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Journal Prestige (SJR): 4.435
Citation Impact (citeScore): 6
Number of Followers: 542  
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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: 1097 - 1098
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db19-ti06
      Issue No: Vol. 68, No. 6 (2019)
  • The cGAS-cGAMP-STING Pathway: A Molecular Link Between Immunity and
    • Authors: Bai; J.; Liu, F.
      Pages: 1099 - 1108
      Abstract: It has been appreciated for many years that there is a strong association between metabolism and immunity in advanced metazoan organisms. Distinct immune signatures and signaling pathways have been found not only in immune but also in metabolic cells. The newly discovered DNA-sensing cGAS-cGAMP-STING pathway mediates type I interferon inflammatory responses in immune cells to defend against viral and bacterial infections. Recent studies show that this pathway is also activated by host DNA aberrantly localized in the cytosol, contributing to increased sterile inflammation, insulin resistance, and the development of nonalcoholic fatty liver disease (NAFLD). Potential interactions of the cGAS-cGAMP-STING pathway with mTORC1 signaling, autophagy, and apoptosis have been reported, suggesting an important role of the cGAS-cGAMP-STING pathway in the networking and coordination of these important biological processes. However, the regulation, mechanism of action, and tissue-specific role of the cGAS-cGAMP-STING signaling pathway in metabolic disorders remain largely elusive. It is also unclear whether targeting this signaling pathway is effective for the prevention and treatment of obesity-induced metabolic diseases. Answers to these questions would provide new insights for developing effective therapeutic interventions for metabolic diseases such as insulin resistance, NAFLD, and type 2 diabetes.
      Keywords: Obesity-Animal
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/dbi18-0052
      Issue No: Vol. 68, No. 6 (2019)
  • Sodium-Glucose Cotransporter 2 Inhibitors: A Case Study in Translational
    • Authors: Beitelshees; A. L.; Leslie, B. R.; Taylor, S. I.
      Pages: 1109 - 1120
      Abstract: Sodium–glucose cotransporter 2 (SGLT2) inhibitors are the most recently approved class of diabetes drugs. Unlike other agents, SGLT2 inhibitors act on the kidney to promote urinary glucose excretion. SGLT2 inhibitors provide multiple benefits, including decreased HbA1c, body weight, and blood pressure. These drugs have received special attention because they decrease the risk of major adverse cardiovascular events and slow progression of diabetic kidney disease (1–3). Balanced against these impressive benefits, the U.S. Food and Drug Administration–approved prescribing information describes a long list of side effects: genitourinary infections, ketoacidosis, bone fractures, amputations, acute kidney injury, perineal necrotizing fasciitis, and hyperkalemia. This review provides a physiological perspective to understanding the multiple actions of these drugs complemented by a clinical perspective toward balancing benefits and risks.
      Keywords: Clinical Therapeutics/New Technology-Oral Agents
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/dbi18-0006
      Issue No: Vol. 68, No. 6 (2019)
  • {beta}-Cell Fate in Human Insulin Resistance and Type 2 Diabetes: A
           Perspective on Islet Plasticity
    • Authors: Mezza; T.; Cinti, F.; Cefalo, C. M. A.; Pontecorvi, A.; Kulkarni, R. N.; Giaccari, A.
      Pages: 1121 - 1129
      Abstract: Although it is well established that type 2 diabetes (T2D) is generally due to the progressive loss of β-cell insulin secretion against a background of insulin resistance, the actual correlation of reduced β-cell mass to its defective function continues to be debated. There is evidence that a compensatory increase in β-cell mass, and the consequent insulin secretion, can effectively cope with states of insulin resistance, until hyperglycemia supervenes. Recent data strongly indicate that the mechanisms by which islets are able to compensate in response to insulin resistance in peripheral tissues is secondary to hyperplasia, as well as the activation of multiple cellular machineries with diverse functions. Importantly, islet cells exhibit plasticity in altering their endocrine commitment; for example, by switching from secretion of glucagon to secretion of insulin and back (transdifferentiation) or from an active secretory state to a nonsecretory quiescent state (dedifferentiation) and back. Lineage tracing (a method used to track each cell though its differentiation process) has demonstrated these potentials in murine models. A limitation to drawing conclusions from human islet research is that most studies are derived from human autopsy and/or organ donor samples, which lack in vivo functional and metabolic profiling. In this review, we specifically focus on evidence of islet plasticity in humans—from the normal state, progressing to insulin resistance to overt T2D—to explain the seemingly contradictory results from different cross-sectional studies in the literature. We hope the discussion on this intriguing scenario will provide a forum for the scientific community to better understand the disease and in the long term pave the way for personalized therapies.
      Keywords: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db18-0856
      Issue No: Vol. 68, No. 6 (2019)
  • Fpr2 Deficiency Alleviates Diet-Induced Insulin Resistance Through
           Reducing Body Weight Gain and Inhibiting Inflammation Mediated by
           Macrophage Chemotaxis and M1 Polarization
    • Authors: Chen; X.; Zhuo, S.; Zhu, T.; Yao, P.; Yang, M.; Mei, H.; Li, N.; Ma, F.; Wang, J. M.; Chen, S.; Ye, R. D.; Li, Y.; Le, Y.
      Pages: 1130 - 1142
      Abstract: Obesity and related inflammation are critical for the pathogenesis of insulin resistance, but the underlying mechanisms are not fully understood. Formyl peptide receptor 2 (FPR2) plays important roles in host immune responses and inflammation-related diseases. We found that Fpr2 expression was elevated in the white adipose tissue of high-fat diet (HFD)–induced obese mice and db/db mice. The systemic deletion of Fpr2 alleviated HFD-induced obesity, insulin resistance, hyperglycemia, hyperlipidemia, and hepatic steatosis. Furthermore, Fpr2 deletion in HFD-fed mice elevated body temperature, reduced fat mass, and inhibited inflammation by reducing macrophage infiltration and M1 polarization in metabolic tissues. Bone marrow transplantations between wild-type and Fpr2–/– mice and myeloid-specific Fpr2 deletion demonstrated that Fpr2-expressing myeloid cells exacerbated HFD-induced obesity, insulin resistance, glucose/lipid metabolic disturbances, and inflammation. Mechanistic studies revealed that Fpr2 deletion in HFD-fed mice enhanced energy expenditure probably through increasing thermogenesis in skeletal muscle; serum amyloid A3 and other factors secreted by adipocytes induced macrophage chemotaxis via Fpr2; and Fpr2 deletion suppressed macrophage chemotaxis and lipopolysaccharide-, palmitate-, and interferon-–induced macrophage M1 polarization through blocking their signals. Altogether, our studies demonstrate that myeloid Fpr2 plays critical roles in obesity and related metabolic disorders via regulating muscle energy expenditure, macrophage chemotaxis, and M1 polarization.
      Keywords: Obesity-Animal
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db18-0469
      Issue No: Vol. 68, No. 6 (2019)
  • Sympathetic Denervation of the Common Hepatic Artery Lessens Glucose
           Intolerance in the Fat- and Fructose-Fed Dog
    • Authors: Kraft; G.; Vrba, A.; Scott, M.; Allen, E.; Edgerton, D. S.; Williams, P. E.; Vafai, S. B.; Azamian, B. R.; Cherrington, A. D.
      Pages: 1143 - 1155
      Abstract: This study assessed the effectiveness of surgical sympathetic denervation of the common hepatic artery (CHADN) in improving glucose tolerance. CHADN eliminated norepinephrine content in the liver and partially decreased it in the pancreas and the upper gut. We assessed oral glucose tolerance at baseline and after 4 weeks of high-fat high-fructose (HFHF) feeding. Dogs were then randomized to sham surgery (SHAM) (n = 9) or CHADN surgery (n = 11) and retested 2.5 or 3.5 weeks later while still on the HFHF diet. CHADN improved glucose tolerance by ~60% in part because of enhanced insulin secretion, as indicated by an increase in the insulinogenic index. In a subset of dogs (SHAM, n = 5; CHADN, n = 6), a hyperinsulinemic-hyperglycemic clamp was used to assess whether CHADN could improve hepatic glucose metabolism independent of a change in insulin release. CHADN reduced the diet-induced defect in net hepatic glucose balance by 37%. In another subset of dogs (SHAM, n = 4; CHADN, n = 5) the HFHF diet was continued for 3 months postsurgery and the improvement in glucose tolerance caused by CHADN continued. In conclusion, CHADN has the potential to enhance postprandial glucose clearance in states of diet-induced glucose intolerance.
      Keywords: Integrated Physiology-Central Nervous System Regulation of Metabolism
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db18-1209
      Issue No: Vol. 68, No. 6 (2019)
  • Identification of Insulin-Responsive Transcription Factors That Regulate
           Glucose Production by Hepatocytes
    • Authors: Wang; L.; Liu, Q.; Kitamoto, T.; Hou, J.; Qin, J.; Accili, D.
      Pages: 1156 - 1167
      Abstract: Hepatocyte glucose production is a complex process that integrates cell-autonomous mechanisms with cellular signaling, enzyme activity modulation, and gene transcription. Transcriptional mechanisms controlling glucose production are redundant and involve nuclear hormone receptors and unliganded transcription factors (TFs). Our knowledge of this circuitry is incomplete. Here we used DNA affinity purification followed by mass spectrometry to probe the network of hormone-regulated TFs by using phosphoenolpyruvate carboxykinase (Pck1) and glucose-6-phosphatase (G6pc) in liver and primary hepatocytes as model systems. The repertoire of insulin-regulated TFs is unexpectedly broad and diverse. Whereas in liver the two test promoters are regulated by largely overlapping sets of TFs, in primary hepatocytes Pck1 and G6pc regulation diverges. Insulin treatment preferentially results in increased occupancy by the two promoters, consistent with a model in which the hormone’s primary role is to recruit corepressors rather than to clear activators. Nine insulin-responsive TFs are present in both models, but only FoxK1, FoxA2, ZFP91, and ZHX3 require an intact Pck1p insulin response sequence for binding. Knockdown of FoxK1 in primary hepatocytes decreased both glucose production and insulin’s ability to suppress it. The findings expand the repertoire of insulin-dependent TFs and identify FoxK1 as a contributor to insulin signaling.
      Keywords: Insulin Action-Cellular and Molecular Metabolism
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db18-1236
      Issue No: Vol. 68, No. 6 (2019)
  • Altered In Vivo Lipid Fluxes and Cell Dynamics in Subcutaneous Adipose
           Tissues Are Associated With the Unfavorable Pattern of Fat Distribution in
           Obese Adolescent Girls
    • Authors: Nouws; J.; Fitch, M.; Mata, M.; Santoro, N.; Galuppo, B.; Kursawe, R.; Narayan, D.; Vash-Margita, A.; Pierpont, B.; Shulman, G. I.; Hellerstein, M.; Caprio, S.
      Pages: 1168 - 1177
      Abstract: Patterns of abdominal fat distribution (for example, a high vs. low visceral adipose tissue [VAT]/[VAT + subcutaneous adipose tissue (SAT)] ratio), independent of obesity, during adolescence carry a high risk for insulin resistance and type 2 diabetes. Longitudinal follow-up of a cohort of obese adolescents has recently revealed that a high ratio (high VAT/[VAT + SAT]) is a major determinant of fatty liver and metabolic impairment over time, with these effects being more pronounced in girls than in boys. To unravel the underlying metabolic alterations associated with the unfavorable VAT/(VAT + SAT) phenotype, we used the 2H2O labeling method to measure the turnover of adipose lipids and cells in the subcutaneous abdominal and gluteal/femoral adipose tissue (SAT) of weight-stable obese adolescent girls with a similar level of obesity but discordant VAT/(VAT + SAT) ratios. Girls with the unfavorable (high VAT/[VAT + SAT]) phenotype exhibited higher in vivo rates of triglyceride (TG) turnover (representing both lipolysis and synthesis at steady state), without significant differences in de novo lipogenesis in both abdominal and gluteal depots, compared with obese girls with the favorable phenotype. Moreover, mature adipocytes had higher turnover, with no difference in stromal vascular cell proliferation in both depots in the metabolically unfavorable phenotype. The higher TG turnover rates were significantly correlated with higher intrahepatic fat stores. These findings are contrary to the hypothesis that impaired capacity to deposit TGs or proliferation of new mature adipocytes are potential mechanisms for ectopic fat distribution in this setting. In summary, these results suggest that increased turnover of TGs (lipolysis) and of mature adipocytes in both abdominal and gluteal SAT may contribute to metabolic impairment and the development of fatty liver, even at this very early stage of disease.
      Keywords: Insulin Action-Adipocyte Biology
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db18-1162
      Issue No: Vol. 68, No. 6 (2019)
  • A Unique Role of Carboxylesterase 3 (Ces3) in {beta}-Adrenergic
           Signaling-Stimulated Thermogenesis
    • Authors: Yang; L.; Li, X.; Tang, H.; Gao, Z.; Zhang, K.; Sun, K.
      Pages: 1178 - 1196
      Abstract: Carboxylesterase 3 (Ces3) is a hydrolase with a wide range of activities in liver and adipose tissue. In this study, we identified Ces3 as a major lipid droplet surface-targeting protein in adipose tissue upon cold exposure by liquid chromatography—tandem mass spectrometry. To investigate the function of Ces3 in the β-adrenergic signaling–activated adipocytes, we applied WWL229, a specific Ces3 inhibitor, or genetic inhibition by siRNA to Ces3 on isoproterenol (ISO)–treated 3T3-L1 and brown adipocyte cells. We found that blockage of Ces3 by WWL229 or siRNA dramatically attenuated the ISO-induced lipolytic effect in the cells. Furthermore, Ces3 inhibition led to impaired mitochondrial function measured by Seahorse. Interestingly, Ces3 inhibition attenuated an ISO-induced thermogenic program in adipocytes by downregulating Ucp1 and Pgc1α genes via peroxisome proliferator–activated receptor . We further confirmed the effects of Ces3 inhibition in vivo by showing that the thermogenesis in adipose tissues was significantly attenuated in WWL229-treated or adipose tissue–specific Ces3 heterozygous knockout (Adn-Cre-Ces3flx/wt) mice. As a result, the mice exhibited dramatically impaired ability to defend their body temperature in coldness. In conclusion, our study highlights a lipolytic signaling induced by Ces3 as a unique process to regulate thermogenesis in adipose tissue.
      Keywords: Obesity-Animal
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db18-1210
      Issue No: Vol. 68, No. 6 (2019)
  • Deficiency of ZnT8 Promotes Adiposity and Metabolic Dysfunction by
           Increasing Peripheral Serotonin Production
    • Authors: Mao; Z.; Lin, H.; Su, W.; Li, J.; Zhou, M.; Li, Z.; Zhou, B.; Yang, Q.; Zhou, M.; Pan, K.; He, J.; Zhang, W.
      Pages: 1197 - 1209
      Abstract: ZnT8 is a zinc transporter enriched in pancreatic β-cells, and its polymorphism is associated with increased susceptibility to type 2 diabetes. However, the exact role of ZnT8 in systemic energy metabolism remains elusive. In this study, we found that ZnT8 knockout mice displayed increased adiposity without obvious weight gain. We also observed that the intestinal tract morphology, motility, and gut microbiota were changed in ZnT8 knockout mice. Further study demonstrated that ZnT8 was expressed in enteroendocrine cells, especially in 5-hydroxytryptamine (5-HT)–positive enterochromaffin cells. Lack of ZnT8 resulted in an elevated circulating 5-HT level owing to enhanced expression of tryptophan hydroxylase 1. Blocking 5-HT synthesis in ZnT8-deficient mice restored adiposity, high-fat diet–induced obesity, and glucose intolerance. Moreover, overexpression of human ZnT8 diabetes high-risk allele R325W increased 5-HT levels relative to the low-risk allele in RIN14B cells. Our study revealed an unexpected role of ZnT8 in regulating peripheral 5-HT biogenesis and intestinal microenvironment, which might contribute to the increased risk of obesity and type 2 diabetes.
      Keywords: Integrated Physiology-Other Hormones
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db18-1321
      Issue No: Vol. 68, No. 6 (2019)
  • Celastrol Reduces Obesity in MC4R Deficiency and Stimulates Sympathetic
           Nerve Activity Affecting Metabolic and Cardiovascular Functions
    • Authors: Saito; K.; Davis, K. C.; Morgan, D. A.; Toth, B. A.; Jiang, J.; Singh, U.; Berglund, E. D.; Grobe, J. L.; Rahmouni, K.; Cui, H.
      Pages: 1210 - 1220
      Abstract: Leptin resistance is a hallmark of obesity with unclear etiology. Celastrol, a compound found in the roots of the Tripterygium wilfordii and known to reduce endoplasmic reticulum (ER) stress, has recently emerged as a promising candidate to treat obesity by improving leptin sensitivity. However, the underlying neural mechanisms by which celastrol reduces obesity remain unclear. Using three different mouse models of obesity—diet-induced obesity (DIO), leptin receptor (LepR)-null, and melanocortin 4 receptor (MC4R)-null mice—in this study, we show that systemic celastrol administration substantially reduces food intake and body weight in MC4R-null comparable to DIO, proving the MC4R-independent antiobesity effect of celastrol. Body weight reduction was due to decreases in both fat and lean mass, and modest but significant body weight reduction was also observed in nonobese wild-type and LepR-null mice. Unexpectedly, celastrol upregulated proinflammatory cytokines without affecting genes involved in ER stress. Importantly, celastrol steadily increased sympathetic nerve activity to the brown fat and kidney with concordant increases of resting metabolic rate and arterial pressure. Our results suggest a previously unappreciated mechanism of action of celastrol in the regulation of energy homeostasis and highlight the need for careful consideration of its development as a safe antiobesity medication.
      Keywords: Obesity-Animal
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db18-1167
      Issue No: Vol. 68, No. 6 (2019)
  • Hepatocyte-Specific Ablation or Whole-Body Inhibition of Xanthine
           Oxidoreductase in Mice Corrects Obesity-Induced Systemic Hyperuricemia
           Without Improving Metabolic Abnormalities
    • Authors: Harmon; D. B.; Mandler, W. K.; Sipula, I. J.; Dedousis, N.; Lewis, S. E.; Eckels, J. T.; Du, J.; Wang, Y.; Huckestein, B. R.; Pagano, P. J.; Cifuentes-Pagano, E.; Homanics, G. E.; Vant Erve, T. J.; Stefanovic-Racic, M.; Jurczak, M. J.; ODoherty, R. M.; Kelley, E. E.
      Pages: 1221 - 1229
      Abstract: Systemic hyperuricemia (HyUA) in obesity/type 2 diabetes facilitated by elevated activity of xanthine oxidoreductase (XOR), which is the sole source of uric acid (UA) in mammals, has been proposed to contribute to the pathogenesis of insulin resistance/dyslipidemia in obesity. Here, the effects of hepatocyte-specific ablation of Xdh, the gene encoding XOR (HXO), and whole-body pharmacologic inhibition of XOR (febuxostat) on obesity-induced insulin resistance/dyslipidemia were assessed. Deletion of hepatocyte Xdh substantially lowered liver and plasma UA concentration. When exposed to an obesogenic diet, HXO and control floxed (FLX) mice became equally obese, but systemic HyUA was absent in HXO mice. Despite this, obese HXO mice became as insulin resistant and dyslipidemic as obese FLX mice. Similarly, febuxostat dramatically lowered plasma and tissue UA and XOR activity in obese wild-type mice without altering obesity-associated insulin resistance/dyslipidemia. These data demonstrate that hepatocyte XOR activity is a critical determinant of systemic UA homeostasis, that deletion of hepatocyte Xdh is sufficient to prevent systemic HyUA of obesity, and that neither prevention nor correction of HyUA improves insulin resistance/dyslipidemia in obesity. Thus, systemic HyUA, although clearly a biomarker of the metabolic abnormalities of obesity, does not appear to be causative.
      Keywords: Obesity-Animal
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db18-1198
      Issue No: Vol. 68, No. 6 (2019)
  • Heterogeneity of the Human Pancreatic Islet
    • Authors: Dybala; M. P.; Hara, M.
      Pages: 1230 - 1239
      Abstract: Pancreatic β-cells play a pivotal role in maintaining normoglycemia. Recent studies have revealed that the β-cell is not a homogeneous cell population but, rather, is heterogeneous in a number of properties such as electrical activity, gene expression, and cell surface markers. Identification of specific β-cell subpopulations altered in diabetic conditions would open a new avenue to develop targeted therapeutic interventions. As intense studies of β-cell heterogeneity are anticipated in the next decade, it is important that heterogeneity of the islet be recognized. Many studies in the past were undertaken with a small sample of islets, which might overlook important individual variance. In this study, by systematic analyses of the human islet in two and three dimensions, we demonstrate islet heterogeneity in size, number, architecture, cellular composition, and capillary density. There is no stereotypic human islet, and thus, a sufficient number of islets should be examined to ensure study reproducibility.
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db19-0072
      Issue No: Vol. 68, No. 6 (2019)
  • Dynamic Immune Phenotypes of B and T Helper Cells Mark Distinct Stages of
           T1D Progression
    • Authors: Habib; T.; Long, S. A.; Samuels, P. L.; Brahmandam, A.; Tatum, M.; Funk, A.; Hocking, A. M.; Cerosaletti, K.; Mason, M. T.; Whalen, E.; Rawlings, D. J.; Greenbaum, C.; Buckner, J. H.; the Type 1 Diabetes TrialNet Study Group
      Pages: 1240 - 1250
      Abstract: Multiple studies of B- and T-cell compartments and their response to stimuli demonstrate alterations in established type 1 diabetes (T1D). Yet it is not known whether these alterations reflect immune mechanisms that initiate islet autoimmunity, promote disease progression, or are secondary to disease. To address these questions, we used samples from the TrialNet Pathway to Prevention study to investigate T-cell responses to interleukin (IL)-2 and regulatory T cell–mediated suppression, the composition of the B-cell compartment, and B-cell responses to B-cell receptor and IL-21 receptor engagement. These studies revealed stage-dependent T- and B-cell functional and immune phenotypes; namely, early features that differentiate autoantibody-positive at-risk first-degree relatives (FDRs) from autoantibody-negative FDRs and persisted through clinical diagnosis; late features that arose at or near T1D diagnosis; and dynamic features that were enhanced early and blunted at later disease stages, indicating evolving responses along the continuum of T1D. We further explored how these specific phenotypes are influenced by therapeutic interventions. Our integrated studies provide unique insights into stable and dynamic stage-specific immune states and define novel immune phenotypes of potential clinical relevance.
      Keywords: Immunology
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db18-1081
      Issue No: Vol. 68, No. 6 (2019)
  • T-Cell-Specific PTPN2 Deficiency in NOD Mice Accelerates the Development
           of Type 1 Diabetes and Autoimmune Comorbidities
    • Authors: Wiede; F.; Brodnicki, T. C.; Goh, P. K.; Leong, Y. A.; Jones, G. W.; Yu, D.; Baxter, A. G.; Jones, S. A.; Kay, T. W. H.; Tiganis, T.
      Pages: 1251 - 1266
      Abstract: Genome-wide association studies have identified PTPN2 as an important non-MHC gene for autoimmunity. Single nucleotide polymorphisms that reduce PTPN2 expression have been linked with the development of various autoimmune disorders, including type 1 diabetes. The tyrosine phosphatase PTPN2 attenuates T-cell receptor and cytokine signaling in T cells to maintain peripheral tolerance, but the extent to which PTPN2 deficiency in T cells might influence type 1 diabetes onset remains unclear. NOD mice develop spontaneous autoimmune type 1 diabetes similar to that seen in humans. In this study, T-cell PTPN2 deficiency in NOD mice markedly accelerated the onset and increased the incidence of type 1 diabetes as well as that of other disorders, including colitis and Sjögren syndrome. Although PTPN2 deficiency in CD8+ T cells alone was able to drive the destruction of pancreatic β-cells and the onset of diabetes, T-cell–specific PTPN2 deficiency was also accompanied by increased CD4+ T-helper type 1 differentiation and T-follicular-helper cell polarization and increased the abundance of B cells in pancreatic islets as seen in human type 1 diabetes. These findings causally link PTPN2 deficiency in T cells with the development of type 1 diabetes and associated autoimmune comorbidities.
      Keywords: Immunology
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db18-1362
      Issue No: Vol. 68, No. 6 (2019)
  • Low-Dose Anti-Thymocyte Globulin Preserves C-Peptide, Reduces HbA1c, and
           Increases Regulatory to Conventional T-Cell Ratios in New-Onset Type 1
           Diabetes: Two-Year Clinical Trial Data
    • Authors: Haller; M. J.; Long, S. A.; Blanchfield, J. L.; Schatz, D. A.; Skyler, J. S.; Krischer, J. P.; Bundy, B. N.; Geyer, S. M.; Warnock, M. V.; Miller, J. L.; Atkinson, M. A.; Becker, D. J.; Baidal, D. A.; DiMeglio, L. A.; Gitelman, S. E.; Goland, R.; Gottlieb, P. A.; Herold, K. C.; Marks, J. B.; Moran, A.; Rodriguez, H.; Russell, W. E.; Wilson, D. M.; Greenbaum, C. J.; for the Type 1 Diabetes TrialNet ATG-GCSF Study Group; Type 1 Diabetes TrialNet ATG-GCSF Study Group
      Pages: 1267 - 1276
      Abstract: A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test–stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P < 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.
      Keywords: Immunology
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db19-0057
      Issue No: Vol. 68, No. 6 (2019)
  • Cardiac Autonomic Function Is Associated With Myocardial Flow Reserve in
           Type 1 Diabetes
    • Authors: Zobel; E. H.; Hasbak, P.; Winther, S. A.; Hansen, C. S.; Fleischer, J.; von Scholten, B. J.; Holmvang, L.; Kjaer, A.; Rossing, P.; Hansen, T. W.
      Pages: 1277 - 1286
      Abstract: The link between cardiac autonomic neuropathy and risk of cardiovascular disease is highlighted as an area in which research is needed. This study was undertaken to evaluate the association between measures of cardiac autonomic function and cardiac vascular function in type 1 diabetes using new and sensitive methods. This was a cross-sectional study in patients with type 1 diabetes, stratified by normoalbuminuria (n = 30) and macroalbuminuria (n = 30), and in healthy control subjects (n = 30). Cardiac autonomic function was evaluated using heart rate variability (HRV) indices, cardiovascular autonomic reflex tests (CARTs), and cardiac 123I-metaiodobenzylguanidine (MIBG) imaging. Cardiac vascular function was assessed as myocardial flow reserve (MFR) measured by cardiac 82Rb-positron emission tomography/computed tomography. The measures of cardiac autonomic function (except low frequency–to–high frequency ratio and the Valsalva test ratio) were positively correlated to MFR in unadjusted analysis. All the HRV indices lost significance after adjustment for age and heart rate. After further adjustment for relevant cardiovascular risk factors, the late heart-to-mediastinum ratio directly measuring the function of adrenergic receptors and sympathetic integrity (from the MIBG scintigraphy) and the 30-to-15 ratio (a CART), remained positively associated with MFR (P ≤ 0.04). Cardiac autonomic dysfunction, including loss of cardiac sympathetic integrity in type 1 diabetes, is associated with and may contribute to impaired myocardial blood flow regulation.
      Keywords: Complications-Neuropathy
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db18-1313
      Issue No: Vol. 68, No. 6 (2019)
  • Ameliorating Methylglyoxal-Induced Progenitor Cell Dysfunction for Tissue
           Repair in Diabetes
    • Authors: Li; H.; OMeara, M.; Zhang, X.; Zhang, K.; Seyoum, B.; Yi, Z.; Kaufman, R. J.; Monks, T. J.; Wang, J.-M.
      Pages: 1287 - 1302
      Abstract: Patient-derived progenitor cell (PC) dysfunction is severely impaired in diabetes, but the molecular triggers that contribute to mechanisms of PC dysfunction are not fully understood. Methylglyoxal (MGO) is one of the highly reactive dicarbonyl species formed during hyperglycemia. We hypothesized that the MGO scavenger glyoxalase 1 (GLO1) reverses bone marrow-derived PC (BMPC) dysfunction through augmenting the activity of an important endoplasmic reticulum stress sensor, inositol-requiring enzyme 1α (IRE1α), resulting in improved diabetic wound healing. BMPCs were isolated from adult male db/db type 2 diabetic mice and their healthy corresponding control db/+ mice. MGO at the concentration of 10 µmol/L induced immediate and severe BMPC dysfunction, including impaired network formation, migration, and proliferation and increased apoptosis, which were rescued by adenovirus-mediated GLO1 overexpression. IRE1α expression and activation in BMPCs were significantly attenuated by MGO exposure but rescued by GLO1 overexpression. MGO can diminish IRE1α RNase activity by directly binding to IRE1α in vitro. In a diabetic mouse cutaneous wound model in vivo, cell therapies using diabetic cells with GLO1 overexpression remarkably accelerated wound closure by enhancing angiogenesis compared with diabetic control cell therapy. Augmenting tissue GLO1 expression by adenovirus-mediated gene transfer or with the small-molecule inducer trans-resveratrol and hesperetin formulation also improved wound closure and angiogenesis in diabetic mice. In conclusion, our data suggest that GLO1 rescues BMPC dysfunction and facilitates wound healing in diabetic animals, at least partly through preventing MGO-induced impairment of IRE1α expression and activity. Our results provide important knowledge for the development of novel therapeutic approaches targeting MGO to improve PC-mediated angiogenesis and tissue repair in diabetes.
      Keywords: Foot Care-Lower Extremities
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db18-0933
      Issue No: Vol. 68, No. 6 (2019)
  • Diabetes-Associated Myelopoiesis Drives Stem Cell Mobilopathy Through an
           OSM-p66Shc Signaling Pathway
    • Authors: Albiero; M.; Ciciliot, S.; Tedesco, S.; Menegazzo, L.; DAnna, M.; Scattolini, V.; Cappellari, R.; Zuccolotto, G.; Rosato, A.; Cignarella, A.; Giorgio, M.; Avogaro, A.; Fadini, G. P.
      Pages: 1303 - 1314
      Abstract: Diabetes impairs the mobilization of hematopoietic stem/progenitor cells (HSPCs) from the bone marrow (BM), which can worsen the outcomes of HSPC transplantation and of diabetic complications. In this study, we examined the oncostatin M (OSM)–p66Shc pathway as a mechanistic link between HSPC mobilopathy and excessive myelopoiesis. We found that streptozotocin-induced diabetes in mice skewed hematopoiesis toward the myeloid lineage via hematopoietic-intrinsic p66Shc. The overexpression of Osm resulting from myelopoiesis prevented HSPC mobilization after granulocyte colony-stimulating factor (G-CSF) stimulation. The intimate link between myelopoiesis and impaired HSPC mobilization after G-CSF stimulation was confirmed in human diabetes. Using cross-transplantation experiments, we found that deletion of p66Shc in the hematopoietic or nonhematopoietic system partially rescued defective HSPC mobilization in diabetes. Additionally, p66Shc mediated the diabetes-induced BM microvasculature remodeling. Ubiquitous or hematopoietic restricted Osm deletion phenocopied p66Shc deletion in preventing diabetes-associated myelopoiesis and mobilopathy. Mechanistically, we discovered that OSM couples myelopoiesis to mobilopathy by inducing Cxcl12 in BM stromal cells via nonmitochondrial p66Shc. Altogether, these data indicate that cell-autonomous activation of the OSM-p66Shc pathway leads to diabetes-associated myelopoiesis, whereas its transcellular hematostromal activation links myelopoiesis to mobilopathy. Targeting the OSM-p66Shc pathway is a novel strategy to disconnect mobilopathy from myelopoiesis and restore normal HSPC mobilization.
      Keywords: Immunology
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db19-0080
      Issue No: Vol. 68, No. 6 (2019)
  • FGF19 Analog as a Surgical Factor Mimetic That Contributes to Metabolic
           Effects Beyond Glucose Homeostasis
    • Authors: DePaoli; A. M.; Zhou, M.; Kaplan, D. D.; Hunt, S. C.; Adams, T. D.; Learned, R. M.; Tian, H.; Ling, L.
      Pages: 1315 - 1328
      Abstract: Bariatric surgery has proven to be the most effective treatment for controlling hyperglycemia in severely obese patients with diabetes. We show that fibroblast growth factor 19 (FGF19), a gut hormone, is rapidly induced by bariatric surgery in rodents and humans. Administration of FGF19 achieves diabetes remission independent of weight loss in animal models of diabetes, supporting a role for FGF19 in the hormonal remodeling that restores metabolic function after the surgery. Through an unbiased, systematic screen in diabetic mice, we identified selective, safe, and effective FGF19 analogs. Unexpectedly, a lead FGF19 analog, NGM282, did not correct hyperglycemia in patients with type 2 diabetes. In contrast, administration of NGM282 resulted in a rapid, robust, and sustained reduction in liver fat content and an improvement in liver histology in patients with nonalcoholic steatohepatitis, faithfully replicating another key benefit of bariatric surgery. Our work identifies a strategy for replacing the surgery with an equally effective, but less invasive, treatment for nonalcoholic steatohepatitis.
      Keywords: Clinical Therapeutics/New Technology-Non-Insulin Injectables
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db18-1305
      Issue No: Vol. 68, No. 6 (2019)
  • Long-Acting Neurotensin Synergizes With Liraglutide to Reverse Obesity
           Through a Melanocortin-Dependent Pathway
    • Authors: Ratner; C.; He, Z.; Grunddal, K. V.; Skov, L. J.; Hartmann, B.; Zhang, F.; Feuchtinger, A.; Bjerregaard, A.; Christoffersen, C.; Tschöp, M. H.; Finan, B.; DiMarchi, R. D.; Leinninger, G. M.; Williams, K. W.; Clemmensen, C.; Holst, B.
      Pages: 1329 - 1340
      Abstract: Neurotensin (NT), a gut hormone and neuropeptide, increases in circulation after bariatric surgery in rodents and humans and inhibits food intake in mice. However, its potential to treat obesity and the subsequent metabolic dysfunctions have been difficult to assess owing to its short half-life in vivo. Here, we demonstrate that a long-acting, pegylated analog of the NT peptide (P-NT) reduces food intake, body weight, and adiposity in diet-induced obese mice when administered once daily for 6 days. Strikingly, when P-NT was combined with the glucagon-like peptide 1 mimetic liraglutide, the two peptides synergized to reduce food intake and body weight relative to each monotherapy, without inducing a taste aversion. Further, P-NT and liraglutide coadministration improved glycemia and reduced steatohepatitis. Finally, we show that the melanocortin pathway is central for P-NT–induced anorexia and necessary for the full synergistic effect of P-NT and liraglutide combination therapy. Overall, our data suggest that P-NT and liraglutide combination therapy could be an enhanced treatment for obesity with improved tolerability compared with liraglutide monotherapy.
      Keywords: Obesity-Animal
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db18-1009
      Issue No: Vol. 68, No. 6 (2019)
  • Skeletal Muscle-Specific Activation of Gq Signaling Maintains Glucose
    • Authors: Bone; D. B. J.; Meister, J.; Knudsen, J. R.; Dattaroy, D.; Cohen, A.; Lee, R.; Lu, H.; Metzger, D.; Jensen, T. E.; Wess, J.
      Pages: 1341 - 1352
      Abstract: Skeletal muscle (SKM) insulin resistance plays a central role in the pathogenesis of type 2 diabetes. Because G-protein–coupled receptors (GPCRs) represent excellent drug targets, we hypothesized that activation of specific functional classes of SKM GPCRs might lead to improved glucose homeostasis in type 2 diabetes. At present, little is known about the in vivo metabolic roles of the various distinct GPCR signaling pathways operative in SKM. In this study, we tested the hypothesis that selective activation of SKM Gq signaling can improve SKM glucose uptake and whole-body glucose homeostasis under physiological and pathophysiological conditions. Studies with transgenic mice expressing a Gq-linked designer GPCR selectively in SKM cells demonstrated that receptor-mediated activation of SKM Gq signaling greatly promoted glucose uptake into SKM and significantly improved glucose homeostasis in obese, glucose-intolerant mice. These beneficial metabolic effects required the activity of SKM AMPK. In contrast, obese mutant mice that lacked both Gαq and Gα11 selectively in SKM showed severe deficits in glucose homeostasis. Moreover, GPCR-mediated activation of Gq signaling also stimulated glucose uptake in primary human SKM cells. Taken together, these findings strongly suggest that agents capable of enhancing SKM Gq signaling may prove useful as novel antidiabetic drugs.
      Keywords: Integrated Physiology-Muscle
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db18-0796
      Issue No: Vol. 68, No. 6 (2019)
  • Nine Amino Acids Are Associated With Decreased Insulin Secretion and
           Elevated Glucose Levels in a 7.4-Year Follow-up Study of 5,181 Finnish Men
    • Authors: Vangipurapu; J.; Stancakova, A.; Smith, U.; Kuusisto, J.; Laakso, M.
      Pages: 1353 - 1358
      Abstract: Several amino acids (AAs) have been shown to be associated with insulin resistance and increased risk of type 2 diabetes, but no previous studies have investigated the association of AAs with insulin secretion in a longitudinal setting. Our study included 5,181 participants of the cross-sectional METabolic Syndrome In Men (METSIM) study having metabolomics data on 20 AAs. A total of 4,851 had a 7.4-year follow-up visit. Nine AAs (phenylalanine, tryptophan, tyrosine, alanine, isoleucine, leucine, valine, aspartate, and glutamate) were significantly (P < 5.8 x 10–5) associated with decreases in insulin secretion (disposition index) and the elevation of fasting or 2-h glucose levels. Five of these AAs (tyrosine, alanine, isoleucine, aspartate, and glutamate) were also found to be significantly associated with an increased risk of incident type 2 diabetes after adjustment for confounding factors. Our study is the first population-based large cohort to report that AAs are associated not only with insulin resistance but also with decreased insulin secretion.
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db18-1076
      Issue No: Vol. 68, No. 6 (2019)
  • Issues and Events
    • Pages: 1359 - 1359
      PubDate: 2019-05-20T12:00:31-07:00
      DOI: 10.2337/db19-ie06
      Issue No: Vol. 68, No. 6 (2019)
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