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Liu L. Karter A. Sattar N. Type 2 diabetes in migrant south Asians: Mechanisms, mitigation, and management. Lancet Diabetes Endocrinol.

McKeigue P. Relation of central obesity and insulin resistance with high diabetes prevalence and cardiovascular risk in South Asians. Haines L. Rising incidence of type 2 diabetes in children in the U. Fuchsberger C. The genetic architecture of type 2 diabetes. McCarthy M. Genomics, type 2 diabetes, and obesity. Dimas A. Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.

Flannick J. Type 2 diabetes: Genetic data sharing to advance complex disease research. Franks P. Gene-environment and gene-treatment interactions in type 2 diabetes: Progress, pitfalls, and prospects. Bellou V. Risk factors for type 2 diabetes mellitus: An exposure-wide umbrella review of meta-analyses.

Carey V. Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women. Sinha R. Assessment of skeletal muscle triglyceride content by 1 H nuclear magnetic resonance spectroscopy in lean and obese adolescents: Relationships to insulin sensitivity, total body fat, and central adiposity. Hillier T. Complications in young adults with early-onset type 2 diabetes: Losing the relative protection of youth. Weinstein A. Relationship of physical activity vs body mass index with type 2 diabetes in women.

Lynch J. Moderately intense physical activities and high levels of cardiorespiratory fitness reduce the risk of non-insulin-dependent diabetes mellitus in middle-aged men.

Venkatasamy V. Strasser B. Physical activity in obesity and metabolic syndrome. Ross R. Does exercise without weight loss improve insulin sensitivity? Cerf M. Beta cell dysfunction and insulin resistance. Lausanne ; 4 Zheng Y. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Bunney P. Orexin activation counteracts decreases in nonexercise activity thermogenesis NEAT caused by high-fat diet.

Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Diabetes Rev. Halban P.

Proinsulin processing in the regulated and the constitutive secretory pathway. Boland B. The dynamic plasticity of insulin production in beta-cells. Rorsman P. Seino S. Dynamics of insulin secretion and the clinical implications for obesity and diabetes. Islam M. The ryanodine receptor calcium channel of beta-cells: Molecular regulation and physiological significance.

Cuinas A. Activation of PKA and Epac proteins by cyclic AMP depletes intracellular calcium stores and reduces calcium availability for vasoconstriction. Life Sci.

Lustig K. Expression cloning of an ATP receptor from mouse neuroblastoma cells. Simon J. Characterisation of a recombinant P2Y purinoceptor. Valera S. A new class of ligand-gated ion channel defined by P2x receptor for extracellular ATP. Blachier F. Effect of exogenous ATP upon inositol phosphate production, cationic fluxes and insulin release in pancreatic islet cells.

Christensen A. The Beta Cell in Type 2 Diabetes. Diabetes Rep. Yamamoto W. Endoplasmic reticulum stress alters ryanodine receptor function in the murine pancreatic beta cell. Hoang Do O. Insulin secretion from beta cells within intact islets: Location matters. Liu M. Biosynthesis, structure, and folding of the insulin precursor protein.

Diabetes Obes. Dali-Youcef N. Metabolic inflammation: Connecting obesity and insulin resistance. Hummasti S. Endoplasmic reticulum stress and inflammation in obesity and diabetes. Roca-Rivada A. Giacco F. Oxidative stress and diabetic complications. Graciano M. Regulation of insulin secretion and reactive oxygen species production by free fatty acids in pancreatic islets.

Esser N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res. Pradhan A. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. Vandanmagsar B. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Association A. Shamsuzzaman A. Independent association between plasma leptin and C-reactive protein in healthy humans.

Leeuwenburgh C. Aging and exercise training in skeletal muscle: Responses of glutathione and antioxidant enzyme systems. Polak K. New markers of insulin resistance in polycystic ovary syndrome. Bostrom P. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis.

Handschin C. The role of exercise and PGC1alpha in inflammation and chronic disease. Park K. Circulating irisin in relation to insulin resistance and the metabolic syndrome. El-Lebedy D. Novel adipokines vaspin and irisin as risk biomarkers for cardiovascular diseases in type 2 diabetes mellitus.

Diabetes Metab. Lynch S. Ochoa-Reparaz J. Gut microbiome and the risk factors in central nervous system autoimmunity. FEBS Lett. Scarpellini E. Obesity and metabolic syndrome: An inflammatory condition. Biagi E. Aging of the human metaorganism: The microbial counterpart. Age Dordrecht ; 34 — Sircana A. Cani P. Metabolic endotoxemia initiates obesity and insulin resistance.

Tan J. The role of short-chain fatty acids in health and disease. Tang C. Neis E. The role of microbial amino acid metabolism in host metabolism. Shan Z. Association between microbiota-dependent metabolite trimethylamine-N-oxide and type 2 diabetes. Turner R. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: Progressive requirement for multiple therapies UKPDS The Steno-2 study.

Intensive multifactorial intervention reduces the occurrence of cardiovascular disease in patients with type 2 diabetes. Holman R. Ihnat M. Ceriello A. Engerman R. Pathogenesis of diabetic retinopathy. Olsen A. Heritable transmission of diabetic metabolic memory in zebrafish correlates with DNA hypomethylation and aberrant gene expression.

Simmons D. Epigenetic Influences and Disease. Rosen E. Epigenetics and Epigenomics: Implications for Diabetes and Obesity.

Wahid F. MicroRNAs: Synthesis, mechanism, function, and recent clinical trials. LaPierre M. MicroRNAs as stress regulators in pancreatic beta cells and diabetes. Esguerra J. MicroRNAs in islet hormone secretion. Ofori J. Latreille M. MicroRNA-7a regulates pancreatic beta cell function. Poy M. Reddy M. Epigenetic mechanisms in diabetic complications and metabolic memory.

Blomen V. Stable transmission of reversible modifications: Maintenance of epigenetic information through the cell cycle. Bogdanovic O. Mosammaparast N. Reversal of histone methylation: Biochemical and molecular mechanisms of histone demethylases. Breving K. The complexities of microRNA regulation: Mirandering around the rules. Brasacchio D. Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail.

Miao F. In vivo chromatin remodeling events leading to inflammatory gene transcription under diabetic conditions. Epigenetic mechanisms in diabetic vascular complications. Al-Haddad R. Epigenetic changes in diabetes. In the last decades, the concept of CSC hierarchical arrangement has changed our understanding of tumor cell heterogeneity. Schematic representation of the major signaling pathways involved in cancer stem cell biology. A gradient of BMP and Hh signaling, with relatively high activity in the villus and less activity within the crypt, regulates cell renewal and lineage specification.

Wnt and Notch signaling gradients in the opposite direction highest expression at the crypt base play an important role in maintaining the stem cell compartment. The Wnt pathway is involved in many biological processes and is essential for epithelial intestinal homeostasis Figure 2 [ 16 ]. The Wnt signaling pathway has a role also in human intestinal CSCs.

Injection of Wnt high cells in mice results in more effective tumor formation compared with Wnt low cells. For instance, in , Lugli et al. In the intestinal epithelium, SOX9 expression pattern in the SC compartment almost perfectly overlaps with that of the proliferative marker Ki SOX9-deficient mice exhibit higher cell proliferation, extensive colon hyperplasia with numerous enlarged crypts.

However, SOX9 deletion is not sufficient to induce malignancy [ 25 ]. SOX9 has several pro-oncogenic properties, including the ability to promote cell proliferation, to inhibit senescence and to collaborate with other oncogenes in neoplastic transformation [ 26 ]. SOX9 mutation rate is higher in more advanced tumors and is correlated with activated KRAS, an oncogene frequently mutated during CRC development, thus facilitating transformation and tumor progression [ 29 ].

In addition, strong MiniSOX9 expression is observed in CRC tumor tissue, while it is undetectable in the adjacent normal tissue [ 30 ]. Nevertheless, SOX9 protein level could not be clearly associated with patient prognosis [ 31 ]. KLF4 was originally identified as a gut-enriched transcription factor in the intestine and is expressed in terminally differentiated columnar intestinal epithelial cells [ 32 ].

KLF4 regulates intestinal epithelial homeostasis and has a critical role in the development and terminal differentiation of goblet cells [ 32 ]. Additionally, KLF4 overexpression in human adenocarcinoma cells leads to reduced [3H]-thymidine uptake, whereas inhibition of KFL4 expression increases DNA synthesis, confirming that KLF4 plays an essential role in colon cell growth arrest [ 36 ]. Surprisingly, despite its tumor suppressor activity, KLF4 is overexpressed in colon CSC-enriched spheroids compared with the parental CRC cells from which the spheroids were derived [ 37 ].

Moreover, KLF4 knock-down affects the stemness phenotype and decreases the malignant profile of these CSC-enriched spheroid cells, in line with its role in reprogramming murine fibroblasts into stem cells [ 37 , 38 ]. In agreement with its tumor suppressor activity, KLF4 expression is frequently lost in CRC and its downregulation is strongly associated with tumor development.

Moreover, loss of heterozygosity on chromosome 9q31, where the KLF4 gene is localized, is frequently found in human CRC, and could lead to uncontrolled cell proliferation and to a SC-like phenotype of differentiated cells [ 33 ]. Low KLF4 expression levels are also found in colon adenomas and metastases [ 33 ]. Lee et al. However and surprisingly, they observed that high KLF4 level in normal tissue is correlated with high KLF4 expression in tumors and is associated with poor patient survival [ 39 ].

Additional investigations are needed to elucidate these data; nevertheless, KLF4 expression levels in normal and tumor tissues are prognostic markers for CRC. The transcription factor KLF5 can interact with several components of different signaling pathways e.

In physiological conditions, KLF5 is strongly expressed by intestinal progenitor and stem cells, suggesting a role in cell proliferation control [ 41 ]. Inhibition of KLF5 gene expression in CRC cell lines reduces cell proliferation and transformation as well as anchorage-independent growth [ 42 ]. In patients with CRC, intestinal tumor progression is associated with KLF5 gene upregulation in the primary tumor and also in metastases, compared with healthy tissues [ 41 ]. These findings indicate that KLF5 is a major regulator of intestinal SC proliferation in normal and pathological conditions.

The Notch signaling cascade is one of the major pathway involved in intestinal homeostasis and in the direct regulation of cell fate [ 43 ]. This turns the CSL complex from a transcriptional repressor into a transcriptional activator. This is known as the canonical Notch pathway [ 17 , 43 , 44 ]. In the colon, Notch signaling is an essential gatekeeper of intestinal progenitors and clearly plays an important role in the maintenance of the colon crypt compartment [ 45 ] Figure 2.

Using small-molecule inhibitors and short hairpin RNA-mediated knock-down, it has been demonstrated that Notch prevents apoptosis of colon cancer-initiating cells CCICs and is critical for self-renewal [ 46 ]. In CRC, the Notch pathway is strongly activated compared with normal tissue.

Moreover, expression analysis of resection biopsies from patients with CRC showed that Notch1 expression level is correlated with poor prognosis and is a good predictive marker of cancer progression [ 48 ]. Intriguingly, the expression level of Notch2 is negatively correlated with that of Notch1 in CRC and Notch2 has anti-tumoral properties [ 48 ]. These opposite features could be used to develop a fine prognostic marker of CRC progression and recurrence.

BMI1 is a downstream target of Notch signaling and a key component of the Polycomb group [ 49 ]. BMI1 is expressed in almost all tissue types and regulates a myriad of cellular processes that are critical for cell growth, cell fate decision, development, senescence, aging, DNA damage repair, apoptosis and SC self-renewal [ 49 , 50 ].

Additionally, BMI1 loss decreases murine intestinal SC proliferation and promotes their differentiation into goblet cells [ 49 ].

BMI1 also contributes to the tumor-initiating and self-renewal abilities of human CRC cells because its downregulation inhibits tumor cell growth and is associated with reduction of tumor-initiating cells [ 51 ].

Indeed, a recent study demonstrated that BMI1 represses E-cadherin expression in colon CSCs, thus promoting metastasis formation via epithelial to mesenchymal transition [ 50 ]. BMI1 mRNA and protein are overexpressed in colorectal adenomas and carcinomas compared with normal tissues [ 53 ]. A gradient of BMI1 expression has been reported in human colon precancerous and cancerous tissues and is correlated with the cancer stage, suggesting that BMI1 contributes to CRC progression [ 53 ].

Consequently, high proportion of CSCs in a tumor could be an indicator of poor prognosis [ 31 , 54 , 55 ]. The Hedgehog Hh signaling pathway is a key regulator of intestinal homeostasis. Hh proteins are part of a family of secreted proteins that are involved in the development and maintenance of the gastrointestinal tract [ 17 ]. Aberrant activation of the Hh signaling pathway is associated with tumorigenesis in various tissues.

The roles of Hh signaling differ at each CRC stage, from adenoma to adenocarcinoma [ 56 ]. IHH regulates intestinal SC fates by interfering with the maturation and localization of the underlying stromal cells that in turn generate signaling molecules needed for the maintenance of the intestinal SC niche [ 56 ] Figure 2. IHH, expressed by differentiated enterocytes, indirectly inhibits Wnt signaling at the crypt base and reduces the number of proliferating precursor cells [ 17 , 57 ].

A decrease in Hh signaling is correlated with the expansion of the intestinal SC pool, with blunted enterocyte differentiation and activation of the Wnt pathway. In addition, specific Hh activation in murine stromal cells induces complex transcriptional changes, leading to loss of colon SC-specific gene expression and upregulation of epithelial differentiation markers [ 58 ]. Overexpression of members of the Hh signaling pathway is associated with poor survival and adverse clinical features [ 59 ].

However, in metastatic CRC, treatment with vismodegib, an Hh pathway inhibitor, in combination with standard chemotherapy, does not significantly improve patient survival [ 60 ]. The BMP pathway regulates many cellular mechanisms, including apoptosis and cell growth, depending on the specific cellular context. SMAD transcription factors are the main downstream effectors of BMP signaling that plays key roles in adult gut homeostasis, inflammation and cancer.

Specific inhibition of BMP signaling in intestinal epithelial cell does not lead to initiation of colon tumors in vivo , while suppression in mesenchymal myofibroblasts is associated with spontaneous tumor formation. This suggests that inhibition of BMP signaling in the mesenchymal cells surrounding the intestinal epithelium acts as a trigger of gastrointestinal tumorigenesis [ 61 ].

Recommendations for antithrombotic treatment in stable coronary artery disease patients undergoing percutaneous coronary intervention. These recommendations refer to stents that are supported by large-scale randomized trials with clinical endpoint evaluation leading to an unconditional CE mark. The evidence supporting this recommendation comes from two studies where the zotarolimus-eluting Endeavour stent was investigated in conjunction with a 3 month DAPT regimen.

The activation of blood platelets and the coagulation cascade plays a key role in the initial phase and evolution of an ACS. These trials have been reviewed extensively in a number of meta-analyses. The study demonstrated similar risk patterns for both ischaemia and bleeding when comparing the two drugs. Of note, while prior studies reported a reduced bleeding risk with bivalirudin vs.

Due to its short half-life and favourable results in some of the studies, bivalirudin may be considered as an alternative to UFH in selected cases. Patients may undergo cardiac catheterization after a conservative treatment phase and these patients are commonly treated with fondaparinux during the conservative treatment phase.

Enoxaparin should be considered as anticoagulant for PCI in patients pre-treated with subcutaneous enoxaparin. Nevertheless, it should be considered for bail-out situations or thrombotic complications, and may be used for high-risk PCI in patients without pre-treatment with P2Y 12 -inhibitors.

The available evidence on cangrelor suggests that the potential benefit is independent of the clinical presentation. Recently, the SMART-DATE Smart Angioplasty Research Team-safety of 6-month duration of Dual Antiplatelet Therapy after percutaneous coronary intervention in patients with acute coronary syndromes prospective multicentre randomized trial supported this notion in the setting of contemporary interventional practice.

The authors stated that the increased risk of MI with 6 month DAPT and the wide non-inferiority margin prevented them from concluding that short-term DAPT was safe in this setting, and suggested that prolonged DAPT should remain the standard of care in patients with ACS without excessive risk of bleeding.

Further on, switching and especially a de-escalation of DAPT switching from potent P2Y 12 -inhibitors to clopidogrel was subject to a number of randomized clinical trials. Of note, rivaroxaban has not been investigated in a background of potent P2Y 12 -inhibitors. Recommendations for antithrombotic treatment in patients with non-ST-elevation acute coronary syndromes undergoing percutaneous coronary intervention.

Recommendations for post-interventional and maintenance treatment in patients with non-ST-elevation acute coronary syndromes and ST-elevation myocardial infarction undergoing percutaneous coronary intervention. Randomized data on a comparison of ticagrelor vs. When potent P2Y 12 receptor inhibitors are contraindicated or are not available, clopidogrel should be given for primary PCI instead. Likewise, the incidence of a combined ischaemic endpoint death, MI, stroke, stent thrombosis, and urgent revascularization did not differ between the two treatment arms.

A number of RCTs compared bivalirudin vs. Of note, the bail-out scenarios have never been addressed in randomized controlled trials. For reasons discussed above see sections Recommendations for antithrombotic treatment in ST-elevation myocardial infarction patients undergoing percutaneous coronary intervention. Accordingly, the recommendation tables in this section are taken from the Focused Update.

For a detailed discussion, we refer the reader to the Focused Update. Compared with OAC therapy alone, the addition of DAPT to OAC therapy results in a two- to three-fold increase in bleeding complications, suggesting that every effort should be undertaken to avoid bleeding Table 8. Of note, previous randomized studies evaluating the duration of triple therapy or the benefit of NOACs vs.

The rate of bleeding events peaked within the first 30 days of initiation of triple therapy, and was twice as high when compared with the rate of acute coronary events including recurrent MI and stent thrombosis. For these reasons, the duration of triple therapy should be minimized depending on bleeding and ischaemic risks see Tables 8 to 10 for guidance in decision-making.

In stabilized event-free patients, discontinuation of any antiplatelet agent at 1 year after stenting is encouraged, while dual therapy may be continued beyond 1 year according to the stent-driven risk shown in Table 9. However, as compared with triple therapy, an increase in both MI 4. Although statistical significance was missed, these findings raise concern about the efficacy of the lower dabigatran dose in combination with single antiplatelet therapy in preventing coronary events.

Thus, the mg b. At present, evidence for a dual treatment approach is available for VKA, rivaroxaban, and dabigatran, but none of these studies were powered to assess the efficacy of preventing stent thrombosis or thrombo-embolic events and only RE-DUAL used a NOAC dose that was previously shown to be effective in the prevention of thrombo-embolic events.

Edoxaban is currently being investigated in a setting of triple treatment in the ENTRUST-AF-PCI Evaluation of the safety and efficacy of an edoxaban-based antithrombotic regimen in patients with atrial fibrillation following successful percutaneous coronary intervention trial ClinicalTrials.

Adapted from Valgimigli et al. Unfavourable patient profile for a combination of oral anticoagulant and antiplatelet therapy. Dual antiplatelet therapy duration in patients with indication for oral anticoagulation. Apixaban 5 mg b. Figure 11 illustrates applicable DAPT algorithms in patients with an indication for OAC undergoing PCI with the respective classes of recommendations for the different treatment regimens. Algorithm for dual antiplatelet therapy in patients with an indication for oral anticoagulation undergoing percutaneous coronary intervention.

See the Supplementary Data. The value of pre-hospital pre-treatment with prasugrel in STEMI patients, as well as the safety and efficacy of ticagrelor given at hospital admission in NSTE-ACS patients, has not been addressed in dedicated randomized studies.

The clinical benefit of a short-term DAPT duration followed by long-term ticagrelor monotherapy and stopping aspirin remains unknown. Operator experience influences outcomes, particularly in critical, complex situations. Greater total experience of an entire hospital team—consisting of the supporting members in the operating room or catheterization laboratory and those responsible for postoperative care—results in more favourable outcomes.

Studies have suggested that the volume of CABG surgery in a hospital significantly impacts in-hospital mortality, although no consistent cut-offs for volume were used in these studies. Apart from hospital volume, higher surgeon volume also appears to be inversely related to operative mortality. Birkmeyer et al. Several studies suggest that quality measures are more important than volume per se. Numerous studies have investigated the relationship between the volume of procedures and outcomes of PCI, suggesting a volume—outcome relationship at the operator level, as well as at the institutional level.

A large study in the USA reported that, in a cohort of 36 patients undergoing primary PCI, in-hospital mortality was significantly lower in institutions with higher primary PCI volumes 5. A European training programme in interventional cardiology has been proposed by the EAPCI in order to ensure the high quality of patient care and clinical excellence. However, the pace at which proficiency reaches certain acceptable standards differs from trainee to trainee.

Myocardial revascularization must be accompanied by medical therapy and other secondary prevention strategies for risk factor modification and permanent lifestyle changes. These measures are discussed in detail in the European Guidelines on Cardiovascular Disease Prevention that were published in The need to detect restenosis has reduced in the DES era. Nevertheless, the recurrence of symptoms or ischaemia due to disease progression or restenosis deserves attention.

Strategies for follow-up and management in patients after myocardial revascularization. In all studies to date on the optimal follow-up after PCI, the gain from discovering patients with restenosis is obscured by the high rate of false positive exercise ECG tests indicating ischaemia. Therefore, simple exercise ECG testing is not recommended for follow-up and a non-invasive imaging approach is preferred. Specific studies to clarify which subset of patients benefits more from a specific follow-up approach are missing.

More studies are needed to assess the role of CT angiography in patient surveillance after myocardial revascularization. Myocardial revascularization is performed for the relief of symptoms of myocardial ischaemia and the improvement of prognosis. In SCAD, the prognostic benefit is dependent on the extent of myocardium subject to ischaemia.

The prognostic and symptomatic benefits of myocardial revascularization critically depend on the completeness of revascularization. Therefore, the ability to achieve complete revascularization is a key issue when choosing the appropriate treatment strategy. This calls for the Heart Team to be consulted to develop individualized treatment concepts, with respect for the preferences of the patient who has been informed about early and late outcomes.

Radial access is preferred for any PCI irrespective of clinical presentation, unless there are overriding procedural considerations. Based on this judgement, treatment durations for DAPT after DES that are as short as 1 month or even as long as lifelong may be reasonable.

Off-pump surgery with no-touch aorta for high-risk patients should be considered when expertise exists. The disclosure forms of all experts involved in the development of these Guidelines are available on the ESC website www. ESC entities having participated in the development of this document:. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating.

Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies.

Eur Heart J ; 34 : — Google Scholar. Diagnostic accuracy of fractional flow reserve from anatomic CT angiography. JAMA ; : — J Am Coll Cardiol ; 63 : — Clinical outcomes of fractional flow reserve by computed tomographic angiography-guided diagnostic strategies vs.

Eur Heart J ; 36 : — Eur Heart J ; 37 : — Ffluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: A randomized, controlled trial PARR J Am Coll Cardiol ; 50 : — The International Society for Heart Lung Transplantation listing criteria for heart transplantation: A year update.

J Heart Lung Transplant ; 35 : 1 — J Heart Lung Transplant ; 32 : — Myocardial viability and survival in ischemic left ventricular dysfunction. N Engl J Med ; : — Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: A meta-analysis.

J Am Coll Cardiol ; 39 : — Identification of therapeutic benefit from revascularization in patients with left ventricular systolic dysfunction: Inducible ischemia versus hibernating myocardium. Circ Cardiovasc Imaging ; 6 : — Circulation ; : — Long-term follow-up after deferral of percutaneous transluminal coronary angioplasty of intermediate stenosis on the basis of coronary pressure measurement. J Am Coll Cardiol ; 31 : — Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: A randomized trial.

J Am Coll Cardiol ; 49 : — Significance of intermediate values of fractional flow reserve in patients with coronary artery disease. Use of the instantaneous wave-free ratio or fractional flow reserve in PCI.

Instantaneous wave-free ratio versus fractional flow reserve to guide PCI. Outcome impact of coronary revascularization strategy reclassification with fractional flow reserve at time of diagnostic angiography: Insights from a large French multicenter fractional flow reserve registry. Does routine pressure wire assessment influence management strategy at coronary angiography for diagnosis of chest pain? Circ Cardiovasc Interv ; 7 : — Impact of routine fractional flow reserve evaluation during coronary angiography on management strategy and clinical outcome: One-year results of the POST-IT.

Circ Cardiovasc Interv ; 9 : e Circ Cardiovasc Interv ; 10 : e Routine fractional flow reserve combined to diagnostic coronary angiography as a one-stop procedure: Episode 3. Prognostic value of fractional flow reserve: Linking physiologic severity to clinical outcomes. J Am Coll Cardiol ; 64 : — Long-term outcomes following fractional flow reserve-guided treatment of angiographically ambiguous left main coronary artery disease: A meta-analysis of prospective cohort studies.

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Circ Cardiovasc Interv ; 6 : — Fractional flow reserve-guided versus angiography-guided coronary artery bypass graft surgery. Sign In. ESC Publications. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Table of contents. Abbreviations and acronyms. Journal Article. Corresponding authors. Oxford Academic. Miguel Sousa-Uva. Following the activation, the endocytosis of the insulin receptor is the primary physiological mechanism through which the duration and intensity of insulin signaling are controlled.

Hyperinsulinemia accelerates insulin receptor endocytosis and affects the presence of adequate functional insulin receptors at the plasma membrane resulting in insulin resistance [ ]. Apart from accelerated insulin receptor endocytosis, insulin-stimulated insulin receptor kinase activity is also decreased in diabetic patients [ ]. Compromised insulin signaling in T2DM fails to activate glucose metabolic enzymes like glucokinase and hexokinase resulting in hyperglycemia. The rising insulin levels should be normalized over time because of the renal insulin clearance mechanism.

But compromised renal insulin clearance rate in diabetic subjects results in abnormally high plasma levels of insulin hyperinsulinemia [ , ]. Hyperinsulinemia and hyperglycemia in theory cannot trigger alpha cells to secrete glucagon. But it has been observed that T2DM patients with insulin resistance, hyperinsulinemia, and hyperglycemia also have abnormally high plasma levels of glucagon [ ].

T2D has also been attributed to altering the gene expression of key proteins participating in the processes of insulin secretion and function. ATP also enhances insulin granular priming prior to the exocytosis and thus regulates insulin quantity by initiating the modification of proinsulin into insulin inside the insulin granule.

Hyperglycemia-induced production of AGE products and the subsequent activation of AGE receptors further promote the release of cytochrome and caspase activation [ ]. Glucolipotoxicity induces a cascade of events that starts from mitochondrial dysfunction leading to oxidative stress ROS which further leads to ER stress which results in improper protein unfolding response and results in the loss of GSIS and inflammation and activated autophagy.

These above-mentioned cascades of events represent altered cell signaling pathways, lipogenic and pro-apoptotic genes, and proteins, increased expression of cytokines, and accumulation of lipids molecules like di and triacylglycerols, cholesterol, and cholesterol esters.

Dedifferentiation is defined as the ability of a cell to revert to its progenitor-like stage developmental stage. This also explains the abnormally high levels of glucagon observed in T2D patients with hyperglycemia, where glucose fails to down-regulate the glucagon gene expression. DNA methylation, chromatin modifications, and post-translational modifications of histones have been implicated as the main epigenetic mechanisms.

Activation of their transcriptional activity results in the formation of miRNAs. As discussed earlier, different molecular components are involved in the secretion of insulin in response to the rising blood glucose levels. The insulin gene transcription results in the generation of mRNA which is translated in preproinsulin and cleaved into proinsulin in the endoplasmic reticulum [ , , , ].

Insulin gene ins1 expression has been found to be compromised after the deletion or inactivation of Dicer1 gene [ 27 , 28 ]. Interestingly these correlations were found to be absent in the isolated islets of glucose-intolerant diabetic donors [ ].

All these proteins are vital in the insulin gene transcriptional activity as well as the insulin signaling via insulin receptors. This is particularly important as GLP-1 receptor agonists are primary drugs used by T2DM patients to increase insulin levels.

This transcription factor upregulates the granuphilin protein gene expression. Granuphilin protein blocks the exocytosis of secretory granules in endocrine cells.

The characteristic hallmark of T2D is the dysregulation of lipid metabolism and subsequent obesity. It has been demonstrated that in cultured human islets, the miRNA level increased after the exposure to pro-inflammatory cytokines and decreased exposure to high glucose concentrations but interestingly miRNA levels were unchanged after the palmitate exposure [ ].

When INS-1 cells were supplemented with miRNAp inhibitors a significant increase in the cellular viability and palmitate-induced apoptosis was observed [ ].

As the mechanisms involved in the biogenesis of microRNAs are well understood, it is plausible to assume that microRNAs represent attractive therapeutic targets. Selective inhibition of Dicer molecules by using specific siRNAs or pharmacological tools and selective modulation of a single microRNA. Specific microRNAs involved in diabetes represent a new class of specialized biomarkers for the early detection of diabetes. As microRNAs are biochemically quite stable in the extracellular fluid like blood, they represent a very good biomarker for diagnostics.

Further in-depth studies are needed to assess the predictive value of serum levels of microRNAs in relation to the disease progression. Novel therapeutic approaches need to be devised for the prevention and treatment of metabolic disorders.

Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Impact of this chapter. Abstract Recent reports of diabetes susceptibility loci located on the non-coding regions of the genome highlight the importance of epigenetic control in health and disease.

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