Journal Cover Diabetes
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   ISSN (Print) 0012-1797 - ISSN (Online) 1939-327X
   Published by American Diabetes Association Homepage  [4 journals]
  • In This Issue of Diabetes
    • Pages: 783 - 784
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db18-ti05
      Issue No: Vol. 67, No. 5 (2018)
  • Metabolic Karma--The Atherogenic Legacy of Diabetes: The 2017 Edwin
           Bierman Award Lecture
    • Authors: Cooper; M. E.; El-Osta, A.; Allen, T. J.; Watson, A. M. D.; Thomas, M. C.; Jandeleit-Dahm, K. A. M.
      Pages: 785 - 790
      Abstract: Cardiovascular disease, despite all the recent advances in treatment of the various risk factors, remains the major cause of mortality in both type 1 and type 2 diabetes. Experimental models of diabetes-associated atherosclerosis, despite their limitations in recapitulating the human context, have assisted in the elucidation of molecular and cellular pathways implicated in the development and progression of macrovascular injury in diabetes. Our own studies have emphasized the role of oxidative stress and advanced glycation and identified potential targets for vasoprotective therapies in the setting of diabetes. Furthermore, it has been clearly shown that previous episodes of hyperglycemia play a key role in promoting end-organ injury in diabetes, as shown in clinical trials such as the UK Prospective Diabetes Study (UKPDS), Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Observational Study (ADVANCE-ON), and the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC). The cause of this phenomenon, known as metabolic memory, remains to be elucidated, but it appears that epigenetic pathways, including glucose-induced histone methylation, play a central role. Further delineation of these pathways and their link to not only glucose but also other factors implicated in vascular injury should lead to more rational, potentially more effective therapies to retard diabetes-associated cardiovascular disease.
      Keywords: Complications-Macrovascular-Atherosclerotic Cardiovascular Disease and Human Diabetes
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/dbi18-0010
      Issue No: Vol. 67, No. 5 (2018)
  • Perilipin 3 Deficiency Stimulates Thermogenic Beige Adipocytes Through
           PPAR{alpha} Activation
    • Authors: Lee; Y. K.; Sohn, J. H.; Han, J. S.; Park, Y. J.; Jeon, Y. G.; Ji, Y.; Dalen, K. T.; Sztalryd, C.; Kimmel, A. R.; Kim, J. B.
      Pages: 791 - 804
      Abstract: Beige adipocytes can dissipate energy as heat. Elaborate communication between metabolism and gene expression is important in the regulation of beige adipocytes. Although lipid droplet (LD) binding proteins play important roles in adipose tissue biology, it remains unknown whether perilipin 3 (Plin3) is involved in the regulation of beige adipocyte formation and thermogenic activities. In this study, we demonstrate that Plin3 ablation stimulates beige adipocytes and thermogenic gene expression in inguinal white adipose tissue (iWAT). Compared with wild-type mice, Plin3 knockout mice were cold tolerant and displayed enhanced basal and stimulated lipolysis in iWAT, inducing peroxisome proliferator–activated receptor α (PPARα) activation. In adipocytes, Plin3 deficiency promoted PPARα target gene and uncoupling protein 1 expression and multilocular LD formation upon cold stimulus. Moreover, fibroblast growth factor 21 expression and secretion were upregulated, which was attributable to activated PPARα in Plin3-deficient adipocytes. These data suggest that Plin3 acts as an intrinsic protective factor preventing futile beige adipocyte formation by limiting lipid metabolism and thermogenic gene expression.
      Keywords: Integrated Physiology-Other Hormones
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-0983
      Issue No: Vol. 67, No. 5 (2018)
  • Amylin Selectively Signals Onto POMC Neurons in the Arcuate Nucleus of the
    • Authors: Lutz; T. A.; Coester, B.; Whiting, L.; Dunn-Meynell, A. A.; Boyle, C. N.; Bouret, S. G.; Levin, B. E.; Le Foll, C.
      Pages: 805 - 817
      Abstract: Amylin phosphorylates ERK (p-ERK) in the area postrema to reduce eating and synergizes with leptin to phosphorylate STAT3 in the arcuate (ARC) and ventromedial (VMN) hypothalamic nuclei to reduce food intake and body weight. The current studies assessed potential amylin and amylin-leptin ARC/VMN interactions on ERK signaling and their roles in postnatal hypothalamic pathway development. In amylin knockout mice, the density of agouti-related protein (AgRP)-immunoreactive (IR) fibers in the hypothalamic paraventricular nucleus (PVN) was increased, while the density of α-melanocyte–stimulating hormone (αMSH) fibers was decreased. In mice deficient of the amylin receptor components RAMP1/3, both AgRP and αMSH-IR fiber densities were decreased, while only αMSH-IR fiber density was decreased in rats injected neonatally in the ARC/VMN with an adeno-associated virus short hairpin RNA against the amylin core receptor. Amylin induced p-ERK in ARC neurons, 60% of which was present in POMC-expressing neurons, with none in NPY neurons. An amylin-leptin interaction was shown by an additive effect on ARC ERK signaling in neonatal rats and a 44% decrease in amylin-induced p-ERK in the ARC of leptin receptor–deficient and of ob/ob mice. Together, these results suggest that amylin directly acts, through a p-ERK–mediated process, on POMC neurons to enhance ARC-PVN αMSH pathway development.
      Keywords: Integrated Physiology-Central Nervous System Regulation of Metabolism
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-1347
      Issue No: Vol. 67, No. 5 (2018)
  • Hepatic F-Box Protein FBXW7 Maintains Glucose Homeostasis Through
           Degradation of Fetuin-A
    • Authors: Zhao; J.; Xiong, X.; Li, Y.; Liu, X.; Wang, T.; Zhang, H.; Jiao, Y.; Jiang, J.; Zhang, H.; Tang, Q.; Gao, X.; Li, X.; Lu, Y.; Liu, B.; Hu, C.; Li, X.
      Pages: 818 - 830
      Abstract: Type 2 diabetes mellitus (T2DM) has become one of the most serious and long-term threats to human health. However, the molecular mechanism that links obesity to insulin resistance remains largely unknown. Here, we show that F-box and WD repeat domain-containing 7 (FBXW7), an E3 ubiquitin protein ligase, is markedly downregulated in the liver of two obese mouse models and obese human subjects. We further identify a functional low-frequency human FBXW7 coding variant (p.Ala204Thr) in the Chinese population, which is associated with elevated blood glucose and T2DM risk. Notably, mice with liver-specific knockout of FBXW7 develop hyperglycemia, glucose intolerance, and insulin resistance even on a normal chow diet. Conversely, overexpression of FBXW7 in the liver not only prevents the development of high-fat diet–induced insulin resistance but also attenuates the disease signature of obese mice. Mechanistically, FBXW7 directly binds to hepatokine fetuin-A to induce its ubiquitination and subsequent proteasomal degradation, comprising an important mechanism maintaining glucose homeostasis. Thus, we provide evidence showing a beneficial role of FBXW7 in glucose homeostasis.
      Keywords: Integrated Physiology-Liver
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-1348
      Issue No: Vol. 67, No. 5 (2018)
  • Reduced Nonexercise Activity Attenuates Negative Energy Balance in Mice
           Engaged in Voluntary Exercise
    • Authors: Lark; D. S.; Kwan, J. R.; McClatchey, P. M.; James, M. N.; James, F. D.; Lighton, J. R. B.; Lantier, L.; Wasserman, D. H.
      Pages: 831 - 840
      Abstract: Exercise alone is often ineffective for treating obesity despite the associated increase in metabolic requirements. Decreased nonexercise physical activity has been implicated in this resistance to weight loss, but the mechanisms responsible are unclear. We quantified the metabolic cost of nonexercise activity, or "off-wheel" activity (OWA), and voluntary wheel running (VWR) and examined whether changes in OWA during VWR altered energy balance in chow-fed C57BL/6J mice (n = 12). Energy expenditure (EE), energy intake, and behavior (VWR and OWA) were continuously monitored for 4 days with locked running wheels followed by 9 days with unlocked running wheels. Unlocking the running wheels increased EE as a function of VWR distance. The metabolic cost of exercise (kcal/m traveled) decreased with increasing VWR speed. Unlocking the wheel led to a negative energy balance but also decreased OWA, which was predicted to mitigate the expected change in energy balance by ~45%. A novel behavioral circuit involved repeated bouts of VWR, and roaming was discovered and represented novel predictors of VWR behavior. The integrated analysis described here reveals that the weight loss effects of voluntary exercise can be countered by a reduction in nonexercise activity.
      Keywords: Exercise
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-1293
      Issue No: Vol. 67, No. 5 (2018)
  • Catestatin Inhibits Obesity-Induced Macrophage Infiltration and
           Inflammation in the Liver and Suppresses Hepatic Glucose Production,
           Leading to Improved Insulin Sensitivity
    • Authors: Ying; W.; Mahata, S.; Bandyopadhyay, G. K.; Zhou, Z.; Wollam, J.; Vu, J.; Mayoral, R.; Chi, N.-W.; Webster, N. J. G.; Corti, A.; Mahata, S. K.
      Pages: 841 - 848
      Abstract: The activation of Kupffer cells (KCs) and monocyte-derived recruited macrophages (McMs) in the liver contributes to obesity-induced insulin resistance and type 2 diabetes. Mice with diet-induced obesity (DIO mice) treated with chromogranin A peptide catestatin (CST) showed several positive results. These included decreased hepatic/plasma lipids and plasma insulin, diminished expression of gluconeogenic genes, attenuated expression of proinflammatory genes, increased expression of anti-inflammatory genes in McMs, and inhibition of the infiltration of McMs resulting in improvement of insulin sensitivity. Systemic CST knockout (CST-KO) mice on normal chow diet (NCD) ate more food, gained weight, and displayed elevated blood glucose and insulin levels. Supplementation of CST normalized glucose and insulin levels. To verify that the CST deficiency caused macrophages to be very proinflammatory in CST-KO NCD mice and produced glucose intolerance, we tested the effects of (sorted with FACS) F4/80+Ly6C– cells (representing KCs) and F4/80–Ly6C+ cells (representing McMs) on hepatic glucose production (HGP). Both basal HGP and glucagon-induced HGP were markedly increased in hepatocytes cocultured with KCs and McMs from NCD-fed CST-KO mice, and the effect was abrogated upon pretreatment of CST-KO macrophages with CST. Thus, we provide a novel mechanism of HGP suppression through CST-mediated inhibition of macrophage infiltration and function.
      Keywords: Integrated Physiology-Liver
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-0788
      Issue No: Vol. 67, No. 5 (2018)
  • Regulation of KATP Channel Trafficking in Pancreatic {beta}-Cells by
           Protein Histidine Phosphorylation
    • Authors: Srivastava; S.; Li, Z.; Soomro, I.; Sun, Y.; Wang, J.; Bao, L.; Coetzee, W. A.; Stanley, C. A.; Li, C.; Skolnik, E. Y.
      Pages: 849 - 860
      Abstract: Protein histidine phosphatase 1 (PHPT-1) is an evolutionarily conserved 14-kDa protein that dephosphorylates phosphohistidine. PHPT-1–/– mice were generated to gain insight into the role of PHPT-1 and histidine phosphorylation/dephosphorylation in mammalian biology. PHPT-1–/– mice exhibited neonatal hyperinsulinemic hypoglycemia due to impaired trafficking of KATP channels to the plasma membrane in pancreatic β-cells in response to low glucose and leptin and resembled patients with congenital hyperinsulinism (CHI). The defect in KATP channel trafficking in PHPT-1–/– β-cells was due to the failure of PHPT-1 to directly activate transient receptor potential channel 4 (TRPC4), resulting in decreased Ca2+ influx and impaired downstream activation of AMPK. Thus, these studies demonstrate a critical role for PHPT-1 in normal pancreatic β-cell function and raise the possibility that mutations in PHPT-1 and/or TRPC4 may account for yet to be defined cases of CHI.
      Keywords: Islet Biology-Signal Transduction
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-1433
      Issue No: Vol. 67, No. 5 (2018)
  • HLA-B*07, HLA-DRB1*07, HLA-DRB1*12, and HLA-C*03:02 Strongly Associate
           With BMI: Data From 1.3 Million Healthy Chinese Adults
    • Authors: Shen; J.; Guo, T.; Wang, T.; Zhen, Y.; Ma, X.; Wang, Y.; Zhang, Z.-X.; Cai, J.-P.; Mao, W.; Zhu, F.-M.; Li, J.-P.; Wang, Z.-L.; Zhang, D.-M.; Liu, M.-L.; Shan, X.-Y.; Zhang, B.-W.; Zhu, C.-F.; Deng, Z.-H.; Yu, W.-J.; Chen, Q.; Li, G.-L.; Yang, T.; Lu, S.; Pan, Q.-Q.; Fan, S.; Wang, X.-Y.; Zhao, X.; Bi, X.-Y.; Qiao, Y.-H.; Su, P.-C.; Lv, R.; Li, G.-Y.; Li, H.-C.; Pei, B.; Jiao, L.-X.; Shen, G.; Liu, J.; Feng, Z.-H.; Su, Y.-P.; Xie, Y.-B.; Di, W.-Y.; Wang, X.-Y.; Liu, X.; Zhang, X.-P.; Du, D.; Liu, Q.; Han, Y.; Chen, J.-W.; Gu, M.; Baier, L. J.; on behalf of the China Marrow Donor Program
      Pages: 861 - 871
      Abstract: Strong associations between HLA alleles and infectious and autoimmune diseases are well established. Although obesity is also associated with these diseases, the relationship between HLA and obesity has not been systematically investigated in a large cohort. In the current study, we analyzed the association of HLA alleles with BMI using data from 1.3 million healthy adult donors from the Chinese Marrow Donor Program (CMDP). We found 23 HLA alleles, including 12 low-resolution and 11 high-resolution alleles, were significantly associated with BMI after correction for multiple testing. Alleles associated with high BMI were enriched in haplotypes that were common in both Chinese and European populations, whereas the alleles associated with low BMI were enriched in haplotypes common only in Asians. Alleles B*07, DRB1*07, DRB1*12, and C*03:02 provided the strongest associations with BMI (P = 6.89 x 10–10, 1.32 x 10–9, 1.52 x 10–9, and 4.45 x 10–8, respectively), where B*07 and DRB1*07 also had evidence for sex-specific effects (Pheterogeneity = 0.0067 and 0.00058, respectively). These results, which identify associations between alleles of HLA-B, DRB1, and C with BMI in Chinese young adults, implicate a novel biological connection between HLA alleles and obesity.
      Keywords: Obesity-Human
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-0852
      Issue No: Vol. 67, No. 5 (2018)
  • CDKN2A/B T2D Genome-Wide Association Study Risk SNPs Impact Locus Gene
           Expression and Proliferation in Human Islets
    • Authors: Kong; Y.; Sharma, R. B.; Ly, S.; Stamateris, R. E.; Jesdale, W. M.; Alonso, L. C.
      Pages: 872 - 884
      Abstract: Genome-wide association studies link the CDKN2A/B locus with type 2 diabetes (T2D) risk, but mechanisms increasing risk remain unknown. The CDKN2A/B locus encodes cell cycle inhibitors p14, p15, and p16; MTAP; and ANRIL, a long noncoding RNA. The goal of this study was to determine whether CDKN2A/B T2D risk SNPs impact locus gene expression, insulin secretion, or β-cell proliferation in human islets. Islets from donors without diabetes (n = 95) were tested for SNP genotype (rs10811661, rs2383208, rs564398, and rs10757283), gene expression (p14, p15, p16, MTAP, ANRIL, PCNA, KI67, and CCND2), insulin secretion (n = 61), and β-cell proliferation (n = 47). Intriguingly, locus genes were coregulated in islets in two physically overlapping cassettes: p14-p16-ANRIL, which increased with age, and MTAP-p15, which did not. Risk alleles at rs10811661 and rs2383208 were differentially associated with expression of ANRIL, but not p14, p15, p16, or MTAP, in age-dependent fashion, such that younger homozygous risk donors had higher ANRIL expression, equivalent to older donor levels. We identified several risk SNP combinations that may impact locus gene expression, suggesting possible mechanisms by which SNPs impact locus biology. Risk allele carriers at ANRIL coding SNP rs564398 had reduced β-cell proliferation index. In conclusion, CDKN2A/B locus SNPs may impact T2D risk by modulating islet gene expression and β-cell proliferation.
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-1055
      Issue No: Vol. 67, No. 5 (2018)
  • Elevated Medium-Chain Acylcarnitines Are Associated With Gestational
           Diabetes Mellitus and Early Progression to Type 2 Diabetes and Induce
           Pancreatic {beta}-Cell Dysfunction
    • Authors: Batchuluun; B.; Al Rijjal, D.; Prentice, K. J.; Eversley, J. A.; Burdett, E.; Mohan, H.; Bhattacharjee, A.; Gunderson, E. P.; Liu, Y.; Wheeler, M. B.
      Pages: 885 - 897
      Abstract: Specific circulating metabolites have emerged as important risk factors for the development of diabetes. The acylcarnitines (acylCs) are a family of metabolites known to be elevated in type 2 diabetes (T2D) and linked to peripheral insulin resistance. However, the effect of acylCs on pancreatic β-cell function is not well understood. Here, we profiled circulating acylCs in two diabetes cohorts: 1) women with gestational diabetes mellitus (GDM) and 2) women with recent GDM who later developed impaired glucose tolerance (IGT), new-onset T2D, or returned to normoglycemia within a 2-year follow-up period. We observed a specific elevation in serum medium-chain (M)-acylCs, particularly hexanoyl- and octanoylcarnitine, among women with GDM and individuals with T2D without alteration in long-chain acylCs. Mice treated with M-acylCs exhibited glucose intolerance, attributed to impaired insulin secretion. Murine and human islets exposed to elevated levels of M-acylCs developed defects in glucose-stimulated insulin secretion and this was directly linked to reduced mitochondrial respiratory capacity and subsequent ability to couple glucose metabolism to insulin secretion. In conclusion, our study reveals that an elevation in circulating M-acylCs is associated with GDM and early stages of T2D onset and that this elevation directly impairs β-cell function.
      Keywords: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-1150
      Issue No: Vol. 67, No. 5 (2018)
  • Role of Protein Phosphatase 1 and Inhibitor of Protein Phosphatase 1 in
           Nitric Oxide-Dependent Inhibition of the DNA Damage Response in Pancreatic
    • Authors: Oleson; B. J.; Naatz, A.; Proudfoot, S. C.; Yeo, C. T.; Corbett, J. A.
      Pages: 898 - 910
      Abstract: Nitric oxide is produced at micromolar levels by pancreatic β-cells during exposure to proinflammatory cytokines. While classically viewed as damaging, nitric oxide also activates pathways that promote β-cell survival. We have shown that nitric oxide, in a cell type–selective manner, inhibits the DNA damage response (DDR) and, in doing so, protects β-cells from DNA damage–induced apoptosis. This study explores potential mechanisms by which nitric oxide inhibits DDR signaling. We show that inhibition of DDR signaling (measured by H2AX formation and the phosphorylation of KAP1) is selective for nitric oxide, as other forms of reactive oxygen/nitrogen species do not impair DDR signaling. The kinetics and broad range of DDR substrates that are inhibited suggest that protein phosphatase activation may be one mechanism by which nitric oxide attenuates DDR signaling in β-cells. While protein phosphatase 1 (PP1) is a primary regulator of DDR signaling and an inhibitor of PP1 (IPP1) is selectively expressed only in β-cells, disruption of either IPP1 or PP1 does not modify the inhibitory actions of nitric oxide on DDR signaling in β-cells. These findings support a PP1-independent mechanism by which nitric oxide selectively impairs DDR signaling and protects β-cells from DNA damage–induced apoptosis.
      Keywords: Islet Biology-Apoptosis
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-1062
      Issue No: Vol. 67, No. 5 (2018)
  • Postnatal Ontogenesis of the Islet Circadian Clock Plays a Contributory
           Role in {beta}-Cell Maturation Process
    • Authors: Rakshit; K.; Qian, J.; Gaonkar, K. S.; Dhawan, S.; Colwell, C. S.; Matveyenko, A. V.
      Pages: 911 - 922
      Abstract: Development of cell replacement therapies in diabetes requires understanding of the molecular underpinnings of β-cell maturation. The circadian clock regulates diverse cellular functions important for regulation of β-cell function and turnover. However, postnatal ontogenesis of the islet circadian clock and its potential role in β-cell maturation remain unknown. To address this, we studied wild-type Sprague-Dawley as well as Period1 luciferase transgenic (Per1:LUC) rats to determine circadian clock function, clock protein expression, and diurnal insulin secretion during islet development and maturation process. We additionally studied β-cell–specific Bmal1-deficient mice to elucidate a potential role of this key circadian transcription factor in β-cell functional and transcriptional maturation. We report that emergence of the islet circadian clock 1) occurs during the early postnatal period, 2) depends on the establishment of global behavioral circadian rhythms, and 3) leads to the induction of diurnal insulin secretion and gene expression. Islet cell maturation was also characterized by induction in the expression of circadian transcription factor BMAL1, deletion of which altered postnatal development of glucose-stimulated insulin secretion and the associated transcriptional network. Postnatal development of the islet circadian clock contributes to early-life β-cell maturation and should be considered for optimal design of future β-cell replacement strategies in diabetes.
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-0850
      Issue No: Vol. 67, No. 5 (2018)
  • Improved Murine MHC-Deficient HLA Transgenic NOD Mouse Models for Type 1
           Diabetes Therapy Development
    • Authors: Racine; J. J.; Stewart, I.; Ratiu, J.; Christianson, G.; Lowell, E.; Helm, K.; Allocco, J.; Maser, R. S.; Chen, Y.-G.; Lutz, C. M.; Roopenian, D.; Schloss, J.; DiLorenzo, T. P.; Serreze, D. V.
      Pages: 923 - 935
      Abstract: Improved mouse models for type 1 diabetes (T1D) therapy development are needed. T1D susceptibility is restored to normally resistant NOD.β2m–/– mice transgenically expressing human disease–associated HLA-A*02:01 or HLA-B*39:06 class I molecules in place of their murine counterparts. T1D is dependent on pathogenic CD8+ T-cell responses mediated by these human class I variants. NOD.β2m–/–-A2.1 mice were previously used to identify β-cell autoantigens presented by this human class I variant to pathogenic CD8+ T cells and for testing therapies to attenuate such effectors. However, NOD.β2m–/– mice also lack nonclassical MHC I family members, including FcRn, required for antigen presentation, and maintenance of serum IgG and albumin, precluding therapies dependent on these molecules. Hence, we used CRISPR/Cas9 to directly ablate the NOD H2-Kd and H2-Db classical class I variants either individually or in tandem (cMHCI–/–). Ablation of the H2-Ag7 class II variant in the latter stock created NOD mice totally lacking in classical murine MHC expression (cMHCI/II–/–). NOD-cMHCI–/– mice retained nonclassical MHC I molecule expression and FcRn activity. Transgenic expression of HLA-A2 or -B39 restored pathogenic CD8+ T-cell development and T1D susceptibility to NOD-cMHCI–/– mice. These next-generation HLA-humanized NOD models may provide improved platforms for T1D therapy development.
      Keywords: Immunology
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-1467
      Issue No: Vol. 67, No. 5 (2018)
  • Detection and Characterization of CD8+ Autoreactive Memory Stem T Cells in
           Patients With Type 1 Diabetes
    • Authors: Vignali; D.; Cantarelli, E.; Bordignon, C.; Canu, A.; Citro, A.; Annoni, A.; Piemonti, L.; Monti, P.
      Pages: 936 - 945
      Abstract: Stem memory T cells (Tscm) constitute the earliest developmental stage of memory T cells, displaying stem cell–like properties, such as self-renewal capacity. Their superior immune reconstitution potential has sparked interest in cancer immune therapy, vaccine development, and immune reconstitution, whereas their role in autoimmunity is largely unexplored. Here we show that autoreactive CD8+ Tscm specific for β-cell antigens GAD65, insulin, and IGRP are present in patients with type 1 diabetes (T1D). In vitro, the generation of autoreactive Tscm from naive precursors required the presence of the homeostatic cytokine interleukin-7 (IL-7). IL-7 promotes glucose uptake via overexpression of GLUT1 and upregulation of the glycolytic enzyme hexokinase 2. Even though metabolism depends on glucose uptake, the subsequent oxidation of pyruvate in the mitochondria was necessary for Tscm generation from naive precursors. In patients with T1D, high expression of GLUT1 was a hallmark of circulating Tscm, and targeting glucose uptake via GLUT1 using the selective inhibitor WZB117 resulted in inhibition of Tscm generation and expansion. Our results suggest that autoreactive Tscm are present in patients with T1D and can be selectively targeted by inhibition of glucose metabolism.
      Keywords: Immunology
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-1390
      Issue No: Vol. 67, No. 5 (2018)
  • A Novel Strategy to Prevent Advanced Atherosclerosis and Lower Blood
           Glucose in a Mouse Model of Metabolic Syndrome
    • Authors: Kanter; J. E.; Kramer, F.; Barnhart, S.; Duggan, J. M.; Shimizu-Albergine, M.; Kothari, V.; Chait, A.; Bouman, S. D.; Hamerman, J. A.; Hansen, B. F.; Olsen, G. S.; Bornfeldt, K. E.
      Pages: 946 - 959
      Abstract: Cardiovascular disease caused by atherosclerosis is the leading cause of mortality associated with type 2 diabetes and metabolic syndrome. Insulin therapy is often needed to improve glycemic control, but it does not clearly prevent atherosclerosis. Upon binding to the insulin receptor (IR), insulin activates distinct arms of downstream signaling. The IR-Akt arm is associated with blood glucose lowering and beneficial effects, whereas the IR-Erk arm might exert less desirable effects. We investigated whether selective activation of the IR-Akt arm, leaving the IR-Erk arm largely inactive, would result in protection from atherosclerosis in a mouse model of metabolic syndrome. The insulin mimetic peptide S597 lowered blood glucose and activated Akt in insulin target tissues, mimicking insulin’s effects, but only weakly activated Erk and even prevented insulin-induced Erk activation. Strikingly, S597 retarded atherosclerotic lesion progression through a process associated with protection from leukocytosis, thereby reducing lesional accumulation of inflammatory Ly6Chi monocytes. S597-mediated protection from leukocytosis was accompanied by reduced numbers of the earliest bone marrow hematopoietic stem cells and reduced IR-Erk activity in hematopoietic stem cells. This study provides a conceptually novel treatment strategy for advanced atherosclerosis associated with metabolic syndrome and type 2 diabetes.
      Keywords: Complications-Macrovascular-Cellular Mechanisms of Atherogenesis in Diabetes
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-0744
      Issue No: Vol. 67, No. 5 (2018)
  • RAGE Deletion Confers Renoprotection by Reducing Responsiveness to
           Transforming Growth Factor-{beta} and Increasing Resistance to Apoptosis
    • Authors: Hagiwara; S.; Sourris, K.; Ziemann, M.; Tieqiao, W.; Mohan, M.; McClelland, A. D.; Brennan, E.; Forbes, J.; Coughlan, M.; Harcourt, B.; Penfold, S.; Wang, B.; Higgins, G.; Pickering, R.; El-Osta, A.; Thomas, M. C.; Cooper, M. E.; Kantharidis, P.
      Pages: 960 - 973
      Abstract: Signaling via the receptor of advanced glycation end products (RAGE)—though complex and not fully elucidated in the setting of diabetes—is considered a key injurious pathway in the development of diabetic nephropathy (DN). We report here that RAGE deletion resulted in increased expression of fibrotic markers (collagen I and IV, fibronectin) and the inflammatory marker MCP-1 in primary mouse mesangial cells (MCs) and in kidney cortex. RNA sequencing analysis in MCs from RAGE–/– and wild-type mice confirmed these observations. Nevertheless, despite these gene expression changes, decreased responsiveness to transforming growth factor-β was identified in RAGE–/– mice. Furthermore, RAGE deletion conferred a more proliferative phenotype in MCs and reduced susceptibility to staurosporine-induced apoptosis. RAGE restoration experiments in RAGE–/– MCs largely reversed these gene expression changes, resulting in reduced expression of fibrotic and inflammatory markers. This study highlights that protection against DN in RAGE knockout mice is likely to be due in part to the decreased responsiveness to growth factor stimulation and an antiapoptotic phenotype in MCs. Furthermore, it extends our understanding of the role of RAGE in the progression of DN, as RAGE seems to play a key role in modulating the sensitivity of the kidney to injurious stimuli such as prosclerotic cytokines.
      Keywords: Complications-Nephropathy-Basic and Experimental Science
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-0538
      Issue No: Vol. 67, No. 5 (2018)
  • Fibroblast Growth Factor 21 Protects Photoreceptor Function in Type 1
           Diabetic Mice
    • Authors: Fu; Z.; Wang, Z.; Liu, C.-H.; Gong, Y.; Cakir, B.; Liegl, R.; Sun, Y.; Meng, S. S.; Burnim, S. B.; Arellano, I.; Moran, E.; Duran, R.; Poblete, A.; Cho, S. S.; Talukdar, S.; Akula, J. D.; Hellström, A.; Smith, L. E. H.
      Pages: 974 - 985
      Abstract: Retinal neuronal abnormalities occur before vascular changes in diabetic retinopathy. Accumulating experimental evidence suggests that neurons control vascular pathology in diabetic and other neovascular retinal diseases. Therefore, normalizing neuronal activity in diabetes may prevent vascular pathology. We investigated whether fibroblast growth factor 21 (FGF21) prevented retinal neuronal dysfunction in insulin-deficient diabetic mice. We found that in diabetic neural retina, photoreceptor rather than inner retinal function was most affected and administration of the long-acting FGF21 analog PF-05231023 restored the retinal neuronal functional deficits detected by electroretinography. PF-05231023 administration protected against diabetes-induced disorganization of photoreceptor segments seen in retinal cross section with immunohistochemistry and attenuated the reduction in the thickness of photoreceptor segments measured by optical coherence tomography. PF-05231023, independent of its downstream metabolic modulator adiponectin, reduced inflammatory marker interleukin-1β (IL-1β) mRNA levels. PF-05231023 activated the AKT-nuclear factor erythroid 2–related factor 2 pathway and reduced IL-1β expression in stressed photoreceptors. PF-05231023 administration did not change retinal expression of vascular endothelial growth factor A, suggesting a novel therapeutic approach for the prevention of early diabetic retinopathy by protecting photoreceptor function in diabetes.
      Keywords: Complications-Retinopathy
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-0830
      Issue No: Vol. 67, No. 5 (2018)
  • Urinary IgG4 and Smad1 Are Specific Biomarkers for Renal Structural and
           Functional Changes in Early Stages of Diabetic Nephropathy
    • Authors: Doi; T.; Moriya, T.; Fujita, Y.; Minagawa, N.; Usami, M.; Sasaki, T.; Abe, H.; Kishi, S.; Murakami, T.; Ouchi, M.; Ichien, G.; Yamamoto, K.; Ikeda, H.; Koezuka, Y.; Takamatsu, N.; Shima, K.; Mauer, M.; Nagai, K.; Tominaga, T.
      Pages: 986 - 993
      Abstract: Diabetic nephropathy (DN) is the major cause of end-stage kidney disease, but early biomarkers of DN risk are limited. Herein we examine urinary IgG4 and Smad1 as additional early DN biomarkers. We recruited 815 patients with type 2 diabetes; 554 patients fulfilled the criteria of an estimated glomerular filtration rate (eGFR)>60 mL/min and no macroalbuminuria at baseline, with follow-up for 5 years. Patients without macroalbuminuria were also recruited for renal biopsies. Urinary IgG4 and Smad1 were determined by enzyme-linked immunoassays using specific antibodies. The specificity, sensitivity, and reproducibility were confirmed for each assay. Increased urinary IgG4 was significantly associated with lower eGFR. The level of urinary IgG4 also significantly correlated with surface density of peripheral glomerular basement membrane (Sv PGBM/Glom), whereas Smad1 was associated with the degree of mesangial expansion—both classic pathological findings in DN. Baseline eGFR did not differ between any groups; however, increases in both urinary IgG4 and Smad1 levels at baseline significantly predicted later development of eGFR decline in patients without macroalbuminuria. These data suggest that urinary IgG4 and Smad1 at relatively early stages of DN reflect underlying DN lesions and are relevant to later clinical outcomes.
      Keywords: Complications-Nephropathy-Clinical and Translational Research
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-1043
      Issue No: Vol. 67, No. 5 (2018)
  • Altered Odor-Induced Brain Activity as an Early Manifestation of Cognitive
           Decline in Patients With Type 2 Diabetes
    • Authors: Zhang; Z.; Zhang, B.; Wang, X.; Zhang, X.; Yang, Q. X.; Qing, Z.; Lu, J.; Bi, Y.; Zhu, D.
      Pages: 994 - 1006
      Abstract: Type 2 diabetes is reported to be associated with olfactory dysfunction and cognitive decline. However, whether and how olfactory neural circuit abnormalities involve cognitive impairment in diabetes remains uncovered. This study thus aimed to investigate olfactory network alterations and the associations of odor-induced brain activity with cognitive and metabolic parameters in type 2 diabetes. Participants with normal cognition, including 51 patients with type 2 diabetes and 41 control subjects without diabetes, underwent detailed cognitive assessment, olfactory behavior tests, and odor-induced functional MRI measurements. Olfactory brain regions showing significantly different activation between the two groups were selected for functional connectivity analysis. Compared with the control subjects, patients with diabetes demonstrated significantly lower olfactory threshold score, decreased brain activation, and disrupted functional connectivity in the olfactory network. Positive associations of the disrupted functional connectivity with decreased neuropsychology test scores and reduced pancreatic function were observed in patients with diabetes. Notably, the association between pancreatic function and executive function was mediated by olfactory behavior and olfactory functional connectivity. Our results suggested the alteration of olfactory network is present before clinically measurable cognitive decrements in type 2 diabetes, bridging the gap between the central olfactory system and cognitive decline in diabetes.
      Keywords: Complications-Neuropathy
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-1274
      Issue No: Vol. 67, No. 5 (2018)
  • Metabolic Syndrome Is Associated With Impaired Diastolic Function
           Independently of MRI-Derived Myocardial Extracellular Volume: The MESA
    • Authors: Ladeiras-Lopes; R.; Moreira, H. T.; Bettencourt, N.; Fontes-Carvalho, R.; Sampaio, F.; Ambale-Venkatesh, B.; Wu, C.; Liu, K.; Bertoni, A. G.; Ouyang, P.; Bluemke, D. A.; Lima, J. A.
      Pages: 1007 - 1012
      Abstract: The relationship of metabolic syndrome (MetS) and insulin resistance (one of its key pathophysiological mediators) with diastolic dysfunction and myocardial fibrosis is not well understood. This study aimed to evaluate the association of MetS with diastolic function and myocardial extracellular matrix (ECM) using cardiac MRI (CMRI) in a large community-based population. This cross-sectional analysis included 1,582 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with left ventricular ejection fraction ≥50% and no history of cardiac events. Diastolic function was assessed using tagged CMRI parameters including end-diastolic strain rate (EDSR) and strain relaxation index (SRI). ECM was evaluated using extracellular volume (ECV) quantification. Participants’ mean age was 67.4 ± 8.6 years, and 48.1% were males. MetS was present in 533 individuals (33.7%), and type 2 diabetes in 250 (15.8%). In the multivariable analyses, MetS (irrespective of the presence of type 2 diabetes) and higher insulin resistance were associated with impaired diastolic function (higher SRI and lower EDSR), independent of ECV. In conclusion, MetS, irrespective of the presence of type 2 diabetes, was independently associated with impaired diastole. These functional myocardial changes seem to result from intrinsic cardiomyocyte alterations, irrespective of the myocardial interstitium (including fibrosis).
      Keywords: Epidemiology-Cardiovascular Disease
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-1496
      Issue No: Vol. 67, No. 5 (2018)
  • Circulating miRNA Profiles Associated With Hyperglycemia in Patients With
           Type 1 Diabetes
    • Authors: Satake; E.; Pezzolesi, M. G.; Md Dom, Z. I.; Smiles, A. M.; Niewczas, M. A.; Krolewski, A. S.
      Pages: 1013 - 1023
      Abstract: We investigated plasma microRNA (miRNA) profiles associated with variation of hyperglycemia, measured as hemoglobin A1c (HbA1c), in two panels of patients with type 1 diabetes (T1D). Using the HTG Molecular Diagnostics EdgeSeq platform, 2,083 miRNAs were measured in plasma from 71 patients included in a screening panel. Quantitative real-time PCR was used to measure the candidate miRNAs in plasma from 95 patients included in an independent replication panel. We found 10 miRNAs replicated in both panels and 4 with high statistical significance. The strongest positive correlations with HbA1c were found with miR-125b-5p (rs = 0.40, P = 6.0 x 10–5) and miR-365a-3p (rs = 0.35, P = 5.9 x 10–4). The strongest negative correlations were found with miR-5190 (rs = –0.30, P = 0.003) and miR-770-5p (rs = –0.27, P = 0.008). Pathway analysis revealed that 50 Kyoto Encyclopedia of Genes and Genomes pathways were significantly enriched by genes targeted by these four miRNAs. The axon guidance signaling pathway was enriched (P < 1 x 10–7) by genes targeted by all four miRNAs. In addition, three other pathways (Rap1 signaling, focal adhesion, and neurotrophin signaling) were also significantly enriched but with genes targeted by only by three of the identified miRNAs. In conclusion, our study identified four circulating miRNAs that were influenced by variation in hyperglycemia. Dysregulation of these miRNAs, which are associated with hyperglycemia in patients with T1D, may contribute to the development of diabetes complications. However, there are multitudes of possible mechanisms/pathways through which dysregulation of these miRNAs may impact risk of diabetes complications.
      Keywords: Genetics-Type 1 Diabetes
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-1207
      Issue No: Vol. 67, No. 5 (2018)
  • Fetal Genotype and Maternal Glucose Have Independent and Additive Effects
           on Birth Weight
    • Authors: Hughes; A. E.; Nodzenski, M.; Beaumont, R. N.; Talbot, O.; Shields, B. M.; Scholtens, D. M.; Knight, B. A.; Lowe, W. L.; Hattersley, A. T.; Freathy, R. M.
      Pages: 1024 - 1029
      Abstract: Maternal glycemia is a key determinant of birth weight, but recent large-scale genome-wide association studies demonstrated an important contribution of fetal genetics. It is not known whether fetal genotype modifies the impact of maternal glycemia or whether it acts through insulin-mediated growth. We tested the effects of maternal fasting plasma glucose (FPG) and a fetal genetic score for birth weight on birth weight and fetal insulin in 2,051 European mother-child pairs from the Exeter Family Study of Childhood Health (EFSOCH) and the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. The fetal genetic score influenced birth weight independently of maternal FPG and impacted growth at all levels of maternal glycemia. For mothers with FPG in the top tertile, the frequency of large for gestational age (birth weight ≥90th centile) was 31.1% for offspring with the highest tertile genetic score and only 14.0% for those with the lowest tertile genetic score. Unlike maternal glucose, the fetal genetic score was not associated with cord insulin or C-peptide. Similar results were seen for HAPO participants of non-European ancestry (n = 2,842 pairs). This work demonstrates that for any level of maternal FPG, fetal genetics has a major impact on fetal growth and acts predominantly through independent mechanisms.
      Keywords: Pregnancy-Basic Science/Translational
      PubDate: 2018-04-20T12:00:27-07:00
      DOI: 10.2337/db17-1188
      Issue No: Vol. 67, No. 5 (2018)
  • Erratum. Engineering Glucose Responsiveness Into Insulin. Diabetes
    • Authors: Kaarsholm; N. C.; Lin, S.; Yan, L.; Kelly, T.; van Heek, M.; Mu, J.; Wu, M.; Dai, G.; Cui, Y.; Zhu, Y.; Carballo-Jane, E.; Reddy, V.; Zafian, P.; Huo, P.; Shi, S.; Antochshuk, V.; Ogawa, A.; Liu, F.; Souza, S. C.; Seghezzi, W.; Duffy, J. L.; Erion, M.; Nargund, R. P.; Kelley, D. E.
      Pages: 1030 - 1030
      PubDate: 2018-04-20T12:00:28-07:00
      DOI: 10.2337/db18-er05a
      Issue No: Vol. 67, No. 5 (2018)
  • Issues and Events
    • Pages: 1031 - 1031
      PubDate: 2018-04-20T12:00:28-07:00
      DOI: 10.2337/db18-ie05
      Issue No: Vol. 67, No. 5 (2018)
School of Mathematical and Computer Sciences
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