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Journal Prestige (SJR): 4.435
Citation Impact (citeScore): 6
Number of Followers: 576  
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ISSN (Print) 0012-1797 - ISSN (Online) 1939-327X
Published by American Diabetes Association Homepage  [4 journals]
  • The Heating Microenvironment: Intercellular Cross Talk Within Thermogenic
           Adipose Tissue
    • Authors: Knights; A. J.; Wu, J.; Tseng, Y.-H.
      Pages: 1599 - 1604
      Abstract: Adipose tissue serves as the body’s primary energy storage site; however, findings in recent decades have transformed our understanding of the multifaceted roles of this adaptable organ. The ability of adipose tissue to undergo energy expenditure through heat generation is termed adaptive thermogenesis, a process carried out by thermogenic adipocytes. Adipocytes are the primary parenchymal cell type in adipose tissue, yet these cells are sustained within a rich stromal vascular microenvironment comprised of adipose stem cells and progenitors, immune cells, neuronal cells, fibroblasts, and endothelial cells. Intricate cross talk between these diverse cell types is essential in regulating the activation of thermogenic fat, and the past decade has shed significant light on how this intercellular communication functions. This review will draw upon recent findings and current perspectives on the sophisticated repertoire of cellular and molecular features that comprise the adipose thermogenic milieu.
      Keywords: Insulin Action-Adipocyte Biology
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db20-0303
      Issue No: Vol. 69, No. 8 (2020)
  • A New FGF21 Analog for the Treatment of Fatty Liver Disease
    • Authors: Kleinert; M.; Müller, T. D.
      Pages: 1605 - 1607
      Keywords: Integrated Physiology-Liver
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/dbi20-0025
      Issue No: Vol. 69, No. 8 (2020)
  • Smarter Modeling to Enable a Smarter Insulin
    • Authors: Taylor; S. I.; DiMarchi, R. D.
      Pages: 1608 - 1610
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/dbi20-0011
      Issue No: Vol. 69, No. 8 (2020)
  • The Effects of B1344, a Novel Fibroblast Growth Factor 21 Analog, on
           Nonalcoholic Steatohepatitis in Nonhuman Primates
    • Authors: Cui; A.; Li, J.; Ji, S.; Ma, F.; Wang, G.; Xue, Y.; Liu, Z.; Gao, J.; Han, J.; Tai, P.; Wang, T.; Chen, J.; Ma, X.; Li, Y.
      Pages: 1611 - 1623
      Abstract: Nonalcoholic steatohepatitis has emerged as a major cause of liver diseases with no effective therapies. Here, we evaluate the efficacies and pharmacokinetics of B1344, a long-acting polyethylene glycolylated (PEGylated) fibroblast growth factor 21 analog, in a nongenetically modified nonhuman primate species that underwent liver biopsy and demonstrate the potential for efficacies in humans. B1344 is sufficient to selectively activate signaling from the βKlotho/FGFR1c receptor complex. In cynomolgus monkeys with nonalcoholic fatty liver disease (NAFLD), administration of B1344 via subcutaneous injection for 11 weeks caused a profound reduction of hepatic steatosis, inflammation, and fibrosis, along with amelioration of liver injury and hepatocyte death, as evidenced by liver biopsy specimen and biochemical analysis. Moreover, improvement of metabolic parameters was observed in the monkeys, including reduction of body weight and improvement of lipid profiles and glycemic control. To determine the role of B1344 in the progression of murine NAFLD independent of obesity, B1344 was administered to mice fed a methionine- and choline-deficient diet. Consistently, B1344 administration prevented the mice from lipotoxicity damage and nonalcoholic steatohepatitis in a dose-dependent manner. These results provide preclinical validation for an innovative therapeutic approach to NAFLD and support further clinical testing of B1344 for treating nonalcoholic steatohepatitis and other metabolic diseases in humans.
      Keywords: Integrated Physiology-Liver
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db20-0209
      Issue No: Vol. 69, No. 8 (2020)
  • Lactation Versus Formula Feeding: Insulin, Glucose, and Fatty Acid
           Metabolism During the Postpartum Period
    • Authors: Ramos-Roman; M. A.; Syed-Abdul, M. M.; Adams-Huet, B.; Casey, B. M.; Parks, E. J.
      Pages: 1624 - 1635
      Abstract: Milk production may involve a transient development of insulin resistance in nonmammary tissues to support redistribution of maternal macronutrients to match the requirements of the lactating mammary gland. In the current study, adipose and liver metabolic responses were measured in the fasting state and during a two-step (10 and 20 mU/m2/min) hyperinsulinemic-euglycemic clamp with stable isotopes, in 6-week postpartum women who were lactating (n = 12) or formula-feeding (n = 6) their infants and who were closely matched for baseline characteristics (e.g., parity, body composition, and intrahepatic lipid). When controlling for the low insulin concentrations of both groups, the lactating women exhibited a fasting rate of endogenous glucose production (EGP) that was 2.6-fold greater and a lipolysis rate that was 2.3-fold greater than the formula-feeding group. During the clamp, the groups exhibited similar suppression rates of EGP and lipolysis. In the lactating women only, higher prolactin concentrations were associated with greater suppression rates of lipolysis and lower intrahepatic lipid and plasma triacylglycerol concentrations. These data suggest that whole-body alterations in glucose transport may be organ specific and facilitate nutrient partitioning during lactation. Recapitulating a shift toward noninsulin-mediated glucose uptake could be an early postpartum strategy to enhance lactation success in women at risk for delayed onset of milk production.
      Keywords: Pregnancy-Basic Science/Translational
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db19-1226
      Issue No: Vol. 69, No. 8 (2020)
  • Reciprocity Between Skeletal Muscle AMPK Deletion and Insulin Action in
           Diet-Induced Obese Mice
    • Authors: Lantier; L.; Williams, A. S.; Williams, I. M.; Guerin, A.; Bracy, D. P.; Goelzer, M.; Foretz, M.; Viollet, B.; Hughey, C. C.; Wasserman, D. H.
      Pages: 1636 - 1649
      Abstract: Insulin resistance due to overnutrition places a burden on energy-producing pathways in skeletal muscle (SkM). Nevertheless, energy state is not compromised. The hypothesis that the energy sensor AMPK is necessary to offset the metabolic burden of overnutrition was tested using chow-fed and high-fat (HF)–fed SkM-specific AMPKα1α2 knockout (mdKO) mice and AMPKα1α2lox/lox littermates (wild-type [WT]). Lean mdKO and WT mice were phenotypically similar. HF-fed mice were equally obese and maintained lean mass regardless of genotype. Results did not support the hypothesis that AMPK is protective during overnutrition. Paradoxically, mdKO mice were more insulin sensitive. Insulin-stimulated SkM glucose uptake was approximately twofold greater in mdKO mice in vivo. Furthermore, insulin signaling, SkM GLUT4 translocation, hexokinase activity, and glycolysis were increased. AMPK and insulin signaling intersect at mammalian target of rapamycin (mTOR), a critical node for cell proliferation and survival. Basal mTOR activation was reduced by 50% in HF-fed mdKO mice, but was normalized by insulin stimulation. Mitochondrial function was impaired in mdKO mice, but energy charge was preserved by AMP deamination. Results show a surprising reciprocity between SkM AMPK signaling and insulin action that manifests with diet-induced obesity, as insulin action is preserved to protect fundamental energetic processes in the muscle.
      Keywords: Integrated Physiology-Muscle
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db19-1074
      Issue No: Vol. 69, No. 8 (2020)
  • Antioxidant Effects of N-Acetylcysteine Prevent Programmed Metabolic
           Disease in Mice
    • Authors: Charron; M. J.; Williams, L.; Seki, Y.; Du, X. Q.; Chaurasia, B.; Saghatelian, A.; Summers, S. A.; Katz, E. B.; Vuguin, P. M.; Reznik, S. E.
      Pages: 1650 - 1661
      Abstract: An adverse maternal in utero and lactation environment can program offspring for increased risk for metabolic disease. The aim of this study was to determine whether N-acetylcysteine (NAC), an anti-inflammatory antioxidant, attenuates programmed susceptibility to obesity and insulin resistance in offspring of mothers on a high-fat diet (HFD) during pregnancy. CD1 female mice were acutely fed a standard breeding chow or HFD. NAC was added to the drinking water (1 g/kg) of the treatment cohorts from embryonic day 0.5 until the end of lactation. NAC treatment normalized HFD-induced maternal weight gain and oxidative stress, improved the maternal lipidome, and prevented maternal leptin resistance. These favorable changes in the in utero environment normalized postnatal growth, decreased white adipose tissue (WAT) and hepatic fat, improved glucose and insulin tolerance and antioxidant capacity, reduced leptin and insulin, and increased adiponectin in HFD offspring. The lifelong metabolic improvements in the offspring were accompanied by reductions in proinflammatory gene expression in liver and WAT and increased thermogenic gene expression in brown adipose tissue. These results, for the first time, provide a mechanistic rationale for how NAC can prevent the onset of metabolic disease in the offspring of mothers who consume a typical Western HFD.
      Keywords: Integrated Physiology-Muscle
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db19-1129
      Issue No: Vol. 69, No. 8 (2020)
  • Excessive Glucocorticoids During Pregnancy Impair Fetal Brown Fat
           Development and Predispose Offspring to Metabolic Dysfunctions
    • Authors: Chen; Y.-T.; Hu, Y.; Yang, Q.-Y.; Son, J. S.; Liu, X.-D.; de Avila, J. M.; Zhu, M.-J.; Du, M.
      Pages: 1662 - 1674
      Abstract: Maternal stress during pregnancy exposes fetuses to hyperglucocorticoids, which increases the risk of metabolic dysfunctions in offspring. Despite being a key tissue for maintaining metabolic health, the impacts of maternal excessive glucocorticoids (GC) on fetal brown adipose tissue (BAT) development and its long-term thermogenesis and energy expenditure remain unexamined. For testing, pregnant mice were administered dexamethasone (DEX), a synthetic GC, in the last trimester of gestation, when BAT development is the most active. DEX offspring had glucose, insulin resistance, and adiposity and also displayed cold sensitivity following cold exposure. In BAT of DEX offspring, Ppargc1a expression was suppressed, together with reduced mitochondrial density, and the brown progenitor cells sorted from offspring BAT demonstrated attenuated brown adipogenic capacity. Increased DNA methylation in Ppargc1a promoter had a fetal origin; elevated DNA methylation was also detected in neonatal BAT and brown progenitors. Mechanistically, fetal GC exposure increased GC receptor/DNMT3b complex in binding to the Ppargc1a promoter, potentially driving its de novo DNA methylation and transcriptional silencing, which impaired fetal BAT development. In summary, maternal GC exposure during pregnancy increases DNA methylation in the Ppargc1a promoter, which epigenetically impairs BAT thermogenesis and energy expenditure, predisposing offspring to metabolic dysfunctions.
      Keywords: Obesity-Animal
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db20-0009
      Issue No: Vol. 69, No. 8 (2020)
  • Exercise-Induced Increases in Insulin Sensitivity After Bariatric Surgery
           Are Mediated By Muscle Extracellular Matrix Remodeling
    • Authors: Dantas; W. S.; Roschel, H.; Murai, I. H.; Gil, S.; Davuluri, G.; Axelrod, C. L.; Ghosh, S.; Newman, S. S.; Zhang, H.; Shinjo, S. K.; das Neves, W.; Merege-Filho, C.; Teodoro, W. R.; Capelozzi, V. L.; Pereira, R. M.; Benatti, F. B.; de Sa-Pinto, A. L.; de Cleva, R.; Santo, M. A.; Kirwan, J. P.; Gualano, B.
      Pages: 1675 - 1691
      Abstract: Exercise seems to enhance the beneficial effect of bariatric (Roux-en-Y gastric bypass [RYGB]) surgery on insulin resistance. We hypothesized that skeletal muscle extracellular matrix (ECM) remodeling may underlie these benefits. Women were randomized to either a combined aerobic and resistance exercise training program following RYGB (RYGB + ET) or standard of care (RYGB). Insulin sensitivity was assessed by oral glucose tolerance test. Muscle biopsy specimens were obtained at baseline and 3 and 9 months after surgery and subjected to comprehensive phenotyping, transcriptome profiling, molecular pathway identification, and validation in vitro. Exercise training improved insulin sensitivity beyond surgery alone (e.g., Matsuda index: RYGB 123% vs. RYGB + ET 325%; P ≤ 0.0001). ECM remodeling was reduced by surgery alone, with an additive benefit of surgery and exercise training (e.g., collagen I: RYGB –41% vs. RYGB + ET –76%; P ≤ 0.0001). Exercise and RYGB had an additive effect on enhancing insulin sensitivity, but surgery alone did not resolve insulin resistance and ECM remodeling. We identified candidates modulated by exercise training that may become therapeutic targets for treating insulin resistance, in particular, the transforming growth factor-β1/SMAD 2/3 pathway and its antagonist follistatin. Exercise-induced increases in insulin sensitivity after bariatric surgery are at least partially mediated by muscle ECM remodeling.
      Keywords: Exercise
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db19-1180
      Issue No: Vol. 69, No. 8 (2020)
  • Dextran Sulfate Protects Pancreatic {beta}-Cells, Reduces Autoimmunity,
           and Ameliorates Type 1 Diabetes
    • Authors: Lu; G.; Rausell-Palamos, F.; Zhang, J.; Zheng, Z.; Zhang, T.; Valle, S.; Rosselot, C.; Berrouet, C.; Conde, P.; Spindler, M. P.; Graham, J. G.; Homann, D.; Garcia-Ocana, A.
      Pages: 1692 - 1707
      Abstract: A failure in self-tolerance leads to autoimmune destruction of pancreatic β-cells and type 1 diabetes (T1D). Low-molecular-weight dextran sulfate (DS) is a sulfated semisynthetic polysaccharide with demonstrated cytoprotective and immunomodulatory properties in vitro. However, whether DS can protect pancreatic β-cells, reduce autoimmunity, and ameliorate T1D is unknown. In this study, we report that DS, but not dextran, protects human β-cells against cytokine-mediated cytotoxicity in vitro. DS also protects mitochondrial function and glucose-stimulated insulin secretion and reduces chemokine expression in human islets in a proinflammatory environment. Interestingly, daily treatment with DS significantly reduces diabetes incidence in prediabetic NOD mice and, most importantly, reverses diabetes in early-onset diabetic NOD mice. DS decreases β-cell death, enhances islet heparan sulfate (HS)/HS proteoglycan expression, and preserves β-cell mass and plasma insulin in these mice. DS administration also increases the expression of the inhibitory costimulatory molecule programmed death-1 (PD-1) in T cells, reduces interferon-+CD4+ and CD8+ T cells, and enhances the number of FoxP3+ cells. Collectively, these studies demonstrate that the action of one single molecule, DS, on β-cell protection, extracellular matrix preservation, and immunomodulation can reverse diabetes in NOD mice, highlighting its therapeutic potential for the treatment of T1D.
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db19-0725
      Issue No: Vol. 69, No. 8 (2020)
  • m6A mRNA Methylation Controls Functional Maturation in Neonatal Murine
    • Authors: Wang; Y.; Sun, J.; Lin, Z.; Zhang, W.; Wang, S.; Wang, W.; Wang, Q.; Ning, G.
      Pages: 1708 - 1722
      Abstract: The N6-methyladenosine (m6A) RNA modification is essential during embryonic development of various organs. However, its role in embryonic and early postnatal islet development remains unknown. Mice in which RNA methyltransferase-like 3/14 (Mettl3/14) were deleted in Ngn3+ endocrine progenitors (Mettl3/14nKO) developed hyperglycemia and hypoinsulinemia at 2 weeks after birth. We found that Mettl3/14 specifically regulated both functional maturation and mass expansion of neonatal β-cells before weaning. Transcriptome and m6A methylome analyses provided m6A-dependent mechanisms in regulating cell identity, insulin secretion, and proliferation in neonatal β-cells. Importantly, we found that Mettl3/14 were dispensable for β-cell differentiation but directly regulated essential transcription factor MafA expression at least partially via modulating its mRNA stability. Failure to maintain this modification impacted the ability to fulfill β-cell functional maturity. In both diabetic db/db mice and patients with type 2 diabetes (T2D), decreased Mettl3/14 expression in β-cells was observed, suggesting its possible role in T2D. Our study unraveled the essential role of Mettl3/14 in neonatal β-cell development and functional maturation, both of which determined functional β-cell mass and glycemic control in adulthood.
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db19-0906
      Issue No: Vol. 69, No. 8 (2020)
  • Unbiased Profiling of the Human Proinsulin Biosynthetic Interaction
           Network Reveals a Role for Peroxiredoxin 4 in Proinsulin Folding
    • Authors: Tran; D. T.; Pottekat, A.; Mir, S. A.; Loguercio, S.; Jang, I.; Campos, A. R.; Scully, K. M.; Lahmy, R.; Liu, M.; Arvan, P.; Balch, W. E.; Kaufman, R. J.; Itkin-Ansari, P.
      Pages: 1723 - 1734
      Abstract: The β-cell protein synthetic machinery is dedicated to the production of mature insulin, which requires the proper folding and trafficking of its precursor, proinsulin. The complete network of proteins that mediate proinsulin folding and advancement through the secretory pathway, however, remains poorly defined. Here we used affinity purification and mass spectrometry to identify, for the first time, the proinsulin biosynthetic interaction network in human islets. Stringent analysis established a central node of proinsulin interactions with endoplasmic reticulum (ER) folding factors, including chaperones and oxidoreductases, that is remarkably conserved in both sexes and across three ethnicities. The ER-localized peroxiredoxin PRDX4 was identified as a prominent proinsulin-interacting protein. In β-cells, gene silencing of PRDX4 rendered proinsulin susceptible to misfolding, particularly in response to oxidative stress, while exogenous PRDX4 improved proinsulin folding. Moreover, proinsulin misfolding induced by oxidative stress or high glucose was accompanied by sulfonylation of PRDX4, a modification known to inactivate peroxiredoxins. Notably, islets from patients with type 2 diabetes (T2D) exhibited significantly higher levels of sulfonylated PRDX4 than islets from healthy individuals. In conclusion, we have generated the first reference map of the human proinsulin interactome to identify critical factors controlling insulin biosynthesis, β-cell function, and T2D.
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db20-0245
      Issue No: Vol. 69, No. 8 (2020)
  • Low-Dose Interleukin-2 Combined With Rapamycin Led to an Expansion of
           CD4+CD25+FOXP3+ Regulatory T Cells and Prolonged Human Islet Allograft
           Survival in Humanized Mice
    • Authors: Hu; M.; Hawthorne, W. J.; Nicholson, L.; Burns, H.; Qian, Y. W.; Liuwantara, D.; Jimenez Vera, E.; Chew, Y. V.; Williams, L.; Yi, S.; Keung, K.; Watson, D.; Rogers, N.; Alexander, S. I.; OConnell, P. J.
      Pages: 1735 - 1748
      Abstract: Islet transplantation is an emerging therapy for type 1 diabetes and hypoglycemic unawareness. However, a key challenge for islet transplantation is cellular rejection and the requirement for long-term immunosuppression. In this study, we established a diabetic humanized NOD-scidIL2Rnull (NSG) mouse model of T-cell–mediated human islet allograft rejection and developed a therapeutic regimen of low-dose recombinant human interleukin-2 (IL-2) combined with low-dose rapamycin to prolong graft survival. NSG mice that had received renal subcapsular human islet allografts and were transfused with 1 x 107 of human spleen mononuclear cells reconstituted human CD45+ cells that were predominantly CD3+ T cells and rejected their grafts with a median survival time of 27 days. IL-2 alone (0.3 x 106 IU/m2 or 1 x 106 IU/m2) or rapamycin alone (0.5–1 mg/kg) for 3 weeks did not prolong survival. However, the combination of rapamycin with IL-2 for 3 weeks significantly prolonged human islet allograft survival. Graft survival was associated with expansion of CD4+CD25+FOXP3+ regulatory T cells (Tregs) and enhanced transforming growth factor-β production by CD4+ T cells. CD8+ T cells showed reduced interferon- production and reduced expression of perforin-1. The combination of IL-2 and rapamycin has the potential to inhibit human islet allograft rejection by expanding CD4+FOXP3+ Tregs in vivo and suppressing effector cell function and could be the basis of effective tolerance-based regimens.
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db19-0525
      Issue No: Vol. 69, No. 8 (2020)
  • NKG2D Signaling Within the Pancreatic Islets Reduces NOD Diabetes and
           Increases Protective Central Memory CD8+ T-Cell Numbers
    • Authors: Trembath; A. P.; Krausz, K. L.; Sharma, N.; Gerling, I. C.; Mathews, C. E.; Markiewicz, M. A.
      Pages: 1749 - 1762
      Abstract: NKG2D is implicated in autoimmune diabetes. However, the role of this receptor in diabetes pathogenesis is unclear owing to conflicting results with studies involving global inhibition of NKG2D signaling. We found that NKG2D and its ligands are present in human pancreata, with expression of NKG2D and its ligands increased in the islets of patients with type 1 diabetes. To directly assess the role of NKG2D in the pancreas, we generated NOD mice that express an NKG2D ligand in β-islet cells. Diabetes was reduced in these mice. The reduction corresponded with a decrease in the effector to central memory CD8+ T-cell ratio. Further, NKG2D signaling during in vitro activation of both mouse and human CD8+ T cells resulted in an increased number of central memory CD8+ T cells and diabetes protection by central memory CD8+ T cells in vivo. Taken together, these studies demonstrate that there is a protective role for central memory CD8+ T cells in autoimmune diabetes and that this protection is enhanced with NKG2D signaling. These findings stress the importance of anatomical location when determining the role NKG2D signaling plays, as well as when developing therapeutic strategies targeting this pathway, in type 1 diabetes development.
      Keywords: Immunology
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db19-0979
      Issue No: Vol. 69, No. 8 (2020)
  • Failed Genetic Protection: Type 1 Diabetes in the Presence of
    • Authors: Simmons; K. M.; Mitchell, A. M.; Alkanani, A. A.; McDaniel, K. A.; Baschal, E. E.; Armstrong, T.; Pyle, L.; Yu, L.; Michels, A. W.
      Pages: 1763 - 1769
      Abstract: Certain HLA class II genes increase the risk for type 1 diabetes (T1D) development while others provide protection from disease development. HLA class II alleles encode MHC proteins on antigen-presenting cells, which function to present peptides and activate CD4 T cells. The DRB1*15:01 (DR15)-DQA1*01:02-DQB1*06:02 (DQ6) haplotype provides dominant protection across all stages of T1D and is a common haplotype found in Caucasians. However, it is present in
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db20-0038
      Issue No: Vol. 69, No. 8 (2020)
  • Brain Function Differences in Children With Type 1 Diabetes: A Functional
           MRI Study of Working Memory
    • Authors: Foland-Ross; L. C.; Tong, G.; Mauras, N.; Cato, A.; Aye, T.; Tansey, M.; White, N. H.; Weinzimer, S. A.; Englert, K.; Shen, H.; Mazaika, P. K.; Reiss, A. L.; for the Diabetes Research in Children Network (DirecNet)
      Pages: 1770 - 1778
      Abstract: Glucose is a primary fuel source to the brain, yet the influence of dysglycemia on neurodevelopment in children with type 1 diabetes remains unclear. We examined brain activation using functional MRI in 80 children with type 1 diabetes (mean ± SD age 11.5 ± 1.8 years; 46% female) and 47 children without diabetes (control group) (age 11.8 ± 1.5 years; 51% female) as they performed a visuospatial working memory (N-back) task. Results indicated that in both groups, activation scaled positively with increasing working memory load across many areas, including the frontoparietal cortex, caudate, and cerebellum. Between groups, children with diabetes exhibited reduced performance on the N-back task relative to children in the control group, as well as greater modulation of activation (i.e., showed greater increase in activation with higher working memory load). Post hoc analyses indicated that greater modulation was associated in the diabetes group with better working memory function and with an earlier age of diagnosis. These findings suggest that increased modulation may occur as a compensatory mechanism, helping in part to preserve working memory ability, and further, that children with an earlier onset require additional compensation. Future studies that test whether these patterns change as a function of improved glycemic control are warranted.
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db20-0123
      Issue No: Vol. 69, No. 8 (2020)
  • Endothelial Overexpression of Metallothionein Prevents Diabetes-Induced
           Impairment in Ischemia Angiogenesis Through Preservation of
           HIF-1{alpha}/SDF-1/VEGF Signaling in Endothelial Progenitor Cells
    • Authors: Wang; K.; Dai, X.; He, J.; Yan, X.; Yang, C.; Fan, X.; Sun, S.; Chen, J.; Xu, J.; Deng, Z.; Fan, J.; Yuan, X.; Liu, H.; Carlson, E. C.; Shen, F.; Wintergerst, K. A.; Conklin, D. J.; Epstein, P. N.; Lu, C.; Tan, Y.
      Pages: 1779 - 1792
      Abstract: Diabetes-induced oxidative stress is one of the major contributors to dysfunction of endothelial progenitor cells (EPCs) and impaired endothelial regeneration. Thus, we tested whether increasing antioxidant protein metallothionein (MT) in EPCs promotes angiogenesis in a hind limb ischemia (HLI) model in endothelial MT transgenic (JTMT) mice with high-fat diet– and streptozocin-induced diabetes. Compared with littermate wild-type (WT) diabetic mice, JTMT diabetic mice had improved blood flow recovery and angiogenesis after HLI. Similarly, transplantation of JTMT bone marrow–derived mononuclear cells (BM-MNCs) stimulated greater blood flow recovery in db/db mice with HLI than did WT BM-MNCs. The improved recovery was associated with augmented EPC mobilization and angiogenic function. Further, cultured EPCs from patients with diabetes exhibited decreased MT expression, increased cell apoptosis, and impaired tube formation, while cultured JTMT EPCs had enhanced cell survival, migration, and tube formation in hypoxic/hyperglycemic conditions compared with WT EPCs. Mechanistically, MT overexpression enhanced hypoxia-inducible factor 1α (HIF-1α), stromal cell–derived factor (SDF-1), and vascular endothelial growth factor (VEGF) expression and reduced oxidative stress in ischemic tissues. MT’s pro-EPC effects were abrogated by siRNA knockdown of HIF-1α without affecting its antioxidant action. These results indicate that endothelial MT overexpression is sufficient to protect against diabetes-induced impairment of angiogenesis by promoting EPC function, most likely through upregulation of HIF-1α/SDF-1/VEGF signaling and reducing oxidative stress.
      Keywords: Complications-Macrovascular-Cellular Mechanisms of Atherogenesis in Diabetes
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db19-0829
      Issue No: Vol. 69, No. 8 (2020)
  • PPAR{gamma} Deacetylation Confers the Antiatherogenic Effect and Improves
           Endothelial Function in Diabetes Treatment
    • Authors: Liu; L.; Fan, L.; Chan, M.; Kraakman, M. J.; Yang, J.; Fan, Y.; Aaron, N.; Wan, Q.; Carrillo-Sepulveda, M. A.; Tall, A. R.; Tabas, I.; Accili, D.; Qiang, L.
      Pages: 1793 - 1803
      Abstract: Cardiovascular disease (CVD) is the leading cause of death in patients with diabetes, and tight glycemic control fails to reduce the risk of developing CVD. Thiazolidinediones (TZDs), a class of peroxisome proliferator–activated receptor (PPAR) agonists, are potent insulin sensitizers with antiatherogenic properties, but their clinical use is limited by side effects. PPAR deacetylation on two lysine residues (K268 and K293) induces brown remodeling of white adipose tissue and uncouples the adverse effects of TZDs from insulin sensitization. Here we show that PPAR deacetylation confers antiatherogenic properties and retains the insulin-sensitizing effects of TZD while circumventing its detriments. We generated mice homozygous with mice with deacetylation-mimetic PPAR mutations K268R/K293R (2KR) on an LDL-receptor knockout (Ldlr–/–) background. 2KR:Ldlr–/– mice showed smaller atherosclerotic lesion areas than Ldlr–/– mice, particularly in aortic arches. With rosiglitazone treatment, 2KR:Ldlr–/– mice demonstrated a residual antiatherogenic response and substantial protection against bone loss and fluid retention. The antiatherosclerotic effect of 2KR was attributed to the protection of endothelium, indicated by improved endothelium-dependent vasorelaxation and repressed expression of proatherogenic factors including inducible nitric oxide synthase, interleukin-6, and NADPH oxidase 2. Therefore, manipulating PPAR acetylation is a promising therapeutic strategy to control risk of CVD in diabetes treatment.
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db20-0217
      Issue No: Vol. 69, No. 8 (2020)
  • Determinants of Treatment Response in Painful Diabetic Peripheral
           Neuropathy: A Combined Deep Sensory Phenotyping and Multimodal Brain MRI
    • Authors: Wilkinson; I. D.; Teh, K.; Heiberg-Gibbons, F.; Awadh, M.; Kelsall, A.; Shillo, P.; Sloan, G.; Tesfaye, S.; Selvarajah, D.
      Pages: 1804 - 1814
      Abstract: Painful diabetic peripheral neuropathy (DPN) is difficult to manage, as treatment response is often varied. The primary aim of this study was to examine differences in pain phenotypes between responders and nonresponders to intravenous lidocaine treatment using quantitative sensory testing. The secondary aim was to explore differences in brain structure and functional connectivity with treatment response. Forty-five consecutive patients who received intravenous lidocaine treatment for painful DPN were screened. Twenty-nine patients who met the eligibility criteria (responders, n = 14, and nonresponders, n = 15) and 26 healthy control subjects underwent detailed sensory profiling. Subjects also underwent multimodal brain MRI. A greater proportion of patients with the irritable (IR) nociceptor phenotype were responders to intravenous lidocaine treatment compared with nonresponders. The odds ratio of responding to intravenous lidocaine was 8.67 times greater (95% CI 1.4–53.8) for the IR nociceptor phenotype. Responders to intravenous lidocaine also had significantly greater mean primary somatosensory cortex cortical volume and functional connectivity between the insula cortex and the corticolimbic circuitry. This study provides preliminary evidence for a mechanism-based approach for individualizing therapy in patients with painful DPN.
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db20-0029
      Issue No: Vol. 69, No. 8 (2020)
  • Connecting Rodent and Human Pharmacokinetic Models for the Design and
           Translation of Glucose-Responsive Insulin
    • Authors: Yang; J. F.; Gong, X.; Bakh, N. A.; Carr, K.; Phillips, N. F. B.; Ismail-Beigi, F.; Weiss, M. A.; Strano, M. S.
      Pages: 1815 - 1826
      Abstract: Despite considerable progress, development of glucose-responsive insulins (GRIs) still largely depends on empirical knowledge and tedious experimentation—especially on rodents. To assist the rational design and clinical translation of the therapeutic, we present a Pharmacokinetic Algorithm Mapping GRI Efficacies in Rodents and Humans (PAMERAH) built upon our previous human model. PAMERAH constitutes a framework for predicting the therapeutic efficacy of a GRI candidate from its user-specified mechanism of action, kinetics, and dosage, which we show is accurate when checked against data from experiments and literature. Results from simulated glucose clamps also agree quantitatively with recent GRI publications. We demonstrate that the model can be used to explore the vast number of permutations constituting the GRI parameter space and thereby identify the optimal design ranges that yield desired performance. A design guide aside, PAMERAH more importantly can facilitate GRI’s clinical translation by connecting each candidate’s efficacies in rats, mice, and humans. The resultant mapping helps to find GRIs that appear promising in rodents but underperform in humans (i.e., false positives). Conversely, it also allows for the discovery of optimal human GRI dynamics not captured by experiments on a rodent population (false negatives). We condense such information onto a "translatability grid" as a straightforward, visual guide for GRI development.
      Keywords: Clinical Therapeutics/New Technology-Insulins
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db19-0879
      Issue No: Vol. 69, No. 8 (2020)
  • Slowed Metabolic Decline After 1 Year of Oral Insulin Treatment Among
           Individuals at High Risk for Type 1 Diabetes in the Diabetes Prevention
           Trial-Type 1 (DPT-1) and TrialNet Oral Insulin Prevention Trials
    • Authors: Sosenko; J. M.; Skyler, J. S.; Herold, K. C.; Schatz, D. A.; Haller, M. J.; Pugliese, A.; Cleves, M.; Geyer, S.; Rafkin, L. E.; Matheson, D.; Palmer, J. P.; for the Type 1 Diabetes TrialNet Study Group
      Pages: 1827 - 1832
      Abstract: We assessed whether oral insulin slowed metabolic decline after 1 year of treatment in individuals at high risk for type 1 diabetes. Two oral insulin trials that did not show efficacy overall and had type 1 diabetes as the primary end point were analyzed: the Diabetes Prevention Trial–Type 1 (DPT-1) and the TrialNet oral insulin trials. Oral glucose tolerance tests at baseline and after 1 year of treatment were analyzed. Among those at high risk (with a Diabetes Prevention Trial–Type 1 Risk Score [DPTRS] ≥6.75), the area under the curve (AUC) C-peptide increased significantly from baseline to 1 year in each oral insulin group, whereas the AUC glucose increased significantly in each placebo group. At 1 year, the AUC C-peptide/AUC glucose (AUC Ratio) was significantly higher in the oral insulin group than in the placebo group in each trial (P < 0.05; P = 0.057 when adjusted for age in the TrialNet trial) and in both trials combined (P < 0.01 with or without adjustment for age). For a DPTRS
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db20-0166
      Issue No: Vol. 69, No. 8 (2020)
  • Longitudinal Analysis of Serum Cytokine Levels and Gut Microbial Abundance
           Links IL-17/IL-22 With Clostridia and Insulin Sensitivity in Humans
    • Authors: Zhou; X.; Johnson, J. S.; Spakowicz, D.; Zhou, W.; Zhou, Y.; Sodergren, E.; Snyder, M.; Weinstock, G. M.
      Pages: 1833 - 1842
      Abstract: Recent studies using mouse models suggest that interaction between the gut microbiome and IL-17/IL-22–producing cells plays a role in the development of metabolic diseases. We investigated this relationship in humans using data from the prediabetes study of the Integrated Human Microbiome Project (iHMP). Specifically, we addressed the hypothesis that early in the onset of metabolic diseases there is a decline in serum levels of IL-17/IL-22, with concomitant changes in the gut microbiome. Clustering iHMP study participants on the basis of longitudinal IL-17/IL-22 profiles identified discrete groups. Individuals distinguished by low levels of IL-17/IL-22 were linked to established markers of metabolic disease, including insulin sensitivity. These individuals also displayed gut microbiome dysbiosis, characterized by decreased diversity, and IL-17/IL-22–related declines in the phylum Firmicutes, class Clostridia, and order Clostridiales. This ancillary analysis of the iHMP data therefore supports a link between the gut microbiome, IL-17/IL-22, and the onset of metabolic diseases. This raises the possibility for novel, microbiome-related therapeutic targets that may effectively alleviate metabolic diseases in humans as they do in animal models.
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db19-0592
      Issue No: Vol. 69, No. 8 (2020)
  • Circulating Protein Signatures and Causal Candidates for Type 2 Diabetes
    • Authors: Gudmundsdottir; V.; Zaghlool, S. B.; Emilsson, V.; Aspelund, T.; Ilkov, M.; Gudmundsson, E. F.; Jonsson, S. M.; Zilhao, N. R.; Lamb, J. R.; Suhre, K.; Jennings, L. L.; Gudnason, V.
      Pages: 1843 - 1853
      Abstract: The increasing prevalence of type 2 diabetes poses a major challenge to societies worldwide. Blood-based factors like serum proteins are in contact with every organ in the body to mediate global homeostasis and may thus directly regulate complex processes such as aging and the development of common chronic diseases. We applied a data-driven proteomics approach, measuring serum levels of 4,137 proteins in 5,438 elderly Icelanders, and identified 536 proteins associated with prevalent and/or incident type 2 diabetes. We validated a subset of the observed associations in an independent case-control study of type 2 diabetes. These protein associations provide novel biological insights into the molecular mechanisms that are dysregulated prior to and following the onset of type 2 diabetes and can be detected in serum. A bidirectional two-sample Mendelian randomization analysis indicated that serum changes of at least 23 proteins are downstream of the disease or its genetic liability, while 15 proteins were supported as having a causal role in type 2 diabetes.
      Keywords: Integrated Physiology-Muscle
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db19-1070
      Issue No: Vol. 69, No. 8 (2020)
  • Erratum. TFAM Enhances Fat Oxidation and Attenuates High-Fat Diet-Induced
           Insulin Resistance in Skeletal Muscle. Diabetes 2019;68:1552-1564
    • Authors: Koh; J.-H.; Johnson, M. L.; Dasari, S.; LeBrasseur, N. K.; Vuckovic, I.; Henderson, G. C.; Cooper, S. A.; Manjunatha, S.; Ruegsegger, G. N.; Shulman, G. I.; Lanza, I. R.; Nair, K. S.
      Pages: 1854 - 1854
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db20-er08a
      Issue No: Vol. 69, No. 8 (2020)
  • Erratum. Diabetic Nephropathy Alters the Distribution of Circulating
           Angiogenic MicroRNAs Among Extracellular Vesicles, HDL, and Ago-2.
           Diabetes 2019;68:2287-2300
    • Authors: Florijn; B. W.; Duijs, J. M. G. J.; Levels, J. H.; Dallinga-Thie, G. M.; Wang, Y.; Boing, A. N.; Yuana, Y.; Stam, W.; Limpens, R. W. A. L.; Au, Y. W.; Nieuwland, R.; Rabelink, T. J.; Reinders, M. E. J.; Jan van Zonneveld, A.; Bijkerk, R.
      Pages: 1855 - 1855
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db20-er08b
      Issue No: Vol. 69, No. 8 (2020)
  • Issues and Events
    • Pages: 1856 - 1856
      PubDate: 2020-07-20T11:45:32-07:00
      DOI: 10.2337/db20-ie08
      Issue No: Vol. 69, No. 8 (2020)
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