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Journal Cover Diabetes
  [SJR: 5.185]   [H-I: 269]   [460 followers]  Follow
   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: 349 - 350
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/db18-ti03
      Issue No: Vol. 67, No. 3 (2018)
  • Closing in on the Mechanisms of Pulsatile Insulin Secretion
    • Authors: Bertram; R.; Satin, L. S.; Sherman, A. S.
      Pages: 351 - 359
      Abstract: Insulin secretion from pancreatic islet β-cells occurs in a pulsatile fashion, with a typical period of ~5 min. The basis of this pulsatility in mouse islets has been investigated for more than four decades, and the various theories have been described as either qualitative or mathematical models. In many cases the models differ in their mechanisms for rhythmogenesis, as well as other less important details. In this Perspective, we describe two main classes of models: those in which oscillations in the intracellular Ca2+ concentration drive oscillations in metabolism, and those in which intrinsic metabolic oscillations drive oscillations in Ca2+ concentration and electrical activity. We then discuss nine canonical experimental findings that provide key insights into the mechanism of islet oscillations and list the models that can account for each finding. Finally, we describe a new model that integrates features from multiple earlier models and is thus called the Integrated Oscillator Model. In this model, intracellular Ca2+ acts on the glycolytic pathway in the generation of oscillations, and it is thus a hybrid of the two main classes of models. It alone among models proposed to date can explain all nine key experimental findings, and it serves as a good starting point for future studies of pulsatile insulin secretion from human islets.
      Keywords: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/dbi17-0004
      Issue No: Vol. 67, No. 3 (2018)
  • Ligand-Dependent Interaction of PPAR{delta} With T-Cell Protein Tyrosine
           Phosphatase 45 Enhances Insulin Signaling
    • Authors: Yoo; T.; Ham, S. A.; Lee, W. J.; Hwang, S. I.; Park, J.-A.; Hwang, J. S.; Hur, J.; Shin, H.-C.; Han, S. G.; Lee, C.-H.; Han, D. W.; Paek, K. S.; Seo, H. G.
      Pages: 360 - 371
      Abstract: Peroxisome proliferator–activated receptor (PPAR) plays a pivotal role in metabolic homeostasis through its effect on insulin signaling. Although diverse genomic actions of PPAR are postulated, the specific molecular mechanisms whereby PPAR controls insulin signaling have not been fully elucidated. We demonstrate here that short-term activation of PPAR results in the formation of a stable complex with nuclear T-cell protein tyrosine phosphatase 45 (TCPTP45) isoform. This interaction of PPAR with TCPTP45 blocked translocation of TCPTP45 into the cytoplasm, thereby preventing its interaction with the insulin receptor, which inhibits insulin signaling. Interaction of PPAR with TCPTP45 blunted interleukin 6–induced insulin resistance, leading to retention of TCPTP45 in the nucleus, thereby facilitating deactivation of the signal transducer and activator of transcription 3 (STAT3)–suppressor of cytokine signaling 3 (SOCS3) signal. Finally, GW501516-activated PPAR improved insulin signaling and glucose intolerance in mice fed a high-fat diet through its interaction with TCPTP45. This novel interaction of PPAR constitutes the most upstream component identified of the mechanism downregulating insulin signaling.
      Keywords: Insulin Action-Cellular and Molecular Metabolism
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/db17-0499
      Issue No: Vol. 67, No. 3 (2018)
  • Glutamine-Elicited Secretion of Glucagon-Like Peptide 1 Is Governed by an
           Activated Glutamate Dehydrogenase
    • Authors: Andersson; L. E.; Shcherbina, L.; Al-Majdoub, M.; Vishnu, N.; Arroyo, C. B.; Aste Carrara, J.; Wollheim, C. B.; Fex, M.; Mulder, H.; Wierup, N.; Spegel, P.
      Pages: 372 - 384
      Abstract: Glucagon-like peptide 1 (GLP-1), secreted from intestinal L cells, glucose dependently stimulates insulin secretion from β-cells. This glucose dependence prevents hypoglycemia, rendering GLP-1 analogs a useful and safe treatment modality in type 2 diabetes. Although the amino acid glutamine is a potent elicitor of GLP-1 secretion, the responsible mechanism remains unclear. We investigated how GLP-1 secretion is metabolically coupled in L cells (GLUTag) and in vivo in mice using the insulin-secreting cell line INS-1 832/13 as reference. A membrane-permeable glutamate analog (dimethylglutamate [DMG]), acting downstream of electrogenic transporters, elicited similar alterations in metabolism as glutamine in both cell lines. Both DMG and glutamine alone elicited GLP-1 secretion in GLUTag cells and in vivo, whereas activation of glutamate dehydrogenase (GDH) was required to stimulate insulin secretion from INS-1 832/13 cells. Pharmacological inhibition in vivo of GDH blocked secretion of GLP-1 in response to DMG. In conclusion, our results suggest that nonelectrogenic nutrient uptake and metabolism play an important role in L cell stimulus-secretion coupling. Metabolism of glutamine and related analogs by GDH in the L cell may explain why GLP-1 secretion, but not that of insulin, is activated by these secretagogues in vivo.
      Keywords: Integrated Physiology-Other Hormones
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/db16-1441
      Issue No: Vol. 67, No. 3 (2018)
  • A Targeted RNAi Screen Identifies Endocytic Trafficking Factors That
           Control GLP-1 Receptor Signaling in Pancreatic {beta}-Cells
    • Authors: Buenaventura; T.; Kanda, N.; Douzenis, P. C.; Jones, B.; Bloom, S. R.; Chabosseau, P.; Correa, I. R.; Bosco, D.; Piemonti, L.; Marchetti, P.; Johnson, P. R.; Shapiro, A. M. J.; Rutter, G. A.; Tomas, A.
      Pages: 385 - 399
      Abstract: The glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) is a key target for type 2 diabetes (T2D) treatment. Because endocytic trafficking of agonist-bound receptors is one of the most important routes for regulation of receptor signaling, a better understanding of this process may facilitate the development of new T2D therapeutic strategies. Here, we screened 29 proteins with known functions in G protein–coupled receptor trafficking for their role in GLP-1R potentiation of insulin secretion in pancreatic β-cells. We identify five (clathrin, dynamin1, AP2, sorting nexins [SNX] SNX27, and SNX1) that increase and four (huntingtin-interacting protein 1 [HIP1], HIP14, GASP-1, and Nedd4) that decrease insulin secretion from murine insulinoma MIN6B1 cells in response to the GLP-1 analog exendin-4. The roles of HIP1 and the endosomal SNX1 and SNX27 were further characterized in mouse and human β-cell lines and human islets. While HIP1 was required for the coupling of cell surface GLP-1R activation with clathrin-dependent endocytosis, the SNXs were found to control the balance between GLP-1R plasma membrane recycling and lysosomal degradation and, in doing so, determine the overall β-cell incretin responses. We thus identify key modulators of GLP-1R trafficking and signaling that might provide novel targets to enhance insulin secretion in T2D.
      Keywords: Islet Biology-Signal Transduction
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/db17-0639
      Issue No: Vol. 67, No. 3 (2018)
  • Sucrose Nonfermenting-Related Kinase Regulates Both Adipose Inflammation
           and Energy Homeostasis in Mice and Humans
    • Authors: Li; J.; Feng, B.; Nie, Y.; Jiao, P.; Lin, X.; Huang, M.; An, R.; He, Q.; Zhou, H. E.; Salomon, A.; Sigrist, K. S.; Wu, Z.; Liu, S.; Xu, H.
      Pages: 400 - 411
      Abstract: Sucrose nonfermenting-related kinase (SNRK) is a member of the AMPK-related kinase family, and its physiological role in adipose energy homeostasis and inflammation remains unknown. We previously reported that SNRK is ubiquitously and abundantly expressed in both white adipose tissue (WAT) and brown adipose tissue (BAT), but SNRK expression diminishes in adipose tissue in obesity. In this study we report novel experimental findings from both animal models and human genetics. SNRK is essential for survival; SNRK globally deficient pups die within 24 h after birth. Heterozygous mice are characterized by inflamed WAT and less BAT. Adipocyte-specific ablation of SNRK causes inflammation in WAT, ectopic lipid deposition in liver and muscle, and impaired adaptive thermogenesis in BAT. These metabolic disorders subsequently lead to decreased energy expenditure, higher body weight, and insulin resistance. We further confirm the significant association of common variants of the SNRK gene with obesity risk in humans. Through applying a phosphoproteomic approach, we identified eukaryotic elongation factor 1 and histone deacetylase 1/2 as potential SNRK substrates. Taking these data together, we conclude that SNRK represses WAT inflammation and is essential to maintain BAT thermogenesis, making it a novel therapeutic target for treating obesity and associated metabolic disorders.
      Keywords: Obesity-Animal
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/db17-0745
      Issue No: Vol. 67, No. 3 (2018)
  • The p300 and CBP Transcriptional Coactivators Are Required for {beta}-Cell
           and {alpha}-Cell Proliferation
    • Authors: Wong; C. K.; Wade-Vallance, A. K.; Luciani, D. S.; Brindle, P. K.; Lynn, F. C.; Gibson, W. T.
      Pages: 412 - 422
      Abstract: p300 (EP300) and CBP (CREBBP) are transcriptional coactivators with histone acetyltransferase activity. Various β-cell transcription factors can recruit p300/CBP, and thus the coactivators could be important for β-cell function and health in vivo. We hypothesized that p300/CBP contribute to the development and proper function of pancreatic islets. To test this, we bred and studied mice lacking p300/CBP in their islets. Mice lacking either p300 or CBP in islets developed glucose intolerance attributable to impaired insulin secretion, together with reduced α- and β-cell area and islet insulin content. These phenotypes were exacerbated in mice with only a single copy of p300 or CBP expressed in islets. Removing p300 in pancreatic endocrine progenitors impaired proliferation of neonatal α- and β-cells. Mice lacking all four copies of p300/CBP in pancreatic endocrine progenitors failed to establish α- and β-cell mass postnatally. Transcriptomic analyses revealed significant overlaps between p300/CBP-downregulated genes and genes downregulated in Hnf1α-null islets and Nkx2.2-null islets, among others. Furthermore, p300/CBP are important for the acetylation of H3K27 at loci downregulated in Hnf1α-null islets. We conclude that p300 and CBP are limiting cofactors for islet development, and hence for postnatal glucose homeostasis, with some functional redundancy.
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/db17-0237
      Issue No: Vol. 67, No. 3 (2018)
  • SRp55 Regulates a Splicing Network That Controls Human Pancreatic
           {beta}-Cell Function and Survival
    • Authors: Juan-Mateu; J.; Alvelos, M. I.; Turatsinze, J.-V.; Villate, O.; Lizarraga-Mollinedo, E.; Grieco, F. A.; Marroqui, L.; Bugliani, M.; Marchetti, P.; Eizirik, D. L.
      Pages: 423 - 436
      Abstract: Progressive failure of insulin-producing β-cells is the central event leading to diabetes, but the signaling networks controlling β-cell fate remain poorly understood. Here we show that SRp55, a splicing factor regulated by the diabetes susceptibility gene GLIS3, has a major role in maintaining the function and survival of human β-cells. RNA sequencing analysis revealed that SRp55 regulates the splicing of genes involved in cell survival and death, insulin secretion, and c-Jun N-terminal kinase (JNK) signaling. In particular, SRp55-mediated splicing changes modulate the function of the proapoptotic proteins BIM and BAX, JNK signaling, and endoplasmic reticulum stress, explaining why SRp55 depletion triggers β-cell apoptosis. Furthermore, SRp55 depletion inhibits β-cell mitochondrial function, explaining the observed decrease in insulin release. These data unveil a novel layer of regulation of human β-cell function and survival, namely alternative splicing modulated by key splicing regulators such as SRp55, that may cross talk with candidate genes for diabetes.
      Keywords: Islet Biology-Apoptosis
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/db17-0736
      Issue No: Vol. 67, No. 3 (2018)
  • Pancreatic Pericytes Support {beta}-Cell Function in a Tcf7l2-Dependent
    • Authors: Sakhneny; L.; Rachi, E.; Epshtein, A.; Guez, H. C.; Wald-Altman, S.; Lisnyansky, M.; Khalifa-Malka, L.; Hazan, A.; Baer, D.; Priel, A.; Weil, M.; Landsman, L.
      Pages: 437 - 447
      Abstract: Polymorphism in TCF7L2, a component of the canonical Wnt signaling pathway, has a strong association with β-cell dysfunction and type 2 diabetes through a mechanism that has yet to be defined. β-Cells rely on cells in their microenvironment, including pericytes, for their proper function. Here, we show that Tcf7l2 activity in pancreatic pericytes is required for β-cell function. Transgenic mice in which Tcf7l2 was selectively inactivated in their pancreatic pericytes exhibited impaired glucose tolerance due to compromised β-cell function and glucose-stimulated insulin secretion. Inactivation of pericytic Tcf7l2 was associated with impaired expression of genes required for β-cell function and maturity in isolated islets. In addition, we identified Tcf7l2-dependent pericytic expression of secreted factors shown to promote β-cell function, including bone morphogenetic protein 4 (BMP4). Finally, we show that exogenous BMP4 is sufficient to rescue the impaired glucose-stimulated insulin secretion of transgenic mice, pointing to a potential mechanism through which pericytic Tcf7l2 activity affects β-cells. To conclude, we suggest that pancreatic pericytes produce secreted factors, including BMP4, in a Tcf7l2-dependent manner to support β-cell function. Our findings thus propose a potential cellular mechanism through which abnormal TCF7L2 activity predisposes individuals to diabetes and implicates abnormalities in the islet microenvironment in this disease.
      Keywords: Islet Biology-Signal Transduction
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/db17-0697
      Issue No: Vol. 67, No. 3 (2018)
  • GATA6 Controls Insulin Biosynthesis and Secretion in Adult {beta}-Cells
    • Authors: Villamayor; L.; Rodriguez-Seguel, E.; Araujo, R.; Carrasco, M.; Bru-Tari, E.; Mellado-Gil, J. M.; Gauthier, B. R.; Martinelli, P.; Quesada, I.; Soria, B.; Martin, F.; Cano, D. A.; Rojas, A.
      Pages: 448 - 460
      Abstract: GATA4 and GATA6 play essential, but redundant, roles in pancreas formation in mice, and GATA6 mutations cause pancreatic agenesis in humans. GATA6 mutations have also recently been linked to adult-onset diabetes, with subclinical or no exocrine insufficiency, suggesting an important role for GATA6 in human β-cell physiology. To investigate the role of GATA6 in the adult endocrine pancreas, we generated mice in which Gata6 is specifically inactivated in the pancreas. These mice develop glucose intolerance. Islets deficient in GATA6 activity display decreased insulin content and impaired insulin secretion. Gata6-deficient β-cells exhibit ultrastructural abnormalities, including increased immature insulin granules, swollen mitochondria, and disorganized endoplasmic reticulum. We also demonstrate that Pdx1 expression in adult β-cells depends on GATA sites in transgenic reporter mice and that loss of GATA6 greatly affects β-cell–specific gene expression. These findings demonstrate the essential role of GATA6 in β-cell function.
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/db17-0364
      Issue No: Vol. 67, No. 3 (2018)
  • MondoA Is an Essential Glucose-Responsive Transcription Factor in Human
           Pancreatic {beta}-Cells
    • Authors: Richards; P.; Rachdi, L.; Oshima, M.; Marchetti, P.; Bugliani, M.; Armanet, M.; Postic, C.; Guilmeau, S.; Scharfmann, R.
      Pages: 461 - 472
      Abstract: Although the mechanisms by which glucose regulates insulin secretion from pancreatic β-cells are now well described, the way glucose modulates gene expression in such cells needs more understanding. Here, we demonstrate that MondoA, but not its paralog carbohydrate-responsive element–binding protein, is the predominant glucose-responsive transcription factor in human pancreatic β-EndoC-βH1 cells and in human islets. In high-glucose conditions, MondoA shuttles to the nucleus where it is required for the induction of the glucose-responsive genes arrestin domain–containing protein 4 (ARRDC4) and thioredoxin interacting protein (TXNIP), the latter being a protein strongly linked to β-cell dysfunction and diabetes. Importantly, increasing cAMP signaling in human β-cells, using forskolin or the glucagon-like peptide 1 mimetic Exendin-4, inhibits the shuttling of MondoA and potently inhibits TXNIP and ARRDC4 expression. Furthermore, we demonstrate that silencing MondoA expression improves glucose uptake in EndoC-βH1 cells. These results highlight MondoA as a novel target in β-cells that coordinates transcriptional response to elevated glucose levels.
      Keywords: Islet Biology-Signal Transduction
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/db17-0595
      Issue No: Vol. 67, No. 3 (2018)
  • Highly Angiogenic, Nonthrombogenic Bone Marrow Mononuclear Cell-Derived
           Spheroids in Intraportal Islet Transplantation
    • Authors: Oh; B. J.; Jin, S.-M.; Hwang, Y.; Choi, J. M.; Lee, H.-S.; Kim, G.; Kim, G.; Park, H. J.; Kim, P.; Kim, S. J.; Kim, J. H.
      Pages: 473 - 485
      Abstract: Highly angiogenic bone marrow mononuclear cell–derived spheroids (BM-spheroids), formed by selective proliferation of the CD31+CD14+CD34+ monocyte subset via three-dimensional (3D) culture, have had robust angiogenetic capacity in rodent syngeneic renal subcapsular islet transplantation. We wondered whether the efficacy of BM-spheroids could be demonstrated in clinically relevant intraportal islet transplantation models without increasing the risk of portal thrombosis. The thrombogenic potential of intraportally infused BM-spheroids was compared with that of mesenchymal stem cells (MSCs) and MSC-derived spheroids (MSC-spheroids). The angiogenic efficacy and persistence in portal sinusoids of BM-spheroids were examined in rodent syngeneic and primate allogeneic intraportal islet transplantation models. In contrast to MSCs and MSC-spheroids, intraportal infusion of BM-spheroids did not evoke portal thrombosis. BM-spheroids had robust angiogenetic capacity in both the rodent and primate intraportal islet transplantation models and improved posttransplant glycemic outcomes. MRI and intravital microscopy findings revealed the persistence of intraportally infused BM-spheroids in portal sinusoids. Intraportal cotransplantation of allogeneic islets with autologous BM-spheroids in nonhuman primates further confirmed the clinical feasibility of this approach. In conclusion, cotransplantation of BM-spheroids enhances intraportal islet transplantation outcome without portal thrombosis in mice and nonhuman primates. Generating BM-spheroids by 3D culture prevented the rapid migration and disappearance of intraportally infused therapeutic cells.
      Keywords: Transplantation
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/db17-0705
      Issue No: Vol. 67, No. 3 (2018)
  • Excitatory GABAergic Action and Increased Vasopressin Synthesis in
           Hypothalamic Magnocellular Neurosecretory Cells Underlie the High Plasma
           Level of Vasopressin in Diabetic Rats
    • Authors: Kim; Y.-B.; Kim, W. B.; Jung, W. W.; Jin, X.; Kim, Y. S.; Kim, B.; Han, H. C.; Block, G. D.; Colwell, C. S.; Kim, Y. I.
      Pages: 486 - 495
      Abstract: Diabetes mellitus (DM) is associated with increased plasma levels of arginine-vasopressin (AVP), which may aggravate hyperglycemia and nephropathy. However, the mechanisms by which DM may cause the increased AVP levels are not known. Electrophysiological recordings in supraoptic nucleus (SON) slices from streptozotocin (STZ)-induced DM rats and vehicle-treated control rats revealed that -aminobutyric acid (GABA) functions generally as an excitatory neurotransmitter in the AVP neurons of STZ rats, whereas it usually evokes inhibitory responses in the cells of control animals. Furthermore, Western blotting analyses of Cl– transporters in the SON tissues indicated that Na+-K+-2Cl– cotransporter isotype 1 (a Cl– importer) was upregulated and K+-Cl– cotransporter isotype 2 (KCC2; a Cl– extruder) was downregulated in STZ rats. Treatment with CLP290 (a KCC2 activator) significantly lowered blood AVP and glucose levels in STZ rats. Last, investigation that used rats expressing an AVP-enhanced green fluorescent protein fusion gene showed that AVP synthesis in AVP neurons was much more intense in STZ rats than in control rats. We conclude that altered Cl– homeostasis that makes GABA excitatory and enhanced AVP synthesis are important changes in AVP neurons that would increase AVP secretion in DM. Our data suggest that Cl– transporters in AVP neurons are potential targets of antidiabetes treatments.
      Keywords: Integrated Physiology-Other Hormones
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/db17-1042
      Issue No: Vol. 67, No. 3 (2018)
  • Defective Amplifying Pathway of {beta}-Cell Secretory Response to Glucose
           in Type 2 Diabetes: Integrated Modeling of In Vitro and In Vivo Evidence
    • Authors: Grespan; E.; Giorgino, T.; Arslanian, S.; Natali, A.; Ferrannini, E.; Mari, A.
      Pages: 496 - 506
      Abstract: In vivo studies have investigated the role of β-cell dysfunction in type 2 diabetes (T2D), whereas in vitro research on islets has elucidated key mechanisms that control the insulin secretion rate. However, the relevance of the cellular mechanisms identified in vitro (i.e., the triggering and amplifying pathways) has not been established in vivo. Furthermore, the mechanisms underpinning β-cell dysfunction in T2D remain undetermined. We propose a unifying explanation of several characteristic features of insulin secretion both in vitro and in vivo by using a mathematical model. The model describes the triggering and amplifying pathways and reproduces a variety of in vitro and in vivo tests in subjects with and without T2D, identifies the mechanisms modulating first-phase insulin secretion rate in response to basal hyperglycemia or insulin resistance, and shows that β-cell dysfunction in T2D can be explained by an impaired amplifying pathway with no need to postulate defects in intracellular calcium handling.
      Keywords: Integrated Physiology-Insulin Secretion In Vivo
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/db17-1039
      Issue No: Vol. 67, No. 3 (2018)
  • Metallothionein Preserves Akt2 Activity and Cardiac Function via
           Inhibiting TRB3 in Diabetic Hearts
    • Authors: Gu; J.; Yan, X.; Dai, X.; Wang, Y.; Lin, Q.; Xiao, J.; Zhou, S.; Zhang, J.; Wang, K.; Zeng, J.; Xin, Y.; Barati, M. T.; Zhang, C.; Bai, Y.; Li, Y.; Epstein, P. N.; Wintergerst, K. A.; Li, X.; Tan, Y.; Cai, L.
      Pages: 507 - 517
      Abstract: Cardiac insulin resistance is a key pathogenic factor for diabetic cardiomyopathy (DCM), but the mechanism remains largely unclear. We found that diabetic hearts exhibited decreased phosphorylation of total Akt and isoform Akt2 but not Akt1 in wild-type (WT) male FVB mice, which was accompanied by attenuation of Akt downstream glucose metabolic signal. All of these signal changes were not observed in metallothionein cardiac-specific transgenic (MT-TG) hearts. Furthermore, insulin-induced glucose metabolic signals were attenuated only in WT diabetic hearts. In addition, diabetic hearts exhibited increased Akt-negative regulator tribbles pseudokinase 3 (TRB3) expression only in WT mice, suggesting that MT may preserve Akt2 function via inhibiting TRB3. Moreover, MT prevented tert-butyl hydroperoxide (tBHP)–reduced insulin-stimulated Akt2 phosphorylation in MT-TG cardiomyocytes, which was abolished by specific silencing of Akt2. Specific silencing of TRB3 blocked tBHP inhibition of insulin-stimulated Akt2 phosphorylation in WT cardiomyocytes, whereas overexpression of TRB3 in MT-TG cardiomyocytes and hearts abolished MT preservation of insulin-stimulated Akt2 signals and MT prevention of DCM. Most importantly, supplementation of Zn to induce MT preserved cardiac Akt2 signals and prevented DCM. These results suggest that diabetes-inhibited cardiac Akt2 function via TRB3 upregulation leads to aberrant cardiac glucose metabolism. MT preservation of cardiac Akt2 function by inhibition of TRB3 prevents DCM.
      Keywords: Complications-Macrovascular-Atherosclerotic Cardiovascular Disease and Human Diabetes
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/db17-0219
      Issue No: Vol. 67, No. 3 (2018)
  • DPP-4 Inhibitors Improve Diabetic Wound Healing via Direct and Indirect
           Promotion of Epithelial-Mesenchymal Transition and Reduction of Scarring
    • Authors: Long; M.; Cai, L.; Li, W.; Zhang, L.; Guo, S.; Zhang, R.; Zheng, Y.; Liu, X.; Wang, M.; Zhou, X.; Wang, H.; Li, X.; Li, L.; Zhu, Z.; Yang, G.; Zheng, H.
      Pages: 518 - 531
      Abstract: Patients with diabetes often experience multiple disease complications. Hypoglycemic agents can have both positive and negative effects on diabetic complications, which should be carefully assessed when personalized treatment strategies are developed. In this study we report that dipeptidyl peptidase 4 inhibitors (DPP-4is), a group of widely used antihyperglycemic agents, can improve diabetic wound healing, independent of their beneficial effects on glycemic control. In particular, DPP-4is promoted the migration and epithelial-mesenchymal transition of keratinocytes, directly and indirectly, by inducing stromal cell-derived factor 1α production of fibroblasts in vitro and in diabetic mice. In addition, DPP-4is attenuated collagen synthesis and deposition, which may diminish scar formation. Furthermore, the results of a randomized clinical trial (NCT02742233) involving 67 patients with type 2 diabetes supported the role of DPP-4i treatment in diabetic wound healing. Our findings support the application of DPP-4i as a preferred option for treating ulcers in patients with diabetes.
      Keywords: Foot Care-Lower Extremities
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/db17-0934
      Issue No: Vol. 67, No. 3 (2018)
  • Erratum. Effect of Losartan on Prevention and Progression of Early
           Diabetic Nephropathy in American Indians With Type 2 Diabetes. Diabetes
    • Authors: Weil; E. J.; Fufaa, G.; Jones, L. I.; Lovato, T.; Lemley, K. V.; Hanson, R. L.; Knowler, W. C.; Bennett, P. H.; Yee, B.; Myers, B. D.; Nelson, R. G.
      Pages: 532 - 532
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/db18-er03a
      Issue No: Vol. 67, No. 3 (2018)
  • Erratum. Recessively Inherited LRBA Mutations Cause Autoimmunity
           Presenting as Neonatal Diabetes. Diabetes 2017;66:2316-2322
    • Authors: Johnson; M. B.; De Franco, E.; Lango Allen, H.; Al Senani, A.; Elbarbary, N.; Siklar, Z.; Berberoglu, M.; Imane, Z.; Haghighi, A.; Razavi, Z.; Ullah, I.; Alyaarubi, S.; Gardner, D.; Ellard, S.; Hattersley, A. T.; Flanagan, S. E.
      Pages: 532 - 532
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/db18-er03b
      Issue No: Vol. 67, No. 3 (2018)
  • Issues and Events
    • Pages: 533 - 533
      PubDate: 2018-02-20T12:50:31-08:00
      DOI: 10.2337/db18-ie03
      Issue No: Vol. 67, No. 3 (2018)
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