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Journal Cover Diabetes
  [SJR: 5.185]   [H-I: 269]   [406 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: 2533 - 2534
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db17-ti10
      Issue No: Vol. 66, No. 10 (2017)
       
  • Sirtuin 6 Builds a Wall Against Inflammation, Trumping Diabetes
    • Authors: Giblin; W.; Lombard, D. B.
      Pages: 2535 - 2537
      Keywords: Obesity-Human
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/dbi17-0025
      Issue No: Vol. 66, No. 10 (2017)
       
  • New Tricks for Nrf2: Therapeutic Targeting to Restore BK-{beta}1
           Expression'
    • Authors: Chapple; S. J.; Mann, G. E.
      Pages: 2538 - 2540
      Keywords: Obesity-Animal
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/dbi17-0024
      Issue No: Vol. 66, No. 10 (2017)
       
  • Bone Regulates Browning and Energy Metabolism Through Mature
           Osteoblast/Osteocyte PPAR{gamma} Expression
    • Authors: Brun; J.; Berthou, F.; Trajkovski, M.; Maechler, P.; Foti, M.; Bonnet, N.
      Pages: 2541 - 2554
      Abstract: Peroxisome proliferator–activated receptor (PPAR) is a master regulator of energy metabolism. In bone, it is known to regulate osteoblast differentiation and osteoclast activity. Whether PPAR expression in bone cells, particularly osteocytes, regulates energy metabolism remains unknown. Here, we show that mature osteoblast/osteocyte-specific ablation of PPAR in mice (Ocy-PPAR–/–) alters body composition with age, namely, to produce less fat and more lean mass, and enhances insulin sensitivity and energy expenditure compared with wild-type mice. In addition, Ocy-PPAR–/– mice exhibit more bone density, structure, and strength by uncoupling bone formation from resorption. When challenged with a high-fat diet, Ocy-PPAR–/– mice retain glycemic control, with increased browning of the adipose tissue, decreased gluconeogenesis, and less hepatic steatosis. Moreover, these metabolic effects, particularly an increase in fatty acid oxidation, cannot be explained by decarboxylated osteocalcin changes, suggesting existence of other osteokines that are under the control of PPAR. We further identify bone morphogenetic protein 7 as one of them. Hence, osteocytes coregulate bone and glucose homeostasis through a PPAR regulatory pathway, and its inhibition could be clinically relevant for the prevention of glucose metabolic disorders.
      Keywords: Integrated Physiology-Other Hormones
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db17-0116
      Issue No: Vol. 66, No. 10 (2017)
       
  • Disruption of Lipid Uptake in Astroglia Exacerbates Diet-Induced Obesity
    • Authors: Gao; Y.; Layritz, C.; Legutko, B.; Eichmann, T. O.; Laperrousaz, E.; Moulle, V. S.; Cruciani-Guglielmacci, C.; Magnan, C.; Luquet, S.; Woods, S. C.; Eckel, R. H.; Yi, C.-X.; Garcia-Caceres, C.; Tschöp, M. H.
      Pages: 2555 - 2563
      Abstract: Neuronal circuits in the brain help to control feeding behavior and systemic metabolism in response to afferent nutrient and hormonal signals. Although astrocytes have historically been assumed to have little relevance for such neuroendocrine control, we investigated whether lipid uptake via lipoprotein lipase (LPL) in astrocytes is required to centrally regulate energy homeostasis. Ex vivo studies with hypothalamus-derived astrocytes showed that LPL expression is upregulated by oleic acid, whereas it is decreased in response to palmitic acid or triglycerides. Likewise, astrocytic LPL deletion reduced the accumulation of lipid droplets in those glial cells. Consecutive in vivo studies showed that postnatal ablation of LPL in glial fibrillary acidic protein–expressing astrocytes induced exaggerated body weight gain and glucose intolerance in mice exposed to a high-fat diet. Intriguingly, astrocytic LPL deficiency also triggered increased ceramide content in the hypothalamus, which may contribute to hypothalamic insulin resistance. We conclude that hypothalamic LPL functions in astrocytes to ensure appropriately balanced nutrient sensing, ceramide distribution, body weight regulation, and glucose metabolism.
      Keywords: Integrated Physiology-Central Nervous System Regulation of Metabolism
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db16-1278
      Issue No: Vol. 66, No. 10 (2017)
       
  • Hepatic but Not Extrahepatic Insulin Clearance Is Lower in African
           American Than in European American Women
    • Authors: Piccinini; F.; Polidori, D. C.; Gower, B. A.; Bergman, R. N.
      Pages: 2564 - 2570
      Abstract: African Americans (AAs) tend to have higher plasma insulin concentrations than European Americans (EAs); the increased insulin concentrations have been attributed to increased secretion and/or decreased insulin clearance by liver or other tissues. This work characterizes the contributions of hepatic versus extrahepatic insulin degradation related to ethnic differences between AAs and EAs. By using a recently developed mathematical model that uses insulin and C-peptide measurements from the insulin-modified, frequently sampled intravenous glucose tolerance test (FSIGT), we estimated hepatic versus extrahepatic insulin clearance in 29 EA and 18 AA healthy women. During the first 20 min of the FSIGT, plasma insulin was approximately twice as high in AAs as in EAs. In contrast, insulin was similar in AAs and EAs after the 20–25 min intravenous insulin infusion. Hepatic insulin first-pass extraction was two-thirds lower in AAs versus EAs in the overnight-fasted state. In contrast, extrahepatic insulin clearance was not lower in AAs than in EAs. The difference in insulin degradation between AAs and EAs can be attributed totally to liver clearance. The mechanism underlying reduced insulin degradation in AAs remains to be clarified, as does the relative importance of reduced liver clearance to increased risk for type 2 diabetes.
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db17-0413
      Issue No: Vol. 66, No. 10 (2017)
       
  • DDB1-Mediated CRY1 Degradation Promotes FOXO1-Driven Gluconeogenesis in
           Liver
    • Authors: Tong; X.; Zhang, D.; Charney, N.; Jin, E.; VanDommelon, K.; Stamper, K.; Gupta, N.; Saldate, J.; Yin, L.
      Pages: 2571 - 2582
      Abstract: Targeted protein degradation through ubiquitination is an important step in the regulation of glucose metabolism. Here, we present evidence that the DDB1-CUL4A ubiquitin E3 ligase functions as a novel metabolic regulator that promotes FOXO1-driven hepatic gluconeogenesis. In vivo, hepatocyte-specific Ddb1 deletion leads to impaired hepatic gluconeogenesis in the mouse liver but protects mice from high-fat diet–induced hyperglycemia. Lack of Ddb1 downregulates FOXO1 protein expression and impairs FOXO1-driven gluconeogenic response. Mechanistically, we discovered that DDB1 enhances FOXO1 protein stability via degrading the circadian protein cryptochrome 1 (CRY1), a known target of DDB1 E3 ligase. In the Cry1 depletion condition, insulin fails to reduce the nuclear FOXO1 abundance and suppress gluconeogenic gene expression. Chronic depletion of Cry1 in the mouse liver not only increases FOXO1 protein but also enhances hepatic gluconeogenesis. Thus, we have identified the DDB1-mediated CRY1 degradation as an important target of insulin action on glucose homeostasis.
      Keywords: Integrated Physiology-Liver
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db16-1600
      Issue No: Vol. 66, No. 10 (2017)
       
  • Opposite Regulation of Insulin Sensitivity by Dietary Lipid Versus
           Carbohydrate Excess
    • Authors: Lundsgaard; A.-M.; Sjoberg, K. A.; Hoeg, L. D.; Jeppesen, J.; Jordy, A. B.; Serup, A. K.; Fritzen, A. M.; Pilegaard, H.; Myrmel, L. S.; Madsen, L.; Wojtaszewski, J. F. P.; Richter, E. A.; Kiens, B.
      Pages: 2583 - 2595
      Abstract: To understand the mechanisms in lipid-induced insulin resistance, a more physiological approach is to enhance fatty acid (FA) availability through the diet. Nine healthy men ingested two hypercaloric diets (in 75% excess of habitual caloric intake) for 3 days, enriched in unsaturated FA (78 energy % [E%] fat) (UNSAT) or carbohydrates (80 E% carbohydrate) (CHO) as well as a eucaloric control diet (CON). Compared with CON, the UNSAT diet reduced whole-body and leg glucose disposal during a hyperinsulinemic-euglycemic clamp, while decreasing hepatic glucose production. In muscle, diacylglycerol (DAG) and intramyocellular triacylglycerol were increased. The accumulated DAG was sn-1,3 DAG, which is known not to activate PKC, and insulin signaling was intact. UNSAT decreased PDH-E1α protein content and increased inhibitory PDH-E1α Ser300 phosphorylation and FA oxidation. CHO increased whole-body and leg insulin sensitivity, while increasing hepatic glucose production. After CHO, muscle PDH-E1α Ser300 phosphorylation was decreased, and glucose oxidation increased. After UNSAT, but not CHO, muscle glucose-6-phosphate content was 103% higher compared with CON during the clamp. Thus, PDH-E1α expression and covalent regulation, and hence the tricarboxylic acid cycle influx of pyruvate-derived acetyl-CoA relative to β-oxidation–derived acetyl-CoA, are suggested to impact on insulin-stimulated glucose uptake. Taken together, the oxidative metabolic fluxes of glucose and FA are powerful and opposite regulators of insulin action in muscle.
      Keywords: Insulin Action-Cellular and Molecular Metabolism
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db17-0046
      Issue No: Vol. 66, No. 10 (2017)
       
  • Adipocyte-Specific Deficiency of De Novo Sphingolipid Biosynthesis Leads
           to Lipodystrophy and Insulin Resistance
    • Authors: Lee; S.-Y.; Lee, H.-Y.; Song, J.-H.; Kim, G.-T.; Jeon, S.; Song, Y.-J.; Lee, J. S.; Hur, J.-H.; Oh, H. H.; Park, S.-Y.; Shim, S.-M.; Yoo, H. J.; Lee, B. C.; Jiang, X.-C.; Choi, C. S.; Park, T.-S.
      Pages: 2596 - 2609
      Abstract: Sphingolipids have been implicated in the etiology of chronic metabolic diseases. Here, we investigated whether sphingolipid biosynthesis is associated with the development of adipose tissues and metabolic diseases. SPTLC2, a subunit of serine palmitoyltransferase, was transcriptionally upregulated in the adipose tissues of obese mice and in differentiating adipocytes. Adipocyte-specific SPTLC2-deficient (aSPTLC2 KO) mice had markedly reduced adipose tissue mass. Fatty acids that were destined for the adipose tissue were instead shunted to liver and caused hepatosteatosis. This impaired fat distribution caused systemic insulin resistance and hyperglycemia, indicating severe lipodystrophy. Mechanistically, sphingosine 1-phosphate (S1P) was reduced in the adipose tissues of aSPTLC2 KO mice, and this inhibited adipocyte proliferation and differentiation via the downregulation of S1P receptor 1 and decreased activity of the peroxisome proliferator–activator receptor . In addition, downregulation of SREBP (sterol regulatory element–binding protein)-1c prevented adipogenesis of aSPTLC2 KO adipocytes. Collectively, our observations suggest that the tight regulation of de novo sphingolipid biosynthesis and S1P signaling plays an important role in adipogenesis and hepatosteatosis.
      Keywords: Obesity-Animal
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db16-1232
      Issue No: Vol. 66, No. 10 (2017)
       
  • Recruitment of Epac2A to Insulin Granule Docking Sites Regulates Priming
           for Exocytosis
    • Authors: Alenkvist; I.; Gandasi, N. R.; Barg, S.; Tengholm, A.
      Pages: 2610 - 2622
      Abstract: Epac is a cAMP-activated guanine nucleotide exchange factor that mediates cAMP signaling in various types of cells, including β-cells, where it is involved in the control of insulin secretion. Upon activation, the protein redistributes to the plasma membrane, but the underlying molecular mechanisms and functional consequences are unclear. Using quantitative high-resolution microscopy, we found that cAMP elevation caused rapid binding of Epac2A to the β-cell plasma membrane, where it accumulated specifically at secretory granules and rendered them more prone to undergo exocytosis. cAMP-dependent membrane binding required the high-affinity cyclic nucleotide-binding (CNB) and Ras association domains, but not the disheveled–Egl-10–pleckstrin domain. Although the N-terminal low-affinity CNB domain (CNB-A) was dispensable for the translocation to the membrane, it was critical for directing Epac2A to the granule sites. Epac1, which lacks the CNB-A domain, was recruited to the plasma membrane but did not accumulate at granules. We conclude that Epac2A controls secretory granule release by binding to the exocytosis machinery, an effect that is enhanced by prior cAMP-dependent accumulation of the protein at the plasma membrane.
      Keywords: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db17-0050
      Issue No: Vol. 66, No. 10 (2017)
       
  • Thyroid Hormone Coordinates Pancreatic Islet Maturation During the
           Zebrafish Larval-to-Juvenile Transition to Maintain Glucose Homeostasis
    • Authors: Matsuda; H.; Mullapudi, S. T.; Zhang, Y.; Hesselson, D.; Stainier, D. Y. R.
      Pages: 2623 - 2635
      Abstract: Thyroid hormone (TH) signaling promotes tissue maturation and adult organ formation. Developmental transitions alter an organism's metabolic requirements, and it remains unclear how development and metabolic demands are coordinated. We used the zebrafish as a model to test whether and how TH signaling affects pancreatic islet maturation, and consequently glucose homeostasis, during the larval to juvenile transition. We found that exogenous TH precociously activates the β-cell differentiation genes pax6b and mnx1 while downregulating arxa, a master regulator of α-cell development and function. Together, these effects induced hypoglycemia, at least in part by increasing insulin and decreasing glucagon expression. We visualized TH target tissues using a novel TH-responsive reporter line and found that both α- and β-cells become targets of endogenous TH signaling during the larval-to-juvenile transition. Importantly, endogenous TH is required during this transition for the functional maturation of α- and β-cells in order to maintain glucose homeostasis. Thus, our study sheds new light on the regulation of glucose metabolism during major developmental transitions.
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db16-1476
      Issue No: Vol. 66, No. 10 (2017)
       
  • Apoptosis Repressor With Caspase Recruitment Domain Ameliorates
           Amyloid-Induced {beta}-Cell Apoptosis and JNK Pathway Activation
    • Authors: Templin; A. T.; Samarasekera, T.; Meier, D. T.; Hogan, M. F.; Mellati, M.; Crow, M. T.; Kitsis, R. N.; Zraika, S.; Hull, R. L.; Kahn, S. E.
      Pages: 2636 - 2645
      Abstract: Islet amyloid is present in more than 90% of individuals with type 2 diabetes, where it contributes to β-cell apoptosis and insufficient insulin secretion. Apoptosis repressor with caspase recruitment domain (ARC) binds and inactivates components of the intrinsic and extrinsic apoptosis pathways and was recently found to be expressed in islet β-cells. Using a human islet amyloid polypeptide transgenic mouse model of islet amyloidosis, we show ARC knockdown increases amyloid-induced β-cell apoptosis and loss, while ARC overexpression decreases amyloid-induced apoptosis, thus preserving β-cells. These effects occurred in the absence of changes in islet amyloid deposition, indicating ARC acts downstream of amyloid formation. Because islet amyloid increases c-Jun N-terminal kinase (JNK) pathway activation, we investigated whether ARC affects JNK signaling in amyloid-forming islets. We found ARC knockdown enhances JNK pathway activation, whereas ARC overexpression reduces JNK, c-Jun phosphorylation, and c-Jun target gene expression (Jun and Tnf). Immunoprecipitation of ARC from mouse islet lysates showed ARC binds JNK, suggesting interaction between JNK and ARC decreases amyloid-induced JNK phosphorylation and downstream signaling. These data indicate that ARC overexpression diminishes amyloid-induced JNK pathway activation and apoptosis in the β-cell, a strategy that may reduce β-cell loss in type 2 diabetes.
      Keywords: Islet Biology-Apoptosis
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db16-1352
      Issue No: Vol. 66, No. 10 (2017)
       
  • SMAD3/Stat3 Signaling Mediates {beta}-Cell Epithelial-Mesenchymal
           Transition in Chronic Pancreatitis-Related Diabetes
    • Authors: Xiao; X.; Fischbach, S.; Zhang, T.; Chen, C.; Sheng, Q.; Zimmerman, R.; Patnaik, S.; Fusco, J.; Ming, Y.; Guo, P.; Shiota, C.; Prasadan, K.; Gangopadhyay, N.; Husain, S. Z.; Dong, H.; Gittes, G. K.
      Pages: 2646 - 2658
      Abstract: Many patients with chronic pancreatitis develop diabetes (chronic pancreatitis–related diabetes [CPRD]) through an undetermined mechanism. Here we used long-term partial pancreatic duct ligation (PDL) as a model to study CPRD. We found that long-term PDL induced significant β-cell dedifferentiation, followed by a time-dependent decrease in functional β-cell mass—all specifically in the ligated tail portion of the pancreas (PDL-tail). High levels of transforming growth factor β1 (TGFβ1) were detected in the PDL-tail and were mainly produced by M2 macrophages at the early stage and by activated myofibroblasts at the later stage. Loss of β-cell mass was then found to result from TGFβ1-triggered epithelial-mesenchymal transition (EMT) by β-cells, rather than resulting directly from β-cell apoptosis. Mechanistically, TGFβ1-treated β-cells activated expression of the EMT regulator gene Snail in a SMAD3/Stat3-dependent manner. Moreover, forced expression of forkhead box protein O1 (FoxO1), an antagonist for activated Stat3, specifically in β-cells ameliorated β-cell EMT and β-cell loss and prevented the onset of diabetes in mice undergoing PDL. Together, our data suggest that chronic pancreatitis may trigger TGFβ1-mediated β-cell EMT to lead to CPRD, which could substantially be prevented by sustained expression of FoxO1 in β-cells.
      Keywords: Islet Biology-Signal Transduction
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db17-0537
      Issue No: Vol. 66, No. 10 (2017)
       
  • Myeloid Sirtuin 6 Deficiency Causes Insulin Resistance in High-Fat
           
    • Authors: Lee; Y.; Ka, S.-O.; Cha, H.-N.; Chae, Y.-N.; Kim, M.-K.; Park, S.-Y.; Bae, E. J.; Park, B.-H.
      Pages: 2659 - 2668
      Abstract: Obesity-related insulin resistance is closely associated with macrophage accumulation and subsequent cytokine release in local tissues. Sirtuin 6 (Sirt6) is known to exert an anti-inflammatory function, but its role in macrophages in the context of obesity has not been investigated. We generated myeloid-specific Sirt6 knockout (mS6KO) mice and investigated the metabolic characteristics after high-fat diet (HFD) feeding for 16 weeks. Compared with their wild-type littermates, HFD-fed mS6KO mice exhibited greater increases in body weight, fasting blood glucose and insulin levels, hepatic steatosis, glucose intolerance, and insulin resistance. Gene expression, histology, and flow cytometric analyses demonstrated that liver and adipose tissue inflammation were elevated in HFD-fed mS6KO mice relative to wild type, with a greater accumulation of F4/80+CD11b+CD11c+ adipose tissue macrophages. Myeloid Sirt6 deletion facilitated proinflammatory M1 polarization of bone marrow macrophages and augmented the migration potential of macrophages toward adipose-derived chemoattractants. Mechanistically, Sirt6 deletion in macrophages promoted the activation of nuclear factor-B (NF-B) and endogenous production of interleukin-6, which led to STAT3 activation and the positive feedback circuits for NF-B stimulation; this cross talk expedited an M1 polarization. We conclude that Sirt6 in macrophages is required for the prevention of obesity-associated tissue inflammation and insulin resistance.
      Keywords: Immunology
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db16-1446
      Issue No: Vol. 66, No. 10 (2017)
       
  • Low-Dose Persistent Organic Pollutants Impair Insulin Secretory Function
           of Pancreatic {beta}-Cells: Human and In Vitro Evidence
    • Authors: Lee; Y.-M.; Ha, C.-M.; Kim, S.-A.; Thoudam, T.; Yoon, Y.-R.; Kim, D.-J.; Kim, H.-C.; Moon, H.-B.; Park, S.; Lee, I.-K.; Lee, D.-H.
      Pages: 2669 - 2680
      Abstract: Low-dose persistent organic pollutants (POPs), especially organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs), have emerged as a new risk factor for type 2 diabetes. We evaluated whether chronic exposure to low-dose POPs affects insulin secretory function of β-cells in humans and in vitro cells. Serum concentrations of OCPs and PCBs were measured in 200 adults without diabetes. Mathematical model–based insulin secretion indices were estimated by using a 2-h seven-sample oral glucose tolerance test. Insulin secretion by INS-1E β-cells was measured after 48 h of treatment with three OCPs or one PCB mixture. Static second-phase insulin secretion significantly decreased with increasing serum concentrations of OCPs. Adjusted means were 63.2, 39.3, 44.1, 39.3, 39.7, and 22.3 across six categories of a summary measure of OCPs (Ptrend = 0.02). Dynamic first-phase insulin secretion remarkably decreased with increasing concentrations of OCPs among only insulin-sensitive individuals (Ptrend = 0.02); the insulin levels among individuals with high OCPs were ~30% of those with low OCPs. Compared with OCPs, PCBs showed weaker associations. The decreased insulin secretion by INS-1E β-cells was observed for even 1 pmol/L OCP. The data from human and in vitro cell experiments suggest that chronic exposure to low-dose POPs, especially OCPs, can induce pancreatic β-cell dysfunction.
      Keywords: Epidemiology-Other
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db17-0188
      Issue No: Vol. 66, No. 10 (2017)
       
  • Role of Nrf2 Signaling in the Regulation of Vascular BK Channel {beta}1
           Subunit Expression and BK Channel Function in High-Fat Diet-Induced
           Diabetic Mice
    • Authors: Lu; T.; Sun, X.; Li, Y.; Chai, Q.; Wang, X.-L.; Lee, H.-C.
      Pages: 2681 - 2690
      Abstract: The large conductance Ca2+-activated K+ (BK) channel β1-subunit (BK-β1) is a key modulator of BK channel electrophysiology and the downregulation of BK-β1 protein expression in vascular smooth muscle cells (SMCs) underlies diabetic vascular dysfunction. In this study, we hypothesized that the nuclear factor erythroid-2–related factor 2 (Nrf2) signaling pathway plays a significant role in the regulation of coronary BK channel function and vasodilation in high-fat diet (HFD)–induced obese/diabetic mice. We found that the protein expressions of BK-β1 and Nrf2 were markedly downregulated, whereas those of the nuclear factor-B (NF-B) and the muscle ring finger protein 1 (MuRF1 [a ubiquitin E3 ligase for BK-β1]) were significantly upregulated in HFD mouse arteries. Adenoviral expression of Nrf2 suppressed the protein expressions of NF-B and MuRF1 but enhanced BK-β1 mRNA and protein expressions in cultured coronary SMCs. Knockdown of Nrf2 resulted in reciprocal changes of these proteins. Patch-clamp studies showed that coronary BK-β1–mediated channel activation was diminished in HFD mice. Importantly, the activation of Nrf2 by dimethyl fumarate significantly reduced the body weight and blood glucose levels of HFD mice, enhanced BK-β1 transcription, and attenuated MuRF1-dependent BK-β1 protein degradation, which in turn restored coronary BK channel function and BK channel–mediated coronary vasodilation in HFD mice. Hence, Nrf2 is a novel regulator of BK channel function with therapeutic implications in diabetic vasculopathy.
      Keywords: Complications-Macrovascular-Atherosclerotic Cardiovascular Disease and Human Diabetes
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db17-0181
      Issue No: Vol. 66, No. 10 (2017)
       
  • NADPH Oxidase Nox5 Accelerates Renal Injury in Diabetic Nephropathy
    • Authors: Jha; J. C.; Banal, C.; Okabe, J.; Gray, S. P.; Hettige, T.; Chow, B. S. M.; Thallas-Bonke, V.; De Vos, L.; Holterman, C. E.; Coughlan, M. T.; Power, D. A.; Skene, A.; Ekinci, E. I.; Cooper, M. E.; Touyz, R. M.; Kennedy, C. R.; Jandeleit-Dahm, K.
      Pages: 2691 - 2703
      Abstract: NADPH oxidase–derived excessive production of reactive oxygen species (ROS) in the kidney plays a key role in mediating renal injury in diabetes. Pathological changes in diabetes include mesangial expansion and accumulation of extracellular matrix (ECM) leading to glomerulosclerosis. There is a paucity of data about the role of the Nox5 isoform of NADPH oxidase in animal models of diabetic nephropathy since Nox5 is absent in the mouse genome. Thus, we examined the role of Nox5 in human diabetic nephropathy in human mesangial cells and in an inducible human Nox5 transgenic mouse exposed to streptozotocin-induced diabetes. In human kidney biopsies, Nox5 was identified to be expressed in glomeruli, which appeared to be increased in diabetes. Colocalization demonstrated Nox5 expression in mesangial cells. In vitro, silencing of Nox5 in human mesangial cells was associated with attenuation of the hyperglycemia and TGF-β1–induced enhanced ROS production, increased expression of profibrotic and proinflammatory mediators, and increased TRPC6, PKC-α, and PKC-β expression. In vivo, vascular smooth muscle cell/mesangial cell–specific overexpression of Nox5 in a mouse model of diabetic nephropathy showed enhanced glomerular ROS production, accelerated glomerulosclerosis, mesangial expansion, and ECM protein (collagen IV and fibronectin) accumulation as well as increased macrophage infiltration and expression of the proinflammatory chemokine MCP-1. Collectively, this study provides evidence of a role for Nox5 and its derived ROS in promoting progression of diabetic nephropathy.
      Keywords: Complications-Nephropathy-Clinical and Translational Research
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db16-1585
      Issue No: Vol. 66, No. 10 (2017)
       
  • Genetic Susceptibility, Change in Physical Activity, and Long-term Weight
           Gain
    • Authors: Wang; T.; Huang, T.; Heianza, Y.; Sun, D.; Zheng, Y.; Ma, W.; Jensen, M. K.; Kang, J. H.; Wiggs, J. L.; Pasquale, L. R.; Rimm, E. B.; Manson, J. E.; Hu, F. B.; Willett, W. C.; Qi, L.
      Pages: 2704 - 2712
      Abstract: Whether change in physical activity over time modifies the genetic susceptibility to long-term weight gain is unknown. We calculated a BMI–genetic risk score (GRS) based on 77 BMI-associated single nucleotide polymorphisms (SNPs) and a body fat percentage (BF%)-GRS based on 12 BF%-associated SNPs in 9,390 women from the Nurses’ Health Study (NHS) and 5,291 men from the Health Professionals Follow-Up Study (HPFS). We analyzed the interactions between each GRS and change in physical activity on BMI/body weight change within five 4-year intervals from 1986 to 2006 using multivariable generalized linear models with repeated-measures analyses. Both the BMI-GRS and the BF%-GRS were associated with long-term increases in BMI/weight, and change in physical activity consistently interacted with the BF%-GRS on BMI change in the NHS (P for interaction = 0.025) and HPFS (P for interaction = 0.001). In the combined cohorts, 4-year BMI change per 10-risk allele increment was –0.02 kg/m2 among participants with greatest increase in physical activity and 0.24 kg/m2 among those with greatest decrease in physical activity (P for interaction < 0.001), corresponding to 0.01 kg versus 0.63 kg weight changes every 4 years (P for interaction = 0.001). Similar but marginal interactions were observed for the BMI-GRS (P for interaction = 0.045). Our data indicate that the genetic susceptibility to weight gain may be diminished by increasing physical activity.
      Keywords: Obesity-Human
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db17-0071
      Issue No: Vol. 66, No. 10 (2017)
       
  • Structural Basis and Genotype-Phenotype Correlations of INSR Mutations
           Causing Severe Insulin Resistance
    • Authors: Hosoe; J.; Kadowaki, H.; Miya, F.; Aizu, K.; Kawamura, T.; Miyata, I.; Satomura, K.; Ito, T.; Hara, K.; Tanaka, M.; Ishiura, H.; Tsuji, S.; Suzuki, K.; Takakura, M.; Boroevich, K. A.; Tsunoda, T.; Yamauchi, T.; Shojima, N.; Kadowaki, T.
      Pages: 2713 - 2723
      Abstract: The insulin receptor (INSR) gene was analyzed in four patients with severe insulin resistance, revealing five novel mutations and a deletion that removed exon 2. A patient with Donohue syndrome (DS) had a novel p.V657F mutation in the second fibronectin type III domain (FnIII-2), which contains the α-β cleavage site and part of the insulin-binding site. The mutant INSR was expressed in Chinese hamster ovary cells, revealing that it reduced insulin proreceptor processing and impaired activation of downstream signaling cascades. Using online databases, we analyzed 82 INSR missense mutations and demonstrated that mutations causing DS were more frequently located in the FnIII domains than those causing the milder type A insulin resistance (P = 0.016). In silico structural analysis revealed that missense mutations predicted to severely impair hydrophobic core formation and stability of the FnIII domains all caused DS, whereas those predicted to produce localized destabilization and to not affect folding of the FnIII domains all caused the less severe Rabson-Mendenhall syndrome. These results suggest the importance of the FnIII domains, provide insight into the molecular mechanism of severe insulin resistance, will aid early diagnosis, and will provide potential novel targets for treating extreme insulin resistance.
      Keywords: Pediatrics-Obesity and Type 2 Diabetes
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db17-0301
      Issue No: Vol. 66, No. 10 (2017)
       
  • Erratum. Weight Loss After Bariatric Surgery Reverses Insulin-Induced
           Increases in Brain Glucose Metabolism of the Morbidly Obese. Diabetes
           2013;62:2747-2751
    • Authors: Tuulari; J. J.; Karlsson, H. K.; Hirvonen, J.; Hannukainen, J. C.; Bucci, M.; Helmiö, M.; Ovaska, J.; Soinio, M.; Salminen, P.; Savisto, N.; Nummenmaa, L.; Nuutila, P.
      Pages: 2724 - 2724
      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db17-er10a
      Issue No: Vol. 66, No. 10 (2017)
       
  • Erratum. Association Between Long-term Exposure to Air Pollution and
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    • Authors: Wolf; K.; Popp, A.; Schneider, A.; Breitner, S.; Hampel, R.; Rathmann, W.; Herder, C.; Roden, M.; Koenig, W.; Meisinger, C.; Peters, A.; for the KORA-Study Group
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      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db17-er10b
      Issue No: Vol. 66, No. 10 (2017)
       
  • Issues and Events
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      PubDate: 2017-09-20T12:04:32-07:00
      DOI: 10.2337/db17-ie10
      Issue No: Vol. 66, No. 10 (2017)
       
 
 
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