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NAD+ AND Insulin

N F Shimkina, Yu G Nad', E R Barantsevich
: The study aims to examine the neurological complications of patients with type 1 diabetes treated with different methods of insulin therapy. MATERIAL AND METHODS: Thirty-four patients, aged from 18 to 40 years, with diabetes mellitus type 1 receiving insulinotherapy, with a duration of the disease 14.25±9.25 years, have been examined. By the time of the study the patients of the first group have been treated with continuous subcutaneous insulin infusion therapy (CSII) for 4...
2016: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
Arnaldo H de Souza, Laila R B Santos, Leticia P Roma, Mohammed Bensellam, Angelo R Carpinelli, Jean-Christophe Jonas
High glucose-induced oxidative stress and increased NADPH oxidase-2 (NOX2) activity may contribute to the progressive decline of the functional β-cell mass in type 2 diabetes. To test that hypothesis, we characterized, in islets from male NOX2 knockout (NOX2-KO) and wild-type (WT) C57BL/6J mice cultured for up to 3 weeks at 10 or 30 mmol/l glucose (G10 or G30), the in vitro effects of glucose on cytosolic oxidative stress using probes sensing glutathione oxidation (GRX1-roGFP2), thiol oxidation (roGFP1) or H2O2 (roGFP2-Orp1), on β-cell stimulus-secretion coupling events and on β-cell apoptosis...
September 22, 2016: Molecular and Cellular Endocrinology
Nan Hu, Jun Ren, Yingmei Zhang
Insulin resistance contributes to the high prevalence of type 2 diabetes mellitus, leading to cardiac anomalies. Emerging evidence depicts a pivotal role for mitochondrial injury in oxidative metabolism and insulin resistance. Mitochondrial aldehyde dehydrogenase (ALDH2) is one of metabolic enzymes detoxifying aldehydes although its role in insulin resistance remains elusive. This study was designed to evaluate the impact of ALDH2 overexpression on insulin resistance-induced myocardial damage and mechanisms involved with a focus on autophagy...
September 12, 2016: Oncotarget
Valentina Guzmán-Pérez, Christiane Bumke-Vogt, Monika Schreiner, Inga Mewis, Andrea Borchert, Andreas F H Pfeiffer
Nasturtium (Tropaeolum majus L.) contains high concentrations of benzylglcosinolate. We found that a hydrolysis product of benzyl glucosinolate-the benzyl isothiocyanate (BITC)-modulates the intracellular localization of the transcription factor Forkhead box O 1 (FOXO1). FoxO transcription factors can antagonize insulin effects and trigger a variety of cellular processes involved in tumor suppression, longevity, development and metabolism. The current study evaluated the ability of BITC-extracted as intact glucosinolate from nasturtium and hydrolyzed with myrosinase-to modulate i) the insulin-signaling pathway, ii) the intracellular localization of FOXO1 and, iii) the expression of proteins involved in gluconeogenesis, antioxidant response and detoxification...
2016: PloS One
Golam M Uddin, Neil A Youngson, David A Sinclair, Margaret J Morris
Obesity is well known to be a major cause of several chronic metabolic diseases, which can be partially counteracted by exercise. This is due, in part, to an upregulation of mitochondrial activity through increased nicotinamide adenine dinucleotide (NAD(+)). Recent studies have shown that NAD(+) levels can be increased by using the NAD(+) precursor, nicotinamide mononucleotide (NMN) leading to the suggestion that NMN could be a useful intervention in diet related metabolic disorders. In this study we compared the metabolic, and especially mitochondrial-associated, effects of exercise and NMN in ameliorating the consequences of high-fat diet (HFD) induced obesity in mice...
2016: Frontiers in Pharmacology
Julius Kieswich, Sophie R Sayers, Marta F Silvestre, Steven M Harwood, Muhammad M Yaqoob, Paul W Caton
AIMS/HYPOTHESIS: Serum extracellular nicotinamide phosphoribosyltransferase (eNAMPT) concentrations are elevated in type 2 diabetes. However, the relationship between abnormally elevated serum eNAMPT and type 2 diabetes pathophysiology is unclear. eNAMPT circulates in functionally and structurally distinct monomeric and dimeric forms. Dimeric eNAMPT promotes NAD biosynthesis. The role of eNAMPT-monomer is unclear but it may have NAD-independent proinflammatory effects. However, studies of eNAMPT in type 2 diabetes have not distinguished between monomeric and dimeric forms...
November 2016: Diabetologia
Kelly L Stromsdorfer, Shintaro Yamaguchi, Myeong Jin Yoon, Anna C Moseley, Michael P Franczyk, Shannon C Kelly, Nathan Qi, Shin-Ichiro Imai, Jun Yoshino
Obesity is associated with adipose tissue dysfunction and multi-organ insulin resistance. However, the mechanisms of such obesity-associated systemic metabolic complications are not clear. Here, we characterized mice with adipocyte-specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting NAD(+) biosynthetic enzyme known to decrease in adipose tissue of obese and aged rodents and people. We found that adipocyte-specific Nampt knockout mice had severe insulin resistance in adipose tissue, liver, and skeletal muscle and adipose tissue dysfunction, manifested by increased plasma free fatty acid concentrations and decreased plasma concentrations of a major insulin-sensitizing adipokine, adiponectin...
August 16, 2016: Cell Reports
Arata Fukushima, Gary D Lopaschuk
Alterations in cardiac energy metabolism are an important contributor to the cardiac pathology associated with obesity, diabetes, and heart failure. High rates of fatty acid β-oxidation with cardiac insulin resistance represent a cardiac metabolic hallmark of diabetes and obesity, while a marginal decrease in fatty acid oxidation and a prominent decrease in insulin-stimulated glucose oxidation are commonly seen in the early stages of heart failure. Alterations in post-translational control of energy metabolic processes have recently been identified as an important contributor to these metabolic changes...
July 29, 2016: Biochimica et Biophysica Acta
Jheelam Banerjee, Antje Bruckbauer, Michael B Zemel
BACKGROUND: We have previously shown leucine (Leu) to activate Sirt1 by lowering its KM for NAD(+), thereby amplifying the effects of other sirtuin activators and improving insulin sensitivity. Metformin (Met) converges on this pathway both indirectly (via AMPK) and by direct activation of Sirt1, and we recently found Leu to synergize with Met to improve insulin sensitivity and glycemic control while achieving ~80% dose-reduction in diet-induced obese mice. Accordingly, we sought here to define the mechanism of this interaction...
November 2016: Metabolism: Clinical and Experimental
Hao-Hao Zhang, Xiao-Jun Ma, Li-Na Wu, Yan-Yan Zhao, Peng-Yu Zhang, Ying-Hui Zhang, Ming-Wei Shao, Fei Liu, Fei Li, Gui-Jun Qin
Insufficient insulin produced by pancreatic β-cells in the control of blood sugar is a central feature of the etiology of diabetes. Reports have shown that endoplasmic reticulum (ER) stress is fundamentally involved in β-cell dysfunction. In this study, we hypothesized that NAD-dependent deacetylase sirtuin-3 (SIRT3), an important regulator of cell metabolism, protects pancreatic β-cells from ER stress-mediated apoptosis. To validate our hypothesis, a rat diabetic model was established by a high-fat diet (HFD)...
September 2016: Molecular and Cellular Biochemistry
Trillian Gregg, Chetan Poudel, Brian A Schmidt, Rashpal S Dhillon, Sophia M Sdao, Nathan A Truchan, Emma L Baar, Luis A Fernandez, John M Denu, Kevin W Eliceiri, Jeremy D Rogers, Michelle E Kimple, Dudley W Lamming, Matthew J Merrins
Aging is accompanied by impaired glucose homeostasis and an increased risk of type 2 diabetes, culminating in the failure of insulin secretion from pancreatic β-cells. To investigate the effects of age on β-cell metabolism, we established a novel assay to directly image islet metabolism with NAD(P)H fluorescence lifetime imaging (FLIM). We determined that impaired mitochondrial activity underlies an age-dependent loss of insulin secretion in human islets. NAD(P)H FLIM revealed a comparable decline in mitochondrial function in the pancreatic islets of aged mice (≥24 months), the result of 52% and 57% defects in flux through complex I and II, respectively, of the electron transport chain...
September 2016: Diabetes
Emma A Heart, Shpetim Karandrea, Xiaomei Liang, Maren E Balke, Patrick A Beringer, Elyse M Bobczynski, Delaine Zayas-Bazán Burgos, Tiffany Richardson, Joshua P Gray
Exposure to chemotherapeutic agents has been linked to an increased risk of type 2 diabetes (T2D), a disease characterized by both the peripheral insulin resistance and impaired glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. Using the rat β-cell line INS-1 832/13 and isolated mouse pancreatic islets, we investigated the effect of the chemotherapeutic drug doxorubicin (Adriamycin) on pancreatic β-cell survival and function. Exposure of INS-1 832/13 cells to doxorubicin caused impairment of GSIS, cellular viability, an increase in cellular toxicity, as soon as 6 h post-exposure...
August 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Samuel A J Trammell, Benjamin J Weidemann, Ankita Chadda, Matthew S Yorek, Amey Holmes, Lawrence J Coppey, Alexander Obrosov, Randy H Kardon, Mark A Yorek, Charles Brenner
Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD(+) metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD...
May 27, 2016: Scientific Reports
Leonardo F Ferreira, Orlando Laitano
The only known function of NAD(P)H oxidases is to produce reactive oxygen species (ROS). Skeletal muscles express three isoforms of NAD(P)H oxidases (Nox1, Nox2, and Nox4) that have been identified as critical modulators of redox homeostasis. Nox2 acts as the main source of skeletal muscle ROS during contractions, participates in insulin signaling and glucose transport, and mediates the myocyte response to osmotic stress. Nox2 and Nox4 contribute to skeletal muscle abnormalities elicited by angiotensin II, muscular dystrophy, heart failure, and high fat diet...
September 2016: Free Radical Biology & Medicine
Kyril Turpaev, Nils Welsh
We presently report that treatment with tyrphostin AG-126 (2-(3-hydroxy-4-nitrobenzylidene)malononitrile) and ten other aromatic malononitrile compounds (AMN) improves the resistance of insulin-producing βTC6, RIN-5AH, and MIN6 cells to oxidative stress and pro-inflammatory cytokines. On the molecular level AMN compounds promote nuclear accumulation of the Nrf2 transcription factor and expression of the cytoprotective genes heme ogygenase 1 (HO-1) and NAD(P)H/quinone oxidoreductase 1 (NQO1), inhibit cytokine-dependent inducible nitric oxide synthase (iNOS) induction, suppress intracellular production of reactive oxygen species in βTC6 and counteract to impairments of glucose-stimulated insulin secretion induced by pro-inflammatory cytokines in MIN6 cells...
August 5, 2016: European Journal of Pharmacology
Can-Can Zhou, Xi Yang, Xia Hua, Jian Liu, Mao-Bing Fan, Guo-Qiang Li, Jie Song, Tian-Ying Xu, Zhi-Yong Li, Yun-Feng Guan, Pei Wang, Chao-Yu Miao
BACKGROUND AND PURPOSE: Ageing is an important risk factor of non-alcoholic fatty liver disease (NAFLD). Here, we investigated whether the deficiency of nicotinamide adenine dinucleotide (NAD(+) ), a ubiquitous coenzyme, links ageing with NAFLD. EXPERIMENTAL APPROACH: Hepatic concentrations of NAD(+) , protein levels of nicotinamide phosphoribosyltransferase (NAMPT) and several other critical enzymes regulating NAD(+) biosynthesis, were compared in middle-aged and aged mice or patients...
August 2016: British Journal of Pharmacology
Tomoji Maeda, Chiaki Tanabe-Fujimura, Yu Fujita, Chihiro Abe, Yoshino Nanakida, Kun Zou, Junjun Liu, Shuyu Liu, Toshihiro Nakajima, Hiroto Komano
Homocysteine-induced endoplasmic reticulum (ER) protein (Herp) is an ER stress-inducible key regulatory component of ER-associated degradation (ERAD) that has been implicated in insulin hypersecretion in diabetic mouse models. Herp expression is tightly regulated. Additionally, Herp is a highly labile protein and interacts with various proteins, which are characteristic features of ubiquitinated protein. Previously, we reported that ubiquitination is not required for Herp degradation. In addition, we found that the lysine residues of Herp (which are ubiquitinated by E3 ubiquitin ligase) are not sufficient for regulation of Herp degradation...
May 13, 2016: Biochemical and Biophysical Research Communications
Rebecca A S Palu, Carl S Thummel
SIRT1 is a member of the sirtuin family of NAD+-dependent deacetylases, which couple cellular metabolism to systemic physiology. Although studies in mouse models have defined a central role for SIRT1 in maintaining metabolic health, the molecular mechanisms remain unclear. Here we show that loss of the Drosophila SIRT1 homolog sir2 leads to the age-progressive onset of hyperglycemia, obesity, glucose intolerance, and insulin resistance. Tissue-specific functional studies show that Sir2 is both necessary and sufficient in the fat body (analogous to the mammalian liver) to maintain glucose homeostasis and peripheral insulin sensitivity...
April 2016: PLoS Genetics
Irena Audzeyenka, Dorota Rogacka, Agnieszka Piwkowska, Michal Rychlowski, Joanna Beata Bierla, Elżbieta Czarnowska, Stefan Angielski, Maciej Jankowski
Autophagy is an intracellular defense mechanism responsible for the turnover of damaged or non-functional cellular constituents. This process provides cells with energy and essential compounds under unfavorable environmental conditions-such as oxidative stress and hyperglycemia, which are both observed in diabetes. The most common diabetes complication is diabetic nephropathy (DN), which can lead to renal failure. This condition often includes impaired podocyte function. Here we investigated autophagic activity in rat podocytes cultured with a high insulin concentration (300nM)...
June 2016: International Journal of Biochemistry & Cell Biology
Arata Fukushima, Shintaro Kinugawa, Shingo Takada, Junichi Matsumoto, Takaaki Furihata, Wataru Mizushima, Masaya Tsuda, Takashi Yokota, Shouji Matsushima, Koichi Okita, Hiroyuki Tsutsui
Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11)...
May 15, 2016: European Journal of Pharmacology
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