Genome-Wide Association Study and Functional Characterization Identifies Candidate Genes for Insulin-Stimulated Glucose Uptake

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in \u3e55,000 participants from three ancestry groups. We identified ten new loci (P \u3c 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits

Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

Celecoxib and Pioglitazone as Potential Therapeutics for Regulating TGF-beta-Induced Hyaluronan in Dysthyroid Myopathy

PURPOSE. To investigate the role of extraocular muscles (EOM) myoblasts in Graves ophthalmopathy (GO) pathology and the effect of a cyclooxygenase (COX)-2 inhibitor and a peroxisome proliferator-activated receptor (PPAR)-gamma agonist in its treatment. METHODS. Myoblasts were isolated and cultured from EOM of 10 patients with GO and 4 without (non-GO). The cultured myoblasts were treated with IFN-gamma, insulin-like growth factor (IGF)-1, IL-1 beta, and TNF-alpha, and the effect on PPAR-gamma, COX-2, TGF-beta, and thyroid stimulating hormone receptor (TSH-R) expressions were assessed using real-time (RT)-PCR, ELISA, and Western blot. The effect of a COX-2 inhibitor and a PPAR-gamma agonist on the expression of TGF-beta, hyaluronan synthases (HAS)-1, -2, and -3, and hyaluronan (HA) were further evaluated. RESULTS. Real-time PCR showed significant upregulation in PPAR-gamma, COX-2, TGF-beta, and TSH-R mRNA expression in GO myoblasts when treated with TNF-alpha but not in the non-GO. While IFN-gamma and IGF-1 had no significant effect, IL-1 beta did upregulate COX-2 expression. These results were further confirmed by ELISA and Western blotting. Tumor necrosis factor alpha-induced TGF-beta in turn significantly increased HA expression and HAS3 level, but not HAS1 and HAS2. The cyclooxygenase 2 inhibitor and PPAR-gamma agonist substantially diminished this TNF-alpha-induced TGF-beta, HA, and HAS3 expression. CONCLUSIONS. These results demonstrate the role of EOM myoblasts in the pathogenesis of GO. The cyclooxygenase 2 inhibitor and PPAR-gamma agonist in this study are potential treatments for GO due to their ability to suppress TNF-alpha-induced TGF-beta, HAS, and HA upregulation

Strategies in Surgical Decompression for Thyroid Eye Disease

Surgical management of thyroid eye disease- (TED-) associated morbidity has been plagued by the complex interplay of different operative techniques. Orbital decompression is the well-recognized procedure for disfiguring exophthalmos and dysthyroid optic neuropathy (DON). There are numerous published techniques described for the removal of the orbital bone, fat, or a combination. The diverse studies are noncomparative as they include different indications, stages of disease, and methods of evaluation. Thus, it is difficult to conclude the most efficient decompression technique. To obtain effective and predictable results, it is therefore important to propose a logical and acceptable clinical guideline to customize patient treatment. Herein, we developed an algorithm based on the presence of DON, preoperative existing diplopia, and severity of proptosis which were defined by patient’s disabling symptoms together with a set of ocular signs reflecting visual function or cosmesis. More specifically, we aimed to assess the minimal but effective surgical technique with acceptable potential complications to achieve therapeutic efficacy. Transcaruncular or inferomedial decompressions are indicated in restoring optic nerve function in patients with DON associated with mild or moderate to severe proptosis, respectively. Inferomedial or fatty decompressions are effective to treat patients with existing diplopia associated with mild or moderate to severe proptosis, respectively. Fatty or balanced decompressions can improve disfiguring exophthalmos in patients without existing diplopia associated with mild to moderate or severe proptosis, respectively. Inferomedial or 3-wall decompressions are preferred to address facial rehabilitation in patients associated with very severe proptosis but without preoperative diplopia

Endogenous Clostridium perfringens Panophthalmitis with Potential Entry Port from Diverticulitis Exacerbated by Proliferative Diabetic Retinopathy

Purpose. To report a rapid endogenous fulminating panophthalmitis from Clostridium perfringens in a patient with diverticulitis and proliferative diabetic retinopathy. Methods. A 61-year-old female with poorly controlled diabetes mellitus, active proliferative diabetic retinopathy, and recent diverticulitis presented with conjunctival injection, ocular discharge, and sudden onset of painful vision loss of the left eye. Patient denied history of ocular trauma, intraocular surgery, or intravenous drug abuse. Examination revealed an erythematous, proptotic eye with restricted extraocular movements, mucopurulent discharge, diffuse corneal edema, and vitreous haze and cell. Orbital computed tomography (CT) confirmed no retained intraocular foreign body. Results. Despite 48 hours of treatment with systemic broad spectrum antimicrobial therapy (vancomycin, meropenem, and amphotericin B), patient underwent enucleation due to declined condition and progressive infection. Patient’s culture revealed gram-positive bacillus microbes (Clostridium perfringens). Patient’s subsequent CT abdomen showed resolved diverticulitis after antimicrobial therapy. Conclusion. Although rare, Clostridium perfringens infection can be a cause of rapid loss of vision from fulminate endogenous panophthalmitis. Urgent extensive systemic work-up to identify potential port of entry from visceral pathology and rapid removal of source of infection are pivotal to avoid high rate of mortality

Fornix deepening reconstruction in conjunctivochalasis surgery

PURPOSE: To assess the extent of inferior fornix shortening in conjunctivochalasis (CCh) and to evaluate whether fornix deepening reconstruction can restore the fornix tear reservoir in patients with CCh. MATERIALS AND METHODS: This was a retrospective review of five patients (3 unilateral and 2 bilateral eyes, total 7 eyes) with CCh who underwent fornix deepening reconstruction with conjunctival recession and amniotic membrane transplantation. Postsurgical outcome measures included changes in fornix depth with correlation to basal tear volumes, symptoms, corneal staining, and conjunctival inflammation. RESULTS: For the three patients with unilateral surgery, both the fornix depth (8.3 ± 1.5 mm) and wetting length (9.3 ± 8.5 mm) of the operative eyes were less than the fellow eyes (10.3 ± 1.5 mm and 10.3 ± 8.5 mm, respectively). At 5.3 ± 2.7 months (range 1.7–8.7) postoperatively, the fornix depth increased significantly by 2.0 ± 1.1 mm (P = 0.02). Deepening of the fornix depth was accompanied by overwhelming symptomatic relief (91.5%) that could be subdivided into complete relief (87.5%) and partial relief (4%) of symptoms, with blurred vision being the most notably relieved symptom (P = 0.03). Furthermore, superficial punctate keratitis and conjunctival inflammation were significantly improved at follow-up (P = 0.008 and 0.05, respectively). CONCLUSION: Deepening of the fornix to restore the tear reservoir is an important surgical objective that may change the tear hydrodynamic state to provide a stable tear film and improve outcomes in CCh

Corneal Nerve Regeneration after Self-Retained Cryopreserved Amniotic Membrane in Dry Eye Disease

Purpose. To evaluate the efficacy of self-retained cryopreserved amniotic membrane (CAM) in promoting corneal nerve regeneration and improving corneal sensitivity in dry eye disease (DED). Methods. In this prospective randomized clinical trial, subjects with DED were randomized to receive CAM (study group) or conventional maximum treatment (control). Changes in signs and symptoms, corneal sensitivity, topography, and in vivo confocal microscopy (IVCM) were evaluated at baseline, 1 month, and 3 months. Results. Twenty subjects (age 66.9 ± 8.9) were enrolled and 17 completed all follow-up visits. Signs and symptoms were significantly improved in the study group yet remained constant in the control. IVCM showed a significant increase in corneal nerve density in the study group (12,241 ± 5083 μm/mm2 at baseline, 16,364 ± 3734 μm/mm2 at 1 month, and 18,827 ± 5453 μm/mm2 at 3 months, p=0.015) but was unchanged in the control. This improvement was accompanied with a significant increase in corneal sensitivity (3.25 ± 0.6 cm at baseline, 5.2 ± 0.5 cm at 1 month, and 5.6 ± 0.4 cm at 3 months, p<0.001) and corneal topography only in the study group. Conclusions. Self-retained CAM is a promising therapy for corneal nerve regeneration and accelerated recovery of the ocular surface health in patients with DED. The study is registered at clinicaltrials.gov with trial identifier: NCT02764814

The trans-ancestral genomic architecture of glycemic traits

Abstract Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P &lt; 5 x 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution