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Diabetes
Journal Prestige (SJR): 4.435
Citation Impact (citeScore): 6
Number of Followers: 496  
 
  Full-text available via subscription Subscription journal
ISSN (Print) 0012-1797 - ISSN (Online) 1939-327X
Published by American Diabetes Association Homepage  [4 journals]
  • Comment on Bu et al. Insulin Regulates Lipolysis and Fat Mass by
           Upregulating Growth/Differentiation Factor 3 in Adipose Tissue
           Macrophages. Diabetes 2018;67:1761-1772
    • Authors: Ibanez C. F.
      Keywords: Insulin Action-Adipocyte Biology
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db18-0984
      Issue No: Vol. 67, No. 12 (2018)
       
  • Response to Comment on Bu et al. Insulin Regulates Lipolysis and Fat Mass
           by Upregulating Growth/Differentiation Factor 3 in Adipose Tissue
           Macrophages. Diabetes 2018;67:1761-1772
    • Authors: Izumi T.
      Keywords: Insulin Action-Adipocyte Biology
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/dbi18-0037
      Issue No: Vol. 67, No. 12 (2018)
       
  • In This Issue of Diabetes
    • Pages: 2483 - 2484
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db18-ti12
      Issue No: Vol. 67, No. 12 (2018)
       
  • Targeting Metabolism, Insulin Resistance, and Diabetes to Treat
           Nonalcoholic Steatohepatitis
    • Authors: Finck B. N.
      Pages: 2485 - 2493
      Abstract: Obesity, insulin resistance, and diabetes are strongly linked to the accumulation of excessive lipids in the liver parenchyma, a condition known as nonalcoholic fatty liver disease (NAFLD). Given its association with obesity and related metabolic diseases, it is not surprising that the prevalence of NAFLD has dramatically increased in the past few decades. NAFLD has become the most common liver disease in many areas of the world. The term, NAFLD, encompasses a spectrum of disorders that ranges from simple steatosis to steatosis with inflammatory lesions (nonalcoholic steatohepatitis [NASH]). Although simple steatosis might be relatively benign, epidemiologic studies have linked NASH to greatly increased risk of developing cirrhosis and hepatocellular carcinoma. Yet despite this, there are no approved treatments for the disease, and it remains a significant unmet medical need. This Perspective will review some of the relevant literature on the topic and examine approved and experimental NASH therapeutic concepts that target intermediary metabolism, insulin resistance, and diabetes to treat this emerging public health problem.
      Keywords: Integrated Physiology-Liver
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/dbi18-0024
      Issue No: Vol. 67, No. 12 (2018)
       
  • CETP Inhibition Improves HDL Function but Leads to Fatty Liver and Insulin
           Resistance in CETP-Expressing Transgenic Mice on a High-Fat Diet
    • Authors: Zhu; L.; Luu, T.; Emfinger, C. H.; Parks, B. A.; Shi, J.; Trefts, E.; Zeng, F.; Kuklenyik, Z.; Harris, R. C.; Wasserman, D. H.; Fazio, S.; Stafford, J. M.
      Pages: 2494 - 2506
      Abstract: In clinical trials, inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels but does not robustly improve cardiovascular outcomes. Approximately two-thirds of trial participants are obese. Lower plasma CETP activity is associated with increased cardiovascular risk in human studies, and protective aspects of CETP have been observed in mice fed a high-fat diet (HFD) with regard to metabolic outcomes. To define whether CETP inhibition has different effects depending on the presence of obesity, we performed short-term anacetrapib treatment in chow- and HFD-fed CETP transgenic mice. Anacetrapib raised HDL cholesterol and improved aspects of HDL functionality, including reverse cholesterol transport, and HDL’s antioxidative capacity in HFD-fed mice was better than in chow-fed mice. Anacetrapib worsened the anti-inflammatory capacity of HDL in HFD-fed mice. The HDL proteome was markedly different with anacetrapib treatment in HFD- versus chow-fed mice. Despite benefits on HDL, anacetrapib led to liver triglyceride accumulation and insulin resistance in HFD-fed mice. Overall, our results support a physiologic importance of CETP in protecting from fatty liver and demonstrate context selectivity of CETP inhibition that might be important in obese subjects.
      Keywords: Diabetic Dyslipidemia
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db18-0474
      Issue No: Vol. 67, No. 12 (2018)
       
  • Effect of Chronic Hyperglycemia on Glucose Metabolism in Subjects With
           Normal Glucose Tolerance
    • Authors: Shannon; C.; Merovci, A.; Xiong, J.; Tripathy, D.; Lorenzo, F.; McClain, D.; Abdul-Ghani, M.; Norton, L.; DeFronzo, R. A.
      Pages: 2507 - 2517
      Abstract: Chronic hyperglycemia causes insulin resistance, but the inheritability of glucotoxicity and the underlying mechanisms are unclear. We examined the effect of 3 days of hyperglycemia on glucose disposal, enzyme activities, insulin signaling, and protein O-GlcNAcylation in skeletal muscle of individuals without (FH–) or with (FH+) family history of type 2 diabetes. Twenty-five subjects with normal glucose tolerance received a [3-3H]glucose euglycemic insulin clamp, indirect calorimetry, and vastus-lateralis biopsies before and after 3 days of saline (n = 5) or glucose (n = 10 FH– and 10 FH+) infusion to raise plasma glucose by ~45 mg/dL. At baseline, FH+ had lower insulin-stimulated glucose oxidation and total glucose disposal (TGD) but similar nonoxidative glucose disposal and basal endogenous glucose production (bEGP) compared with FH–. After 3 days of glucose infusion, bEGP and glucose oxidation were markedly increased, whereas nonoxidative glucose disposal and TGD were lower versus baseline, with no differences between FH– and FH+ subjects. Hyperglycemia doubled skeletal muscle glycogen content and impaired activation of glycogen synthase (GS), pyruvate dehydrogenase, and Akt, but protein O-GlcNAcylation was unchanged. Insulin resistance develops to a similar extent in FH– and FH+ subjects after chronic hyperglycemia, without increased protein O-GlcNAcylation. Decreased nonoxidative glucose disposal due to impaired GS activation appears to be the primary deficit in skeletal muscle glucotoxicity.
      Keywords: Integrated Physiology-Muscle
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db18-0439
      Issue No: Vol. 67, No. 12 (2018)
       
  • Distinct Neuronal Projections From the Hypothalamic Ventromedial Nucleus
           Mediate Glycemic and Behavioral Effects
    • Authors: Faber; C. L.; Matsen, M. E.; Velasco, K. R.; Damian, V.; Phan, B. A.; Adam, D.; Therattil, A.; Schwartz, M. W.; Morton, G. J.
      Pages: 2518 - 2529
      Abstract: The hypothalamic ventromedial nucleus (VMN) is implicated both in autonomic control of blood glucose and in behaviors including fear and aggression, but whether these divergent effects involve the same or distinct neuronal subsets and their projections is unknown. To address this question, we used an optogenetic approach to selectively activate the subset of VMN neurons that express neuronal nitric oxide synthase 1 (VMNNOS1 neurons) implicated in glucose counterregulation. We found that photoactivation of these neurons elicits 1) robust hyperglycemia achieved by activation of counterregulatory responses usually reserved for the physiological response to hypoglycemia and 2) defensive immobility behavior. Moreover, we show that the glucagon, but not corticosterone, response to insulin-induced hypoglycemia is blunted by photoinhibition of the same neurons. To investigate the neurocircuitry by which VMNNOS1 neurons mediate these effects, and to determine whether these diverse effects are dissociable from one another, we activated downstream VMNNOS1 projections in either the anterior bed nucleus of the stria terminalis (aBNST) or the periaqueductal gray (PAG). Whereas glycemic responses are fully recapitulated by activation of VMNNOS1 projections to the aBNST, freezing immobility occurred only upon activation of VMNNOS1 terminals in the PAG. These findings support previous evidence of a VMN->aBNST neurocircuit involved in glucose counterregulation and demonstrate that activation of VMNNOS1 neuronal projections supplying the PAG robustly elicits defensive behaviors.
      Keywords: Integrated Physiology-Central Nervous System Regulation of Metabolism
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db18-0380
      Issue No: Vol. 67, No. 12 (2018)
       
  • Paternal Exercise Improves Glucose Metabolism in Adult Offspring
    • Authors: Stanford; K. I.; Rasmussen, M.; Baer, L. A.; Lehnig, A. C.; Rowland, L. A.; White, J. D.; So, K.; De Sousa-Coelho, A. L.; Hirshman, M. F.; Patti, M.-E.; Rando, O. J.; Goodyear, L. J.
      Pages: 2530 - 2540
      Abstract: Poor paternal diet has emerged as a risk factor for metabolic disease in offspring, and alterations in sperm may be a major mechanism mediating these detrimental effects of diet. Although exercise in the general population is known to improve health, the effects of paternal exercise on sperm and offspring metabolic health are largely unknown. Here, we studied 7-week-old C57BL/6 male mice fed a chow or high-fat diet and housed either in static cages (sedentary) or cages with attached running wheels (exercise trained). After 3 weeks, one cohort of males was sacrificed and cauda sperm obtained, while the other cohort was bred with chow-fed sedentary C57BL/6 females. Offspring were chow fed, sedentary, and studied during the first year of life. We found that high-fat feeding of sires impairs glucose tolerance and increases the percentage of fat mass in both male and female offspring at 52 weeks of age. Strikingly, paternal exercise suppresses the effects of paternal high-fat diet on offspring, reversing the observed impairment in glucose tolerance, percentage of fat mass, and glucose uptake in skeletal muscles of the offspring. These changes in offspring phenotype are accompanied by changes in sperm physiology, as, for example, high-fat feeding results in decreased sperm motility, an effect normalized in males subject to exercise training. Deep sequencing of sperm reveals pronounced effects of exercise training on multiple classes of small RNAs, as multiple changes to the sperm RNA payload observed in animals consuming a high-fat diet are suppressed by exercise training. Thus, voluntary exercise training of male mice results in pronounced improvements in the metabolic health of adult male and female offspring. We provide the first in-depth analysis of small RNAs in sperm from exercise-trained males, revealing a marked change in the levels of multiple small RNAs with the potential to alter phenotypes in the next generation.
      Keywords: Exercise
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db18-0667
      Issue No: Vol. 67, No. 12 (2018)
       
  • miR-30a Remodels Subcutaneous Adipose Tissue Inflammation to Improve
           Insulin Sensitivity in Obesity
    • Authors: Koh; E.-H.; Chernis, N.; Saha, P. K.; Xiao, L.; Bader, D. A.; Zhu, B.; Rajapakshe, K.; Hamilton, M. P.; Liu, X.; Perera, D.; Chen, X.; York, B.; Trauner, M.; Coarfa, C.; Bajaj, M.; Moore, D. D.; Deng, T.; McGuire, S. E.; Hartig, S. M.
      Pages: 2541 - 2553
      Abstract: Chronic inflammation accompanies obesity and limits subcutaneous white adipose tissue (WAT) expandability, accelerating the development of insulin resistance and type 2 diabetes mellitus. MicroRNAs (miRNAs) influence expression of many metabolic genes in fat cells, but physiological roles in WAT remain poorly characterized. Here, we report that expression of the miRNA miR-30a in subcutaneous WAT corresponds with insulin sensitivity in obese mice and humans. To examine the hypothesis that restoration of miR-30a expression in WAT improves insulin sensitivity, we injected adenovirus (Adv) expressing miR-30a into the subcutaneous fat pad of diabetic mice. Exogenous miR-30a expression in the subcutaneous WAT depot of obese mice coupled improved insulin sensitivity and increased energy expenditure with decreased ectopic fat deposition in the liver and reduced WAT inflammation. High-throughput proteomic profiling and RNA-Seq suggested that miR-30a targets the transcription factor STAT1 to limit the actions of the proinflammatory cytokine interferon- (IFN-) that would otherwise restrict WAT expansion and decrease insulin sensitivity. We further demonstrated that miR-30a opposes the actions of IFN-, suggesting an important role for miR-30a in defending adipocytes against proinflammatory cytokines that reduce peripheral insulin sensitivity. Together, our data identify a critical molecular signaling axis, elements of which are involved in uncoupling obesity from metabolic dysfunction.
      Keywords: Insulin Action-Adipocyte Biology
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db17-1378
      Issue No: Vol. 67, No. 12 (2018)
       
  • miRNA Regulation of the Hyperproliferative Phenotype of Vascular Smooth
           Muscle Cells in Diabetes
    • Authors: Torella; D.; Iaconetti, C.; Tarallo, R.; Marino, F.; Giurato, G.; Veneziano, C.; Aquila, I.; Scalise, M.; Mancuso, T.; Cianflone, E.; Valeriano, C.; Marotta, P.; Tamme, L.; Vicinanza, C.; Sasso, F. C.; Cozzolino, D.; Torella, M.; Weisz, A.; Indolfi, C.
      Pages: 2554 - 2568
      Abstract: Harnessing the mechanisms underlying the exacerbated vascular remodeling in diabetes mellitus (DM) is pivotal to prevent the high toll of vascular diseases in patients with DM. miRNA regulates vascular smooth muscle cell (VSMC) phenotypic switch. However, miRNA modulation of the detrimental diabetic VSMC phenotype is underexplored. Streptozotocin-induced type 1 DM (T1DM) Wistar rats and type 2 DM (T2DM) Zucker rats underwent right carotid artery experimental angioplasty, and global miRNA/mRNA expression profiling was obtained by RNA sequencing (RNA-Seq). Two days after injury, a set of six miRNAs were found to be uniquely downregulated or upregulated in VSMCs both in T1DM and T2DM. Among these miRNAs, miR-29c and miR-204 were the most significantly misregulated in atherosclerotic plaques from patients with DM. miR-29c overexpression and miR-204 inhibition per se attenuated VSMC phenotypic switch in DM. Concomitant miR-29c overexpression and miR-204 inhibition fostered an additive reduction in VSMC proliferation. Epithelial membrane protein 2 (Emp2) and Caveolin-1 (Cav1) mRNAs were identified as direct targets of miR-29c and miR-204, respectively. Importantly, contemporary miR-29c overexpression and miR-204 inhibition in the injured artery robustly reduced arterial stenosis in DM rats. Thus, contemporaneous miR-29c activation and miR-204 inhibition in DM arterial tissues is necessary and sufficient to prevent the exaggerated VSMC growth upon injury.
      Keywords: Complications-Macrovascular-Atherosclerotic Cardiovascular Disease and Human Diabetes
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db17-1434
      Issue No: Vol. 67, No. 12 (2018)
       
  • Pygo2 Regulates Adiposity and Glucose Homeostasis via
           {beta}-Catenin-Axin2-GSK3{beta} Signaling Pathway
    • Authors: Xie; Y.-Y.; Mo, C.-L.; Cai, Y.-H.; Wang, W.-J.; Hong, X.-X.; Zhang, K.-K.; Liu, Q.-F.; Liu, Y.-J.; Hong, J.-J.; He, T.; Zheng, Z.-Z.; Mo, W.; Li, B.-A.
      Pages: 2569 - 2584
      Abstract: Wnt/β-catenin signaling plays a key role in regulating adipogenesis through indirectly inhibiting the expression of C/EBPα and peroxisome proliferator–activated receptor (PPAR); however, the detailed molecular mechanism remains poorly understood. Moreover, the factor(s) that determines the Wnt/β-catenin output level during adipogenesis is also not completely defined. In this study, we showed that Pygo2 exhibited a declined expression pattern during adipocyte differentiation, resulting in an attenuated Wnt/β-catenin output level. The mechanism study indicated that Pygo2 inhibition led to the downregulation of Axin2, a constitutive Wnt target, in the cytoplasm. Consequently, Axin2-bound GSK3β was released and translocated into the nucleus to phosphorylate C/EBPβ and Snail, resulting in an increase in the DNA binding activity of C/EBPβ and decreased protein stability of Snail, which subsequently activated the expression of C/EBPα and PPAR. Consistent with this, embryonic fibroblasts from Pygo2–/– mice exhibited spontaneous adipocyte differentiation, and adipocyte precursor–specific Pygo2-deficient mice exhibited increased adiposity with decreased energy expenditure. We further showed impaired glucose tolerance and decreased systemic insulin sensitivity in Pygo2-deficient mice. Our study revealed an association between Pygo2 function and obesity or diabetes.
      Keywords: Obesity-Animal
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db18-0311
      Issue No: Vol. 67, No. 12 (2018)
       
  • Obesity-Associated miR-199a/214 Cluster Inhibits Adipose Browning via
           PRDM16-PGC-1{alpha} Transcriptional Network
    • Authors: He; L.; Tang, M.; Xiao, T.; Liu, H.; Liu, W.; Li, G.; Zhang, F.; Xiao, Y.; Zhou, Z.; Liu, F.; Hu, F.
      Pages: 2585 - 2600
      Abstract: miRNAs are important regulators of differentiation, development, and function of brown and beige fat cells. In this study, we identify the role of the miR-199a/214 cluster in the regulation of brown and beige adipocyte development and thermogenesis in vitro and in vivo. We show that expression of the miR-199a/214 cluster is dramatically decreased during brown and beige adipocyte differentiation and in response to cold exposure or β-adrenergic receptor activation. The cluster levels are significantly upregulated in the adipose tissues of obese mice and human subjects. Overexpression of the miR-199a/214 cluster suppresses brown adipocyte differentiation and inhibits thermogenic gene expression and mitochondrial respiration, whereas knockdown of the cluster increases thermogenic gene expression and mitochondrial function in beige adipocytes. In addition, inhibition of the miR-199a/214 cluster promotes beiging effects in vivo. We further show that miR-199a/214 suppresses brown adipocyte differentiation and beige fat development by directly targeting PRDM16 and peroxisome PGC-1α, two key transcriptional regulators of adipose browning. Together, these observations reveal that the miR-199a/214 cluster is a key negative regulator of brown and beige fat development and thermogenesis.
      Keywords: Obesity-Animal
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db18-0626
      Issue No: Vol. 67, No. 12 (2018)
       
  • Glucagon-Like Peptide 1 Increases {beta}-Cell Regeneration by Promoting
           {alpha}- to {beta}-Cell Transdifferentiation
    • Authors: Lee; Y.-S.; Lee, C.; Choung, J.-S.; Jung, H.-S.; Jun, H.-S.
      Pages: 2601 - 2614
      Abstract: Glucagon-like peptide 1 (GLP-1) can increase pancreatic β-cells, and α-cells could be a source for new β-cell generation. We investigated whether GLP-1 increases β-cells through α-cell transdifferentiation. New β-cells originating from non–β-cells were significantly increased in recombinant adenovirus expressing GLP-1 (rAd-GLP-1)–treated RIP-CreER;R26-YFP mice. Proliferating α-cells were increased in islets of rAd-GLP-1–treated mice and αTC1 clone 9 (αTC1-9) cells treated with exendin-4, a GLP-1 receptor agonist. Insulin+glucagon+ cells were significantly increased by rAd-GLP-1 or exendin-4 treatment in vivo and in vitro. Lineage tracing to label the glucagon-producing α-cells showed a higher proportion of regenerated β-cells from α-cells in rAd-GLP-1–treated Glucagon-rtTA;Tet-O-Cre;R26-YFP mice than rAd producing β-galactosidase–treated mice. In addition, exendin-4 increased the expression and secretion of fibroblast growth factor 21 (FGF21) in αTC1-9 cells and β-cell–ablated islets. FGF21 treatment of β-cell–ablated islets increased the expression of pancreatic and duodenal homeobox-1 and neurogenin-3 and significantly increased insulin+glucagon+ cells. Generation of insulin+glucagon+ cells by exendin-4 was significantly reduced in islets transfected with FGF21 small interfering RNA or islets of FGF21 knockout mice. Generation of insulin+ cells by rAd-GLP-1 treatment was significantly reduced in FGF21 knockout mice compared with wild-type mice. We suggest that GLP-1 has an important role in α-cell transdifferentiation to generate new β-cells, which might be mediated, in part, by FGF21 induction.
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db18-0155
      Issue No: Vol. 67, No. 12 (2018)
       
  • Haploinsufficiency of Insm1 Impairs Postnatal Baseline {beta}-Cell Mass
    • Authors: Tao; W.; Zhang, Y.; Ma, L.; Deng, C.; Duan, H.; Liang, X.; Liao, R.; Lin, S.; Nie, T.; Chen, W.; Wang, C.; Birchmeier, C.; Jia, S.
      Pages: 2615 - 2625
      Abstract: Baseline β-cell mass is established during the early postnatal period when β-cells expand. In this study, we show that heterozygous ablation of Insm1 decreases baseline β-cell mass and subsequently impairs glucose tolerance. When exposed to a high-fat diet or on an ob/ob background, glucose intolerance was more severe in Insm1+/lacZ mice compared with Insm1+/+ mice, although no further decrease in the β-cell mass was detected. In islets of early postnatal Insm1+/lacZ mice, the cell cycle was prolonged in β-cells due to downregulation of the cell cycle gene Ccnd1. Although Insm1 had a low affinity for the Ccnd1 promoter compared with other binding sites, binding affinity was strongly dependent on Insm1 levels. We observed dramatically decreased binding of Insm1 to the Ccnd1 promoter after downregulation of Insm1 expression. Furthermore, downregulation of Ccnd1 resulted in a prolonged cell cycle, and overexpression of Ccnd1 rescued cell cycle abnormalities observed in Insm1-deficient β-cells. We conclude that decreases in Insm1 interfere with β-cell specification during the early postnatal period and impair glucose homeostasis during metabolic stress in adults. Insm1 levels are therefore a factor that can influence the development of diabetes.
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db17-1330
      Issue No: Vol. 67, No. 12 (2018)
       
  • Syntaxin 4 Expression in Pancreatic {beta}-Cells Promotes Islet Function
           and Protects Functional {beta}-Cell Mass
    • Authors: Oh; E.; Ahn, M.; Afelik, S.; Becker, T. C.; Roep, B. O.; Thurmond, D. C.
      Pages: 2626 - 2639
      Abstract: Syntaxin 4 (Stx4) enrichment in human and mouse islet grafts improves the success of transplants in reversing streptozotocin (STZ)-induced diabetes in mice, although the underlying molecular mechanisms remain elusive. Toward a further understanding of this, human islets and inducible transgenic mice that selectively overexpress Stx4 in islet β-cells (βTG-Stx4) were challenged with proinflammatory stressors in vitro and in vivo. Remarkably, βTG-Stx4 mice resisted the loss of β-cell mass and the glucose intolerance that multiple low doses of STZ induce. Under standard conditions, glucose tolerance was enhanced and mice maintained normal fasting glycemia and insulinemia. Conversely, Stx4 heterozygous knockout mice succumbed rapidly to STZ-induced glucose intolerance compared with their wild-type littermates. Human islet β-cells overexpressing Stx4 exhibited enhanced insulin secretory capability; resilience against proinflammatory cytokine–induced apoptosis; and reduced expression of the CXCL9, CXCL10, and CXCL11 genes coordinate with decreased activation/nuclear localization of nuclear factor-B. Finding ways to boost Stx4 expression presents a novel potential therapeutic avenue for promoting islet function and preserving β-cell mass.
      Keywords: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db18-0259
      Issue No: Vol. 67, No. 12 (2018)
       
  • Increase Functional {beta}-Cell Mass in Subcutaneous Alginate Capsules
           With Porcine Prenatal Islet Cells but Loss With Human Adult Islet Cells
    • Authors: De Mesmaeker; I.; Robert, T.; Suenens, K. G.; Stange, G. M.; Van Hulle, F.; Ling, Z.; Tomme, P.; Jacobs-Tulleneers-Thevissen, D.; Keymeulen, B.; Pipeleers, D. G.
      Pages: 2640 - 2649
      Abstract: Alginate (Alg)-encapsulated porcine islet cell grafts are developed to overcome limitations of human islet transplantation. They can generate functional implants in animals when prepared from fetal, perinatal, and adult pancreases. Implants have not yet been examined for efficacy to establish sustained, metabolically adequate functional β-cell mass (FBM) in comparison with human islet cells. This study in immune-compromised mice demonstrates that subcutaneous implants of Alg-encapsulated porcine prenatal islet cells with 4 x 105 β-cells form, over 10 weeks, a FBM that results in glucose-induced plasma C-peptide >2 ng/mL and metabolic control over the following 10 weeks, with higher efficiency than nonencapsulated, while failing in peritoneum. This intracapsular FBM formation involves β-cell replication, increasing number fourfold, and maturation toward human adult β-cells. Subcutaneous Alg-encapsulated human islet cells with similar β-cell number establish implants with plasma C-peptide >2 ng/mL for the first 10 weeks, with nonencapsulated cells failing; their β-cells do not replicate but progressively die (>70%), explaining C-peptide decline and insufficient metabolic control. An Alg matrix thus helps establish β-cell functions in subcutis. It allows formation of sustained metabolically adequate FBM by immature porcine β-cells with proliferative activity but not by human adult islet cells. These findings define conditions for evaluating its immune-protecting properties.
      Keywords: Transplantation
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db18-0709
      Issue No: Vol. 67, No. 12 (2018)
       
  • Reduced GLP-1 Secretion at 30 Minutes After a 75-g Oral Glucose Load Is
           Observed in Gestational Diabetes Mellitus: A Prospective Cohort Study
    • Authors: Sukumar; N.; Bagias, C.; Goljan, I.; Weldeselassie, Y.; Gharanei, S.; Tan, B. K.; Holst, J. J.; Saravanan, P.
      Pages: 2650 - 2656
      Abstract: Glucagon-like peptide 1 (GLP-1) levels may be reduced in type 2 diabetes, but whether a similar impairment exists in gestational diabetes mellitus (GDM) has not been established. We studied this in a prospective cohort study of pregnant women (n = 144) during oral glucose tolerance test (OGTT). GLP-1, glucose, and insulin were sampled at 30-min intervals during a 2-h 75-g OGTT, and indices of insulin secretion and sensitivity were calculated. In a nested case-control study, women with GDM (n = 19) had 12% lower total GLP-1 secretion area under the curve (AUC) compared with control subjects matched for age, ethnicity, and gestational age (n = 19), selected from within the lowest quartile of glucose120 min values in our cohort. GDM had lower GLP-1 response in the first 30 min (19% lower GLP-130 min and 17% lower AUC0–30 min) after adjustment for possible confounders. Their glucose levels began to diverge at 30 min of the OGTT with increasing insulin levels, and by 120 min, their insulin levels were three times higher. In a secondary cohort of 57 women that included "high-normal" glucose120 min values, low GLP-1 AUC0–30 min was independently associated with lower indices of insulin secretion and sensitivity. In conclusion, we have observed that women with GDM have lower GLP-1 response at 30 min of an OGTT and hyperglycemia at 120 min despite significant hyperinsulinemia.
      Keywords: Pregnancy-Clinical/Epidemiology
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db18-0254
      Issue No: Vol. 67, No. 12 (2018)
       
  • Lipoxins Protect Against Inflammation in Diabetes-Associated
           Atherosclerosis
    • Authors: Brennan; E. P.; Mohan, M.; McClelland, A.; de Gaetano, M.; Tikellis, C.; Marai, M.; Crean, D.; Dai, A.; Beuscart, O.; Derouiche, S.; Gray, S. P.; Pickering, R.; Tan, S. M.; Godson-Treacy, M.; Sheehan, S.; Dowdall, J. F.; Barry, M.; Belton, O.; Ali-Shah, S. T.; Guiry, P. J.; Jandeleit-Dahm, K.; Cooper, M. E.; Godson, C.; Kantharidis, P.
      Pages: 2657 - 2667
      Abstract: Increasing evidence points to the fact that defects in the resolution of inflammatory pathways predisposes individuals to the development of chronic inflammatory diseases, including diabetic complications such as accelerated atherosclerosis. The resolution of inflammation is dynamically regulated by the production of endogenous modulators of inflammation, including lipoxin A4 (LXA4). Here, we explored the therapeutic potential of LXA4 and a synthetic LX analog (Benzo-LXA4) to modulate diabetic complications in the streptozotocin-induced diabetic ApoE–/– mouse and in human carotid plaque tissue ex vivo. The development of diabetes-induced aortic plaques and inflammatory responses of aortic tissue, including the expression of vcam-1, mcp-1, il-6, and il-1β, was significantly attenuated by both LXA4 and Benzo-LXA4 in diabetic ApoE–/– mice. Importantly, in mice with established atherosclerosis, treatment with LXs for a 6-week period, initiated 10 weeks after diabetes onset, led to a significant reduction in aortic arch plaque development (19.22 ± 2.01% [diabetic]; 12.67 ± 1.68% [diabetic + LXA4]; 13.19 ± 1.97% [diabetic + Benzo-LXA4]). Secretome profiling of human carotid plaque explants treated with LXs indicated changes to proinflammatory cytokine release, including tumor necrosis factor-α and interleukin-1β. LXs also inhibited platelet-derived growth factor–stimulated vascular smooth muscle cell proliferation and transmigration and endothelial cell inflammation. These data suggest that LXs may have therapeutic potential in the context of diabetes-associated vascular complications.
      Keywords: Complications-Macrovascular-Atherosclerotic Cardiovascular Disease and Human Diabetes
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db17-1317
      Issue No: Vol. 67, No. 12 (2018)
       
  • Histone H3 Serine 10 Phosphorylation Facilitates Endothelial Activation in
           Diabetic Kidney Disease
    • Authors: Alghamdi; T. A.; Batchu, S. N.; Hadden, M. J.; Yerra, V. G.; Liu, Y.; Bowskill, B. B.; Advani, S. L.; Geldenhuys, L.; Siddiqi, F. S.; Majumder, S.; Advani, A.
      Pages: 2668 - 2681
      Abstract: The posttranslational histone modifications that epigenetically affect gene transcription extend beyond conventionally studied methylation and acetylation patterns. By examining the means by which podocytes influence the glomerular endothelial phenotype, we identified a role for phosphorylation of histone H3 on serine residue 10 (phospho-histone H3Ser10) in mediating endothelial activation in diabetes. Culture media conditioned by podocytes exposed to high glucose caused glomerular endothelial vascular cell adhesion protein 1 (VCAM-1) upregulation and was enriched for the chemokine CCL2. A neutralizing anti-CCL2 antibody prevented VCAM-1 upregulation in cultured glomerular endothelial cells, and knockout of the CCL2 receptor CCR2 diminished glomerular VCAM-1 upregulation in diabetic mice. CCL2/CCR2 signaling induced glomerular endothelial VCAM-1 upregulation through a pathway regulated by p38 mitogen-activated protein kinase, mitogen- and stress-activated protein kinases 1/2 (MSK1/2), and phosphorylation of H3Ser10, whereas MSK1/2 inhibition decreased H3Ser10 phosphorylation at the VCAM1 promoter. Finally, increased phospho-histone H3Ser10 levels were observed in the kidneys of diabetic endothelial nitric oxide synthase knockout mice and in the glomeruli of humans with diabetic kidney disease. These findings demonstrate the influence that histone protein phosphorylation may have on gene activation in diabetic kidney disease. Histone protein phosphorylation should be borne in mind when considering epigenetic targets amenable to therapeutic manipulation in diabetes.
      Keywords: Complications-Nephropathy-Basic and Experimental Science
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db18-0124
      Issue No: Vol. 67, No. 12 (2018)
       
  • FOXO1 Deletion Reverses the Effect of Diabetic-Induced Impaired Fracture
           Healing
    • Authors: Alharbi; M. A.; Zhang, C.; Lu, C.; Milovanova, T. N.; Yi, L.; Ryu, J. D.; Jiao, H.; Dong, G.; OConnor, J. P.; Graves, D. T.
      Pages: 2682 - 2694
      Abstract: Type 1 diabetes impairs fracture healing. We tested the hypothesis that diabetes affects chondrocytes to impair fracture healing through a mechanism that involves the transcription factor FOXO1. Type 1 diabetes was induced by streptozotocin in mice with FOXO1 deletion in chondrocytes (Col2α1Cre+.FOXO1L/L) or littermate controls (Col2α1Cre–.FOXO1L/L) and closed femoral fractures induced. Diabetic mice had 77% less cartilage and 30% less bone than normoglycemics evaluated histologically and by micro-computed tomography. Both were reversed with lineage-specific FOXO1 ablation. Diabetic mice had a threefold increase in osteoclasts and a two- to threefold increase in RANKL mRNA or RANKL-expressing chondrocytes compared with normoglycemics. Both parameters were rescued by FOXO1 ablation in chondrocytes. Conditions present in diabetes, high glucose (HG), and increased advanced glycation end products (AGEs) stimulated FOXO1 association with the RANKL promoter in vitro, and overexpression of FOXO1 increased RANKL promoter activity in luciferase reporter assays. HG and AGE stimulated FOXO1 nuclear localization, which was reversed by insulin and inhibitors of TLR4, histone deacetylase, nitric oxide, and reactive oxygen species. The results indicate that chondrocytes play a prominent role in diabetes-impaired fracture healing and that high levels of glucose, AGEs, and tumor necrosis factor-α, which are elevated by diabetes, alter RANKL expression in chondrocytes via FOXO1.
      Keywords: Immunology
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db18-0340
      Issue No: Vol. 67, No. 12 (2018)
       
  • Insulin Resistance and Vulnerability to Cardiac Ischemia
    • Authors: Jelenik; T.; Flögel, U.; Alvarez-Hernandez, E.; Scheiber, D.; Zweck, E.; Ding, Z.; Rothe, M.; Mastrototaro, L.; Kohlhaas, V.; Kotzka, J.; Knebel, B.; Müller-Wieland, D.; Moellendorf, S.; Gödecke, A.; Kelm, M.; Westenfeld, R.; Roden, M.; Szendroedi, J.
      Pages: 2695 - 2702
      Abstract: Hepatic and myocardial ectopic lipid deposition has been associated with insulin resistance (IR) and cardiovascular risk. Lipid overload promotes increased hepatic oxidative capacity, oxidative stress, and impaired mitochondrial efficiency, driving the progression of nonalcoholic fatty liver disease (NAFLD). We hypothesized that higher lipid availability promotes ischemia-induced cardiac dysfunction and decreases myocardial mitochondrial efficiency. Mice with adipose tissue–specific overexpression of sterol element–binding protein 1c as model of lipid overload with combined NAFLD-IR and controls underwent reperfused acute myocardial infarcts (AMIs). Whereas indexes of left ventricle (LV) contraction were similar in both groups at baseline, NAFLD-IR showed severe myocardial dysfunction post-AMI, with prominent LV reshaping and increased end-diastolic and end-systolic volumes. Hearts of NAFLD-IR displayed hypertrophy, steatosis, and IR due to 18:1/18:1-diacylglycerol–mediated protein kinase C (PKC) activation. Myocardial fatty acid–linked respiration and oxidative stress were increased, whereas mitochondrial efficiency was decreased. In humans, decreased myocardial mitochondrial efficiency of ventricle biopsies related to IR and troponin levels, a marker of impaired myocardial integrity. Taken together, increased lipid availability and IR favor susceptibility to ischemia-induced cardiac dysfunction. The diacylglycerol-PKC pathway and reduced mitochondrial efficiency both caused by myocardial lipotoxicity may contribute to the impaired LV compensation of the noninfarcted region of the myocardium.
      Keywords: Complications-Macrovascular-Atherosclerotic Cardiovascular Disease and Human Diabetes
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db18-0449
      Issue No: Vol. 67, No. 12 (2018)
       
  • Genetic Determinants of Glycemic Traits and the Risk of Gestational
           Diabetes Mellitus
    • Authors: Powe; C. E.; Nodzenski, M.; Talbot, O.; Allard, C.; Briggs, C.; Leya, M. V.; Perron, P.; Bouchard, L.; Florez, J. C.; Scholtens, D. M.; Lowe, W. L.; Hivert, M.-F.
      Pages: 2703 - 2709
      Abstract: Many common genetic polymorphisms are associated with glycemic traits and type 2 diabetes (T2D), but knowledge about genetic determinants of glycemic traits in pregnancy is limited. We tested genetic variants known to be associated with glycemic traits and T2D in the general population for associations with glycemic traits in pregnancy and gestational diabetes mellitus (GDM). Participants in two cohorts (Genetics of Glucose regulation in Gestation and Growth [Gen3G] and Hyperglycemia and Adverse Pregnancy Outcome [HAPO]) underwent oral glucose tolerance testing at 24–32 weeks’ gestation. We built genetic risk scores (GRSs) for elevated fasting glucose and insulin, reduced insulin secretion and sensitivity, and T2D, using variants discovered in studies of nonpregnant individuals. We tested for associations between these GRSs, glycemic traits in pregnancy, and GDM. In both cohorts, the fasting glucose GRS was strongly associated with fasting glucose. The insulin secretion and sensitivity GRSs were also significantly associated with these traits in Gen3G, where insulin measurements were available. The fasting insulin GRS was weakly associated with fasting insulin (Gen3G) or C-peptide (HAPO). In HAPO (207 GDM case subjects), all five GRSs (T2D, fasting glucose, fasting insulin, insulin secretion, and insulin sensitivity) were significantly associated with GDM. In Gen3G (43 GDM case subjects), both the T2D and insulin secretion GRSs were associated with GDM; effect sizes for the other GRSs were similar to those in HAPO. Thus, despite the profound changes in glycemic physiology during pregnancy, genetic determinants of fasting glucose, fasting insulin, insulin secretion, and insulin sensitivity discovered outside of pregnancy influence GDM risk.
      Keywords: Pregnancy-Clinical/Epidemiology
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db18-0203
      Issue No: Vol. 67, No. 12 (2018)
       
  • Erratum. The Adiponectin Paradox for All-Cause and Cardiovascular
           Mortality. Diabetes 2018;67:12-22
    • Authors: Menzaghi; C.; Trischitta, V.
      Pages: 2710 - 2710
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db18-er12a
      Issue No: Vol. 67, No. 12 (2018)
       
  • Issues and Events
    • Pages: 2711 - 2711
      PubDate: 2018-11-20T12:00:29-08:00
      DOI: 10.2337/db18-ie12
      Issue No: Vol. 67, No. 12 (2018)
       
 
 
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