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Diabetes
Journal Prestige (SJR): 4.435
Citation Impact (citeScore): 6
Number of Followers: 522  
 
  Full-text available via subscription Subscription journal
ISSN (Print) 0012-1797 - ISSN (Online) 1939-327X
Published by American Diabetes Association Homepage  [4 journals]
  • In This Issue of Diabetes
    • Pages: 679 - 680
      PubDate: 2019-03-20T12:00:27-07:00
      DOI: 10.2337/db19-ti04
      Issue No: Vol. 68, No. 4 (2019)
       
  • Diabetes Takes New Steps to Increase Transparency and Reproducibility
    • Authors: Myers; M. G.; on behalf of the Diabetes Editorial Team
      Pages: 681 - 682
      PubDate: 2019-03-20T12:00:27-07:00
      DOI: 10.2337/dbi19-0008
      Issue No: Vol. 68, No. 4 (2019)
       
  • Determining the Effects of Combined Liraglutide and Phentermine on
           Metabolic Parameters, Blood Pressure, and Heart Rate in Lean and Obese
           Male Mice
    • Authors: Simonds; S. E.; Pryor, J. T.; Koegler, F. H.; Buch-Rasmussen, A. S.; Kelly, L. E.; Grove, K. L.; Cowley, M. A.
      Pages: 683 - 695
      Abstract: Liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, and phentermine, a psychostimulant structurally related to amphetamine, are drugs approved for the treatment of obesity and hyperphagia. There is significant interest in combination use of liraglutide and phentermine for weight loss; however, both drugs have been reported to induce systemic hemodynamic changes, and as such the therapeutic window for this drug combination needs to be determined. To understand their impact on metabolic and cardiovascular physiology, we tested the effects of these drugs alone and in combination for 21 days in lean and obese male mice. The combination of liraglutide and phentermine, at 100 μg/kg/day and 10 mg/kg/day, respectively, produced the largest reduction in body weight in both lean and diet-induced obese (DIO) mice, when compared with both vehicle and monotherapy-treated mice. In lean mice, combination treatment at the aforementioned doses significantly increased heart rate and reduced blood pressure, whereas in DIO mice, combination therapy induced a transient increase in heart rate and decreased blood pressure. These studies demonstrate that in obese mice, the combination of liraglutide and phentermine may reduce body weight but only induce modest improvements in cardiovascular functions. Conversely, in lean mice, the additional weight loss from combination therapy does not improve cardiovascular parameters.
      Keywords: Obesity-Animal
      PubDate: 2019-03-20T12:00:27-07:00
      DOI: 10.2337/db18-1149
      Issue No: Vol. 68, No. 4 (2019)
       
  • Insulin Therapy for Gestational Diabetes Mellitus Does Not Fully Protect
           Offspring From Diet-Induced Metabolic Disorders
    • Authors: Zhu; H.; Chen, B.; Cheng, Y.; Zhou, Y.; Yan, Y.-S.; Luo, Q.; Jiang, Y.; Sheng, J.-Z.; Ding, G.-L.; Huang, H.-F.
      Pages: 696 - 708
      Abstract: Gestational diabetes mellitus (GDM) is associated with an increased risk of metabolic disorders in offspring in later life. Although mounting evidence suggests that therapy for GDM could improve neonatal health, whether the therapy confers long-term metabolic benefits to offspring in their later adult lives is not known. Here, using a mouse model of diabetes in the latter half of pregnancy to mimic human GDM, we find that the efficient insulin therapy for GDM confers significant protection against glucose intolerance and obesity in offspring fed a normal chow diet. However, the therapy fails to protect offspring when challenged with a high-fat diet, especially for male offspring. Genome-wide DNA methylation profiling of pancreatic islets from male offspring identified hypermethylated regions in several genes that regulate insulin secretion, including Abcc8, Cav1.2, and Cav2.3 that encode KATP or Ca2+ channels, which are associated with reduced gene expression and impaired insulin secretion. This finding suggests a methylation-mediated epigenetic mechanism for GDM-induced intergenerational glucose intolerance. It highlights that even efficient insulin therapy for GDM is insufficient to fully protect adult offspring from diet-induced metabolic disorders.
      Keywords: Pregnancy-Basic Science/Translational
      PubDate: 2019-03-20T12:00:27-07:00
      DOI: 10.2337/db18-1151
      Issue No: Vol. 68, No. 4 (2019)
       
  • Absence of TXNIP in Humans Leads to Lactic Acidosis and Low Serum
           Methionine Linked to Deficient Respiration on Pyruvate
    • Authors: Katsu-Jimenez; Y.; Vazquez-Calvo, C.; Maffezzini, C.; Halldin, M.; Peng, X.; Freyer, C.; Wredenberg, A.; Gimenez-Cassina, A.; Wedell, A.; Arner, E. S. J.
      Pages: 709 - 723
      Abstract: Thioredoxin-interacting protein (TXNIP) is an α-arrestin that can bind to and inhibit the antioxidant protein thioredoxin (TXN). TXNIP expression is induced by glucose and promotes β-cell apoptosis in the pancreas, and deletion of its gene in mouse models protects against diabetes. TXNIP is currently studied as a potential new target for antidiabetic drug therapy. In this study, we describe a family with a mutation in the TXNIP gene leading to nondetectable expression of TXNIP protein. Symptoms of affected family members include lactic acidosis and low serum methionine levels. Using patient-derived TXNIP-deficient fibroblasts and myoblasts, we show that oxidative phosphorylation is impaired in these cells when given glucose and pyruvate but normalized with malate. Isolated mitochondria from these cells appear to have normal respiratory function. The cells also display a transcriptional pattern suggestive of a high basal activation of the Nrf2 transcription factor. We conclude that a complete lack of TXNIP in human is nonlethal and leads to specific metabolic distortions that are, at least in part, linked to a deficient respiration on pyruvate. The results give important insights into the impact of TXNIP in humans and thus help to further advance the development of antidiabetic drugs targeting this protein.
      Keywords: Integrated Physiology-Macronutrient Metabolism and Food Intake
      PubDate: 2019-03-20T12:00:27-07:00
      DOI: 10.2337/db18-0557
      Issue No: Vol. 68, No. 4 (2019)
       
  • A Candidate-Gene Approach Identifies Novel Associations Between Common
           Variants in/Near Syndromic Obesity Genes and BMI in Pediatric and Adult
           European Populations
    • Authors: Wang; D. X.; Kaur, Y.; Alyass, A.; Meyre, D.
      Pages: 724 - 732
      Abstract: We hypothesized that monogenic syndromic obesity genes are also involved in the polygenic variation of BMI. Single-marker, tag single nucleotide polymorphism (tagSNP) and gene-based analysis were performed on common variants near 54 syndromic obesity genes. We used publicly available data from meta-analyses of European BMI genome-wide association studies conducted by the Genetic Investigation of ANthropometric Traits (GIANT) Consortium and the UK Biobank (UKB) (N = 681,275 adults). A total of 33 loci were identified, of which 19 of 33 (57.6%) were located at SNPs previously identified by the GIANT Consortium and UKB meta-analysis, 11 of 33 (33.3%) were located at novel SNPs, and 3 of 33 (9.1%) were novel genes identified with gene-based analysis. Both single-marker and tagSNP analyses mapped the previously identified 19 SNPs by the GIANT Consortium and UKB meta-analysis. Gene-based analysis confirmed 15 of 19 (78.9%) of the novel SNPs’ associated genes. Of the 11 novel loci, 8 were identified with single-marker analysis and the remaining 3 were identified with tagSNP analysis. Gene-based analysis confirmed 4 of 11 (36.3%) of these loci. Meta-analysis with the Early Growth Genetics (EGG) Consortium (N = 35,668 children) was conducted post hoc for top SNPs, confirming 17 of 33 (51.5%) loci, of which 5 were novel. This study supports evidence for a continuum between rare monogenic syndromic and common polygenic forms of obesity.
      Keywords: Obesity-Human
      PubDate: 2019-03-20T12:00:27-07:00
      DOI: 10.2337/db18-0986
      Issue No: Vol. 68, No. 4 (2019)
       
  • Endoplasmic Reticulum-Associated Degradation (ERAD) Has a Critical Role in
           Supporting Glucose-Stimulated Insulin Secretion in Pancreatic {beta}-Cells
           
    • Authors: Hu; Y.; Gao, Y.; Zhang, M.; Deng, K.-Y.; Singh, R.; Tian, Q.; Gong, Y.; Pan, Z.; Liu, Q.; Boisclair, Y. R.; Long, Q.
      Pages: 733 - 746
      Abstract: The molecular underpinnings of β-cell dysfunction and death leading to diabetes are not fully elucidated. The objective of the current study was to investigate the role of endoplasmic reticulum–associated degradation (ERAD) in pancreatic β-cells. Chemically induced ERAD deficiency in the rat insulinoma cell line INS-1 markedly reduced glucose-stimulated insulin secretion (GSIS). The mechanistic basis for this effect was studied in cells and mice lacking ERAD as a consequence of genetic ablation of the core ERAD protein SEL1L. Targeted disruption of SEL1L in INS-1 cells and in mouse pancreatic β-cells impaired ERAD and led to blunted GSIS. Additionally, mice with SEL1L deletion in β-cells were chronically hyperglycemic after birth and increasingly glucose intolerant over time. SEL1L absence caused an entrapment of proinsulin in the endoplasmic reticulum compartment in both INS-1 cells and mouse pancreatic β-cells. Both folding-competent and folding-deficient proinsulin can physiologically interact with and be efficiently degraded by HRD1, the E3 ubiquitin ligase subunit of the ERAD complex. GSIS impairment in insulinoma cells was accompanied by a reduced intracellular Ca2+ ion level, overproduction of reactive oxygen species, and lowered mitochondrial membrane potential. Together, these findings suggest that ERAD plays a pivotal role in supporting pancreatic β-cell function by targeting wild-type and folding-deficient proinsulin for proteosomal degradation. ERAD deficiency may contribute to the development of diabetes by affecting proinsulin processing in the ER, intracellular Ca2+ concentration, and mitochondrial function.
      Keywords: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism
      PubDate: 2019-03-20T12:00:27-07:00
      DOI: 10.2337/db18-0624
      Issue No: Vol. 68, No. 4 (2019)
       
  • Endoplasmic Reticulum Chaperone Glucose-Regulated Protein 94 Is Essential
           for Proinsulin Handling
    • Authors: Ghiasi; S. M.; Dahlby, T.; Hede Andersen, C.; Haataja, L.; Petersen, S.; Omar-Hmeadi, M.; Yang, M.; Pihl, C.; Bresson, S. E.; Khilji, M. S.; Klindt, K.; Cheta, O.; Perone, M. J.; Tyrberg, B.; Prats, C.; Barg, S.; Tengholm, A.; Arvan, P.; Mandrup-Poulsen, T.; Marzec, M. T.
      Pages: 747 - 760
      Abstract: Although endoplasmic reticulum (ER) chaperone binding to mutant proinsulin has been reported, the role of protein chaperones in the handling of wild-type proinsulin is underinvestigated. Here, we have explored the importance of glucose-regulated protein 94 (GRP94), a prominent ER chaperone known to fold insulin-like growth factors, in proinsulin handling within β-cells. We found that GRP94 coimmunoprecipitated with proinsulin and that inhibition of GRP94 function and/or expression reduced glucose-dependent insulin secretion, shortened proinsulin half-life, and lowered intracellular proinsulin and insulin levels. This phenotype was accompanied by post-ER proinsulin misprocessing and higher numbers of enlarged insulin granules that contained amorphic material with reduced immunogold staining for mature insulin. Insulin granule exocytosis was accelerated twofold, but the secreted insulin had diminished bioactivity. Moreover, GRP94 knockdown or knockout in β-cells selectively activated protein kinase R–like endoplasmic reticulum kinase (PERK), without increasing apoptosis levels. Finally, GRP94 mRNA was overexpressed in islets from patients with type 2 diabetes. We conclude that GRP94 is a chaperone crucial for proinsulin handling and insulin secretion.
      Keywords: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism
      PubDate: 2019-03-20T12:00:27-07:00
      DOI: 10.2337/db18-0671
      Issue No: Vol. 68, No. 4 (2019)
       
  • Bromodomain and Extra Terminal Protein Inhibitors Promote Pancreatic
           Endocrine Cell Fate
    • Authors: Huijbregts; L.; Petersen, M. B. K.; Berthault, C.; Hansson, M.; Aiello, V.; Rachdi, L.; Grapin-Botton, A.; Honore, C.; Scharfmann, R.
      Pages: 761 - 773
      Abstract: Bromodomain and extraterminal (BET) proteins are epigenetic readers that interact with acetylated lysines of histone tails. Recent studies have demonstrated their role in cancer progression because they recruit key components of the transcriptional machinery to modulate gene expression. However, their role during embryonic development of the pancreas has never been studied. Using mouse embryonic pancreatic explants and human induced pluripotent stem cells (hiPSCs), we show that BET protein inhibition with I-BET151 or JQ1 enhances the number of neurogenin3 (NEUROG3) endocrine progenitors. In mouse explants, BET protein inhibition further led to increased expression of β-cell markers but in the meantime, strongly downregulated Ins1 expression. Similarly, although acinar markers, such as Cpa1 and CelA, were upregulated, Amy expression was repressed. In hiPSCs, BET inhibitors strongly repressed C-peptide and glucagon during endocrine differentiation. Explants and hiPSCs were then pulsed with BET inhibitors to increase NEUROG3 expression and further chased without inhibitors. Endocrine development was enhanced in explants with higher expression of insulin and maturation markers, such as UCN3 and MAFA. In hiPSCs, the outcome was different because C-peptide expression remained lower than in controls, but ghrelin expression was increased. Altogether, by using two independent models of pancreatic development, we show that BET proteins regulate multiple aspects of pancreatic development.
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2019-03-20T12:00:27-07:00
      DOI: 10.2337/db18-0224
      Issue No: Vol. 68, No. 4 (2019)
       
  • {beta}-Cell-Derived Angiopoietin-1 Regulates Insulin Secretion and Glucose
           Homeostasis by Stabilizing the Islet Microenvironment
    • Authors: Park; H. S.; Kim, H. Z.; Park, J. S.; Lee, J.; Lee, S.-P.; Kim, H.; Ahn, C. W.; Nakaoka, Y.; Koh, G. Y.; Kang, S.
      Pages: 774 - 786
      Abstract: Islets are highly vascularized for prompt insulin secretion. Although angiopoietin-1 (Ang1) is a well-known angiogenic factor, its role in glucose homeostasis remains largely unknown. The objective of this study was to investigate whether and how Ang1 contributes to glucose homeostasis in response to metabolic challenge. We used inducible systemic Ang1 knockout (Ang1sys–/–) and β-cell–specific Ang1 knockout (Ang1β-cell–/–) mice fed a high-fat diet for 24 weeks. Although the degree of insulin sensitivity did not differ between Ang1sys–/– and Ang1sys+/+ mice, serum insulin levels were lower in Ang1sys–/– mice, resulting in significant glucose intolerance. Similar results were observed in Ang1β-cell–/– mice, suggesting a critical role of β-cell–derived Ang1 in glucose homeostasis. There were no differences in β-cell area or vasculature density, but glucose-stimulated insulin secretion was significantly decreased, and PDX-1 expression and GLUT2 localization were altered in Ang1β-cell–/– compared with Ang1β-cell+/+ mice. These effects were associated with less pericyte coverage, disorganized endothelial cell ultrastructure, and enhanced infiltration of inflammatory cells and upregulation of adhesion molecules in the islets of Ang1β-cell–/– mice. In conclusion, β-cell–derived Ang1 regulates insulin secretion and glucose homeostasis by stabilizing the blood vessels in the islet and may be a novel therapeutic target for diabetes treatment in the future.
      Keywords: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism
      PubDate: 2019-03-20T12:00:27-07:00
      DOI: 10.2337/db18-0864
      Issue No: Vol. 68, No. 4 (2019)
       
  • Epitope Stealing as a Mechanism of Dominant Protection by HLA-DQ6 in Type
           1 Diabetes
    • Authors: van Lummel; M.; Buis, D. T. P.; Ringeling, C.; de Ru, A. H.; Pool, J.; Papadopoulos, G. K.; van Veelen, P. A.; Reijonen, H.; Drijfhout, J. W.; Roep, B. O.
      Pages: 787 - 795
      Abstract: The heterozygous DQ2/8 (DQA1*05:01-DQB1*02:01/DQA1*03:01-DQB1*03:02) genotype confers the highest risk in type 1 diabetes (T1D), whereas the DQ6/8 (DQA1*02:01-DQB1*06:02/DQA1*03:01-DQB1*03:02) genotype is protective. The mechanism of dominant protection by DQ6 (DQB1*06:02) is unknown. We tested the hypothesis that DQ6 interferes with peptide binding to DQ8 by competition for islet epitope ("epitope stealing") by analysis of the islet ligandome presented by HLA-DQ6/8 and -DQ8/8 on dendritic cells pulsed with islet autoantigens preproinsulin (PPI), GAD65, and IA-2, followed by competition assays using a newly established "epitope-stealing" HLA/peptide-binding assay. HLA-DQ ligandome analysis revealed a distinct DQ6 peptide-binding motif compared with the susceptible DQ2/8 molecules. PPI and IA-2 peptides were identified from DQ6, of DQ6/8 heterozygous dendritic cells, but no DQ8 islet peptides were retrieved. Insulin B6-23, a highly immunogenic CD4 T-cell epitope in patients with T1D, bound to both DQ6 and DQ8. Yet, binding of InsB6-23 to DQ8 was prevented by DQ6. We obtained first functional evidence of a mechanism of dominant protection from disease, in which HLA molecules associated with protection bind islet epitopes in a different, competing, HLA-binding register, leading to "epitope stealing" and conceivably diverting the immune response from islet epitopes presented by disease-susceptible HLA molecules in the absence of protective HLA.
      Keywords: Immunology
      PubDate: 2019-03-20T12:00:27-07:00
      DOI: 10.2337/db18-0501
      Issue No: Vol. 68, No. 4 (2019)
       
  • Structural and Functional Abnormalities of the Primary Somatosensory
           Cortex in Diabetic Peripheral Neuropathy: A Multimodal MRI Study
    • Authors: Selvarajah; D.; Wilkinson, I. D.; Fang, F.; Sankar, A.; Davies, J.; Boland, E.; Harding, J.; Rao, G.; Gandhi, R.; Tracey, I.; Tesfaye, S.
      Pages: 796 - 806
      Abstract: Diabetic distal symmetrical peripheral polyneuropathy (DSP) results in decreased somatosensory cortical gray matter volume, indicating that the disease process may produce morphological changes in the brains of those affected. However, no study has examined whether changes in brain volume alter the functional organization of the somatosensory cortex and how this relates to the various painful DSP clinical phenotypes. In this case-controlled, multimodal brain MRI study of 44 carefully phenotyped subjects, we found significant anatomical and functional changes in the somatosensory cortex. Subjects with painful DSP insensate have the lowest somatosensory cortical thickness, with expansion of the area representing pain in the lower limb to include face and lip regions. Furthermore, there was a significant relationship between anatomical and functional changes within the somatosensory cortex and severity of the peripheral neuropathy. These data suggest a dynamic plasticity of the brain in DSP driven by the neuropathic process. It demonstrates, for the first time in our knowledge, a pathophysiological relationship between a clinically painful DSP phenotype and alterations in the somatosensory cortex.
      Keywords: Complications-Neuropathy
      PubDate: 2019-03-20T12:00:27-07:00
      DOI: 10.2337/db18-0509
      Issue No: Vol. 68, No. 4 (2019)
       
  • Opposing Effects of Neuropilin-1 and -2 on Sensory Nerve Regeneration in
           Wounded Corneas: Role of Sema3C in Ameliorating Diabetic Neurotrophic
           Keratopathy
    • Authors: Lee; P. S.-Y.; Gao, N.; Dike, M.; Shkilnyy, O.; Me, R.; Zhang, Y.; Yu, F.-S. X.
      Pages: 807 - 818
      Abstract: The diabetic cornea exhibits pathological alterations, such as delayed epithelial wound healing and nerve regeneration. We investigated the role of semaphorin (SEMA) 3C in corneal wound healing and reinnervation in normal and diabetic B6 mice. Wounding induced the expression of SEMA3A, SEMA3C, and their receptor neuropilin-2 (NRP2), but not NRP1, in normal corneal epithelial cells; this upregulation was suppressed for SEMA3C and NRP2 in diabetic corneas. Injections of Sema3C-specific small interfering RNA and NRP2-neutralizing antibodies in wounded mice resulted in a decrease in the rate of wound healing and regenerating nerve fibers, whereas exogenous SEMA3C had opposing effects in diabetic corneas. NRP1 neutralization, on the other hand, decreased epithelial wound closure but increased sensory nerve regeneration in diabetic corneas, suggesting a detrimental role in nerve regeneration. Taken together, epithelium-expressed SEMA3C plays a role in corneal epithelial wound closure and sensory nerve regeneration. The hyperglycemia-suppressed SEMA3C/NRP2 signaling may contribute to the pathogenesis of diabetic neurotrophic keratopathy, and SEMA3C might be used as an adjunctive therapeutic for treating the disease.
      Keywords: Complications-Neuropathy
      PubDate: 2019-03-20T12:00:27-07:00
      DOI: 10.2337/db18-1172
      Issue No: Vol. 68, No. 4 (2019)
       
  • Proximal Tubular Cell-Specific Ablation of Carnitine Acetyltransferase
           Causes Tubular Disease and Secondary Glomerulosclerosis
    • Authors: Kruger; C.; Nguyen, T.-T.; Breaux, C.; Guillory, A.; Mangelli, M.; Fridianto, K. T.; Kovalik, J.-P.; Burk, D. H.; Noland, R. C.; Mynatt, R.; Stadler, K.
      Pages: 819 - 831
      Abstract: Proximal tubular epithelial cells are highly energy demanding. Their energy need is covered mostly from mitochondrial fatty acid oxidation. Whether derailments in fatty acid metabolism and mitochondrial dysfunction are forerunners of tubular damage has been suggested but is not entirely clear. Here we modeled mitochondrial overload by creating mice lacking the enzyme carnitine acetyltransferase (CrAT) in the proximal tubules, thus limiting a primary mechanism to export carbons under conditions of substrate excess. Mice developed tubular disease and, interestingly, secondary glomerulosclerosis. This was accompanied by increased levels of apoptosis regulator and fibrosis markers, increased oxidative stress, and abnormal profiles of acylcarnitines and organic acids suggesting profound impairments in all major forms of nutrient metabolism. When mice with CrAT deletion were fed a high-fat diet, kidney disease was more severe and developed faster. Primary proximal tubular cells isolated from the knockout mice displayed energy deficit and impaired respiration before the onset of pathology, suggesting mitochondrial respiratory abnormalities as a potential underlying mechanism. Our findings support the hypothesis that derailments of mitochondrial energy metabolism may be causative to chronic kidney disease. Our results also suggest that tubular injury may be a primary event followed by secondary glomerulosclerosis, raising the possibility that focusing on normalizing tubular cell mitochondrial function and energy balance could be an important preventative strategy.
      Keywords: Complications-Nephropathy-Basic and Experimental Science
      PubDate: 2019-03-20T12:00:27-07:00
      DOI: 10.2337/db18-0090
      Issue No: Vol. 68, No. 4 (2019)
       
  • Neurovascular Response to Pressure in Patients With Diabetic Foot Ulcer
    • Authors: Vouillarmet; J.; Josset-Lamaugarny, A.; Michon, P.; Saumet, J. L.; Koitka-Weber, A.; Henni, S.; Fromy, B.; Sigaudo-Roussel, D.
      Pages: 832 - 836
      Abstract: Diabetic foot ulcer (DFU) is a problem worldwide, and prevention is crucial. We hypothesized that the inability of the skin to respond to pressure is involved in DFU pathogenesis and could be an important predictive factor to take into account. We included 29 patients with DFU and 30 patients with type 2 diabetes without DFU. Neuropathy and skin blood flow at rest were assessed in response to acetylcholine, sodium nitroprusside, local heating (42°C), and to nonnoxious locally applied pressure. Results were compared with those obtained from 10 healthy age-matched control subjects. Vasodilatation in response to pressure was significantly impaired in both groups with diabetes compared with healthy subjects. The vasodilator capacity to pressure was significantly lower in patients with DFU compared with those without DFU, despite the absence of significant difference in cutaneous pressure perception threshold and vascular reactivity to acetylcholine, sodium nitroprusside, and heat. This pronounced alteration of neurovascular response to pressure in patients with DFU is a good marker of skin vulnerability and could be used to better predict individuals at risk.
      Keywords: Complications-Neuropathy
      PubDate: 2019-03-20T12:00:27-07:00
      DOI: 10.2337/db18-0694
      Issue No: Vol. 68, No. 4 (2019)
       
  • Potential of Allogeneic Adipose-Derived Stem Cell-Hydrogel Complex for
           Treating Diabetic Foot Ulcers
    • Authors: Moon; K.-C.; Suh, H.-S.; Kim, K.-B.; Han, S.-K.; Young, K.-W.; Lee, J.-W.; Kim, M.-H.
      Pages: 837 - 846
      Abstract: Mesenchymal stem cells (MSCs) may hold great promise for treating diabetic wounds. However, it is difficult for a clinician to use MSCs because they have not been commercialized. Meanwhile, a new commercial drug that contains adipose-derived stem cells (ASCs) has been developed. The purpose of this study was to examine the potential of allogeneic ASC sheets for treating diabetic foot ulcers. Fifty-nine patients with diabetic foot ulcers were randomized to either the ASC treatment group (n = 30) or a control group treated with polyurethane film (n = 29). Either an allogeneic ASC sheet or polyurethane film was applied on diabetic wounds weekly. These wounds were evaluated for a maximum of 12 weeks. Complete wound closure was achieved for 73% in the treatment group and 47% in the control group at week 8. Complete wound closure was achieved for 82% in the treatment group and 53% in the control group at week 12. The Kaplan-Meier median times to complete closure were 28.5 and 63.0 days for the treatment group and the control group, respectively. There were no serious adverse events related to allogeneic ASC treatment. Thus, allogeneic ASCs might be effective and safe to treat diabetic foot ulcers.
      Keywords: Foot Care-Lower Extremities
      PubDate: 2019-03-20T12:00:27-07:00
      DOI: 10.2337/db18-0699
      Issue No: Vol. 68, No. 4 (2019)
       
  • Genetic Contribution to the Divergence in Type 1 Diabetes Risk Between
           Children From the General Population and Children From Affected Families
    • Authors: Hippich; M.; Beyerlein, A.; Hagopian, W. A.; Krischer, J. P.; Vehik, K.; Knoop, J.; Winker, C.; Toppari, J.; Lernmark, A.; Rewers, M. J.; Steck, A. K.; She, J.-X.; Akolkar, B.; Robertson, C. C.; Onengut-Gumuscu, S.; Rich, S. S.; Bonifacio, E.; Ziegler, A.-G.; the TEDDY Study Group
      Pages: 847 - 857
      Abstract: The risk for autoimmunity and subsequently type 1 diabetes is 10-fold higher in children with a first-degree family history of type 1 diabetes (FDR children) than in children in the general population (GP children). We analyzed children with high-risk HLA genotypes (n = 4,573) in the longitudinal TEDDY birth cohort to determine how much of the divergent risk is attributable to genetic enrichment in affected families. Enrichment for susceptible genotypes of multiple type 1 diabetes–associated genes and a novel risk gene, BTNL2, was identified in FDR children compared with GP children. After correction for genetic enrichment, the risks in the FDR and GP children converged but were not identical for multiple islet autoantibodies (hazard ratio [HR] 2.26 [95% CI 1.6–3.02]) and for diabetes (HR 2.92 [95% CI 2.05–4.16]). Convergence varied depending upon the degree of genetic susceptibility. Risks were similar in the highest genetic susceptibility group for multiple islet autoantibodies (14.3% vs .12.7%) and diabetes (4.8% vs. 4.1%) and were up to 5.8-fold divergent for children in the lowest genetic susceptibility group, decreasing incrementally in GP children but not in FDR children. These findings suggest that additional factors enriched within affected families preferentially increase the risk of autoimmunity and type 1 diabetes in lower genetic susceptibility strata.
      Keywords: Genetics-Type 1 Diabetes
      PubDate: 2019-03-20T12:00:27-07:00
      DOI: 10.2337/db18-0882
      Issue No: Vol. 68, No. 4 (2019)
       
  • Genetic Determinants of Glycated Hemoglobin in Type 1 Diabetes
    • Authors: Syreeni; A.; Sandholm, N.; Cao, J.; Toppila, I.; Maahs, D. M.; Rewers, M. J.; Snell-Bergeon, J. K.; Costacou, T.; Orchard, T. J.; Caramori, M. L.; Mauer, M.; Klein, B. E. K.; Klein, R.; Valo, E.; Parkkonen, M.; Forsblom, C.; Harjutsalo, V.; Paterson, A. D.; for the DCCT/EDIC Research Group; Groop, P.-H.; on behalf of the FinnDiane Study Group
      Pages: 858 - 867
      Abstract: Glycated hemoglobin (HbA1c) is an important measure of glycemia in diabetes. HbA1c is influenced by environmental and genetic factors both in people with and in people without diabetes. We performed a genome-wide association study (GWAS) for HbA1c in a Finnish type 1 diabetes (T1D) cohort, FinnDiane. Top results were examined for replication in T1D cohorts DCCT/EDIC, WESDR, CACTI, EDC, and RASS, and a meta-analysis was performed. Three SNPs in high linkage disequilibrium on chromosome 13 near relaxin family peptide receptor 2 (RXFP2) were associated with HbA1c in FinnDiane at genome-wide significance (P < 5 x 10–8). The minor alleles of rs2085277 and rs1360072 were associated with higher HbA1c also in the meta-analysis with RASS (P < 5 x 10–8), where these variants had minor allele frequencies ≥1%. Furthermore, these SNPs were associated with HbA1c in an East Asian population without diabetes (P ≤ 0.013). A weighted genetic risk score created from 55 HbA1c-associated variants from the literature was associated with HbA1c in FinnDiane but explained only a small amount of variation. Understanding the genetic basis of glycemic control and HbA1c may lead to better prevention of diabetes complications.
      Keywords: Genetics-Type 1 Diabetes
      PubDate: 2019-03-20T12:00:28-07:00
      DOI: 10.2337/db18-0573
      Issue No: Vol. 68, No. 4 (2019)
       
  • Issues and Events
    • Pages: 868 - 868
      PubDate: 2019-03-20T12:00:28-07:00
      DOI: 10.2337/db19-ie04
      Issue No: Vol. 68, No. 4 (2019)
       
 
 
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