Characterization of Human Subcutaneous Adipose Tissue and Validation of the Banking Procedure for Autologous Transplantation.

Adipose tissue (AT) is composed of a heterogeneous population which comprises both progenitor and differentiated cells. This heterogeneity allows a variety of roles for the AT, including regenerative functions. In fact, autologous AT is commonly used to repair soft tissue defects, and its cryopreservation could be a useful strategy to reduce the patient discomfort caused by multiple harvesting procedures. Our work aimed to characterize the cryopreserved AT and to validate its storage for up to three years for clinical applications. AT components (stromal vascular fraction-SVF and mature adipocytes) were isolated in fresh and cryopreserved samples using enzymatic digestion, and cell viability was assessed by immunofluorescence (IF) staining. Live, apoptotic and necrotic cells were quantified using cytometry by evaluating phosphatidylserine binding to fluorescent-labeled Annexin V. A multiparametric cytometry was also used to measure adipogenic (CD34+CD90+CD31-CD45-) and endothelial (CD34+CD31+CD45-) precursors and endothelial mature cells (CD34-CD31+CD45-). The maintenance of adipogenic abilities was evaluated using in vitro differentiation of SVF cultures and fluorescent lipid staining. We demonstrated that AT that is cryopreserved for up to three years maintains its differentiation potential and cellular composition. Given our results, a clinical study was started, and two patients had successful transplants without any complications using autologous cryopreserved AT.

Adipogenic progenitors in different organs: Pathophysiological implications.

In physiological conditions, the adipose organ resides in well-defined areas, where it acts providing an energy supply and as an endocrine organ involved in the control of whole-body energy metabolism. Adipose tissue adipokines connect the body's nutritional status to the regulation of energy balance. When it surrounds organs, it provides also for mechanical protection. Adipose tissue has a complex and heterogenous cellular composition that includes adipocytes, adipose tissue-derived stromal and stem cells (ASCs) which are mesenchymal stromal cells, and endothelial and immune cells, which signal to each other and to other tissues to maintain homeostasis. In obesity and in other nutrition related diseases, as well as in age-related diseases, biological and functional changes of adipose tissue give rise to several complications. Obesity triggers alterations of ASCs, impairing adipose tissue remodeling and adipose tissue function, which induces low-grade systemic inflammation, progressive insulin resistance and other metabolic disorders. Adipose tissue grows by hyperplasia recruiting new ASCs and by hypertrophy, up to its expandability limit. To overcome this limitation and to store the excess of nutrients, adipose tissue develops ectopically, involving organs such as muscle, bone marrow and the heart. The origin of ectopic adipose organ is not clearly elucidated, and a possible explanation lies in the stimulation of the adipogenic differentiation of mesenchymal precursor cells which normally differentiate toward a lineage specific for the organ in which they reside. The chronic exposition of these newly-formed adipose depots to the pathological environment, will confer to them all the phenotypic characteristics of a dysfunctional adipose tissue, perpetuating the organ alterations. Visceral fat, but also ectopic fat, either in the liver, muscle or heart, can increase the risk of developing insulin resistance, type 2 diabetes, and cardiovascular diseases. Being able to prevent and to target dysfunctional adipose tissue will avoid the progression towards the complications of obesity and other nutrition-related diseases. The aim of this review is to summarize some of the knowledge regarding the presence of adipose tissue in particular tissues (where it is not usually present), describing the composition of its adipogenic precursors, and the interactions responsible for the development of organ pathologies.

In vitro chronic glycation induces AGEs accumulation reducing insulin-stimulated glucose uptake and increasing GLP1R in adipocytes.

Intracellular AGEs accumulation increases RAGE and GLP1R and reduces glucose uptake in adipocytes.

Edmonton Obesity Staging System: an improvement by cardiopulmonary exercise testing.

BACKGROUND/OBJECTIVES: Different approaches are used to classify obesity severity. Beyond classical anthropometric measurements, the Edmonton Obesity Staging System (EOSS) considers medical, physical and psychological parameters. However, this method has some limitations, principally due to the absence of an objective measure for physical impairment. The aim of our study is thus to overcome this limitation suggesting a new functional parameter obtained by cardiopulmonary exercise testing (CPET), i.e., cardiorespiratory fitness (CRF), expressed as weight-adjusted peak oxygen consumption (VO2peak/kg). SUBJECTS/METHODS: This observational cross-sectional study conducted on a population of 843 patients affected by obesity finally enrolled 500 subjects. Every patient underwent clinical, anthropometric, biochemical assessment and CPET. First, participants have been classified according to standard EOSS in five stages. Second, patients were reclassified according to the new modified EOSS (EOSS-CRF) based on their age- and gender-appropriate VO2peak/kg percentiles as reported in the healthy normal-weight population of the FRIEND registry. RESULTS: VO2peak/kg was significantly different between standard EOSS classes 1 and 2 and classes 1 and 3 (ANCOVA p model = 0.004), whereas patients in classes 2 and 3 showed similar CRF. The EOSS-CRF classification varied in number of patients in each class compared to EOSS, particularly with a shift from class 2 to class 3. Moreover, CRF showed that physical impairment is less addressed by EOSS when compared to EOSS-CRF. CONCLUSIONS: The integration of EOSS with CRF allowed us to assign to each patient a severity index that considers not only clinical parameters, but also their functional impairment through a quantitative and prognostically important parameter (VO2peak/kg). This improvement of the staging system may also provide a better approach to identify individuals at increased risk of mortality leading to targeted therapeutic management and prognostic risk stratification for patients with obesity.

Neurocognitive assessment and DNA sequencing expand the phenotype and genotype spectrum of Alström syndrome.

Alström syndrome (OMIM#203800) is an ultra-rare autosomal recessive monogenic disease presenting pathogenic variants in ALMS1 (chromosome 2p13). It is characterized by early onset of blindness, hearing loss and systemic comorbidities, with delayed development without cognitive impairment. We aimed to investigate the cognitive functions and describe new pathogenic variants in Alström syndrome patients. Nineteen patients (13 adults, 6 children) underwent a thorough clinical, genetic, laboratory, instrumental, and neurocognitive assessment. Six new pathogenic variants in ALMS1 including the first described in exon 6 were identified. Four patients displayed a "mild phenotype" characterized by slow disease onset or absence of complications, including childhood obesity and association with at least one pathogenic variant in exon 5 or 6. At neurocognitive testing, a significant proportion of patients had deficits in three neurocognitive domains: similarities, phonological memory, and apraxia. In particular, 53% of patients showed difficulties in the auditory working memory test. We found ideomotor and buccofacial apraxia in 74% of patients. "Mild phenotype" patients performed better on auditory working memory and ideomotor apraxia test than "typical phenotype" ones (91.9 + 16.3% vs. 41.7 + 34.5% of correct answers, Z = 64.5, p < .01 and 92.5 + 9.6 vs. 61.7 + 26.3, Z = 61, p < .05, respectively). Deficits in auditory working memory, ideomotor, and buccofacial apraxia were found in these patients and fewer neuropsychological deficits were found in the "mild" phenotype group. Furthermore, in the "mild" phenotype group, it was found that all pathogenic variants are localized before exon 8.

White Adipose Tissue Expansion in Multiple Symmetric Lipomatosis Is Associated with Upregulation of CK2, AKT and ERK1/2.

Multiple symmetric lipomatosis (MSL) is a rare disorder characterized by overgrowing lipomatous tissue (LT) in the subcutaneous adipose tissue (SAT). What LT is and how it expands are not completely understood; previous data suggested that it could derive from brown AT precursors. In six MSL type I patients, we compared LT morphology by histological and immunohistochemistry (IHC) analysis, gene expression, by qPCR, kinase activity, by Western Blot and in vitro assay to paired-control SAT using AT from patients with pheochromocytoma as a human browning reference. In the stromal vascular fraction (SVF), we quantified adipose stem cells (ASCs) by flow cytometry, the proliferation rate, white and beige adipogenic potential and clonogenicity and adipogenicity by a limiting dilution assay. LT displayed white AT morphology and expression pattern and did not show increased levels of the brown-specific marker UCP1. In LT, we evidenced AKT, CK2 and ERK1/2 hyperactivation. LT-SVF contained increased ASCs, proliferated faster, sprouted clones and differentiated into adipocytes better than the control, displaying enhanced white adipogenic potential but not increased browning compared to SAT. In conclusion, LT is a white AT depot expanding by hyperplasia through increased stemness and enhanced white adipogenesis upregulating AKT, CK2 and ERK1/2, which could represent new targets to counteract MSL.

Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia.

We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease-associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype-phenotype relations for the WFS1 gene. The presence of biallelic loss-of-function variants predicted Wolfram syndrome defined by insulin-dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%-83%) and specificity of 92% (83%-97%). The presence of minor loss-of-function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%-100%]; specificity 78% [73%-82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next-generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org.

Increased mitochondrial calcium uniporter in adipocytes underlies mitochondrial alterations associated with insulin resistance.

Intracellular calcium influences an array of pathways and affects cellular processes. With the rapidly progressing research investigating the molecular identity and the physiological roles of the mitochondrial calcium uniporter (MCU) complex, we now have the tools to understand the functions of mitochondrial Ca2+ in the regulation of pathophysiological processes. Herein, we describe the role of key MCU complex components in insulin resistance in mouse and human adipose tissue. Adipose tissue gene expression was analyzed from several models of obese and diabetic rodents and in 72 patients with obesity as well as in vitro insulin-resistant adipocytes. Genetic manipulation of MCU activity in 3T3-L1 adipocytes allowed the investigation of the role of mitochondrial calcium uptake. In insulin-resistant adipocytes, mitochondrial calcium uptake increased and several MCU components were upregulated. Similar results were observed in mouse and human visceral adipose tissue (VAT) during the progression of obesity and diabetes. Intriguingly, subcutaneous adipose tissue (SAT) was spared from overt MCU fluctuations. Furthermore, MCU expression returned to physiological levels in VAT of patients after weight loss by bariatric surgery. Genetic manipulation of mitochondrial calcium uptake in 3T3-L1 adipocytes demonstrated that changes in mitochondrial calcium concentration ([Ca2+]mt) can affect mitochondrial metabolism, including oxidative enzyme activity, mitochondrial respiration, membrane potential, and reactive oxygen species formation. Finally, our data suggest a strong relationship between [Ca2+]mt and the release of IL-6 and TNFα in adipocytes. Altered mitochondrial calcium flux in fat cells may play a role in obesity and diabetes and may be associated with the differential metabolic profiles of VAT and SAT.

Functional avidity-driven activation-induced cell death shapes CTL immunodominance.

Immunodominance is a complex phenomenon that relies on a mere numerical concept, while being potentially influenced at every step of the immune response. We investigated the mechanisms leading to the establishment of CTL immunodominance in a retroviral model and found that the previously defined subdominant Env-specific CD8(+) T cells are endowed with an unexpectedly higher functional avidity than is the immunodominant Gag-recognizing counterpart. This high avidity, along with the Env Ag overload, results in a supraoptimal TCR engagement. The overstimulation makes Env-specific T lymphocytes more susceptible to apoptosis, thus hampering their expansion and leading to an unintentional "immune kamikazing." Therefore, Ag-dependent, hyperactivation-induced cell death can be regarded as a novel mechanism in the establishment of the immunodominance that restrains and opposes the expansion of high-avidity T cells in favor of lower-affinity populations.

Pituitary morphovolumetric changes in Alström syndrome.

PURPOSE: Alström syndrome (AS) is a rare monogenic ciliopathy characterized by cone-code dystrophy, leading to early blindness, and obesity. Early endocrinological dysfunctions, especially growth hormone deficiency and hypogonadism, are detected in about half of AS patients. This MRI study investigates the presence of pituitary gland abnormalities in a large cohort of AS patients. METHODS: Pituitary morphological changes (gland flattening with partial or total empty sella) were evaluated on midsagittal high-resolution T1-weighted images of 32 AS patients (mean-age 23.2±9.4 years; range: 6-45, 15 females) and 21 unrelated healthy subjects (mean age 23.2±11.2 years; range: 6-43; 10 females). RESULTS: Among AS patients, 11/32 (34%) had total empty sella and 6/32 (19%) partial empty sella, while 3/21 (14%) of controls had partial empty sella and none presented with total empty sella (P<0.005). AS patients harboring a total or partial empty sella did not differ from those with normal pituitary gland for gender (P=0.98), BMI (P=0.10) or visual impairment (P=0.21), while the presence of empty sella was associated with an older age (P=0.007) being especially frequent above the age of 30. CONCLUSIONS: Total or partial empty sella appears commonly during the course of AS. Pituitary gland flattening might represent the morphological underpinning of subtle endocrinologic dysfunctions and raises the need to further investigate the pituitary function in this rare ciliopathy.

Alström Syndrome: Mutation Spectrum of ALMS1.

Alström Syndrome (ALMS), a recessive, monogenic ciliopathy caused by mutations in ALMS1, is typically characterized by multisystem involvement including early cone-rod retinal dystrophy and blindness, hearing loss, childhood obesity, type 2 diabetes mellitus, cardiomyopathy, fibrosis, and multiple organ failure. The precise function of ALMS1 remains elusive, but roles in endosomal and ciliary transport and cell cycle regulation have been shown. The aim of our study was to further define the spectrum of ALMS1 mutations in patients with clinical features of ALMS. Mutational analysis in a world-wide cohort of 204 families identified 109 novel mutations, extending the number of known ALMS1 mutations to 239 and highlighting the allelic heterogeneity of this disorder. This study represents the most comprehensive mutation analysis in patients with ALMS, identifying the largest number of novel mutations in a single study worldwide. Here, we also provide an overview of all ALMS1 mutations identified to date.

Obesity, the Adipose Organ and Cancer in Humans: Association or Causation?

Epidemiological observations, experimental studies and clinical data show that obesity is associated with a higher risk of developing different types of cancer; however, proof of a cause-effect relationship that meets the causality criteria is still lacking. Several data suggest that the adipose organ could be the protagonist in this crosstalk. In particular, the adipose tissue (AT) alterations occurring in obesity parallel some tumour behaviours, such as their theoretically unlimited expandability, infiltration capacity, angiogenesis regulation, local and systemic inflammation and changes to the immunometabolism and secretome. Moreover, AT and cancer share similar morpho-functional units which regulate tissue expansion: the adiponiche and tumour-niche, respectively. Through direct and indirect interactions involving different cellular types and molecular mechanisms, the obesity-altered adiponiche contributes to cancer development, progression, metastasis and chemoresistance. Moreover, modifications to the gut microbiome and circadian rhythm disruption also play important roles. Clinical studies clearly demonstrate that weight loss is associated with a decreased risk of developing obesity-related cancers, matching the reverse-causality criteria and providing a causality correlation between the two variables. Here, we provide an overview of the methodological, epidemiological and pathophysiological aspects, with a special focus on clinical implications for cancer risk and prognosis and potential therapeutic interventions.

Hematopoietic Stem Cells and Metabolic Deterioration in Alström Syndrome, a Rare Genetic Model of the Metabolic Syndrome.

Alström syndrome (AS) is a rare genetic disease caused by ALMS1 mutations, characterized by short stature, and vision and hearing loss. Patients with AS develop the metabolic syndrome, long-term organ complications, and die prematurely. We explored the association between AS and a shortage of hematopoietic stem/progenitor cells (HSPCs), which is linked to metabolic diseases and predicts diabetic complications. We included patients with AS at a national referral center. We measured HSPCs with flow cytometry at baseline and follow-up. We followed patients up to January 2022 for metabolic worsening and end-organ damage. We evaluated HSPC levels and mobilization as well as bone marrow histology in a murine model of AS. In 23 patients with AS, we found significantly lower circulating HSPCs than in healthy blood donors (-40%; P = .002) and age/sex-matched patients (-25%; P = .022). Longitudinally, HSPCs significantly declined by a further 20% in patients with AS over a median of 36 months (interquartile range 30-44). Patients with AS who displayed metabolic deterioration over 5.3 years had lower levels of HSPCs, both at baseline and at last observation, than those who did not deteriorate. Alms1-mutated mice were obese and insulin resistant and displayed significantly reduced circulating HSPCs, despite no overt hematological abnormality. Contrary to what was observed in diabetic mice, HSPC mobilization and bone marrow structure were unaffected. We found depletion of HSPCs in patients with AS, which was recapitulated in Alms1-mutated mice. Larger and longer studies will be needed to establish HSPCs shortage as a driver of metabolic deterioration leading to end-organ damage in AS.

Down-staging of obesity one year after bariatric surgery: a new proposal of Edmonton obesity staging system.

Background: Different approaches are used to classify obesity severity. The Edmonton Obesity Staging System (EOSS) considers medical, physical and psychological parameters. A new modified EOSS with a different functional evaluation method, measuring Cardiorespiratory Fitness (CRF), has been recently proposed, EOSS-CRF. Bariatric surgery (BS) is one of the most efficient treatments of obesity and all aspect of related disorders. No studies have yet applied EOSS-CRF after BS. Therefore, the aim of this study was to evaluate modifications in EOSS and EOSS-CRF before and after BS. Methods: This observational study finally enrolled 72 patients affected by obesity. A multi-disciplinary assessment in order to evaluate eligibility to surgical treatment has been performed, including anamnesis, physical evaluation, anthropometric data measurement, biochemical blood exams and cardiopulmonary exercise testing. One year after BS the same protocol was applied. Patients have been classified according to EOSS and EOSS-CRF before and one year after BS. Results: After BS, patients categorized in classes associated to severe obesity (EOSS ≥ 2 or EOSS-CRF ≥ 2) reduced significantly. Using EOSS, patients without functional impairment were 61% before surgery and 69% after BS (p=0.383). Using EOSS-CRF, patients considered without functional impairment were only 9.7% before BS; this percentage significantly raised to 50% after BS (p<0.001). The impact of functional domains before and after BS is different in grading patients in EOSS and EOSS-CRF, respectively. Conclusions: Improvements obtained after BS are adequately summarized by EOSS and EOSS-CRF. The EOSS-CRF grading method for functional impairment seems to better reflect the known amelioration obtained after BS. Objective measurements of CRF may provide additional value to classify severity of obesity, also in the follow-up after BS.

The progression from obesity to type 2 diabetes in Alström syndrome.

BACKGROUND: Alström syndrome (ALMS) is a rare autosomal recessive monogenic disease associated with obesity, hyperinsulinemia, and alterations of glucose metabolism that often lead to the development of type 2 diabetes at a young age. OBJECTIVE: To study the relationship between weight and metabolism in a group of ALMS patients and matched controls. RESEARCH DESIGN AND METHODS: Fifteen ALMS patients (eight males, seven females; aged 3-51) were compared in a cross-sectional study with an age- and weight-matched control population. Anthropometric parameters, fat mass, glucose and insulin secretion in basal and dynamic oral glucose tolerance test (OGTT) conditions were measured. Furthermore, anthropometric and body composition data were obtained from an international group of 27 ALMS patients (13 males, 14 females, age range: 4-29 yr). RESULTS: In ALMS we observed an inverse correlation between age and standard deviation scores for height, weight, and body mass index. The OGTT glycemic curves of ALMS subjects were similar to those of age-matched controls, whereas insulin response was clearly greater. In ALMS individuals the insulin response showed a reduction with age. We documented pathologic values of the derived indices homeostasis model assessment of insulin resistance (HOMA-IR), insulin sensitivity index, HOMA%ß-cell and insulinogenic index in ALMS, but unlike the insulin-resistance indices, the ß-cell function indices showed a significant reduction with age. CONCLUSIONS: In ALMS the progression from the early onset obesity toward the impaired fasting glucose or impaired glucose tolerance and overt diabetes is mostly because of a progressive failure of ß-cell insulin secretion without any further worsening of insulin resistance with age, even in the presence of weight reduction.

Metabolic Slowing Vanished 5 Years After Sleeve Gastrectomy in Patients With Obesity and Prediabetes/Diabetes.

BACKGROUND: Resting energy expenditure (REE) decreases after weight loss more than expected according to body composition changes. Metabolic adaptation (MA) or metabolic slowing represents the difference between measured (m) and predicted (p) REE, and it is not clear whether it persists in the long-term. The aim of this study is to evaluate MA occurring 1 year (V1) and 5 years (V5) after laparoscopic sleeve gastrectomy (LSG) in patients with obesity and normal glucose tolerance, prediabetes (preDM) and type 2 diabetes (T2DM). METHODS: We reassessed 37 patients (14 males/23 females) of 44.8 ±â€…10 years old, since they registered all the biochemical, body composition, and REE assessments at baseline (V0), V1, and V5. Physical activity (PA) was assessed by interview and questionnaire. RESULTS: Patients displayed a percentage of weight loss of 31.5 ±â€…7.4% at V1 and a weight regain of 8.9 ±â€…7.5% at V5. Comparing V1 and V5, fat mass showed a slight increase (P = 0.011), while free fat mass remained unchanged (P = 0.304). PA improved at V1 (P < 0.001), remaining stable at V5 (P = 0.9). Measured REE (mREE) displayed a 31.2% reduction with a corresponding decrease of predicted REE (pREE) of 21.4% at V1, compared with V0 (P = 0.005), confirming a significant MA at V1. Conversely, no difference between mREE and pREE was observed at V5 (P = 0.112). CONCLUSION: Our results suggested that only patients with preDM and T2DM displayed MA at V1, which vanished 5 years after LSG. Patients who practiced more PA prevent MA after surgery-induced wight loss.

Case Report:Pregnancy and birth in a mild phenotype of Alström syndrome.

Background: Alström syndrome (AS) is an ultrarare multisystemic progressive disease caused by autosomal recessive variations of the ALMS1 gene (2p13). AS is characterized by double sensory impairment, cardiomyopathy, childhood obesity, extreme insulin resistance, early nonalcoholic fatty liver disease, renal dysfunction, respiratory disease, endocrine and urologic disorders. In female AS patients, hyperandrogenism has been described but fertility issues and conception have not been investigated so far. Case: This case report describes the spontaneous conception, pregnancy, and birth in a 27-year-old woman with AS, characterized by a mild phenotype with late onset of visual impairment, residual perception of light, and hypertension. Before pregnancy, menses were regular with increased levels of dihydrotestosterone and androstanediol glucuronide in the follicular phase, and the ovaries and endometrium were normal during vaginal ultrasound. A thorough clinical follow-up of the maternal and fetal conditions was carried out. A weight gain of 10 kg during pregnancy was recorded, and serial blood and urine tests were all within the normal range, except for mild anemia. The course of pregnancy was uneventful up to 34 weeks of gestation when preeclampsia developed with an abnormally high level of blood pressure and edema in the lower limbs. At 35 weeks + 3 days of gestation, an urgent cesarean section was performed, and a healthy male weighing 1,950 g was born. Histological examination of the placenta showed partial signs of flow obstruction, limited abruption areas, congested fetal vessels and villi, and a small single infarcted area. Conclusion: The present case demonstrates for the first time that conceiving is possible for patients with ALMS. Particular attention should be given to the management of AS systemic comorbidities through the course of pregnancy.

ASCs and their role in obesity and metabolic diseases.

We describe adipose stromal/stem cells (ASCs) in the structural/functional context of the adipose tissue (AT) stem niche (adiponiche), including cell-cell interactions and the microenvironment, and emphasize findings obtained in humans and in lineage-tracing models. ASCs have distinctive markers, 'colors', and anatomical 'locations' which influence their functions. Each adiponiche component can become impaired, thereby contributing to the pathological AT alterations seen in obesity and metabolic diseases. We discuss adiposopathy with a focus on adiponiche dysfunction, and underline the mechanisms that control AT expansion and energy balance. Better understanding of adiponiche regulation and ASC features could help to identify therapeutic targets that favor weight loss and counteract weight regain, and also contribute to innovative strategies for regenerative medicine.

Alström syndrome: an ultra-rare monogenic disorder as a model for insulin resistance, type 2 diabetes mellitus and obesity.

BACKGROUND: Alström syndrome (ALMS) is a monogenic ultra-rare disorder with a prevalence of one per million inhabitants caused by pathogenic variants of ALMS1 gene. ALMS1 is located on chromosome 2p13, spans 23 exons and encodes a predicted 461.2-kDa protein of 4169 amino acids. The infantile cone-rod dystrophy with nystagmus and severe visual impairment is the earliest and most consistent clinical manifestation of ALMS. In addition, infantile transient cardiomyopathy, early childhood obesity with hyperphagia, deafness, insulin resistance (IR), type 2 diabetes mellitus (T2DM), systemic fibrosis and progressive renal or liver dysfunction are common findings. ALMS1 encodes a large ubiquitously expressed protein that is associated with the centrosome and the basal body of primary cilium. CURRENT RESEARCH: The localisation of ALMS1 to the ciliary basal body suggests its contribution to ciliogenesis and/or normal ciliary function, or centriolar stability. ALMS1 regulate glucose transport through the actin cytoskeleton, which plays an important role in insulin-stimulated GLUT4 transport. Both extreme IR and ß-cell failure are the two determinant factors responsible for the development of glucose metabolism alterations in ALMS. TREATMENT: Currently, there is no known cure for ALMS other than managing the underlying systemic diseases. When possible, individuals with ALMS and families should be referred to a centre of expertise and followed by a multidisciplinary team. Lifestyle modification, aerobic exercise and dietary induced weight loss are highly recommended as primary treatment for ALMS patients with T2DM and obesity. CONCLUSION: Managing a rare disease requires not only medical care but also a support network including patient associations.

Liver Fibrosis and Steatosis in Alström Syndrome: A Genetic Model for Metabolic Syndrome.

Alström syndrome (ALMS) is an ultra-rare monogenic disease characterized by insulin resistance, multi-organ fibrosis, obesity, type 2 diabetes mellitus (T2DM), and hypertriglyceridemia with high and early incidence of non-alcoholic fatty liver disease (NAFLD). We evaluated liver fibrosis quantifying liver stiffness (LS) by shear wave elastography (SWE) and steatosis using ultrasound sonographic (US) liver/kidney ratios (L/K) in 18 patients with ALMS and 25 controls, and analyzed the contribution of metabolic and genetic alterations in NAFLD progression. We also genetically characterized patients. LS and L/K values were significantly higher in patients compared with in controls (p < 0.001 versus p = 0.013). In patients, LS correlated with the Fibrosis-4 Index and age, while L/K was associated with triglyceride levels. LS showed an increasing trend in patients with metabolic comorbidities and displayed a significant correlation with waist circumference, the homeostasis model assessment, and glycated hemoglobin A1c. SWE and US represent promising tools to accurately evaluate early liver fibrosis and steatosis in adults and children with ALMS during follow-up. We described a new pathogenic variant of exon 8 in ALMS1. Patients with ALMS displayed enhanced steatosis, an early increased age-dependent LS that is associated with obesity and T2DM but also linked to genetic alterations, suggesting that ALMS1 could be involved in liver fibrogenesis.