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Journal Cover Diabetes
  [SJR: 5.185]   [H-I: 269]   [452 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: 167 - 168
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db18-ti02
      Issue No: Vol. 67, No. 2 (2018)
  • Cellular Energy Sensing and Metabolism--Implications for Treating
           Diabetes: The 2017 Outstanding Scientific Achievement Award Lecture
    • Authors: Steinberg G. R.
      Pages: 169 - 179
      Abstract: The Outstanding Scientific Achievement Award recognizes distinguished scientific achievement in the field of diabetes, taking into consideration independence of thought and originality. Gregory R. Steinberg, PhD, professor of medicine, Canada Research Chair, J. Bruce Duncan Endowed Chair in Metabolic Diseases, and codirector of the Metabolism and Childhood Obesity Research Program at McMaster University, Hamilton, Ontario, Canada, received the prestigious award at the American Diabetes Association’s 77th Scientific Sessions, 9–13 June 2017, in San Diego, CA. He presented the Outstanding Scientific Achievement Award Lecture, "Cellular Energy Sensing and Metabolism—Implications for Treating Diabetes," on Monday, 12 June 2017.The survival of all cells is dependent on the constant challenge to match energetic demands with nutrient availability, a task that is mediated through a highly conserved network of metabolic fuel sensors that orchestrate both cellular and whole-organism energy balance. A mismatch between cellular energy demand and nutrient availability is a key factor contributing to the development of type 2 diabetes; thus, understanding the fundamental mechanisms by which cells sense nutrient availability and demand may lead to the development of new treatments. Glucose-lowering therapies, such as caloric restriction, exercise, and metformin, all induce an energetic challenge that results in the activation of the cellular energy sensor AMP-activated protein kinase (AMPK). Activation of AMPK in turn suppresses lipid synthesis and inflammation while increasing glucose uptake, fatty acid oxidation, and mitochondrial function. In contrast, high levels of nutrient availability suppress AMPK activity while also increasing the production of peripheral serotonin, a gut-derived endocrine factor that suppresses β-adrenergic–induced activation of brown adipose tissue. Identifying new ways to manipulate these two ancient fuel gauges by activating AMPK and inhibiting peripheral serotonin may lead to the development of new therapies for treating type 2 diabetes.
      Keywords: Insulin Action-Signal Transduction, Insulin, and Other Hormones
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/dbi17-0039
      Issue No: Vol. 67, No. 2 (2018)
  • "NO" to Autophagy: Fat Does the Trick for Diabetes
    • Authors: Zhang K.
      Pages: 180 - 181
      Keywords: Integrated Physiology-Liver
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/dbi17-0048
      Issue No: Vol. 67, No. 2 (2018)
  • In Vivo Visualization of {beta}-Cells by Targeting of GPR44
    • Authors: Eriksson; O.; Johnström, P.; Cselenyi, Z.; Jahan, M.; Selvaraju, R. K.; Jensen-Waern, M.; Takano, A.; Sörhede Winzell, M.; Halldin, C.; Skrtic, S.; Korsgren, O.
      Pages: 182 - 192
      Abstract: GPR44 expression has recently been described as highly β-cell selective in the human pancreas and constitutes a tentative surrogate imaging biomarker in diabetes. A radiolabeled small-molecule GPR44 antagonist, [11C]AZ12204657, was evaluated for visualization of β-cells in pigs and nonhuman primates by positron emission tomography as well as in immunodeficient mice transplanted with human islets under the kidney capsule. In vitro autoradiography of human and animal pancreatic sections from subjects without and with diabetes, in combination with insulin staining, was performed to assess β-cell selectivity of the radiotracer. Proof of principle of in vivo targeting of human islets by [11C]AZ12204657 was shown in the immunodeficient mouse transplantation model. Furthermore, [11C]AZ12204657 bound by a GPR44-mediated mechanism in pancreatic sections from humans and pigs without diabetes, but not those with diabetes. In vivo [11C]AZ12204657 bound specifically to GPR44 in pancreas and spleen and could be competed away dose-dependently in nondiabetic pigs and nonhuman primates. [11C]AZ12204657 is a first-in-class surrogate imaging biomarker for pancreatic β-cells by targeting the protein GPR44.
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db17-0764
      Issue No: Vol. 67, No. 2 (2018)
  • S-Nitrosoglutathione Reductase Dysfunction Contributes to
           Obesity-Associated Hepatic Insulin Resistance via Regulating Autophagy
    • Authors: Qian; Q.; Zhang, Z.; Orwig, A.; Chen, S.; Ding, W.-X.; Xu, Y.; Kunz, R. C.; Lind, N. R. L.; Stamler, J. S.; Yang, L.
      Pages: 193 - 207
      Abstract: Obesity is associated with elevated intracellular nitric oxide (NO) production, which promotes nitrosative stress in metabolic tissues such as liver and skeletal muscle, contributing to insulin resistance. The onset of obesity-associated insulin resistance is due, in part, to the compromise of hepatic autophagy, a process that leads to lysosomal degradation of cellular components. However, it is not known how NO bioactivity might impact autophagy in obesity. Here, we establish that S-nitrosoglutathione reductase (GSNOR), a major protein denitrosylase, provides a key regulatory link between inflammation and autophagy, which is disrupted in obesity and diabetes. We demonstrate that obesity promotes S-nitrosylation of lysosomal proteins in the liver, thereby impairing lysosomal enzyme activities. Moreover, in mice and humans, obesity and diabetes are accompanied by decreases in GSNOR activity, engendering nitrosative stress. In mice with a GSNOR deletion, diet-induced obesity increases lysosomal nitrosative stress and impairs autophagy in the liver, leading to hepatic insulin resistance. Conversely, liver-specific overexpression of GSNOR in obese mice markedly enhances lysosomal function and autophagy and, remarkably, improves insulin action and glucose homeostasis. Furthermore, overexpression of S-nitrosylation–resistant variants of lysosomal enzymes enhances autophagy, and pharmacologically and genetically enhancing autophagy improves hepatic insulin sensitivity in GSNOR-deficient hepatocytes. Taken together, our data indicate that obesity-induced protein S-nitrosylation is a key mechanism compromising the hepatic autophagy, contributing to hepatic insulin resistance.
      Keywords: Obesity-Animal
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db17-0223
      Issue No: Vol. 67, No. 2 (2018)
  • Adipocyte JAK2 Regulates Hepatic Insulin Sensitivity Independently of Body
           Composition, Liver Lipid Content, and Hepatic Insulin Signaling
    • Authors: Corbit; K. C.; Camporez, J. P. G.; Edmunds, L. R.; Tran, J. L.; Vera, N. B.; Erion, D. M.; Deo, R. C.; Perry, R. J.; Shulman, G. I.; Jurczak, M. J.; Weiss, E. J.
      Pages: 208 - 221
      Abstract: Disruption of hepatocyte growth hormone (GH) signaling through disruption of Jak2 (JAK2L) leads to fatty liver. Previously, we demonstrated that development of fatty liver depends on adipocyte GH signaling. We sought to determine the individual roles of hepatocyte and adipocyte Jak2 on whole-body and tissue insulin sensitivity and liver metabolism. On chow, JAK2L mice had hepatic steatosis and severe whole-body and hepatic insulin resistance. However, concomitant deletion of Jak2 in hepatocytes and adipocytes (JAK2LA) completely normalized insulin sensitivity while reducing liver lipid content. On high-fat diet, JAK2L mice had hepatic steatosis and insulin resistance despite protection from diet-induced obesity. JAK2LA mice had higher liver lipid content and no protection from obesity but retained exquisite hepatic insulin sensitivity. AKT activity was selectively attenuated in JAK2L adipose tissue, whereas hepatic insulin signaling remained intact despite profound hepatic insulin resistance. Therefore, JAK2 in adipose tissue is epistatic to liver with regard to insulin sensitivity and responsiveness, despite fatty liver and obesity. However, hepatocyte autonomous JAK2 signaling regulates liver lipid deposition under conditions of excess dietary fat. This work demonstrates how various tissues integrate JAK2 signals to regulate insulin/glucose and lipid metabolism.
      Keywords: Insulin Action-Adipocyte Biology
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db17-0524
      Issue No: Vol. 67, No. 2 (2018)
  • Regulation of Lipolytic Response and Energy Balance by Melanocortin 2
           Receptor Accessory Protein (MRAP) in Adipocytes
    • Authors: Zhang; X.; Saarinen, A. M.; Campbell, L. E.; De Filippis, E. A.; Liu, J.
      Pages: 222 - 234
      Abstract: Melanocortin 2 receptor accessory protein (MRAP) is highly expressed in adrenal gland and adipose tissue. In adrenal cells, MRAP is essential for adrenocorticotropic hormone (ACTH)–induced activation of the cAMP/protein kinase A (PKA) pathway by melanocortin 2 receptor (MC2R), leading to glucocorticoid production and secretion. Although ACTH was known to stimulate PKA-dependent lipolysis, the functional involvement of MRAP in adipocyte metabolism remains incompletely defined. Herein, we found that knockdown or overexpression of MRAP in 3T3-L1 adipocytes reduced or increased ACTH-induced lipolysis, respectively. Moreover, an unbiased proteomics screen and coimmunoprecipitation analysis identified Gαs as a novel interacting partner of MRAP. An MRAP mutant disabled in Gαs association failed to augment the activation of PKA and lipolytic response to ACTH. Furthermore, compared with wild-type mice, transgenic mice (aP2-MRAP) overexpressing MRAP fat specifically exhibited increased lipolytic response to ACTH. When fed a high-fat diet (HFD), the transgenic mice displayed a significant decrease in the gain of adiposity and body weight as well as an improvement in glucose and insulin tolerance. These phenotypes were accompanied by increased adipose expression of genes for mitochondrial fatty acid oxidation and thermogenesis, and overall energy expenditure. Collectively, our data strongly suggest that MRAP plays a critical role in the regulation of ACTH-induced adipose lipolysis and whole-body energy balance.
      Keywords: Insulin Action-Adipocyte Biology
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db17-0862
      Issue No: Vol. 67, No. 2 (2018)
  • Exosomes From Adipose-Derived Stem Cells Attenuate Adipose Inflammation
           and Obesity Through Polarizing M2 Macrophages and Beiging in White Adipose
    • Authors: Zhao; H.; Shang, Q.; Pan, Z.; Bai, Y.; Li, Z.; Zhang, H.; Zhang, Q.; Guo, C.; Zhang, L.; Wang, Q.
      Pages: 235 - 247
      Abstract: Adipose-derived stem cells (ADSCs) play critical roles in controlling obesity-associated inflammation and metabolic disorders. Exosomes from ADSCs exert protective effects in several diseases, but their roles in obesity and related pathological conditions remain unclear. In this study, we showed that treatment of obese mice with ADSC-derived exosomes facilitated their metabolic homeostasis, including improved insulin sensitivity (27.8% improvement), reduced obesity, and alleviated hepatic steatosis. ADSC-derived exosomes drove alternatively activated M2 macrophage polarization, inflammation reduction, and beiging in white adipose tissue (WAT) of diet-induced obese mice. Mechanistically, exosomes from ADSCs transferred into macrophages to induce anti-inflammatory M2 phenotypes through the transactivation of arginase-1 by exosome-carried active STAT3. Moreover, M2 macrophages induced by ADSC-derived exosomes not only expressed high levels of tyrosine hydroxylase responsible for catecholamine release, but also promoted ADSC proliferation and lactate production, thereby favoring WAT beiging and homeostasis in response to high-fat challenge. These findings delineate a novel exosome-mediated mechanism for ADSC–macrophage cross talk that facilitates immune and metabolic homeostasis in WAT, thus providing potential therapy for obesity and diabetes.
      Keywords: Obesity-Animal
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db17-0356
      Issue No: Vol. 67, No. 2 (2018)
  • Longitudinal Analysis of Genetic Susceptibility and BMI Throughout Adult
    • Authors: Song; M.; Zheng, Y.; Qi, L.; Hu, F. B.; Chan, A. T.; Giovannucci, E. L.
      Pages: 248 - 255
      Abstract: Little is known about the genetic influence on BMI trajectory throughout adulthood. We created a genetic risk score (GRS) comprising 97 adult BMI-associated variants among 9,971 women and 6,405 men of European ancestry. Serial measures of BMI were assessed from 18 (women) or 21 (men) years to 85 years of age. We also examined BMI change in early (from 18 or 21 to 45 years of age), middle (from 45 to 65 years of age), and late adulthood (from 65 to 80 years of age). GRS was positively associated with BMI across all ages, with stronger associations in women than in men. The associations increased from early to middle adulthood, peaked at 45 years of age in men and at 60 years of age in women (0.91 and 1.35 kg/m2 per 10-allele increment, respectively) and subsequently declined in late adulthood. For women, each 10-allele increment in the GRS was associated with an average BMI gain of 0.54 kg/m2 in early adulthood, whereas no statistically significant association was found for BMI change in middle or late adulthood or for BMI change in any life period in men. Our findings indicate that genetic predisposition exerts a persistent effect on adiposity throughout adult life and increases early adulthood weight gain in women.
      Keywords: Obesity-Human
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db17-1156
      Issue No: Vol. 67, No. 2 (2018)
  • miR-204 Controls Glucagon-Like Peptide 1 Receptor Expression and Agonist
    • Authors: Jo; S.; Chen, J.; Xu, G.; Grayson, T. B.; Thielen, L. A.; Shalev, A.
      Pages: 256 - 264
      Abstract: Glucagon-like peptide 1 receptor (GLP1R) agonists are widely used to treat diabetes. However, their function is dependent on adequate GLP1R expression, which is downregulated in diabetes. GLP1R is highly expressed on pancreatic β-cells, and activation by endogenous incretin or GLP1R agonists increases cAMP generation, which stimulates glucose-induced β-cell insulin secretion and helps maintain glucose homeostasis. We now have discovered that the highly β-cell–enriched microRNA, miR-204, directly targets the 3' UTR of GLP1R and thereby downregulates its expression in the β-cell–derived rat INS-1 cell line and primary mouse and human islets. Furthermore, in vivo deletion of miR-204 promoted islet GLP1R expression and enhanced responsiveness to GLP1R agonists, resulting in improved glucose tolerance, cAMP production, and insulin secretion as well as protection against diabetes. Since we recently identified thioredoxin-interacting protein (TXNIP) as an upstream regulator of miR-204, we also assessed whether in vivo deletion of TXNIP could mimic that of miR-204. Indeed, it also enhanced islet GLP1R expression and GLP1R agonist–induced insulin secretion and glucose tolerance. Thus, the present studies show for the first time that GLP1R is under the control of a microRNA, miR-204, and uncover a previously unappreciated link between TXNIP and incretin action.
      Keywords: Islet Biology-Signal Transduction
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db17-0506
      Issue No: Vol. 67, No. 2 (2018)
  • Clec16a, Nrdp1, and USP8 Form a Ubiquitin-Dependent Tripartite Complex
           That Regulates {beta}-Cell Mitophagy
    • Authors: Pearson; G.; Chai, B.; Vozheiko, T.; Liu, X.; Kandarpa, M.; Piper, R. C.; Soleimanpour, S. A.
      Pages: 265 - 277
      Abstract: Mitophagy is a cellular quality-control pathway, which is essential for elimination of unhealthy mitochondria. While mitophagy is critical to pancreatic β-cell function, the posttranslational signals governing β-cell mitochondrial turnover are unknown. Here, we report that ubiquitination is essential for the assembly of a mitophagy regulatory complex, comprised of the E3 ligase Nrdp1, the deubiquitinase enzyme USP8, and Clec16a, a mediator of β-cell mitophagy with unclear function. We discover that the diabetes gene Clec16a encodes an E3 ligase, which promotes nondegradative ubiquitin conjugates to direct its mitophagy effectors and stabilize the Clec16a-Nrdp1-USP8 complex. Inhibition of the Clec16a pathway by the chemotherapeutic lenalidomide, a selective ubiquitin ligase inhibitor associated with new-onset diabetes, impairs β-cell mitophagy, oxygen consumption, and insulin secretion. Indeed, patients treated with lenalidomide develop compromised β-cell function. Moreover, the β-cell Clec16a-Nrdp1-USP8 mitophagy complex is destabilized and dysfunctional after lenalidomide treatment as well as after glucolipotoxic stress. Thus, the Clec16a-Nrdp1-USP8 complex relies on ubiquitin signals to promote mitophagy and maintain mitochondrial quality control necessary for optimal β-cell function.
      Keywords: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db17-0321
      Issue No: Vol. 67, No. 2 (2018)
  • Glucocorticoids Reprogram {beta}-Cell Signaling to Preserve Insulin
    • Authors: Fine; N. H. F.; Doig, C. L.; Elhassan, Y. S.; Vierra, N. C.; Marchetti, P.; Bugliani, M.; Nano, R.; Piemonti, L.; Rutter, G. A.; Jacobson, D. A.; Lavery, G. G.; Hodson, D. J.
      Pages: 278 - 290
      Abstract: Excessive glucocorticoid exposure has been shown to be deleterious for pancreatic β-cell function and insulin release. However, glucocorticoids at physiological levels are essential for many homeostatic processes, including glycemic control. We show that corticosterone and cortisol and their less active precursors 11-dehydrocorticosterone (11-DHC) and cortisone suppress voltage-dependent Ca2+ channel function and Ca2+ fluxes in rodent as well as in human β-cells. However, insulin secretion, maximal ATP/ADP responses to glucose, and β-cell identity were all unaffected. Further examination revealed the upregulation of parallel amplifying cAMP signals and an increase in the number of membrane-docked insulin secretory granules. Effects of 11-DHC could be prevented by lipotoxicity and were associated with paracrine regulation of glucocorticoid activity because global deletion of 11β-hydroxysteroid dehydrogenase type 1 normalized Ca2+ and cAMP responses. Thus, we have identified an enzymatically amplified feedback loop whereby glucocorticoids boost cAMP to maintain insulin secretion in the face of perturbed ionic signals. Failure of this protective mechanism may contribute to diabetes in states of glucocorticoid excess, such as Cushing syndrome, which are associated with frank dyslipidemia.
      Keywords: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db16-1356
      Issue No: Vol. 67, No. 2 (2018)
  • Photobiomodulation Inhibits Long-term Structural and Functional Lesions of
           Diabetic Retinopathy
    • Authors: Cheng; Y.; Du, Y.; Liu, H.; Tang, J.; Veenstra, A.; Kern, T. S.
      Pages: 291 - 298
      Abstract: Previous studies demonstrated that brief (3 to 4 min) daily application of light at 670 nm to diabetic rodents inhibited molecular and pathophysiologic processes implicated in the pathogenesis of diabetic retinopathy (DR) and reversed diabetic macular edema in small numbers of patients studied. Whether or not this therapy would inhibit the neural and vascular lesions that characterize the early stages of the retinopathy was unknown. We administered photobiomodulation (PBM) therapy daily for 8 months to streptozotocin-diabetic mice and assessed effects of PBM on visual function, retinal capillary permeability, and capillary degeneration using published methods. Vitamin D receptor and Cyp24a1 transcripts were quantified by quantitative real-time PCR, and the abundance of c-Kit+ stem cells in blood and retina were assessed. Long-term daily administration of PBM significantly inhibited the diabetes-induced leakage and degeneration of retinal capillaries and also significantly inhibited the diabetes-induced reduction in visual function. PBM also inhibited diabetes-induced reductions in retinal Cyp24a1 mRNA levels and numbers of circulating stem cells (CD45–/c-Kit+), but these effects may not account for the beneficial effects of PBM on the retinopathy. PBM significantly inhibits the functional and histopathologic features of early DR, and these effects likely are mediated via multiple mechanisms.
      Keywords: Complications-Retinopathy
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db17-0803
      Issue No: Vol. 67, No. 2 (2018)
  • Engineering Glucose Responsiveness Into Insulin
    • Authors: Kaarsholm; N. C.; Lin, S.; Yan, L.; Kelly, T.; van Heek, M.; Mu, J.; Wu, M.; Dai, G.; Cui, Y.; Zhu, Y.; Carballo-Jane, E.; Reddy, V.; Zafian, P.; Huo, P.; Shi, S.; Antochshuk, V.; Ogawa, A.; Liu, F.; Souza, S. C.; Seghezzi, W.; Duffy, J. L.; Erion, M.; Nargund, R. P.; Kelley, D. E.
      Pages: 299 - 308
      Abstract: Insulin has a narrow therapeutic index, reflected in a small margin between a dose that achieves good glycemic control and one that causes hypoglycemia. Once injected, the clearance of exogenous insulin is invariant regardless of blood glucose, aggravating the potential to cause hypoglycemia. We sought to create a "smart" insulin, one that can alter insulin clearance and hence insulin action in response to blood glucose, mitigating risk for hypoglycemia. The approach added saccharide units to insulin to create insulin analogs with affinity for both the insulin receptor (IR) and mannose receptor C-type 1 (MR), which functions to clear endogenous mannosylated proteins, a principle used to endow insulin analogs with glucose responsivity. Iteration of these efforts culminated in the discovery of MK-2640, and its in vitro and in vivo preclinical properties are detailed in this report. In glucose clamp experiments conducted in healthy dogs, as plasma glucose was lowered stepwise from 280 mg/dL to 80 mg/dL, progressively more MK-2640 was cleared via MR, reducing by ~30% its availability for binding to the IR. In dose escalations studies in diabetic minipigs, a higher therapeutic index for MK-2640 (threefold) was observed versus regular insulin (1.3-fold).
      Keywords: Clinical Therapeutics/New Technology-Glucose Monitoring and Sensing
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db17-0577
      Issue No: Vol. 67, No. 2 (2018)
  • Mechanisms to Elevate Endogenous GLP-1 Beyond Injectable GLP-1 Analogs and
           Metabolic Surgery
    • Authors: Briere; D. A.; Bueno, A. B.; Gunn, E. J.; Michael, M. D.; Sloop, K. W.
      Pages: 309 - 320
      Abstract: Therapeutic engineering of glucagon-like peptide 1 (GLP-1) has enabled development of new medicines to treat type 2 diabetes. These injectable analogs achieve robust glycemic control by increasing concentrations of "GLP-1 equivalents" (~50 pmol/L). Similar levels of endogenous GLP-1 occur after gastric bypass surgery, and mechanistic studies indicate glucose lowering by these procedures is driven by GLP-1. Therefore, because of the remarkable signaling and secretory capacity of the GLP-1 system, we sought to discover mechanisms that increase GLP-1 pharmacologically. To study active GLP-1, glucose-dependent insulinotropic polypeptide receptor (Gipr)–deficient mice receiving background dipeptidyl peptidase 4 (DPP4) inhibitor treatment were characterized as a model for evaluating oral agents that increase circulating GLP-1. A somatostatin receptor 5 antagonist, which blunts inhibition of GLP-1 release, and agonists for TGR5 and GPR40, which stimulate GLP-1 secretion, were investigated alone and in combination with the DPP4 inhibitor sitagliptin; these only modestly increased GLP-1 (~5–30 pmol/L). However, combining molecules to simultaneously intervene at multiple regulatory nodes synergistically elevated active GLP-1 to unprecedented concentrations (~300–400 pmol/L), drastically reducing glucose in Gipr null and Leprdb/db mice in a GLP-1 receptor–dependent manner. Our studies demonstrate that complementary pathways can be engaged to robustly increase GLP-1 without invasive surgical or injection regimens.
      Keywords: Integrated Physiology-Other Hormones
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db17-0607
      Issue No: Vol. 67, No. 2 (2018)
  • The Synthetic Microneurotrophin BNN27 Affects Retinal Function in Rats
           With Streptozotocin-Induced Diabetes
    • Authors: Iban-Arias; R.; Lisa, S.; Mastrodimou, N.; Kokona, D.; Koulakis, E.; Iordanidou, P.; Kouvarakis, A.; Fothiadaki, M.; Papadogkonaki, S.; Sotiriou, A.; Katerinopoulos, H. E.; Gravanis, A.; Charalampopoulos, I.; Thermos, K.
      Pages: 321 - 333
      Abstract: BNN27, a C17-spiroepoxy derivative of DHEA, was shown to have antiapoptotic properties via mechanisms involving the nerve growth factor receptors (tropomyosin-related kinase A [TrkA]/neurotrophin receptor p75 [p75NTR]). In this study, we examined the effects of BNN27 on neural/glial cell function, apoptosis, and inflammation in the experimental rat streptozotocin (STZ) model of diabetic retinopathy (DR). The ability of BNN27 to activate the TrkA receptor and regulate p75NTR expression was investigated. BNN27 (2,10, and 50 mg/kg i.p. for 7 days) administration 4 weeks post–STZ injection (paradigm A) reversed the diabetes-induced glial activation and loss of function of amacrine cells (brain nitric oxide synthetase/tyrosine hydroxylase expression) and ganglion cell axons via a TrkA receptor (TrkAR)-dependent mechanism. BNN27 activated/phosphorylated the TrkAY490 residue in the absence but not the presence of TrkAR inhibitor and abolished the diabetes-induced increase in p75NTR expression. However, it had no effect on retinal cell death (TUNEL+ cells). A similar result was observed when BNN27 (10 mg/kg i.p.) was administered at the onset of diabetes, every other day for 4 weeks (paradigm B). However, BNN27 decreased the activation of caspase-3 in both paradigms. Finally, BNN27 reduced the proinflammatory (TNFα and IL-1β) and increased the anti-inflammatory (IL-10 and IL-4) cytokine levels. These findings suggest that BNN27 has the pharmacological profile of a therapeutic for DR, since it targets both the neurodegenerative and inflammatory components of the disease.
      Keywords: Complications-Retinopathy
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db17-0391
      Issue No: Vol. 67, No. 2 (2018)
  • A Partial Loss-of-Function Variant in AKT2 Is Associated With Reduced
           Insulin-Mediated Glucose Uptake in Multiple Insulin-Sensitive Tissues: A
           Genotype-Based Callback Positron Emission Tomography Study
    • Authors: Latva-Rasku; A.; Honka, M.-J.; Stancakova, A.; Koistinen, H. A.; Kuusisto, J.; Guan, L.; Manning, A. K.; Stringham, H.; Gloyn, A. L.; Lindgren, C. M.; T2D-GENES Consortium; Collins, F. S.; Mohlke, K. L.; Scott, L. J.; Karjalainen, T.; Nummenmaa, L.; Boehnke, M.; Nuutila, P.; Laakso, M.
      Pages: 334 - 342
      Abstract: Rare fully penetrant mutations in AKT2 are an established cause of monogenic disorders of glucose metabolism. Recently, a novel partial loss-of-function AKT2 coding variant (p.Pro50Thr) was identified that is nearly specific to Finns (frequency 1.1%), with the low-frequency allele associated with an increase in fasting plasma insulin level and risk of type 2 diabetes. The effects of the p.Pro50Thr AKT2 variant (p.P50T/AKT2) on insulin-stimulated glucose uptake (GU) in the whole body and in different tissues have not previously been investigated. We identified carriers (N = 20) and matched noncarriers (N = 25) for this allele in the population-based Metabolic Syndrome in Men (METSIM)study and invited these individuals back for positron emission tomography study with [18F]-fluorodeoxyglucose during euglycemic hyperinsulinemia. When we compared p.P50T/AKT2 carriers to noncarriers, we found a 39.4% reduction in whole-body GU (P = 0.006) and a 55.6% increase in the rate of endogenous glucose production (P = 0.038). We found significant reductions in GU in multiple tissues—skeletal muscle (36.4%), liver (16.1%), brown adipose (29.7%), and bone marrow (32.9%)—and increases of 16.8–19.1% in seven tested brain regions. These data demonstrate that the p.P50T substitution of AKT2 influences insulin-mediated GU in multiple insulin-sensitive tissues and may explain, at least in part, the increased risk of type 2 diabetes in p.P50T/AKT2 carriers.
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db17-1142
      Issue No: Vol. 67, No. 2 (2018)
  • Erratum. Adipocyte Glucocorticoid Receptor Deficiency Attenuates Aging-
           and HFD-Induced Obesity and Impairs the Feeding-Fasting Transition.
           Diabetes 2017;66:272-286
    • Authors: Mueller; K. M.; Hartmann, K.; Kaltenecker, D.; Vettorazzi, S.; Bauer, M.; Mauser, L.; Amann, S.; Jall, S.; Fischer, K.; Esterbauer, H.; Müller, T. D.; Tschöp, M. H.; Magnes, C.; Haybaeck, J.; Scherer, T.; Bordag, N.; Tuckermann, J. P.; Moriggl, R.
      Pages: 343 - 344
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db18-er02a
      Issue No: Vol. 67, No. 2 (2018)
  • Expression of Concern. The IR1152 Mutant Insulin Receptor Selectively
           Impairs Insulin Action in Skeletal Muscle but Not in Liver. Diabetes
           2000;49:1194-1202. DOI: 10.2337/diabetes.49.7.1194. PMID: 10909978
    • Authors: Caruso; M.; Miele, C.; Oliva, A.; Condorelli, G.; Oriente, F.; Riccardi, G.; Capaldo, B.; Fiory, F.; Accili, D.; Formisano, P.; Beguinot, F.
      Pages: 345 - 345
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db17-ec2017a
      Issue No: Vol. 67, No. 2 (2018)
  • Expression of Concern. Protein Kinase C (PKC)-{alpha} Activation Inhibits
           PKC-{zeta} and Mediates the Action of PED/PEA-15 on Glucose Transport in
           the L6 Skeletal Muscle Cells. Diabetes 2001;50:1244-1252. DOI:
           10.2337/diabetes.50.6.1244. PMID: 11375323
    • Authors: Condorelli; G.; Vigliotta, G.; Trencia, A.; Maitan, M. A.; Caruso, M.; Miele, C.; Oriente, F.; Santopietro, S.; Formisano, P.; Beguinot, F.
      Pages: 345 - 346
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db17-ec2017b
      Issue No: Vol. 67, No. 2 (2018)
  • Expression of Concern. Prep1 Controls Insulin Glucoregulatory Function in
           Liver by Transcriptional Targeting of SHP1 Tyrosine Phosphatase. Diabetes
           2011;60:138-147. DOI: 10.2337/db10-0860. PMID: 20864515
    • Authors: Oriente; F.; Iovino, S.; Cabaro, S.; Cassese, A.; Longobardi, E.; Miele, C.; Ungaro, P.; Formisano, P.; Blasi, F.; Beguinot, F.
      Pages: 346 - 347
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db17-ec2017c
      Issue No: Vol. 67, No. 2 (2018)
  • Issues and Events
    • Pages: 348 - 348
      PubDate: 2018-01-22T12:00:28-08:00
      DOI: 10.2337/db18-ie02
      Issue No: Vol. 67, No. 2 (2018)
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