Aims/hypothesis
Screening programmes can detect cases of undiagnosed diabetes earlier than symptomatic or incidental diagnosis. However, the improvement in time to diagnosis achieved by screening ...programmes compared with routine clinical care is unclear. We aimed to use the UK Biobank population-based study to provide the first population-based estimate of the reduction in time to diabetes diagnosis that could be achieved by HbA
1c
-based screening in middle-aged adults.
Methods
We studied UK Biobank participants aged 40–70 years with HbA
1c
measured at enrolment (but not fed back to participants/clinicians) and linked primary and secondary healthcare data (
n
=179,923) and identified those with a pre-existing diabetes diagnosis (
n
=13,077, 7.3%). Among the remaining participants (
n
=166,846) without a diabetes diagnosis, we used an elevated enrolment HbA
1c
level (≥48 mmol/mol ≥6.5%) to identify those with undiagnosed diabetes. For this group, we used Kaplan–Meier analysis to assess the time between enrolment HbA
1c
measurement and subsequent clinical diabetes diagnosis up to 10 years, and Cox regression to identify clinical factors associated with delayed diabetes diagnosis.
Results
In total, 1.0% (1703/166,846) of participants without a diabetes diagnosis had undiagnosed diabetes based on calibrated HbA
1c
levels at UK Biobank enrolment, with a median HbA
1c
level of 51.3 mmol/mol (IQR 49.1–57.2) (6.8% 6.6–7.4). These participants represented an additional 13.0% of diabetes cases in the study population relative to the 13,077 participants with a diabetes diagnosis. The median time to clinical diagnosis for those with undiagnosed diabetes was 2.2 years, with a median HbA
1c
at clinical diagnosis of 58.2 mmol/mol (IQR 51.0–80.0) (7.5% 6.8–9.5). Female participants with lower HbA
1c
and BMI measurements at enrolment experienced the longest delay to clinical diagnosis.
Conclusions/interpretation
Our population-based study shows that HbA
1c
screening in adults aged 40–70 years can reduce the time to diabetes diagnosis by a median of 2.2 years compared with routine clinical care. The findings support the use of HbA
1c
screening to reduce the time for which individuals are living with undiagnosed diabetes.
Graphical abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Serotonin reuptake inhibitors and receptor agonists are used to treat obesity, anxiety and depression. Here we studied the role of the serotonin 2C receptor (5-HT
R) in weight regulation and ...behavior. Using exome sequencing of 2,548 people with severe obesity and 1,117 control individuals without obesity, we identified 13 rare variants in the gene encoding 5-HT
R (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Knock-in male mice harboring a human loss-of-function HTR2C variant developed obesity and reduced social exploratory behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity. Using the 5-HT
R agonist lorcaserin, we found that depolarization of appetite-suppressing proopiomelanocortin neurons was impaired in knock-in mice. In conclusion, we demonstrate that 5-HT
R is involved in the regulation of human appetite, weight and behavior. Our findings suggest that melanocortin receptor agonists might be effective in treating severe obesity in individuals carrying HTR2C variants. We suggest that HTR2C should be included in diagnostic gene panels for severe childhood-onset obesity.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Background
Diabetes (regardless of type) and obesity are associated with a range of musculoskeletal disorders. The causal mechanisms driving these associations are unknown for many upper ...limb pathologies. We used genetic techniques to test the causal link between glycemia, obesity and musculoskeletal conditions.
Methods
In the UK Biobank’s unrelated European cohort (N = 379 708) we performed mendelian randomisation (MR) analyses to test for a causal effect of long-term high glycaemia and adiposity on four musculoskeletal pathologies: frozen shoulder, Dupuytren’s disease, carpal tunnel syndrome and trigger finger. We also performed single-gene MR using rare variants in the GCK gene.
Results
Using MR, we found evidence that long-term high glycaemia has a causal role in the aetiology of upper limb conditions. A 10-mmol/mol increase in genetically predicted haemoglobin A1C (HbA1c) was associated with frozen shoulder: odds ratio (OR) = 1.50 95% confidence interval (CI), 1.20–1.88, Dupuytren’s disease: OR = 1.17 (95% CI, 1.01–1.35), trigger finger: OR = 1.30 (95% CI, 1.09–1.55) and carpal tunnel syndrome: OR = 1.20 (95% CI, 1.09–1.33). Carriers of GCK mutations have increased odds of frozen shoulder: OR = 7.16 (95% CI, 2.93–17.51) and carpal tunnel syndrome: OR = 2.86 (95% CI, 1.50–5.44) but not Dupuytren’s disease or trigger finger. We found evidence that an increase in genetically predicted body mass index (BMI) of 5 kg/m2 was associated with carpal tunnel syndrome: OR = 1.13 (95% CI, 1.10–1.16) and associated negatively with Dupuytren’s disease: OR = 0.94 (95% CI, 0.90–0.98), but no evidence of association with frozen shoulder or trigger finger. Trigger finger (OR 1.96 (95% CI, 1.42–2.69) P = 3.6e-05) and carpal tunnel syndrome OR 1.63 (95% CI, 1.36–1.95) P = 8.5e-08 are associated with genetically predicted unfavourable adiposity increase of one standard deviation of body fat.
Conclusions
Our study consistently demonstrates a causal role of long-term high glycaemia in the aetiology of upper limb musculoskeletal conditions. Clinicians treating diabetes patients should be aware of these complications in clinic, specifically those managing the care of GCK mutation carriers. Upper limb musculoskeletal conditions should be considered diabetes complications.
Src homology 2 B adapter protein 1 (SH2B1) modulates signaling by a variety of ligands that bind to receptor tyrosine kinases or JAK-associated cytokine receptors, including leptin, insulin, growth ...hormone (GH), and nerve growth factor (NGF). Targeted deletion of Sh2b1 in mice results in increased food intake, obesity, and insulin resistance, with an intermediate phenotype seen in heterozygous null mice on a high-fat diet. We identified SH2B1 loss-of-function mutations in a large cohort of patients with severe early-onset obesity. Mutation carriers exhibited hyperphagia, childhood-onset obesity, disproportionate insulin resistance, and reduced final height as adults. Unexpectedly, mutation carriers exhibited a spectrum of behavioral abnormalities that were not reported in controls, including social isolation and aggression. We conclude that SH2B1 plays a critical role in the control of human food intake and body weight and is implicated in maladaptive human behavior.
The role of the mechanical environment in defining tissue function, development and growth has been shown to be fundamental. Assessment of the changes in stiffness of tissue matrices at multiple ...scales has relied mostly on invasive and often specialist equipment such as AFM or mechanical testing devices poorly suited to the cell culture workflow.In this paper, we have developed a unbiased passive optical coherence elastography method, exploiting ambient vibrations in the sample that enables real-time noninvasive quantitative profiling of cells and tissues. We demonstrate a robust method that decouples optical scattering and mechanical properties by actively compensating for scattering associated noise bias and reducing variance. The efficiency for the method to retrieve ground truth is validated in silico and in vitro, and exemplified for key applications such as time course mechanical profiling of bone and cartilage spheroids, tissue engineering cancer models, tissue repair models and single cell. Our method is readily implementable with any commercial optical coherence tomography system without any hardware modifications, and thus offers a breakthrough in on-line tissue mechanical assessment of spatial mechanical properties for organoids, soft tissues and tissue engineering.
Recent developments in genetics and genomics are providing a detailed and systematic characterization of the genetic underpinnings of common metabolic diseases and traits, highlighting the inherent ...complexity within systems for homeostatic control and the many ways in which that control can fail. The genetic architecture underlying these common metabolic phenotypes is complex, with each trait influenced by hundreds of loci spanning a range of allele frequencies and effect sizes. Here, we review the growing appreciation of this complexity and how this has fostered the implementation of genome-scale approaches that deliver robust mechanistic inference and unveil new strategies for translational exploitation.
The genetic architecture of metabolic traits and diseases is complex, but recent advances are enabling the characterization of loci and mechanisms that control metabolic phenotypes and opening new avenues for translational strategies
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Common genetic variants at the ARL15 locus are associated with plasma adiponectin, insulin and HDL cholesterol concentrations, obesity, and coronary atherosclerosis. The ARL15 gene encodes a small ...GTP-binding protein whose function is currently unknown. In this study adipocyte-autonomous roles for ARL15 were investigated using conditional knockdown of Arl15 in murine 3T3-L1 (pre)adipocytes. Arl15 knockdown in differentiated adipocytes impaired adiponectin secretion but not adipsin secretion or insulin action, while in preadipocytes it impaired adipogenesis. In differentiated adipocytes GFP-tagged ARL15 localized predominantly to the Golgi with lower levels detected at the plasma membrane and intracellular vesicles, suggesting involvement in intracellular trafficking. Sequencing of ARL15 in 375 severely insulin resistant patients identified four rare heterozygous variants, including an early nonsense mutation in a proband with femorogluteal lipodystrophy and non classical congenital adrenal hyperplasia, and an essential splice site mutation in a proband with partial lipodystrophy and a history of childhood yolk sac tumour. No nonsense or essential splice site mutations were found in 2,479 controls, while five such variants were found in the ExAC database. These findings provide evidence that ARL15 plays a role in adipocyte differentiation and adiponectin secretion, and raise the possibility that human ARL15 haploinsufficiency predisposes to lipodystrophy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Of 300 persons selected for early-onset obesity, hyperphagia, and consanguineous parentage, 8 had mutations in the leptin-receptor gene (
LEPR
). Biochemical and clinical analyses of the affected ...subjects suggest that the assay of serum leptin levels is not an appropriate screening tool for
LEPR
mutations and that the
LEPR
protein product may not be the only leptin receptor in humans.
Biochemical and clinical analyses suggest that the assay of serum leptin levels is not an appropriate screening tool for
LEPR
mutations and that the
LEPR
protein product may not be the only leptin receptor in humans.
The assessment of patients with severe early-onset obesity conventionally includes screening for potentially treatable neurologic and endocrine conditions and identifying known genetic conditions so that appropriate genetic counseling and, in some cases, treatment can be instituted.
1
Classically, patients with genetic obesity syndromes have been identified in childhood as a result of associated mental retardation and developmental abnormalities.
2
However, several monogenic disorders have been identified in which obesity itself is the predominant presenting feature. These disorders result from disruption of the hypothalamic leptin–melanocortin signaling pathway.
3
–
8
Twelve subjects with congenital leptin deficiency due to loss-of-function mutations in the gene encoding leptin . . .
Tre-2, BUB2, CDC16, 1 domain family member 4 (TBC1D4) (AS160) is a Rab-GTPase activating protein implicated in insulin-stimulated glucose transporter 4 (GLUT4) translocation in adipocytes and ...myotubes. To determine whether loss-of-function mutations in TBC1D4 might impair GLUT4 translocation and cause insulin resistance in humans, we screened the coding regions of this gene in 156 severely insulin-resistant patients. A female presenting at age 11 years with acanthosis nigricans and extreme postprandial hyperinsulinemia was heterozygous for a premature stop mutation (R363X) in TBC1D4. After demonstrating reduced expression of wild-type TBC1D4 protein and expression of the truncated protein in lymphocytes from the proband, we further characterized the biological effects of the truncated protein in 3T3L1 adipocytes. Prematurely truncated TBC1D4 protein tended to increase basal cell membrane GLUT4 levels (P = 0.053) and significantly reduced insulin-stimulated GLUT4 cell membrane translocation (P < 0.05). When coexpressed with wild-type TBC1D4, the truncated protein dimerized with full-length TBC1D4, suggesting that the heterozygous truncated variant might interfere with its wild-type counterpart in a dominant negative fashion. Two overweight family members with the mutation also manifested normal fasting glucose and insulin levels but disproportionately elevated insulin levels following an oral glucose challenge. This family provides unique genetic evidence of TBC1D4 involvement in human insulin action.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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