\r\n\tThis book chapter’s main theme will be focused on transmission dynamics, pathogenesis, mechanisms of host interaction and response, epigenetics and markers, molecular diagnosis, RNA interacting proteins, RNA binding proteins, advanced development of tools for diagnosis, possible development of concepts for vaccines and anti drugs for RNA viruses, immunological mechanisms, treatment, prevention and control. \r\n\t
",isbn:"978-1-80355-667-3",printIsbn:"978-1-80355-666-6",pdfIsbn:"978-1-80355-668-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"52f8a3a1486912beae40b34ac557fed3",bookSignature:"Ph.D. Yogendra Shah",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11369.jpg",keywords:"HIV, Dengue, Zika, West Nile Virus, Chikungunya, Rabies, SARS-CoV2, MERS-CoV, Hanta Virus, Influenza, Whole Genome Sequencing, DNA Sequencing",numberOfDownloads:217,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 4th 2021",dateEndSecondStepPublish:"November 1st 2021",dateEndThirdStepPublish:"December 31st 2021",dateEndFourthStepPublish:"March 21st 2022",dateEndFifthStepPublish:"May 20th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"9 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Dr. Shah obtained his Ph.D. degree in Veterinary Medicine from Hokkaido University, Japan. 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1. Introduction
Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle wasting disorder caused by mutations in the DMD gene [1, 2], affecting 1 in 3500–5000 male births. Serum creatine kinase (CK) levels are elevated at birth, and motor milestones are delayed. Reduced motor skills between age 3 and 5 years provoke diagnostic evaluation. Quality of life for boys with DMD is further affected early in life, with the inability to keep up with peers of early school age and loss of ambulation by 12 years of age; premature death occurs at 20–30 years of age due to respiratory and cardiac complications (https://www.duchenne.com/about-duchenne; https://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy).
Mutations of the DMD gene cause complete (Duchenne) or partial (Becker) loss of dystrophin protein at the sarcolemma [3]. In normal muscle cells, dystrophin forms a complex with glycoproteins at the sarcolemma, forming a critical link between the extracellular matrix (ECM) and the cytoskeleton [4]. Without the complex, the sarcolemma becomes fragile and is easily disrupted by mechanical stress [4, 5].
Except for corticosteroids, there is currently no effective treatment for DMD [6]. In this chapter, we discuss the potential of mesenchymal stem cells as a therapeutic tool for DMD patients. Many researchers prefer the term ‘mesenchymal stromal cells’ or ‘mesenchymal progenitors’ to mesenchymal stem cells because mesenchymal stem cells with self-renewal and trilineage differentiation potential are a minor subpopulation in tissue-derived primary cultures of mesenchymal cells. In this chapter, however, we uniformly refer to them as mesenchymal stem cells.
2. The pathological changes in DMD muscle
The absence of dystrophin causes loss of the dystrophin-associated protein complex (DAPC) at the sarcolemma. The sarcolemma lacking the complex becomes vulnerable to mechanical stress. In addition, signalling through dystrophin-DAPC-associated molecules such as nNOS is disturbed [4, 5]. As a result, myofibres die in large numbers by contraction-induced mechanical stress, and to regenerate injured myofibres, inflammatory cells begin to remove debris of the muscle tissue; at the same time, muscle satellite cells are activated, proliferate and fuse with damaged myofibres. In the case of DMD, however, the cycle of degeneration and regeneration of myofibres repeats throughout life. Therefore, secondary pathological changes gradually develop, including perturbation of calcium homeostasis, activation of Ca2+-dependent proteases, mitochondrial dysfunction in myofibres, impaired regeneration of myofibres due to exhaustion of satellite cells, prolonged inflammation, disturbed immune response, fibrosis and fatty infiltration, with poor vascular adaptation and functional ischaemia [6]. These secondary pathological changes accelerate the disease course of DMD, resulting in severe loss of myofibres and muscle atrophy. Therefore, in addition to the restoration of dystrophin protein by gene therapy or stem cell therapy, blockage of secondary pathological events is an important therapeutic strategy for DMD (Figure 1).
Figure 1.
Deficiency of dystrophin protein at the sarcolemma causes multiple pathological changes in DMD muscle [6, 7].
3. Muscle stem cells as a cell-based therapy for DMD
Upon injury, muscle satellite cells are activated, proliferate, and either fuse with damaged myofibres or fuse with each other to form new myofibres [8]. In DMD muscle, satellite cells compensate for muscle fibre loss in the early stages of the disease but eventually are exhausted. As a result, in DMD muscle, the myofibres are gradually replaced with fibrous and fatty connective tissue. Therefore, stem cell transplantation is expected to be a potential therapy for DMD [9].
There are different kinds of stem cells with myogenic potential in skeletal muscle. Muscle satellite cells are authentic unipotent skeletal muscle-specific stem cells [8]. Muscle-derived stem cells (MDSCs) [10] and mesangioblasts [11] were reported to be multipotent and transplantable via circulation; therefore, they are expected to be promising tools for cell-based therapies for DMD. Recently, muscle progenitors were induced from pluripotent stem cells as a cell source for cell-based therapy of DMD because induced pluripotent stem cells (iPSCs) can be expanded without losing pluripotency [12]. Myogenic cells induced from iPSCs are usually at a foetal stage and poorly engraft in the muscle of immunodeficient DMD model mice [13, 14].
In addition, muscles affected by muscular dystrophies are in a state of continuous inflammation and are characterised by marked and sustained infiltration of inflammatory and immune cells with fibrosis and adipose replacement. Such pathological microenvironments would not support survival, proliferation, and differentiation of the transplanted stem cells. Therefore, researchers have started to consider not only the properties of stem cells but also the microenvironment.
4. Muscle-resident mesenchymal stem cells (progenitors) are indispensable for muscle homeostasis
Skeletal muscle regenerates when it is injured. The regeneration process is complex but well organised, depending on the interaction among different types of cells: muscle stem/progenitor cells, muscle-resident mesenchymal progenitors and cells involved in inflammatory and innate and adaptive immune responses. Dynamic extracellular matrix (ECM) remodelling is also required for successful muscle regeneration. In the case of a minor traumatic injury, muscle regeneration is rapidly completed by the interplay of these cells. In muscular dystrophies, however, the degeneration/regeneration process is repeated for a long time, causing exhaustion of muscle satellite cells and finally resulting in severe atrophy of skeletal muscles with a loss of myofibres and extensive fibrosis and fat deposition [15].
Fibro/adipogenic progenitors (FAPs) are tissue-resident mesenchymal stem (or stromal or progenitor) cells [16, 17]. Recently, the necessity of FAPs for skeletal muscle regeneration and maintenance was demonstrated using mouse models [18]. The authors demonstrated that depletion of FAPs resulted in loss of expansion of muscle stem cells (MuSCs) and haematopoietic cells after injury and impaired skeletal muscle regeneration [18]. Furthermore, FAP-depleted mice under homeostatic conditions exhibited muscle atrophy and a loss of MuSCs, revealing that FAPs are essential for long-term homeostatic maintenance of skeletal muscle and the MuSC pool [18].
FAPs have dual functions [19, 20]. In small-scale traumatic muscle injury, they are activated, expand and promote muscle regeneration. When regeneration is completed, FAPs are cleared from the regenerated muscle. In pathological conditions, such as muscular dystrophies, they continue to proliferate and contribute to fibrosis and fatty tissue accumulation.
How is the fate of FAPs regulated? Apparently, FAPs are regulated by signals from myogenic cells and immune cells. Altered signals from these cells in dystrophic muscle change the pro-regenerative FAPs to fibrotic and adipogenic types. Recently, Hogarth et al. reported that annexin A2 accumulation in the myofibre matrix promotes adipogenic replacement of FAPs in dysferlin-deficient LGMD2B model mice. The authors also showed that an MMP-14 inhibitor, Batimastat, inhibited adipogenesis of FAP. The authors speculate that Annexin A2 and MMP-14 both prolong the inflammatory environment, therefore causing excessive expansion of FAP in diseased muscle [21]. Pharmacological inhibition of FAP expansion may be a good strategy to prevent fibro/adipogenic changes in dystrophic muscles.
The signals that regulate FAPs remain largely unclear. Interestingly, treating FAPs of young mdx mice with trichostatin A (TSA), a histone deacetylase inhibitor, blocked their fibrotic and adipogenic differentiation and promoted a myogenic fate [22] by changing chromatin structure [23]. TSA treatment decreased the expression of adipogenic genes and upregulated myogenic genes in FAPs [22].
5. Inflammation and immune responses in muscular dystrophies
Inflammatory and immune cells (neutrophils, eosinophils, basophils, macrophage NK cells, dendritic cells, T cells, B cells, etc.) are key regulators of muscle regeneration. In particular, macrophages orchestrate the regeneration process. In the early phase of muscle regeneration, M1 (inflammatory) macrophages remove necrotic tissues by phagocytosis and inhibit fusion of myogenic precursor cells. In the later stage, M2 (regulatory) macrophages gradually replace M1 macrophages and play anti-inflammatory and pro-regenerating roles by promoting the differentiation of myogenic cells and the neovascularization of regenerating muscle regeneration [24].
DMD muscle, which remains dystrophin-deficient, experiences continuous cycles of necrosis and regeneration of myofibres. This causes chronic inflammation and evokes T cell-mediated immune responses, which involves the coexistence of both M1 and M2 macrophages and T cells in the muscle, and it further damages myofibres and exacerbates fibrosis and adipocyte infiltration [6, 25, 26]. Therefore, pharmacological inhibition of excess inflammation and immune response is a reasonable therapeutic strategy for DMD.
6. Mesenchymal stem cells as a therapeutic tool for DMD
As a therapeutic tool for regenerative medicine, mesenchymal stem cells (MSCs) have received significant attention in the recent years due to their high growth potential, paracrine effects, immunomodulatory function and few reported adverse effects [27, 28]. Since MSCs show relatively low immunogenicity due to low expression of major histocompatibility (MHC) antigens and their immunomodulation function, they are being used even in allogeneic settings.
6.1 Definition
To facilitate research on MSCs, the International Society of Cellular Therapy (ISCT) formulated minimal criteria for defining multipotent MSCs in 2006 [29]. First, MSCs must be plastic adherent when maintained in standard culture conditions. Second, MSCs must express CD105, CD73 and CD90 and must not express CD45, CD34, CD14, CD11b, CD79alpha, CD19 and HLA-DR surface molecules. Third, MSCs must differentiate into osteoblasts, adipocytes and chondrocytes under standard in vitro differentiation protocols [29].
6.2 Preparation
Historically, MSCs were isolated from bone marrow [30, 31, 32, 33]. Currently, MSCs are shown to exist in the perivascular niche in nearly all tissues and are prepared from a variety of tissues, such as the umbilical cord [34], placenta [35], adipose tissue [36] and dental tissues [37]. Preparation of MSCs from those tissues is less invasive than it is from BM. MSCs from different tissues have similar functions, but detailed comparative studies revealed that MSCs of different origins possess different properties [38].
6.3 Differentiation
MSCs are multipotent stem cells that undergo self-renewal and differentiate into multiple tissues of the mesenchymal lineage and into a non-mesenchymal lineage, including neurons, glia, endothelial cells, hepatocytes and β cells in the pancreas [27]. This wide range of differentiation capacities is one reason why mesenchymal stem cells are being tested in almost 1000 clinical trials in regenerative medicine for the musculoskeletal system, nervous system, myocardium, liver, skin and immune diseases (http://ClinicalTrial.gov). Importantly, the differentiation potential of MSCs varies according to their origin, method of isolation and in vitro propagation procedures [39, 40, 41].
6.4 Secretome of MSCs
MSCs secrete a variety of bioactive molecules, such as growth factors, chemokines and cytokines. These molecules regulate the survival, proliferation and differentiation of target cells, promote angiogenesis and tissue repair and modulate inflammation and innate or acquired immunity. It is widely accepted that the therapeutic effects of MSCs in preclinical and clinical trials are largely due to their paracrine function [27]. Importantly, the secretome of MSCs varies depending on the age of the donor and the niches where the cells reside [42]. Therefore, it is expected that the therapeutic effects of MSCs with different origins exert will be different.
6.5 Transplanted MSCs ameliorate dystrophic phenotypes of DMD muscle?
6.5.1 Mechanisms of amelioration of the dystrophic phenotype by MSCs
Recently, there has been considerable interest in the clinical application of MSCs for the treatment of muscle diseases. However, the myogenic potential of MSCs is controversial.
Sassoli et al. found that myoblast proliferation was greatly enhanced in coculture with bone marrow MSCs [43]. Myoblasts after coculture expressed higher levels of Notch-1, a key determinant of myoblast activation and proliferation. Interestingly, the effects were mediated by vascular endothelial growth factor (VEGF) secreted by MSCs [43]. A VEGFR2 inhibitor, KRN633, inhibited the positive effects of MSC-CM on C2C12 cell growth and Notch-1 signalling [43]. Linard et al. showed successful regeneration of rump muscle by local transplantation of bone marrow MSCs (BM-MSCs) after severe radiation burn using a pig model [44]. The authors speculate that locally injected BM-MSCs secreted growth factors such as VEGF and promoted angiogenesis. The authors also showed that MSCs supported the maintenance of the satellite cell pool and created a good macrophage M1/M2 balance. Nakamura et al. reported that transplantation of MSCs promoted the regeneration of skeletal muscle in a rat injury model without differentiation into skeletal myofibres. The report suggests that MSCs contribute to the regeneration of skeletal muscle by paracrine mechanisms [45]. Maeda et al. reported that BM-MSCs transplanted into peritoneal cavities of dystrophin/utrophin double-knockout (dko) mice strongly suppressed dystrophic pathology and extended the lifespan of treated mice [46]. The authors speculated that CXCL12 and osteopontin from BM-MSCs improved muscle regeneration. Bouglé et al. also reported that human adipose-derived MSCs improved the muscle phenotype of DMD mice via the paracrine effects of MSCs [47].
In addition to soluble factors, recent studies demonstrated that MSCs secrete a large number of exosomes for intercellular communication [48, 49]. These exosomes are now expected to be a therapeutic tool for many diseases [50, 51]. Nakamura et al. reported that exosomes from MSCs contained miRNAs that promoted muscle regeneration and reduced the fibrotic area [45]. Bier et al. reported that intramuscular transplantation of PL-MSCs in mdx mice decreased the serum CK level, reduced fibrosis in the diaphragm and cardiac muscles and inhibited inflammation, partly via exosomal miR-29c [49]. Thus, MSC exosomes or MSC cytokines may provide a cell-free therapeutic strategy as an alternative to transplanting MSCs.
On the other hand, Saito et al. reported that BM-MSCs and periosteum MSCs differentiated into myofibres and restored dystrophin expression in mdx mice, although the efficiency was low (3%) [52]. Liu et al. showed that FLK-1+ adipose-derived MSCs restored dystrophin expression in mdx mice [53]. Feng et al. reported that intravenously delivered BM-MSCs increased dystrophin expression in mdx mice [54]. Vieira et al. reported that intravenously injected human adipose-derived MSCs successfully reached the muscle of golden retriever muscular dystrophy (GRMD) dogs and that they expressed human dystrophin [55]. Furthermore, Park et al. reported that human tonsil-derived MSCs (T-MSCs) differentiated into myogenic cells in vitro, and transplantation promoted the recovery of muscle function, as demonstrated by gait assessment (footprint analysis); furthermore, such treatment restored the shape of skeletal muscle in mice with a partial myectomy of the gastrocnemius muscle [56]. These reports suggest that MSCs directly contribute to the regeneration of myofibres and restore dystrophin expression.
7. MSCs regulate inflammation and the immune response in muscular dystrophies
In response to damage signals, perivascular MSCs are activated and recruit inflammatory and immune cells and promote inflammation. At a later stage, MSCs begin to suppress inflammation and the immune response. On the other hand, MSCs in circulation are reported to selectively home towards damaged tissue [57]. Once homed, the inflammatory environment stimulates MSCs to produce a large amount of bioactive molecules or to directly interact with inflammatory and immune cells to regulate inflammation and the immune response.
The therapeutic effects of MSCs in preclinical or clinical trials are thought to be partly the result of modulation of innate and adaptive immunity [27], especially through monocyte/macrophage modulation [28]. Inflammation and immune response are part of the pathology of DMD muscle. Therefore, the immunomodulatory functions of MSCs might be useful for the treatment of DMD.
MSCs are supposed to modulate inflammation and the immune response by (a) suppressing the maturation and function of dendritic cells [58, 59, 60], (b) promoting macrophage differentiation towards an M2-like phenotype with high tissue remodelling potential and anti-inflammatory activity [61], (c) inhibiting Th17 generation and function [62, 63], (d) inhibiting Th1 cell generation [64], (e) suppressing NK [65, 66] and T cytotoxic cell function [66], (f) stimulating the generation of Th2 cells [67] and (g) inducing Treg cells [64, 66, 68].
Pinheiro et al. investigated the effects of adipose-derived mesenchymal stem cell (AD-MSC) transplantation on dystrophin-deficient mice. Local injection of AD-MSCs improved histological phenotypes and muscle function [69]. AD-MSCs decreased the muscle content of TNF-α, IL-6, TGF-β1 and oxidative stress but increased the levels of VEGF, IL-10 and IL-4 [69]. MSC-derived IL-4 and IL-10 are reported to convert M1 (pro-inflammatory) macrophages to the M2 (anti-inflammatory) type and promote satellite cell differentiation [70]. These results suggest that transplanted AD-MSCs ameliorated the dystrophic phenotype partly by modulating inflammation.
7.1 Suppression of the immune response by MSCs potentiates gene therapy and cell-based therapy
In a clinical trial of gene therapy using a dystrophin transgene, T cells specific to epitopes of pre-existing dystrophin in revertant fibres were detected, suggesting the existence of autoreactive T-cell immunity against dystrophin before treatment [71]. Currently, exon skipping therapy to restore the reading frame of the DMD gene, and readthrough therapy of premature stop codons (e.g. aminoglycosides or ataluren), is being tested in patients with DMD. The treated patients start to produce dystrophin, which provides new epitopes to them. Suppression of undesirable immune responses against newly produced dystrophin might improve the efficiency of gene therapy.
Transplantation of myogenic cells also evokes innate and acquired immune responses against transplanted cells in the recipient. Therefore, immunosuppression by MSCs is expected to improve the engraftment of transplanted cells and the therapeutic effects of cell therapy. In addition, MSCs support the survival, proliferation, migration and differentiation of myogenic cells by secreting trophic factors.
8. Mesenchymal stem cells induced from pluripotent stem cells (iPSCs)
8.1 MSC-like cells induced from human pluripotent stem cells (iMSCs) have properties that are different from tissue MSCs
Although BM-MSCs are well studied and widely tested in regenerative medicine, the collection procedure for bone marrow is invasive and painful. In addition, adult BM-MSCs cannot be expanded in culture beyond 10 passages [72]. To obtain MSCs with higher proliferative potential, other sources of MSCs are gaining attention, such as the umbilical cord and the placenta. MSCs from these sources proliferate better than BM-MSCs but still show limited proliferative activity [38].
hiPSCs can be expanded in vitro without loss of pluripotency and are therefore an ideal source for deriving mesenchymal stem cells of high quality in a large quantity [73, 74, 75]. In addition, unlike human ES cells, iPSCs are not accompanied by ethical concerns. To date, many protocols have been reported for the deviation of mesenchymal stem cells from human ES cells/iPS cells [73, 74, 75, 76, 77], although the difference in properties among iMSCs induced by different protocols remains to be determined [73, 74, 77]. For clinical use, iMSCs would be generated from well-characterised, pathogen-free, banked iPSCs with known HLA types or from patient-specific iPSCs.
8.2 Are MSCs induced from human pluripotent stem cells (iMSCs) ideal for clinical use?
MSCs induced from human iPS cells are generally characterised as reprogrammed, rejuvenated MSCs with high proliferative activity [78]. A previous study reported that MSCs from human iPSCs could be expanded for approximately 40 passages (120 population doublings) without obvious loss of plasticity or onset of replicative senescence [79]. In addition, iMSCs have been shown to exhibit potent immune-modulatory function and therapeutic properties (Table 1) [83]. Spitzhorn et al. reported that iMSCs did not form tumours after transplantation into the liver [84], but to exclude residual undifferentiated iPS cells, purification of MSCs by FACS using MSC markers and careful evaluation of the risk of tumour formation would be required for each preparation.
BM-MSCs
Induced MSCs from ES/iPS cells
Preparation
Autologous or allogeneic, invasive
Many protocols for deviation scale-up production [73, 74, 75, 76, 77]
Being tested in preclinical and clinical trials without serious side effects
Unlimited source of MSCs; autologous MSCs are available
Genome editing
Difficult
Possible
Table 1.
Comparison of properties of human iMSCs with human BM-MSCs.
8.3 iMSCs for muscle disease
The therapeutic potential of iMSCs has been tested in bone regeneration [83, 85], intestinal healing [86], myocardial disorders [82, 87], limb ischaemia [79] and autoimmune disease [88, 89]. In these studies, iMSCs showed therapeutic effects that were comparable or superior to those of tissue MSCs. In the muscular dystrophy field, there are only a small number of reports so far. Jeong et al. reported that iMSCs transplanted into the tibialis anterior of mdx mice decreased oxidative damage, as evidenced by a reduction in nitrotyrosine levels, and achieved normal dystrophin expression levels [90]. Since direct differentiation of MSCs into myogenic cells is generally limited, the observed effects of iMSCs might be due to the secretion of bioactive molecules that exert immunomodulatory effects and provide trophic support to myogenic cells.
Importantly, however, Liu et al. recently reported that transplantation of BM-MSCs from C57BL/6 mice aggravated inflammation, oxidative stress and fibrosis and impaired regeneration of contusion-injured C57/Bl6 muscle [91]. Although the mechanisms are not clear, the microenvironment in contusion-damaged muscle might induce the transformation of MSCs into the fibrotic phenotype. Caution might be warranted in the clinical application of MSCs to highly fibrotic muscle.
9. Conclusions
MSCs are multifunctional cells. MSCs secrete trophic factors that help regenerate myofibres. In addition, MSCs suppress inflammation and the immune response in dystrophic mice to protect muscle. MSCs are also expected to support the engraftment of transplanted myogenic cells in recipient muscle. Fortunately, recent technology gives us an option to derive MSC-like cells from pluripotent stem cells. Thus, MSCs are a promising next-generation tool for cell-based therapy of DMD (Figure 2).
Figure 2.
Mesenchymal stem cells ameliorate the dystrophic phenotype of DMD muscle. Mesenchymal stem-like cells can be derived from human iPSCs (iMSCs). MSCs, which arrive in the muscle either through direction transplantation or via circulation, secrete a variety of bioactive molecules that promote angiogenesis and support the proliferation and differentiation of satellite cells, thereby promoting muscle regeneration. MSCs also suppress excess inflammatory and immune responses. Whether transplanted MSCs can directly modulate the phenotype of FAPs (resident MSCs) to inhibit fibrosis and fatty replacement remains to be determined. Abbreviations: DC, dendritic cells; NK, natural killer cells; Neu, neutrophil; Mø, macrophage; T, T lymphocytes; B, B lymphocyte.
Acknowledgments
A.E. is supported by the Channel System Program (CPS) of the Egyptian and Japanese governments. This study was supported by (1) ‘Research on refractory musculoskeletal diseases using disease-specific induced pluripotent stem (iPS) cells’ from the Research Center Network for Realization of Regenerative Medicine, Japan Agency for Medical Research and Development (AMED), (2) Grants-in-aid for Scientific Research (C) (16K08725 and 19K075190001) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan and (3) Intramural Research Grants (30-9) for Neurological and Psychiatric Disorders of NCNP.
Conflict of interest
The authors declare no conflicts of interest.
\n',keywords:"mesenchymal stem cells, induced pluripotent stem cells, induced MSCs, Duchenne muscular dystrophy, immune response, paracrine factors, cell transplantation, muscle regeneration, dystrophin, satellite cells, inflammation, skeletal muscle, fibrosis, adipocyte",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/72849.pdf",chapterXML:"https://mts.intechopen.com/source/xml/72849.xml",downloadPdfUrl:"/chapter/pdf-download/72849",previewPdfUrl:"/chapter/pdf-preview/72849",totalDownloads:825,totalViews:0,totalCrossrefCites:2,totalDimensionsCites:3,totalAltmetricsMentions:0,introChapter:null,impactScore:2,impactScorePercentile:78,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"December 4th 2019",dateReviewed:"May 14th 2020",datePrePublished:"July 17th 2020",datePublished:"December 23rd 2020",dateFinished:"July 17th 2020",readingETA:"0",abstract:"Mesenchymal stem cells (MSCs) are multipotent stem cells that can be isolated from both foetal and adult tissues. Several groups demonstrated that transplantation of MSCs promoted the regeneration of skeletal muscle and ameliorated muscular dystrophy in animal models. Mesenchymal stem cells in skeletal muscle, also known as fibro-adipogenic progenitors (FAPs), are essential for the maintenance of skeletal muscle. Importantly, they contribute to fibrosis and fat accumulation in dystrophic muscle. Therefore, MSCs in muscle are a pharmacological target for the treatment of muscular dystrophies. In this chapter, we briefly update the knowledge on mesenchymal stem/progenitor cells and discuss their therapeutic potential as a regenerative medicine treatment of Duchenne muscular dystrophy.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/72849",risUrl:"/chapter/ris/72849",book:{id:"9477",slug:"muscular-dystrophy-research-updates-and-therapeutic-strategies"},signatures:"Ahmed Elhussieny, Ken’ichiro Nogami, Fusako Sakai-Takemura, Yusuke Maruyama, AbdElraouf Omar Abdelbakey, Wael Abou El-kheir, Shin’ichi Takeda and Yuko Miyagoe-Suzuki",authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. The pathological changes in DMD muscle",level:"1"},{id:"sec_3",title:"3. Muscle stem cells as a cell-based therapy for DMD",level:"1"},{id:"sec_4",title:"4. Muscle-resident mesenchymal stem cells (progenitors) are indispensable for muscle homeostasis",level:"1"},{id:"sec_5",title:"5. Inflammation and immune responses in muscular dystrophies",level:"1"},{id:"sec_6",title:"6. Mesenchymal stem cells as a therapeutic tool for DMD",level:"1"},{id:"sec_6_2",title:"6.1 Definition",level:"2"},{id:"sec_7_2",title:"6.2 Preparation",level:"2"},{id:"sec_8_2",title:"6.3 Differentiation",level:"2"},{id:"sec_9_2",title:"6.4 Secretome of MSCs",level:"2"},{id:"sec_10_2",title:"6.5 Transplanted MSCs ameliorate dystrophic phenotypes of DMD muscle?",level:"2"},{id:"sec_10_3",title:"6.5.1 Mechanisms of amelioration of the dystrophic phenotype by MSCs",level:"3"},{id:"sec_13",title:"7. MSCs regulate inflammation and the immune response in muscular dystrophies",level:"1"},{id:"sec_13_2",title:"7.1 Suppression of the immune response by MSCs potentiates gene therapy and cell-based therapy",level:"2"},{id:"sec_15",title:"8. Mesenchymal stem cells induced from pluripotent stem cells (iPSCs)",level:"1"},{id:"sec_15_2",title:"8.1 MSC-like cells induced from human pluripotent stem cells (iMSCs) have properties that are different from tissue MSCs",level:"2"},{id:"sec_16_2",title:"8.2 Are MSCs induced from human pluripotent stem cells (iMSCs) ideal for clinical use?",level:"2"},{id:"sec_17_2",title:"8.3 iMSCs for muscle disease",level:"2"},{id:"sec_19",title:"9. Conclusions",level:"1"},{id:"sec_20",title:"Acknowledgments",level:"1"},{id:"sec_23",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Koenig M, Hoffman EP, Bertelson CJ, et al. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell. 1987;50:509-517. DOI: 10.1016/0092-8674(87)90504-6'},{id:"B2",body:'Guiraud S, Aartsma-Rus NM, Vieira KE, et al. The pathogenesis and therapy of muscular dystrophies. 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Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemia in mice. Circulation. 2010;121:1113-1123. DOI: 10.1161/CIRCULATIONAHA.109.898312'},{id:"B80",body:'Stolzing A, Jones E, McGonagle D, Scutt A. Age-related changes in human bone marrow-derived mesenchymal stem cells: Consequences for cell therapies. Mechanisms of Ageing and Development. 2008;129:163-173. DOI: 10.1016/j.mad.2007.12.002'},{id:"B81",body:'Kang R, Zhou Y, Tan S, et al. Mesenchymal stem cells derived from human induced pluripotent stem cells retain adequate osteogenicity and chondrogenicity but less adipogenicity. Stem Cell Research & Therapy. 2015;6:144. DOI: 10.1186/s13287-015-0137-7'},{id:"B82",body:'Liang Y, Li X, Zhang Y, et al. Induced pluripotent stem cells-derived mesenchymal stem cells attenuate cigarette smoke-induced cardiac remodeling and dysfunction. Frontiers in Pharmacology. 2017;8:501. 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Mesenchymal stem cells (MSC) derived from induced pluripotent stem cells (iPSC) equivalent to adipose-derived MSC in promoting intestinal healing and microbiome normalization in mouse inflammatory bowel disease model. Stem Cells Translational Medicine. 2018;7:456-467. DOI: 10.1002/sctm.17-0305'},{id:"B87",body:'Zhang Y, Liang X, Liao S, et al. Potent paracrine effects of human induced pluripotent stem cell-derived mesenchymal stem cells attenuate doxorubicin-induced cardiomyopathy. Scientific Reports. 2015;5:11235. DOI: 10.1038/srep11235'},{id:"B88",body:'Hao Q , Zhu YG, Monsel A, et al. Study of bone marrow and embryonic stem cell-derived human mesenchymal stem cells for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells Translational Medicine. 2015;4:832-840. DOI: 10.5966/sctm.2015-0006'},{id:"B89",body:'Ferrer L, Kimbrel EA, Lam A, et al. Treatment of perianal fistulas with human embryonic stem cell-derived mesenchymal stem cells: a canine model of human fistulizing Crohn’s disease. Regenerative Medicine. 2016;11:33-43. DOI: 10.2217/rme.15.69'},{id:"B90",body:'Jeong J, Shin K, Lee SB, et al. Patient-tailored application for Duchenne muscular dystrophy on mdx mice based induced mesenchymal stem cells. Experimental and Molecular Pathology. 2014;97:253-258. DOI: 10.1016/j.yexmp.2014.08.001'},{id:"B91",body:'Liu X, Zheng L, Zhou Y, et al. BMSC transplantation aggravates inflammation, oxidative stress, and fibrosis and impairs skeletal muscle regeneration. Frontiers in Physiology. 2019;10:87. DOI: 10.3389/fphys.2019.00087'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Ahmed Elhussieny",address:null,affiliation:'
Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Japan
Department of Neurology, Faculty of Medicine, Minia University, Egypt
Congenital Generalized Lipodystrophy (CGL, Berardinelli-Seip syndrome, BSCL) is a rare autosomal recessive disorder with a prevalence in the range of 1–10 patients per million people [1, 2]. However, in northern areas of Brazil, its prevalence is much higher, amounting to 32.3 patients per million people [3]. We recognize at least four CGL types: Type 1, due to mutations in the AGPAT2 gene, which is located on chromosome 9q34 and encodes the enzyme 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2); Type 2, due to mutations in the BSCL2 gene, which is located on chromosome 11q13 and encodes Seipin; Type 3, due to mutations in the CAV1 gene, which is located on chromosome 7q31 and encodes caveolin-1; and Type 4, due to mutations in the polymerase I and transcript-release factor [PTRF] gene, which is located on chromosome 17q21.2 and encodes cavin [1].
About 95% of CGL patients harbor either AGPAT2 or seipin mutations. The most common CGL is Type 1, and the rarest is Type 3. In Brazil, over 90% of CGL cases are CGL type 2, while in Europe, Middle East, and Japan, most patients have CGL Type 1. CGL patients have an extreme deficiency of fat depots. Therefore, most CGL patients have low serum leptin and adiponectin levels. They usually have elevated circulating serum triglycerides (very-low-density lipoproteins plus chylomicrons) and develop severe steatosis within their lean organs, such as the liver and skeletal muscles. Lipotoxicity of these organs produces in CGL patients an insulin-resistant state that does not respond to current treatments.
Two key metabolic features are prominent in these patients: much-elevated gluconeogenesis along with much-reduced insulin-mediated skeletal muscle glucose uptake. Usually, by the second decade of life, these patients develop type 2 diabetes requiring very high insulin doses. Hypertriglyceridemia in these patients is very difficult to treat, and it may manifest itself as cutaneous xanthomas. The best current treatment for CGL is recombinant leptin [4], but this is not widely available. Besides, leptin therapy is associated with weight loss in these patients.
The first two reported patients—both of pediatric age—were described in Brazil by Dr. Waldemar Berardinelli in 1954 [5]. In 1959, the Norwegian pediatrician Martin Seip published the report of three additional patients [6]. Berardinelli-Seip syndrome has been hard to understand and therefore, very difficult to treat.
To advance the knowledge on CGL, several groups attempted to generate transgenic murine models of the disease. In 1998, two transgenic models of murine lipoatrophy were simultaneously published [7, 8]. The A-ZIP/F1 transgenic mouse model had an extreme fat deficiency, whereas the aP2-SREBP-1c mouse model had only a moderate fat deficiency.
In 1994, leptin (a cytokine produced by the adipocytes having endocrine actions) was discovered [9]. In 1999, Shimomura et al. [10] showed that recombinant leptin reversed diabetes in the aP2-SREBP-1c mouse model of CGL and concluded that insulin resistance was secondary to the severe hypoleptinemia found in these animals. However, the A-ZIP/F1 mouse model responded poorly to exogenous leptin [11]. By contrast, in 2002, a study demonstrated that total adrenalectomy in A-ZIP/F1 diabetic mice induced a substantial metabolic improvement by increasing liver and muscle insulin sensitivity [12]. The authors attributed these improvements to the adrenalectomy-induced disappearance of chronic hypercorticosteronemia. Moreover, leptin treatment in A-ZIP/F1 mice reduced their elevated circulating corticosterone levels. So, it was conceivable that hypoleptinemia was behind the adrenal axis overactivation and the subsequent hypercorticosteronemic state exhibited by this mouse model.
In 2002, recombinant methionyl human leptin (metreleptin) reversed insulin resistance in nine women with congenital or acquired lipodystrophy and serum leptin levels <4 ng/mL [4]. In 2014, recombinant human leptin (metreleptin; Myalept®) received FDA approval to treat lipodystrophies [13]. In 2009, Cortés et al. generated the AGPAT2-deficient mouse, a transgenic animal model of lipoatrophy resembling CGL Type 1 [14]. In 2011, Cui et al. [15] reported that seipin ablation in mice results in severe generalized lipodystrophy. In 2012, Chen et al. [16] confirmed that inactivation of seipin in mice leads to severe lipodystrophy. Also, these authors shed light on the mechanisms involved in the process. They found that in vitro differentiation of murine embryonic fibroblast and stromal vascular cells had normal early-phase adipocyte differentiation, but a striking failure of terminal differentiation. This unsuccessful adipogenesis was secondary to a runaway cyclic AMP-dependent lipolysis and silencing of the transcription factors regulating adipogenesis. In vitro adipogenesis was rescued by inhibitors of lipolysis, but not by peroxisome proliferator-activated receptor (PPAR)-gamma agonists, such as pioglitazone. A recent review [17] suggests a central role of unrestrained lipolysis in the genesis of lipoatrophy of seipin-deficient individuals. In summary, seipin stimulates adipogenesis and inhibits cyclic AMP-dependent lipolysis.
The pathophysiology of the AGPAT2-deficient patients is cloudier compared with the situation of the homologous seipin-deficient patients. In 2016, Cautivo et al. [18] showed that the AGPAT2 gene is essential for the postnatal development and maintenance of white and brown adipose tissue.
A simplistic belief is that AGPAT2 deficiency impairs lipogenesis, while seipin deficiency impairs normal adipogenesis. Both conditions result in triglyceride (TG)-depleted adipocytes. However, a TG-depleted adipocyte also results from ablation of perilipin in murine adipose tissue. Nevertheless, in the latter situation, the TG-depleted adipocyte secretes an increased, rather than a reduced, amount of leptin [19]. Thus, a TG-depleted adipocyte is not necessarily associated with hypoleptinemia. In other words, the exact mechanism by which AGPAT2 deficiency leads to hypoleptinemia is unknown. Overall, hypoleptinemia seems to be a commonality in generalized lipodystrophies. Therefore, the biggest investigational challenge is to figure out how hypoleptinemia and severe insulin resistance are linked together in CGL.
Herein, we report an extraordinary experience with a patient with Berardinelli-Seip syndrome (1986–1988) seen before the leptin era. At that time, we hypothesized that CGL was somehow the consequence of the local excess of cortisol action on the adipocyte. To test our daring hypothesis, we used mifepristone, a potent anti-glucocorticoid drug. Having previous experience with the drug on a patient with a previously operated-on, recurrent ectopic adrenal cancer and severe Cushing’s syndrome [20], we anticipated that mifepristone would probably produce an overactivation of the hypothalamic–pituitary–adrenal axis. For this reason, following 9 weeks of mifepristone therapy alone, we briefly added ketoconazole to the treatment to partially block cortisol synthesis. We devised this therapeutic strategy to reduce serum cortisol levels, seeking to reinforce the anti-glucocorticoid effect of mifepristone. Finally, we stopped ketoconazole to reduce the anti-glucocorticoid action of the combined intervention. Overall, our results with the abovementioned anti-glucocorticoid approach permitted us to surmise that total adrenalectomy would benefit the patient.
1.1 Case report
A 16-year-old female patient entered the Endocrine Unit of the University Hospital (Hospital José Joaquín Aguirre, Universidad de Chile, Santiago) with a recent diagnosis of type 2 diabetes. Her parents were first cousins. Since she was born, pediatricians were intrigued by her peculiar appearance, characterized by scarcity of subcutaneous fat, muscular prominence, and abdominal distension.
Our patient had an acromegaloid face, scarcity of subcutaneous adipose tissue, conservation of mechanical fat, severe acanthosis nigricans, prominent veins, and muscular prominence. She had a voracious appetite and exhibited eruptive xanthomas (sparing the face and the chest) especially over her palms and elbows.
She also had clinical hyperandrogenism, including facial and scalp seborrhea and mild clitoromegaly. She had a history of recurrent periods of amenorrhea. Her liver and spleen were notoriously enlarged, producing a prominent abdomen. A mild thyromegaly and a small umbilical hernia were present. The normal intellectual development and the presence of mechanical fat (located in palms, soles, joints, and retro-orbital space) in our patient suggested that she was AGPAT2-deficient rather than seipin-deficient. We did not have her DNA sequenced since this technique debuted in CGL cases just in the current century.
Fasting serum glucose, insulin, and triglycerides were 225 mg/dL, >400 mU/L, and 7400 mg/dL, respectively (normal levels: ≤99 mg/dL, ≤13 mU/L, and ≤ 150 mg/dL, respectively). The patient was diagnosed with Berardinelli-Seip syndrome and polycystic ovary syndrome.
We treated her with high insulin doses with disappointing results, which attested to the presence of an extreme insulin resistance. Given the acute pancreatitis risk, we carried out an unsuccessful attempt to reduce her extremely high levels of serum triglycerides with high doses of omega-3-rich fish oil (up to 20 grams per day). Our medical staff thoroughly discussed the case and reached a consensus: she was not treatable with conventional medications.
1.2 Rethinking the patient from scratch
We realized that, to help the patient, we had to rethink her. For us, the extreme scarcity of body fat in our patient was the key to understanding how to deal with her disease. We reviewed the available literature (years 1986–1988) regarding adipogenesis, lipogenesis, and lipolysis. We looked at the fat storage within the adipocyte like a “bank account” of fat. An “empty adipocyte” could result from deficient lipogenesis or increased lipolysis.
We learned that serum insulin levels stimulate lipoprotein lipase (LPL). LPL provokes the lipolysis of circulating serum chylomicrons and very-low-density lipoprotein particles (VLDL). Then, free fatty acid (FFA) molecules enter the adipocyte to initiate lipogenesis. Three FFA molecules bind to a single acyl-glycerol molecule to form the triacylglycerol molecule (triglyceride or TG) stored within lipid droplets inside the cytoplasm. The stored TG molecule may be subjected to a hormone-sensitive lipase (HSL)-mediated lipolysis, releasing FFAs and glycerol into the circulation. Even minute amounts of circulating insulin can tonically inhibit HSL.
When hepatic glycogenolysis is exhausted at dawn, serum glucose and insulin levels fall, interrupting the HSL inhibition. For us, a piece of crucial information was that cortisol exerts a permissive role on the HSL activation in the cytosol of the adipocyte. In other words, the HSL is inactive in the absence of cortisol inside the cytosol of the adipocyte. Cortisol reaches the cytosol of the adipocyte through the internalization of extracellular, inactive cortisone. This inactive cortisone is transformed inside the cytosol into physiologically active cortisol by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In turn, cortisol stimulates HSL acutely, whereas it stimulates LPL chronically. Acute lipolysis occurs when energy is required: the released FFA and glycerol molecules provide the liver with substrates to increase glucose production at dawn. These tips summarize what we learned about lipogenesis and lipolysis by reviewing the available literature. By understanding the physiological roles of leptin, our comprehension of adipose tissue physiology has grown a great deal. This new knowledge will allow us to reinterpret our extraordinary findings.
1.3 The decision to initiate an anti-glucocorticoid-centered, experimental therapeutic approach
Theoretically, fat depletion in CGL may be secondary to defects either in adipogenesis or lipogenesis. However, other possibilities may exist. We hypothesized that cortisol-mediated, unrestrained lipolysis was at the core of the CGL in our patient.
The main advantage of our daring—and even naïve—hypothesis was its testability. Serendipitously, we did have access to mifepristone (RU-486), a potent anti-progesterone and anti-glucocorticoid steroidal drug. We had previously treated with mifepristone for 5 months a patient with recurrent hepatic adrenal rest cancer-mediated hypercortisolism. Before that experience, back in 1985, we had postulated in a Lancet letter [21] that glucocorticoid-producing adrenal cancers might be glucocorticoid-dependent. We had observed a striking, rapid disappearance of liver and lung metastases after using ketoconazole (1200 mg/day) on a female patient to block excessive cortisol synthesis by adrenal cancer. Roussel-Uclaf kindly donated 1000 pills of mifepristone (200 mg each) to treat this patient with an ectopic adrenal cancer. That trial taught us what to expect from the mifepristone administration. However, when the hypercortisolism spectacularly faded away after 5 months of treatment, the patient declared herself cured, refusing further treatment. Unfortunately, she died less than a year after stopping treatment. We, therefore, were left with a substantial amount of available mifepristone pills.
Also, we had extensive experience with ketoconazole in several cases of Cushing’s syndrome (seen from 1983 through 1988). In 1983, we successfully used ketoconazole to treat hypercortisolism in a patient with an adrenal rest tumor of the liver. This success permitted us to remove her ectopic adrenal tumor from the liver, resulting in an apparent surgical cure. We reported this experience in 1985 [20]. Up until then, nobody else had published a clinical trial with ketoconazole in Cushing’s syndrome. This initial, positive experience paved the way for us to acquire expertise in using ketoconazole in Cushing’s syndrome.
The endocrinologists of our Unit discussed the complex situation of our patient with CGL. At the time, we did not have an Ethics Committee at the University Hospital. Therefore, our group reached a medical consensus: to offer an experimental mifepristone treatment to the patient and her family. We explained to them that we had nothing else to offer. The patient and her family agreed to receive a trial of mifepristone therapy. We used the same dose of mifepristone (600 mg daily, divided into three 200 mg pills) that we had previously used in our patient with ectopic adrenal cancer. So, after a whole year of unsuccessful therapies, we were ready to proceed with an experimental, unheard-of, therapeutic approach on our 18-year-old patient.
2. Material and methods
2.1 Experimental protocol (1988)
2.1.1 First course of anti-glucocorticoid treatment alone
Mifepristone therapy alone (600 mg/day, given as three 200-mg pills, at 7 AM, 3 PM, and 11 PM) was administered orally for 9 weeks. The anti-glucocorticoid action of the drug would negate the cortisol-mediated negative feedback on secretion of CRF (corticotropin releasing factor) and ACTH (adrenocorticotropic hormone). Therefore, we anticipated an overactive hypothalamic–pituitary–adrenal axis (“adrenal axis”, for short). High circulating cortisol levels will not produce glucocorticoid actions in the presence of mifepristone. Instead, they will stimulate the mineralocorticoid receptor in the distal renal tubule (cortisol-induced hypermineralocortisolism).
For this reason, we measured the mean daily serum cortisol values (individual values were measured at 8 AM, 3 PM, and 11 PM) and urinary free cortisol on day 63 of the trial at the end of this first phase. To monitor the expected metabolic changes, we serially measured serum fasting glucose, insulin, and triglycerides during this period.
2.1.2 Anti-glucocorticoid treatment plus partial blockade of cortisol synthesis
Mifepristone (600 mg/day) plus ketoconazole (800 mg/day, divided into four 200-mg pills given every 6 hours) combination therapy was administered for 1 week.
Ketoconazole was expected to produce a partial blockade of the enhanced mifepristone-induced adrenal cortisol synthesis, thus reducing the prevailing hypercortisolemia. We devised this therapeutic addition to reinforce the anti-glucocorticoid effect of mifepristone. We measured the daily mean serum cortisol values and urinary free cortisol on day 70 of the trial, at the end of the second phase of treatment. We also measured daily serum fasting glucose, insulin, and triglycerides to evaluate the response to the addition of ketoconazole.
2.1.3 Second course of anti-glucocorticoid treatment alone
Mifepristone therapy alone (600 mg/day, given as 200-mg pills, at 7 AM, 3 PM, and 11 PM) was administered orally for 2 weeks. We expected to witness a deterioration of both circulating fasting glucose and triglycerides by stopping ketoconazole. We did not measure cortisol values in serum and urine during this phase.
The whole anti-glucocorticoid intervention (mifepristone alone or combined with ketoconazole) lasted 12 weeks. Acanthosis nigricans and eruptive xanthomas virtually disappeared during the trial (Figure 1). Moreover, the patient gained 7 kilograms.
Figure 1.
Local acanthosis nigricans and eruptive xanthomas, as seen before (A) and after (B) the anti-glucocorticoid intervention. The peculiar aspect of a fat-devoid mesentery at surgery is also shown (C).
This intervention produced a striking amelioration of fasting serum insulin and triglyceride levels, as shown in Table 1. However, as we predicted, the patient experienced an overactivation of the adrenal axis, reflected by very high daily mean serum cortisol and urinary free cortisol excretion at the end of the 9th week (Table 2). The mifepristone-induced adrenal axis overactivity revealed itself as a clinical hypermineralocortisolism. The patient had arterial hypertension (160/100 mmHg), hypokalemia (3.4 mEq/L), and inappropriate urinary potassium loss (56 mEq/day). We interpreted this phenomenon as a mifepristone-induced hypercortisolism overwhelming the cortisol-inactivating capacity of the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2); this enzyme—located in the distal tubule of the nephron—converts active cortisol into inactive cortisone, thus preventing cortisol-induced activation of the local mineralocorticoid receptor. Mifepristone blocks the glucocorticoid receptor, but not the mineralocorticoid receptor. So, excess cortisol stimulates the mineralocorticoid receptor of the distal kidney tubule, provoking excess renal sodium reabsorption and excess urinary potassium excretion.
Weeks
Serum fasting triglycerides (mg/dL)
Fasting glycemia (mg/dL)
Fasting insulinemia (mU/L)
Baseline
7400
225
>400
Week 1
6310
145
>400
Week 2
3625
250
10.0
Week 3
1220
280
20.0
Week 4
1210
230
18.0
Week 5
1200
290
n/a
Week 6
1500
230
10.0
Week 7
1750
225
11.0
Week 8
1500
224
10.5
Week 9
617
227
8.0
Table 1.
Assessment of metabolic parameters at baseline and after initiation of mifepristone therapy alone (600 mg/day). Mifepristone alone (600 mg/day) reduced serum triglycerides first (1 week) and then reduced serum fasting insulin levels in 2 weeks. Serum fasting glucose levels were unchanged for 9 weeks. At the end of the 9th week, serum levels of triglycerides were just 8.3% of the baseline value. Similarly, fasting insulin levels were less than 2% of the baseline value. Abbreviations: n/a, not available.
Intervention
24-hour urinary-free cortisol (UFC) (mcg/24 h; normal values, ≤100)
Mean daily serum cortisol* (mcg/dL)
Mifepristone therapy alone (63rd day)
1130
48.5
Mifepristone plus ketoconazole combination therapy (70th day)
630
26
Table 2.
Assessment of adrenal function at the end of the prolonged mifepristone therapy alone and at the end of the mifepristone plus ketoconazole combination therapy. At the end of the administration of mifepristone alone, 24-h urinary free cortisol (UFC) and mean daily serum cortisol values were grossly elevated, reflecting a mifepristone-induced adrenal hyperactivity. One week after adding ketoconazole to mifepristone, there was almost a 50% decrease in these values, reflecting the ability of ketoconazole to block adrenal cortisol synthesis. *we calculated the mean daily serum cortisol values (individual values were measured at 8 AM, 3 PM, and 11 PM).
3.2 Mifepristone (600 mg/day) plus ketoconazole (800 mg/day) combination therapy (a single week)
As predicted, the addition of ketoconazole (an antifungal agent capable of inhibiting cortisol synthesis) enhanced the anti-glucocorticoid effect of mifepristone, as reflected by a further reduction of the serum levels of triglycerides and fasting insulin and glucose levels (Table 3). These effects paralleled a drop of mean daily total serum cortisol and urinary free cortisol excretion, as shown in Table 2. Table 4 shows a striking reduction of serum insulin values observed during an oral glucose tolerance test (OGTT) performed with 75 g of glucose on the last day of the combined administration, compared with the values observed 2 years earlier.
Days (Starting from Week 10)
Serum fasting triglycerides (mg/dL)
Fasting glycemia (mg/dL)
Fasting insulinemia (mU/L)
Day 1
380
180
12.0
Day 2
375
145
17.5
Day 3
300
122
13.0
Day 4
250
121
13.5
Day 5
240
135
13.6
Day 6
220
129
7.5
Day 7
230
138
7.0
Table 3.
Assessment of metabolic parameters during mifepristone (600 mg/day) plus ketoconazole (800 mg/day) combination therapy. The addition of ketoconazole to mifepristone for 7 days notoriously reduced serum fasting levels of triglycerides, glucose, and insulin to near-normal values.
Serum insulin levels (mU/L) measured during oral glucose tolerance tests (OGTT) performed (with 75 g of glucose) at baseline (1986) and during the mifepristone plus ketoconazole combination therapy (1988). Serum insulin levels observed during the OGTT performed at the end of the combined anti-glucocorticoid administration (1988) were strikingly reduced, as compared with values observed during the baseline OGTT (performed in 1986).
3.3 Second course of mifepristone therapy alone, 600 mg/day (2 weeks)
We observed a progressive deterioration of serum triglyceride and glucose values after stopping ketoconazole (Table 5). Unfortunately, we did not measure cortisol values during this period.
Weeks
Serum fasting triglycerides (mg/dL)
Fasting glycemia (mg/dL)
Fasting insulinemia (mU/L)
11
360
160
n/a
12
438
200
n/a
Table 5.
Assessment of metabolic parameters during the second course of mifepristone therapy alone (600 mg/day). There was a substantial increase in fasting triglyceride and glucose levels after the discontinuation of ketoconazole for 7 days. Abbreviations: n/a, not available.
3.4 Summary of metabolic changes observed during the anti-glucocorticoid intervention
As observed in Table 1, mifepristone therapy alone took 2 weeks to substantially reduce serum fasting triglyceride and insulin levels, while serum fasting glucose was unchanged during this phase of anti-glucocorticoid intervention. The 1-week addition of ketoconazole produced a further reduction of serum triglycerides and a rapid drop of serum fasting glucose values (Table 3). However, over the next 2 weeks of the trial with mifepristone therapy alone, we observed a clear rise in serum triglyceride and glucose values (Table 5).
3.5 The decision to perform total (bilateral) adrenalectomy and its results
None of the observations that we made during our protocol execution negated our working hypothesis. Regarding definitive therapy for lipoatrophic diabetes, mifepristone administration was ruled out for its limited availability and expected complications. By contrast, bilateral adrenalectomy, along with a limited cortisol replacement therapy, would reduce fat exposure to high, lipolysis-inducing cortisol levels. The family and the patient agreed to the surgical procedure. After surgery, we administered a reduced but safe amount of hydrocortisone (15 mg/day, divided into daily doses: 10 mg at 8 AM and 5 mg at 3 PM). In addition, we administered fludrocortisone 0.1 mg daily to avoid excessive urinary sodium loss.
At the time of adrenalectomy, surgeons were surprised to observe a fat-devoid mesentery (Figure 1). The patient recovered uneventfully from the surgical procedure. After adrenalectomy, we measured fasting glucose levels daily, and we performed an OGTT (with 75 g of glucose) 2 weeks later (Table 6).
Minutes
0’
30’
60’
90’
120’
Serum glucose (mg/dL)
98
140
148
195
210
Serum insulin (mU/L)
10
45
53
47
52
Table 6.
Serum glucose and insulin values during the oral glucose tolerance test (OGTT) performed (with 75 g of glucose) 13 days following bilateral adrenalectomy, under hydrocortisone (15 mg/day) plus fludrocortisone (0.1 mg/day) replacement therapy. Serum glucose values were within the lowest diabetic range, while hyperinsulinemia was absent.
Twenty-four hours after the adrenalectomy, fasting serum glucose was within the normal range, followed by occasional minimal increments above the normal range in the next 2 weeks. The OGTT results showed a fasting glucose level within the normal range and a 2-h glucose level in the low diabetic range. The insulin values during the OGTT were within the normal range, although with an unusual trajectory (Table 6).
We performed successful adrenalectomy in our lipoatrophic patient 14 years before the adrenalectomy success observed in transgenic A-ZIP/F1 lipoatrophic mice [12].
3.6 Patient discharge and follow-up
We discharged the patient from the hospital (1988) medicated with hydrocortisone (10 mg at 8 AM and 5 mg at 3 PM) plus fludrocortisone (0.1 mg at 8 AM). We instructed her to double the fludrocortisone dose in the summer. Subsequently, she opted to be taken care of by the National Health Service (NHS) due to financial reasons. We never had the opportunity to discuss the case with her new attending diabetologists.
Likely, the idea of using a reduced but safe amount of oral hydrocortisone in this patient did not appeal to her new attending physicians. Besides, the NHS in Chile did not provide fludrocortisone at that time, so the patient likely overdosed with hydrocortisone. Despite these shortcomings, the patient got pregnant twice, having a spontaneous abortion in 2002. In 2003, aged 34, she got pregnant again and delivered a premature, 28-week baby. Her attending obstetricians reviewed the literature and discovered a single case with successful pregnancy in women with CGL [22]. They described the difficult pregnancy in a local obstetrics journal [23]. Even though triglyceride levels remained elevated (below 2000 mg/dL), these levels were substantially lower compared with those observed when we first met her (7100 mg/dL). However, the obstetrics report mentioned one episode of acute pancreatitis antedating her second pregnancy.
We presented our experience in 1989 at The Endocrine Society Meeting in Seattle [24] (Figure 2). However, at that time, we could not write up a paper reporting our findings simply because we could not offer a rational explanation for them.
Figure 2.
The facsimile of our abstract, as it was published in the proceedings of the Endocrine Society Seventy-First Annual Meeting; June 21–24, 1989, Seattle, Washington (USA).
4. Discussion
To reinterpret the therapeutic findings in this teenager, we must briefly revise crucial new knowledge accumulated in the decades since we treated her.
4.1 Extreme adipose tissue insulin resistance (Adipo-IR) at the core of CGL?
Insulin action on the adipocyte stimulates adipogenesis and lipogenesis while inhibiting lipolysis. Extreme insulin resistance in the adipose tissue (Adipo-IR) should severely reduce adipogenesis and lipogenesis. At the same time, Adipo-IR should increase lipolysis, leading to an “empty adipocyte” syndrome. It is conceivable that glucocorticoid action on the adipocyte somehow mediates Adipo-IR. Once the adipocyte becomes triglyceride-depleted, leptin secretion should severely fall, resulting in hypoleptinemia. The latter may lead to adrenal hyperactivity (as seen in murine models of CGL), resulting in hypercorticosteronemia [12]. In patients with CGL, the hypothetical high circulating free cortisol levels (elevated serum total cortisol levels plus hyperinsulinemia-induced low transcortin levels) would perpetuate the increased lipolysis.
Adipo-IR is present at both extremes of adipocyte’s triglyceride storage: triglyceride-replete adipocytes and empty adipocytes (as seen in obesity and CGL, respectively). In both cases, ectopic triglyceride storage in lean organs (liver, muscle, pancreatic beta cell, and skin) replaces further adipocyte triglyceride storage. Lipotoxicity in the liver increases the hepatic glucose output. Lipotoxicity in muscles reduces their insulin-mediated glucose uptake. Finally, beta-cell lipotoxicity induces cell apoptosis. The degree of lean tissue lipotoxicity is severe in CGL patients with “empty adipocytes.” By contrast, in obese subjects, lipotoxicity is considerably lighter (triglyceride-replete adipocytes). If mifepristone administration ameliorates Adipo-IR, it is logical to expect a metabolic improvement of both CGL and obesity.
4.2 Mifepristone and adipose tissue insulin sensitivity
We know that mifepristone improves glucose tolerance and insulin sensitivity in patients with Cushing’s syndrome [25]. However, the specific effect of the drug on adipose tissue’s insulin sensitivity had remained unexplored. In 2021, an NIH group reported that mifepristone improves adipose tissue insulin sensitivity in insulin-resistant individuals [26]. Sixteen overweight or obese subjects with prediabetes or mild type 2 diabetes (without Cushing’s syndrome) received either mifepristone (200 mg/day; 50 mg 4 times a day) or placebo for 9 days with a washout period of 8 weeks. At baseline and following mifepristone and placebo administration, the subjects had a 75-g OGTT and a frequently sampled intravenous glucose tolerance test (FSIVGTT). Whole-body insulin sensitivity was estimated on these subjects calculating three indices: Insulin Sensitivity Index (SI), Matsuda index (MI), and Oral Glucose Insulin Sensitivity Index (OGIS). These indices were not modified by mifepristone 200 mg daily. However, there were significant improvements in the adipose tissue insulin resistance index (Adipo-IR index) (a surrogate marker of fasting adipose-tissue insulin resistance, calculated as the product of fasting insulin and fasting free fatty acids) and in the adipose tissue insulin sensitivity index (Adipo-SI index, defined as the ratio of the slope of the linear decrease in natural log transformed free fatty acids during the first 90 minutes of the FSIVGTT and the area under the curve of serum insulin during that 90-minute period) [26]. In addition, mifepristone increased insulin clearance but did not modify either insulin secretion or beta-cell glucose sensitivity. Mifepristone use reduced fasting serum glucose, insulin, and triglycerides. Also, the areas under the curve of daily serum ACTH and cortisol values were significantly higher during mifepristone administration. Urinary free cortisol values also rose significantly. Thus, mifepristone 200 mg/day (divided into four 50-mg daily doses) administered to 16 insulin-resistant subjects reproduced our findings using 600 mg daily (divided into three 200 mg doses): serum and urinary cortisol values rose, while serum glucose, insulin, and triglyceride values fell.
Therefore, mifepristone (600 mg/day) should have improved the adipose tissue insulin sensitivity in our patient. Since we did not measure serum FFAs, we cannot evaluate the Adipo-IR index in our patient. However, using a raw estimation of adipose tissue’s insulin resistance—the product of insulin (mU/L) times fasting triglycerides (mg/dL), we obtain the following results: mifepristone alone: at baseline, >2,960,000; 9th week, 4936; mifepristone plus ketoconazole combination therapy: first day, 4560; 7th day, 1610. As a reference, a person with a fasting serum insulin value of 13 mU/mL and 150 mg/dL of fasting triglycerides would have a calculated value of 1950 for this parameter. Therefore, this raw estimation of the adipose tissue’s insulin resistance shows a strikingly positive effect of mifepristone, which is further reinforced by the addition of ketoconazole (>99.9% reduction).
A recent Chinese study on the Adipo-IR index and metabolic syndrome [27] reported mean data from six groups of subjects (three groups for each sex) on insulin and triglyceride values. These data allowed us the calculation of our raw adipose tissue insulin resistance index in 20 control females (612.4), 26 obese women without metabolic syndrome (1165.0), and 85 obese women with metabolic syndrome (3017.9). There was a strong, positive correlation of 0.958 between their published averaged Adipo-IR indices and their corresponding calculated raw Adipo-IR indices.
So, this proposed raw estimation of adipose tissue insulin resistance should be helpful in the clinical setting. Both a serum fasting triglyceride value >130 mg/dL and a serum fasting insulin value >13.2 mU/L suggest the presence of insulin resistance. Therefore, a value above 1716 (13.2 times 130) for this raw index would strongly indicate the presence of adipose tissue insulin resistance. Likely, values for this surrogate index in non-insulin-resistant individuals should be less than 1000 (corresponding to a serum insulin value around 7.5 mU/L and a serum triglyceride value around 130 mg/dL).
4.3 Adrenalectomy and insulin resistance
When we received this patient, we knew that patients with Addison’s disease were lean, insulin-sensitive, and prone to hypoglycemia. On the contrary, patients with Cushing’s syndrome are obese, insulin-resistant, and prone to hyperglycemia. Glucocorticoids promote both obesity and insulin resistance, thus deteriorating diabetes control. By contrast, adrenalectomy benefits diabetes control in patients with Cushing’s syndrome. Of course, we did not know in 1988 that adrenalectomy would improve diabetes in A-ZIP/F1 lipoatrophic mice [12]. Adrenalectomy in this murine model of CGL ameliorates liver and muscle insulin sensitivity. The fact that mice lacking leptin synthesis or leptin action (ob/ob and db/db mice, respectively) are both obese and insulin-resistant [28] suggests that leptin action somehow protects them from insulin resistance. The beneficial effects of adrenalectomy in rodents lacking leptin action [29] indicate that the adrenal gland is necessary for these mice to develop insulin resistance. In summary, we need to find the intermediate steps between insufficient leptin action and insulin resistance. In experimental animals with hypoleptinemia, the adrenal gland appears to mediate the development of insulin resistance.
4.4 The new knowledge on Berardinelli-Seip syndrome and its relationship with leptin
The clinical and metabolic improvements observed in our patient during the anti-glucocorticoid intervention were beyond our expectations. The significant weight gain of our patient is encouraging and particularly intriguing. It suggests de novo storage of triglycerides in the patient’s fat depots. If this latter supposition is true, then one wonders whether the supposedly much-reduced leptin and adiponectin levels at baseline rose when fat progressively accumulated within the adipocytes during anti-glucocorticoid therapy. Future research will probably answer these intriguing questions. Although we realized that the anti-glucocorticoid therapy notoriously improved the abnormal adipocyte physiology of our patient, we did not disclose the mechanism(s) involved. In any case, the beneficial effects of the anti-glucocorticoid treatment support the notion of a detrimental action of endogenous cortisol on the adipocyte physiology in this CGL patient.
Now, we can attempt to offer a rational explanation concerning the effects of mifepristone in our patient with Berardinelli-Seip Syndrome. Nowadays, we know several key pieces of crucial importance, such as the discovery of leptin and its functions [9]. A key concept is that leptin exerts an inhibitory effect on the hypothalamic–pituitary–adrenal axis [30]. Moreover, the loss of leptin-induced inhibition of the hypothalamic–pituitary–adrenal axis provokes gross metabolic dysfunctions. For instance, hepatic gluconeogenesis is largely augmented in murine models of poorly controlled type 1 diabetes, having severely low insulin levels [31]. Shortly after leptin discovery, it was evident that CGL patients exhibited severe hypoleptinemia [32]. In 1998, the new era of transgenic mice with lipoatrophic diabetes introduced revolutionary concepts in the field [7, 8]. The less fat-deficient mice responded well to leptin treatment, whereas the severely fat-devoid A-ZIP/F1 mice responded poorly. These mice exhibit hypercorticosteronemia, indicating an overactivity of their adrenal axes. Intravenous leptin infusions reduce adrenal gland overactivity in these mice. When these A-ZIP/F1 mice were adrenalectomized to abate their hypercorticosteronemia, they experienced significant increments in peripheral and hepatic insulin sensitivity [12]. Again, another piece of evidence is that an adrenal gland is necessary for these leptin-deficient mice to develop diabetes.
Patients with CGL treated with recombinant leptin usually respond well to the hormone [4]. To our knowledge, nobody has yet reported that patients with CGL have an overactive adrenal axis, in parallel with the findings observed in murine models of CGL. Unfortunately, it did not occur to us to evaluate the hypothalamic–pituitary–adrenal axis before the trial began. On the other hand, transcortin (also known as CBG or corticosteroid-binding globulin; the protein produced in the liver that transports cortisol in the blood) expression is reduced by hyperinsulinemia [33]. Patients with CGL should theoretically exhibit high levels of serum free cortisol secondary to both hypoleptinemia-induced adrenal gland overactivity and low transcortin levels (due to hyperinsulinemia-induced reduction in hepatic secretion of transcortin).
If leptin deficiency in humans indeed results in the lack of leptin-mediated inhibition of the hypothalamic–pituitary–adrenal axis, a logical consequence of this hormonal deficiency would be the overactivity of the adrenal glands. This situation would be revealed either by high serum total or free cortisol levels, paralleling the hypercorticosteronemia of leptin-deficient rodents. Lipolysis in insulin-resistant subjects should increase due to resistance to insulin-induced HSL inhibition. If the adrenal axis becomes overactive, the permissive role of cortisol on HSL activation should increase. A foreseeable result of this phenomenon is an enhanced lipolysis. The high efflux of FFAs and glycerol in the blood will increase hepatic gluconeogenesis, thus impairing glucose homeostasis. Under this situation, triglycerides would migrate from the adipocytes (normotopic storage) into lean organs (ectopic storage). Fat relocation should produce a “triglyceride-depleted adipocyte.” On the other hand, fat relocation and ectopic fat accumulation should reduce leptin secretion and induce lipotoxicity in lean organs such as the liver, skeletal muscles, and endocrine pancreas.
5. Conclusions
a) If hypoleptinemia drives adrenal axis hyperactivity in CGL (Figure 3), three interventions (recombinant leptin, anti-glucocorticoids, and bilateral adrenalectomy) should reduce fat exposure to cortisol action in CGL patients (Figure 4). Moreover, on the horizon, the nonpeptide, oral ACTH antagonist CRN04894 [34] might become a promising therapeutic alternative. If ACTH antagonists reach the market and prove safe for chronic use, administration of these drugs in CGL patients may be beneficial due to their adrenal-blocking properties.
Figure 3.
Potential pathophysiological mechanisms underlying the hypoleptinemia-induced hyperactivity of the hypothalamic–pituitary–adrenal axis (adrenal axis, for short) and subsequent unrestrained adipose tissue lipolysis. Since leptin restrains the hypothalamic–pituitary–adrenal axis, any cause of severe hypoleptinemia (CGL, severe hypoinsulinemia of diabetic ketoacidosis, and prolonged fasting) should result in an overactive adrenal axis. Fat exposure to excess serum cortisol should stimulate adipocyte hormone-sensitive lipase (HSL) and increase lipolysis. Abbreviations: FFA, free fatty acids; TG, triglycerides.
Figure 4.
Predicted therapeutic interventions aimed at reducing fat exposure to excessive cortisol levels in patients with Berardinelli-Seip syndrome (congenital generalized lipodystrophy). According to our hypothesis, adrenalectomy (a), anti-glucocorticoid therapy (b), and leptin replacement (c) should result in a restrained activity of the hypothalamic–pituitary–adrenal axis (adrenal axis, for short), reducing fat depots exposure to free cortisol levels. The same effects should result from using future ACTH antagonists (d). Consequently, any of these four interventions should diminish the degree of lipolysis. In turn, reduced lipolysis should ameliorate ectopic fat storage in lean organs (liver, muscle, pancreatic beta cells, and skin), improving tissue insulin sensitivity. Abbreviation: ACTH, adrenocorticotropic hormone; FFA, free fatty acids.
b) Mifepristone is not suitable for patients with CGL, since it induces adrenal axis overactivity. This fact anticipates complications such as adrenal hyperplasia and hypercortisolemia-induced hypermineralocortisolism.
c) Bilateral, total adrenalectomy might become a feasible therapeutic alternative for CGL patients. Currently, laparoscopic adrenalectomy entails a low long-term risk to patients. Adrenalectomized patients are perfectly able to manage their hormone replacement therapy.
d) The exact mechanism by which anti-glucocorticoid therapy resulted in the notable metabolic improvement observed in our patient remains unknown and should be investigated. Simultaneous defects in adipogenesis, lipogenesis, and lipolysis may cause lipodystrophy in patients with CGL. “Runaway lipolysis” by itself as the single culprit of lipodystrophy remains an unproven possibility.
e) The storage of fat in adipose tissue depends on the correct functioning of adipogenesis, lipogenesis, and lipolysis, working as a whole process. It may be plausible that a failure in just one of these three elements is sufficient to derange the whole process, leading to lipodystrophy.
f) An urgent task is to study the status of the adrenal axis in patients with untreated CGL. If this axis turns out to be overactive, future clinical trials with anti-glucocorticoids in patients with CGL are warranted.
Acknowledgments
This author is indebted to several people that facilitated this work. In the first place, thanks are due to Harold Michelsen, MD (deceased), who asked me to develop a therapeutic strategy for this complex patient after the lack of success of the usual medicines to treat her diabetes and dyslipidemia. This author is also grateful to the endocrinology colleagues in our Unit, who were brave enough to endorse our proposed—unheard-of—strategy to attempt a rational treatment of our patient. This author is also grateful to our patient and her family, who trusted our Unit in times of therapeutical uncertainty. They not only accepted the anti-glucocorticoid therapeutic approach but also dared to try bilateral, irreversible adrenalectomy after our metabolic success. Lastly, but not least, this author must thank Inés Vega, RN, and her crew for helping the patient along the road to achieving better health.
Conflicts of interest
The author declares no conflict of interest.
\n',keywords:"Berardinelli-Seip syndrome, hypoleptinemia, hypothalamic–pituitary–adrenal-axis overactivity, unrestrained lipolysis, mifepristone, ketoconazole",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/80855.pdf",chapterXML:"https://mts.intechopen.com/source/xml/80855.xml",downloadPdfUrl:"/chapter/pdf-download/80855",previewPdfUrl:"/chapter/pdf-preview/80855",totalDownloads:36,totalViews:0,totalCrossrefCites:0,dateSubmitted:"December 7th 2021",dateReviewed:"February 1st 2022",datePrePublished:"March 16th 2022",datePublished:null,dateFinished:"March 15th 2022",readingETA:"0",abstract:"A female teenager was diagnosed in 1986 with Berardinelli-Seip syndrome (congenital generalized lipodystrophy). Following the predictable failure of the usual treatments for her severe type 2 diabetes and hypertriglyceridemia, we decided to treat her with a novel anti-glucocorticoid-centered approach. In 1988, we treated her with mifepristone alone (9 weeks), then with mifepristone combined with ketoconazole (1 week), and again, with mifepristone alone (2 weeks). Acanthosis nigricans, as well as eruptive xanthomas, experienced complete regression following the anti-glucocorticoid therapy. Moreover, the patient gained 7 kilograms. Besides, there was a striking metabolic amelioration with mifepristone therapy. The addition of ketoconazole strongly reduced the relevant mifepristone-induced hypercortisolemia within 1 week. Fasting serum glucose, insulin, and triglycerides fell from day 1 to day 7 without reaching values within the normal range. Two weeks after ketoconazole withdrawal (while keeping mifepristone administration), serum triglyceride and glucose values rose significantly. Eleven days after bilateral adrenalectomy, fasting glucose values were within normal limits or slightly above. An oral glucose tolerance test (75-g OGTT) performed 13 days after surgery showed insulin values within normal limits, fasting serum glucose values within the normal range, and a 2-h serum glucose value in the diabetic range. These findings were consistent with our working hypothesis proposing that Berardinelli-Seip syndrome is due to cortisol-mediated unrestrained lipolysis.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/80855",risUrl:"/chapter/ris/80855",signatures:"Patricio H. Contreras",book:{id:"11261",type:"book",title:"Insulin Resistance - Evolving Concepts and Treatment Strategies",subtitle:null,fullTitle:"Insulin Resistance - Evolving Concepts and Treatment Strategies",slug:null,publishedDate:null,bookSignature:"Dr. Marco Infante",coverURL:"https://cdn.intechopen.com/books/images_new/11261.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-502-7",printIsbn:"978-1-80355-501-0",pdfIsbn:"978-1-80355-503-4",isAvailableForWebshopOrdering:!0,editors:[{id:"409412",title:"Dr.",name:"Marco",middleName:null,surname:"Infante",slug:"marco-infante",fullName:"Marco Infante"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1 Case report",level:"2"},{id:"sec_2_2",title:"1.2 Rethinking the patient from scratch",level:"2"},{id:"sec_3_2",title:"1.3 The decision to initiate an anti-glucocorticoid-centered, experimental therapeutic approach",level:"2"},{id:"sec_5",title:"2. Material and methods",level:"1"},{id:"sec_5_2",title:"2.1 Experimental protocol (1988)",level:"2"},{id:"sec_5_3",title:"2.1.1 First course of anti-glucocorticoid treatment alone",level:"3"},{id:"sec_6_3",title:"2.1.2 Anti-glucocorticoid treatment plus partial blockade of cortisol synthesis",level:"3"},{id:"sec_7_3",title:"2.1.3 Second course of anti-glucocorticoid treatment alone",level:"3"},{id:"sec_10",title:"3. Results",level:"1"},{id:"sec_10_2",title:"3.1 Mifepristone therapy alone, 600 mg/day (9 weeks)",level:"2"},{id:"sec_11_2",title:"3.2 Mifepristone (600 mg/day) plus ketoconazole (800 mg/day) combination therapy (a single week)",level:"2"},{id:"sec_12_2",title:"3.3 Second course of mifepristone therapy alone, 600 mg/day (2 weeks)",level:"2"},{id:"sec_13_2",title:"3.4 Summary of metabolic changes observed during the anti-glucocorticoid intervention",level:"2"},{id:"sec_14_2",title:"3.5 The decision to perform total (bilateral) adrenalectomy and its results",level:"2"},{id:"sec_15_2",title:"3.6 Patient discharge and follow-up",level:"2"},{id:"sec_17",title:"4. Discussion",level:"1"},{id:"sec_17_2",title:"4.1 Extreme adipose tissue insulin resistance (Adipo-IR) at the core of CGL?",level:"2"},{id:"sec_18_2",title:"4.2 Mifepristone and adipose tissue insulin sensitivity",level:"2"},{id:"sec_19_2",title:"4.3 Adrenalectomy and insulin resistance",level:"2"},{id:"sec_20_2",title:"4.4 The new knowledge on Berardinelli-Seip syndrome and its relationship with leptin",level:"2"},{id:"sec_22",title:"5. Conclusions",level:"1"},{id:"sec_23",title:"Acknowledgments",level:"1"},{id:"sec_26",title:"Conflicts of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Mantzoros CS. Lipodystrophic syndromes. Uptodate. Topic updated 8th June 2021'},{id:"B2",body:'Tsoukas MA, Mantzoros CS. Lipodystrophy syndromes. Chapter 37. In: Jameson JL, DeGroot LJ, editors. Endocrinology: Adult and Pediatric. 7th ed. 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Plasma total and glycosylated corticosteroid-binding globulin levels are associated with insulin secretion. The Journal of Clinical Endocrinology and Metabolism. 1999;84:3192-3196. DOI: 10.1210/jcem.84.9.5946'},{id:"B34",body:'Fowler MA, Kusnetzow AK, Han S, Reinhart R, Kim SH, et al. Effects of CRN04894, a nonpeptide orally bioavailable ACTH antagonist, on corticosterone in rodent models of ACTH excess. Endocrine Society’s annual ENDO 2021 Oral Sessions. Available from: https://crinetics.com/wp-content/uploads/2021/03/Melissa_Effects-of-CRN04894-a-Nonpeptide-Orally-Bioavailable-ACTH-Antagonist-on-Corticosterone-in-Rodent-Models-of-ACTH-Excess.pdf [Accessed: December 13, 2021]'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Patricio H. Contreras",address:"pathomero@gmail.com",affiliation:'
Fundación Médica San Cristóbal, Santiago, Chile
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In our mission to support the dissemination of knowledge, we travel throughout the world to present our publications and support our Authors and Academic Editors. We attend international symposia, conferences, workshops and book fairs as well as business meetings with science, academic and publishing professionals. Take a look at the current events.
",metaTitle:"IntechOpen events",metaDescription:"In our mission to support the dissemination of knowledge, we travel worldwide to present our publications, authors and editors at international symposia, conferences, and workshops, as well as attend business meetings with science, academia and publishing professionals. We are always happy to host our scientists in our office to discuss further collaborations. Take a look at where we’ve been, who we’ve met and where we’re going.",metaKeywords:null,canonicalURL:"/page/events",contentRaw:'[{"type":"htmlEditorComponent","content":"
Upcoming Events
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IntechOpen Journals Webinar - Introduction to Open Science
26 November - 04 December 2022, Guadalajara, Mexico
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IntechOpen Represented by LSR Libros Servicios y Representaciones SA de CV
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He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. 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Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:{name:"Association for Computing Machinery",country:{name:"United States of America"}}},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:"Manufacturing and Technology Integrated Campus – SENAI CIMATEC",institution:null},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:'"Politechnica" University Timişoara',institution:null},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"426586",title:"Dr.",name:"Oladunni A.",middleName:null,surname:"Daramola",slug:"oladunni-a.-daramola",fullName:"Oladunni A. Daramola",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Federal University of Technology",country:{name:"Nigeria"}}},{id:"357014",title:"Prof.",name:"Leon",middleName:null,surname:"Bobrowski",slug:"leon-bobrowski",fullName:"Leon Bobrowski",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Bialystok University of Technology",country:{name:"Poland"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"354126",title:"Dr.",name:"Setiawan",middleName:null,surname:"Hadi",slug:"setiawan-hadi",fullName:"Setiawan Hadi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Padjadjaran University",country:{name:"Indonesia"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"332603",title:"Prof.",name:"Kumar S.",middleName:null,surname:"Ray",slug:"kumar-s.-ray",fullName:"Kumar S. Ray",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Statistical Institute",country:{name:"India"}}},{id:"415409",title:"Prof.",name:"Maghsoud",middleName:null,surname:"Amiri",slug:"maghsoud-amiri",fullName:"Maghsoud Amiri",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Allameh Tabataba'i University",country:{name:"Iran"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. 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Novel computational algorithms for image analysis, scene understanding, biometrics, deep learning and their software or hardware implementations for natural and medical images, robotics, VR/AR, applications are some research directions relevant to this topic.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",hasOnlineFirst:!0,hasPublishedBooks:!1,annualVolume:11420,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. 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His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null,series:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403"},editorialBoard:[{id:"1177",title:"Prof.",name:"António",middleName:"J. 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