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Journal Cover Diabetes
  [SJR: 5.185]   [H-I: 269]   [425 followers]  Follow
    
   Full-text available via subscription Subscription journal
   ISSN (Print) 0012-1797 - ISSN (Online) 1939-327X
   Published by American Diabetes Association Homepage  [4 journals]
  • In This Issue of Diabetes
    • Pages: 2935 - 2936
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-ti12
      Issue No: Vol. 66, No. 12 (2017)
       
  • Granzyme A in the Pathogenesis of Type 1 Diabetes: The Yes and the No
    • Authors: Mandrup-Poulsen T.
      Pages: 2937 - 2939
      Keywords: Immunology
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/dbi17-0037
      Issue No: Vol. 66, No. 12 (2017)
       
  • Direct Analysis of Insulin-Specific T Cells Provides New Insights
    • Authors: James E. A.
      Pages: 2940 - 2941
      Keywords: Immunology
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/dbi17-0041
      Issue No: Vol. 66, No. 12 (2017)
       
  • Chronic Intermittent Hypoxia Impairs Insulin Sensitivity but Improves
           Whole-Body Glucose Tolerance by Activating Skeletal Muscle AMPK
    • Authors: Thomas; A.; Belaidi, E.; Moulin, S.; Horman, S.; van der Zon, G. C.; Viollet, B.; Levy, P.; Bertrand, L.; Pepin, J.-L.; Godin-Ribuot, D.; Guigas, B.
      Pages: 2942 - 2951
      Abstract: Obstructive sleep apnea syndrome is a highly prevalent disease resulting in transient respiratory arrest and chronic intermittent hypoxia (cIH). cIH is associated with insulin resistance and impaired metabolic homeostasis in rodents and humans, but the exact underlying mechanisms remain unclear. In the current study, we investigated the effects of 2 weeks of cIH (1-min cycle, fraction of inspired oxygen 21–5%, 8 h/day) on whole-body insulin sensitivity and glucose tolerance in lean mice. Although food intake and body weight were reduced compared with normoxia, cIH induced systemic insulin resistance in a hypoxia-inducible factor 1–independent manner and impaired insulin signaling in liver, white adipose tissue, and skeletal muscle. Unexpectedly, cIH improved whole-body glucose tolerance independently of changes in body weight and glucose-induced insulin response. This effect was associated with elevated phosphorylation of Thr172-AMPK and Ser237-TBC1 domain family member 1 (TBC1D1) in skeletal muscle, suggesting a tissue-specific AMPK-dependent increase in TBC1D1-driven glucose uptake. Remarkably, although food intake, body weight, and systemic insulin sensitivity were still affected, the improvement in glucose tolerance by cIH was abolished in muscle-specific AMPKα1α2–deficient mice. We conclude that cIH impairs insulin sensitivity while improving whole-body glucose tolerance by promoting specific activation of the skeletal muscle AMPK pathway.
      Keywords: Integrated Physiology-Macronutrient Metabolism and Food Intake
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-0186
      Issue No: Vol. 66, No. 12 (2017)
       
  • Adipocyte Liver Kinase b1 Suppresses Beige Adipocyte Renaissance Through
           Class IIa Histone Deacetylase 4
    • Authors: Wang; Y.; Paulo, E.; Wu, D.; Wu, Y.; Huang, W.; Chawla, A.; Wang, B.
      Pages: 2952 - 2963
      Abstract: Uncoupling protein 1+ beige adipocytes are dynamically regulated by environment in rodents and humans; cold induces formation of beige adipocytes, whereas warm temperature and nutrient excess lead to their disappearance. Beige adipocytes can form through de novo adipogenesis; however, how "beiging" characteristics are maintained afterward is largely unknown. In this study, we show that beige adipocytes formed postnatally in subcutaneous inguinal white adipose tissue lost thermogenic gene expression and multilocular morphology at the adult stage, but cold restored their beiging characteristics, a phenomenon termed beige adipocyte renaissance. Ablation of these postnatal beige adipocytes inhibited cold-induced beige adipocyte formation in adult mice. Furthermore, we demonstrated that beige adipocyte renaissance was governed by liver kinase b1 and histone deacetylase 4 in white adipocytes. Although neither presence nor thermogenic function of uncoupling protein 1+ beige adipocytes contributed to metabolic fitness in adipocyte liver kinase b1–deficient mice, our results reveal an unexpected role of white adipocytes in maintaining properties of preexisting beige adipocytes.
      Keywords: Obesity-Animal
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-0296
      Issue No: Vol. 66, No. 12 (2017)
       
  • Dissociation Between Hormonal Counterregulatory Responses and Cerebral
           Glucose Metabolism During Hypoglycemia
    • Authors: Lee; J. J.; Khoury, N.; Shackleford, A. M.; Nelson, S.; Herrera, H.; Antenor-Dorsey, J. A.; Semenkovich, K.; Shimony, J. S.; Powers, W. J.; Cryer, P. E.; Arbelaez, A. M.
      Pages: 2964 - 2972
      Abstract: Hypoglycemia is the most common complication of diabetes, causing morbidity and death. Recurrent hypoglycemia alters the cascade of physiological and behavioral responses that maintain euglycemia. The extent to which these responses are normally triggered by decreased whole-brain cerebral glucose metabolism (CMRglc) has not been resolved by previous studies. We measured plasma counterregulatory hormonal responses and whole-brain CMRglc (along with blood-to-brain glucose transport rates and brain glucose concentrations) with 1-[11C]-d-glucose positron emission tomography during hyperinsulinemic glucose clamps at nominal plasma glucose concentrations of 90, 75, 60, and 45 mg/dL (5.0, 4.2, 3.3, and 2.5 mmol/L) in 18 healthy young adults. Clear evidence of hypoglycemic physiological counterregulation was first demonstrated between 75 mg/dL (4.2 mmol/L) and 60 mg/dL (3.3 mmol/L) with increases in both plasma epinephrine (P = 0.01) and glucagon (P = 0.01). In contrast, there was no statistically significant change in CMRglc (P = 1.0) between 75 mg/dL (4.2 mmol/L) and 60 mg/dL (3.3 mmol/L), whereas CMRglc significantly decreased (P = 0.02) between 60 mg/dL (3.3 mmol/L) and 45 mg/dL (2.5 mmol/L). Therefore, the increased epinephrine and glucagon secretion with declining plasma glucose concentrations is not in response to a decrease in whole-brain CMRglc.
      Keywords: Integrated Physiology-Central Nervous System Regulation of Metabolism
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-0574
      Issue No: Vol. 66, No. 12 (2017)
       
  • JNK Activation of BIM Promotes Hepatic Oxidative Stress, Steatosis, and
           Insulin Resistance in Obesity
    • Authors: Litwak; S. A.; Pang, L.; Galic, S.; Igoillo-Esteve, M.; Stanley, W. J.; Turatsinze, J.-V.; Loh, K.; Thomas, H. E.; Sharma, A.; Trepo, E.; Moreno, C.; Gough, D. J.; Eizirik, D. L.; de Haan, J. B.; Gurzov, E. N.
      Pages: 2973 - 2986
      Abstract: The members of the BCL-2 family are crucial regulators of the mitochondrial pathway of apoptosis in normal physiology and disease. Besides their role in cell death, BCL-2 proteins have been implicated in the regulation of mitochondrial oxidative phosphorylation and cellular metabolism. It remains unclear, however, whether these proteins have a physiological role in glucose homeostasis and metabolism in vivo. In this study, we report that fat accumulation in the liver increases c-Jun N-terminal kinase–dependent BCL-2 interacting mediator of cell death (BIM) expression in hepatocytes. To determine the consequences of hepatic BIM deficiency in diet-induced obesity, we generated liver-specific BIM-knockout (BLKO) mice. BLKO mice had lower hepatic lipid content, increased insulin signaling, and improved global glucose metabolism. Consistent with these findings, lipogenic and lipid uptake genes were downregulated and lipid oxidation enhanced in obese BLKO mice. Mechanistically, BIM deficiency improved mitochondrial function and decreased oxidative stress and oxidation of protein tyrosine phosphatases, and ameliorated activation of peroxisome proliferator–activated receptor /sterol regulatory element-binding protein 1/CD36 in hepatocytes from high fat–fed mice. Importantly, short-term knockdown of BIM rescued obese mice from insulin resistance, evidenced by reduced fat accumulation and improved insulin sensitivity. Our data indicate that BIM is an important regulator of liver dysfunction in obesity and a novel therapeutic target for restoring hepatocyte function.
      Keywords: Obesity-Animal
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-0348
      Issue No: Vol. 66, No. 12 (2017)
       
  • RNA Binding Protein Ybx2 Regulates RNA Stability During Cold-Induced Brown
           Fat Activation
    • Authors: Xu; D.; Xu, S.; Kyaw, A. M. M.; Lim, Y. C.; Chia, S. Y.; Chee Siang, D. T.; Alvarez-Dominguez, J. R.; Chen, P.; Leow, M. K.-S.; Sun, L.
      Pages: 2987 - 3000
      Abstract: Recent years have seen an upsurge of interest in brown adipose tissue (BAT) to combat the epidemic of obesity and diabetes. How its development and activation are regulated at the posttranscriptional level, however, has yet to be fully understood. RNA binding proteins (RBPs) lie in the center of posttranscriptional regulation. To systemically study the role of RBPs in BAT, we profiled >400 RBPs in different adipose depots and identified Y-box binding protein 2 (Ybx2) as a novel regulator in BAT activation. Knockdown of Ybx2 blocks brown adipogenesis, whereas its overexpression promotes BAT marker expression in brown and white adipocytes. Ybx2-knockout mice could form BAT but failed to express a full thermogenic program. Integrative analysis of RNA sequencing and RNA-immunoprecipitation study revealed a set of Ybx2’s mRNA targets, including Pgc1α, that were destabilized by Ybx2 depletion during cold-induced activation. Thus, Ybx2 is a novel regulator that controls BAT activation by regulating mRNA stability.
      Keywords: Obesity-Animal
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-0655
      Issue No: Vol. 66, No. 12 (2017)
       
  • Objectively Measured Physical Activity, Sedentary Behavior, and Genetic
           Predisposition to Obesity in U.S. Hispanics/Latinos: Results From the
           Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
    • Authors: Moon; J.-Y.; Wang, T.; Sofer, T.; North, K. E.; Isasi, C. R.; Cai, J.; Gellman, M. D.; Moncrieft, A. E.; Sotres-Alvarez, D.; Argos, M.; Kaplan, R. C.; Qi, Q.
      Pages: 3001 - 3012
      Abstract: Studies using self-reported data suggest a gene–physical activity interaction on obesity, yet the influence of sedentary behavior, distinct from a lack of physical activity, on genetic associations with obesity remains unclear. We analyzed interactions of accelerometer-measured moderate to vigorous physical activity (MVPA) and time spent sedentary with genetic variants on obesity among 9,645 U.S. Hispanics/Latinos. An overall genetic risk score (GRS), a central nervous system (CNS)–related GRS, and a non-CNS-related GRS were calculated based on 97 BMI-associated single nucleotide polymorphisms (SNPs). Genetic association with BMI was stronger in individuals with lower MVPA (first tertile) versus higher MVPA (third tertile) (β = 0.78 kg/m2 [SE, 0.10 kg/m2] vs. 0.39 kg/m2 [0.09 kg/m2] per SD increment of GRS; Pinteraction = 0.005), and in those with more time spent sedentary (third tertile) versus less time spent sedentary (first tertile) (β = 0.73 kg/m2 [SE, 0.10 kg/m2] vs. 0.44 kg/m2 [0.09 kg/m2]; Pinteraction = 0.006). Similar significant interaction patterns were observed for obesity risk, body fat mass, fat percentage, fat mass index, and waist circumference, but not for fat-free mass. The CNS-related GRS, but not the non-CNS-related GRS, showed significant interactions with MVPA and sedentary behavior, with effects on BMI and other adiposity traits. Our data suggest that both increasing physical activity and reducing sedentary behavior may attenuate genetic associations with obesity, although the independence of these interaction effects needs to be investigated further.
      Keywords: Obesity-Human
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-0573
      Issue No: Vol. 66, No. 12 (2017)
       
  • Glucose-Induced Changes in Gene Expression in Human Pancreatic Islets:
           Causes or Consequences of Chronic Hyperglycemia
    • Authors: Ottosson-Laakso; E.; Krus, U.; Storm, P.; Prasad, R. B.; Oskolkov, N.; Ahlqvist, E.; Fadista, J.; Hansson, O.; Groop, L.; Vikman, P.
      Pages: 3013 - 3028
      Abstract: Dysregulation of gene expression in islets from patients with type 2 diabetes (T2D) might be causally involved in the development of hyperglycemia, or it could develop as a consequence of hyperglycemia (i.e., glucotoxicity). To separate the genes that could be causally involved in pathogenesis from those likely to be secondary to hyperglycemia, we exposed islets from human donors to normal or high glucose concentrations for 24 h and analyzed gene expression. We compared these findings with gene expression in islets from donors with normal glucose tolerance and hyperglycemia (including T2D). The genes whose expression changed in the same direction after short-term glucose exposure, as in T2D, were considered most likely to be a consequence of hyperglycemia. Genes whose expression changed in hyperglycemia but not after short-term glucose exposure, particularly those that also correlated with insulin secretion, were considered the strongest candidates for causal involvement in T2D. For example, ERO1LB, DOCK10, IGSF11, and PRR14L were downregulated in donors with hyperglycemia and correlated positively with insulin secretion, suggesting a protective role, whereas TMEM132C was upregulated in hyperglycemia and correlated negatively with insulin secretion, suggesting a potential pathogenic role. This study provides a catalog of gene expression changes in human pancreatic islets after exposure to glucose.
      Keywords: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-0311
      Issue No: Vol. 66, No. 12 (2017)
       
  • Stress-Induced MicroRNA-708 Impairs {beta}-Cell Function and Growth
    • Authors: Rodriguez-Comas; J.; Moreno-Asso, A.; Moreno-Vedia, J.; Martin, M.; Castano, C.; Marza-Florensa, A.; Bofill-De Ros, X.; Mir-Coll, J.; Montane, J.; Fillat, C.; Gasa, R.; Novials, A.; Servitja, J.-M.
      Pages: 3029 - 3040
      Abstract: The pancreatic β-cell transcriptome is highly sensitive to external signals such as glucose oscillations and stress cues. MicroRNAs (miRNAs) have emerged as key factors in gene expression regulation. Here, we aimed to identify miRNAs that are modulated by glucose in mouse pancreatic islets. We identified miR-708 as the most upregulated miRNA in islets cultured at low glucose concentrations, a setting that triggers a strong stress response. miR-708 was also potently upregulated by triggering endoplasmic reticulum (ER) stress with thapsigargin and in islets of ob/ob mice. Low-glucose induction of miR-708 was blocked by treatment with the chemical chaperone 4-phenylbutyrate, uncovering the involvement of ER stress in this response. An integrative analysis identified neuronatin (Nnat) as a potential glucose-regulated target of miR-708. Indeed, Nnat expression was inversely correlated with miR-708 in islets cultured at different glucose concentrations and in ob/ob mouse islets and was reduced after miR-708 overexpression. Consistent with the role of Nnat in the secretory function of β-cells, miR-708 overexpression impaired glucose-stimulated insulin secretion (GSIS), which was recovered by NNAT overexpression. Moreover, miR-708 inhibition recovered GSIS in islets cultured at low glucose. Finally, miR-708 overexpression suppressed β-cell proliferation and induced β-cell apoptosis. Collectively, our results provide a novel mechanism of glucose regulation of β-cell function and growth by repressing stress-induced miR-708.
      Keywords: Islet Biology-Apoptosis
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db16-1569
      Issue No: Vol. 66, No. 12 (2017)
       
  • Granzyme A Deficiency Breaks Immune Tolerance and Promotes Autoimmune
           Diabetes Through a Type I Interferon-Dependent Pathway
    • Authors: Mollah; Z. U. A.; Quah, H. S.; Graham, K. L.; Jhala, G.; Krishnamurthy, B.; Dharma, J. F. M.; Chee, J.; Trivedi, P. M.; Pappas, E. G.; Mackin, L.; Chu, E. P. F.; Akazawa, S.; Fynch, S.; Hodson, C.; Deans, A. J.; Trapani, J. A.; Chong, M. M. W.; Bird, P. I.; Brodnicki, T. C.; Thomas, H. E.; Kay, T. W. H.
      Pages: 3041 - 3050
      Abstract: Granzyme A is a protease implicated in the degradation of intracellular DNA. Nucleotide complexes are known triggers of systemic autoimmunity, but a role in organ-specific autoimmune disease has not been demonstrated. To investigate whether such a mechanism could be an endogenous trigger for autoimmunity, we examined the impact of granzyme A deficiency in the NOD mouse model of autoimmune diabetes. Granzyme A deficiency resulted in an increased incidence in diabetes associated with accumulation of ssDNA in immune cells and induction of an interferon response in pancreatic islets. Central tolerance to proinsulin in transgenic NOD mice was broken on a granzyme A–deficient background. We have identified a novel endogenous trigger for autoimmune diabetes and an in vivo role for granzyme A in maintaining immune tolerance.
      Keywords: Immunology
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-0517
      Issue No: Vol. 66, No. 12 (2017)
       
  • Increased Effector Memory Insulin-Specific CD4+ T Cells Correlate With
           Insulin Autoantibodies in Patients With Recent-Onset Type 1 Diabetes
    • Authors: Spanier; J. A.; Sahli, N. L.; Wilson, J. C.; Martinov, T.; Dileepan, T.; Burrack, A. L.; Finger, E. B.; Blazar, B. R.; Michels, A. W.; Moran, A.; Jenkins, M. K.; Fife, B. T.
      Pages: 3051 - 3060
      Abstract: Type 1 diabetes (T1D) results from T cell–mediated destruction of insulin-producing β-cells. Insulin represents a key self-antigen in disease pathogenesis, as recent studies identified proinsulin-responding T cells from inflamed pancreatic islets of organ donors with recent-onset T1D. These cells respond to an insulin B-chain (InsB) epitope presented by the HLA-DQ8 molecule associated with high T1D risk. Understanding insulin-specific T-cell frequency and phenotype in peripheral blood is now critical. We constructed fluorescent InsB10–23:DQ8 tetramers, stained peripheral blood lymphocytes directly ex vivo, and show DQ8+ patients with T1D have increased tetramer+ CD4+ T cells compared with HLA-matched control subjects without diabetes. Patients with a shorter disease duration had higher frequencies of insulin-reactive CD4+ T cells, with most of these cells being antigen experienced. We also demonstrate that the number of insulin tetramer+ effector memory cells is directly correlated with insulin antibody titers, suggesting insulin-specific T- and B-cell interactions. Notably, one of four control subjects with tetramer+ cells was a first-degree relative who had insulin-specific cells with an effector memory phenotype, potentially representing an early marker of T-cell autoimmunity. Our results suggest that studying InsB10–23:DQ8 reactive T-cell frequency and phenotype may provide a biomarker of disease activity in patients with T1D and those at risk.
      Keywords: Immunology
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-0666
      Issue No: Vol. 66, No. 12 (2017)
       
  • Type 1 Interferons Potentiate Human CD8+ T-Cell Cytotoxicity Through a
           STAT4- and Granzyme B-Dependent Pathway
    • Authors: Newby; B. N.; Brusko, T. M.; Zou, B.; Atkinson, M. A.; Clare-Salzler, M.; Mathews, C. E.
      Pages: 3061 - 3071
      Abstract: Events defining the progression to human type 1 diabetes (T1D) have remained elusive owing to the complex interaction between genetics, the immune system, and the environment. Type 1 interferons (T1-IFN) are known to be a constituent of the autoinflammatory milieu within the pancreas of patients with T1D. However, the capacity of IFNα/β to modulate human activated autoreactive CD8+ T-cell (cytotoxic T lymphocyte) responses within the islets of patients with T1D has not been investigated. Here, we engineer human β-cell–specific cytotoxic T lymphocytes and demonstrate that T1-IFN augments cytotoxicity by inducing rapid phosphorylation of STAT4, resulting in direct binding at the granzyme B promoter within 2 h of exposure. The current findings provide novel insights concerning the regulation of effector function by T1-IFN in human antigen-experienced CD8+ T cells and provide a mechanism by which the presence of T1-IFN potentiates diabetogenicity within the autoimmune islet.
      Keywords: Immunology
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-0106
      Issue No: Vol. 66, No. 12 (2017)
       
  • Hyperlipidemia-Induced MicroRNA-155-5p Improves {beta}-Cell Function by
           Targeting Mafb
    • Authors: Zhu; M.; Wei, Y.; Geissler, C.; Abschlag, K.; Corbalan Campos, J.; Hristov, M.; Möllmann, J.; Lehrke, M.; Karshovska, E.; Schober, A.
      Pages: 3072 - 3084
      Abstract: A high-fat diet increases bacterial lipopolysaccharide (LPS) in the circulation and thereby stimulates glucagon-like peptide 1 (GLP-1)–mediated insulin secretion by upregulating interleukin-6 (IL-6). Although microRNA-155-5p (miR-155-5p), which increases IL-6 expression, is upregulated by LPS and hyperlipidemia and patients with familial hypercholesterolemia less frequently develop diabetes, the role of miR-155-5p in the islet stress response to hyperlipidemia is unclear. In this study, we demonstrate that hyperlipidemia-associated endotoxemia upregulates miR-155-5p in murine pancreatic β-cells, which improved glucose metabolism and the adaptation of β-cells to obesity-induced insulin resistance. This effect of miR-155-5p is because of suppression of v-maf musculoaponeurotic fibrosarcoma oncogene family, protein B, which promotes β-cell function through IL-6–induced GLP-1 production in α-cells. Moreover, reduced GLP-1 levels are associated with increased obesity progression, dyslipidemia, and atherosclerosis in hyperlipidemic Mir155 knockout mice. Hence, induction of miR-155-5p expression in β-cells by hyperlipidemia-associated endotoxemia improves the adaptation of β-cells to insulin resistance and represents a protective mechanism in the islet stress response.
      Keywords: Islet Biology-Signal Transduction
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-0313
      Issue No: Vol. 66, No. 12 (2017)
       
  • Increased Lipolysis, Diminished Adipose Tissue Insulin Sensitivity, and
           Impaired {beta}-Cell Function Relative to Adipose Tissue Insulin
           Sensitivity in Obese Youth With Impaired Glucose Tolerance
    • Authors: Kim; J. Y.; Nasr, A.; Tfayli, H.; Bacha, F.; Michaliszyn, S. F.; Arslanian, S.
      Pages: 3085 - 3090
      Abstract: Despite evidence of insulin resistance and β-cell dysfunction in glucose metabolism in youth with prediabetes, the relationship between adipose tissue insulin sensitivity (ATIS) and β-cell function remains unknown. We investigated whole-body lipolysis, ATIS, and β-cell function relative to ATIS (adipose disposition index [DI]) in obese youth with impaired glucose tolerance (IGT) versus normal glucose tolerance (NGT). Whole-body lipolysis (glycerol appearance rate [GlyRa], [2H5]glycerol at baseline and during a hyperinsulinemic-euglycemic clamp), lipid oxidation (indirect calorimetry), insulin secretion (2-h hyperglycemic clamp), and body composition (dual-energy X-ray absorptiometry) were examined. Adipose DI was calculated as ATIS: (1/GlyRa x fasting insulin) x first-phase insulin secretion. Despite similar percent body fat, youth with IGT versus NGT had higher GlyRa, lower ATIS at baseline and during hyperinsulinemia, and higher lipid oxidation. Adipose DI was ~43% lower in youth with IGT and correlated positively with glucose DI. The lower ATIS and diminished adipose DI in IGT versus NGT is in line with the compromised glucose metabolism reflected in impaired β-cell function relative to peripheral insulin resistance. We conclude that youth with IGT manifest a global decline in insulin sensitivity, including impaired insulin action in suppressing lipolysis and lipid oxidation, accompanied by β-cell dysfunction in fat and glucose metabolism, enhancing their risk of type 2 diabetes.
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-0551
      Issue No: Vol. 66, No. 12 (2017)
       
  • Severe Hypoglycemia-Induced Fatal Cardiac Arrhythmias Are Augmented by
           Diabetes and Attenuated by Recurrent Hypoglycemia
    • Authors: Reno; C. M.; VanderWeele, J.; Bayles, J.; Litvin, M.; Skinner, A.; Jordan, A.; Daphna-Iken, D.; Fisher, S. J.
      Pages: 3091 - 3097
      Abstract: We previously demonstrated that insulin-mediated severe hypoglycemia induces lethal cardiac arrhythmias. However, whether chronic diabetes and insulin deficiency exacerbates, and whether recurrent antecedent hypoglycemia ameliorates, susceptibility to arrhythmias remains unknown. Thus, adult Sprague-Dawley rats were randomized into four groups: 1) nondiabetic (NONDIAB), 2) streptozotocin-induced insulin deficiency (STZ), 3) STZ with antecedent recurrent (3 days) hypoglycemia (~40–45 mg/dL, 90 min) (STZ+RH), and 4) insulin-treated STZ (STZ+Ins). Following treatment protocols, all rats underwent hyperinsulinemic (0.2 units ⋅ kg–1 ⋅ min–1), severe hypoglycemic (10–15 mg/dL) clamps for 3 h with continuous electrocardiographic recordings. During matched nadirs of severe hypoglycemia, rats in the STZ+RH group required a 1.7-fold higher glucose infusion rate than those in the STZ group, consistent with the blunted epinephrine response. Second-degree heart block was increased 12- and 6.8-fold in the STZ and STZ+Ins groups, respectively, compared with the NONDIAB group, yet this decreased 5.4-fold in the STZ+RH group compared with the STZ group. Incidence of third-degree heart block in the STZ+RH group was 5.6%, 7.8-fold less than the incidence in the STZ group (44%). Mortality due to severe hypoglycemia was 5% in the STZ+RH group, 6.2-fold less than that in the STZ group (31%). In summary, severe hypoglycemia–induced cardiac arrhythmias were increased by insulin deficiency and diabetes and reduced by antecedent recurrent hypoglycemia. In this model, recurrent moderate hypoglycemia reduced fatal severe hypoglycemia–induced cardiac arrhythmias.
      Keywords: Complications-Hypoglycemia
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-0306
      Issue No: Vol. 66, No. 12 (2017)
       
  • Retinal Microperimetry: A New Tool for Identifying Patients With Type 2
           Diabetes at Risk for Developing Alzheimer Disease
    • Authors: Ciudin; A.; Simo-Servat, O.; Hernandez, C.; Arcos, G.; Diego, S.; Sanabria, A.; Sotolongo, O.; Hernandez, I.; Boada, M.; Simo, R.
      Pages: 3098 - 3104
      Abstract: Type 2 diabetes is associated with a high risk of cognitive impairment and dementia. Therefore, strategies are needed to identify patients who are at risk for dementia. Given that the retina is a brain-derived tissue, it may provide a noninvasive way to examine brain pathology. The aims of this study were to evaluate whether retinal sensitivity 1) correlates with the specific parameters of brain imaging related to cognitive impairment and 2) discriminates patients with diabetes with mild cognitive impairment (MCI) from those with normal cognition and those with Alzheimer disease (AD). For this purpose, a prospective, nested case-control study was performed and included 35 patients with type 2 diabetes without cognitive impairment, 35 with MCI, and 35 with AD. Retinal sensitivity was assessed by Macular Integrity Assessment microperimetry, and a neuropsychological evaluation was performed. Brain neurodegeneration was assessed by MRI and fludeoxyglucose-18 positron emission tomography (18FDG-PET). A significant correlation was found between retinal sensitivity and the MRI and 18FDG-PET parameters related to brain neurodegeneration. Retinal sensitivity was related to cognitive status (normocognitive > MCI > AD; P < 0.0001). Our results suggest that retinal sensitivity assessed by microperimetry is related to brain neurodegeneration and could be a useful biomarker for identifying patients with type 2 diabetes who are at risk for developing AD.
      Keywords: Complications-Retinopathy
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-0382
      Issue No: Vol. 66, No. 12 (2017)
       
  • Effect of Exercise-Induced Lactate Elevation on Brain Lactate Levels
           During Hypoglycemia in Patients With Type 1 Diabetes and Impaired
           Awareness of Hypoglycemia
    • Authors: Wiegers; E. C.; Rooijackers, H. M.; Tack, C. J.; Groenewoud, H. J. M. M.; Heerschap, A.; de Galan, B. E.; van der Graaf, M.
      Pages: 3105 - 3110
      Abstract: Since altered brain lactate handling has been implicated in the development of impaired awareness of hypoglycemia (IAH) in type 1 diabetes, the capacity to transport lactate into the brain during hypoglycemia may be relevant in its pathogenesis. High-intensity interval training (HIIT) increases plasma lactate levels. We compared the effect of HIIT-induced hyperlacticacidemia on brain lactate during hypoglycemia between 1) patients with type 1 diabetes and IAH, 2) patients with type 1 diabetes and normal awareness of hypoglycemia, and 3) healthy participants without diabetes (n = 6 per group). All participants underwent a hypoglycemic (2.8 mmol/L) clamp after performing a bout of HIIT on a cycle ergometer. Before HIIT (baseline) and during hypoglycemia, brain lactate levels were determined continuously with J-difference–editing 1H-MRS, and time curves were analyzed using nonlinear mixed-effects modeling. At the beginning of hypoglycemia (after HIIT), brain lactate levels were elevated in all groups but most pronounced in patients with IAH. During hypoglycemia, brain lactate decreased ~30% below baseline in patients with IAH but returned to baseline levels and remained there in the other two groups. Our results support the concept of enhanced lactate transport as well as increased lactate oxidation in patients with type 1 diabetes and IAH.
      Keywords: Complications-Hypoglycemia
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-0794
      Issue No: Vol. 66, No. 12 (2017)
       
  • MicroRNA-146a Mimics Reduce the Peripheral Neuropathy in Type 2 Diabetic
           Mice
    • Authors: Liu; X. S.; Fan, B.; Szalad, A.; Jia, L.; Wang, L.; Wang, X.; Pan, W.; Zhang, L.; Zhang, R.; Hu, J.; Zhang, X. M.; Chopp, M.; Zhang, Z. G.
      Pages: 3111 - 3121
      Abstract: MicroRNA-146a (miR-146a) regulates multiple immune diseases. However, the role of miR-146a in diabetic peripheral neuropathy (DPN) has not been investigated. We found that mice (db/db) with type 2 diabetes exhibited substantial downregulation of miR-146a in sciatic nerve tissue. Systemic administration of miR-146a mimics to diabetic mice elevated miR-146a levels in plasma and sciatic nerve tissue and substantially increased motor and sensory nerve conduction velocities by 29 and 11%, respectively, and regional blood flow by 50% in sciatic nerve tissue. Treatment with miR-146a mimics also considerably decreased the response in db/db mice to thermal stimuli thresholds. Histopathological analysis showed that miR-146a mimics markedly augmented the density of fluorescein isothiocyanate–dextran-perfused blood vessels and increased the number of intraepidermal nerve fibers, myelin thickness, and axonal diameters of sciatic nerves. In addition, miR-146a treatment reduced and increased classically and alternatively activated macrophage phenotype markers, respectively. Analysis of miRNA target array revealed that miR-146a mimics greatly suppressed expression of many proinflammatory genes and downstream related cytokines. Collectively, our data indicate that treatment of diabetic mice with miR-146a mimics robustly reduces DPN and that suppression of hyperglycemia-induced proinflammatory genes by miR-146a mimics may underlie its therapeutic effect.
      Keywords: Complications-Neuropathy
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db16-1182
      Issue No: Vol. 66, No. 12 (2017)
       
  • The Influence of Type 1 Diabetes Genetic Susceptibility Regions, Age, Sex,
           and Family History on the Progression From Multiple Autoantibodies to Type
           1 Diabetes: A TEDDY Study Report
    • Authors: Krischer; J. P.; Liu, X.; Lernmark, A.; Hagopian, W. A.; Rewers, M. J.; She, J.-X.; Toppari, J.; Ziegler, A.-G.; Akolkar, B.; on behalf of the TEDDY Study Group
      Pages: 3122 - 3129
      Abstract: This article seeks to determine whether factors related to autoimmunity risk remain significant after the initiation of two or more diabetes-related autoantibodies and continue to contribute to type 1 diabetes (T1D) risk among autoantibody-positive children in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Characteristics included are age at multiple autoantibody positivity, sex, selected high-risk HLA-DR-DQ genotypes, relationship to a family member with T1D, autoantibody at seroconversion, INS gene (rs1004446_A), and non-HLA gene polymorphisms identified by the Type 1 Diabetes Genetics Consortium (T1DGC). The risk of progression to T1D was not different among those with or without a family history of T1D (P = 0.39) or HLA-DR-DQ genotypes (P = 0.74). Age at developing multiple autoantibodies (hazard ratio = 0.96 per 1-month increase in age; 95% CI 0.95, 0.97; P < 0.001) and the type of first autoantibody (when more than a single autoantibody was the first-appearing indication of seroconversion [P = 0.006]) were statistically significant. Female sex was also a significant risk factor (P = 0.03). Three single nucleotide polymorphisms were associated with increased diabetes risk (rs10517086_A [P = 0.03], rs1534422_G [P = 0.006], and rs2327832_G [P = 0.03] in TNFAIP3) and one with decreased risk (rs1004446_A in INS [P = 0.006]). The TEDDY data suggest that non-HLA gene polymorphisms may play a different role in the initiation of autoimmunity than they do in progression to T1D once autoimmunity has appeared. The strength of these associations may be related to the age of the population and the high-risk HLA-DR-DQ subtypes studied.
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-0261
      Issue No: Vol. 66, No. 12 (2017)
       
  • Genetically Determined Plasma Lipid Levels and Risk of Diabetic
           Retinopathy: A Mendelian Randomization Study
    • Authors: Sobrin; L.; Chong, Y. H.; Fan, Q.; Gan, A.; Stanwyck, L. K.; Kaidonis, G.; Craig, J. E.; Kim, J.; Liao, W.-L.; Huang, Y.-C.; Lee, W.-J.; Hung, Y.-J.; Guo, X.; Hai, Y.; Ipp, E.; Pollack, S.; Hancock, H.; Price, A.; Penman, A.; Mitchell, P.; Liew, G.; Smith, A. V.; Gudnason, V.; Tan, G.; Klein, B. E. K.; Kuo, J.; Li, X.; Christiansen, M. W.; Psaty, B. M.; Sandow, K.; Asian Genetic Epidemiology Network Consortium; Jensen, R. A.; Klein, R.; Cotch, M. F.; Wang, J. J.; Jia, Y.; Chen, C. J.; Chen, Y.-D. I.; Rotter, J. I.; Tsai, F.-J.; Hanis, C. L.; Burdon, K. P.; Wong, T. Y.; Cheng, C.-Y.
      Pages: 3130 - 3141
      Abstract: Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.
      Keywords: Complications-Retinopathy
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-0398
      Issue No: Vol. 66, No. 12 (2017)
       
  • Erratum. Deletion of ATF4 in AgRP Neurons Promotes Fat Loss Mainly via
           Increasing Energy Expenditure. Diabetes 2017;66:640-650
    • Authors: Deng; J.; Yuan, F.; Guo, Y.; Xiao, Y.; Niu, Y.; Deng, Y.; Han, X.; Guan, Y.; Chen, S.; Guo, F.
      Pages: 3142 - 3142
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-er12a
      Issue No: Vol. 66, No. 12 (2017)
       
  • Erratum. Pathophysiological Mechanism of Bone Loss in Type 2 Diabetes
           Involves Inverse Regulation of Osteoblast Function by PGC-1{alpha} and
           Skeletal Muscle Atrogenes: AdipoR1 as a Potential Target for Reversing
           Diabetes-Induced Osteopenia. Diabetes 2015;64:2609-2623
    • Authors: Khan; M. P.; Singh, A. K.; Joharapurkar, A. A.; Yadav, M.; Shree, S.; Kumar, H.; Gurjar, A.; Mishra, J. S.; Tiwari, M. C.; Nagar, G. K.; Kumar, S.; Ramachandran, R.; Sharan, A.; Jain, M. R.; Trivedi, A. K.; Maurya, R.; Godbole, M. M.; Gayen, J. R.; Sanyal, S.; Chattopadhyay, N.
      Pages: 3142 - 3143
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-er12b
      Issue No: Vol. 66, No. 12 (2017)
       
  • Erratum. Mediobasal Hypothalamic SIRT1 Is Essential for Resveratrols
           Effects on Insulin Action in Rats. Diabetes 2011;60:2691-2700
    • Authors: Knight; C. M.; Gutierrez-Juarez, R.; Lam, T. K. T.; Arrieta-Cruz, I.; Huang, L.; Schwartz, G.; Barzilai, N.; Rossetti, L.
      Pages: 3143 - 3144
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-er12c
      Issue No: Vol. 66, No. 12 (2017)
       
  • Erratum. Direct Substrate Delivery Into Mitochondrial Fission-Deficient
           Pancreatic Islets Rescues Insulin Secretion. Diabetes 2017;66:1247-1257
    • Authors: Kabra; U. D.; Pfuhlmann, K.; Migliorini, A.; Keipert, S.; Lamp, D.; Korsgren, O.; Gegg, M.; Woods, S. C.; Pfluger, P. T.; Lickert, H.; Affourtit, C.; Tschöp, M. H.; Jastroch, M.
      Pages: 3144 - 3144
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-er12d
      Issue No: Vol. 66, No. 12 (2017)
       
  • Erratum. DDB1-Mediated CRY1 Degradation Promotes FOXO1-Driven
           Gluconeogenesis in Liver. Diabetes 2017;66:2571-2582
    • Authors: Tong; X.; Zhang, D.; Charney, N.; Jin, E.; VanDommelon, K.; Stamper, K.; Gupta, N.; Saldate, J.; Yin, L.
      Pages: 3144 - 3144
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-er12e
      Issue No: Vol. 66, No. 12 (2017)
       
  • Erratum. Genetic Disruption of Adenosine Kinase in Mouse Pancreatic
           {beta}-Cells Protects Against High-Fat Diet-Induced Glucose Intolerance.
           Diabetes 2017;66:1928-1938
    • Authors: Navarro; G.; Abdolazami, Y.; Zhao, Z.; Xu, H.; Lee, S.; Armstrong, N. A.; Annes, J. P.
      Pages: 3145 - 3145
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-er12f
      Issue No: Vol. 66, No. 12 (2017)
       
  • Issues and Events
    • Pages: 3146 - 3146
      PubDate: 2017-11-21T12:01:01-08:00
      DOI: 10.2337/db17-ie12
      Issue No: Vol. 66, No. 12 (2017)
       
 
 
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