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Journal Cover Diabetes
  [SJR: 5.185]   [H-I: 269]   [412 followers]  Follow
    
   Full-text available via subscription Subscription journal
   ISSN (Print) 0012-1797 - ISSN (Online) 1939-327X
   Published by American Diabetes Association Homepage  [4 journals]
  • In This Issue of Diabetes
    • Pages: 2727 - 2728
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db17-ti11
      Issue No: Vol. 66, No. 11 (2017)
       
  • The Gastrointestinal Tract as an Integrator of Mechanical and Hormonal
           Response to Nutrient Ingestion
    • Authors: Vella; A.; Camilleri, M.
      Pages: 2729 - 2737
      Abstract: Glucose tolerance after meal ingestion in vivo is the result of multiple processes that occur in parallel. Insulin secretion together with reciprocal inhibition of glucagon secretion contributes to glucose tolerance. However, other factors beyond glucose effectiveness and insulin action require consideration. The absorption of ingested nutrients and their subsequent systemic rate of appearance largely depend on the rate of delivery of nutrients to the proximal small intestine. This is determined by the integrated response of the upper gastrointestinal tract to a meal. While gastric emptying is probably the most significant component, other factors need to be considered. This review will examine all processes that could potentially alter the fraction and rate of appearance of ingested nutrients in the peripheral circulation. Several of these processes may be potential therapeutic targets for the prevention and treatment of diabetes. Indeed, there is increased interest in gastrointestinal contributions to nutritional homeostasis, as demonstrated by the advent of antidiabetes therapies that alter gastrointestinal motility, the effect of bariatric surgery on diabetes remission, and the potential of the intestinal microbiome as a modulator of human metabolism. The overall goal of this review is to examine current knowledge of the gastrointestinal contributions to metabolic control.
      Keywords: Integrated Physiology-Macronutrient Metabolism and Food Intake
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/dbi17-0021
      Issue No: Vol. 66, No. 11 (2017)
       
  • Area IV Knockout Reveals How Pdx1 Is Regulated in Postnatal {beta}-Cell
           Development
    • Authors: Cox; A. R.; Kushner, J. A.
      Pages: 2738 - 2740
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/dbi17-0036
      Issue No: Vol. 66, No. 11 (2017)
       
  • Give GWAS a Chance
    • Authors: Meyre D.
      Pages: 2741 - 2742
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/dbi17-0026
      Issue No: Vol. 66, No. 11 (2017)
       
  • Fatty Acid Metabolic Remodeling During Type 2 Diabetes Remission After
           Bariatric Surgery
    • Authors: Grenier-Larouche; T.; Carreau, A.-M.; Geloën, A.; Frisch, F.; Biertho, L.; Marceau, S.; Lebel, S.; Hould, F.-S.; Richard, D.; Tchernof, A.; Carpentier, A. C.
      Pages: 2743 - 2755
      Abstract: Hypertrophic remodeling of white adipose tissues is associated with overexposure of lean organs to circulating triglycerides (TGs) and nonesterified fatty acids (NEFAs), ultimately leading to insulin resistance. Bariatric surgery promotes type 2 diabetes (T2D) remission through a succession of weight loss–dependent and –independent mechanisms. However, the longitudinal contribution of adipocyte size reduction and fatty acid metabolic handling remain unknown. Here we show that severely obese participants with T2D display hypertriglyceridemia and excessive systemic lipolysis during intravenous lipid overload. Three days after biliopancreatic diversion with duodenal switch (DS), whole-body glycerol turnover was normalized and associated with lower HOMA–insulin resistance index. A mean excess weight loss of 84% was achieved 12 months after DS. The smaller subcutaneous adipocyte size predicted better glycemic control in T2D. TG disposal and acylcarnitine production during lipid overload, along with muscle insulin sensitivity, improved with weight loss. Nevertheless, systemic NEFA fluxes and NEFA spillover remained similar, suggesting that increased NEFA storage capacity per volume of adipose tissue exactly compensated for the decrease in fat mass during weight loss. In conclusion, T2D remission after DS is mainly associated with greater circulating TG disposal, lower systemic lipolysis, and better fatty acid handling by lean tissues.
      Keywords: Integrated Physiology-Macronutrient Metabolism and Food Intake
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db17-0414
      Issue No: Vol. 66, No. 11 (2017)
       
  • Downregulation of Insulin Sensitivity After Oral Glucose Administration:
           Evidence for the Anti-Incretin Effect
    • Authors: Salinari; S.; Mingrone, G.; Bertuzzi, A.; Previti, E.; Capristo, E.; Rubino, F.
      Pages: 2756 - 2763
      Abstract: Intestinal nutrients stimulate insulin secretion more potently than intravenous (IV) glucose administration under similar plasma glucose levels (incretin effect). According to the anti-incretin theory, intestinal nutrients should also cause a reduction of insulin sensitivity and/or secretion (anti-incretin effect) to defend against hyperinsulinemia-hypoglycemia. An exaggerated anti-incretin effect could contribute to insulin resistance/type 2 diabetes, whereas reduction of anti-incretin signals might explain diabetes improvement after bariatric surgery. In this study, we tested some of the predictions made by the anti-incretin theory. Eight healthy volunteers and eight severely obese subjects with insulin resistance were studied. Insulin secretion, insulin sensitivity, Ra, and disposition index were measured after oral glucose tolerance test and isoglycemic IV glucose injection (IGIV). Obese subjects were studied before and after intestinal bypass surgery (biliopancreatic diversion [BPD]). The d-xylose test and lactulose-to-rhamnose ratio were used to test for possible malabsorption of glucose after surgery. Monte Carlo mathematical simulations were used to test whether insulin secretion induced by oral glucose could cause hypoglycemia when coupled with the levels of insulin sensitivity measured during IGIV. Despite isoglycemic conditions, insulin sensitivity was lower during oral than during IV glucose administration. This difference was amplified in obese subjects and reduced to normal after BPD. No evidence of glucose malabsorption was found. Mathematical simulations showed that hypoglycemia would occur if insulin sensitivity were not reduced by oral glucose stimulation. This study demonstrates an anti-incretin effect of intestinal glucose stimulation, which downregulates insulin sensitivity. The findings support a new model for how foodborne factors can induce insulin-resistance and provide a possible explanation for the improvement of insulin resistance/diabetes after gastrointestinal bypass surgery.
      Keywords: Insulin Action-Cellular and Molecular Metabolism
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db17-0234
      Issue No: Vol. 66, No. 11 (2017)
       
  • Opioid Receptor Activation Impairs Hypoglycemic Counterregulation in
           Humans
    • Authors: Carey; M.; Gospin, R.; Goyal, A.; Tomuta, N.; Sandu, O.; Mbanya, A.; Lontchi-Yimagou, E.; Hulkower, R.; Shamoon, H.; Gabriely, I.; Hawkins, M.
      Pages: 2764 - 2773
      Abstract: Although intensive glycemic control improves outcomes in type 1 diabetes mellitus (T1DM), iatrogenic hypoglycemia limits its attainment. Recurrent and/or antecedent hypoglycemia causes blunting of protective counterregulatory responses, known as hypoglycemia-associated autonomic failure (HAAF). To determine whether and how opioid receptor activation induces HAAF in humans, 12 healthy subjects without diabetes (7 men, age 32.3 ± 2.2 years, BMI 25.1 ± 1.0 kg/m2) participated in two study protocols in random order over two consecutive days. On day 1, subjects received two 120-min infusions of either saline or morphine (0.1 μg/kg/min), separated by a 120-min break (all euglycemic). On day 2, subjects underwent stepped hypoglycemic clamps (nadir 60 mg/dL) with evaluation of counterregulatory hormonal responses, endogenous glucose production (EGP, using 6,6-D2-glucose), and hypoglycemic symptoms. Morphine induced an ~30% reduction in plasma epinephrine response together with reduced EGP and hypoglycemia-associated symptoms on day 2. Therefore, we report the first studies in humans demonstrating that pharmacologic opioid receptor activation induces some of the clinical and biochemical features of HAAF, thus elucidating the individual roles of various receptors involved in HAAF’s development and suggesting novel pharmacologic approaches for safer intensive glycemic control in T1DM.
      Keywords: Complications-Hypoglycemia
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db16-1478
      Issue No: Vol. 66, No. 11 (2017)
       
  • Growth Differentiation Factor 15 Mediates Systemic Glucose Regulatory
           Action of T-Helper Type 2 Cytokines
    • Authors: Lee; S. E.; Kang, S. G.; Choi, M. J.; Jung, S.-B.; Ryu, M. J.; Chung, H. K.; Chang, J. Y.; Kim, Y. K.; Lee, J. H.; Kim, K. S.; Kim, H. J.; Lee, H. K.; Yi, H.-S.; Shong, M.
      Pages: 2774 - 2788
      Abstract: T-helper type 2 (Th2) cytokines, including interleukin (IL)-13 and IL-4, produced in adipose tissue, are critical regulators of intra-adipose and systemic lipid and glucose metabolism. Furthermore, IL-13 is a potential therapy for insulin resistance in obese mouse models. Here, we examined mediators produced by adipocytes that are responsible for regulating systemic glucose homeostasis in response to Th2 cytokines. We used RNA sequencing data analysis of cultured adipocytes to screen factors secreted in response to recombinant IL-13. Recombinant IL-13 induced expression of growth differentiation factor 15 (GDF15) via the Janus kinase-activated STAT6 pathway. In vivo administration of α-galactosylceramide or IL-33 increased IL-4 and IL-13 production, thereby increasing GDF15 levels in adipose tissue and in plasma of mice; however, these responses were abrogated in STAT6 knockout mice. Moreover, administration of recombinant IL-13 to wild-type mice fed a high-fat diet (HFD) improved glucose intolerance; this was not the case for GDF15 knockout mice fed the HFD. Taken together, these data suggest that GDF15 is required for IL-13–induced improvement of glucose intolerance in mice fed an HFD. Thus, beneficial effects of Th2 cytokines on systemic glucose metabolism and insulin sensitivity are mediated by GDF15. These findings open up a potential pharmacological route for reversing insulin resistance associated with obesity.
      Keywords: Integrated Physiology-Other Hormones
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db17-0333
      Issue No: Vol. 66, No. 11 (2017)
       
  • Hepatic GALE Regulates Whole-Body Glucose Homeostasis by Modulating Tff3
           Expression
    • Authors: Zhu; Y.; Zhao, S.; Deng, Y.; Gordillo, R.; Ghaben, A. L.; Shao, M.; Zhang, F.; Xu, P.; Li, Y.; Cao, H.; Zagnitko, O.; Scott, D. A.; Gupta, R. K.; Xing, C.; Zhang, B. B.; Lin, H. V.; Scherer, P. E.
      Pages: 2789 - 2799
      Abstract: Transcripts of key enzymes in the Leloir pathway of galactose metabolism in mouse livers are significantly increased after chronic high-fat/high-sucrose feeding. UDP-galactose-4-epimerase (GALE) is the last enzyme in this pathway that converts UDP-galactose to UDP-glucose and was previously identified as a downstream target of the endoplasmic reticulum (ER) stress effector spliced X-box binding protein 1, suggesting an interesting cross talk between galactose and glucose metabolism in the context of hepatic ER stress and whole-body metabolic fitness. However, its specific role in glucose metabolism is not established. Using an inducible and tissue-specific mouse model, we report that hepatic overexpression of Gale increases gluconeogenesis from pyruvate and impairs glucose tolerance. Conversely, genetic reduction of Gale in liver improves glucose tolerance. Transcriptional profiling identifies trefoil factor 3 (Tff3) as one of the downstream targets of GALE. Restoration of Tff3 expression corrects glucose intolerance in Gale-overexpressing mice. These studies reveal a new link between hepatic GALE activity and whole-body glucose homeostasis via regulation of hepatic Tff3 expression.
      Keywords: Integrated Physiology-Liver
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db17-0323
      Issue No: Vol. 66, No. 11 (2017)
       
  • Hypoxia in Combination With Muscle Contraction Improves Insulin Action and
           Glucose Metabolism in Human Skeletal Muscle via the HIF-1{alpha} Pathway
    • Authors: Görgens; S. W.; Benninghoff, T.; Eckardt, K.; Springer, C.; Chadt, A.; Melior, A.; Wefers, J.; Cramer, A.; Jensen, J.; Birkeland, K. I.; Drevon, C. A.; Al-Hasani, H.; Eckel, J.
      Pages: 2800 - 2807
      Abstract: Skeletal muscle insulin resistance is the hallmark of type 2 diabetes and develops long before the onset of the disease. It is well accepted that physical activity improves glycemic control, but the knowledge on underlying mechanisms mediating the beneficial effects remains incomplete. Exercise is accompanied by a decrease in intramuscular oxygen levels, resulting in induction of HIF-1α. HIF-1α is a master regulator of gene expression and might play an important role in skeletal muscle function and metabolism. Here we show that HIF-1α is important for glucose metabolism and insulin action in skeletal muscle. By using a genome-wide gene expression profiling approach, we identified RAB20 and TXNIP as two novel exercise/HIF-1α–regulated genes in skeletal muscle. Loss of Rab20 impairs insulin-stimulated glucose uptake in human and mouse skeletal muscle by blocking the translocation of GLUT4 to the cell surface. In addition, exercise/HIF-1α downregulates the expression of TXNIP, a well-known negative regulator of insulin action. In conclusion, we are the first to demonstrate that HIF-1α is a key regulator of glucose metabolism in skeletal muscle by directly controlling the transcription of RAB20 and TXNIP. These results hint toward a novel function of HIF-1α as a potential pharmacological target to improve skeletal muscle insulin sensitivity.
      Keywords: Integrated Physiology-Muscle
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db16-1488
      Issue No: Vol. 66, No. 11 (2017)
       
  • Endothelial SHIP2 Suppresses Nox2 NADPH Oxidase-Dependent Vascular
           Oxidative Stress, Endothelial Dysfunction, and Systemic Insulin Resistance
           
    • Authors: Watt; N. T.; Gage, M. C.; Patel, P. A.; Viswambharan, H.; Sukumar, P.; Galloway, S.; Yuldasheva, N. Y.; Imrie, H.; Walker, A. M. N.; Griffin, K. J.; Makava, N.; Skromna, A.; Bridge, K.; Beech, D. J.; Schurmans, S.; Wheatcroft, S. B.; Kearney, M. T.; Cubbon, R. M.
      Pages: 2808 - 2821
      Abstract: Shc homology 2–containing inositol 5' phosphatase-2 (SHIP2) is a lipid phosphatase that inhibits insulin signaling downstream of phosphatidylinositol 3-kinase (PI3K); its role in vascular function is poorly understood. To examine its role in endothelial cell (EC) biology, we generated mice with catalytic inactivation of one SHIP2 allele selectively in ECs (ECSHIP2/+). Hyperinsulinemic-euglycemic clamping studies revealed that ECSHIP2/+ was resistant to insulin-stimulated glucose uptake in adipose tissue and skeletal muscle compared with littermate controls. ECs from ECSHIP2/+ mice had increased basal expression and activation of PI3K downstream targets, including Akt and endothelial nitric oxide synthase, although incremental activation by insulin and shear stress was impaired. Insulin-mediated vasodilation was blunted in ECSHIP2/+ mice, as was aortic nitric oxide bioavailability. Acetylcholine-induced vasodilation was also impaired in ECSHIP2/+ mice, which was exaggerated in the presence of a superoxide dismutase/catalase mimetic. Superoxide abundance was elevated in ECSHIP2/+ ECs and was suppressed by PI3K and NADPH oxidase 2 inhibitors. These findings were phenocopied in healthy human ECs after SHIP2 silencing. Our data suggest that endothelial SHIP2 is required to maintain normal systemic glucose homeostasis and prevent oxidative stress-induced endothelial dysfunction.
      Keywords: Insulin Action-Signal Transduction, Insulin, and Other Hormones
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db17-0062
      Issue No: Vol. 66, No. 11 (2017)
       
  • Tbx15 Defines a Glycolytic Subpopulation and White Adipocyte Heterogeneity
    • Authors: Lee; K. Y.; Sharma, R.; Gase, G.; Ussar, S.; Li, Y.; Welch, L.; Berryman, D. E.; Kispert, A.; Bluher, M.; Kahn, C. R.
      Pages: 2822 - 2829
      Abstract: Tbx15 is a member of the T-box gene family of mesodermal developmental genes. We have recently shown that Tbx15 plays a critical role in the formation and metabolic programming of glycolytic myofibers in skeletal muscle. Tbx15 is also differentially expressed among white adipose tissue (WAT) in different body depots. In the current study, using three independent methods, we show that even within a single WAT depot, high Tbx15 expression is restricted to a subset of preadipocytes and mature white adipocytes. Gene expression and metabolic profiling demonstrate that the Tbx15Hi preadipocyte and adipocyte subpopulations of cells are highly glycolytic, whereas Tbx15Low preadipocytes and adipocytes in the same depot are more oxidative and less glycolytic. Likewise, in humans, expression of TBX15 in subcutaneous and visceral WAT is positively correlated with markers of glycolytic metabolism and inversely correlated with obesity. Furthermore, overexpression of Tbx15 is sufficient to reduce oxidative and increase glycolytic metabolism in cultured adipocytes. Thus, Tbx15 differentially regulates oxidative and glycolytic metabolism within subpopulations of white adipocytes and preadipocytes. This leads to a functional heterogeneity of cellular metabolism within WAT that has potential impact in the understanding of human metabolic diseases.
      Keywords: Obesity-Human
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db17-0218
      Issue No: Vol. 66, No. 11 (2017)
       
  • Defining a Novel Role for the Pdx1 Transcription Factor in Islet
           {beta}-Cell Maturation and Proliferation During Weaning
    • Authors: Spaeth; J. M.; Gupte, M.; Perelis, M.; Yang, Y.-P.; Cyphert, H.; Guo, S.; Liu, J.-H.; Guo, M.; Bass, J.; Magnuson, M. A.; Wright, C.; Stein, R.
      Pages: 2830 - 2839
      Abstract: The transcription factor encoded by the Pdx1 gene is a critical transcriptional regulator, as it has fundamental actions in the formation of all pancreatic cell types, islet β-cell development, and adult islet β-cell function. Transgenic- and cell line–based experiments have identified 5'-flanking conserved sequences that control pancreatic and β-cell type–specific transcription, which are found within areas I (bp –2694 to –2561), II (bp –2139 to –1958), III (bp –1879 to –1799), and IV (bp –6200 to –5670). Because of the presence in area IV of binding sites for transcription factors associated with pancreas development and islet cell function, we analyzed how an endogenous deletion mutant affected Pdx1 expression embryonically and postnatally. The most striking result was observed in male Pdx1IV mutant mice after 3 weeks of birth (i.e., the onset of weaning), with only a small effect on pancreas organogenesis and no deficiencies in their female counterparts. Compromised Pdx1 mRNA and protein levels in weaned male mutant β-cells were tightly linked with hyperglycemia, decreased β-cell proliferation, reduced β-cell area, and altered expression of Pdx1-bound genes that are important in β-cell replication, endoplasmic reticulum function, and mitochondrial activity. We discuss the impact of these novel findings to Pdx1 gene regulation and islet β-cell maturation postnatally.
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db16-1516
      Issue No: Vol. 66, No. 11 (2017)
       
  • Atrial Natriuretic Peptide Affects Stimulus-Secretion Coupling of
           Pancreatic {beta}-Cells
    • Authors: Undank; S.; Kaiser, J.; Sikimic, J.; Düfer, M.; Krippeit-Drews, P.; Drews, G.
      Pages: 2840 - 2848
      Abstract: Atrial natriuretic peptide (ANP) influences glucose homeostasis and possibly acts as a link between the cardiovascular system and metabolism, especially in metabolic disorders like diabetes. The current study evaluated effects of ANP on β-cell function by the use of a β-cell–specific knockout of the ANP receptor with guanylate cyclase activity (βGC-A-KO). ANP augmented insulin secretion at the threshold glucose concentration of 6 mmol/L and decreased KATP single-channel activity in β-cells of control mice but not of βGC-A-KO mice. In wild-type β-cells but not β-cells lacking functional KATP channels (SUR1-KO), ANP increased electrical activity, suggesting no involvement of other ion channels. At 6 mmol/L glucose, ANP readily elicited Ca2+ influx in control β-cells. This effect was blunted in β-cells of βGC-A-KO mice, and the maximal cytosolic Ca2+ concentration was lower. Experiments with inhibitors of protein kinase G (PKG), protein kinase A (PKA), phosphodiesterase 3B (PDE3B), and a membrane-permeable cyclic guanosine monophosphate (cGMP) analog on KATP channel activity and insulin secretion point to participation of the cGMP/PKG and cAMP/PKA/Epac (exchange protein directly activated by cAMP) directly activated by cAMP Epac pathways in the effects of ANP on β-cell function; the latter seems to prevail. Moreover, ANP potentiated the effect of glucagon-like peptide 1 (GLP-1) on glucose-induced insulin secretion, which could be caused by a cGMP-mediated inhibition of PDE3B, which in turn reduces cAMP degradation.
      Keywords: Islet Biology-Signal Transduction
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db17-0392
      Issue No: Vol. 66, No. 11 (2017)
       
  • The Myokine Irisin Is Released in Response to Saturated Fatty Acids and
           Promotes Pancreatic {beta}-Cell Survival and Insulin Secretion
    • Authors: Natalicchio; A.; Marrano, N.; Biondi, G.; Spagnuolo, R.; Labarbuta, R.; Porreca, I.; Cignarelli, A.; Bugliani, M.; Marchetti, P.; Perrini, S.; Laviola, L.; Giorgino, F.
      Pages: 2849 - 2856
      Abstract: This study explored the role of irisin as a new pancreatic β-cell secretagogue and survival factor and its potential role in the communication between skeletal muscle and pancreatic β-cells under lipotoxic conditions. Recombinant irisin stimulated insulin biosynthesis and glucose-stimulated insulin secretion (GSIS) in a PKA-dependent manner and prevented saturated fatty acid–induced apoptosis in human and rat pancreatic β-cells, as well as in human and murine pancreatic islets, via AKT/BCL2 signaling. Treatment of myotubes with 0.5 mmol/L palmitate for 4 h, but not with oleate, promoted an increase in irisin release in the culture medium. Moreover, increased serum levels of irisin were observed in mice fed with a high-fat diet. Mouse serum rich in irisin and the conditioned medium from myotubes exposed to palmitate for 4 h significantly reduced apoptosis of murine pancreatic islets and insulin-secreting INS-1E cells, respectively, and this was abrogated in the presence of an irisin-neutralizing antibody. Finally, in vivo administration of irisin improved GSIS and increased β-cell proliferation. In conclusion, irisin can promote β-cell survival and enhance GSIS and may thus participate in the communication between skeletal muscle and β-cells under conditions of excess saturated fatty acids.
      Keywords: Integrated Physiology-Other Hormones
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db17-0002
      Issue No: Vol. 66, No. 11 (2017)
       
  • Pancreatic {beta}-Cell-Derived IP-10/CXCL10 Isletokine Mediates Early Loss
           of Graft Function in Islet Cell Transplantation
    • Authors: Yoshimatsu; G.; Kunnathodi, F.; Saravanan, P. B.; Shahbazov, R.; Chang, C.; Darden, C. M.; Zurawski, S.; Boyuk, G.; Kanak, M. A.; Levy, M. F.; Naziruddin, B.; Lawrence, M. C.
      Pages: 2857 - 2867
      Abstract: Pancreatic islets produce and secrete cytokines and chemokines in response to inflammatory and metabolic stress. The physiological role of these "isletokines" in health and disease is largely unknown. We observed that islets release multiple inflammatory mediators in patients undergoing islet transplants within hours of infusion. The proinflammatory cytokine interferon-–induced protein 10 (IP-10/CXCL10) was among the highest released, and high levels correlated with poor islet transplant outcomes. Transgenic mouse studies confirmed that donor islet–specific expression of IP-10 contributed to islet inflammation and loss of β-cell function in islet grafts. The effects of islet-derived IP-10 could be blocked by treatment of donor islets and recipient mice with anti–IP-10 neutralizing monoclonal antibody. In vitro studies showed induction of the IP-10 gene was mediated by calcineurin-dependent NFAT signaling in pancreatic β-cells in response to oxidative or inflammatory stress. Sustained association of NFAT and p300 histone acetyltransferase with the IP-10 gene required p38 and c-Jun N-terminal kinase mitogen-activated protein kinase (MAPK) activity, which differentially regulated IP-10 expression and subsequent protein release. Overall, these findings elucidate an NFAT-MAPK signaling paradigm for induction of isletokine expression in β-cells and reveal IP-10 as a primary therapeutic target to prevent β-cell–induced inflammatory loss of graft function after islet cell transplantation.
      Keywords: Islet Biology-Signal Transduction
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db17-0578
      Issue No: Vol. 66, No. 11 (2017)
       
  • Long-term Hyperglycemia Naturally Induces Dental Caries but Not
           Periodontal Disease in Type 1 and Type 2 Diabetic Rodents
    • Authors: Nakahara; Y.; Ozaki, K.; Matsuura, T.
      Pages: 2868 - 2874
      Abstract: Periodontal disease (PD) in patients with diabetes is described as the sixth complication of diabetes. We have previously shown that diabetes increases dental caries, and carious inflammation might have a strong effect on the adjacent periodontal tissue in diabetic rodent models. However, the possibility that hyperglycemia may induce PD in diabetic animals could not be completely eliminated. The goal of this study was to confirm the presence of PD in diabetic animal models by preventing carious inflammation with fluoride administration. F344 rats injected with alloxan (type 1 diabetic model) and db/db mice (type 2 diabetic model) were given either tap water alone or tap water containing fluoride. A cariostatic effect of fluoride was evident in the diabetic animals. Meanwhile, fluoride treatment drastically attenuated periodontal inflammation in addition to preventing dental caries. Furthermore, with fluoride treatment, periodontitis was notably nonexistent in the periodontal tissue surrounding the normal molars, whereas the caries-forming process was clearly observed in the teeth that were enveloped with persistent periodontitis, suggesting that enhanced periodontal inflammation might have been derived from the dental caries in the diabetic rodents rather than from the PD. In conclusion, long-term hyperglycemia naturally induces dental caries but not PD in type 1 and type 2 diabetic rodents.
      Keywords: Diabetes Education
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db17-0291
      Issue No: Vol. 66, No. 11 (2017)
       
  • Inhibition of 12/15-Lipoxygenase Protects Against {beta}-Cell Oxidative
           Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes
    • Authors: Hernandez-Perez; M.; Chopra, G.; Fine, J.; Conteh, A. M.; Anderson, R. M.; Linnemann, A. K.; Benjamin, C.; Nelson, J. B.; Benninger, K. S.; Nadler, J. L.; Maloney, D. J.; Tersey, S. A.; Mirmira, R. G.
      Pages: 2875 - 2887
      Abstract: Islet β-cell dysfunction and aggressive macrophage activity are early features in the pathogenesis of type 1 diabetes (T1D). 12/15-Lipoxygenase (12/15-LOX) is induced in β-cells and macrophages during T1D and produces proinflammatory lipids and lipid peroxides that exacerbate β-cell dysfunction and macrophage activity. Inhibition of 12/15-LOX provides a potential therapeutic approach to prevent glycemic deterioration in T1D. Two inhibitors recently identified by our groups through screening efforts, ML127 and ML351, have been shown to selectively target 12/15-LOX with high potency. Only ML351 exhibited no apparent toxicity across a range of concentrations in mouse islets, and molecular modeling has suggested reduced promiscuity of ML351 compared with ML127. In mouse islets, incubation with ML351 improved glucose-stimulated insulin secretion in the presence of proinflammatory cytokines and triggered gene expression pathways responsive to oxidative stress and cell death. Consistent with a role for 12/15-LOX in promoting oxidative stress, its chemical inhibition reduced production of reactive oxygen species in both mouse and human islets in vitro. In a streptozotocin-induced model of T1D in mice, ML351 prevented the development of diabetes, with coincident enhancement of nuclear Nrf2 in islet cells, reduced β-cell oxidative stress, and preservation of β-cell mass. In the nonobese diabetic mouse model of T1D, administration of ML351 during the prediabetic phase prevented dysglycemia, reduced β-cell oxidative stress, and increased the proportion of anti-inflammatory macrophages in insulitis. The data provide the first evidence to date that small molecules that target 12/15-LOX can prevent progression of β-cell dysfunction and glycemic deterioration in models of T1D.
      Keywords: Islet Biology-Apoptosis
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db17-0215
      Issue No: Vol. 66, No. 11 (2017)
       
  • An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
    • Authors: Scott; R. A.; Scott, L. J.; Mägi, R.; Marullo, L.; Gaulton, K. J.; Kaakinen, M.; Pervjakova, N.; Pers, T. H.; Johnson, A. D.; Eicher, J. D.; Jackson, A. U.; Ferreira, T.; Lee, Y.; Ma, C.; Steinthorsdottir, V.; Thorleifsson, G.; Qi, L.; Van Zuydam, N. R.; Mahajan, A.; Chen, H.; Almgren, P.; Voight, B. F.; Grallert, H.; Müller-Nurasyid, M.; Ried, J. S.; Rayner, N. W.; Robertson, N.; Karssen, L. C.; van Leeuwen, E. M.; Willems, S. M.; Fuchsberger, C.; Kwan, P.; Teslovich, T. M.; Chanda, P.; Li, M.; Lu, Y.; Dina, C.; Thuillier, D.; Yengo, L.; Jiang, L.; Sparso, T.; Kestler, H. A.; Chheda, H.; Eisele, L.; Gustafsson, S.; Franberg, M.; Strawbridge, R. J.; Benediktsson, R.; Hreidarsson, A. B.; Kong, A.; Sigurthsson, G.; Kerrison, N. D.; Luan, J.; Liang, L.; Meitinger, T.; Roden, M.; Thorand, B.; Esko, T.; Mihailov, E.; Fox, C.; Liu, C.-T.; Rybin, D.; Isomaa, B.; Lyssenko, V.; Tuomi, T.; Couper, D. J.; Pankow, J. S.; Grarup, N.; Have, C. T.; Jorgensen, M. E.; Jorgensen, T.; Linneberg, A.; Cornelis, M. C.; van Dam, R. M.; Hunter, D. J.; Kraft, P.; Sun, Q.; Edkins, S.; Owen, K. R.; Perry, J. R. B.; Wood, A. R.; Zeggini, E.; Tajes-Fernandes, J.; Abecasis, G. R.; Bonnycastle, L. L.; Chines, P. S.; Stringham, H. M.; Koistinen, H. A.; Kinnunen, L.; Sennblad, B.; Mühleisen, T. W.; Nöthen, M. M.; Pechlivanis, S.; Baldassarre, D.; Gertow, K.; Humphries, S. E.; Tremoli, E.; Klopp, N.; Meyer, J.; Steinbach, G.; Wennauer, R.; Eriksson, J. G.; Männistö, S.; Peltonen, L.; Tikkanen, E.; Charpentier, G.; Eury, E.; Lobbens, S.; Gigante, B.; Leander, K.; McLeod, O.; Bottinger, E. P.; Gottesman, O.; Ruderfer, D.; Blüher, M.; Kovacs, P.; Tonjes, A.; Maruthur, N. M.; Scapoli, C.; Erbel, R.; Jöckel, K.-H.; Moebus, S.; de Faire, U.; Hamsten, A.; Stumvoll, M.; Deloukas, P.; Donnelly, P. J.; Frayling, T. M.; Hattersley, A. T.; Ripatti, S.; Salomaa, V.; Pedersen, N. L.; Boehm, B. O.; Bergman, R. N.; Collins, F. S.; Mohlke, K. L.; Tuomilehto, J.; Hansen, T.; Pedersen, O.; Barroso, I.; Lannfelt, L.; Ingelsson, E.; Lind, L.; Lindgren, C. M.; Cauchi, S.; Froguel, P.; Loos, R. J. F.; Balkau, B.; Boeing, H.; Franks, P. W.; Barricarte Gurrea, A.; Palli, D.; van der Schouw, Y. T.; Altshuler, D.; Groop, L. C.; Langenberg, C.; Wareham, N. J.; Sijbrands, E.; van Duijn, C. M.; Florez, J. C.; Meigs, J. B.; Boerwinkle, E.; Gieger, C.; Strauch, K.; Metspalu, A.; Morris, A. D.; Palmer, C. N. A.; Hu, F. B.; Thorsteinsdottir, U.; Stefansson, K.; Dupuis, J.; Morris, A. P.; Boehnke, M.; McCarthy, M. I.; Prokopenko, I.; for the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium Scott, R. A.; Scott, L. J.; Mägi, R.; Marullo, L.; Gaulton, K. J.; Kaakinen, M.; Pervjakova, N.; Pers, T. H.; Johnson, A. D.; Eicher, J. D.; Jackson, A. U.; Ferreira, T.; Lee, Y.; Ma, C.; Steinthorsdottir, V.; Thorleifsson, G.; Qi, L.; Van Zuydam, N. R.; Mahajan, A.; Chen, H.; Almgren, P.; Voight, B. F.; Grallert, H.; Müller-Nurasyid, M.; Ried, J. S.; Rayner, N. W.; Robertson, N.; Karssen, L. C.; van Leeuwen, E. M.; Willems, S. M.; Fuchsberger, C.; Kwan, P.; Teslovich, T. M.; Chanda, P.; Li, M.; Lu, Y.; Dina, C.; Thuillier, D.; Yengo, L.; Jiang, L.; Sparso, T.; Kestler, H. A.; Chheda, H.; Eisele, L.; Gustafsson, S.; Franberg, M.; Strawbridge, R. J.; Benediktsson, R.; Hreidarsson, A. B.; Kong, A.; Sigurthsson, G.; Kerrison, N. D.; Luan, J.; Liang, L.; Meitinger, T.; Roden, M.; Thorand, B.; Esko, T.; Mihailov, E.; Fox, C.; Liu, C.-T.; Rybin, D.; Isomaa, B.; Lyssenko, V.; Tuomi, T.; Couper, D. J.; Pankow, J. S.; Grarup, N.; Have, C. T.; Jorgensen, M. E.; Jorgensen, T.; Linneberg, A.; Cornelis, M. C.; van Dam, R. M.; Hunter, D. J.; Kraft, P.; Sun, Q.; Edkins, S.; Owen, K. R.; Perry, J. R. B.; Wood, A. R.; Zeggini, E.; Tajes-Fernandes, J.; Abecasis, G. R.; Bonnycastle, L. L.; Chines, P. S.; Stringham, H. M.; Koistinen, H. A.; Kinnunen, L.; Sennblad, B.; Mühleisen, T. W.; Nöthen, M. M.; Pechlivanis, S.; Baldassarre, D.; Gertow, K.; Humphries, S. E.; Tremoli, E.; Klopp, N.; Meyer, J.; Steinbach, G.; Wennauer, R.; Eriksson, J. G.; Männistö, S.; Peltonen, L.; Tikkanen, E.; Charpentier, G.; Eury, E.; Lobbens, S.; Gigante, B.; Leander, K.; McLeod, O.; Bottinger, E. P.; Gottesman, O.; Ruderfer, D.; Blüher, M.; Kovacs, P.; Tonjes, A.; Maruthur, N. M.; Scapoli, C.; Erbel, R.; Jöckel, K.-H.; Moebus, S.; de Faire, U.; Hamsten, A.; Stumvoll, M.; Deloukas, P.; Donnelly, P. J.; Frayling, T. M.; Hattersley, A. T.; Ripatti, S.; Salomaa, V.; Pedersen, N. L.; Boehm, B. O.; Bergman, R. N.; Collins, F. S.; Mohlke, K. L.; Tuomilehto, J.; Hansen, T.; Pedersen, O.; Barroso, I.; Lannfelt, L.; Ingelsson, E.; Lind, L.; Lindgren, C. M.; Cauchi, S.; Froguel, P.; Loos, R. J. F.; Balkau, B.; Boeing, H.; Franks, P. W.; Barricarte Gurrea, A.; Palli, D.; van der Schouw, Y. T.; Altshuler, D.; Groop, L. C.; Langenberg, C.; Wareham, N. J.; Sijbrands, E.; van Duijn, C. M.; Florez, J. C.; Meigs, J. B.; Boerwinkle, E.; Gieger, C.; Strauch, K.; Metspalu, A.; Morris, A. D.; Palmer, C. N. A.; Hu, F. B.; Thorsteinsdottir, U.; Stefansson, K.; Dupuis, J.; Morris, A. P.; Boehnke, M.; McCarthy, M. I.; Prokopenko, I.; for the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
      Pages: 2888 - 2902
      Abstract: To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10–8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action–associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db16-1253
      Issue No: Vol. 66, No. 11 (2017)
       
  • A Loss-of-Function Splice Acceptor Variant in IGF2 Is Protective for Type
           2 Diabetes
    • Authors: Mercader; J. M.; Liao, R. G.; Bell, A. D.; Dymek, Z.; Estrada, K.; Tukiainen, T.; Huerta-Chagoya, A.; Moreno-Macias, H.; Jablonski, K. A.; Hanson, R. L.; Walford, G. A.; Moran, I.; Chen, L.; Agarwala, V.; Ordonez-Sanchez, M. L.; Rodriguez-Guillen, R.; Rodriguez-Torres, M.; Segura-Kato, Y.; Garcia-Ortiz, H.; Centeno-Cruz, F.; Barajas-Olmos, F.; Caulkins, L.; Puppala, S.; Fontanillas, P.; Williams, A. L.; Bonas-Guarch, S.; Hartl, C.; Ripke, S.; Diabetes Prevention Program Research Group; Tooley, K.; Lane, J.; Zerrweck, C.; Martinez-Hernandez, A.; Cordova, E. J.; Mendoza-Caamal, E.; Contreras-Cubas, C.; Gonzalez-Villalpando, M. E.; Cruz-Bautista, I.; Munoz-Hernandez, L.; Gomez-Velasco, D.; Alvirde, U.; Henderson, B. E.; Wilkens, L. R.; Le Marchand, L.; Arellano-Campos, O.; Riba, L.; Harden, M.; Broad Genomics Platform; Gabriel, S.; T2D-GENES Consortium; Abboud, H. E.; Cortes, M. L.; Revilla-Monsalve, C.; Islas-Andrade, S.; Soberon, X.; Curran, J. E.; Jenkinson, C. P.; DeFronzo, R. A.; Lehman, D. M.; Hanis, C. L.; Bell, G. I.; Boehnke, M.; Blangero, J.; Duggirala, R.; Saxena, R.; MacArthur, D.; Ferrer, J.; McCarroll, S. A.; Torrents, D.; Knowler, W. C.; Baier, L. J.; Burtt, N.; Gonzalez-Villalpando, C.; Haiman, C. A.; Aguilar-Salinas, C. A.; Tusie-Luna, T.; Flannick, J.; Jacobs, S. B. R.; Orozco, L.; Altshuler, D.; Florez, J. C.; on behalf of the SIGMA T2D Genetics Consortium
      Pages: 2903 - 2914
      Abstract: Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the IGF2 gene associated with ~20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between IGF2 exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage–dependent reduction in the expression of IGF2 isoform 2. In individuals who do not carry the protective allele, expression of IGF2 isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in IGF2 isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing IGF2 isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction.
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db17-0187
      Issue No: Vol. 66, No. 11 (2017)
       
  • A Mendelian Randomization Study of Metabolite Profiles, Fasting Glucose,
           and Type 2 Diabetes
    • Authors: Liu; J.; van Klinken, J. B.; Semiz, S.; van Dijk, K. W.; Verhoeven, A.; Hankemeier, T.; Harms, A. C.; Sijbrands, E.; Sheehan, N. A.; van Duijn, C. M.; Demirkan, A.
      Pages: 2915 - 2926
      Abstract: Mendelian randomization (MR) provides us the opportunity to investigate the causal paths of metabolites in type 2 diabetes and glucose homeostasis. We developed and tested an MR approach based on genetic risk scoring for plasma metabolite levels, utilizing a pathway-based sensitivity analysis to control for nonspecific effects. We focused on 124 circulating metabolites that correlate with fasting glucose in the Erasmus Rucphen Family (ERF) study (n = 2,564) and tested the possible causal effect of each metabolite with glucose and type 2 diabetes and vice versa. We detected 14 paths with potential causal effects by MR, following pathway-based sensitivity analysis. Our results suggest that elevated plasma triglycerides might be partially responsible for increased glucose levels and type 2 diabetes risk, which is consistent with previous reports. Additionally, elevated HDL components, i.e., small HDL triglycerides, might have a causal role of elevating glucose levels. In contrast, large (L) and extra large (XL) HDL lipid components, i.e., XL-HDL cholesterol, XL-HDL–free cholesterol, XL-HDL phospholipids, L-HDL cholesterol, and L-HDL–free cholesterol, as well as HDL cholesterol seem to be protective against increasing fasting glucose but not against type 2 diabetes. Finally, we demonstrate that genetic predisposition to type 2 diabetes associates with increased levels of alanine and decreased levels of phosphatidylcholine alkyl-acyl C42:5 and phosphatidylcholine alkyl-acyl C44:4. Our MR results provide novel insight into promising causal paths to and from glucose and type 2 diabetes and underline the value of additional information from high-resolution metabolomics over classic biochemistry.
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db17-0199
      Issue No: Vol. 66, No. 11 (2017)
       
  • Haptoglobin 1-1 Genotype Modulates the Association of Glycemic Control
           With Hippocampal Volume in Elderly Individuals With Type 2 Diabetes
    • Authors: Livny; A.; Ravona-Springer, R.; Heymann, A.; Priess, R.; Kushnir, T.; Tsarfaty, G.; Rabinov, L.; Moran, R.; Tik, N.; Moshier, E.; Cooper, I.; Greenbaum, L.; Silverman, J.; Levy, A.; Sano, M.; Bendlin, B. B.; Buchman, A. S.; Schnaider-Beeri, M.
      Pages: 2927 - 2932
      Abstract: Recent evidence suggests that glycemic control is associated with cognitive function in older patients with type 2 diabetes who are carriers of the haptoglobin (Hp) 1-1 genotype compared with noncarriers. We assessed whether poor glycemic control in Hp 1-1 carriers is more strongly associated with smaller hippocampal volume than in noncarriers. Hippocampal volume was generated from high-resolution structural T1 MRI obtained for 224 participants (28 Hp 1-1 carriers [12.5%] and 196 noncarriers [87.5%]) from the Israel Diabetes and Cognitive Decline (IDCD) study, who had a mean (SD) number of years in the Maccabi Healthcare Services (MHS) registry of 8.35 (2.63) and a mean (SD) HbA1c level of 6.66 (0.73)% [49 mmol/mol]. A stronger negative association between right hippocampal volume and HbA1c was found in patients with the Hp 1-1 genotype, with a 0.032-mL decrease in right hippocampal volume per 14% increase in HbA1c (P = 0.0007) versus a 0.009-mL decrease in Hp 1-1 noncarriers (P = 0.047), after adjusting for total intracranial volume, age, sex, follow-up years in the registry, and cardiovascular factor (interaction, P = 0.025). This indicates that 29.66% of the total variance in right hippocampal volume is explained by HbA1c levels among Hp 1-1 carriers and that 3.22% is explained by HbA1c levels among Hp 1-1 noncarriers. Our results suggest that the hippocampus of Hp 1-1 carriers may be more vulnerable to the insults of poor glycemic control.
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db16-0987
      Issue No: Vol. 66, No. 11 (2017)
       
  • Issues and Events
    • Pages: 2933 - 2933
      PubDate: 2017-10-23T12:00:32-07:00
      DOI: 10.2337/db17-ie11
      Issue No: Vol. 66, No. 11 (2017)
       
 
 
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