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Journal Prestige (SJR): 4.435
Citation Impact (citeScore): 6
Number of Followers: 465  
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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: 1209 - 1210
      PubDate: 2018-06-22T12:05:03-07:00
      DOI: 10.2337/db18-ti07
      Issue No: Vol. 67, No. 7 (2018)
  • Learning From Past Failures of Oral Insulin Trials
    • Authors: Michels; A. W.; Gottlieb, P. A.
      Pages: 1211 - 1215
      Abstract: Very recently one of the largest type 1 diabetes prevention trials using daily administration of oral insulin or placebo was completed. After 9 years of study enrollment and follow-up, the randomized controlled trial failed to delay the onset of clinical type 1 diabetes, which was the primary end point. The unfortunate outcome follows the previous large-scale trial, the Diabetes Prevention Trial–Type 1 (DPT-1), which again failed to delay diabetes onset with oral insulin or low-dose subcutaneous insulin injections in a randomized controlled trial with relatives at risk for type 1 diabetes. These sobering results raise the important question, "Where does the type 1 diabetes prevention field move next'" In this Perspective, we advocate for a paradigm shift in which smaller mechanistic trials are conducted to define immune mechanisms and potentially identify treatment responders. The stage is set for these interventions in individuals at risk for type 1 diabetes as Type 1 Diabetes TrialNet has identified thousands of relatives with islet autoantibodies and general population screening for type 1 diabetes risk is under way. Mechanistic trials will allow for better trial design and patient selection based upon molecular markers prior to large randomized controlled trials, moving toward a personalized medicine approach for the prevention of type 1 diabetes.
      PubDate: 2018-06-22T12:05:03-07:00
      DOI: 10.2337/dbi17-0043
      Issue No: Vol. 67, No. 7 (2018)
  • Strength in Numbers: Opportunities for Enhancing the Development of
           Effective Treatments for Type 1 Diabetes--The TrialNet Experience
    • Authors: Greenbaum; C. J.; Speake, C.; Krischer, J.; Buckner, J.; Gottlieb, P. A.; Schatz, D. A.; Herold, K. C.; Atkinson, M. A.
      Pages: 1216 - 1225
      Abstract: The early to mid-1980s were an inflection point in the history of type 1 diabetes research. Two landmark events occurred: the initiation of immune-based interventions seeking to prevent type 1 diabetes and the presentation of an innovative model describing the disorder’s natural history. Both formed the basis for hundreds of subsequent studies designed to achieve a dramatic therapeutic goal—a means to prevent and/or reverse type 1 diabetes. However, the need to screen large numbers of individuals and prospectively monitor them using immunologic and metabolic tests for extended periods of time suggested such efforts would require a large collaborative network. Hence, the National Institutes of Health formed the landmark Diabetes Prevention Trial-Type 1 (DPT-1) in the mid-1990s, an effort that led to Type 1 Diabetes TrialNet. TrialNet studies have helped identify novel biomarkers; delineate type 1 diabetes progression, resulting in identification of highly predictable stages defined by the accumulation of autoantibodies (stage 1), dysglycemia (stage 2), and disease meeting clinical criteria for diagnosis (stage 3); and oversee numerous clinical trials aimed at preventing disease progression. Such efforts pave the way for stage-specific intervention trials with improved hope that a means to effectively disrupt the disorder’s development will be identified.
      Keywords: Immunology
      PubDate: 2018-06-22T12:05:03-07:00
      DOI: 10.2337/db18-0065
      Issue No: Vol. 67, No. 7 (2018)
  • Cannabinoid Type 1 Receptors Are Upregulated During Acute Activation of
           Brown Adipose Tissue
    • Authors: Lahesmaa; M.; Eriksson, O.; Gnad, T.; Oikonen, V.; Bucci, M.; Hirvonen, J.; Koskensalo, K.; Teuho, J.; Niemi, T.; Taittonen, M.; Lahdenpohja, S.; U Din, M.; Haaparanta-Solin, M.; Pfeifer, A.; Virtanen, K. A.; Nuutila, P.
      Pages: 1226 - 1236
      Abstract: Activating brown adipose tissue (BAT) could provide a potential approach for the treatment of obesity and metabolic disease in humans. Obesity is associated with upregulation of the endocannabinoid system, and blocking the cannabinoid type 1 receptor (CB1R) has been shown to cause weight loss and to decrease cardiometabolic risk factors. These effects may be mediated partly via increased BAT metabolism, since there is evidence that CB1R antagonism activates BAT in rodents. To investigate the significance of CB1R in BAT function, we quantified the density of CB1R in human and rodent BAT using the positron emission tomography radioligand [18F]FMPEP-d2 and measured BAT activation in parallel with the glucose analog [18F]fluorodeoxyglucose. Activation by cold exposure markedly increased CB1R density and glucose uptake in the BAT of lean men. Similarly, β3-receptor agonism increased CB1R density in the BAT of rats. In contrast, overweight men with reduced BAT activity exhibited decreased CB1R in BAT, reflecting impaired endocannabinoid regulation. Image-guided biopsies confirmed CB1R mRNA expression in human BAT. Furthermore, CB1R blockade increased glucose uptake and lipolysis of brown adipocytes. Our results highlight that CB1Rs are significant for human BAT activity, and the CB1Rs provide a novel therapeutic target for BAT activation in humans.
      Keywords: Obesity-Human
      PubDate: 2018-06-22T12:05:03-07:00
      DOI: 10.2337/db17-1366
      Issue No: Vol. 67, No. 7 (2018)
  • Morning Hyperinsulinemia Primes the Liver for Glucose Uptake and Glycogen
           Storage Later in the Day
    • Authors: Moore; M. C.; Smith, M. S.; Farmer, B.; Coate, K. C.; Kraft, G.; Shiota, M.; Williams, P. E.; Cherrington, A. D.
      Pages: 1237 - 1245
      Abstract: We observed that a 4-h morning (AM) duodenal infusion of glucose versus saline doubled hepatic glucose uptake (HGU) and storage during a hyperinsulinemic–hyperglycemic (HIHG) clamp that afternoon (PM). To separate the effects of AM hyperglycemia versus AM hyperinsulinemia on the PM response, we used hepatic balance and tracer ([3-3H]glucose) techniques in conscious dogs. From 0 to 240 min, dogs underwent a euinsulinemic-hyperglycemic (GLC; n = 7) or hyperinsulinemic-euglycemic (INS; n = 8) clamp. Tracer equilibration and basal sampling occurred from 240 to 360 min, followed by an HIHG clamp (360–600 min; four times basal insulin, two times basal glycemia) with portal glucose infusion (4 mg ⋅ kg–1 ⋅ min–1). In the HIHG clamp, HGU (5.8 ± 0.9 vs. 3.3 ± 0.3 mg ⋅ kg–1 ⋅ min–1) and net glycogen storage (6.0 ± 0.8 vs. 2.9 ± 0.5 mg ⋅ kg–1 ⋅ min–1) were approximately twofold greater in INS than in GLC. PM hepatic glycogen content (1.9 ± 0.2 vs. 1.3 ± 0.2 g/kg body weight) and glycogen synthase (GS) activity were also greater in INS versus GLC, whereas glycogen phosphorylase (GP) activity was reduced. Thus AM hyperinsulinemia, but not AM hyperglycemia, enhanced the HGU response to a PM HIHG clamp by augmenting GS and reducing GP activity. AM hyperinsulinemia can prime the liver to extract and store glucose more effectively during subsequent same-day meals, potentially providing a tool to improve glucose control.
      Keywords: Integrated Physiology-Liver
      PubDate: 2018-06-22T12:05:03-07:00
      DOI: 10.2337/db17-0979
      Issue No: Vol. 67, No. 7 (2018)
  • TCPTP Regulates Insulin Signaling in AgRP Neurons to Coordinate Glucose
           Metabolism With Feeding
    • Authors: Dodd; G. T.; Lee-Young, R. S.; Brüning, J. C.; Tiganis, T.
      Pages: 1246 - 1257
      Abstract: Insulin regulates glucose metabolism by eliciting effects on peripheral tissues as well as the brain. Insulin receptor (IR) signaling inhibits AgRP-expressing neurons in the hypothalamus to contribute to the suppression of hepatic glucose production (HGP) by insulin, whereas AgRP neuronal activation attenuates brown adipose tissue (BAT) glucose uptake. The tyrosine phosphatase TCPTP suppresses IR signaling in AgRP neurons. Hypothalamic TCPTP is induced by fasting and degraded after feeding. Here we assessed the influence of TCPTP in AgRP neurons in the control of glucose metabolism. TCPTP deletion in AgRP neurons (Agrp-Cre;Ptpn2fl/fl) enhanced insulin sensitivity, as assessed by the increased glucose infusion rates, and reduced HGP during hyperinsulinemic-euglycemic clamps, accompanied by increased [14C]-2-deoxy-d-glucose uptake in BAT and browned white adipose tissue. TCPTP deficiency in AgRP neurons promoted the intracerebroventricular insulin-induced repression of hepatic gluconeogenesis in otherwise unresponsive food-restricted mice, yet had no effect in fed/satiated mice where hypothalamic TCPTP levels are reduced. The improvement in glucose homeostasis in Agrp-Cre;Ptpn2fl/fl mice was corrected by IR heterozygosity (Agrp-Cre;Ptpn2fl/fl;Insrfl/+), causally linking the effects on glucose metabolism with the IR signaling in AgRP neurons. Our findings demonstrate that TCPTP controls IR signaling in AgRP neurons to coordinate HGP and brown/beige adipocyte glucose uptake in response to feeding/fasting.
      Keywords: Obesity-Animal
      PubDate: 2018-06-22T12:05:03-07:00
      DOI: 10.2337/db17-1485
      Issue No: Vol. 67, No. 7 (2018)
  • Ceramide Transporter CERT Is Involved in Muscle Insulin Signaling Defects
           Under Lipotoxic Conditions
    • Authors: Bandet; C. L.; Mahfouz, R.; Veret, J.; Sotiropoulos, A.; Poirier, M.; Giussani, P.; Campana, M.; Philippe, E.; Blachnio-Zabielska, A.; Ballaire, R.; Le Liepvre, X.; Bourron, O.; Berkes, D.; Gorski, J.; Ferre, P.; Le Stunff, H.; Foufelle, F.; Hajduch, E.
      Pages: 1258 - 1271
      Abstract: One main mechanism of insulin resistance (IR), a key feature of type 2 diabetes, is the accumulation of saturated fatty acids (FAs) in the muscles of obese patients with type 2 diabetes. Understanding the mechanism that underlies lipid-induced IR is an important challenge. Saturated FAs are metabolized into lipid derivatives called ceramides, and their accumulation plays a central role in the development of muscle IR. Ceramides are produced in the endoplasmic reticulum (ER) and transported to the Golgi apparatus through a transporter called CERT, where they are converted into various sphingolipid species. We show that CERT protein expression is reduced in all IR models studied because of a caspase-dependent cleavage. Inhibiting CERT activity in vitro potentiates the deleterious action of lipotoxicity on insulin signaling, whereas overexpression of CERT in vitro or in vivo decreases muscle ceramide content and improves insulin signaling. In addition, inhibition of caspase activity prevents ceramide-induced insulin signaling defects in C2C12 muscle cells. Altogether, these results demonstrate the importance of physiological ER-to-Golgi ceramide traffic to preserve muscle cell insulin signaling and identify CERT as a major actor in this process.
      Keywords: Insulin Action-Cellular and Molecular Metabolism
      PubDate: 2018-06-22T12:05:03-07:00
      DOI: 10.2337/db17-0901
      Issue No: Vol. 67, No. 7 (2018)
  • Regulation of Insulin Receptor Pathway and Glucose Metabolism by CD36
    • Authors: Samovski; D.; Dhule, P.; Pietka, T.; Jacome-Sosa, M.; Penrose, E.; Son, N.-H.; Flynn, C. R.; Shoghi, K. I.; Hyrc, K. L.; Goldberg, I. J.; Gamazon, E. R.; Abumrad, N. A.
      Pages: 1272 - 1284
      Abstract: During reduced energy intake, skeletal muscle maintains homeostasis by rapidly suppressing insulin-stimulated glucose utilization. Loss of this adaptation is observed with deficiency of the fatty acid transporter CD36. A similar loss is also characteristic of the insulin-resistant state where CD36 is dysfunctional. To elucidate what links CD36 to muscle glucose utilization, we examined whether CD36 signaling might influence insulin action. First, we show that CD36 deletion specific to skeletal muscle reduces expression of insulin signaling and glucose metabolism genes. It decreases muscle ceramides but impairs glucose disposal during a meal. Second, depletion of CD36 suppresses insulin signaling in primary-derived human myotubes, and the mechanism is shown to involve functional CD36 interaction with the insulin receptor (IR). CD36 promotes tyrosine phosphorylation of IR by the Fyn kinase and enhances IR recruitment of P85 and downstream signaling. Third, pretreatment for 15 min with saturated fatty acids suppresses CD36-Fyn enhancement of IR phosphorylation, whereas unsaturated fatty acids are neutral or stimulatory. These findings define mechanisms important for muscle glucose metabolism and optimal insulin responsiveness. Potential human relevance is suggested by genome-wide analysis and RNA sequencing data that associate genetically determined low muscle CD36 expression to incidence of type 2 diabetes.
      Keywords: Insulin Action-Signal Transduction, Insulin, and Other Hormones
      PubDate: 2018-06-22T12:05:03-07:00
      DOI: 10.2337/db17-1226
      Issue No: Vol. 67, No. 7 (2018)
  • Loss of OcaB Prevents Age-Induced Fat Accretion and Insulin Resistance by
           Altering B-Lymphocyte Transition and Promoting Energy Expenditure
    • Authors: Carter; S.; Miard, S.; Caron, A.; Salle-Lefort, S.; St-Pierre, P.; Anhe, F. F.; Lavoie-Charland, E.; Blais-Lecours, P.; Drolet, M.-C.; Lefebvre, J. S.; Lacombe, J.; Deshaies, Y.; Couet, J.; Laplante, M.; Ferron, M.; Bosse, Y.; Marette, A.; Richard, D.; Marsolais, D.; Picard, F.
      Pages: 1285 - 1296
      Abstract: The current demographic shift toward an aging population has led to a robust increase in the prevalence of age-associated metabolic disorders. Recent studies have demonstrated that the etiology of obesity-related insulin resistance that develops with aging differs from that induced by high-calorie diets. Whereas the role of adaptive immunity in changes in energy metabolism driven by nutritional challenges has recently gained attention, its impact on aging remains mostly unknown. Here we found that the number of follicular B2 lymphocytes and expression of the B-cell-specific transcriptional coactivator OcaB increase with age in spleen and in intra-abdominal epididymal white adipose tissue (eWAT), concomitantly with higher circulating levels of IgG and impaired glucose homeostasis. Reduction of B-cell maturation and Ig production—especially that of IgG2c—by ablation of OcaB prevented age-induced glucose intolerance and insulin resistance and promoted energy expenditure by stimulating fatty acid utilization in eWAT and brown adipose tissue. Transfer of wild-type bone marrow in OcaB–/– mice replenished the eWAT B2-cell population and IgG levels, which diminished glucose tolerance, insulin sensitivity, and energy expenditure while increasing body weight gain in aged mice. Thus these findings demonstrate that upon aging, modifications in B-cell-driven adaptive immunity contribute to glucose intolerance and fat accretion.
      Keywords: Obesity-Animal
      PubDate: 2018-06-22T12:05:03-07:00
      DOI: 10.2337/db17-0558
      Issue No: Vol. 67, No. 7 (2018)
  • Mice Carrying a Dominant-Negative Human PI3K Mutation Are Protected From
           Obesity and Hepatic Steatosis but Not Diabetes
    • Authors: Solheim; M. H.; Winnay, J. N.; Batista, T. M.; Molven, A.; Njolstad, P. R.; Kahn, C. R.
      Pages: 1297 - 1309
      Abstract: Phosphatidylinositol 3-kinase (PI3K) plays a central role in insulin signaling, glucose metabolism, cell growth, cell development, and apoptosis. A heterozygous missense mutation (R649W) in the p85α regulatory subunit gene of PI3K (PIK3R1) has been identified in patients with SHORT (Short stature, Hyperextensibility/Hernia, Ocular depression, Rieger anomaly, and Teething delay) syndrome, a disorder characterized by postnatal growth retardation, insulin resistance, and partial lipodystrophy. Knock-in mice with the same heterozygous mutation mirror the human phenotype. In this study, we show that Pik3r1 R649W knock-in mice fed a high-fat diet (HFD) have reduced weight gain and adipose accumulation. This is accompanied by reduced expression of several genes involved in lipid metabolism. Interestingly, despite the lower level of adiposity, the HFD knock-in mice are more hyperglycemic and more insulin-resistant than HFD-fed control mice. Likewise, when crossed with genetically obese ob/ob mice, the ob/ob mice carrying the heterozygous R649W mutation were protected from obesity and hepatic steatosis but developed a severe diabetic state. Together, our data demonstrate a central role of PI3K in development of obesity and fatty liver disease, separating these effects from the role of PI3K in insulin resistance and the resultant hyperglycemia.
      Keywords: Insulin Action-Adipocyte Biology
      PubDate: 2018-06-22T12:05:03-07:00
      DOI: 10.2337/db17-1509
      Issue No: Vol. 67, No. 7 (2018)
  • Increased Hepatic PDGF-AA Signaling Mediates Liver Insulin Resistance in
           Obesity-Associated Type 2 Diabetes
    • Authors: Abderrahmani; A.; Yengo, L.; Caiazzo, R.; Canouil, M.; Cauchi, S.; Raverdy, V.; Plaisance, V.; Pawlowski, V.; Lobbens, S.; Maillet, J.; Rolland, L.; Boutry, R.; Queniat, G.; Kwapich, M.; Tenenbaum, M.; Bricambert, J.; Saussenthaler, S.; Anthony, E.; Jha, P.; Derop, J.; Sand, O.; Rabearivelo, I.; Leloire, A.; Pigeyre, M.; Daujat-Chavanieu, M.; Gerbal-Chaloin, S.; Dayeh, T.; Lassailly, G.; Mathurin, P.; Staels, B.; Auwerx, J.; Schürmann, A.; Postic, C.; Schafmayer, C.; Hampe, J.; Bonnefond, A.; Pattou, F.; Froguel, P.
      Pages: 1310 - 1321
      Abstract: In type 2 diabetes (T2D), hepatic insulin resistance is strongly associated with nonalcoholic fatty liver disease (NAFLD). In this study, we hypothesized that the DNA methylome of livers from patients with T2D compared with livers of individuals with normal plasma glucose levels can unveil some mechanism of hepatic insulin resistance that could link to NAFLD. Using DNA methylome and transcriptome analyses of livers from obese individuals, we found that hypomethylation at a CpG site in PDGFA (encoding platelet-derived growth factor α) and PDGFA overexpression are both associated with increased T2D risk, hyperinsulinemia, increased insulin resistance, and increased steatohepatitis risk. Genetic risk score studies and human cell modeling pointed to a causative effect of high insulin levels on PDGFA CpG site hypomethylation, PDGFA overexpression, and increased PDGF-AA secretion from the liver. We found that PDGF-AA secretion further stimulates its own expression through protein kinase C activity and contributes to insulin resistance through decreased expression of insulin receptor substrate 1 and of insulin receptor. Importantly, hepatocyte insulin sensitivity can be restored by PDGF-AA–blocking antibodies, PDGF receptor inhibitors, and by metformin, opening therapeutic avenues. Therefore, in the liver of obese patients with T2D, the increased PDGF-AA signaling contributes to insulin resistance, opening new therapeutic avenues against T2D and possibly NAFLD.
      Keywords: Obesity-Human
      PubDate: 2018-06-22T12:05:03-07:00
      DOI: 10.2337/db17-1539
      Issue No: Vol. 67, No. 7 (2018)
  • T3 Induces Both Markers of Maturation and Aging in Pancreatic {beta}-Cells
    • Authors: Aguayo-Mazzucato; C.; Lee, T. B.; Matzko, M.; DiIenno, A.; Rezanejad, H.; Ramadoss, P.; Scanlan, T.; Zavacki, A. M.; Larsen, P. R.; Hollenberg, A.; Colton, C.; Sharma, A.; Bonner-Weir, S.
      Pages: 1322 - 1331
      Abstract: Previously, we showed that thyroid hormone (TH) triiodothyronine (T3) enhanced β-cell functional maturation through induction of Mafa. High levels of T3 have been linked to decreased life span in mammals and low levels to lengthened life span, suggesting a relationship between TH and aging. Here, we show that T3 increased p16Ink4a (a β-cell senescence marker and effector) mRNA in rodent and human β-cells. The kinetics of Mafa and p16Ink4a induction suggested both genes as targets of TH via TH receptors (THRs) binding to specific response elements. Using specific agonists CO23 and GC1, we showed that p16Ink4a expression was controlled by THRA and Mafa by THRB. Using chromatin immunoprecipitation and a transient transfection yielding biotinylated THRB1 or THRA isoforms to achieve specificity, we determined that THRA isoform bound to p16Ink4a, whereas THRB1 bound to Mafa but not to p16Ink4a. On a cellular level, T3 treatment accelerated cell senescence as shown by increased number of β-cells with acidic β-galactosidase activity. Our data show that T3 can simultaneously induce both maturation (Mafa) and aging (p16Ink4a) effectors and that these dichotomous effects are mediated through different THR isoforms. These findings may be important for further improving stem cell differentiation protocols to produce functional β-cells for replacement therapies in diabetes.
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2018-06-22T12:05:03-07:00
      DOI: 10.2337/db18-0030
      Issue No: Vol. 67, No. 7 (2018)
  • Doc2b Protects {beta}-Cells Against Inflammatory Damage and Enhances
    • Authors: Aslamy; A.; Oh, E.; Olson, E. M.; Zhang, J.; Ahn, M.; Moin, A. S. M.; Tunduguru, R.; Salunkhe, V. A.; Veluthakal, R.; Thurmond, D. C.
      Pages: 1332 - 1344
      Abstract: Loss of functional β-cell mass is an early feature of type 1 diabetes. To release insulin, β-cells require soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) complexes, as well as SNARE complex regulatory proteins like double C2 domain–containing protein β (Doc2b). We hypothesized that Doc2b deficiency or overabundance may confer susceptibility or protection, respectively, to the functional β-cell mass. Indeed, Doc2b+/– knockout mice show an unusually severe response to multiple-low-dose streptozotocin (MLD-STZ), resulting in more apoptotic β-cells and a smaller β-cell mass. In addition, inducible β-cell–specific Doc2b-overexpressing transgenic (βDoc2b-dTg) mice show improved glucose tolerance and resist MLD-STZ–induced disruption of glucose tolerance, fasting hyperglycemia, β-cell apoptosis, and loss of β-cell mass. Mechanistically, Doc2b enrichment enhances glucose-stimulated insulin secretion (GSIS) and SNARE activation and prevents the appearance of apoptotic markers in response to cytokine stress and thapsigargin. Furthermore, expression of a peptide containing the Doc2b tandem C2A and C2B domains is sufficient to confer the beneficial effects of Doc2b enrichment on GSIS, SNARE activation, and apoptosis. These studies demonstrate that Doc2b enrichment in the β-cell protects against diabetogenic and proapoptotic stress. Furthermore, they identify a Doc2b peptide that confers the beneficial effects of Doc2b and may be a therapeutic candidate for protecting functional β-cell mass.
      Keywords: Islet Biology-Apoptosis
      PubDate: 2018-06-22T12:05:03-07:00
      DOI: 10.2337/db17-1352
      Issue No: Vol. 67, No. 7 (2018)
  • Human Proislet Peptide Promotes Pancreatic Progenitor Cells to Ameliorate
           Diabetes Through FOXO1/Menin-Mediated Epigenetic Regulation
    • Authors: Jiang; Z.; Shi, D.; Tu, Y.; Tian, J.; Zhang, W.; Xing, B.; Wang, J.; Liu, S.; Lou, J.; Gustafsson, J.-A.; Hua, X.; Ma, X.
      Pages: 1345 - 1355
      Abstract: We investigated how human proislet peptide (HIP) regulates differentiation of human fetus–derived pancreatic progenitor cells (HFPPCs) and explored the potential link between HIP signaling and the menin pathway, which is key to regulating pancreatic islet differentiation. The data show that HIP promoted expression of proislet transcription factors (TFs), including PDX-1, MAFA, and NKX6.1, as well as other maturation markers of β-cells, such as insulin, GLUT2, KIR6.2, SUR1, and VDCC. Moreover, HIP increased insulin content and promoted the ability of HFPPCs to normalize blood glucose in diabetic mice. HIP inhibited the TF FOXO1 by increasing AKT-mediated phosphorylation. HIP-induced repression of FOXO1 suppressed menin expression, leading to reducing menin binding to the promoter of the three key proislet TFs, decreasing recruitment of H3K9 methyltransferase SUV39H1, and thus reducing repressive H3K9me3 at the promoter. These coordinated actions lead to increased expression of the proislet TFs, resulting in induction of HFPPC differentiation. Consistently, constitutive activation of FOXO1 blocks HIP-induced transcription of these TFs. Together, these studies unravel the crucial role of the HIP/AKT/FOXO/menin axis in epigenetically controlling expression of proislet TFs, regulating the differentiation of HFPPCs, and normalizing blood glucose in diabetic mice.
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2018-06-22T12:05:03-07:00
      DOI: 10.2337/db17-0885
      Issue No: Vol. 67, No. 7 (2018)
  • Modifying Enzymes Are Elicited by ER Stress, Generating Epitopes That Are
           Selectively Recognized by CD4+ T Cells in Patients With Type 1 Diabetes
    • Authors: Marre; M. L.; McGinty, J. W.; Chow, I.-T.; DeNicola, M. E.; Beck, N. W.; Kent, S. C.; Powers, A. C.; Bottino, R.; Harlan, D. M.; Greenbaum, C. J.; Kwok, W. W.; Piganelli, J. D.; James, E. A.
      Pages: 1356 - 1368
      Abstract: In spite of tolerance mechanisms, some individuals develop T-cell–mediated autoimmunity. Posttranslational modifications that increase the affinity of epitope presentation and/or recognition represent one means through which self-tolerance mechanisms can be circumvented. We investigated T-cell recognition of peptides that correspond to modified β-cell antigens in subjects with type 1 diabetes. Modified peptides elicited enhanced proliferation by autoreactive T-cell clones. Endoplasmic reticulum (ER) stress in insulinoma cells increased cytosolic calcium and the activity of tissue transglutaminase 2 (tTG2). Furthermore, stressed human islets and insulinomas elicited effector responses from T cells specific for modified peptides, suggesting that ER stress–derived tTG2 activity generated deamidated neoepitopes that autoreactive T cells recognized. Patients with type 1 diabetes had large numbers of T cells specific for these epitopes in their peripheral blood. T cells with these specificities were also isolated from the pancreatic draining lymph nodes of cadaveric donors with established diabetes. Together, these results suggest that self-antigens are enzymatically modified in β-cells during ER stress, giving rise to modified epitopes that could serve to initiate autoimmunity or to further broaden the antigenic repertoire, activating potentially pathogenic CD4+ T cells that may not be effectively eliminated by negative selection.
      Keywords: Immunology
      PubDate: 2018-06-22T12:05:03-07:00
      DOI: 10.2337/db17-1166
      Issue No: Vol. 67, No. 7 (2018)
  • Supplemental Oxygen Improves In Vivo Mitochondrial Oxidative
           Phosphorylation Flux in Sedentary Obese Adults With Type 2 Diabetes
    • Authors: Cree-Green; M.; Scalzo, R. L.; Harrall, K.; Newcomer, B. R.; Schauer, I. E.; Huebschmann, A. G.; McMillin, S.; Brown, M. S.; Orlicky, D.; Knaub, L.; Nadeau, K. J.; McClatchey, P. M.; Bauer, T. A.; Regensteiner, J. G.; Reusch, J. E. B.
      Pages: 1369 - 1379
      Abstract: Type 2 diabetes is associated with impaired exercise capacity. Alterations in both muscle perfusion and mitochondrial function can contribute to exercise impairment. We hypothesized that impaired muscle mitochondrial function in type 2 diabetes is mediated, in part, by decreased tissue oxygen delivery and would improve with oxygen supplementation. Ex vivo muscle mitochondrial content and respiration assessed from biopsy samples demonstrated expected differences in obese individuals with (n = 18) and without (n = 17) diabetes. Similarly, in vivo mitochondrial oxidative phosphorylation capacity measured in the gastrocnemius muscle via 31P-MRS indicated an impairment in the rate of ADP depletion with rest (27 ± 6 s [diabetes], 21 ± 7 s [control subjects]; P = 0.008) and oxidative phosphorylation (P = 0.046) in type 2 diabetes after isometric calf exercise compared with control subjects. Importantly, the in vivo impairment in oxidative capacity resolved with oxygen supplementation in adults with diabetes (ADP depletion rate 5.0 s faster, P = 0.012; oxidative phosphorylation 0.046 ± 0.079 mmol/L/s faster, P = 0.027). Multiple in vivo mitochondrial measures related to HbA1c. These data suggest that oxygen availability is rate limiting for in vivo mitochondrial oxidative exercise recovery measured with 31P-MRS in individuals with uncomplicated diabetes. Targeting muscle oxygenation could improve exercise function in type 2 diabetes.
      Keywords: Integrated Physiology-Muscle
      PubDate: 2018-06-22T12:05:03-07:00
      DOI: 10.2337/db17-1124
      Issue No: Vol. 67, No. 7 (2018)
  • MCP-1 Feedback Loop Between Adipocytes and Mesenchymal Stromal Cells
           Causes Fat Accumulation and Contributes to Hematopoietic Stem Cell
           Rarefaction in the Bone Marrow of Patients With Diabetes
    • Authors: Ferland-McCollough; D.; Maselli, D.; Spinetti, G.; Sambataro, M.; Sullivan, N.; Blom, A.; Madeddu, P.
      Pages: 1380 - 1394
      Abstract: Fat accumulates in bone marrow (BM) of patients with diabetes. In this study, we investigated the mechanisms and consequences of this phenomenon. BM mesenchymal stromal cells (BM-MSCs) from patients with type 2 diabetes (T2D) constitutively express adipogenic markers and robustly differentiate into adipocytes (ADs) upon in vitro induction as compared with BM-MSCs from subjects without diabetes. Moreover, BM-ADs from subjects with T2D (T2D BM-ADs) paracrinally stimulate a transcriptional adipogenic program in BM-MSCs. Antagonism of MCP-1, a chemokine pivotally expressed in T2D BM-ADs, prevented the T2D BM-AD secretome from converting BM-MSCs into ADs. Mechanistic validation of human data was next performed in an obese T2D mouse model. Systemic antagonism of MCP-1 improved metabolic control, reduced BM fat, and increased osteocyte density. It also indirectly re-established the abundance of long-term versus short-term hematopoietic stem cells. We reveal a diabetic feedback loop in which 1) BM-MSCs are constitutively inclined to make ADs, and 2) mature BM-ADs, via secreted MCP-1, relentlessly fuel BM-MSC determination into new fat. Pharmacological inhibition of MCP-1 signaling can contrast this vicious cycle, restoring, at least in part, the balance between adipogenesis and hematopoiesis in BM from subjects with T2D.
      Keywords: Insulin Action-Adipocyte Biology
      PubDate: 2018-06-22T12:05:03-07:00
      DOI: 10.2337/db18-0044
      Issue No: Vol. 67, No. 7 (2018)
  • Relation of Aortic Stiffness to Left Ventricular Remodeling in Younger
           Adults With Type 2 Diabetes
    • Authors: Gulsin; G. S.; Swarbrick, D. J.; Hunt, W. H.; Levelt, E.; Graham-Brown, M. P. M.; Parke, K. S.; Wormleighton, J. V.; Lai, F. Y.; Yates, T.; Wilmot, E. G.; Webb, D. R.; Davies, M. J.; McCann, G. P.
      Pages: 1395 - 1400
      Abstract: Individuals with type 2 diabetes have a three- to fivefold increased risk of developing heart failure. Diabetic cardiomyopathy is typified by left ventricular (LV) concentric remodeling, which is a recognized predictor of adverse cardiovascular events. Although the mechanisms underlying LV remodeling in type 2 diabetes are unclear, progressive aortic stiffening may be a key determinant. The aim of this study was to assess the relationship between aortic stiffness and LV geometry in younger adults with type 2 diabetes, using multiparametric cardiovascular MRI. We prospectively recruited 80 adults (aged 18–65 years) with type 2 diabetes and no cardiovascular disease and 20 age- and sex-matched healthy control subjects. All subjects underwent comprehensive bio-anthropometric assessment and cardiac MRI, including measurement of aortic stiffness by aortic distensibility (AD). Type 2 diabetes was associated with increased LV mass, concentric LV remodeling, and lower AD compared with control subjects. On multivariable linear regression, AD was independently associated with concentric LV remodeling in type 2 diabetes. Aortic stiffness may therefore be a potential therapeutic target to prevent the development of heart failure in type 2 diabetes.
      Keywords: Complications-Macrovascular-Atherosclerotic Cardiovascular Disease and Human Diabetes
      PubDate: 2018-06-22T12:05:03-07:00
      DOI: 10.2337/db18-0112
      Issue No: Vol. 67, No. 7 (2018)
  • GPR119 Agonism Increases Glucagon Secretion During Insulin-Induced
    • Authors: Li; N. X.; Brown, S.; Kowalski, T.; Wu, M.; Yang, L.; Dai, G.; Petrov, A.; Ding, Y.; Dlugos, T.; Wood, H. B.; Wang, L.; Erion, M.; Sherwin, R.; Kelley, D. E.
      Pages: 1401 - 1413
      Abstract: Insulin-induced hypoglycemia in diabetes is associated with impaired glucagon secretion. In this study, we tested whether stimulation of GPR119, a G-protein–coupled receptor expressed in pancreatic islet as well as enteroendocrine cells and previously shown to stimulate insulin and incretin secretion, might enhance glucagon secretion during hypoglycemia. In the study, GPR119 agonists were applied to isolated islets or perfused pancreata to assess insulin and glucagon secretion during hypoglycemic or hyperglycemic conditions. Insulin infusion hypoglycemic clamps were performed with or without GPR119 agonist pretreatment to assess glucagon counterregulation in healthy and streptozotocin (STZ)-induced diabetic rats, including those exposed to recurrent bouts of insulin-induced hypoglycemia that leads to suppression of hypoglycemia-induced glucagon release. Hypoglycemic clamp studies were also conducted in GPR119 knockout (KO) mice to evaluate whether the pharmacological stimulatory actions of GPR119 agonists on glucagon secretion during hypoglycemia were an on-target effect. The results revealed that GPR119 agonist-treated pancreata or cultured islets had increased glucagon secretion during low glucose perfusion. In vivo, GPR119 agonists also significantly increased glucagon secretion during hypoglycemia in healthy and STZ-diabetic rats, a response that was absent in GPR119 KO mice. In addition, impaired glucagon counterregulatory responses were restored by a GPR119 agonist in STZ-diabetic rats that were exposed to antecedent bouts of hypoglycemia. Thus, GPR119 agonists have the ability to pharmacologically augment glucagon secretion, specifically in response to hypoglycemia in diabetic rodents. Whether this effect might serve to diminish the occurrence and severity of iatrogenic hypoglycemia during intensive insulin therapy in patients with diabetes remains to be established.
      Keywords: Clinical Therapeutics/New Technology-Pharmacological Treatment of Complications
      PubDate: 2018-06-22T12:05:04-07:00
      DOI: 10.2337/db18-0031
      Issue No: Vol. 67, No. 7 (2018)
  • A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects
           With Type 2 Diabetes
    • Authors: van Zuydam; N. R.; Ahlqvist, E.; Sandholm, N.; Deshmukh, H.; Rayner, N. W.; Abdalla, M.; Ladenvall, C.; Ziemek, D.; Fauman, E.; Robertson, N. R.; McKeigue, P. M.; Valo, E.; Forsblom, C.; Harjutsalo, V.; Finnish Diabetic Nephropathy Study (FinnDiane); Perna, A.; Rurali, E.; Marcovecchio, M. L.; Igo, R. P.; Salem, R. M.; Perico, N.; Lajer, M.; Käräjämäki, A.; Imamura, M.; Kubo, M.; Takahashi, A.; Sim, X.; Liu, J.; van Dam, R. M.; Jiang, G.; Tam, C. H. T.; Luk, A. O. Y.; Lee, H. M.; Lim, C. K. P.; Szeto, C. C.; So, W. Y.; Chan, J. C. N.; Hong Kong Diabetes Registry Theme-based Research Scheme Project Group; Ang, S. F.; Dorajoo, R.; Wang, L.; Clara, T. S. H.; McKnight, A.-J.; Duffy, S.; Warren 3 Macrovascular hard endpoints for Innovative diabetes Tools (SUMMIT) Consortium; Brosnan, M. J.; Palmer, C. N. A.; Groop, P.-H.; Colhoun, H. M.; Groop, L. C.; McCarthy, M. I.
      Pages: 1414 - 1427
      Abstract: Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10–8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
      Keywords: Complications-Macrovascular-Cellular Mechanisms of Atherogenesis in Diabetes
      PubDate: 2018-06-22T12:05:04-07:00
      DOI: 10.2337/db17-0914
      Issue No: Vol. 67, No. 7 (2018)
  • Genetic Variants in CPA6 and PRPF31 Are Associated With Variation in
           Response to Metformin in Individuals With Type 2 Diabetes
    • Authors: Rotroff; D. M.; Yee, S. W.; Zhou, K.; Marvel, S. W.; Shah, H. S.; Jack, J. R.; Havener, T. M.; Hedderson, M. M.; Kubo, M.; Herman, M. A.; Gao, H.; Mychaleckyi, J. C.; McLeod, H. L.; Doria, A.; Giacomini, K. M.; Pearson, E. R.; Wagner, M. J.; Buse, J. B.; Motsinger-Reif, A. A.; MetGen Investigators; ACCORD/ACCORDion Investigators
      Pages: 1428 - 1440
      Abstract: Metformin is the first-line treatment for type 2 diabetes (T2D). Although widely prescribed, the glucose-lowering mechanism for metformin is incompletely understood. Here, we used a genome-wide association approach in a diverse group of individuals with T2D from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial to identify common and rare variants associated with HbA1c response to metformin treatment and followed up these findings in four replication cohorts. Common variants in PRPF31 and CPA6 were associated with worse and better metformin response, respectively (P < 5 x 10–6), and meta-analysis in independent cohorts displayed similar associations with metformin response (P = 1.2 x 10–8 and P = 0.005, respectively). Previous studies have shown that PRPF31(+/–) knockout mice have increased total body fat (P = 1.78 x 10–6) and increased fasted circulating glucose (P = 5.73 x 10–6). Furthermore, rare variants in STAT3 associated with worse metformin response (q
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2018-06-22T12:05:04-07:00
      DOI: 10.2337/db17-1164
      Issue No: Vol. 67, No. 7 (2018)
  • mtDNA Haplogroup N9a Increases the Risk of Type 2 Diabetes by Altering
           Mitochondrial Function and Intracellular Mitochondrial Signals
    • Authors: Fang; H.; Hu, N.; Zhao, Q.; Wang, B.; Zhou, H.; Fu, Q.; Shen, L.; Chen, X.; Shen, F.; Lyu, J.
      Pages: 1441 - 1453
      Abstract: Mitochondrial DNA (mtDNA) haplogroups have been associated with the incidence of type 2 diabetes (T2D); however, their underlying role in T2D remains poorly elucidated. Here, we report that mtDNA haplogroup N9a was associated with an increased risk of T2D occurrence in Southern China (odds ratio 1.999 [95% CI 1.229–3.251], P = 0.005). By using transmitochondrial technology, we demonstrated that the activity of respiratory chain complexes was lower in the case of mtDNA haplogroup N9a (N9a1 and N9a10a) than in three non-N9a haplogroups (D4j, G3a2, and Y1) and that this could lead to alterations in mitochondrial function and mitochondrial redox status. Transcriptome analysis revealed that OXPHOS function and metabolic regulation differed markedly between N9a and non-N9a cybrids. Furthermore, in N9a cybrids, insulin-stimulated glucose uptake might be inhibited at least partially through enhanced stimulation of ERK1/2 phosphorylation and subsequent TLR4 activation, which was found to be mediated by the elevated redox status in N9a cybrids. Although it remains unclear whether other signaling pathways (e.g., Wnt pathway) contribute to the T2D susceptibility of haplogroup N9a, our data indicate that in the case of mtDNA haplogroup N9a, T2D is affected, at least partially through ERK1/2 overstimulation and subsequent TLR4 activation.
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2018-06-22T12:05:04-07:00
      DOI: 10.2337/db17-0974
      Issue No: Vol. 67, No. 7 (2018)
  • Issues and Events
    • Pages: 1454 - 1454
      PubDate: 2018-06-22T12:05:04-07:00
      DOI: 10.2337/db18-ie07
      Issue No: Vol. 67, No. 7 (2018)
School of Mathematical and Computer Sciences
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