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Aim: To examine the real‐world efficacy of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) in monogenic obesity in patients with Alström syndrome (ALMS). Methods: We screened 72 UK adult patients with ALMS and offered treatment to 34 patients meeting one of the following criteria: body mass index of 25 kg/m2 or higher, insulin resistance, suboptimal glycaemic control on antihyperglycaemic medications or non‐alcoholic fatty liver disease. Results: In total, 30 patients, with a mean age of 31 ± 11 years and a male to‐female ratio of 2:1, completed 6 months of treatment with GLP‐1 RAs either in the form of semaglutide or exenatide. On average, treatment with GLP‐1 RAs reduced body weight by 5.4 ± 1.7 (95% confidence interval [CI] 3.6‐7) kg and HbA1c by 12 ± 3.3 (95% CI 8.7‐15.3) mmol/mol, equating to 6% weight loss (P <.01) and 1.1% absolute reduction in HbA1c (P <.01). Significant improvements were also observed in serum total cholesterol, triglycerides, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol and alanine aminotransferase. The improvement of metabolic variables in our cohort of monogenic syndromic obesity was comparable with data for polygenic obesity, irrespective of weight loss. Conclusions: Data from our centre highlight the non‐inferiority of GLP‐1 RAs in monogenic syndromic obesity to the available GLP‐1 RA‐use data in polygenic obesity, therefore, these agents can be considered as a treatment option in patients with ALMS, as well as other forms of monogenic obesity. [ABSTRACT FROM AUTHOR]

Background Sinus of Valsalva aneurysm (SVA) is a rare but potentially life-threatening condition. Acute myocardial infarction (MI) is a rare consequence of aneurysmal dilatation of one or more sinuses of Valsalva. We present a case of an unruptured and partially thrombosed left SVA, presenting as anterior MI and congestive heart failure. Case summary A 55-year-old gentleman was admitted with pulmonary oedema and a late presenting ST-elevation MI with Q wave. After initial treatment on furosemide infusion, a coronary angiography showed significant stenosis in both his left main stem (LMS) and left anterior descending artery (LAD). This is likely a result of external compression, potentially from the enlarged left sinus of Valsalva. A subsequent transthoracic echocardiogram and transoesophageal echocardiogram (TOE) confirmed large SVA involving the left coronary cusp measured 9.9 cm compressing both LMS and LAD. Discussion Left SVAs are rare and frequently asymptomatic, typically being identified incidentally. Due to the close proximity of the left coronary system, they can present with myocardial ischaemia due to extrinsic compression of the coronary system. We were able to perform a comprehensive multi-modality assessment of left SVA, which helped establish this unusual diagnosis and guide management. Transthoracic echocardiogram and TOE helped assess the SVA and demonstrated the thrombus in situ , aortic valve insufficiency, and cardiac function. The computed tomography scan aided in accurately defining the extent of the aneurysm and the extent of compression of the left coronary system and cardiac magnetic resonance scan was able to demonstrate viability in LAD and circumflex territory. [ABSTRACT FROM AUTHOR]

Obesity is a major risk factor for insulin resistance (IR) and its attendant complications. The pathogenic mechanisms linking them remain poorly understood, partly due to a lack of intermediary monogenic human phenotypes. Here, we report on a monogenic form of IR-prone obesity, Alström syndrome (ALMS). Twenty-three subjects with monogenic or polygenic obesity underwent hyperinsulinemic-euglycemic clamping with concomitant adipose tissue (AT) microdialysis and an in-depth analysis of subcutaneous AT histology. We have shown a relative AT failure in a monogenic obese cohort, a finding supported by observations in a novel conditional mouse model (Almsflin/flin ) and ALMS1-silenced human primary adipocytes, whereas selective reactivation of ALMS1 gene in AT of an ALMS conditional knockdown mouse model (Almsflin/flin; Adipo-Cre+/- ) restores systemic insulin sensitivity and glucose tolerance. Hence, we show for the first time the relative AT failure in human obese cohorts to be a major determinant of accelerated IR without evidence of lipodystrophy. These new insights into adipocyte-driven IR may assist development of AT-targeted therapeutic strategies for diabetes. [ABSTRACT FROM AUTHOR]

Background Alström syndrome (AS) is a rare autosomal recessive ciliopathy with a wide spectrum of clinical features, including cone–rod retinal dystrophy, neuronal deafness, severe insulin resistance and major organ failure. The characteristics of renal disease in the syndrome have not been systematically described. The aim of this study is to define the onset and progression of renal disease in AS. Method Prospective observational cohort study. Setting and Participants Thirty-two adult subjects from a national specialist clinic in UK and 86 subjects from an international AS registry were studied. Outcomes First, an international registry cross-sectional study across all age groups to determine change in kidney function was performed. Secondly, a detailed assessment was carried out of adult AS patients with serial follow-up to determine incidence, aetiology and progression of renal disease. Analytical approach Generalized estimating equations were used to evaluate the relationship between age and estimated glomerular filtration rate (eGFR). Associations between patient factors and eGFR levels were then assessed in the adult AS cohort. Results The international registry study of the renal function of 118 subjects with AS (median age 21 years) showed a rapid decline with age, at an average of −16.7 and −10.9 mL/min/1.73 m2 per decade in males and females, respectively. In a UK national cohort of 32 patients with AS (median age 22 years), 20/32 (63%) had chronic kidney disease (CKD) Stage 3 or above based on eGFR <60 mL/min/1.73 m2 or evidence of albuminuria. Hyperuricaemia was noted in 25/32 (79%). Structural abnormalities such as nephrocalcinosis without hypercalcaemia and cysts were observed in 20/32 (63%) subjects. Lower urinary tract symptoms were frequent in 17/19 (70%) of AS patients. Histological evidence showed mixed tubulo-interstitial and glomerular disease. Conclusions This is the first study to demonstrate that renal disease is the hallmark of AS, which starts early and progresses with age, leading to a high prevalence of advanced CKD at young age. AS should be considered in the differential diagnosis of rare genetic renal diseases. [ABSTRACT FROM AUTHOR]

The study aim was to comprehensively assess physiological function and muscle morphology in chronically trained older individuals against untrained young and older individuals. In a cross-sectional design, 15 young untrained controls (YC) (20 ± 2.7 years, 78.9 ± 13.3 kg), 12 untrained older controls (OC) (69.8 ± 4.1 years, 77.5 ± 14.2 kg), and 14 endurance-trained master athletes (MA) (67.1 ± 4.1 years, 68.7 ± 6.5 kg) underwent assessments of body composition, aerobic capacity, strength, muscle architecture, and fiber-type morphology. Skeletal muscle index was lower and body fat greater in OC versus MA. Estimated VO2max (mL·kg−1·minute−1) was similar between MA and YC, but lower in OC. Isometric leg strength normalized to fat-free mass was similar between groups, whereas normalized isometric arm strength was greater in YC than MA. Myosin heavy chain (MHC) I fiber area was greater in MA than OC, while MHC II fiber area was greater in YC than OC. MHC II fiber myonuclear domain size was greater in YC than OC and MA, whereas MA had greater MHC I and MHC II fiber capillarization than OC and YC. Satellite cell content was similar between groups. Chronic endurance training enhances indices of muscle morphology and improves body composition and aerobic capacity in older age, with potentially important implications for healthspan extension. [ABSTRACT FROM AUTHOR]