Journal Cover
Diabetes
Journal Prestige (SJR): 4.435
Citation Impact (citeScore): 6
Number of Followers: 555  
 
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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: 1 - 2
      PubDate: 2019-12-20T12:00:04-08:00
      DOI: 10.2337/db20-ti01
      Issue No: Vol. 69, No. 1 (2019)
       
  • Brain and Body: A Review of Central Nervous System Contributions to
           Movement Impairments in Diabetes
    • Authors: Ferris; J. K.; Inglis, J. T.; Madden, K. M.; Boyd, L. A.
      Pages: 3 - 11
      Abstract: Diabetes is associated with a loss of somatosensory and motor function, leading to impairments in gait, balance, and manual dexterity. Data-driven neuroimaging studies frequently report a negative impact of diabetes on sensorimotor regions in the brain; however, relationships with sensorimotor behavior are rarely considered. The goal of this review is to consider existing diabetes neuroimaging evidence through the lens of sensorimotor neuroscience. We review evidence for diabetes-related disruptions to three critical circuits for movement control: the cerebral cortex, the cerebellum, and the basal ganglia. In addition, we discuss how central nervous system (CNS) degeneration might interact with the loss of sensory feedback from the limbs due to peripheral neuropathy to result in motor impairments in individuals with diabetes. We argue that our understanding of movement impairments in individuals with diabetes is incomplete without the consideration of disease complications in both the central and peripheral nervous systems. Neuroimaging evidence for disrupted central sensorimotor circuitry suggests that there may be unrecognized behavioral impairments in individuals with diabetes. Applying knowledge from the existing literature on CNS contributions to motor control and motor learning in healthy individuals provides a framework for hypothesis generation for future research on this topic.
      PubDate: 2019-12-20T12:00:04-08:00
      DOI: 10.2337/db19-0321
      Issue No: Vol. 69, No. 1 (2019)
       
  • Longitudinal Pattern of First-Phase Insulin Response Is Associated With
           Genetic Variants Outside the Class II HLA Region in Children With Multiple
           Autoantibodies
    • Authors: Koskinen; M. K.; Mikk, M.-L.; Laine, A.-P.; Lempainen, J.; Löyttyniemi, E.; Vähäsalo, P.; Hekkala, A.; Härkönen, T.; Kiviniemi, M.; Simell, O.; Knip, M.; Veijola, R.; Ilonen, J.; Toppari, J.
      Pages: 12 - 19
      Abstract: A declining first-phase insulin response (FPIR) is associated with positivity for multiple islet autoantibodies, irrespective of class II HLA DR-DQ genotype. We examined the associations of FPIR with genetic variants outside the HLA DR-DQ region in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study in children with and without multiple autoantibodies. Association between FPIR and class I alleles A*24 and B*39 and eight single nucleotide polymorphisms outside the HLA region were analyzed in 438 children who had one or more FPIR results available after seroconversion. Hierarchical linear mixed models were used to analyze repeated measurements of FPIR. In children with multiple autoantibodies, the change in FPIR over time was significantly different between those with various PTPN2 (rs45450798), FUT2 (rs601338), CTSH (rs3825932), and IKZF4 (rs1701704) genotypes in at least one of the models. In general, children carrying susceptibility alleles for type 1 diabetes experienced a more rapid decline in insulin secretion compared with children without susceptibility alleles. The presence of the class I HLA A*24 allele was also associated with a steeper decline of FPIR over time in children with multiple autoantibodies. Certain genetic variants outside the class II HLA region may have a significant impact on the longitudinal pattern of FPIR.
      PubDate: 2019-12-20T12:00:04-08:00
      DOI: 10.2337/db19-0329
      Issue No: Vol. 69, No. 1 (2019)
       
  • RNF20 Functions as a Transcriptional Coactivator for PPAR{gamma} by
           Promoting NCoR1 Degradation in Adipocytes
    • Authors: Jeon; Y. G.; Lee, J. H.; Ji, Y.; Sohn, J. H.; Lee, D.; Kim, D. W.; Yoon, S. G.; Shin, K. C.; Park, J.; Seong, J. K.; Cho, J.-Y.; Choe, S. S.; Kim, J. B.
      Pages: 20 - 34
      Abstract: Adipose tissue is the key organ coordinating whole-body energy homeostasis. Although it has been reported that ring finger protein 20 (RNF20) regulates lipid metabolism in the liver and kidney, the roles of RNF20 in adipose tissue have not been explored. Here, we demonstrate that RNF20 promotes adipogenesis by potentiating the transcriptional activity of peroxisome proliferator–activated receptor- (PPAR). Under normal chow diet feeding, Rnf20 defective (Rnf20+/–) mice exhibited reduced fat mass with smaller adipocytes compared with wild-type littermates. In addition, high-fat diet–fed Rnf20+/– mice alleviated systemic insulin resistance accompanied by a reduced expansion of fat tissue. Quantitative proteomic analyses revealed significantly decreased levels of PPAR target proteins in adipose tissue of Rnf20+/– mice. Mechanistically, RNF20 promoted proteasomal degradation of nuclear corepressor 1 (NCoR1), which led to stimulation of the transcriptional activity of PPAR. Collectively, these data suggest that RNF20-NCoR1 is a novel axis in adipocyte biology through fine-tuning the transcriptional activity of PPAR.
      Keywords: Obesity-Animal
      PubDate: 2019-12-20T12:00:04-08:00
      DOI: 10.2337/db19-0508
      Issue No: Vol. 69, No. 1 (2019)
       
  • Fat-Specific Knockout of Mecp2 Upregulates Slpi to Reduce Obesity by
           Enhancing Browning
    • Authors: Liu; C.; Wang, J.; Wei, Y.; Zhang, W.; Geng, M.; Yuan, Y.; Chen, Y.; Sun, Y.; Chen, H.; Zhang, Y.; Xiong, M.; Li, Y.; Zheng, L.; Huang, K.
      Pages: 35 - 47
      Abstract: Abnormalities of methyl-CpG binding protein 2 (Mecp2) cause neurological disorders with metabolic dysfunction; however, its role in adipose tissues remains unclear. Here, we report upregulated Mecp2 in white adipose tissues (WAT) of obese humans, as well as in obese mice and during in vitro adipogenesis. Normal chow–fed adipocyte-specific Mecp2 knockout mice (Mecp2Adi KO mice) showed a lean phenotype, with downregulated lipogenic genes and upregulated thermogenic genes that were identified using RNA sequencing. Consistently, the deficiency of Mecp2 in adipocytes protected mice from high-fat diet (HFD)–induced obesity and inhibited in vitro adipogenesis. Furthermore, Mecp2Adi KO mice showed increased browning under different stimuli, including cold treatment. Mechanistically, Mecp2 bound to the promoter of secretory leukocyte protease inhibitor (Slpi) and negatively regulated its expression. Knockdown of Slpi in inguinal WAT of Mecp2Adi KO mice prevented cold-induced browning. Moreover, recombinant SLPI treatment reduced the HFD-induced obesity via enhancing browning. Together, our results suggest a novel non–central nervous system function of Mecp2 in obesity by suppressing browning, at least partially, through regulating adipokine Slpi.
      PubDate: 2019-12-20T12:00:04-08:00
      DOI: 10.2337/db19-0502
      Issue No: Vol. 69, No. 1 (2019)
       
  • Atorvastatin Targets the Islet Mevalonate Pathway to Dysregulate mTOR
           Signaling and Reduce {beta}-Cell Functional Mass
    • Authors: Shen; L.; Gu, Y.; Qiu, Y.; Cheng, T.; Nie, A.; Cui, C.; Fu, C.; Li, T.; Li, X.; Fu, L.; Wang, Y.; Ni, Q.; Wang, Q.; Wang, W.; Feng, B.
      Pages: 48 - 59
      Abstract: Statins are cholesterol-lowering agents that increase the incidence of diabetes and impair glucose tolerance via their detrimental effects on nonhepatic tissues, such as pancreatic islets, but the underlying mechanism has not been determined. In atorvastatin (ator)-treated high-fat diet–fed mice, we found reduced pancreatic β-cell size and β-cell mass, fewer mature insulin granules, and reduced insulin secretion and glucose tolerance. Transcriptome profiling of primary pancreatic islets showed that ator inhibited the expression of pancreatic transcription factor, mechanistic target of rapamycin (mTOR) signaling, and small G protein (sGP) genes. Supplementation of the mevalonate pathway intermediate geranylgeranyl pyrophosphate (GGPP), which is produced by 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, significantly restored the attenuated mTOR activity, v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) expression, and β-cell function after ator, lovastatin, rosuvastatin, and fluvastatin treatment; this effect was potentially mediated by sGP prenylation. Rab5a, the sGP in pancreatic islets most affected by ator treatment, was found to positively regulate mTOR signaling and β-cell function. Rab5a knockdown mimicked the effect of ator treatment on β-cells. Thus, ator impairs β-cell function by regulating sGPs, for example, Rab5a, which subsequently attenuates islet mTOR signaling and reduces functional β-cell mass. GGPP supplementation could constitute a new approach for preventing statin-induced hyperglycemia.
      PubDate: 2019-12-20T12:00:04-08:00
      DOI: 10.2337/db19-0178
      Issue No: Vol. 69, No. 1 (2019)
       
  • Temporal Analysis of Amylase Expression in Control, Autoantibody-Positive,
           and Type 1 Diabetes Pancreatic Tissues
    • Authors: Kusmartseva; I.; Beery, M.; Hiller, H.; Padilla, M.; Selman, S.; Posgai, A.; Nick, H. S.; Campbell-Thompson, M.; Schatz, D. A.; Haller, M. J.; Wasserfall, C. H.; Atkinson, M. A.
      Pages: 60 - 66
      Abstract: Within the human pancreas, exocrine and endocrine cells control secretion of digestive enzymes and production of hormones to maintain metabolic homeostasis, respectively. While the vast majority of type 1 diabetes research efforts have focused on endocrine function and autoimmunity, recent studies identified a series of unique features (e.g., reduced weight and volume, increased density of leukocytes) within the exocrine pancreas in this disease, but the mechanisms underlying these aberrancies are unknown. Therefore, we histologically assessed amylase, insulin, glucagon, lipase, and/or trypsinogen in 78 organ donor pancreata from birth through adulthood in control subjects and those at various stages of type 1 diabetes. While amylase-positive (AMY+) acinar cells were detectable in pancreata from all study groups, tissues from individuals>2 years of age contained clusters of acinar cells devoid of amylase (AMY–). A majority of these AMY– cell clusters localized proximal to islets (i.e., peri-islet). Additionally, most AMY– clusters were positive for the exocrine enzymes lipase and trypsinogen. Interestingly, type 1 diabetes pancreata displayed significant reductions in the frequency of these AMY– cell clusters. These results support a contribution of the islet-acinar axis in pancreatic development and underscore a potential role for the exocrine pancreas in the pathogenesis of type 1 diabetes.
      PubDate: 2019-12-20T12:00:04-08:00
      DOI: 10.2337/db19-0554
      Issue No: Vol. 69, No. 1 (2019)
       
  • RILP Restricts Insulin Secretion Through Mediating Lysosomal Degradation
           of Proinsulin
    • Authors: Zhou; Y.; Liu, Z.; Zhang, S.; Zhuang, R.; Liu, H.; Liu, X.; Qiu, X.; Zhang, M.; Zheng, Y.; Li, L.; Hong, W.; Wang, T.
      Pages: 67 - 82
      Abstract: Insulin secretion is tightly regulated by membrane trafficking. RILP (Rab7 interacting lysosomal protein) regulates the endocytic trafficking, but its role in insulin secretion has not been investigated. In this study, we found that overexpression of RILP inhibited insulin secretion in both the β-cell lines and freshly isolated islets. Consequently, the expression of RILP in islets suppressed the ability to recover the glucose homeostasis in type 1 diabetes mice upon transplantation. Of physiological relevance is that RILP expression was upregulated in the diabetic mouse islets. Mechanistically, overexpression of RILP induced insulin granule clustering, decreased the number of proinsulin-containing granules in β-cells, and significantly promoted proinsulin degradation. Conversely, RILP depletion sustained proinsulin and increased insulin secretion. The proinsulin degradation induced by RILP expression was inhibited by lysosomal inhibitors and was Rab7-dependent. Finally, we showed that RILP interacts with insulin granule–associated Rab26 to restrict insulin secretion. This study presents a new pathway regulating insulin secretion and mechanically demonstrates a novel function of RILP in modulating insulin secretion through mediating the lysosomal degradation of proinsulin.
      PubDate: 2019-12-20T12:00:04-08:00
      DOI: 10.2337/db19-0086
      Issue No: Vol. 69, No. 1 (2019)
       
  • Complement C5a Induces Renal Injury in Diabetic Kidney Disease by
           Disrupting Mitochondrial Metabolic Agility
    • Authors: Tan; S. M.; Ziemann, M.; Thallas-Bonke, V.; Snelson, M.; Kumar, V.; Laskowski, A.; Nguyen, T.-V.; Huynh, K.; Clarke, M. V.; Libianto, R.; Baker, S. T.; Skene, A.; Power, D. A.; MacIsaac, R. J.; Henstridge, D. C.; Wetsel, R. A.; El-Osta, A.; Meikle, P. J.; Wilson, S. G.; Forbes, J. M.; Cooper, M. E.; Ekinci, E. I.; Woodruff, T. M.; Coughlan, M. T.
      Pages: 83 - 98
      Abstract: The sequelae of diabetes include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury associated with a disruption in mitochondrial metabolic agility, inflammation, and fibrosis. We explored the role of the innate immune complement component C5a, a potent mediator of inflammation, in the pathogenesis of DKD in clinical and experimental diabetes. Marked systemic elevation in C5a activity was demonstrated in patients with diabetes; conventional renoprotective agents did not therapeutically target this elevation. C5a and its receptor (C5aR1) were upregulated early in the disease process and prior to manifest kidney injury in several diverse rodent models of diabetes. Genetic deletion of C5aR1 in mice conferred protection against diabetes-induced renal injury. Transcriptomic profiling of kidney revealed diabetes-induced downregulation of pathways involved in mitochondrial fatty acid metabolism. Interrogation of the lipidomics signature revealed abnormal cardiolipin remodeling in diabetic kidneys, a cardinal sign of disrupted mitochondrial architecture and bioenergetics. In vivo delivery of an orally active inhibitor of C5aR1 (PMX53) reversed the phenotypic changes and normalized the renal mitochondrial fatty acid profile, cardiolipin remodeling, and citric acid cycle intermediates. In vitro exposure of human renal proximal tubular epithelial cells to C5a led to altered mitochondrial respiratory function and reactive oxygen species generation. These experiments provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD by disrupting mitochondrial agility, thereby establishing a new immunometabolic signaling pathway in DKD.
      PubDate: 2019-12-20T12:00:04-08:00
      DOI: 10.2337/db19-0043
      Issue No: Vol. 69, No. 1 (2019)
       
  • CTRP13 Preserves Endothelial Function by Targeting GTP Cyclohydrolase 1 in
           Diabetes
    • Authors: Wang; C.; Chao, Y.; Xu, W.; Liang, M.; Deng, S.; Zhang, D.; Huang, K.
      Pages: 99 - 111
      Abstract: Endothelial dysfunction plays a crucial role in the progress of diabetic vasculopathy. C1q/tumor necrosis factor–related protein 13 (CTRP13) is a secreted adipokine that can ameliorate atherosclerosis and vascular calcification. However, the role of CTRP13 in regulating endothelial function in diabetes has yet to be explored. In this study, CTRP13 treatment improved endothelium-dependent relaxation in the aortae and mesenteric arteries of both db/db mice and streptozotocin-injected mice. CTRP13 supplement also rescued the impaired endothelium-dependent relaxation ex vivo in the db/db mouse aortae and in high glucose (HG)–treated mouse aortae. Additionally, CTRP13 treatment reduced reactive oxygen species overproduction and improved nitric oxide (NO) production and endothelial NO synthase (eNOS) coupling in the aortae of diabetic mice and in HG-treated human umbilical vein endothelial cells. Mechanistically, CTRP13 could increase GTP cyclohydrolase 1 (GCH1) expression and tetrahydrobiopterin (BH4) levels to ameliorate eNOS coupling. More importantly, CTRP13 rescued HG-induced inhibition of protein kinase A (PKA) activity. Increased PKA activity enhanced phosphorylation of the peroxisome proliferator–activated receptor α and its recruitment to the GCH1 promoter, thus activating GCH1 transcription and, ultimately, endothelial relaxation. Together, these results suggest that CTRP13 preserves endothelial function in diabetic mice by regulating GCH1/BH4 axis-dependent eNOS coupling, suggesting the therapeutic potential of CTRP13 against diabetic vasculopathy.
      PubDate: 2019-12-20T12:00:04-08:00
      DOI: 10.2337/db19-0635
      Issue No: Vol. 69, No. 1 (2019)
       
  • Interaction Between Type 2 Diabetes Prevention Strategies and Genetic
           Determinants of Coronary Artery Disease on Cardiometabolic Risk Factors
    • Authors: Merino; J.; Jablonski, K. A.; Mercader, J. M.; Kahn, S. E.; Chen, L.; Harden, M.; Delahanty, L. M.; Araneta, M. R. G.; Walford, G. A.; Jacobs, S. B. R.; Ibebuogu, U. N.; Franks, P. W.; Knowler, W. C.; Florez, J. C.; for the Diabetes Prevention Program Research Group; Diabetes Prevention Program Research Group
      Pages: 112 - 120
      Abstract: Coronary artery disease (CAD) is more frequent among individuals with dysglycemia. Preventive interventions for diabetes can improve cardiometabolic risk factors (CRFs), but it is unclear whether the benefits on CRFs are similar for individuals at different genetic risk for CAD. We built a 201-variant polygenic risk score (PRS) for CAD and tested for interaction with diabetes prevention strategies on 1-year changes in CRFs in 2,658 Diabetes Prevention Program (DPP) participants. We also examined whether separate lifestyle behaviors interact with PRS and affect changes in CRFs in each intervention group. Participants in both the lifestyle and metformin interventions had greater improvement in the majority of recognized CRFs compared with placebo (P < 0.001) irrespective of CAD genetic risk (Pinteraction> 0.05). We detected nominal significant interactions between PRS and dietary quality and physical activity on 1-year change in BMI, fasting glucose, triglycerides, and HDL cholesterol in individuals randomized to metformin or placebo, but none of them achieved the multiple-testing correction for significance. This study confirms that diabetes preventive interventions improve CRFs regardless of CAD genetic risk and delivers hypothesis-generating data on the varying benefit of increasing physical activity and improving diet on intermediate cardiovascular risk factors depending on individual CAD genetic risk profile.
      PubDate: 2019-12-20T12:00:04-08:00
      DOI: 10.2337/db19-0097
      Issue No: Vol. 69, No. 1 (2019)
       
  • High Prevalence of a Monogenic Cause in Han Chinese Diagnosed With Type 1
           Diabetes, Partly Driven by Nonsyndromic Recessive WFS1 Mutations
    • Authors: Li; M.; Wang, S.; Xu, K.; Chen, Y.; Fu, Q.; Gu, Y.; Shi, Y.; Zhang, M.; Sun, M.; Chen, H.; Han, X.; Li, Y.; Tang, Z.; Cai, L.; Li, Z.; Shi, Y.; Yang, T.; Polychronakos, C.
      Pages: 121 - 126
      Abstract: It is estimated that ~1% of European ancestry patients clinically diagnosed with type 1 diabetes (T1D) actually have monogenic forms of the disease. Because of the much lower incidence of true T1D in East Asians, we hypothesized that the percentage would be much higher. To test this, we sequenced the exome of 82 Chinese Han patients clinically diagnosed with T1D but negative for three autoantibodies. Analysis focused on established or proposed monogenic diabetes genes. We found credible mutations in 18 of the 82 autoantibody-negative patients (22%). All mutations had consensus pathogenicity support by five algorithms. As in Europeans, the most common gene was HNF1A (MODY3), in 6 of 18 cases. Surprisingly, almost as frequent were diallelic mutations in WFS1, known to cause Wolfram syndrome but also described in nonsyndromic cases. Fasting C-peptide varied widely and was not predictive. Given the 27.4% autoantibody negativity in Chinese and 22% mutation rate, we estimate that ~6% of Chinese with a clinical T1D diagnosis have monogenic diabetes. Our findings support universal sequencing of autoantibody-negative cases as standard of care in East Asian patients with a clinical T1D diagnosis. Nonsyndromic diabetes with WSF1 mutations is not rare in Chinese. Its response to alternative treatments should be investigated.
      PubDate: 2019-12-20T12:00:04-08:00
      DOI: 10.2337/db19-0510
      Issue No: Vol. 69, No. 1 (2019)
       
  • Issues and Events
    • Pages: 127 - 127
      PubDate: 2019-12-20T12:00:04-08:00
      DOI: 10.2337/db20-ie01
      Issue No: Vol. 69, No. 1 (2019)
       
 
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