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Journal Prestige (SJR): 4.435
Citation Impact (citeScore): 6
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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: 1909 - 1910
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/db18-ti10
      Issue No: Vol. 67, No. 10 (2018)
  • A Global Overview of Precision Medicine in Type 2 Diabetes
    • Authors: Fitipaldi; H.; McCarthy, M. I.; Florez, J. C.; Franks, P. W.
      Pages: 1911 - 1922
      Abstract: The detailed characterization of human biology and behaviors is now possible at scale owing to innovations in biomarkers, bioimaging, and wearable technologies; "big data" from electronic medical records, health insurance databases, and other platforms becoming increasingly accessible; and rapidly evolving computational power and bioinformatics methods. Collectively, these advances are creating unprecedented opportunities to better understand diabetes and many other complex traits. Identifying hidden structures within these complex data sets and linking these structures to outcome data may yield unique insights into the risk factors and natural history of diabetes, which in turn may help optimize the prevention and management of the disease. This emerging area is broadly termed "precision medicine." In this Perspective, we give an overview of the evidence and barriers to the development and implementation of precision medicine in type 2 diabetes. We also discuss recently presented paradigms through which complex data might enhance our understanding of diabetes and ultimately our ability to tackle the disease more effectively than ever before.
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/dbi17-0045
      Issue No: Vol. 67, No. 10 (2018)
  • Epigenetics and Epigenomics: Implications for Diabetes and Obesity
    • Authors: Rosen; E. D.; Kaestner, K. H.; Natarajan, R.; Patti, M.-E.; Sallari, R.; Sander, M.; Susztak, K.
      Pages: 1923 - 1931
      Abstract: The American Diabetes Association convened a research symposium, "Epigenetics and Epigenomics: Implications for Diabetes and Obesity" on 17–19 November 2017. International experts in genetics, epigenetics, computational biology, and physiology discussed the current state of understanding of the relationships between genetics, epigenetics, and environment in diabetes and examined existing evidence for the role of epigenetic factors in regulating metabolism and the risk of diabetes and its complications. The authors summarize the presentations, which highlight how the complex interactions between genes and environment may in part be mediated through epigenetic changes and how information about nutritional and other environmental stimuli can be transmitted to the next generation. In addition, the authors present expert consensus on knowledge gaps and research recommendations for the field.
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/db18-0537
      Issue No: Vol. 67, No. 10 (2018)
  • Fatty Acids and Insulin Secretion: From FFAR and Near'
    • Authors: Poitout; V.
      Pages: 1932 - 1934
      Keywords: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/dbi18-0027
      Issue No: Vol. 67, No. 10 (2018)
  • Coordination Among Lipid Droplets, Peroxisomes, and Mitochondria Regulates
           Energy Expenditure Through the CIDE-ATGL-PPAR{alpha} Pathway in Adipocytes
    • Authors: Zhou; L.; Yu, M.; Arshad, M.; Wang, W.; Lu, Y.; Gong, J.; Gu, Y.; Li, P.; Xu, L.
      Pages: 1935 - 1948
      Abstract: Metabolic homeostasis is maintained by an interplay among tissues, organs, intracellular organelles, and molecules. Cidea and Cidec are lipid droplet (LD)–associated proteins that promote lipid storage in brown adipose tissue (BAT) and white adipose tissue (WAT). Using ob/ob/Cidea–/–, ob/ob/Cidec–/–, and ob/ob/Cidea–/–/Cidec–/– mouse models and CIDE-deficient cells, we studied metabolic regulation during severe obesity to identify ways to maintain metabolic homeostasis and promote antiobesity effects. The phenotype of ob/ob/Cidea–/– mice was similar to that of ob/ob mice in terms of serum parameters, adipose tissues, lipid storage, and gene expression. Typical lipodystrophy accompanied by insulin resistance occurred in ob/ob/Cidec–/– mice, with ectopic storage of lipids in the BAT and liver. Interestingly, double deficiency of Cidea and Cidec activated both WAT and BAT to consume more energy and to increase insulin sensitivity compared with their behavior in the other three mouse models. Increased lipolysis, which occurred on the LD surfaces and released fatty acids, led to activated β-oxidation and oxidative phosphorylation in peroxisomes and mitochondria in CIDE-deficient adipocytes. The coordination among LDs, peroxisomes, and mitochondria was regulated by adipocyte triglyceride lipase (ATGL)-peroxisome proliferator–activated receptor α (PPARα). Double deficiency of Cidea and Cidec activated energy consumption in both WAT and BAT, which provided new insights into therapeutic approaches for obesity and diabetes.
      Keywords: Obesity-Animal
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/db17-1452
      Issue No: Vol. 67, No. 10 (2018)
  • Liver Glutamate Dehydrogenase Controls Whole-Body Energy Partitioning
           Through Amino Acid-Derived Gluconeogenesis and Ammonia Homeostasis
    • Authors: Karaca; M.; Martin-Levilain, J.; Grimaldi, M.; Li, L.; Dizin, E.; Emre, Y.; Maechler, P.
      Pages: 1949 - 1961
      Abstract: Ammonia detoxification and gluconeogenesis are major hepatic functions mutually connected through amino acid metabolism. The liver is rich in glutamate dehydrogenase (GDH) that catalyzes the reversible oxidative deamination of glutamate to α-ketoglutarate and ammonia, thus bridging amino acid–to–glucose pathways. Here we generated inducible liver-specific GDH-knockout mice (HepGlud1–/–) to explore the role of hepatic GDH on metabolic homeostasis. Investigation of nitrogen metabolism revealed altered ammonia homeostasis in HepGlud1–/– mice characterized by increased circulating ammonia associated with reduced detoxification process into urea. The abrogation of hepatic GDH also modified energy homeostasis. In the fasting state, HepGlud1–/– mice could barely produce glucose in response to alanine due to impaired liver gluconeogenesis. Compared with control mice, lipid consumption in HepGlud1–/– mice was favored over carbohydrates as a compensatory energy fuel. The changes in energy partitioning induced by the lack of liver GDH modified the circadian rhythm of food intake. Overall, this study demonstrates the central role of hepatic GDH as a major regulator for the maintenance of ammonia and whole-body energy homeostasis.
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/db17-1561
      Issue No: Vol. 67, No. 10 (2018)
  • Acute Nitric Oxide Synthase Inhibition Accelerates Transendothelial
           Insulin Efflux In Vivo
    • Authors: Williams; I. M.; McClatchey, P. M.; Bracy, D. P.; Valenzuela, F. A.; Wasserman, D. H.
      Pages: 1962 - 1975
      Abstract: Before insulin can stimulate glucose uptake in muscle, it must be delivered to skeletal muscle (SkM) through the microvasculature. Insulin delivery is determined by SkM perfusion and the rate of movement of insulin across the capillary endothelium. The endothelium therefore plays a central role in regulating insulin access to SkM. Nitric oxide (NO) is a key regulator of endothelial function and stimulates arterial vasodilation, which increases SkM perfusion and the capillary surface area available for insulin exchange. The effects of NO on transendothelial insulin efflux (TIE), however, are unknown. We hypothesized that acute reduction of endothelial NO would reduce TIE. However, intravital imaging of TIE in mice revealed that reduction of NO by l-NG-nitro-l-arginine methyl ester (l-NAME) enhanced the rate of TIE by ~30% and increased total extravascular insulin delivery. This accelerated TIE was associated with more rapid insulin-stimulated glucose lowering. Sodium nitroprusside, an NO donor, had no effect on TIE in mice. The effects of l-NAME on TIE were not due to changes in blood pressure alone, as a direct-acting vasoconstrictor (phenylephrine) did not affect TIE. These results demonstrate that acute NO synthase inhibition increases the permeability of capillaries to insulin, leading to an increase in delivery of insulin to SkM.
      Keywords: Integrated Physiology-Muscle
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/db18-0288
      Issue No: Vol. 67, No. 10 (2018)
  • Interaction of GLP-1 and Ghrelin on Glucose Tolerance in Healthy Humans
    • Authors: Page; L. C.; Gastaldelli, A.; Gray, S. M.; DAlessio, D. A.; Tong, J.
      Pages: 1976 - 1985
      Abstract: Emerging evidence supports the importance of ghrelin to defend against starvation-induced hypoglycemia. This effect may be mediated by inhibition of glucose-stimulated insulin secretion as well as reduced insulin sensitivity. However, administration of ghrelin during meal consumption also stimulates the release of glucagon-like peptide 1 (GLP-1), an incretin important in nutrient disposition. The objective of this study was to evaluate the interaction between ghrelin and GLP-1 on parameters of glucose tolerance following a mixed-nutrient meal. Fifteen healthy men and women completed the study. Each consumed a standard meal on four separate occasions with a superimposed infusion of 1) saline, 2) ghrelin, 3) the GLP-1 receptor antagonist exendin(9-39) (Ex9), or 4) combined ghrelin and Ex9. Similar to previous studies, infusion of ghrelin caused glucose intolerance, whereas Ex9 had a minimal effect. However, combined ghrelin and Ex9 resulted in greater postprandial glycemia than either alone, and this effect was associated with impaired β-cell function and decreased glucose clearance. These findings suggest that in the fed state, stimulation of GLP-1 mitigates some of the effect of ghrelin on glucose tolerance. This novel interaction between gastrointestinal hormones suggests a system that balances insulin secretion and glucose disposal in the fed and fasting states.
      Keywords: Integrated Physiology-Other Hormones
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/db18-0451
      Issue No: Vol. 67, No. 10 (2018)
  • Endogenous Fatty Acids Are Essential Signaling Factors of Pancreatic
           {beta}-Cells and Insulin Secretion
    • Authors: Hauke; S.; Keutler, K.; Phapale, P.; Yushchenko, D. A.; Schultz, C.
      Pages: 1986 - 1998
      Abstract: The secretion of insulin from β-cells depends on extracellular factors, in particular glucose and other small molecules, some of which act on G-protein–coupled receptors. Fatty acids (FAs) have been discussed as exogenous secretagogues of insulin for decades, especially after the FA receptor GPR40 (G-protein–coupled receptor 40) was discovered. However, the role of FAs as endogenous signaling factors has not been investigated until now. In the present work, we demonstrate that lowering endogenous FA levels in β-cell medium by stringent washing or by the application of FA-free (FAF) BSA immediately reduced glucose-induced oscillations of cytosolic Ca2+ ([Ca2+]i oscillations) in MIN6 cells and mouse primary β-cells, as well as insulin secretion. Mass spectrometry confirmed BSA-mediated removal of FAs, with palmitic, stearic, oleic, and elaidic acid being the most abundant species. [Ca2+]i oscillations in MIN6 cells recovered when BSA was replaced by buffer or as FA levels in the supernatant were restored. This was achieved by recombinant lipase–mediated FA liberation from membrane lipids, by the addition of FA-preloaded FAF-BSA, or by the photolysis of cell-impermeant caged FAs. Our combined data support the hypothesis of FAs as essential endogenous signaling factors for β-cell activity and insulin secretion.
      Keywords: Islet Biology-Signal Transduction
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/db17-1215
      Issue No: Vol. 67, No. 10 (2018)
  • Restoration of Glucose-Stimulated Cdc42-Pak1 Activation and Insulin
           Secretion by a Selective Epac Activator in Type 2 Diabetic Human Islets
    • Authors: Veluthakal; R.; Chepurny, O. G.; Leech, C. A.; Schwede, F.; Holz, G. G.; Thurmond, D. C.
      Pages: 1999 - 2011
      Abstract: Glucose metabolism stimulates cell division control protein 42 homolog (Cdc42)-p21-activated kinase (Pak1) activity and initiates filamentous actin (F-actin) cytoskeleton remodeling in pancreatic β-cells so that cytoplasmic secretory granules can translocate to the plasma membrane where insulin exocytosis occurs. Since glucose metabolism also generates cAMP in β-cells, the cross talk of cAMP signaling with Cdc42-Pak1 activation might be of fundamental importance to glucose-stimulated insulin secretion (GSIS). Previously, the type-2 isoform of cAMP-regulated guanine nucleotide exchange factor 2 (Epac2) was established to mediate a potentiation of GSIS by cAMP-elevating agents. Here we report that nondiabetic human islets and INS-1 832/13 β-cells treated with the selective Epac activator 8-pCPT-2'-O-Me-cAMP-AM exhibited Cdc42-Pak1 activation at 1 mmol/L glucose and that the magnitude of this effect was equivalent to that which was measured during stimulation with 20 mmol/L glucose in the absence of 8-pCPT-2'-O-Me-cAMP-AM. Conversely, the cAMP antagonist Rp-8-Br-cAMPS-pAB prevented glucose-stimulated Cdc42-Pak1 activation, thereby blocking GSIS while also increasing cellular F-actin content. Although islets from donors with type 2 diabetes had profound defects in glucose-stimulated Cdc42-Pak1 activation and insulin secretion, these defects were rescued by the Epac activator so that GSIS was restored. Collectively, these findings indicate an unexpected role for cAMP as a permissive or direct metabolic coupling factor in support of GSIS that is Epac2 and Cdc42-Pak1 regulated.
      Keywords: Islet Biology-Signal Transduction
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/db17-1174
      Issue No: Vol. 67, No. 10 (2018)
  • Validation of 111In-Exendin SPECT for the Determination of the {beta}-Cell
           Mass in BioBreeding Diabetes-Prone Rats
    • Authors: Brom; M.; Joosten, L.; Frielink, C.; Peeters, H.; Bos, D.; van Zanten, M.; Boerman, O.; Gotthardt, M.
      Pages: 2012 - 2018
      Abstract: The changes in β-cell mass (BCM) during the development and progression of diabetes could potentially be measured by radionuclide imaging using radiolabeled exendin. In this study, we investigated the potential of 111In-diethylenetriaminepentaacetic acid–exendin-3 (111In-exendin) in a rat model that closely mimics the development of type 1 diabetes (T1D) in humans: BioBreeding diabetes-prone (BBDP) rats. BBDP rats of 4–18 weeks of age were injected intravenously with 111In-exendin, and single-photon emission computed tomography (SPECT) images were acquired. The accumulation of the radiotracer was measured as well as the BCM and grade of insulitis by histology. 111In-exendin accumulated specifically in the islets, resulting in a linear correlation with the BCM (%) (Pearson r = 0.89, P < 0.0001, and r = 0.64 for SPECT). Insulitis did not have an influence on this correlation. These results indicate that 111In-exendin is a promising tracer to determine the BCM during the development of T1D, irrespective of the degree of insulitis.
      Keywords: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/db17-1312
      Issue No: Vol. 67, No. 10 (2018)
  • The No-Go and Nonsense-Mediated RNA Decay Pathways Are Regulated by
           Inflammatory Cytokines in Insulin-Producing Cells and Human Islets and
           Determine {beta}-Cell Insulin Biosynthesis and Survival
    • Authors: Ghiasi; S. M.; Krogh, N.; Tyrberg, B.; Mandrup-Poulsen, T.
      Pages: 2019 - 2037
      Abstract: Stress-related changes in β-cell mRNA levels result from a balance between gene transcription and mRNA decay. The regulation of RNA decay pathways has not been investigated in pancreatic β-cells. We found that no-go and nonsense-mediated RNA decay pathway components (RDPCs) and exoribonuclease complexes were expressed in INS-1 cells and human islets. Pelo, Dcp2, Dis3L2, Upf2, and Smg1/5/6/7 were upregulated by inflammatory cytokines in INS-1 cells under conditions where central β-cell mRNAs were downregulated. These changes in RDPC mRNA or corresponding protein levels were largely confirmed in INS-1 cells and rat/human islets. Cytokine-induced upregulation of Pelo, Xrn1, Dis3L2, Upf2, and Smg1/6 was reduced by inducible nitric oxide synthase inhibition, as were endoplasmic reticulum (ER) stress, inhibition of Ins1/2 mRNA, and accumulated insulin secretion. Reactive oxygen species inhibition or iron chelation did not affect RDPC expression. Pelo or Xrn1 knockdown (KD) aggravated, whereas Smg6 KD ameliorated, cytokine-induced INS-1 cell death without affecting ER stress; both increased insulin biosynthesis and medium accumulation but not glucose-stimulated insulin secretion in cytokine-exposed INS-1 cells. In conclusion, RDPCs are regulated by inflammatory stress in β-cells. RDPC KD improved insulin biosynthesis, likely by preventing Ins1/2 mRNA clearance. Pelo/Xrn1 KD aggravated, but Smg6 KD ameliorated, cytokine-mediated β-cell death, possibly through prevention of proapoptotic and antiapoptotic mRNA degradation, respectively.
      Keywords: Islet Biology-Apoptosis
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/db18-0073
      Issue No: Vol. 67, No. 10 (2018)
  • Islet-Derived eATP Fuels Autoreactive CD8+ T Cells and Facilitates the
           Onset of Type 1 Diabetes
    • Authors: Tezza; S.; Ben Nasr, M.; DAddio, F.; Vergani, A.; Usuelli, V.; Falzoni, S.; Bassi, R.; Dellepiane, S.; Fotino, C.; Rossi, C.; Maestroni, A.; Solini, A.; Corradi, D.; Giani, E.; Mameli, C.; Bertuzzi, F.; Pezzolesi, M. G.; Wasserfall, C. H.; Atkinson, M. A.; Füchtbauer, E.-M.; Ricordi, C.; Folli, F.; Di Virgilio, F.; Pileggi, A.; Dhe-Paganon, S.; Zuccotti, G. V.; Fiorina, P.
      Pages: 2038 - 2053
      Abstract: Extracellular ATP (eATP) activates T cells by engaging the P2X7R receptor. We identified two loss-of-function P2X7R mutations that are protective against type 1 diabetes (T1D) and thus hypothesized that eATP/P2X7R signaling may represent an early step in T1D onset. Specifically, we observed that in patients with newly diagnosed T1D, P2X7R is upregulated on CD8+ effector T cells in comparison with healthy control subjects. eATP is released at high levels by human/murine islets in vitro in high-glucose/inflammatory conditions, thus upregulating P2X7R on CD8+ T cells in vitro. P2X7R blockade with oxidized ATP reduces the CD8+ T cell–mediated autoimmune response in vitro and delays diabetes onset in NOD mice. Autoreactive CD8+ T-cell activation is highly dependent upon eATP/P2X7R-mediated priming, while a novel sP2X7R recombinant protein abrogates changes in metabolism and the autoimmune response associated with CD8+ T cells. eATP/P2X7R signaling facilitates the onset of autoimmune T1D by fueling autoreactive CD8+ cells and therefore represents a novel targeted therapeutic for the disorder.
      Keywords: Pediatrics-Type 1 Diabetes
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/db17-1227
      Issue No: Vol. 67, No. 10 (2018)
  • PDK4 Deficiency Suppresses Hepatic Glucagon Signaling by Decreasing cAMP
    • Authors: Park; B.-Y.; Jeon, J.-H.; Go, Y.; Ham, H. J.; Kim, J.-E.; Yoo, E. K.; Kwon, W. H.; Jeoung, N.-H.; Jeon, Y. H.; Koo, S.-H.; Kim, B.-G.; He, L.; Park, K.-G.; Harris, R. A.; Lee, I.-K.
      Pages: 2054 - 2068
      Abstract: In fasting or diabetes, gluconeogenic genes are transcriptionally activated by glucagon stimulation of the cAMP-protein kinase A (PKA)–CREB signaling pathway. Previous work showed pyruvate dehydrogenase kinase (PDK) inhibition in skeletal muscle increases pyruvate oxidation, which limits the availability of gluconeogenic substrates in the liver. However, this study found upregulation of hepatic PDK4 promoted glucagon-mediated expression of gluconeogenic genes, whereas knockdown or inhibition of hepatic PDK4 caused the opposite effect on gluconeogenic gene expression and decreased hepatic glucose production. Mechanistically, PDK4 deficiency decreased ATP levels, thus increasing phosphorylated AMPK (p-AMPK), which increased p-AMPK–sensitive phosphorylation of cyclic nucleotide phosphodiesterase 4B (p-PDE4B). This reduced cAMP levels and consequently p-CREB. Metabolic flux analysis showed that the reduction in ATP was a consequence of a diminished rate of fatty acid oxidation (FAO). However, overexpression of PDK4 increased FAO and increased ATP levels, which decreased p-AMPK and p-PDE4B and allowed greater accumulation of cAMP and p-CREB. The latter were abrogated by the FAO inhibitor etomoxir, suggesting a critical role for PDK4 in FAO stimulation and the regulation of cAMP levels. This finding strengthens the possibility of PDK4 as a target against diabetes.
      Keywords: Integrated Physiology-Liver
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/db17-1529
      Issue No: Vol. 67, No. 10 (2018)
  • ADAMTS13 Deficiency Shortens the Life Span of Mice With Experimental
    • Authors: Cassis; P.; Cerullo, D.; Zanchi, C.; Corna, D.; Lionetti, V.; Giordano, F.; Novelli, R.; Conti, S.; Casieri, V.; Matteucci, M.; Locatelli, M.; Taraboletti, G.; Villa, S.; Gastoldi, S.; Remuzzi, G.; Benigni, A.; Zoja, C.
      Pages: 2069 - 2083
      Abstract: In patients with diabetes, impaired activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13), the plasma metalloprotease that cleaves highly thrombogenic von Willebrand factor multimers, is a major risk factor of cardiovascular events. Here, using Adamts13–/– mice made diabetic by streptozotocin, we investigated the impact of the lack of ADAMTS13 on the development of diabetes-associated end-organ complications. Adamts13–/– mice experienced a shorter life span than their diabetic wild-type littermates. It was surprising that animal death was not related to the occurrence of detectable thrombotic events. The lack of ADAMTS13 drastically increased the propensity for ventricular arrhythmias during dobutamine-induced stress in diabetic mice. Cardiomyocytes of diabetic Adamts13–/– mice exhibited an aberrant distribution of the ventricular gap junction connexin 43 and increased phosphorylation of Ca2+/calmodulin-dependent kinase II (CaMKII), and with the consequent CaMKII-induced disturbance in Ca2+ handling, which underlie propensity for arrhythmia. In vitro, thrombospondin 1 (TSP1) promoted, in a paracrine manner, CaMKII phosphorylation in murine HL-1 cardiomyocytes, and ADAMTS13 acted to inhibit TSP1-induced CaMKII activation. In conclusion, the deficiency of ADAMTS13 may underlie the onset of lethal arrhythmias in diabetes through increased CaMKII phosphorylation in cardiomyocytes. Our findings disclose a novel function for ADAMTS13 beyond its antithrombotic activity.
      Keywords: Complications-Macrovascular-Atherosclerotic Cardiovascular Disease and Human Diabetes
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/db17-1508
      Issue No: Vol. 67, No. 10 (2018)
  • GDF11 Improves Angiogenic Function of EPCs in Diabetic Limb Ischemia
    • Authors: Zhang; J.; Li, Y.; Li, H.; Zhu, B.; Wang, L.; Guo, B.; Xiang, L.; Dong, J.; Liu, M.; Xiang, G.
      Pages: 2084 - 2095
      Abstract: Growth differentiation factor 11 (GDF11) has been shown to promote stem cell activity and rejuvenate the function of multiple organs in old mice, but little is known about the functions of GDF11 in the diabetic rat model of hindlimb ischemia. In this study, we found that systematic replenishment of GDF11 rescues angiogenic function of endothelial progenitor cells (EPCs) and subsequently improves vascularization and increases blood flow in diabetic rats with hindlimb ischemia. Conversely, anti-GDF11 monoclonal antibody treatment caused impairment of vascularization and thus, decreased blood flow. In vitro treatment of EPCs with recombinant GDF11 attenuated EPC dysfunction and apoptosis. Mechanistically, the GDF11-mediated positive effects could be attributed to the activation of the transforming growth factor-β/Smad2/3 and protein kinase B/hypoxia-inducible factor 1α pathways. These findings suggest that GDF11 repletion may enhance EPC resistance to diabetes-induced damage, improve angiogenesis, and thus, increase blood flow. This benefit of GDF11 may lead to a new therapeutic approach for diabetic hindlimb ischemia.
      Keywords: Foot Care-Lower Extremities
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/db17-1583
      Issue No: Vol. 67, No. 10 (2018)
  • Inflammation and Immunity Pathways Regulate Genetic Susceptibility to
           Diabetic Nephropathy
    • Authors: Gurley; S. B.; Ghosh, S.; Johnson, S. A.; Azushima, K.; Sakban, R. B.; George, S. E.; Maeda, M.; Meyer, T. W.; Coffman, T. M.
      Pages: 2096 - 2106
      Abstract: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease worldwide, but its molecular pathogenesis is not well defined, and there are no specific treatments. In humans, there is a strong genetic component determining susceptibility to DN. However, specific genes controlling DN susceptibility in humans have not been identified. In this study, we describe a mouse model combining type 1 diabetes with activation of the renin-angiotensin system (RAS), which develops robust kidney disease with features resembling human DN: heavy albuminuria, hypertension, and glomerulosclerosis. Additionally, there is a powerful effect of genetic background regulating susceptibility to nephropathy; the 129 strain is susceptible to kidney disease, whereas the C57BL/6 strain is resistant. To examine the molecular basis of this differential susceptibility, we analyzed the glomerular transcriptome of young mice early in the course of their disease. We find dramatic differences in regulation of immune and inflammatory pathways, with upregulation of proinflammatory pathways in the susceptible (129) strain and coordinate downregulation in the resistant (C57BL/6) strain. Many of these pathways are also upregulated in rat models and in humans with DN. Our studies suggest that genes controlling inflammatory responses, triggered by hyperglycemia and RAS activation, may be critical early determinants of susceptibility to DN.
      Keywords: Complications-Nephropathy-Basic and Experimental Science
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/db17-1323
      Issue No: Vol. 67, No. 10 (2018)
  • Prevention of Severe Hypoglycemia-Induced Brain Damage and Cognitive
           Impairment With Verapamil
    • Authors: Jackson; D. A.; Michael, T.; Vieira de Abreu, A.; Agrawal, R.; Bortolato, M.; Fisher, S. J.
      Pages: 2107 - 2112
      Abstract: People with insulin-treated diabetes are uniquely at risk for severe hypoglycemia-induced brain damage. Because calcium influx may mediate brain damage, we tested the hypothesis that the calcium-channel blocker, verapamil, would significantly reduce brain damage and cognitive impairment caused by severe hypoglycemia. Sprague-Dawley rats (10 weeks old) were randomly assigned to one of three treatments: 1) control hyperinsulinemic (200 mU ⋅ kg–1 ⋅ min–1)-euglycemic (80–100 mg/dL) clamps (n = 14), 2) hyperinsulinemic-hypoglycemic (10–15 mg/dL) clamps (n = 16), or 3) hyperinsulinemic-hypoglycemic clamps, followed by a single treatment with verapamil (20 mg/kg) (n = 11). Compared with euglycemic controls, hypoglycemia markedly increased dead/dying neurons in the hippocampus by 16-fold and cortex by 14-fold. Verapamil treatment strikingly decreased hypoglycemia-induced hippocampal and cortical damage, by 87% and 94%, respectively. Morris Water Maze probe trial results demonstrated that hypoglycemia induced a retention, but not encoding, memory deficit (noted by both abolished target quadrant preference and reduced target quadrant time). Verapamil treatment significantly rescued spatial memory as noted by restoration of target quadrant preference and target quadrant time. In summary, a one-time treatment with verapamil after severe hypoglycemia prevented neural damage and memory impairment caused by severe hypoglycemia. For people with insulin-treated diabetes, verapamil may be a useful drug to prevent hypoglycemia-induced brain damage.
      Keywords: Complications-Hypoglycemia
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/db18-0008
      Issue No: Vol. 67, No. 10 (2018)
  • Regulation of Human Adipose Tissue Activation, Gallbladder Size, and Bile
           Acid Metabolism by a {beta}3-Adrenergic Receptor Agonist
    • Authors: Baskin; A. S.; Linderman, J. D.; Brychta, R. J.; McGehee, S.; Anflick-Chames, E.; Cero, C.; Johnson, J. W.; OMara, A. E.; Fletcher, L. A.; Leitner, B. P.; Duckworth, C. J.; Huang, S.; Cai, H.; Garraffo, H. M.; Millo, C. M.; Dieckmann, W.; Tolstikov, V.; Chen, E. Y.; Gao, F.; Narain, N. R.; Kiebish, M. A.; Walter, P. J.; Herscovitch, P.; Chen, K. Y.; Cypess, A. M.
      Pages: 2113 - 2125
      Abstract: β3-adrenergic receptor (AR) agonists are approved to treat only overactive bladder. However, rodent studies suggest that these drugs could have other beneficial effects on human metabolism. We performed tissue receptor profiling and showed that the human β3-AR mRNA is also highly expressed in gallbladder and brown adipose tissue (BAT). We next studied the clinical implications of this distribution in 12 healthy men given one-time randomized doses of placebo, the approved dose of 50 mg, and 200 mg of the β3-AR agonist mirabegron. There was a more-than-dose-proportional increase in BAT metabolic activity as measured by [18F]-2-fluoro-D-2-deoxy-d-glucose positron emission tomography/computed tomography (medians 0.0 vs. 18.2 vs. 305.6 mL ⋅ mean standardized uptake value [SUVmean] ⋅ g/mL). Only the 200-mg dose elevated both nonesterified fatty acids (68%) and resting energy expenditure (5.8%). Previously undescribed increases in gallbladder size (35%) and reductions in conjugated bile acids were also discovered. Therefore, besides urinary bladder relaxation, the human β3-AR contributes to white adipose tissue lipolysis, BAT thermogenesis, gallbladder relaxation, and bile acid metabolism. This physiology should be considered in the development of more selective β3-AR agonists to treat obesity-related complications.
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/db18-0462
      Issue No: Vol. 67, No. 10 (2018)
  • Issues and Events
    • Pages: 2126 - 2126
      PubDate: 2018-09-20T12:00:28-07:00
      DOI: 10.2337/db18-ie10
      Issue No: Vol. 67, No. 10 (2018)
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