent epidemiological and clinical evidence points to a link between insulin resistance and cancer. The mechanisms for this association are unknown, but hyperinsulinaemia (a hallmark of insulin resistance) and the increase in bioavailable insulin-like growth factor I (IGF-I) appear to have a role in tumor initiation and progression in insulin-resistant patients. Insulin and IGF-I inhibit the hepatic synthesis of sex-hormone binding globulin (SHBG), whereas both hormones stimulate the ovarian synthesis of sex steroids, whose effects, in breast epithelium and endometrium, can promote cellular proliferation and inhibit apoptosis. Furthermore, an increased risk of cancer among insulin-resistant patients can be due to overproduction of reactive oxygen species (ROS) that can damage DNA contributing to mutagenesis and carcinogenesis. On the other hand, it is possible that the abundance of inflammatory cells in adipose tissue of obese and diabetic patients may promote systemic inflammation which can result in a protumorigenic environment. Here, we summarize recent progress on insulin resistance and cancer, focusing on various implicated mechanisms that have been described recently, and discuss how these mechanisms may contribute to cancer initiation and progression.

scholarly journals Non-classical effects of vitamin D

2018 ◽  
Vol 15 (1) ◽  
pp. 12-18
Author(s):  
Lilit V. Egshatyan
Keyword(s):  
Metabolic Disease ◽  
Insulin Resistance ◽  
Vitamin D ◽  
Inflammatory Response ◽  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
Renin Angiotensin System ◽  
Inflammatory Biomarkers ◽  
Angiotensin System ◽  
Normal Metabolism

Some studies support the involvement of vitamin D in modulating the inflammatory response and developing diabetes. Since the activation of inflammatory biomarkers, cytokines and pathways interferes with normal metabolism and disrupts proper insulin signaling and insulin resistance, it is hypothesized that vitamin D could influence lipid and glucose homeostasis by modulating inflammatory response and renin-angiotensin system. In this review discussed the mechanisms of the influence of vitamin D on metabolic disease.

Sign in / Sign up

Export Citation Format

Share Document