Science.gov

Sample records for key insulin regulatory

  1. Identification of a key regulatory element for the basal activity of the human insulin-like growth factor II gene promoter P3.

    PubMed Central

    Rietveld, L E; Holthuizen, P E; Sussenbach, J S

    1997-01-01

    Transcription of the human insulin-like growth factor II (IGF-II) gene is under the control of four promoters (P1-P4) that are differentially active during growth and development. Promoter 3 (P3) is the most active promoter during fetal development as well as in most adult tissues. P3 is also the most active promoter in tumour tissues and cell lines expressing IGF-II. Transient transfections of HeLa and Hep3B cells with truncated promoter constructs revealed that the region between -289 and -183 relative to the transcription start site supports basal promoter activity in both cell lines. Footprint experiments showed that the region between positions -192 and -172 (P3-4) is the only element bound by nuclear proteins. P3-4 is bound by five proteins, of which three proteins (proteins 3, 4 and 5) bind specifically and are expressed at the same levels in HeLa and Hep3B cells. Electrophoretic mobility shift assays and differential footprint experiments revealed the presence of two protein-binding regions within the P3-4 element. Proteins 4 and 5 bind box A (-193 to -188), whereas box B (-183 to -172) is bound by protein 3. From transcription experiments in vitro it can be concluded that Box A is essential for P3 activity. Box A is part of a region 11 dG residues long and is protected by proteins 4 and 5 that bind a contiguous set of six dG residues. DNA-binding of proteins 4 and 5 to box A requires the presence of Zn2+ ions. Thus structural and functional analysis reveals that the P3-4 element is a key regulatory element of P3 that contains two separate binding sites for proteins essential for the basal activity of IGF-II P3. PMID:9581544

  2. Current european regulatory perspectives on insulin analogues.

    PubMed

    Enzmann, Harald G; Weise, Martina

    2011-01-01

    Insulin analogues are increasingly considered as an alternative to human insulin in the therapy of diabetes mellitus. Insulin analogues (IAs) are chemically different from human insulin and may have different pharmacokinetic or pharmacodynamic properties. The significance of the modifications of the insulin molecule for the safety profile of IAs must be considered. This review describes the regulatory procedure and the expectations for the scientific content of European marketing authorization applications for innovative IAs submitted to the European Medicines Agency. Particular consideration is given to a potential cancer hazard. Specific regulatory guidance on how to address a possible carcinogenic or tumor promoting effect of innovative IAs in non-clinical studies is available. After marketing authorization, the factual access of patients to the new product will be determined to great extent by health technology assessment bodies, reimbursement decisions and the price. Whereas the marketing authorization is a European decision, pricing and reimbursement are national or regional responsibilities. The assessment of benefit and risk by the European Medicines Agency is expected to influence future decisions on price and reimbursement on a national or regional level. Collaborations between regulatory agencies and health technology assessment bodies have been initiated on European and national level to facilitate the use of the European Medicines Agency's benefit risk assessment as basis on which to build the subsequent health technology assessment. The option for combined or joint scientific advice procedures with regulators and health technology assessment bodies on European level or on a national level in several European Member States may help applicants to optimize their development program and dossier preparation in regard of both European marketing authorization application and reimbursement decisions. PMID:21736748

  3. Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling.

    PubMed Central

    Shepherd, P R; Withers, D J; Siddle, K

    1998-01-01

    Insulin plays a key role in regulating a wide range of cellular processes. However, until recently little was known about the signalling pathways that are involved in linking the insulin receptor with downstream responses. It is now apparent that the activation of class 1a phosphoinositide 3-kinase (PI 3-kinase) is necessary and in some cases sufficient to elicit many of insulin's effects on glucose and lipid metabolism. The lipid products of PI 3-kinase act as both membrane anchors and allosteric regulators, serving to localize and activate downstream enzymes and their protein substrates. One of the major ways these lipid products of PI 3-kinase act in insulin signalling is by binding to pleckstrin homology (PH) domains of phosphoinositide-dependent protein kinase (PDK) and protein kinase B (PKB) and in the process regulating the phosphorylation of PKB by PDK. Using mechanisms such as this, PI 3-kinase is able to act as a molecular switch to regulate the activity of serine/threonine-specific kinase cascades important in mediating insulin's effects on endpoint responses. PMID:9677303

  4. Nitrogen fixation: key genetic regulatory mechanisms.

    PubMed

    Martinez-Argudo, I; Little, R; Shearer, N; Johnson, P; Dixon, R

    2005-02-01

    The necessity to respond to the level of fixed nitrogen and external oxygen concentrations and to provide sufficient energy for nitrogen fixation imposes common regulatory principles amongst diazotrophs. The NifL-NifA system in Azotobacter vinelandii integrates the signals of redox, fixed-nitrogen and carbon status to regulate nif transcription. Multidomain signalling interactions between NifL and NifA are modulated by redox changes, ligand binding and interaction with the signal-transduction protein GlnK. Under adverse redox conditions (excess oxygen) or when fixed nitrogen is in excess, NifL forms a complex with NifA in which transcriptional activation is prevented. Oxidized NifL forms a binary complex with NifA to inhibit NifA activity. When fixed nitrogen is in excess, the non-covalently modified form of GlnK interacts with NifL to promote the formation of a GlnK-NifL-NifA ternary complex. When the cell re-encounters favourable conditions for nitrogen fixation, it is necessary to deactivate the signals to ensure that the NifL-NifA complex is dissociated so that NifA is free to activate transcription. This is achieved through interactions with 2-oxoglutarate, a key metabolic signal of the carbon status, which binds to the N-terminal GAF (cGMP-specific and stimulated phosphodiesterases, Anabaena adenylate cyclases and Escherichia coli FhlA) domain of NifA. PMID:15667291

  5. Regulatory mode shift of Tbc1d1 is required for acquisition of insulin-responsive GLUT4-trafficking activity

    PubMed Central

    Hatakeyama, Hiroyasu; Kanzaki, Makoto

    2013-01-01

    Tbc1d1 is key to skeletal muscle GLUT4 regulation. By using GLUT4 nanometry combined with a cell-based reconstitution model, we uncover a shift in the regulatory mode of Tbc1d1 by showing that Tbc1d1 temporally acquires insulin responsiveness, which triggers GLUT4 trafficking only after an exercise-mimetic stimulus such as aminoimidazole carboxamide ribonucleotide (AICAR) pretreatment. The functional acquisition of insulin responsiveness requires Ser-237 phosphorylation and an intact phosphotyrosine-binding (PTB) 1 domain. Mutations in PTB1, including R125W (a natural mutant), thus result in complete loss of insulin-responsiveness acquisition, whereas AICAR-responsive GLUT4-liberation activity remains intact. Thus our data provide novel insights into temporal acquisition/memorization of Tbc1d1 insulin responsiveness, relying on the PTB1 domain, possibly a key factor in the beneficial effects of exercise on muscle insulin potency. PMID:23325788

  6. Aerosol Insulin Induces Regulatory CD8 γδ T Cells That Prevent Murine Insulin-dependent Diabetes

    PubMed Central

    Harrison, Leonard C.; Dempsey-Collier, Majella; Kramer, David R.; Takahashi, Kazuma

    1996-01-01

    Cellular immune hyporesponsiveness can be induced by the presentation of soluble protein antigens to mucosal surfaces. Most studies of mucosa-mediated tolerance have used the oral route of antigen delivery and few have examined autoantigens in natural models of autoimmune disease. Insulin is an autoantigen in humans and nonobese diabetic (NOD) mice with insulindependent diabetes mellitus (IDDM). When we administered insulin aerosol to NOD mice after the onset of subclinical disease, pancreatic islet pathology and diabetes incidence were both significantly reduced. Insulin-treated mice had increased circulating antibodies to insulin, absent splenocyte proliferation to the major epitope, insulin B chain amino acids 9–23, which was associated with increased IL-4 and particularly IL-10 secretion, and reduced proliferation to glutamic acid decarboxylase, another islet autoantigen. The ability of splenocytes from insulin-treated mice to suppress the adoptive transfer of diabetes to nondiabetic mice by T cells of diabetic mice was shown to be caused by small numbers of CD8 γδ T cells. These findings reveal a novel mechanism for suppressing cell-mediated autoimmune disease. Induction of regulatory CD8 γδ T cells by aerosol insulin is a therapeutic strategy with implications for the prevention of human IDDM. PMID:8976172

  7. An Overview of Current Regulatory Requirements for Approval of Biosimilar Insulins

    PubMed Central

    Khatami, Hootan; McKinnon, Ross; Home, Philip

    2015-01-01

    Abstract Insulin analog patent expiry is likely to mean that, increasingly, copies of original biopharmaceutical products will be submitted for authorization. Experience with biosimilars in other therapeutic areas suggests that careful regulation and caution are needed. Published guidelines of regulatory authorities around the world on approval of biosimilars and, where available, insulin biosimilars were reviewed. Information was sourced through Internet searching and cross-referencing guidelines. As of August 2014, general biosimilar and insulin-specific guidelines are available in 34 countries and two countries/regulatory domains, respectively. Many guidelines are clearly related to, or partly derived from, the general and insulin-specific European Medicines Agency (EMA) guidelines. Areas covered by these guidelines are fairly consistent, covering preclinical, pharmacokinetic (PK), and pharmacodynamic (PD) studies in humans and clinical areas; however, there are differences in emphasis. The EMA insulin-specific guidelines include detailed criteria on PK/PD studies, as do most other general biosimilar guidelines and, to a lesser extent, clinical studies. The U.S. Food and Drug Administration has general biosimilar guidelines, emphasizing consideration of the whole package of in vitro, biological, and human studies, rather than concentrating on any one aspect. In countries such as Mexico, guidelines are broad, leaving wide discretion to the regulatory authority. In conclusion, from a global perspective, this area of drug regulation is heterogeneous and evolving, and the authors call for an initiative aimed at harmonizing the requirements for biosimilar insulins. PMID:25789689

  8. An Overview of Current Regulatory Requirements for Approval of Biosimilar Insulins.

    PubMed

    Heinemann, Lutz; Khatami, Hootan; McKinnon, Ross; Home, Philip

    2015-07-01

    Insulin analog patent expiry is likely to mean that, increasingly, copies of original biopharmaceutical products will be submitted for authorization. Experience with biosimilars in other therapeutic areas suggests that careful regulation and caution are needed. Published guidelines of regulatory authorities around the world on approval of biosimilars and, where available, insulin biosimilars were reviewed. Information was sourced through Internet searching and cross-referencing guidelines. As of August 2014, general biosimilar and insulin-specific guidelines are available in 34 countries and two countries/regulatory domains, respectively. Many guidelines are clearly related to, or partly derived from, the general and insulin-specific European Medicines Agency (EMA) guidelines. Areas covered by these guidelines are fairly consistent, covering preclinical, pharmacokinetic (PK), and pharmacodynamic (PD) studies in humans and clinical areas; however, there are differences in emphasis. The EMA insulin-specific guidelines include detailed criteria on PK/PD studies, as do most other general biosimilar guidelines and, to a lesser extent, clinical studies. The U.S. Food and Drug Administration has general biosimilar guidelines, emphasizing consideration of the whole package of in vitro, biological, and human studies, rather than concentrating on any one aspect. In countries such as Mexico, guidelines are broad, leaving wide discretion to the regulatory authority. In conclusion, from a global perspective, this area of drug regulation is heterogeneous and evolving, and the authors call for an initiative aimed at harmonizing the requirements for biosimilar insulins. PMID:25789689

  9. Gut Microbiota Is a Key Modulator of Insulin Resistance in TLR 2 Knockout Mice

    PubMed Central

    Caricilli, Andréa M.; Picardi, Paty K.; de Abreu, Lélia L.; Ueno, Mirian; Prada, Patrícia O.; Ropelle, Eduardo R.; Hirabara, Sandro Massao; Castoldi, Ângela; Vieira, Pedro; Camara, Niels O. S.; Curi, Rui; Carvalheira, José B.; Saad, Mário J. A.

    2011-01-01

    Environmental factors and host genetics interact to control the gut microbiota, which may have a role in the development of obesity and insulin resistance. TLR2-deficient mice, under germ-free conditions, are protected from diet-induced insulin resistance. It is possible that the presence of gut microbiota could reverse the phenotype of an animal, inducing insulin resistance in an animal genetically determined to have increased insulin sensitivity, such as the TLR2 KO mice. In the present study, we investigated the influence of gut microbiota on metabolic parameters, glucose tolerance, insulin sensitivity, and signaling of TLR2-deficient mice. We investigated the gut microbiota (by metagenomics), the metabolic characteristics, and insulin signaling in TLR2 knockout (KO) mice in a non-germ free facility. Results showed that the loss of TLR2 in conventionalized mice results in a phenotype reminiscent of metabolic syndrome, characterized by differences in the gut microbiota, with a 3-fold increase in Firmicutes and a slight increase in Bacteroidetes compared with controls. These changes in gut microbiota were accompanied by an increase in LPS absorption, subclinical inflammation, insulin resistance, glucose intolerance, and later, obesity. In addition, this sequence of events was reproduced in WT mice by microbiota transplantation and was also reversed by antibiotics. At the molecular level the mechanism was unique, with activation of TLR4 associated with ER stress and JNK activation, but no activation of the IKKβ-IκB-NFκB pathway. Our data also showed that in TLR2 KO mice there was a reduction in regulatory T cell in visceral fat, suggesting that this modulation may also contribute to the insulin resistance of these animals. Our results emphasize the role of microbiota in the complex network of molecular and cellular interactions that link genotype to phenotype and have potential implications for common human disorders involving obesity, diabetes, and even other

  10. The regulatory system for diabetes mellitus: Modeling rates of glucose infusions and insulin injections

    NASA Astrophysics Data System (ADS)

    Yang, Jin; Tang, Sanyi; Cheke, Robert A.

    2016-08-01

    Novel mathematical models with open and closed-loop control for type 1 or type 2 diabetes mellitus were developed to improve understanding of the glucose-insulin regulatory system. A hybrid impulsive glucose-insulin model with different frequencies of glucose infusions and insulin injections was analyzed, and the existence and uniqueness of the positive periodic solution for type 1 diabetes, which is globally asymptotically stable, was studied analytically. Moreover, permanence of the system for type 2 diabetes was demonstrated which showed that the glucose concentration level is uniformly bounded above and below. To investigate how to prevent hyperinsulinemia and hyperglycemia being caused by this system, we developed a model involving periodic intakes of glucose with insulin injections applied only when the blood glucose level reached a given critical glucose threshold. In addition, our numerical analysis revealed that the period, the frequency and the dose of glucose infusions and insulin injections are crucial for insulin therapies, and the results provide clinical strategies for insulin-administration practices.

  11. Regulatory and Stakeholder Involvement is Key to Successful Project Completion

    SciTech Connect

    Ballinger, K. S.; Coleman, S. J.; Shoemake, J. M.; Olds, T. E.

    2006-07-01

    Order (Tri-Party Agreement).[1] The key governmental or regulatory organizations that can influence the ORP Mission include, the Defense Nuclear Facilities Safety Board, the Office of Civilian Radioactive Waste Management, the U.S. Congress, the U.S. Department of Energy-Headquarters, the U.S. Department of Energy, Richland Operations Office, the U.S. Environmental Protection Agency, the U.S. Nuclear Regulatory Commission, the Washington State Department of Ecology and Health, and the Washington State Occupational Safety and Health Administration. Stakeholders include the concerned citizen groups, the congressionally recognized-Hanford Advisory Board, signatories to regional agreements, Tribal Nations with treaty rights, other DOE sites, other government agencies with cross-cutting programs and local state, county, and municipal governments. [2] ORP understands that while quality work and planning are essential elements of completing their mission, they cannot accomplish it fully without public confidence and trust. Given the length of the mission, many changes will occur in the external environment of national attitudes, priorities, standards, expectations and economic conditions over the life span of the mission. There will be unanticipated events, and difficult periods of change and complex decisions that will occur over the next several years. Under these conditions, the question of how to respond is as important as the quality plans and technical abilities of the ORP. The strategy ORP employs is designed to increase effectiveness and provide meaningful opportunities for public input across many DOE missions, activities and decisions. Diverse minds working together can often come up with better solutions to problems. In addition, if people can participate in decisions that affect them, they are more likely to support those decisions, even when dissention occurs. Public involvement is not a vote, or a popularity contest. Public involvement is a process to give

  12. Brain insulin signaling: a key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes

    PubMed Central

    McNay, Ewan C.; Recknagel, Andrew K.

    2011-01-01

    Understanding of the role of insulin in the brain has gradually expanded, from initial conceptions of the brain as insulin-insensitive through identification of a role in regulation of feeding to recent demonstration of insulin as a key component of hippocampal memory processes. Conversely, systemic insulin resistance such as that seen in type 2 diabetes is associated with a range of cogntive and neural deficits. Here we review the evidence for insulin as a cognitive and neural modulator, including potential effector mechanisms, and examine the impact that type 2 diabetes has on these mechanisms in order to identify likely bases for the cognitive impairments seen in type 2 diabetic patients. PMID:21907815

  13. Key intestinal genes involved in lipoprotein metabolism are downregulated in dyslipidemic men with insulin resistance[S

    PubMed Central

    Couture, Patrick; Tremblay, André J.; Kelly, Isabelle; Lemelin, Valéry; Droit, Arnaud; Lamarche, Benoît

    2014-01-01

    Insulin resistance (IR) is associated with elevated plasma levels of triglyceride-rich lipoproteins (TRLs) of intestinal origin. However, the mechanisms underlying the overaccumulation of apolipoprotein (apo)B-48-containing TRLs in individuals with IR are not yet fully understood. This study examined the relationships between apoB-48-containing TRL kinetics and the expression of key intestinal genes and proteins involved in lipid/lipoprotein metabolism in 14 obese nondiabetic men with IR compared with 10 insulin-sensitive (IS) men matched for waist circumference. The in vivo kinetics of TRL apoB-48 were assessed using a primed-constant infusion of L-[5,5,5-D3]leucine for 12 h with the participants in a constantly fed state. The expression of key intestinal genes and proteins involved in lipid/lipoprotein metabolism was assessed by performing real-time PCR quantification and LC-MS/MS on duodenal biopsy specimens. The TRL apoB-48 pool size and production rate were 102% (P < 0.0001) and 87% (P = 0.01) greater, respectively, in the men with IR versus the IS men. On the other hand, intestinal mRNA levels of sterol regulatory element binding factor-2, hepatocyte nuclear factor-4α, and microsomal triglyceride transfer protein were significantly lower in the men with IR than in the IS men. These data indicate that IR is associated with intestinal overproduction of lipoproteins and significant downregulation of key intestinal genes involved in lipid/lipoprotein metabolism. PMID:24142110

  14. Eat to reproduce: a key role for the insulin signaling pathway in adult insects

    PubMed Central

    Badisco, Liesbeth; Van Wielendaele, Pieter; Vanden Broeck, Jozef

    2013-01-01

    Insects, like all heterotrophic organisms, acquire from their food the nutrients that are essential for anabolic processes that lead to growth (larval stages) or reproduction (adult stage). In adult females, this nutritional input is processed and results in a very specific output, i.e., the production of fully developed eggs ready for fertilization and deposition. An important role in this input-output transition is attributed to the insulin signaling pathway (ISP). The ISP is considered to act as a sensor of the organism's nutritional status and to stimulate the progression of anabolic events when the status is positive. In several insect species belonging to different orders, the ISP has been demonstrated to positively control vitellogenesis and oocyte growth. Whether or not ISP acts herein via a mediator action of lipophilic insect hormones (ecdysteroids and juvenile hormone) remains debatable and might be differently controlled in different insect orders. Most likely, insulin-related peptides, ecdysteroids and juvenile hormone are involved in a complex regulatory network, in which they mutually influence each other and in which the insect's nutritional status is a crucial determinant of the network's output. The current review will present an overview of the regulatory role of the ISP in female insect reproduction and its interaction with other pathways involving nutrients, lipophilic hormones and neuropeptides. PMID:23966944

  15. KWOC (Key-Word-Out-of-Context) Index of US Nuclear Regulatory Commission Regulatory Guide Series

    SciTech Connect

    Jennings, S.D.

    1990-04-01

    To meet the objectives of the program funded by the Department of Energy (DOE)-Nuclear Energy (NE) Technology Support Programs, the Performance Assurance Project Office (PAPO) administers a Performance Assurance Information Program that collects, compiles, and distributes program-related information, reports, and publications for the benefit of the DOE-NE program participants. THE KWOC Index of US Nuclear Regulatory Commission Regulatory Guide Series'' is prepared as an aid in searching for specific topics in the US Nuclear Regulatory Commission, Regulatory Guide Series.

  16. Insulin

    MedlinePlus

    ... pump is connected to your body by a flexible tube that has a tip that sticks under your skin. A cartridge of insulin is put in the pump. The insulin flows through the tube into your body. The pump controls how much insulin goes into your body. The ...

  17. Evidence for a regulatory role of Cullin-RING E3 ubiquitin ligase 7 in insulin signalling§

    PubMed Central

    Kruse, Michael; Hartmann, Thomas; Lempart, Justine; Mühlich, Susanne; Pfeiffer, Andreas F. H.; Field, Loren J.; Charron, Maureen J.; Pan, Zhen-Qiang; Engelhardt, Stefan; Sarikas, Antonio

    2014-01-01

    Dysfunctional regulation of signalling pathways downstream of the insulin receptor plays a pivotal role in the pathogenesis of insulin resistance and type 2 diabetes. In this study we report both in vitro and in vivo experimental evidence for a role of Cullin-RING E3 ubiquitin ligase 7 (CRL7) in the regulation of insulin signalling and glucose homeostasis. We show that Cul7−/− mouse embryonic fibroblasts displayed enhanced AKT and Erk MAP kinase phosphorylation upon insulin stimulation. Depletion of CUL7 by RNA interference in C2C12 myotubes led to increased activation of insulin signalling pathways and cellular glucose uptake, as well as a reduced capacity of these cells to execute insulin-induced degradation of insulin receptor substrate 1 (IRS1). In vivo, heterozygosity of either Cul7 or Fbxw8, both key components of CRL7, resulted in elevated PI3 kinase / AKT activation in skeletal muscle tissue upon insulin stimulation when compared to wild-type controls. Finally, Cul7+/− or Fbxw8+/− mice exhibited enhanced insulin sensitivity and plasma glucose clearance. Collectively, our findings point to a yet unrecognized role of CRL7 in insulin-mediated control of glucose homeostasis by restraining PI3 kinase / AKT activities in skeletal muscle cells. PMID:24219910

  18. PKB/Akt: a key mediator of cell proliferation, survival and insulin responses?

    PubMed

    Lawlor, M A; Alessi, D R

    2001-08-01

    The serine/threonine protein kinase PKB (also known as Akt) is thought to be a key mediator of signal transduction processes. The identification of PKB substrates and the role PKB phosphorylation plays in regulating these molecules have been a major focus of research in recent years. A recently developed motif-profile scoring algorithm that can be used to scan the genome for potential PKB substrates is therefore a useful tool, although additional considerations, such as the evolutionary conservation of the phosphorylation site, must also be taken into account. Recent evidence indicates that PKB plays a key role in cancer progression by stimulating cell proliferation and inhibiting apoptosis and is also probably a key mediator of insulin signalling. These findings indicate that PKB is likely to be a hot drug target for the treatment of cancer, diabetes and stroke. There are, however, a number of pitfalls of methodologies currently employed to study PKB function, and therefore caution should be used in interpretation of such experiments. PMID:11686294

  19. Interchangeability among reference insulin analogues and their biosimilars: regulatory framework, study design and clinical implications.

    PubMed

    Dowlat, H A; Kuhlmann, M K; Khatami, H; Ampudia-Blasco, F J

    2016-08-01

    Biosimilars are regulated differently from small-molecule generic, chemically derived medicines. The complexity of biological products means that small changes in manufacturing or formulation may result in changes in efficacy and safety of the final product. In the face of this complexity, the regulatory landscape for biosimilars continues to evolve, and global harmonization regarding requirements is currently lacking. It is essential that clinicians and patients are reassured that biosimilars are equally safe and effective as their reference product, and this is particularly important when interchangeability, defined as 'changing one medicine for another one which is expected to achieve the same clinical effect in a given clinical setting in any one patient', is considered. Although the automatic substitution (i.e. substitution without input from the prescribing healthcare provider) of biosimilars for reference products is currently not permitted by the majority of countries, this may change in the future. In order to demonstrate interchangeability between reference products and a biosimilar, more stringent and specific studies of the safety and efficacy of biosimilars are likely to be needed; however, guidance on the design of and the need for any such studies is currently limited. The present article provides an overview of the current regulatory framework around the demonstration of interchangeability with biosimilars, with a specific focus on biosimilar insulin analogues, and details experiences with other biosimilar products. In addition, designs for studies to evaluate interchangeability with a biosimilar insulin analogue product are proposed and a discussion about the implications of interchangeability in clinical practice is included. PMID:27097592

  20. Insulin resistance as a key link for the increased risk of cognitive impairment in the metabolic syndrome.

    PubMed

    Kim, Bhumsoo; Feldman, Eva L

    2015-01-01

    Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that includes obesity, diabetes, and dyslipidemia. Accumulating evidence implies that MetS contributes to the development and progression of Alzheimer's disease (AD); however, the factors connecting this association have not been determined. Insulin resistance (IR) is at the core of MetS and likely represent the key link between MetS and AD. In the central nervous system, insulin plays key roles in learning and memory, and AD patients exhibit impaired insulin signaling that is similar to that observed in MetS. As we face an alarming increase in obesity and T2D in all age groups, understanding the relationship between MetS and AD is vital for the identification of potential therapeutic targets. Recently, several diabetes therapies that enhance insulin signaling are being tested for a potential therapeutic benefit in AD and dementia. In this review, we will discuss MetS as a risk factor for AD, focusing on IR and the recent progress and future directions of insulin-based therapies. PMID:25766618

  1. Insulin resistance as a key link for the increased risk of cognitive impairment in the metabolic syndrome

    PubMed Central

    Kim, Bhumsoo; Feldman, Eva L

    2015-01-01

    Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that includes obesity, diabetes, and dyslipidemia. Accumulating evidence implies that MetS contributes to the development and progression of Alzheimer's disease (AD); however, the factors connecting this association have not been determined. Insulin resistance (IR) is at the core of MetS and likely represent the key link between MetS and AD. In the central nervous system, insulin plays key roles in learning and memory, and AD patients exhibit impaired insulin signaling that is similar to that observed in MetS. As we face an alarming increase in obesity and T2D in all age groups, understanding the relationship between MetS and AD is vital for the identification of potential therapeutic targets. Recently, several diabetes therapies that enhance insulin signaling are being tested for a potential therapeutic benefit in AD and dementia. In this review, we will discuss MetS as a risk factor for AD, focusing on IR and the recent progress and future directions of insulin-based therapies. PMID:25766618

  2. Insulin

    NASA Technical Reports Server (NTRS)

    2004-01-01

    The manipulation of organic materials--cells, tissues, and even living organisms--offers many exciting possibilities for the future from organic computers to improved aquaculture. Commercial researchers are using the microgravity environment to produce large near perfect protein crystals Research on insulin has yielded crystals that far surpass the quality of insulin crystals grown on the ground. Using these crystals industry partners are working to develop new and improved treatments for diabetes. Other researchers are exploring the possibility of producing antibiotics using plant cell cultures which could lead to both orbital production and the improvement of ground-based antibiotic production.

  3. Mathematical model of the glucose-insulin regulatory system: From the bursting electrical activity in pancreatic β-cells to the glucose dynamics in the whole body

    NASA Astrophysics Data System (ADS)

    Han, Kyungreem; Kang, Hyuk; Choi, M. Y.; Kim, Jinwoong; Lee, Myung-Shik

    2012-10-01

    A theoretical approach to the glucose-insulin regulatory system is presented. By means of integrated mathematical modeling and extensive numerical simulations, we probe the cell-level dynamics of the membrane potential, intracellular Ca2+ concentration, and insulin secretion in pancreatic β-cells, together with the whole-body level glucose-insulin dynamics in the liver, brain, muscle, and adipose tissues. In particular, the three oscillatory modes of insulin secretion are reproduced successfully. Such comprehensive mathematical modeling may provide a theoretical basis for the simultaneous assessment of the β-cell function and insulin resistance in clinical examination.

  4. Key Role for Ceramides in Mediating Insulin Resistance in Human Muscle Cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Elevated non-esterified fatty acids, triglyceride, diacylglycerol and ceramide have all been associated with insulin resistance in muscle. We set out to investigate the role of intramyocellular lipid metabolites in the induction of insulin resistance in human primary myoblast cultures. Muscle cell...

  5. Ethylene Response Factors: A Key Regulatory Hub in Hormone and Stress Signaling.

    PubMed

    Müller, Maren; Munné-Bosch, Sergi

    2015-09-01

    Ethylene is essential for many developmental processes and a key mediator of biotic and abiotic stress responses in plants. The ethylene signaling and response pathway includes Ethylene Response Factors (ERFs), which belong to the transcription factor family APETALA2/ERF. It is well known that ERFs regulate molecular response to pathogen attack by binding to sequences containing AGCCGCC motifs (the GCC box), a cis-acting element. However, recent studies suggest that several ERFs also bind to dehydration-responsive elements and act as a key regulatory hub in plant responses to abiotic stresses. Here, we review some of the recent advances in our understanding of the ethylene signaling and response pathway, with emphasis on ERFs and their role in hormone cross talk and redox signaling under abiotic stresses. We conclude that ERFs act as a key regulatory hub, integrating ethylene, abscisic acid, jasmonate, and redox signaling in the plant response to a number of abiotic stresses. PMID:26103991

  6. Insulin-like growth factor-1 stimulates regulatory T cells and suppresses autoimmune disease

    PubMed Central

    Bilbao, Daniel; Luciani, Luisa; Johannesson, Bjarki; Piszczek, Agnieszka; Rosenthal, Nadia

    2014-01-01

    The recent precipitous rise in autoimmune diseases is placing an increasing clinical and economic burden on health systems worldwide. Current therapies are only moderately efficacious, often coupled with adverse side effects. Here, we show that recombinant human insulin-like growth factor-1 (rhIGF-1) stimulates proliferation of both human and mouse regulatory T (Treg) cells in vitro and when delivered systemically via continuous minipump, it halts autoimmune disease progression in mouse models of type 1 diabetes (STZ and NOD) and multiple sclerosis (EAE) in vivo. rhIGF-1 administration increased Treg cells in affected tissues, maintaining their suppressive properties. Genetically, ablation of the IGF-1 receptor specifically on Treg cell populations abrogated the beneficial effects of rhIGF-1 administration on the progression of multiple sclerotic symptoms in the EAE model, establishing a direct effect of IGF-1 on Treg cell proliferation. These results establish systemically delivered rhIGF-1 as a specific, effective stimulator of Treg cell action, underscoring the clinical feasibility of manipulating natural tolerance mechanisms to suppress autoimmune disease. PMID:25339185

  7. Insulin Is a Key Modulator of Fetoplacental Endothelium Metabolic Disturbances in Gestational Diabetes Mellitus

    PubMed Central

    Sobrevia, Luis; Salsoso, Rocío; Fuenzalida, Bárbara; Barros, Eric; Toledo, Lilian; Silva, Luis; Pizarro, Carolina; Subiabre, Mario; Villalobos, Roberto; Araos, Joaquín; Toledo, Fernando; González, Marcelo; Gutiérrez, Jaime; Farías, Marcelo; Chiarello, Delia I.; Pardo, Fabián; Leiva, Andrea

    2016-01-01

    Gestational diabetes mellitus (GDM) is a disease of the mother that associates with altered fetoplacental vascular function. GDM-associated maternal hyperglycaemia result in fetal hyperglycaemia, a condition that leads to fetal hyperinsulinemia and altered L-arginine transport and synthesis of nitric oxide, i.e., endothelial dysfunction. These alterations in the fetoplacental endothelial function are present in women with GDM that were under diet or insulin therapy. Since these women and their newborn show normal glycaemia at term, other factors or conditions could be altered and/or not resolved by restoring normal level of circulating D-glucose. GDM associates with metabolic disturbances, such as abnormal handling of the locally released vasodilator adenosine, and biosynthesis and metabolism of cholesterol lipoproteins, or metabolic diseases resulting in endoplasmic reticulum stress and altered angiogenesis. Insulin acts as a potent modulator of all these phenomena under normal conditions as reported in primary cultures of cells obtained from the human placenta; however, GDM and the role of insulin regarding these alterations in this disease are poorly understood. This review focuses on the potential link between insulin and endoplasmic reticulum stress, hypercholesterolemia, and angiogenesis in GDM in the human fetoplacental vasculature. Based in reports in primary culture placental endothelium we propose that insulin is a factor restoring endothelial function in GDM by reversing ERS, hypercholesterolaemia and angiogenesis to a physiological state involving insulin activation of insulin receptor isoforms and adenosine receptors and metabolism in the human placenta from GDM pregnancies. PMID:27065887

  8. Counterregulation of insulin by leptin as key component of autonomic regulation of body weight

    PubMed Central

    Borer, Katarina T

    2014-01-01

    A re-examination of the mechanism controlling eating, locomotion, and metabolism prompts formulation of a new explanatory model containing five features: a coordinating joint role of the (1) autonomic nervous system (ANS); (2) the suprachiasmatic (SCN) master clock in counterbalancing parasympathetic digestive and absorptive functions and feeding with sympathetic locomotor and thermogenic energy expenditure within a circadian framework; (3) interaction of the ANS/SCN command with brain substrates of reward encompassing dopaminergic projections to ventral striatum and limbic and cortical forebrain. These drive the nonhomeostatic feeding and locomotor motivated behaviors in interaction with circulating ghrelin and lateral hypothalamic neurons signaling through melanin concentrating hormone and orexin-hypocretin peptides; (4) counterregulation of insulin by leptin of both gastric and adipose tissue origin through: potentiation by leptin of cholecystokinin-mediated satiation, inhibition of insulin secretion, suppression of insulin lipogenesis by leptin lipolysis, and modulation of peripheral tissue and brain sensitivity to insulin action. Thus weight-loss induced hypoleptimia raises insulin sensitivity and promotes its parasympathetic anabolic actions while obesity-induced hyperleptinemia supresses insulin lipogenic action; and (5) inhibition by leptin of bone mineral accrual suggesting that leptin may contribute to the maintenance of stability of skeletal, lean-body, as well as adipose tissue masses. PMID:25317239

  9. Sirtuin3 Dysfunction Is the Key Determinant of Skeletal Muscle Insulin Resistance by Angiotensin II

    PubMed Central

    Macconi, Daniela; Perico, Luca; Longaretti, Lorena; Morigi, Marina; Cassis, Paola; Buelli, Simona; Perico, Norberto; Remuzzi, Giuseppe; Benigni, Ariela

    2015-01-01

    Background Angiotensin II promotes insulin resistance. The mechanism underlying this abnormality, however, is still poorly defined. In a different setting, skeletal muscle metabolism and insulin signaling are regulated by Sirtuin3. Objective Here, we investigate whether angiotensin II-induced insulin resistance in skeletal muscle is associated with Sirtuin3 dysregulation and whether pharmacological manipulation of Sirtuin3 confers protection. Study Design Parental and GLUT4-myc L6 rat skeletal muscle cells exposed to angiotensin II are used as in vitro models of insulin resistance. GLUT4 translocation, glucose uptake, intracellular molecular signals such as mitochondrial reactive oxygen species, Sirtuin3 protein expression and activity, along with its downstream targets and upstream regulators, are analyzed both in the absence and presence of acetyl-L-carnitine. The role of Sirtuin3 in GLUT4 translocation and intracellular molecular signaling is also studied in Sirtuin3-silenced as well as over-expressing cells. Results Angiotensin II promotes insulin resistance in skeletal muscle cells via mitochondrial oxidative stress, resulting in a two-fold increase in superoxide generation. In this context, reactive oxygen species open the mitochondrial permeability transition pore and significantly lower Sirtuin3 levels and activity impairing the cell antioxidant defense. Angiotensin II-induced Sirtuin3 dysfunction leads to the impairment of AMP-activated protein kinase/nicotinamide phosphoribosyltransferase signaling. Acetyl-L-carnitine, by lowering angiotensin II-induced mitochondrial superoxide formation, prevents Sirtuin3 dysfunction. This phenomenon implies the restoration of manganese superoxide dismutase antioxidant activity and AMP-activated protein kinase activation. Acetyl-L-carnitine protection is abrogated by specific Sirtuin3 siRNA. Conclusions Our data demonstrate that angiotensin II-induced insulin resistance fosters mitochondrial superoxide generation, in

  10. Insulin Delivery Into the Peripheral Circulation: A Key Contributor to Hypoglycemia in Type 1 Diabetes.

    PubMed

    Gregory, Justin M; Kraft, Guillaume; Scott, Melanie F; Neal, Doss W; Farmer, Ben; Smith, Marta S; Hastings, Jon R; Allen, Eric J; Donahue, E Patrick; Rivera, Noelia; Winnick, Jason J; Edgerton, Dale S; Nishimura, Erica; Fledelius, Christian; Brand, Christian L; Cherrington, Alan D

    2015-10-01

    Hypoglycemia limits optimal glycemic control in type 1 diabetes mellitus (T1DM), making novel strategies to mitigate it desirable. We hypothesized that portal (Po) vein insulin delivery would lessen hypoglycemia. In the conscious dog, insulin was infused into the hepatic Po vein or a peripheral (Pe) vein at a rate four times of basal. In protocol 1, a full counterregulatory response was allowed, whereas in protocol 2, glucagon was fixed at basal, mimicking the diminished α-cell response to hypoglycemia seen in T1DM. In protocol 1, glucose fell faster with Pe insulin than with Po insulin, reaching 56 ± 3 vs. 70 ± 6 mg/dL (P = 0.04) at 60 min. The change in area under the curve (ΔAUC) for glucagon was similar between Pe and Po, but the peak occurred earlier in Pe. The ΔAUC for epinephrine was greater with Pe than with Po (67 ± 17 vs. 36 ± 14 ng/mL/180 min). In protocol 2, glucose also fell more rapidly than in protocol 1 and fell faster in Pe than in Po, reaching 41 ± 3 vs. 67 ± 2 mg/dL (P < 0.01) by 60 min. Without a rise in glucagon, the epinephrine responses were much larger (ΔAUC of 204 ± 22 for Pe vs. 96 ± 29 ng/mL/180 min for Po). In summary, Pe insulin delivery exacerbates hypoglycemia, particularly in the presence of a diminished glucagon response. Po vein insulin delivery, or strategies that mimic it (i.e., liver-preferential insulin analogs), should therefore lessen hypoglycemia. PMID:26085570

  11. Insulin counter-regulatory factors, fibrinogen and C-reactive protein during olanzapine administration: effects of the antidiabetic metformin.

    PubMed

    Baptista, Trino; Sandia, Ignacio; Lacruz, Anny; Rangel, Nairy; de Mendoza, Soaira; Beaulieu, Serge; Contreras, Quilianio; Galeazzi, Tatiana; Vargas, Doritza

    2007-03-01

    In this study, the Authors assessed some insulin counter-regulatory factors, fibrinogen and C-reactive protein after olanzapine administration, and the effect of metformin on these variables, 37 patients with chronic schizophrenia were given olanzapine (10 mg/day for 14 weeks). Nineteen patients received metformin (850-2550 mg/day) and 18 received placebo in a randomized, double-blind protocol. The following variables were quantified before and after olanzapine: cortisol, leptin, tumor necrosis factor-alpha, glucagon, growth hormone, fibrinogen and C-reactive protein. Results were correlated with the changes in body weight and the insulin resistance index. We have reported elsewhere that metformin did not prevent olanzapine-induced weight gain, and the insulin resistance index significantly decreased after metformin and placebo; Baptista T, et al. Can J Psychiatry 2006; 51: 192-196. Cortisol, tumor necrosis factor-alpha and fibrinogen levels significantly decreased in both groups. Glucagon significantly increased after metformin (P=0.03). Leptin tended to increase after placebo (P=0.1) and displayed a small nonsignificant reduction after metformin. The C-reactive protein did not change significantly in any group. Contrarily to most published studies, olanzapine was associated with decreased insulin resistance. Decrements in cortisol, fibrinogen and tumor necrosis factor-alpha levels point to an improvement in the metabolic profile. The trend for leptin to increase after placebo, but not after metformin in spite of similar weight gain suggests a beneficial effect of this antidiabetic agent. PMID:17293706

  12. Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects

    PubMed Central

    Nakayama, Maki; McDaniel, Kristen; Fitzgerald-Miller, Lisa; Kiekhaefer, Carol; Snell-Bergeon, Janet K.; Davidson, Howard W.; Rewers, Marian; Yu, Liping; Gottlieb, Peter; Kappler, John W.; Michels, Aaron

    2015-01-01

    Certain class II MHC (MHCII) alleles in mice and humans confer risk for or protection from type 1 diabetes (T1D). Insulin is a major autoantigen in T1D, but how its peptides are presented to CD4 T cells by MHCII risk alleles has been controversial. In the mouse model of T1D, CD4 T cells respond to insulin B-chain peptide (B:9–23) mimotopes engineered to bind the mouse MHCII molecule, IAg7, in an unfavorable position or register. Because of the similarities between IAg7 and human HLA-DQ T1D risk alleles, we examined control and T1D subjects with these risk alleles for CD4 T-cell responses to the same natural B:9–23 peptide and mimotopes. A high proportion of new-onset T1D subjects mounted an inflammatory IFN-γ response much more frequently to one of the mimotope peptides than to the natural peptide. Surprisingly, the control subjects bearing an HLA-DQ risk allele also did. However, these control subjects, especially those with only one HLA-DQ risk allele, very frequently made an IL-10 response, a cytokine associated with regulatory T cells. T1D subjects with established disease also responded to the mimotope rather than the natural B:9–23 peptide in proliferation assays and the proliferating cells were highly enriched in certain T-cell receptor sequences. Our results suggest that the risk of T1D may be related to how an HLA-DQ genotype determines the balance of T-cell inflammatory vs. regulatory responses to insulin, having important implications for the use and monitoring of insulin-specific therapies to prevent diabetes onset. PMID:25831495

  13. Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects.

    PubMed

    Nakayama, Maki; McDaniel, Kristen; Fitzgerald-Miller, Lisa; Kiekhaefer, Carol; Snell-Bergeon, Janet K; Davidson, Howard W; Rewers, Marian; Yu, Liping; Gottlieb, Peter; Kappler, John W; Michels, Aaron

    2015-04-01

    Certain class II MHC (MHCII) alleles in mice and humans confer risk for or protection from type 1 diabetes (T1D). Insulin is a major autoantigen in T1D, but how its peptides are presented to CD4 T cells by MHCII risk alleles has been controversial. In the mouse model of T1D, CD4 T cells respond to insulin B-chain peptide (B:9-23) mimotopes engineered to bind the mouse MHCII molecule, IA(g7), in an unfavorable position or register. Because of the similarities between IA(g7) and human HLA-DQ T1D risk alleles, we examined control and T1D subjects with these risk alleles for CD4 T-cell responses to the same natural B:9-23 peptide and mimotopes. A high proportion of new-onset T1D subjects mounted an inflammatory IFN-γ response much more frequently to one of the mimotope peptides than to the natural peptide. Surprisingly, the control subjects bearing an HLA-DQ risk allele also did. However, these control subjects, especially those with only one HLA-DQ risk allele, very frequently made an IL-10 response, a cytokine associated with regulatory T cells. T1D subjects with established disease also responded to the mimotope rather than the natural B:9-23 peptide in proliferation assays and the proliferating cells were highly enriched in certain T-cell receptor sequences. Our results suggest that the risk of T1D may be related to how an HLA-DQ genotype determines the balance of T-cell inflammatory vs. regulatory responses to insulin, having important implications for the use and monitoring of insulin-specific therapies to prevent diabetes onset. PMID:25831495

  14. Biosimilar insulins: a European perspective.

    PubMed

    DeVries, J H; Gough, S C L; Kiljanski, J; Heinemann, L

    2015-05-01

    Biosimilar insulins are likely to enter clinical practice in Europe in the near future. It is important that clinicians are familiar with and understand the concept of biosimilarity and how a biosimilar drug may differ from its reference product. The present article provides an overview of biosimilars, the European regulatory requirements for biosimilars and safety issues. It also summarizes the current biosimilars approved in Europe and the key clinical issues associated with the use of biosimilar insulins. PMID:25376600

  15. Biosimilar insulins: a European perspective

    PubMed Central

    DeVries, J H; Gough, S C L; Kiljanski, J; Heinemann, L

    2015-01-01

    Biosimilar insulins are likely to enter clinical practice in Europe in the near future. It is important that clinicians are familiar with and understand the concept of biosimilarity and how a biosimilar drug may differ from its reference product. The present article provides an overview of biosimilars, the European regulatory requirements for biosimilars and safety issues. It also summarizes the current biosimilars approved in Europe and the key clinical issues associated with the use of biosimilar insulins. PMID:25376600

  16. Dynamic chromatin environment of key lytic cycle regulatory regions of the Epstein-Barr virus genome.

    PubMed

    Ramasubramanyan, Sharada; Osborn, Kay; Flower, Kirsty; Sinclair, Alison J

    2012-02-01

    The ability of Epstein-Barr virus (EBV) to establish latency allows it to evade the immune system and to persist for the lifetime of its host; one distinguishing characteristic is the lack of transcription of the majority of viral genes. Entry into the lytic cycle is coordinated by the viral transcription factor, Zta (BZLF1, ZEBRA, and EB1), and downstream effectors, while viral genome replication requires the concerted action of Zta and six other viral proteins at the origins of lytic replication. We explored the chromatin context at key EBV lytic cycle promoters (BZLF1, BRLF1, BMRF1, and BALF5) and the origins of lytic replication during latency and lytic replication. We show that a repressive heterochromatin-like environment (trimethylation of histone H3 at lysine 9 [H3K9me3] and lysine 27 [H3K27me3]), which blocks the interaction of some transcription factors with DNA, encompasses the key early lytic regulatory regions. Epigenetic silencing of the EBV genome is also imposed by DNA methylation during latency. The chromatin environment changes during the lytic cycle with activation of histones H3, H4, and H2AX occurring at both the origins of replication and at the key lytic regulatory elements. We propose that Zta is able to reverse the effects of latency-associated repressive chromatin at EBV early lytic promoters by interacting with Zta response elements within the H3K9me3-associated chromatin and demonstrate that these interactions occur in vivo. Since the interaction of Zta with DNA is not inhibited by DNA methylation, it is clear that Zta uses two routes to overcome epigenetic silencing of its genome. PMID:22090141

  17. The effect of insulin on plasma glucose concentrations, expression of hepatic glucose transporters and key gluconeogenic enzymes during the perinatal period in broiler chickens.

    PubMed

    Franssens, Lies; Lesuisse, Jens; Wang, Yufeng; Willems, Els; Willemsen, Hilke; Koppenol, Astrid; Guo, Xiaoquan; Buyse, Johan; Decuypere, Eddy; Everaert, Nadia

    2016-06-01

    Chickens have blood glucose concentrations that are twofold higher than those observed in mammals. Moreover, the insulin sensitivity seems to decrease with postnatal age in both broiler and layer chickens. However, little is known about the response of insulin on plasma glucose concentrations and mRNA abundance of hepatic glucose transporters 1, 2, 3, 8, 9 and 12 (GLUT1, 2, 3, 8, 9 and 12) and three regulatory enzymes of the gluconeogenesis, phosphoenolpyruvate carboxykinase 1 and 2 (PCK1 and 2) or fructose-1,6-biphosphatase 1 (FBP1) in chicks during the perinatal period. In the present study, broiler embryos on embryonic day (ED)16, ED18 or newly-hatched broiler chicks were injected intravenously with bovine insulin (1μg/g body weight (BW)) to examine plasma glucose response and changes in hepatic mRNA abundance of the GLUTs, PCK1 and 2 and FBP1. Results were compared with a non-treated control group and a saline-injected sham group. Plasma glucose levels of insulin-treated ED18 embryos recovered faster from their minimum level than those of insulin-treated ED16 embryos or newly-hatched chicks. In addition, at the minimum plasma glucose level seven hours post-injection (PI), hepatic GLUT2, FBP1 and PCK2 mRNA abundance was decreased in insulin-injected embryos, compared to sham and control groups, being most pronounced when insulin injection occurred on ED16. PMID:26723190

  18. Glucokinase regulatory proten genetic variant interacts with omega-3 PUFA to influence insulin resistance and inflammation in metabolic syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Glucokinase Regulatory Protein (GCKR) plays a central role regulating both hepatic triglyceride and glucose metabolism. Fatty acids are key metabolic regulators, which interact with genetic factors and influence glucose metabolism and other metabolic traits. Omega-3 polyunsaturated fatty acids (n-3...

  19. Islet neogenesis: an apparent key component of long-term pancreas adaptation to increased insulin demand.

    PubMed

    Del Zotto, H; Borelli, M I; Flores, L; García, M E; Gómez Dumm, C L; Chicco, A; Lombardo, Y B; Gagliardino, J J

    2004-11-01

    This study aimed to determine the relative importance of different functional and morphological pancreatic changes induced by the chronic administration of a sucrose-rich diet (SRD) to maintain normal glucose homeostasis. Male Wistar rats were fed either sucrose (SRD) or starch (CD) for 6 and 12 months. At both periods, serum glucose and triacylglycerol levels were significantly higher (P<0.05; paired and unpaired Student's t-test) in SRD rats. Serum insulin levels were significantly lower in SRD only at 12 months. At 6 months, the insulin secretion dose-response curve in SRD rats showed a shift to the left that was no longer observed at 12 months, when SRD islets decreased their response to 16 mM glucose. At 6 months, SRD rats showed a significant increase in beta-cell volume density (Vvi) and islet cell replication rate, together with a decrease in beta-cell apoptotic rate. Changes were not detected in the percentage of PDX-1- and islet neogenesis associated protein (INGAP)-positive cells. Conversely, at 12 months, there was a significant decrease in beta-cell Vvi and in the percentage of PDX-1-positive cells; the islet cell replication rate was not modified, and the number of apoptotic beta-cells increased significantly. No signs of increased neogenesis or INGAP-positive cells were recorded at any period in SRD rats. Our results show that SRD rats are unable to develop functional and morphological pancreatic reactive changes sufficient to maintain normal glucose and triacylglycerol levels for a long period. Such failure could be ascribed to their inability to increase the rate of neogenesis and of INGAP production. PMID:15531720

  20. Cross-phosphorylation of bacterial serine/threonine and tyrosine protein kinases on key regulatory residues

    PubMed Central

    Shi, Lei; Pigeonneau, Nathalie; Ravikumar, Vaishnavi; Dobrinic, Paula; Macek, Boris; Franjevic, Damjan; Noirot-Gros, Marie-Francoise; Mijakovic, Ivan

    2014-01-01

    Bacteria possess protein serine/threonine and tyrosine kinases which resemble eukaryal kinases in their capacity to phosphorylate multiple substrates. We hypothesized that the analogy might extend further, and bacterial kinases may also undergo mutual phosphorylation and activation, which is currently considered as a hallmark of eukaryal kinase networks. In order to test this hypothesis, we explored the capacity of all members of four different classes of serine/threonine and tyrosine kinases present in the firmicute model organism Bacillus subtilis to phosphorylate each other in vitro and interact with each other in vivo. The interactomics data suggested a high degree of connectivity among all types of kinases, while phosphorylation assays revealed equally wide-spread cross-phosphorylation events. Our findings suggest that the Hanks-type kinases PrkC, PrkD, and YabT exhibit the highest capacity to phosphorylate other B. subtilis kinases, while the BY-kinase PtkA and the two-component-like kinases RsbW and SpoIIAB show the highest propensity to be phosphorylated by other kinases. Analysis of phosphorylated residues on several selected recipient kinases suggests that most cross-phosphorylation events concern key regulatory residues. Therefore, cross-phosphorylation events are very likely to influence the capacity of recipient kinases to phosphorylate substrates downstream in the signal transduction cascade. We therefore conclude that bacterial serine/threonine and tyrosine kinases probably engage in a network-type behavior previously described only in eukaryal cells. PMID:25278935

  1. Biosimilar insulins.

    PubMed

    Heinemann, Lutz

    2012-08-01

    Until now most insulin used in developed countries is manufactured and distributed by a small number of multinational companies. Other pharmaceutical companies - many of these are located in countries such as India or China - are also able to manufacture insulin with modern biotechnological methods. Additionally, the patents for many insulin formulations have expired or are going to expire soon. This enables such companies to produce insulins and to apply for market approval of these as biosimilar insulins (BIs) in highly regulated markets such as the EU or the US. To understand the complexity of BIs' approval and usage, scientific and regulatory aspects have to be discussed. Differences in the manufacturing process (none of the insulin-manufacturing procedures are identical) result in the fact that all insulin that might become BIs differ from the originator insulin to some extent. The question is, have such differences in the structure of the insulin molecule and or the purity and so on clinically relevant consequences for the biological effects induced or not. The guidelines already in place in the EU for market approval require that the manufacturer demonstrates that his insulin has a safety and efficacy profile that is similar to that of the 'original' insulin formulation. Recently guidelines for biosimilars were issued in the US; however, these do not cover insulin. Although a challenging approval process for insulins to become BI might be regarded as a hurdle to keep companies out of certain markets, it is fair to say that the potential safety and efficacy issues surrounding BI are substantial and relevant, and do warrant a careful and evidence-driven approval process. Nevertheless, it is very likely that in the next years, BIs will come to the market also in highly regulated markets. PMID:22583127

  2. Key anticipated regulatory issues for clinical use of human induced pluripotent stem cells

    PubMed Central

    Knoepfler, Paul S

    2013-01-01

    The production of human induced pluripotent stem cells (hiPSCs) has greatly expanded the realm of possible stem cell-based regenerative medicine therapies and has particularly exciting potential for autologous therapies. However, future therapies based on hiPSCs will first have to address not only similar regulatory issues as those facing human embryonic stem cells with the US FDA and international regulatory agencies, but also hiPSCs have raised unique concerns as well. While the first possible clinical use of hiPSCs remains down the road, as a field it would be wise for us to anticipate potential roadblocks and begin formulating solutions. In this article, I discuss the potential regulatory issues facing hiPSCs and propose some potential changes in the direction of the field in response. PMID:22830621

  3. Regulatory Lymphocytes Are Key Factors in MHC-Independent Resistance to EAE

    PubMed Central

    Marín, Nieves; Mecha, Miriam; Espejo, Carmen; Mestre, Leyre; Eixarch, Herena; Montalban, Xavier; Álvarez-Cermeño, José C.; Guaza, Carmen; Villar, Luisa M.

    2014-01-01

    Background and Objectives. Resistant and susceptible mouse strains to experimental autoimmune encephalomyelitis (EAE), an inducible demyelinating experimental disease serving as animal model for multiple sclerosis, have been described. We aimed to explore MHC-independent mechanisms inducing resistance to EAE. Methods. For EAE induction, female C57BL/6 (susceptible strain) and CD1 (resistant outbred strain showing heterogeneous MHC antigens) mice were immunized with the 35–55 peptide of myelin oligodendrocyte glycoprotein (MOG35−55). We studied T cell proliferation, regulatory and effector cell subpopulations, intracellular and serum cytokine patterns, and titers of anti-MOG serum antibodies. Results. Upon immunization with MOG35−55, T lymphocytes from susceptible mice but not that of resistant strain were capable of proliferating when stimulated with MOG35−55. Accordingly, resistant mice experienced a rise in regulatory B cells (P = 0.001) and, to a lower extent, in regulatory T cells (P = 0.02) compared with C57BL/6 susceptible mice. As a consequence, MOG35−55-immunized C57BL/6 mice showed higher percentages of CD4+ T cells producing both IFN-gamma (P = 0.02) and IL-17 (P = 0.009) and higher serum levels of IL-17 (P = 0.04) than resistant mice. Conclusions. Expansion of regulatory B and T cells contributes to the induction of resistance to EAE by an MHC-independent mechanism. PMID:24868560

  4. Biosimilar Insulins

    PubMed Central

    Hompesch, Marcus

    2014-01-01

    Until now most of the insulin used in developed countries has been manufactured and distributed by a small number of multinational companies. Beyond the established insulin manufacturers, a number of new players have developed insulin manufacturing capacities based on modern biotechnological methods. Because the patents for many of the approved insulin formulations have expired or are going to expire soon, these not yet established companies are increasingly interested in seeking market approval for their insulin products as biosimilar insulins (BI) in highly regulated markets like the EU and the United States. Differences in the manufacturing process (none of the insulin manufacturing procedures are 100% identical) can lead to insulins that to some extent may differ from the originator insulin. The key questions are if subtle differences in the structure of the insulins, purity, and so on are clinically relevant and may result in different biological effects. The aim of this article is to introduce and discuss basic aspects that may be of relevance with regard to BI. PMID:24876530

  5. Practice tips and tools for the successful use of U-500 regular human insulin: the diabetes educator is key.

    PubMed

    Cochran, Elaine K; Valentine, Virginia; Samaan, Karen H; Corey, Ilene B; Jackson, Jeffrey A

    2014-01-01

    This review provides information to equip diabetes educators to instruct and guide patients in using U-500 human regular insulin (U-500R). The article includes an overview of U-500R pharmacology and clinical data, strategies for outpatient and inpatient use, and tools for patient education. U-500R is useful for treating patients with any type of diabetes who require high doses of insulin. U-500R alleviates the volume-related problems associated with high doses of U-100 insulin, making treatment with high doses of insulin more feasible (because of the need for fewer injections for patients) as well as more cost-efficient and potentially more effective. These tools can help diabetes educators feel more comfortable and confident as they advise and educate patients who receive high-dose U-500R as part of their overall diabetes care plan. The diabetes educator plays a vital role in helping patients use U-500R safely and successfully. PMID:24159006

  6. Downregulation of key regulatory proteins in androgen dependent prostate tumor cells by oncolytic reovirus.

    PubMed

    Gupta-Saraf, Pooja; Meseke, Tyler; Miller, Cathy L

    2015-11-01

    As prostate tumor cell growth depends on hormones, androgen ablation is an effective therapy for prostate cancer (PCa). However, progression of PCa cells to androgen independent growth (castrate resistant prostate cancer, CRPC) results in relapse and mortality. Hypoxia, a microenvironment of low oxygen that modifies the activity of PCa regulatory proteins including the androgen receptor (AR), plays a critical role in progression to CRPC. Therapies targeting hypoxia and the AR may lengthen the time to CRPC progression thereby increasing survival time of PCa patients. Mammalian Orthoreovirus (MRV) has shown promise for the treatment of prostate tumors in vitro and in vivo. In this study, we found that MRV infection induces downregulation of proteins implicated in CRPC progression, interferes with hypoxia-induced AR activity, and induces apoptosis in androgen dependent cells. This suggests MRV possesses traits that could be exploited to create novel therapies for the inhibition of progression to CRPC. PMID:26264969

  7. Genome-Wide Analysis of Wilms' Tumor 1-Controlled Gene Expression in Podocytes Reveals Key Regulatory Mechanisms.

    PubMed

    Kann, Martin; Ettou, Sandrine; Jung, Youngsook L; Lenz, Maximilian O; Taglienti, Mary E; Park, Peter J; Schermer, Bernhard; Benzing, Thomas; Kreidberg, Jordan A

    2015-09-01

    The transcription factor Wilms' tumor suppressor 1 (WT1) is key to podocyte development and viability; however, WT1 transcriptional networks in podocytes remain elusive. We provide a comprehensive analysis of the genome-wide WT1 transcriptional network in podocytes in vivo using chromatin immunoprecipitation followed by sequencing (ChIPseq) and RNA sequencing techniques. Our data show a specific role for WT1 in regulating the podocyte-specific transcriptome through binding to both promoters and enhancers of target genes. Furthermore, we inferred a podocyte transcription factor network consisting of WT1, LMX1B, TCF21, Fox-class and TEAD family transcription factors, and MAFB that uses tissue-specific enhancers to control podocyte gene expression. In addition to previously described WT1-dependent target genes, ChIPseq identified novel WT1-dependent signaling systems. These targets included components of the Hippo signaling system, underscoring the power of genome-wide transcriptional-network analyses. Together, our data elucidate a comprehensive gene regulatory network in podocytes suggesting that WT1 gene regulatory function and podocyte cell-type specification can best be understood in the context of transcription factor-regulatory element network interplay. PMID:25636411

  8. Metabolomic analysis reveals that carnitines are key regulatory metabolites in phase transition of the locusts.

    PubMed

    Wu, Rui; Wu, Zeming; Wang, Xianhui; Yang, Pengcheng; Yu, Dan; Zhao, Chunxia; Xu, Guowang; Kang, Le

    2012-02-28

    Phenotypic plasticity occurs prevalently and plays a vital role in adaptive evolution. However, the underlying molecular mechanisms responsible for the expression of alternate phenotypes remain unknown. Here, a density-dependent phase polyphenism of Locusta migratoria was used as the study model to identify key signaling molecules regulating the expression of phenotypic plasticity. Metabolomic analysis, using high-performance liquid chromatography and gas chromatography-mass spectrometry, showed that solitarious and gregarious locusts have distinct metabolic profiles in hemolymph. A total of 319 metabolites, many of which are involved in lipid metabolism, differed significantly in concentration between the phases. In addition, the time course of changes in the metabolic profiles of locust hemolymph that accompany phase transition was analyzed. Carnitine and its acyl derivatives, which are involved in the lipid β-oxidation process, were identified as key differential metabolites that display robust correlation with the time courses of phase transition. RNAi silencing of two key enzymes from the carnitine system, carnitine acetyltransferase and palmitoyltransferase, resulted in a behavioral transition from the gregarious to solitarious phase and the corresponding changes of metabolic profiles. In contrast, the injection of exogenous acetylcarnitine promoted the acquisition of gregarious behavior in solitarious locusts. These results suggest that carnitines mediate locust phase transition possibly through modulating lipid metabolism and influencing the nervous system of the locusts. PMID:22328148

  9. Metabolomic analysis reveals that carnitines are key regulatory metabolites in phase transition of the locusts

    PubMed Central

    Wu, Rui; Wu, Zeming; Wang, Xianhui; Yang, Pengcheng; Yu, Dan; Zhao, Chunxia; Xu, Guowang; Kang, Le

    2012-01-01

    Phenotypic plasticity occurs prevalently and plays a vital role in adaptive evolution. However, the underlying molecular mechanisms responsible for the expression of alternate phenotypes remain unknown. Here, a density-dependent phase polyphenism of Locusta migratoria was used as the study model to identify key signaling molecules regulating the expression of phenotypic plasticity. Metabolomic analysis, using high-performance liquid chromatography and gas chromatography–mass spectrometry, showed that solitarious and gregarious locusts have distinct metabolic profiles in hemolymph. A total of 319 metabolites, many of which are involved in lipid metabolism, differed significantly in concentration between the phases. In addition, the time course of changes in the metabolic profiles of locust hemolymph that accompany phase transition was analyzed. Carnitine and its acyl derivatives, which are involved in the lipid β-oxidation process, were identified as key differential metabolites that display robust correlation with the time courses of phase transition. RNAi silencing of two key enzymes from the carnitine system, carnitine acetyltransferase and palmitoyltransferase, resulted in a behavioral transition from the gregarious to solitarious phase and the corresponding changes of metabolic profiles. In contrast, the injection of exogenous acetylcarnitine promoted the acquisition of gregarious behavior in solitarious locusts. These results suggest that carnitines mediate locust phase transition possibly through modulating lipid metabolism and influencing the nervous system of the locusts. PMID:22328148

  10. Zinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1.

    PubMed

    van Loo, Karen M J; Schaub, Christina; Pitsch, Julika; Kulbida, Rebecca; Opitz, Thoralf; Ekstein, Dana; Dalal, Adam; Urbach, Horst; Beck, Heinz; Yaari, Yoel; Schoch, Susanne; Becker, Albert J

    2015-01-01

    Temporal lobe epilepsy (TLE) is the most common focal seizure disorder in adults. In many patients, transient brain insults, including status epilepticus (SE), are followed by a latent period of epileptogenesis, preceding the emergence of clinical seizures. In experimental animals, transcriptional upregulation of CaV3.2 T-type Ca(2+)-channels, resulting in an increased propensity for burst discharges of hippocampal neurons, is an important trigger for epileptogenesis. Here we provide evidence that the metal-regulatory transcription factor 1 (MTF1) mediates the increase of CaV3.2 mRNA and intrinsic excitability consequent to a rise in intracellular Zn(2+) that is associated with SE. Adeno-associated viral (rAAV) transfer of MTF1 into murine hippocampi leads to increased CaV3.2 mRNA. Conversely, rAAV-mediated expression of a dominant-negative MTF1 abolishes SE-induced CaV3.2 mRNA upregulation and attenuates epileptogenesis. Finally, data from resected human hippocampi surgically treated for pharmacoresistant TLE support the Zn(2+)-MTF1-CaV3.2 cascade, thus providing new vistas for preventing and treating TLE. PMID:26498180

  11. Zinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1

    PubMed Central

    van Loo, Karen M. J.; Schaub, Christina; Pitsch, Julika; Kulbida, Rebecca; Opitz, Thoralf; Ekstein, Dana; Dalal, Adam; Urbach, Horst; Beck, Heinz; Yaari, Yoel; Schoch, Susanne; Becker, Albert J.

    2015-01-01

    Temporal lobe epilepsy (TLE) is the most common focal seizure disorder in adults. In many patients, transient brain insults, including status epilepticus (SE), are followed by a latent period of epileptogenesis, preceding the emergence of clinical seizures. In experimental animals, transcriptional upregulation of CaV3.2 T-type Ca2+-channels, resulting in an increased propensity for burst discharges of hippocampal neurons, is an important trigger for epileptogenesis. Here we provide evidence that the metal-regulatory transcription factor 1 (MTF1) mediates the increase of CaV3.2 mRNA and intrinsic excitability consequent to a rise in intracellular Zn2+ that is associated with SE. Adeno-associated viral (rAAV) transfer of MTF1 into murine hippocampi leads to increased CaV3.2 mRNA. Conversely, rAAV-mediated expression of a dominant-negative MTF1 abolishes SE-induced CaV3.2 mRNA upregulation and attenuates epileptogenesis. Finally, data from resected human hippocampi surgically treated for pharmacoresistant TLE support the Zn2+-MTF1-CaV3.2 cascade, thus providing new vistas for preventing and treating TLE. PMID:26498180

  12. RNA structure is a key regulatory element in pathological ATM and CFTR pseudoexon inclusion events

    PubMed Central

    Buratti, Emanuele; Dhir, Ashish; Lewandowska, Marzena A.; Baralle, Francisco E.

    2007-01-01

    Genomic variations deep in the intronic regions of pre-mRNA molecules are increasingly reported to affect splicing events. However, there is no general explanation why apparently similar variations may have either no effect on splicing or cause significant splicing alterations. In this work we have examined the structural architecture of pseudoexons previously described in ATM and CFTR patients. The ATM case derives from the deletion of a repressor element and is characterized by an aberrant 5′ss selection despite the presence of better alternatives. The CFTR pseudoexon instead derives from the creation of a new 5′ss that is used while a nearby pre-existing donor-like sequence is never selected. Our results indicate that RNA structure is a major splicing regulatory factor in both cases. Furthermore, manipulation of the original RNA structures can lead to pseudoexon inclusion following the exposure of unused 5′ss already present in their wild-type intronic sequences and prevented to be recognized because of their location in RNA stem structures. Our data show that intrinsic structural features of introns must be taken into account to understand the mechanism of pseudoexon activation in genetic diseases. Our observations may help to improve diagnostics prediction programmes and eventual therapeutic targeting. PMID:17580311

  13. Key regulatory drivers affecting shipments of mixed transuranic waste from Los Alamos National Laboratory to the Waste Isolation Pilot Plant

    SciTech Connect

    Schumann, P.B.; Bacigalupa, G.A.; Kosiewicz, S.T.; Sinkule, B.J.

    1997-02-01

    A number of key regulatory drivers affect the nature, scope, and timing of Los Alamos National Laboratory`s (LANL`s) plans for mixed transuranic (MTRU) waste shipments to the Waste Isolation Pilot Plant (WIPP), which are planned to commence as soon as possible following WIPP`s currently anticipated November, 1997 opening date. This paper provides an overview of some of the key drivers at LANL, particularly emphasizing those associated with the hazardous waste component of LANL`s MTRU waste (MTRU, like any mixed waste, contains both a radioactive and a hazardous waste component). The key drivers discussed here derive from the federal Resource Conservation and Recovery Act (RCRA) and its amendments, including the Federal Facility Compliance Act (FFCAU), and from the New Mexico Hazardous Waste Act (NMHWA). These statutory provisions are enforced through three major mechanisms: facility RCRA permits; the New Mexico Hazardous Waste Management Regulations, set forth in the New Mexico Administrative Code, Title 20, Chapter 4, Part 1: and compliance orders issued to enforce these requirements. General requirements in all three categories will apply to MTRU waste management and characterization activities at both WIPP and LANL. In addition, LANL is subject to facility-specific requirements in its RCRA hazardous waste facility permit, permit conditions as currently proposed in RCRA Part B permit applications presently being reviewed by the New Mexico Environment Department (NNED), and facility-specific compliance orders related to MTRU waste management. Likewise, permitting and compliance-related requirements specific to WIPP indirectly affect LANL`s characterization, packaging, record-keeping, and transportation requirements for MTRU waste. LANL must comply with this evolving set of regulatory requirements to begin shipments of MTRU waste to WIPP in a timely fashion.

  14. Insulin resistance and insulin sensitizers.

    PubMed

    Stumvoll, M; Häring, H

    2001-01-01

    Insulin resistance is a key factor in the pathogenesis of type 2 diabetes mellitus and a co-factor in the development of dyslipidaemia, hypertension and atherosclerosis. The causes of insulin resistance include factors such as obesity and physical inactivity, and there may also be genetic factors. The mechanism of obesity-related insulin resistance involves the release of factors from adipocytes which exert a negative effect on glucose metabolism: free fatty acids, tumour necrosis factor-alpha and the recently discovered hormone, resistin. The two resulting abnormalities observed consistently in glucose-intolerant states are impaired suppression of endogenous glucose production, and impaired stimulation of glucose uptake. Among the genetic factors, a polymorphism (Pro12Ala) in the peroxisome proliferator-activated receptor (PPAR) gamma is associated with a reduced risk of type 2 diabetes mellitus and increased insulin sensitivity, primarily that of lipolysis. On the other hand, the association with insulin resistance of a common polymorphism (Gly972Arg) in the insulin receptor substrate 1, long believed to be a plausible candidate gene, is weak at best. This polymorphism may instead be associated with reduced insulin secretion, which, in view of the recent recognition of the insulin signalling system in beta-cells, results in the development of a novel pathogenic concept. Finally, fine-mapping and positional cloning of the susceptibility locus on chromosome 2 resulted in the identification of a polymorphism (UCSNP-43 G/A) in the calpain-10 gene. In non-diabetic Pima Indians, this polymorphism was associated with insulin resistance of glucose disposal. The pharmacological treatment of insulin resistance has recently acquired a novel class of agents: the thiazolidinediones. They act through regulation of PPARgamma-dependent genes and probably interfere favourably with factors released from adipocytes which mediate obesity-associated insulin resistance. PMID:11684868

  15. Dynamic Transcription Factor Activity Profiles Reveal Key Regulatory Interactions During Megakaryocytic and Erythroid Differentiation

    PubMed Central

    Duncan, Mark T.; Shin, Seungjin; Wu, Jia J.; Mays, Zachary; Weng, Stanley; Bagheri, Neda; Miller, William M.; Shea, Lonnie D.

    2014-01-01

    The directed differentiation toward erythroid (E) or megakaryocytic (MK) lineages by the MK-E progenitor (MEP) could enhance the ex vivo generation of red blood cells and platelets for therapeutic transfusions. The lineage choice at the MEP bifurcation is controlled in large part by activity within the intracellular signal transduction network, the output of which determines the activity of transcription factors (TFs) and ultimately gene expression. Although many TFs have been implicated, E or MK differentiation is a complex process requiring multiple days, and the dynamics of TF activities during commitment and terminal maturation are relatively unexplored. Herein, we applied a living cell array for the large-scale, dynamic quantification of TF activities during MEP bifurcation. A panel of hematopoietic TFs (GATA-1, GATA-2, SCL/TAL1, FLI-1, NF-E2, PU.1, c-Myb) was characterized during E and MK differentiation of bipotent K562 cells. Dynamic TF activity profiles associated with differentiation towards each lineage were identified, and validated with previous reports. From these activity profiles, we show that GATA-1 is an important hub during early hemin- and PMA-induced differentiation, and reveal several characteristic TF interactions for E and MK differentiation that confirm regulatory mechanisms documented in the literature. Additionally, we highlight several novel TF interactions at various stages of E and MK differentiation. Furthermore, we investigated the mechanism by which nicotinamide (NIC) promoted terminal MK maturation using an MK-committed cell line, CHRF-288-11 (CHRF). Concomitant with its enhancement of ploidy, NIC strongly enhanced the activity of three TFs with known involvement in terminal MK maturation: FLI-1, NF-E2, and p53. Dynamic profiling of TF activity represents a novel tool to complement traditional assays focused on mRNA and protein expression levels to understand progenitor cell differentiation. PMID:24853077

  16. Dynamic transcription factor activity profiles reveal key regulatory interactions during megakaryocytic and erythroid differentiation.

    PubMed

    Duncan, Mark T; Shin, Seungjin; Wu, Jia J; Mays, Zachary; Weng, Stanley; Bagheri, Neda; Miller, William M; Shea, Lonnie D

    2014-10-01

    The directed differentiation toward erythroid (E) or megakaryocytic (MK) lineages by the MK-E progenitor (MEP) could enhance the ex vivo generation of red blood cells and platelets for therapeutic transfusions. The lineage choice at the MEP bifurcation is controlled in large part by activity within the intracellular signal transduction network, the output of which determines the activity of transcription factors (TFs) and ultimately gene expression. Although many TFs have been implicated, E or MK differentiation is a complex process requiring multiple days, and the dynamics of TF activities during commitment and terminal maturation are relatively unexplored. Herein, we applied a living cell array for the large-scale, dynamic quantification of TF activities during MEP bifurcation. A panel of hematopoietic TFs (GATA-1, GATA-2, SCL/TAL1, FLI-1, NF-E2, PU.1, c-Myb) was characterized during E and MK differentiation of bipotent K562 cells. Dynamic TF activity profiles associated with differentiation towards each lineage were identified, and validated with previous reports. From these activity profiles, we show that GATA-1 is an important hub during early hemin- and PMA-induced differentiation, and reveal several characteristic TF interactions for E and MK differentiation that confirm regulatory mechanisms documented in the literature. Additionally, we highlight several novel TF interactions at various stages of E and MK differentiation. Furthermore, we investigated the mechanism by which nicotinamide (NIC) promoted terminal MK maturation using an MK-committed cell line, CHRF-288-11 (CHRF). Concomitant with its enhancement of ploidy, NIC strongly enhanced the activity of three TFs with known involvement in terminal MK maturation: FLI-1, NF-E2, and p53. Dynamic profiling of TF activity represents a novel tool to complement traditional assays focused on mRNA and protein expression levels to understand progenitor cell differentiation. PMID:24853077

  17. Prefrontal cortical BDNF: A regulatory key in cocaine- and food-reinforced behaviors.

    PubMed

    Pitts, Elizabeth G; Taylor, Jane R; Gourley, Shannon L

    2016-07-01

    Brain-derived neurotrophic factor (BDNF) affects synaptic plasticity and neural structure and plays key roles in learning and memory processes. Recent evidence also points to important, yet complex, roles for BDNF in rodent models of cocaine abuse and addiction. Here we examine the role of prefrontal cortical (PFC) BDNF in reward-related decision making and behavioral sensitivity to, and responding for, cocaine. We focus on BDNF within the medial and orbital PFC, its regulation by cocaine during early postnatal development and in adulthood, and how BDNF in turn influences responding for drug reinforcement, including in reinstatement models. When relevant, we draw comparisons and contrasts with experiments using natural (food) reinforcers. We also summarize findings supporting, or refuting, the possibility that BDNF in the medial and orbital PFC regulate the development and maintenance of stimulus-response habits. Further investigation could assist in the development of novel treatment approaches for cocaine use disorders. PMID:26923993

  18. Expression of PD-1 Molecule on Regulatory T Lymphocytes in Patients with Insulin-Dependent Diabetes Mellitus

    PubMed Central

    Perri, Valentina; Russo, Benedetta; Crinò, Antonino; Schiaffini, Riccardo; Giorda, Ezio; Cappa, Marco; Rosado, Maria Manuela; Fierabracci, Alessandra

    2015-01-01

    Type 1 diabetes is caused by autoreactive T cells that destroy pancreatic beta cells. Animal models suggested that a CD4+CD25+ population has a regulatory function capable of preventing activation and effector functions of autoreactive T cells. However, the role of CD4+CD25high T cells in autoimmunity and their molecular mechanisms remain the subject of investigation. We therefore evaluated T regulatory cell frequencies and their PD-1 expression in the peripheral blood of long-standing diabetics under basal conditions and after CD3/CD28 stimulation. Under basal conditions, the percentages of T regulatory cells were significantly higher while that of T effector cells were significantly lower in patients than in controls. The ratio of regulatory to effector T cells was higher in patients than that in controls, suggesting that T regulatory cells were functional in patients. Percentages of total PD-1+, PD-1low and PD-1high expressing T regulatory cells did not change in patients and in controls. After stimulation, a defect in T regulatory cell proliferation was observed in diabetics and the percentages of total PD-1+, PD-1low and PD-1high expressing cells were lower in patients. Our data suggest a defective activation of T regulatory cells in long-standing diabetics due to a lower expression of PD-1 on their surface. PMID:26393578

  19. Enhanced Production of Insulin-like Growth Factor I Protein in Escherichia coli by Optimization of Five Key Factors

    PubMed Central

    Ranjbari, Javad; Babaeipour, Valiollah; Vahidi, Hossein; Moghimi, Hamidreza; Mofid, Mohammad Reza; Namvaran, Mohammad Mehdi; Jafari, Sevda

    2015-01-01

    Human insulin-like growth factor I (hIGF-I) is a kind of growth factor with clinical significance in medicine. Up to now, E. coli expression system has been widely used as a host to produce rhIGF-1 with high yields. Batch cultures as non-continuous fermentations were carried out to overproduce rhIGF-I in E. coli. The major objective of this study is over- production of recombinant human insulin-like growth factor I (rhIGF-I) through a developed process by recruiting effective factors in order to achieve the most recombinant protein. In this study we investigated the effect of culture medium, induction temperature and amount of inducer on cell growth and IGF-1 production. Taguchi design of experiments (DOE) method was used as the statistical method. Analysis of experimental data showed that maximum production of rhIGF-I was occurred in 32y culture medium at 32 °C and 0.05 Mm IPTG. Under this condition, 0.694 g/L of rhIGF-I was produced as the inclusion bodies. Following optimization of these three factors, we have also optimized the amount of glucose and induction time in 5 liter top bench bioreactor. Full factorial design of experiment method was used for these two factors as the statistical method. 10 g/L and OD600=5 were selected as the optimum point of Glucose amount and induction time, respectively. Finally, we reached to a concentration of 1.26 g/L rhIGF-1 at optimum condition. PMID:26330880

  20. Enhanced Production of Insulin-like Growth Factor I Protein in Escherichia coli by Optimization of Five Key Factors.

    PubMed

    Ranjbari, Javad; Babaeipour, Valiollah; Vahidi, Hossein; Moghimi, Hamidreza; Mofid, Mohammad Reza; Namvaran, Mohammad Mehdi; Jafari, Sevda

    2015-01-01

    Human insulin-like growth factor I (hIGF-I) is a kind of growth factor with clinical significance in medicine. Up to now, E. coli expression system has been widely used as a host to produce rhIGF-1 with high yields. Batch cultures as non-continuous fermentations were carried out to overproduce rhIGF-I in E. coli. The major objective of this study is over- production of recombinant human insulin-like growth factor I (rhIGF-I) through a developed process by recruiting effective factors in order to achieve the most recombinant protein. In this study we investigated the effect of culture medium, induction temperature and amount of inducer on cell growth and IGF-1 production. Taguchi design of experiments (DOE) method was used as the statistical method. Analysis of experimental data showed that maximum production of rhIGF-I was occurred in 32y culture medium at 32 °C and 0.05 Mm IPTG. Under this condition, 0.694 g/L of rhIGF-I was produced as the inclusion bodies. Following optimization of these three factors, we have also optimized the amount of glucose and induction time in 5 liter top bench bioreactor. Full factorial design of experiment method was used for these two factors as the statistical method. 10 g/L and OD600=5 were selected as the optimum point of Glucose amount and induction time, respectively. Finally, we reached to a concentration of 1.26 g/L rhIGF-1 at optimum condition. PMID:26330880

  1. A Genome-wide Regulatory Network Identifies Key Transcription Factors for Memory CD8+ T Cell Development

    PubMed Central

    Hu, Guangan; Chen, Jianzhu

    2014-01-01

    Memory CD8+ T cell development is defined by the expression of a specific set of memory signature genes (MSGs). Despite recent progress, many components of the transcriptional control of memory CD8+ T cell development are still unknown. To identify transcription factors (TFs) and their interactions in memory CD8+ T cell development, we construct a genome-wide regulatory network and apply it to identify key TFs that regulate MSGs. Most of the known TFs in memory CD8+ T cell development are rediscovered and about a dozen new TFs are also identified. Sox4, Bhlhe40, Bach2 and Runx2 are experimentally verified and Bach2 is further shown to promote both development and recall proliferation of memory CD8+ T cells through Prdm1 and Id3. Gene perturbation study identifies the mode of interactions among the TFs with Sox4 as a hub. The identified TFs and insights into their interactions should facilitate further dissection of molecular mechanisms underlying memory CD8+ T cell development. PMID:24335726

  2. Deep transcriptome sequencing reveals the expression of key functional and regulatory genes involved in the abiotic stress signaling pathways in rice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Drought, salt and cold are the major abiotic stresses that limit the rice production and cause serious threat to food security. The identification of the key functional and regulatory genes in the abiotic stress signaling pathways is important for understanding the molecular basis of abiotic stress ...

  3. Inflammation and Insulin Resistance

    PubMed Central

    de Luca, Carl; Olefsky, Jerrold M.

    2008-01-01

    Obesity-induced chronic inflammation is a key component in the pathogenesis of insulin resistance and the Metabolic syndrome. In this review, we focus on the interconnection between obesity, inflammation and insulin resistance. Pro-inflammatory cytokines can cause insulin resistance in adipose tissue, skeletal muscle and liver by inhibiting insulin signal transduction. The sources of cytokines in insulin resistant states are the insulin target tissue themselves, primarily fat and liver, but to a larger extent the activated tissue resident macrophages. While the initiating factors of this inflammatory response remain to be fully determined, chronic inflammation in these tissues could cause localized insulin resistance via autocrine/paracrine cytokine signaling and systemic insulin resistance via endocrine cytokine signaling all of which contribute to the abnormal metabolic state. PMID:18053812

  4. Identification and Comparison of Aberrant Key Regulatory Networks in Breast, Colon, Liver, Lung, and Stomach Cancers through Methylome Database Analysis

    PubMed Central

    Kim, Byungtak; Kang, Seongeun; Jeong, Gookjoo; Park, Sung-Bin; Kim, Sun Jung

    2014-01-01

    Aberrant methylation of specific CpG sites at the promoter is widely responsible for genesis and development of various cancer types. Even though the microarray-based methylome analyzing techniques have contributed to the elucidation of the methylation change at the genome-wide level, the identification of key methylation markers or top regulatory networks appearing common in highly incident cancers through comparison analysis is still limited. In this study, we in silico performed the genome-wide methylation analysis on each 10 sets of normal and cancer pairs of five tissues: breast, colon, liver, lung, and stomach. The methylation array covers 27,578 CpG sites, corresponding to 14,495 genes, and significantly hypermethylated or hypomethylated genes in the cancer were collected (FDR adjusted p-value <0.05; methylation difference >0.3). Analysis of the dataset confirmed the methylation of previously known methylation markers and further identified novel methylation markers, such as GPX2, CLDN15, and KL. Cluster analysis using the methylome dataset resulted in a diagram with a bipartite mode distinguishing cancer cells from normal cells regardless of tissue types. The analysis further revealed that breast cancer was closest with lung cancer, whereas it was farthest from colon cancer. Pathway analysis identified that either the “cancer” related network or the “cancer” related bio-function appeared as the highest confidence in all the five cancers, whereas each cancer type represents its tissue-specific gene sets. Our results contribute toward understanding the essential abnormal epigenetic pathways involved in carcinogenesis. Further, the novel methylation markers could be applied to establish markers for cancer prognosis. PMID:24842468

  5. New ways of insulin delivery.

    PubMed

    Heinemann, L

    2011-02-01

    The predominant number of papers published from the middle of 2009 to the middle of 2010 about alternative routes of insulin administration (ARIA) were still about inhaled insulin. Long-term experience with Exubera was the topic of a number of publications that are also of relevance for inhaled insulin in general. The clinical trials performed with AIR insulin by Eli Lilly were published in a supplement issue of one diabetes technology journal and most of these will be presented. A number of other publications (also one in a high ranked journal) about their inhaled insulin were from another company: MannKind. The driving force behind Technosphere insulin (TI) - which is the only one still in clinical development - is Al Mann; he has put a lot of his personal fortune in this development. We will know the opinion of the regulatory authorities about TI in the near future; however, I am personally relatively confident that the Food and Drug Administration will provide TI with market approval. The more critical question for me is: will diabetologists and patients jump on this product once it becomes commercially available? Will it become a commercial success? In view of many negative feelings in the scientific community about inhaled insulin, it might be of help that MannKind publish their studies with TI systematically. Acknowledging being a believer in this route of insulin administration myself, one has to state that Exubera and AIR insulin had not offered profound advantages in terms of pharmacokinetic (PK) and pharmacodynamic (PD) properties in comparison with subcutaneously (SC) applied regular human insulin (RHI) and rapid-acting insulin analogues. The time-action profiles of these inhaled insulins were more or less comparable with that of rapid-acting insulin analogues. This is clearly different with TI which exhibits a strong metabolic effect shortly after application and a rapid decline in the metabolic effect thereafter; probably the duration of action is

  6. Optimization of codon composition and regulatory elements for expression of human insulin like growth factor-1 in transgenic chloroplasts and evaluation of structural identity and function

    PubMed Central

    Daniell, Henry; Ruiz, Gricel; Denes, Bela; Sandberg, Laurence; Langridge, William

    2009-01-01

    Background Transgenic chloroplasts are potential bioreactors for recombinant protein production, especially for achievement of high levels of protein expression and proper folding. Production of therapeutic proteins in leaves provides transgene containment by elimination of reproductive structures. Therefore, in this study, human Insulin like Growth Factor-1 is expressed in transgenic chloroplasts for evaluation of structural identity and function. Results Expression of the synthetic Insulin like Growth Factor 1 gene (IGF-1s, 60% AT) was observed in transformed E. coli. However, no native IGF-1 gene (IGF-1n, 41% AT) product was detected in the western blots in E. coli. Site-specific integration of the transgenes into the tobacco chloroplast genome was confirmed after transformation using PCR. Southern blot analysis confirmed that the transgenic lines were homoplasmic. The transgenic plant lines had IGF-1s expression levels of 11.3% of total soluble protein (TSP). The IGF-1n plants contained 9.5% TSP as IGF-1n, suggesting that the chloroplast translation machinery is more flexible than E. coli in codon preference and usage. The expression of IGF-1 was increased up to 32% TSP under continuous illumination by the chloroplast light regulatory elements. IgG-Sepharose affinity column chromatographic separation of Z domain containing chloroplast derived IGF-1 protein, single and two dimensional electrophoresis methods and mass spectrometer analysis confirmed the identity of human IGF-1 in transgenic chloroplasts. Two spots analyzed from 2-D focusing/phoresis acrylamide gel showed the correct amino acid sequence of human IGF-1 and the S. aureus Z-tag. Cell proliferation assays in human HU-3 cells demonstrated the biological activity of chloroplast derived IGF-1 even in the presence of the S. aureus Z tag. Conclusion This study demonstrates that the human Insulin like Growth Factor-1 expressed in transgenic chloroplasts is identical to the native protein and is fully

  7. Changes in cis-regulatory elements of a key floral regulator are associated with divergence of inflorescence architectures.

    PubMed

    Kusters, Elske; Della Pina, Serena; Castel, Rob; Souer, Erik; Koes, Ronald

    2015-08-15

    Higher plant species diverged extensively with regard to the moment (flowering time) and position (inflorescence architecture) at which flowers are formed. This seems largely caused by variation in the expression patterns of conserved genes that specify floral meristem identity (FMI), rather than changes in the encoded proteins. Here, we report a functional comparison of the promoters of homologous FMI genes from Arabidopsis, petunia, tomato and Antirrhinum. Analysis of promoter-reporter constructs in petunia and Arabidopsis, as well as complementation experiments, showed that the divergent expression of leafy (LFY) and the petunia homolog aberrant leaf and flower (ALF) results from alterations in the upstream regulatory network rather than cis-regulatory changes. The divergent expression of unusual floral organs (UFO) from Arabidopsis, and the petunia homolog double top (DOT), however, is caused by the loss or gain of cis-regulatory promoter elements, which respond to trans-acting factors that are expressed in similar patterns in both species. Introduction of pUFO:UFO causes no obvious defects in Arabidopsis, but in petunia it causes the precocious and ectopic formation of flowers. This provides an example of how a change in a cis-regulatory region can account for a change in the plant body plan. PMID:26220938

  8. Insulin Directly Regulates Steroidogenesis via Induction of the Orphan Nuclear Receptor DAX-1 in Testicular Leydig Cells*

    PubMed Central

    Ahn, Seung Won; Gang, Gil-Tae; Kim, Yong Deuk; Ahn, Ryun-Sup; Harris, Robert A.; Lee, Chul-Ho; Choi, Hueng-Sik

    2013-01-01

    Testosterone level is low in insulin-resistant type 2 diabetes. Whether this is due to negative effects of high level of insulin on the testes caused by insulin resistance has not been studied in detail. In this study, we found that insulin directly binds to insulin receptors in Leydig cell membranes and activates phospho-insulin receptor-β (phospho-IR-β), phospho-IRS1, and phospho-AKT, leading to up-regulation of DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) gene expression in the MA-10 mouse Leydig cell line. Insulin also inhibits cAMP-induced and liver receptor homolog-1 (LRH-1)-induced steroidogenic enzyme gene expression and steroidogenesis. In contrast, knockdown of DAX-1 reversed insulin-mediated inhibition of steroidogenesis. Whether insulin directly represses steroidogenesis through regulation of steroidogenic enzyme gene expression was assessed in insulin-injected mouse models and high fat diet-induced obesity. In insulin-injected mouse models, insulin receptor signal pathway was activated and subsequently inhibited steroidogenesis via induction of DAX-1 without significant change of luteinizing hormone or FSH levels. Likewise, the levels of steroidogenic enzyme gene expression and steroidogenesis were low, but interestingly, the level of DAX-1 was high in the testes of high fat diet-fed mice. These results represent a novel regulatory mechanism of steroidogenesis in Leydig cells. Insulin-mediated induction of DAX-1 in Leydig cells of testis may be a key regulatory step of serum sex hormone level in insulin-resistant states. PMID:23589295

  9. Role of GnRH Neurons and Their Neuronal Afferents as Key Integrators between Food Intake Regulatory Signals and the Control of Reproduction.

    PubMed

    Roa, Juan

    2013-01-01

    Reproductive function is regulated by a plethora of signals that integrate physiological and environmental information. Among others, metabolic factors are key components of this circuit since they inform about the propitious timing for reproduction depending on energy availability. This information is processed mainly at the hypothalamus that, in turn, modulates gonadotropin release from the pituitary and, thereby, gonadal activity. Metabolic hormones, such as leptin, insulin, and ghrelin, act as indicators of the energy status and convey this information to the reproductive axis regulating its activity. In this review, we will analyse the central mechanisms involved in the integration of this metabolic information and their contribution to the control of the reproductive function. Particular attention will be paid to summarize the participation of GnRH, Kiss1, NPY, and POMC neurons in this process and their possible interactions to contribute to the metabolic control of reproduction. PMID:24101924

  10. Role of GnRH Neurons and Their Neuronal Afferents as Key Integrators between Food Intake Regulatory Signals and the Control of Reproduction

    PubMed Central

    2013-01-01

    Reproductive function is regulated by a plethora of signals that integrate physiological and environmental information. Among others, metabolic factors are key components of this circuit since they inform about the propitious timing for reproduction depending on energy availability. This information is processed mainly at the hypothalamus that, in turn, modulates gonadotropin release from the pituitary and, thereby, gonadal activity. Metabolic hormones, such as leptin, insulin, and ghrelin, act as indicators of the energy status and convey this information to the reproductive axis regulating its activity. In this review, we will analyse the central mechanisms involved in the integration of this metabolic information and their contribution to the control of the reproductive function. Particular attention will be paid to summarize the participation of GnRH, Kiss1, NPY, and POMC neurons in this process and their possible interactions to contribute to the metabolic control of reproduction. PMID:24101924

  11. Glucocorticoid-Induced Tumour Necrosis Factor Receptor-Related Protein: A Key Marker of Functional Regulatory T Cells

    PubMed Central

    Ronchetti, Simona; Ricci, Erika; Petrillo, Maria Grazia; Cari, Luigi; Migliorati, Graziella; Nocentini, Giuseppe; Riccardi, Carlo

    2015-01-01

    Glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR, TNFRSF18, and CD357) is expressed at high levels in activated T cells and regulatory T cells (Tregs). In this review, we present data from mouse and human studies suggesting that GITR is a crucial player in the differentiation of thymic Tregs (tTregs), and expansion of both tTregs and peripheral Tregs (pTregs). The role of GITR in Treg expansion is confirmed by the association of GITR expression with markers of memory T cells. In this context, it is not surprising that GITR appears to be a marker of active Tregs, as suggested by the association of GITR expression with other markers of Treg activation or cytokines with suppressive activity (e.g., IL-10 and TGF-β), the presence of GITR+ cells in tissues where Tregs are active (e.g., solid tumours), or functional studies on Tregs. Furthermore, some Treg subsets including Tr1 cells express either low or no classical Treg markers (e.g., FoxP3 and CD25) and do express GITR. Therefore, when evaluating changes in the number of Tregs in human diseases, GITR expression must be evaluated. Moreover, GITR should be considered as a marker for isolating Tregs. PMID:25961057

  12. Comparative Study between Transcriptionally- and Translationally-Acting Adenine Riboswitches Reveals Key Differences in Riboswitch Regulatory Mechanisms

    PubMed Central

    Blouin, Simon; Heppell, Benoit; Bastet, Laurène; St-Pierre, Patrick; Massé, Eric; Lafontaine, Daniel A.

    2011-01-01

    Many bacterial mRNAs are regulated at the transcriptional or translational level by ligand-binding elements called riboswitches. Although they both bind adenine, the adenine riboswitches of Bacillus subtilis and Vibrio vulnificus differ by controlling transcription and translation, respectively. Here, we demonstrate that, beyond the obvious difference in transcriptional and translational modulation, both adenine riboswitches exhibit different ligand binding properties and appear to operate under different regulation regimes (kinetic versus thermodynamic). While the B. subtilis pbuE riboswitch fully depends on co-transcriptional binding of adenine to function, the V. vulnificus add riboswitch can bind to adenine after transcription is completed and still perform translation regulation. Further investigation demonstrates that the rate of transcription is critical for the B. subtilis pbuE riboswitch to perform efficiently, which is in agreement with a co-transcriptional regulation. Our results suggest that the nature of gene regulation control, that is transcription or translation, may have a high importance in riboswitch regulatory mechanisms. PMID:21283784

  13. Insulin Resistance in Alzheimer's Disease

    PubMed Central

    Dineley, Kelly T; Jahrling, Jordan B; Denner, Larry

    2014-01-01

    Insulin is a key hormone regulating metabolism. Insulin binding to cell surface insulin receptors engages many signaling intermediates operating in parallel and in series to control glucose, energy, and lipids while also regulating mitogenesis and development. Perturbations in the function of any of these intermediates, which occur in a variety of diseases, cause reduced sensitivity to insulin and insulin resistance with consequent metabolic dysfunction. Chronic inflammation ensues which exacerbates compromised metabolic homeostasis. Since insulin has a key role in learning and memory as well as directly regulating ERK, a kinase required for the type of learning and memory compromised in early Alzheimer's disease (AD), insulin resistance has been identified as a major risk factor for the onset of AD. Animal models of AD or insulin resistance or both demonstrate that AD pathology and impaired insulin signaling form a reciprocal relationship. Of note are human and animal model studies geared toward improving insulin resistance that have led to the identification of the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) as an intervention tool for early AD. Strategic targeting of alternate nodes within the insulin signaling network has revealed disease-stage therapeutic windows in animal models that coalesce with previous and ongoing clinical trial approaches. Thus, exploiting the connection between insulin resistance and AD provides powerful opportunities to delineate therapeutic interventions that slow or block the pathogenesis of AD. PMID:25237037

  14. Transcriptomics profiling of Indian mustard (Brassica juncea) under arsenate stress identifies key candidate genes and regulatory pathways

    PubMed Central

    Srivastava, Sudhakar; Srivastava, Ashish K.; Sablok, Gaurav; Deshpande, Tejaswini U.; Suprasanna, Penna

    2015-01-01

    Arsenic (As) is a non-essential element, a groundwater pollutant, whose uptake by plants produces toxic effects. The use of As-contaminated groundwater for irrigation can affect the crop productivity. Realizing the importance of the Brassica juncea as a crop plant in terms of oil-yield, there is a need to unravel mechanistic details of response to As stress and identify key functional genes and pathways. In this research, we studied time-dependent (4–96 h) transcriptome changes in roots and shoots of B. juncea under arsenate [As(V)] stress using Agilent platform. Among the whole transcriptome profiled genes, a total of 1,285 genes showed significant change in expression pattern upon As(V) exposure. The differentially expressed genes were categorized to various signaling pathways including hormones (jasmonate, abscisic acid, auxin, and ethylene) and kinases. Significant effects were also noticed on genes related to sulfur, nitrogen, CHO, and lipid metabolisms along with photosynthesis. Biochemical assays were conducted using specific inhibitors of glutathione and jasmonate biosynthesis, and kinases. The inhibitor studies revealed interconnection among sulfur metabolism, jasmonate, and kinase signaling pathways. In addition, various transposons also constituted a part of the altered transcriptome. Lastly, we profiled a set of key functional up- and down-regulated genes using real-time RT-PCR, which could act as an early indicators of the As stress. PMID:26347763

  15. Insulin signaling and the regulation of insect diapause.

    PubMed

    Sim, Cheolho; Denlinger, David L

    2013-01-01

    A rich chapter in the history of insect endocrinology has focused on hormonal control of diapause, especially the major roles played by juvenile hormones (JHs), ecdysteroids, and the neuropeptides that govern JH and ecdysteroid synthesis. More recently, experiments with adult diapause in Drosophila melanogaster and the mosquito Culex pipiens, and pupal diapause in the flesh fly Sarcophaga crassipalpis provide strong evidence that insulin signaling is also an important component of the regulatory pathway leading to the diapause phenotype. Insects produce many different insulin-like peptides (ILPs), and not all are involved in the diapause response; ILP-1 appears to be the one most closely linked to diapause in C. pipiens. Many steps in the pathway leading from perception of daylength (the primary environmental cue used to program diapause) to generation of the diapause phenotype remain unknown, but the role for insulin signaling in mosquito diapause appears to be upstream of JH, as evidenced by the fact that application of exogenous JH can rescue the effects of knocking down expression of ILP-1 or the Insulin Receptor. Fat accumulation, enhancement of stress tolerance, and other features of the diapause phenotype are likely linked to the insulin pathway through the action of a key transcription factor, FOXO. This review highlights many parallels for the role of insulin signaling as a regulator in insect diapause and dauer formation in the nematode Caenorhabditis elegans. PMID:23885240

  16. Quantitative Phosphoproteomics Analysis Reveals a Key Role of Insulin Growth Factor 1 Receptor (IGF1R) Tyrosine Kinase in Human Sperm Capacitation*

    PubMed Central

    Wang, Jing; Qi, Lin; Huang, Shaoping; Zhou, Tao; Guo, Yueshuai; Wang, Gaigai; Guo, Xuejiang; Zhou, Zuomin; Sha, Jiahao

    2015-01-01

    One of the most important changes during sperm capacitation is the enhancement of tyrosine phosphorylation. However, the mechanisms of protein tyrosine phosphorylation during sperm capacitation are not well studied. We used label-free quantitative phosphoproteomics to investigate the overall phosphorylation events during sperm capacitation in humans and identified 231 sites with increased phosphorylation levels. Motif analysis using the NetworKIN algorithm revealed that the activity of tyrosine phosphorylation kinases insulin growth factor 1 receptor (IGF1R)/insulin receptor is significantly enriched among the up-regulated phosphorylation substrates during capacitation. Western blotting further confirmed inhibition of IGF1R with inhibitors GSK1904529A and NVP-AEW541, which inhibited the increase in tyrosine phosphorylation levels during sperm capacitation. Additionally, sperm hyperactivated motility was also inhibited by GSK1904529A and NVP-AEW541 but could be up-regulated by insulin growth factor 1, the ligand of IGF1R. Thus, the IGF1R-mediated tyrosine phosphorylation pathway may play important roles in the regulation of sperm capacitation in humans and could be a target for improvement in sperm functions in infertile men. PMID:25693802

  17. A Single Host-Derived Glycan Impacts Key Regulatory Nodes of Symbiont Metabolism in a Coevolved Mutualism

    PubMed Central

    Pan, Min; Schwartzman, Julia A.; Dunn, Anne K.; Lu, Zuhong

    2015-01-01

    ABSTRACT Most animal-microbe mutualistic associations are characterized by nutrient exchange between the partners. When the host provides the nutrients, it can gain the capacity to shape its microbial community, control the stability of the interaction, and promote its health and fitness. Using the bioluminescent squid-vibrio model, we demonstrate how a single host-derived glycan, chitin, regulates the metabolism of Vibrio fischeri at key points in the development and maintenance of the symbiosis. We first characterized the pathways for catabolism of chitin sugars by V. fischeri, demonstrating that the Ccr-dependent phosphoenolpyruvate-pyruvate phosphotransferase system (PTS) prioritizes transport of these sugars in V. fischeri by blocking the uptake of non-PTS carbohydrates, such as glycerol. Next, we found that PTS transport of chitin sugars into the bacterium shifted acetate homeostasis toward a net excretion of acetate and was sufficient to override an activation of the acetate switch by AinS-dependent quorum sensing. Finally, we showed that catabolism of chitin sugars decreases the rate of cell-specific oxygen consumption. Collectively, these three metabolic functions define a physiological shift that favors fermentative growth on chitin sugars and may support optimal symbiont luminescence, the functional basis of the squid-vibrio mutualism. PMID:26173698

  18. Translating PrEP effectiveness into public health impact: key considerations for decision-makers on cost-effectiveness, price, regulatory issues, distributive justice and advocacy for access

    PubMed Central

    Hankins, Catherine; Macklin, Ruth; Warren, Mitchell

    2015-01-01

    Introduction The extraordinary feat of proving the effectiveness of oral pre-exposure prophylaxis (PrEP) in clinical trials in different populations in a variety of settings may prove to have been easier than ensuring it is used well. Decision-makers must make difficult choices to realize the promise of antiretroviral prophylaxis for their countries. This paper outlines key economic, regulatory and distributive justice issues that must be addressed for effective and acceptable PrEP implementation. Discussion In considering the role that PrEP can play in combination prevention programmes, decision-makers must determine who can benefit most from PrEP, how PrEP can be provided safely and efficiently, and what kind of health system support will ensure successful implementation. To do this, they need contextualized information on disease burden by population, analyses of how PrEP services might best be delivered, and projections of the human resource and infrastructure requirements for each potential delivery model. There are cost considerations, varying cost-effectiveness results and regulatory challenges. The principles of ethics can inform thorny discussions about who should be prioritized for oral PrEP and how best to introduce it fairly. We describe the cost-effectiveness of PrEP in different populations at higher risk of HIV exposure, its price in low- and middle-income countries, and the current regulatory situation. We explore the principles of ethics that can inform resource allocation decision-making about PrEP anchored in distributive justice, at a time when universal access to antiretroviral treatment remains to be assured. We then highlight the role of advocacy in moving the PrEP agenda forward. Conclusions The time is ripe now for decisions about whether, how and for whom PrEP should be introduced into a country's HIV response. It has the potential to contribute significantly to high impact HIV prevention if it is tailored to those who can most benefit

  19. Recommendations for Insulin Dose Calculator Risk Management

    PubMed Central

    2014-01-01

    Several studies have shown the usefulness of an automated insulin dose bolus advisor (BA) in achieving improved glycemic control for insulin-using diabetes patients. Although regulatory agencies have approved several BAs over the past decades, these devices are not standardized in their approach to dosage calculation and include many features that may introduce risk to patients. Moreover, there is no single standard of care for diabetes worldwide and no guidance documents for BAs, specifically. Given the emerging and more stringent regulations on software used in medical devices, the approval process is becoming more difficult for manufacturers to navigate, with some manufacturers opting to remove BAs from their products altogether. A comprehensive literature search was performed, including publications discussing: diabetes BA use and benefit, infusion pump safety and regulation, regulatory submissions, novel BAs, and recommendations for regulation and risk management of BAs. Also included were country-specific and international guidance documents for medical device, infusion pump, medical software, and mobile medical application risk management and regulation. No definitive worldwide guidance exists regarding risk management requirements for BAs, specifically. However, local and international guidance documents for medical devices, infusion pumps, and medical device software offer guidance that can be applied to this technology. In addition, risk management exercises that are algorithm-specific can help prepare manufacturers for regulatory submissions. This article discusses key issues relevant to BA use and safety, and recommends risk management activities incorporating current research and guidance. PMID:24876550

  20. Recommendations for Insulin Dose Calculator Risk Management.

    PubMed

    Rees, Christen

    2014-01-01

    Several studies have shown the usefulness of an automated insulin dose bolus advisor (BA) in achieving improved glycemic control for insulin-using diabetes patients. Although regulatory agencies have approved several BAs over the past decades, these devices are not standardized in their approach to dosage calculation and include many features that may introduce risk to patients. Moreover, there is no single standard of care for diabetes worldwide and no guidance documents for BAs, specifically. Given the emerging and more stringent regulations on software used in medical devices, the approval process is becoming more difficult for manufacturers to navigate, with some manufacturers opting to remove BAs from their products altogether. A comprehensive literature search was performed, including publications discussing: diabetes BA use and benefit, infusion pump safety and regulation, regulatory submissions, novel BAs, and recommendations for regulation and risk management of BAs. Also included were country-specific and international guidance documents for medical device, infusion pump, medical software, and mobile medical application risk management and regulation. No definitive worldwide guidance exists regarding risk management requirements for BAs, specifically. However, local and international guidance documents for medical devices, infusion pumps, and medical device software offer guidance that can be applied to this technology. In addition, risk management exercises that are algorithm-specific can help prepare manufacturers for regulatory submissions. This article discusses key issues relevant to BA use and safety, and recommends risk management activities incorporating current research and guidance. PMID:24876550

  1. MicroRNA-16 modulates macrophage polarization leading to improved insulin sensitivity in myoblasts.

    PubMed

    Talari, Malathi; Kapadia, Bandish; Kain, Vasundhara; Seshadri, Sriram; Prajapati, Bhumika; Rajput, Parth; Misra, Parimal; Parsa, Kishore V L

    2015-12-01

    Uncontrolled inflammation leads to several diseases such as insulin resistance, T2D and several types of cancers. The functional role of microRNAs in inflammation induced insulin resistance is poorly studied. MicroRNAs are post-transcriptional regulatory molecules which mediate diverse biological processes. We here show that miR-16 expression levels are down-regulated in different inflammatory conditions such as LPS/IFNγ or palmitate treated macrophages, palmitate exposed myoblasts and insulin responsive tissues of high sucrose diet induced insulin resistant rats. Importantly, forced expression of miR-16 in macrophages impaired the production of TNF-α, IL-6 and IFN-β leading to enhanced insulin stimulated glucose uptake in co-cultured skeletal myoblasts. Further, ectopic expression of miR-16 enhanced insulin stimulated glucose uptake in skeletal myoblasts via the up-regulation of GLUT4 and MEF2A, two key players involved in insulin stimulated glucose uptake. Collectively, our data highlight the important role of miR-16 in ameliorating inflammation induced insulin resistance. PMID:26453808

  2. Cloning, characterization, and embryonic expression analysis of the Drosophila melanogaster gene encoding insulin/relaxin-like peptide.

    PubMed

    Nasonkin, Igor O; Alikasifoglu, Ayfer; Barrette, Terry; Cheng, Michael M; Thomas, Pamela M; Nikitin, Alexey G

    2002-07-12

    Insulin is one of the key peptide hormones that regulates growth and metabolism in vertebrates. Evolutionary conservation of many elements of the insulin/IGF signaling network makes it possible to study the basic genetic function of this pathway in lower metazoan models such as Drosophila. Here we report the cloning and characterization of the gene for Drosophila insulin/relaxin-like peptide (DIRLP). The predicted protein structure of DIRLP greatly resembles typical insulin structure and contains features that differentiate it from the Drosophila juvenile hormone, another member of the insulin family. The Dirlp gene is represented as a single copy in the Drosophila melanogaster genome (compared to multiple copies for Drosophila juvenile hormone) and shows evolutionary conservation of genetic structure. The gene was mapped to the Drosophila chromosome 3, region 67D2. In situ hybridization of whole-mount Drosophila embryos with Dirlp antisense RNA probe reveals early embryonic mesodermal/ventral furrow expression pattern, consistent with earlier observation of the insulin protein immunoreactivity in Drosophila embryos. The in situ hybridization pattern was found to be identical to that obtained during immunohistochemistry analysis of the Drosophila embryos using various insulin monoclonal and polyclonal antibodies that do not recognize Drosophila juvenile hormone, supporting the idea that Dirlp is a possible Drosophila insulin ortholog. Identification of the gene for DIRLP provides a new approach for study of the regulatory pathway of the insulin family of peptides. PMID:12150949

  3. Oral Insulin

    PubMed Central

    2010-01-01

    Oral insulin is an exciting area of research and development in the field of diabetology. This brief review covers the various approaches used in the development of oral insulin, and highlights some of the recent data related to novel oral insulin preparation. PMID:21059246

  4. T helper 2 and regulatory T-cell cytokine production by mast cells: a key factor in the pathogenesis of IgG4-related disease.

    PubMed

    Takeuchi, Mai; Sato, Yasuharu; Ohno, Kyotaro; Tanaka, Satoshi; Takata, Katsuyoshi; Gion, Yuka; Orita, Yorihisa; Ito, Toshihiro; Tachibana, Tomoyasu; Yoshino, Tadashi

    2014-08-01

    IgG4-related disease is a systemic disorder with unique clinicopathological features and uncertain etiological features and is frequently related to allergic disease. T helper 2 and regulatory T-cell cytokines have been reported to be upregulated in the affected tissues; thus, the production of these cytokines by T helper 2 and regulatory T cells has been suggested as an important factor in the pathogenesis of IgG4-related disease. However, it is not yet clear which cells produce these cytokines in IgG4-related disease, and some aspects of the disorder cannot be completely explained by T-cell-related processes. To address this, we analyzed paraffin-embedded sections of tissues from nine cases of IgG4-related submandibular gland disease, five cases of submandibular sialolithiasis, and six cases of normal submandibular gland in order to identify potential key players in the pathogenesis of IgG4-related disease. Real-time polymerase chain reaction analysis confirmed the significant upregulation of interleukin (IL)4, IL10, and transforming growth factor beta 1 (TGFβ1) in IgG4-related disease. Interestingly, immunohistochemical studies indicated the presence of mast cells expressing these cytokines in diseased tissues. In addition, dual immunofluorescence assays identified cells that were double-positive for each cytokine and for KIT, which is expressed by mast cells. In contrast, the distribution of T cells did not correlate with cytokine distribution in affected tissues. We also found that the mast cells were strongly positive for IgE. This observation supports the hypothesis that mast cells are involved in IgG4-related disease, as mast cells are known to be closely related to allergic reactions and are activated in the presence of elevated non-specific IgE levels. In conclusion, our results indicate that mast cells produce T helper 2 and regulatory T-cell cytokines in tissues affected by IgG4-related disease and possibly have an important role in disease

  5. Identification of putative regulatory region of insulin-like androgenic gland hormone gene (IAG) in the prawn Macrobrachium nipponense and proteins that interact with IAG by using yeast two-hybrid system.

    PubMed

    Ma, Ke-Yi; Li, Jia-Le; Qiu, Gao-Feng

    2016-04-01

    Insulin-like androgenic gland hormone gene (IAG) is a sex regulator specifically expressed in male crustaceans, controlling the male sexual differentiation, spermatogenesis and reproductive strategy. Our previous study reported the cloning and characterization of the prawn Macrobrachium nipponense IAG (MnIAG). In this study, we further identified a 2214-bp MnIAG 5'-flanking region, and analyzed its transcription factor binding sites and transcriptional activity. The results showed that there were two potential promoter core sequences, three TATA boxes and one CAAT box existing in the MnIAG 5'-flanking region as well as many potential transcription factor binding sites, such as SRY, Sox-5, GATA-1, etc. Notably, the transcriptional activity was weak in this region, and a negative regulatory region was found in -604 to -231bp. In addition, we constructed M. nipponense yeast libraries and identified proteins interacting with the MnIAG protein by yeast two hybridization assay. The yeast two-hybrid screening yielded ten positive clones, of which five were annotated by NCBI database, namely heat shock protein 21, NADH dehydrogenase, zinc finger protein, beta-N-acetylglucosaminidase and a hypothetical protein. The identification of MnIAG putative regulatory region and proteins that interact with IAG will facilitate our understanding of the regulatory role of MnIAG and provide a foundation for deep insight into the prawn sex differentiation mechanism and signaling transduction pathways. PMID:26979275

  6. An Integrative Approach for Mapping Differentially Expressed Genes and Network Components Using Novel Parameters to Elucidate Key Regulatory Genes in Colorectal Cancer

    PubMed Central

    Sehgal, Manika; Gupta, Rajinder; Moussa, Ahmed; Singh, Tiratha Raj

    2015-01-01

    For examining the intricate biological processes concerned with colorectal cancer (CRC), a systems biology approach integrating several biological components and other influencing factors is essential to understand. We performed a comprehensive system level analysis for CRC which assisted in unravelling crucial network components and many regulatory elements through a coordinated view. Using this integrative approach, the perceptive of complexity hidden in a biological phenomenon is extensively simplified. The microarray analyses facilitated differential expression of 631 significant genes employed in the progression of disease and supplied interesting associated up and down regulated genes like jun, fos and mapk1. The transcriptional regulation of these genes was deliberated widely by examining transcription factors such as hnf4, nr2f1, znf219 and dr1 which directly influence the expression. Further, interactions of these genes/proteins were evaluated and crucial network motifs were detected to associate with the pathophysiology of CRC. The available standard statistical parameters such as z-score, p-value and significance profile were explored for the identification of key signatures from CRC pathway whereas a few novel parameters representing over-represented structures were also designed in the study. The applied approach revealed 5 key genes i.e. kras, araf, pik3r5, ralgds and akt3 via our novel designed parameters illustrating high statistical significance. These novel parameters can assist in scrutinizing candidate markers for diseases having known biological pathways. Further, investigating and targeting these proposed genes for experimental validations, instead being spellbound by the complicated pathway will certainly endow valuable insight in a well-timed systematic understanding of CRC. PMID:26222778

  7. Ganglioside GM3 as a gatekeeper of obesity-associated insulin resistance: Evidence and mechanisms.

    PubMed

    Lipina, Christopher; Hundal, Harinder S

    2015-10-24

    Gangliosides constitute a large family of sialic acid-containing glycosphingolipids which play a key regulatory role in a diverse array of cellular processes, including receptor-associated signalling. Accordingly, the aberrant production of the ganglioside GM3 has been linked to pathophysiological changes associated with obesity, which in turn can lead to metabolic disorders such as insulin resistance and type 2 diabetes mellitus. This review examines the role of GM3 in mediating obesity-induced perturbations in metabolic function, including impaired insulin action. By doing so, we highlight the potential use of therapies targeting GM3 biosynthesis in order to counteract obesity-related metabolic disorders. PMID:26434718

  8. Gestational Diabetes Alters Offspring DNA Methylation Profiles in Human and Rat: Identification of Key Pathways Involved in Endocrine System Disorders, Insulin Signaling, Diabetes Signaling, and ILK Signaling.

    PubMed

    Petropoulos, Sophie; Guillemin, Claire; Ergaz, Zivanit; Dimov, Sergiy; Suderman, Matthew; Weinstein-Fudim, Liza; Ornoy, Asher; Szyf, Moshe

    2015-06-01

    Gestational diabetes is associated with risk for metabolic disease later in life. Using a cross-species approach in rat and humans, we examined the hypothesis that gestational diabetes during pregnancy triggers changes in the methylome of the offspring that might be mediating these risks. We show in a gestation diabetes rat model, the Cohen diabetic rat, that gestational diabetes triggers wide alterations in DNA methylation in the placenta in both candidate diabetes genes and genome-wide promoters, thus providing evidence for a causal relationship between diabetes during pregnancy and DNA methylation alterations. There is a significant overlap between differentially methylated genes in the placenta and the liver of the rat offspring. Several genes differentially methylated in rat placenta exposed to maternal diabetes are also differentially methylated in the human placenta of offspring exposed to gestational diabetes in utero. DNA methylation changes inversely correlate with changes in expression. The changes in DNA methylation affect known functional gene pathways involved in endocrine function, metabolism, and insulin responses. These data provide support to the hypothesis that early-life exposures and their effects on metabolic disease are mediated by DNA methylation changes. This has important diagnostic and therapeutic implications. PMID:25514087

  9. Quantification of key periodontal pathogens in insulin-dependent type 2 diabetic and non-diabetic patients with generalized chronic periodontitis.

    PubMed

    Aemaimanan, Piyamas; Amimanan, Piyawan; Taweechaisupapong, Suwimol

    2013-08-01

    Periodontitis is a common problem in patients with diabetes mellitus (DM), however, differences in the putative periodontal pathogens in subjects with DM compared to non-DM subjects are still inconclusive. The red complex, which includes Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, encompasses the most important pathogens in adult periodontal disease. The aim of the present study was to compare cell numbers of P. gingivalis, T. denticola, T. forsythia and Aggregatibacter actinomycetemcomitans in gingival sulcus of healthy, gingivitis and periodontitis sites of non-diabetes mellitus (NDM), controlled and poorly controlled insulin-dependent DM (CDM and PDM) patients with generalized chronic periodontitis. Subgingival plaque samples were collected from 19 CDM, 19 PDM and 19 NDM patients. Taqman real time-PCR was used to determine bacterial cell number. At subject level, the quantity of red complex bacteria was significantly higher in PDM than those of NDM and positively correlated with HbA1c. At site level (total 342 sites), cell numbers of T. denticola and T. forsythia in healthy sites of CDM and PDM were significantly higher than those of NDM. In gingivitis sites, the numbers of P. gingivalis in CDM and PDM and T. forsythia in PDM were significantly higher than those of NDM while in periodontitis sites, higher quantity of P. gingivalis in PDM was observed. Our study indicated that poor glycemic control is associated with increasing cell numbers of red complex bacteria in subgingival biofilm. PMID:23827459

  10. Maternal and postweaning folic acid supplementation interact to influence body weight, insulin resistance, and food intake regulatory gene expression in rat offspring in a sex-specific manner.

    PubMed

    Huot, Pedro S P; Ly, Anna; Szeto, Ignatius M Y; Reza-López, Sandra A; Cho, Daniel; Kim, Young-In; Anderson, G Harvey

    2016-04-01

    Maternal intake of multivitamins or folic acid above the basal dietary requirement alters the growth and metabolic trajectory of rat offspring. We hypothesized that a modest increase in the folic acid content of maternal diets would alter the offspring's metabolic phenotype, and that these effects could be corrected by matching the folic acid content of the offspring's diet with that of the maternal diet. Female Sprague-Dawley rats were placed on a control or a 2.5× folic acid-supplemented diet prior to mating and during pregnancy and lactation. At weaning, pups from each maternal diet group were randomized to the control or to the 2.5× folic acid-supplemented diet for 25 weeks. Male pups from dams fed the folic acid-supplemented diet were 3.7% heavier than those from control-fed dams and had lower mRNA expression for leptin receptor Obrb isoform (Lepr) (11%) and Agouti-related protein (Agrp) (14%). In contrast, female pups from folic acid-supplemented dams were 5% lighter than those from control-fed dams and had lower proopiomelanocortin (Pomc) (42%), Lepr (32%), and Agrp (13%), but higher neuropeptide Y (Npy) (18%) mRNA expression. Folic acid supplementation ameliorated the alterations induced by maternal folic acid supplementation in male pups and led to the lowest insulin resistance, but the effects were smaller in female pups and led to the highest insulin resistance. In conclusion, maternal folic acid supplementation at 2.5× the control level was associated with alterations in body weight and hypothalamic gene expression in rat offspring in a sex-specific manner, and some of these effects were attenuated by postweaning folic acid supplementation. PMID:26989972

  11. Acetylation of insulin receptor substrate-1 is permissive for tyrosine phosphorylation

    PubMed Central

    Kaiser, Christina; James, Stephen R

    2004-01-01

    Background Insulin receptor substrate (IRS) proteins are key moderators of insulin action. Their specific regulation determines downstream protein-protein interactions and confers specificity on growth factor signalling. Regulatory mechanisms that have been identified include phosphorylation of IRS proteins on tyrosine and serine residues and ubiquitination of lysine residues. This study investigated other potential molecular mechanisms of IRS-1 regulation. Results Using the sos recruitment yeast two-hybrid system we found that IRS-1 and histone deacetylase 2 (HDAC2) interact in the cytoplasmic compartment of yeast cells. The interaction mapped to the C-terminus of IRS-1 and was confirmed through co-immunoprecipitation in vitro of recombinant IRS-1 and HDAC2. HDAC2 bound to IRS-1 in mammalian cells treated with phorbol ester or after prolonged treatment with insulin/IGF-1 and also in the livers of ob/ob mice but not PTP1B knockout mice. Thus, the association occurs under conditions of compromised insulin signalling. We found that IRS-1 is an acetylated protein, of which the acetylation is increased by treatment of cells with Trichostatin A (TSA), an inhibitor of HDAC activity. TSA-induced increases in acetylation of IRS-1 were concomitant with increases in tyrosine phosphorylation in response to insulin. These effects were confirmed using RNA interference against HDAC2, indicating that HDAC2 specifically prevents phosphorylation of IRS-1 by the insulin receptor. Conclusions Our results show that IRS-1 is an acetylated protein, a post-translational modification that has not been previously described. Acetylation of IRS-1 is permissive for tyrosine phosphorylation and facilitates insulin-stimulated signal transduction. Specific inhibition of HDAC2 may increase insulin sensitivity in otherwise insulin resistant conditions. PMID:15522123

  12. The Neuronal Kinesin UNC-104/KIF1A Is a Key Regulator of Synaptic Aging and Insulin Signaling-Regulated Memory.

    PubMed

    Li, Ling-Bo; Lei, Haoyun; Arey, Rachel N; Li, Pengpeng; Liu, Jianfeng; Murphy, Coleen T; Xu, X Z Shawn; Shen, Kang

    2016-03-01

    Aging is the greatest risk factor for a number of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Furthermore, normal aging is associated with a decline in sensory, motor, and cognitive functions. Emerging evidence suggests that synapse alterations, rather than neuronal cell death, are the causes of neuronal dysfunctions in normal aging and in early stages of neurodegenerative diseases. However, little is known about the mechanisms underlying age-related synaptic decline. Here, we uncover a surprising role of the anterograde molecular motor UNC-104/KIF1A as a key regulator of neural circuit deterioration in aging C. elegans. Through analyses of synapse protein localization, synaptic transmission, and animal behaviors, we find that reduced function of UNC-104 accelerates motor circuit dysfunction with age, whereas upregulation of UNC-104 significantly improves motor function at advanced ages and also mildly extends lifespan. In addition, UNC-104-overexpressing animals outperform wild-type controls in associative learning and memory tests. Further genetic analyses suggest that UNC-104 functions downstream of the DAF-2-signaling pathway and is regulated by the FOXO transcription factor DAF-16, which contributes to the effects of DAF-2 in neuronal aging. Together, our cellular, electrophysiological, and behavioral analyses highlight the importance of axonal transport in the maintenance of synaptic structural integrity and function during aging and raise the possibility of targeting kinesins to slow age-related neural circuit dysfunction. PMID:26877087

  13. Immobilization depresses insulin signaling in skeletal muscle.

    PubMed

    Hirose, M; Kaneki, M; Sugita, H; Yasuhara, S; Martyn, J A

    2000-12-01

    Prolonged immobilization depresses insulin-induced glucose transport in skeletal muscle and leads to a catabolic state in the affected areas, with resultant muscle wasting. To elucidate the altered intracellular mechanisms involved in the insulin resistance, we examined insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit (IR-beta) and insulin receptor substrate (IRS)-1 and activation of its further downstream molecule, phosphatidylinositol 3-kinase (PI 3-K), after unilateral hindlimb immobilization in the rat. The contralateral hindlimb served as control. After 7 days of immobilization of the rat, insulin was injected into the portal vein, and tibialis anterior muscles on both sides were extracted. Immobilization reduced insulin-stimulated tyrosine phosphorylation of IR-beta and IRS-1. Insulin-stimulated binding of IRS-1 to p85, the regulatory subunit of PI 3-K, and IRS-1-associated PI 3-K activity were also decreased in the immobilized hindlimb. Although IR-beta and p85 protein levels were unchanged, IRS-1 protein expression was downregulated by immobilization. Thus prolonged immobilization may cause depression of insulin-stimulated glucose transport in skeletal muscle by altering insulin action at multiple points, including the tyrosine phosphorylation, protein expression, and activation of essential components of insulin signaling pathways. PMID:11093909

  14. Insulin Test

    MedlinePlus

    ... people with type 2 diabetes , polycystic ovarian syndrome (PCOS) , prediabetes or heart disease , or metabolic syndrome . A ... resistance), especially in obese individuals and those with PCOS . This test involves an IV-infusion of insulin, ...

  15. Label-Free Proteomic Identification of Endogenous, Insulin-Stimulated Interaction Partners of Insulin Receptor Substrate-1

    NASA Astrophysics Data System (ADS)

    Geetha, Thangiah; Langlais, Paul; Luo, Moulun; Mapes, Rebekka; Lefort, Natalie; Chen, Shu-Chuan; Mandarino, Lawrence J.; Yi, Zhengping

    2011-03-01

    Protein-protein interactions are key to most cellular processes. Tandem mass spectrometry (MS/MS)-based proteomics combined with co-immunoprecipitation (CO-IP) has emerged as a powerful approach for studying protein complexes. However, a majority of systematic proteomics studies on protein-protein interactions involve the use of protein overexpression and/or epitope-tagged bait proteins, which might affect binding stoichiometry and lead to higher false positives. Here, we report an application of a straightforward, label-free CO-IP-MS/MS method, without the use of protein overexpression or protein tags, to the investigation of changes in the abundance of endogenous proteins associated with a bait protein, which is in this case insulin receptor substrate-1 (IRS-1), under basal and insulin stimulated conditions. IRS-1 plays a central role in the insulin signaling cascade. Defects in the protein-protein interactions involving IRS-1 may lead to the development of insulin resistance and type 2 diabetes. HPLC-ESI-MS/MS analyses identified eleven novel endogenous insulin-stimulated IRS-1 interaction partners in L6 myotubes reproducibly, including proteins play an important role in protein dephosphorylation [protein phosphatase 1 regulatory subunit 12A, (PPP1R12A)], muscle contraction and actin cytoskeleton rearrangement, endoplasmic reticulum stress, and protein folding, as well as protein synthesis. This novel application of label-free CO-IP-MS/MS quantification to assess endogenous interaction partners of a specific protein will prove useful for understanding how various cell stimuli regulate insulin signal transduction.

  16. Overview and discussion of the key regulatory issues in implementing the electric utility provisions of the Clean Air Act Amendments of 1990

    SciTech Connect

    Rose, K.; Burns, R.E.

    1991-06-01

    Title 4 of the Clean Air Act Amendments of 1990 (CAAA) created a new regulatory instrument that electric power producers (utilities and others) will be required to possess and expand in order to emit sulfur dioxide (SO{sub 2}) into the atmosphere. The emission allowance system created by the CAAA will be grafted onto an already complex system of state and federal electric utility regulation. How public utility commissions (PUCs) and the Federal Energy Regulatory Commission (FERC) regulate these allowances will greatly affect the decisions that electric utilities under their jurisdiction make to comply with the CAAA and, therefore, the cost of compliance to ratepayers. 2 figs., 9 tabs.

  17. Insulin and insulin like growth factor II endocytosis and signaling via insulin receptor B

    PubMed Central

    2013-01-01

    Background Insulin and insulin-like growth factors (IGFs) act on tetrameric tyrosine kinase receptors controlling essential functions including growth, metabolism, reproduction and longevity. The insulin receptor (IR) binds insulin and IGFs with different affinities triggering different cell responses. Results We showed that IGF-II induces cell proliferation and gene transcription when IR-B is over-expressed. We combined biotinylated ligands with streptavidin conjugated quantum dots and visible fluorescent proteins to visualize the binding of IGF-II and insulin to IR-B and their ensuing internalization. By confocal microscopy and flow cytometry in living cells, we studied the internalization kinetic through the IR-B of both IGF-II, known to elicit proliferative responses, and insulin, a regulator of metabolism. Conclusions IGF-II promotes a faster internalization of IR-B than insulin. We propose that IGF-II differentially activates mitogenic responses through endosomes, while insulin-activated IR-B remains at the plasma membrane. This fact could facilitate the interaction with key effector molecules involved in metabolism regulation. PMID:23497114

  18. A gene browser of colorectal cancer with literature evidence and pre-computed regulatory information to identify key tumor suppressors and oncogenes.

    PubMed

    Zhao, Min; Liu, Yining; Huang, Fuda; Qu, Hong

    2016-01-01

    Colorectal cancer (CRC) is a cancer of growing incidence that associates with a high mortality rate worldwide. There is a poor understanding of the heterogeneity of CRC with regard to causative genetic mutations and gene regulatory mechanisms. Previous studies have identified several susceptibility genes in small-scale experiments. However, the information has not been comprehensively and systematically compiled and interpreted. In this study, we constructed the gbCRC, the first literature-based gene resource for investigating CRC-related human genes. The features of our database include: (i) manual curation of experimentally-verified genes reported in the literature; (ii) comprehensive integration of five reliable data sources; and (iii) pre-computed regulatory patterns involving transcription factors, microRNAs and long non-coding RNAs. In total, 2067 genes associating with 2819 PubMed abstracts were compiled. Comprehensive functional annotations associated with all the genes, including gene expression profiles, homologous genes in other model species, protein-protein interactions, somatic mutations, and potential methylation sites. These comprehensive annotations and this pre-computed regulatory information highlighted the importance of the gbCRC with regard to the unexplored regulatory network of CRC. This information is available in a plain text format that is free to download. PMID:27477450

  19. A gene browser of colorectal cancer with literature evidence and pre-computed regulatory information to identify key tumor suppressors and oncogenes

    PubMed Central

    Zhao, Min; Liu, Yining; Huang, Fuda; Qu, Hong

    2016-01-01

    Colorectal cancer (CRC) is a cancer of growing incidence that associates with a high mortality rate worldwide. There is a poor understanding of the heterogeneity of CRC with regard to causative genetic mutations and gene regulatory mechanisms. Previous studies have identified several susceptibility genes in small-scale experiments. However, the information has not been comprehensively and systematically compiled and interpreted. In this study, we constructed the gbCRC, the first literature-based gene resource for investigating CRC-related human genes. The features of our database include: (i) manual curation of experimentally-verified genes reported in the literature; (ii) comprehensive integration of five reliable data sources; and (iii) pre-computed regulatory patterns involving transcription factors, microRNAs and long non-coding RNAs. In total, 2067 genes associating with 2819 PubMed abstracts were compiled. Comprehensive functional annotations associated with all the genes, including gene expression profiles, homologous genes in other model species, protein-protein interactions, somatic mutations, and potential methylation sites. These comprehensive annotations and this pre-computed regulatory information highlighted the importance of the gbCRC with regard to the unexplored regulatory network of CRC. This information is available in a plain text format that is free to download. PMID:27477450

  20. Insulin resistance and muscle insulin receptor substrate‐1 serine hyperphosphorylation

    PubMed Central

    Stuart, Charles A.; Howell, Mary E. A.; Cartwright, Brian M.; McCurry, Melanie P.; Lee, Michelle L.; Ramsey, Michael W.; Stone, Michael H.

    2014-01-01

    Abstract Insulin resistance in metabolic syndrome subjects is profound in spite of muscle insulin receptor and insulin‐responsive glucose transporter (GLUT4) expression being nearly normal. Insulin receptor tyrosine kinase phosphorylation of insulin receptor substrate‐1 (IRS‐1) at Tyr896 is a necessary step in insulin stimulation of translocation of GLUT4 to the cell surface. Serine phosphorylation of IRS‐1 by some kinases diminishes insulin action in mice. We evaluated the phosphorylation status of muscle IRS‐1 in 33 subjects with the metabolic syndrome and seventeen lean controls. Each underwent euglycemic insulin clamps and a thigh muscle biopsy before and after 8 weeks of either strength or endurance training. Muscle IRS‐1 phosphorylation at six sites was quantified by immunoblots. Metabolic syndrome muscle IRS‐1 had excess phosphorylation at Ser337 and Ser636 but not at Ser307, Ser789, or Ser1101. Ser337 is a target for phosphorylation by glycogen synthase kinase 3 (GSK3) and Ser636 is phosphorylated by c‐Jun N‐terminal kinase 1 (JNK1). Exercise training without weight loss did not change the IRS‐1 serine phosphorylation. These data suggest that baseline hyperphosphorylation of at least two key serines within muscle IRS‐1 diminishes the transmission of the insulin signal and thereby decreases the insulin‐stimulated translocation of GLUT4. Excess fasting phosphorylation of muscle IRS‐1 at Ser636 may be a major cause of the insulin resistance seen in obesity and might prevent improvement in insulin responsiveness when exercise training is not accompanied by weight loss. PMID:25472611

  1. Acute regulation by insulin of phosphatidylinositol-3-kinase, Rad, Glut 4, and lipoprotein lipase mRNA levels in human muscle.

    PubMed

    Laville, M; Auboeuf, D; Khalfallah, Y; Vega, N; Riou, J P; Vidal, H

    1996-07-01

    We have investigated the acute regulation by insulin of the mRNA levels of nine genes involved in insulin action, in muscle biopsies obtained before and at the end of a 3-h euglycemic hyperinsulinemic clamp. Using reverse transcription-competitive PCR, we have measured the mRNAs encoding the two insulin receptor variants, the insulin receptor substrate-1, the p85alpha subunit of phosphatidylinositol-3-kinase, Ras associated to diabetes (Rad), the glucose transporter Glut 4, glycogen synthase, 6-phosphofructo-l-kinase, lipoprotein lipase, and the hormone-sensitive lipase. Insulin infusion induced a significant increase in the mRNA level of Glut 4 (+56 +/- 13%), Rad (+96 +/- 25%), the p85alpha subunit of phosphatidylinositol-3-kinase (+92 +/- 18%) and a decrease in the lipoprotein lipase mRNA level (-49 +/- 5%), while the abundance of the other mRNAs was unaffected. The relative expression of the two insulin receptor variants was not modified. These results demonstrate an acute coordinated regulation by insulin of the expression of genes coding key proteins involved in its action in human skeletal muscle and suggest that Rad and the p85alpha regulatory subunit of phosphatidylinositol-3-kinase can be added to the list of the genes controlled by insulin. PMID:8690802

  2. Diabetes and Insulin

    MedlinePlus

    ... years, but may eventually need insulin to maintain glucose control. What are the different types of insulin? Different ... glulisine • Short-acting: regular human insulin Basal insulin. Controls blood glucose levels between meals and throughout the night. This ...

  3. Insulin-like growth factor binding protein-5 (IGFBP-5) interacts with thrombospondin-1 to induce negative regulatory effects on IGF-I actions.

    PubMed

    Moralez, Anna M; Maile, Laura A; Clarke, Jane; Busby, Walker H; Clemmons, David R

    2005-05-01

    Insulin-like growth factor binding protein-5 (IGFBP-5) and thrombospondin-1 (TS-1) are both present in extracellular matrix (ECM). Both proteins have been shown to bind to one another with high affinity. The purpose of these studies was to determine how the interaction between IGFBP-5 and TS-1 modulates IGF-I actions in porcine aortic smooth muscle cells (pSMC) in culture. The addition of increasing concentrations of TS-1 to pSMC cultures enhanced the protein synthesis and cell migration responses to IGF-I; whereas the addition of IGFBP-5 alone resulted in minimal changes. In contrast, the addition of IGFBP-5 to cultures that were also exposed to IGF-I and TS-1 resulted in inhibition of protein synthesis. When the cell migration response was assessed, the response to IGF-I plus TS-1 was also significantly inhibited by the addition of IGFBP-5, whereas 1.0 microg/ml of IGFBP-5 alone had no effect on the response to IGF-I. To determine the molecular mechanism by which this inhibition occurred, a mutant form of IGFBP-5 that does not bind to IGF-I was tested. This mutant was equipotent compared to native IGFBP-5 in its ability to inhibit both protein synthesis and cell migration responses to IGF-I plus TS-1 thus excluding the possibility that IGFBP-5 was inhibiting the response to TS-1 and IGF-I by inhibiting IGF-I binding to the IGF-I receptor. To determine if an interaction between TS-1 and IGFBP-5 was the primary determinant of the inhibitory effect of IGFBP-5, an IGFBP-5 mutant that bound poorly to TS-1 was utilized. The addition of 1.0 microg/ml of this mutant did not inhibit the protein synthesis or cell migration responses to IGF-I plus TS-1. To determine the mechanism by which IGFBP-5 binding to TS-1 inhibited cellular responses to TS-1 plus IGF-I, TS-1 binding to integrin associated protein (IAP) was assessed. The addition of IGFBP-5 (1.0 microg/ml) inhibited TS-1-IAP association. In contrast, a mutant form of IGFBP-5 that bound poorly to TS-1 had a minimal

  4. Insulin therapies: Current and future trends at dawn.

    PubMed

    Yaturu, Subhashini

    2013-02-15

    Insulin is a key player in the control of hyperglycemia for type 1 diabetes patients and selective individuals in patients of type 2 diabetes. Insulin delivery systems that are currently available for the administration of insulin include insulin syringes, insulin infusion pumps, jet injectors and pens. The traditional and most predictable method for the administration of insulin is by subcutaneous injections. The major drawback of current forms of insulin therapy is their invasive nature. To decrease the suffering, the use of supersonic injectors, infusion pumps, sharp needles and pens has been adopted. Such invasive and intensive techniques have spurred the search for alternative, more acceptable methods for administering insulin. Several non-invasive approaches for insulin delivery are being pursued. The newer methods explored include the artificial pancreas with closed-loop system, transdermal insulin, and buccal, oral and pulmonary routes. This review focuses on the new concepts that are being explored for use in future. PMID:23493823

  5. Insulin therapies: Current and future trends at dawn

    PubMed Central

    Yaturu, Subhashini

    2013-01-01

    Insulin is a key player in the control of hyperglycemia for type 1 diabetes patients and selective individuals in patients of type 2 diabetes. Insulin delivery systems that are currently available for the administration of insulin include insulin syringes, insulin infusion pumps, jet injectors and pens. The traditional and most predictable method for the administration of insulin is by subcutaneous injections. The major drawback of current forms of insulin therapy is their invasive nature. To decrease the suffering, the use of supersonic injectors, infusion pumps, sharp needles and pens has been adopted. Such invasive and intensive techniques have spurred the search for alternative, more acceptable methods for administering insulin. Several non-invasive approaches for insulin delivery are being pursued. The newer methods explored include the artificial pancreas with closed-loop system, transdermal insulin, and buccal, oral and pulmonary routes. This review focuses on the new concepts that are being explored for use in future. PMID:23493823

  6. New Insulin Delivery Recommendations.

    PubMed

    Frid, Anders H; Kreugel, Gillian; Grassi, Giorgio; Halimi, Serge; Hicks, Debbie; Hirsch, Laurence J; Smith, Mike J; Wellhoener, Regine; Bode, Bruce W; Hirsch, Irl B; Kalra, Sanjay; Ji, Linong; Strauss, Kenneth W

    2016-09-01

    Many primary care professionals manage injection or infusion therapies in patients with diabetes. Few published guidelines have been available to help such professionals and their patients manage these therapies. Herein, we present new, practical, and comprehensive recommendations for diabetes injections and infusions. These recommendations were informed by a large international survey of current practice and were written and vetted by 183 diabetes experts from 54 countries at the Forum for Injection Technique and Therapy: Expert Recommendations (FITTER) workshop held in Rome, Italy, in 2015. Recommendations are organized around the themes of anatomy, physiology, pathology, psychology, and technology. Key among the recommendations are that the shortest needles (currently the 4-mm pen and 6-mm syringe needles) are safe, effective, and less painful and should be the first-line choice in all patient categories; intramuscular injections should be avoided, especially with long-acting insulins, because severe hypoglycemia may result; lipohypertrophy is a frequent complication of therapy that distorts insulin absorption, and, therefore, injections and infusions should not be given into these lesions and correct site rotation will help prevent them; effective long-term therapy with insulin is critically dependent on addressing psychological hurdles upstream, even before insulin has been started; inappropriate disposal of used sharps poses a risk of infection with blood-borne pathogens; and mitigation is possible with proper training, effective disposal strategies, and the use of safety devices. Adherence to these new recommendations should lead to more effective therapies, improved outcomes, and lower costs for patients with diabetes. PMID:27594187

  7. Modulation of the cytoplasmic functions of mammalian post-transcriptional regulatory proteins by methylation and acetylation: a key layer of regulation waiting to be uncovered?

    PubMed

    Blee, Tajekesa K P; Gray, Nicola K; Brook, Matthew

    2015-12-01

    Post-transcriptional control of gene expression is critical for normal cellular function and viability and many of the proteins that mediate post-transcriptional control are themselves subject to regulation by post-translational modification (PTM), e.g. phosphorylation. However, proteome-wide studies are revealing new complexities in the PTM status of mammalian proteins, in particular large numbers of novel methylated and acetylated residues are being identified. Here we review studied examples of methylation/acetylation-dependent regulation of post-transcriptional regulatory protein (PTRP) function and present collated PTM data that points to the huge potential for regulation of mRNA fate by these PTMs. PMID:26614674

  8. A novel regulation of IRS1 (insulin receptor substrate-1) expression following short term insulin administration

    PubMed Central

    2005-01-01

    Reduced insulin-mediated glucose transport in skeletal muscle is a hallmark of the pathophysiology of T2DM (Type II diabetes mellitus). Impaired intracellular insulin signalling is implicated as a key underlying mechanism. Attention has focused on early signalling events such as defective tyrosine phosphorylation of IRS1 (insulin receptor substrate-1), a major target for the insulin receptor tyrosine kinase. This is required for normal induction of signalling pathways key to many of the metabolic actions of insulin. Conversely, increased serine/threonine phosphorylation of IRS1 following prolonged insulin exposure (or in obesity) reduces signalling capacity, partly by stimulating IRS1 degradation. We now show that IRS1 levels in human muscle are actually increased 3-fold following 1 h of hyperinsulinaemic euglycaemia. Similarly, transient induction of IRS1 (3-fold) in the liver or muscle of rodents occurs following feeding or insulin injection respectively. The induction by insulin is also observed in cell culture systems, although to a lesser degree, and is not due to reduced proteasomal targeting, increased protein synthesis or gene transcription. Elucidation of the mechanism by which insulin promotes IRS1 stability will permit characterization of the importance of this novel signalling event in insulin regulation of liver and muscle function. Impairment of this process would reduce IRS1 signalling capacity, thereby contributing to the development of hyperinsulinaemia/insulin resistance prior to the appearance of T2DM. PMID:16128672

  9. Determination of a Comprehensive Alternative Splicing Regulatory Network and Combinatorial Regulation by Key Factors during the Epithelial-to-Mesenchymal Transition.

    PubMed

    Yang, Yueqin; Park, Juw Won; Bebee, Thomas W; Warzecha, Claude C; Guo, Yang; Shang, Xuequn; Xing, Yi; Carstens, Russ P

    2016-06-01

    The epithelial-to-mesenchymal transition (EMT) is an essential biological process during embryonic development that is also implicated in cancer metastasis. While the transcriptional regulation of EMT has been well studied, the role of alternative splicing (AS) regulation in EMT remains relatively uncharacterized. We previously showed that the epithelial cell-type-specific proteins epithelial splicing regulatory proteins 1 (ESRP1) and ESRP2 are important for the regulation of many AS events that are altered during EMT. However, the contributions of the ESRPs and other splicing regulators to the AS regulatory network in EMT require further investigation. Here, we used a robust in vitro EMT model to comprehensively characterize splicing switches during EMT in a temporal manner. These investigations revealed that the ESRPs are the major regulators of some but not all AS events during EMT. We determined that the splicing factor RBM47 is downregulated during EMT and also regulates numerous transcripts that switch splicing during EMT. We also determined that Quaking (QKI) broadly promotes mesenchymal splicing patterns. Our study highlights the broad role of posttranscriptional regulation during the EMT and the important role of combinatorial regulation by different splicing factors to fine tune gene expression programs during these physiological and developmental transitions. PMID:27044866

  10. Antigen Receptor-Intrinsic Non-Self: The Key to Understanding Regulatory Lymphocyte-Mediated Idiotypic Control of Adaptive Immune Responses.

    PubMed

    Lemke, Hilmar

    2016-01-01

    The clone-specific or idiotypic characters of B as well as T cell antigen receptors (BCRs/TCRs) are associated with (1) the third-complementarity-determining regions (CDR3s) that are created during V(D)J recombination (they scarcely occur in antibody light chains) and (2) BCR idiotopes created by somatic hypermutations (SHMs) during immune responses. Therefore, BCR/TCR idiotypic sites are antigen receptor-intrinsic Non-Self (AgR-iNS) portions that fulfill two tasks: serving as a crucial component of the epitope-binding paratope and serving as target sites for anti-idiotypic BCR/TCR paratopes of other anti-Non-Self clones that are contained in both normal repertoires. The antigen-induced immune response is thus directed not only toward the environmental stimulus but also against the AgR-iNS portions of the directly and further activated clones that form a subsiding idiotypic cascade. These idiotypic chain reactions form a completely integrated idiotypic control circuit among B and T cells which contains all regulatory T and B cells. However, this circuit cannot be viewed as a network of fixed interacting nodes but rather uses the genetic Self as reference. Hence, AgR-iNS offers a mechanistic understanding of regulatory lymphocyte-mediated idiotypic control of adaptive immune responses and reconciles clonal selection and idiotypic network theories hitherto believed to be incompatible. PMID:27480901

  11. [Insulin receptor defect as a cause of Rabson-Mendenhall syndrome and other rare genetic insulin resistance syndromes].

    PubMed

    Rojek, Aleksandra; Niedziela, Marek

    2010-01-01

    Insulin plays a very important role in maintaining homeostasis of the whole organism. It regulates glucose metabolism, glycogen synthesis, lipid and protein metabolism. Insulin receptors are present in virtually all cells, which is reflected by the diversity of regulatory processes in which this hormone is involved. Any dysfunction of insulin signalling pathway as a result of insulin receptor gene mutations is linked with various forms of insulin resistance, including insulin resistance type A, Donohue or Rabson-Mendenhall syndrome, which differ in the level of severity. Molecular analysis of insulin receptor gene may lead to a better understanding of molecular mechanisms underlying various types of insulin resistance and help to develop a more efficient treatment. They may also be used as a powerful tool in prenatal diagnostics as well as in pregnancy planning. PMID:21092701

  12. Alteration of local adipose tissue trace element homeostasis as a possible mechanism of obesity-related insulin resistance.

    PubMed

    Tinkov, Alexey A; Sinitskii, Anton I; Popova, Elizaveta V; Nemereshina, Olga N; Gatiatulina, Evgenia R; Skalnaya, Margarita G; Skalny, Anatoly V; Nikonorov, Alexandr A

    2015-09-01

    The mechanisms of association between obesity and the related metabolic disturbances in general and insulin resistance in particular are extensively studied. Taking into account a key role of adipose tissue insulin resistance in the development of systemic obesity-related insulin resistance, the estimation of mechanisms linking increased adiposity and impaired insulin signaling in adipocytes will allow to develop novel prophylactic and therapeutic approaches to treatment of these states. A number of trace elements like chromium, zinc, and vanadium have been shown to take part in insulin signaling via various mechanisms. Taking into account a key role of adipocyte in systemic carbohydrate homeostasis it can be asked if trace element homeostasis in adipose tissue may influence regulatory mechanisms of glucose metabolism. We hypothesize that caloric excess through currently unknown mechanisms results in decreased chromium, vanadium, and zinc content in adipocytes. Decreased content of trace elements in the adipose tissue causes impairment of intra-adipocyte insulin signaling subsequently leading to adipose tissue insulin resistance. The latter significantly contributes to systemic insulin resistance and further metabolic disruption in obesity. It is also possible that decreased adipose tissue trace element content is associated with dysregulation of insulin-sensitizing and proinflammatory adipokines also leading to insulin resistance. We hypothesize that insulin resistance and adipokine dysbalance increase the severity of obesity subsequently aggravating alteration of adipose tissue trace element balance. Single indications of high relative adipose tissue trace element content, decreased Cr, V, and Zn content in obese adipose tissue, and tight association between fat tissue chromium, vanadium, and zinc levels and metabolic parameters in obesity may be useful for hypothesis validation. If our hypothesis will be confirmed by later studies, adipose tissue chromium

  13. A new paradigm in ulcerative colitis: regulatory T cells are key factor which induces/exacerbates UC through an immune imbalance.

    PubMed

    Hanai, Hiroyuki; Iida, Takayuki; Ikeya, Kentaro; Abe, Jinrou; Maruyama, Yasuhiko; Shimura, Teruyuki; Sugimoto, Ken; Watanabe, Fumitoshi

    2013-06-01

    Leukocytapheresis (LCAP) appears to remove or inactivate inflammatory cells and to reset immunological responses, resulting to cure responders of ulcerative colitis (UC). The changes of T cell subsets were investigated in UC patients treated with LCAP. Levels of T cell subsets in peripheral blood before and after LCAP were analysed by flow cytometric analysis. Of 20 UC patients, 13 (65%) achieved remission and 2 (10%) showed the improvement of UC symptoms. Ratios of some T cell subtypes such as regulatory T (Treg) cells and memory T cells to CD4(+) T cells changed significantly only in responders. Especially, ratio of resting Treg/CD4(+) T cells was significantly increased after the first LCAP session, and then one of activated Treg/CD4(+) T cells was increased after 2 week. This may lead to the development of a new UC paradigm in which an imbalance in Treg cell subsets triggers the onset and/or exacerbation of UC. PMID:23280396

  14. Technosphere insulin: an inhaled prandial insulin product.

    PubMed

    Neumiller, Joshua J; Campbell, R Keith

    2010-06-01

    Given the important role of insulin in the treatment of diabetes mellitus and in light of common barriers to insulin use, new strategies for insulin delivery by routes other than intravenous and subcutaneous injection have been investigated since the discovery of insulin in the 1920s. Most companies researching and developing pulmonary administration systems for the use of insulin announced the termination of product development following the failure of the first US FDA-approved inhaled insulin product, Exubera. One company in particular continued their pursuit of a useful inhaled insulin product. MannKind Corporation has developed a powder formulation of insulin that allows for a high percentage of the administered insulin to be absorbed via the lung. Their product, AFREZZA (Technosphere insulin), is currently under review by the FDA for use in patients with diabetes. Technosphere insulin appears to overcome some of the barriers that contributed to the market withdrawal of Exubera by the manufacturer. Studies with Technosphere insulin have shown it to be a unique insulin formulation in that it is very rapid acting, has a relatively short duration of action, and is efficacious in terms of improved glycemic control without contributing to increased weight gain or the incidence of hypoglycemia when compared with other prandial insulin products. Additionally, Technosphere insulin has demonstrated a favorable safety and tolerability profile in clinical studies to date. PMID:20462282

  15. The biosimilar insulin landscape: current developments.

    PubMed

    Lavalle-González, Fernando J; Khatami, Hootan

    2014-10-01

    Biosimilar insulins have the potential to increase access to treatment among patients with diabetes mellitus, reduce treatment costs, and expand market competition. The patents for several insulins are soon to expire, meaning there is room for copies of these products--or 'biosimilars'--to join the marketplace. It is vital that similar safety and efficacy to the innovator product is demonstrated for biosimilars. This presents many possible manufacturing and regulatory challenges. Complex manufacturing processes mean that even small differences between manufacturers can have a potential impact on the final product. Several companies are currently developing biosimilar insulins or are already producing these products in emerging markets with different regulatory requirements. For insulin biosimilars to be licensed in more established markets, manufacturers will need to meet the rigid criteria set out by agencies such as the European Medicines Agency and US Food and Drug Administration, and fulfill several pre-clinical, clinical, and pharmacovigilance surveillance criteria. As a result of differing regulatory requirements, there are possible gaps in the publically available clinical data to support the safety and efficacy of biosimilar insulins from around the world current as of July 2014. This review summarizes the current biosimilar insulin landscape. PMID:25414937

  16. Effects of estradiol and genistein on the insulin signaling pathway in the cerebral cortex of aged female rats.

    PubMed

    Morán, Javier; Garrido, Pablo; Cabello, Estefanía; Alonso, Ana; González, Celestino

    2014-10-01

    Menopause leads to a decrease in estrogen production that increases central insulin resistance, contributing to the development of neurodegenerative diseases. We have evaluated the influence of aging and estradiol or genistein treatments on some key stages of the insulin signaling pathway in the cerebral cortex. Young and aged female Wistar rats were ovariectomized and treated acutely with 17β-estradiol (1.4μg/kg body weight), two doses of genistein (10 or 40mg/kg body weight), or vehicle. The cortical expression of several key insulin signaling pathway components was analyzed by western blotting. Our results showed an age-related deterioration in the interactions between the regulatory subunit of phosphatidylinositol 3-kinase (p85α) and the activated form of insulin receptor substrate 1 (p-IRS1tyr612), as well as between p85α and the 46kDa isoform of the estrogen receptor α (ERα46). Moreover, aging also decreased the translocation of glucose transporter-4 (GLUT4) to the plasma membrane. 17β-Estradiol but not genistein reduced the negative impact of aging on central insulin sensitivity by favoring this GLUT4 translocation, and therefore could be neuroprotective against the associated neurodegenerative diseases. However, protein kinase B (Akt) activation by genistein suggests that other possible mechanisms are involved in the neuroprotective effects of this phytoestrogen during the aging process. PMID:25086228

  17. [Insulin resistance - its causes and therapy possibilities].

    PubMed

    Pelikánová, Terezie

    2014-09-01

    Insulin resistance (IR) is defined as a condition where normal plasma free insuconcentrations induce a reduced response of the body. In the narrower sense we understand IR as the impairment of insulin action in the target structure which may arise at any level of the insulin signalling cascade. In the clinical conditions we usually define it as the impairment of insulin action in glucose metabolism, although it is true that the impairment may concern different effects of insulin and different cell structures. The characteristic feature of IR linked to the metabolic syndrome or Type 2 diabetes is defective signalling which affects PI3-kinase branch of insulin signalling cascade. Other insulin actions depending on the signalling through the Ras complex and MAP-kinase, may not be affected. Due to compensatory hyperinsulinemia they may be even increased. The article summarizes some recent findings regarding the structure and regulation of insulin signalling cascade and analyses selected primary and secondary causes of IR which include genetic and epigenetic factors, the microRNA regulation role, metabolic, humoral and immunological factors. The detailed knowledge of the causes of IR opens possibilities of its rational treatment. This is currently based on the treatment of curable causes of IR, i.e. consistent compensation of diabetes, weight reduction, regimen arrangements (diet, physical activity), re-assessment of the need to use corticosteroids in therapy, treatment of coexisting conditions and possibly administration of metformin or pioglitazone.Key words: cytokines - insulin resistance - insulin signalling cascade. PMID:25294764

  18. Steatosis and insulin resistance in hepatitis C: a way out for the virus?

    PubMed

    Del Campo, José A; Romero-Gómez, Manuel

    2009-10-28

    The hepatitis C virus (HCV) induces lipid accumulation in vitro and in vivo. The pathogenesis of steatosis is due to both viral and host factors. Viral steatosis is mostly reported in patients with genotype 3a, whereas metabolic steatosis is often associated with genotype 1 and metabolic syndrome. Several molecular mechanisms responsible for steatosis have been associated with the HCV core protein, which is able to induce gene expression and activity of sterol regulatory element binding protein 1 (SREBP1) and peroxisome proliferator-activated receptor gamma (PPARgamma), increasing the transcription of genes involved in hepatic fatty acid synthesis. Steatosis has been also implicated in viral replication. In infected cells, HCV core protein is targeted to lipid droplets which serve as intracellular storage organelles. These studies have shown that lipid droplets are essential for virus assembly. Thus, HCV promotes steatosis as an efficient mechanism for stable viral replication. Chronic HCV infection can also induce insulin resistance. In patients with HCV, insulin resistance is more strongly associated with viral load than visceral obesity. HCV seems to lead to insulin resistance through interference of intracellular insulin signalling by HCV proteins, mainly, the serine phosphorylation of insulin receptor-1 (IRS-1) and impairment of the downstream Akt signalling pathway. The HCV core protein interferes with in vitro insulin signalling by genotype-specific mechanisms, where the role of suppressor of cytokine signal 7 (SOCS-7) in genotype 3a and mammalian target of rapamycin (mTOR) in genotype 1 in IRS-1 downregulation play key roles. Steatosis and insulin resistance have been associated with fibrosis progression and a reduced rate of sustained response to peginterferon plus ribavirin. PMID:19859993

  19. Structural Analysis of the Regulatory Domain of ExsA, a Key Transcriptional Regulator of the Type Three Secretion System in Pseudomonas aeruginosa

    SciTech Connect

    Shrestha, Manisha; Xiao, Yi; Robinson, Howard; Schubot, Florian D.

    2015-08-28

    Pseudomonas aeruginosa employs a type three secretion system to facilitate infections in mammalian hosts. The operons encoding genes of structural components of the secretion machinery and associated virulence factors are all under the control of the AraC-type transcriptional activator protein, ExsA. ExsA belongs to a unique subfamily of AraC-proteins that is regulated through protein-protein contacts rather than small molecule ligands. Prior to infection, ExsA is inhibited through a direct interaction with the anti-activator ExsD. To activate ExsA upon host cell contact this interaction is disrupted by the anti-antiactivator protein ExsC. Here we report the crystal structure of the regulatory domain of ExsA, which is known to mediate ExsA dimerization as well as ExsD binding. The crystal structure suggests two models for the ExsA dimer. Both models confirmed the previously shown involvement of helix α-3 in ExsA dimerization but one also suggest a role for helix α-2. These structural data are supported by the observation that a mutation in α-2 greatly diminished the ability of ExsA to activate transcription in vitro. Lastly, additional in vitro transcription studies revealed that a conserved pocket, used by AraC and the related ToxT protein for the binding of small molecule regulators, although present in ExsA is not involved in binding of ExsD.

  20. Structural Analysis of the Regulatory Domain of ExsA, a Key Transcriptional Regulator of the Type Three Secretion System in Pseudomonas aeruginosa

    PubMed Central

    Shrestha, Manisha; Xiao, Yi; Robinson, Howard; Schubot, Florian D.

    2015-01-01

    Pseudomonas aeruginosa employs a type three secretion system to facilitate infections in mammalian hosts. The operons encoding genes of structural components of the secretion machinery and associated virulence factors are all under the control of the AraC-type transcriptional activator protein, ExsA. ExsA belongs to a unique subfamily of AraC-proteins that is regulated through protein-protein contacts rather than small molecule ligands. Prior to infection, ExsA is inhibited through a direct interaction with the anti-activator ExsD. To activate ExsA upon host cell contact this interaction is disrupted by the anti-antiactivator protein ExsC. Here we report the crystal structure of the regulatory domain of ExsA, which is known to mediate ExsA dimerization as well as ExsD binding. The crystal structure suggests two models for the ExsA dimer. Both models confirmed the previously shown involvement of helix α-3 in ExsA dimerization but one also suggest a role for helix α-2. These structural data are supported by the observation that a mutation in α-2 greatly diminished the ability of ExsA to activate transcription in vitro. Additional in vitro transcription studies revealed that a conserved pocket, used by AraC and the related ToxT protein for the binding of small molecule regulators, although present in ExsA is not involved in binding of ExsD. PMID:26317977

  1. Insulin Human Inhalation

    MedlinePlus

    Insulin inhalation is used in combination with a long-acting insulin to treat type 1 diabetes (condition in which the body does not produce insulin and therefore cannot control the amount of sugar ...

  2. Giving an insulin injection

    MedlinePlus

    ... One Type of Insulin Wash your hands with soap and water. Dry them well. Check the insulin ... syringe before injecting it. Wash your hands with soap and water. Dry them well. Check the insulin ...

  3. Insulin Lispro Injection

    MedlinePlus

    ... is a short-acting, man-made version of human insulin. Insulin lispro works by replacing the insulin ... niacin (Niacor, Niaspan, in Advicor); certain medications for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) ...

  4. Structural Analysis of the Regulatory Domain of ExsA, a Key Transcriptional Regulator of the Type Three Secretion System in Pseudomonas aeruginosa

    DOE PAGESBeta

    Shrestha, Manisha; Xiao, Yi; Robinson, Howard; Schubot, Florian D.

    2015-08-28

    Pseudomonas aeruginosa employs a type three secretion system to facilitate infections in mammalian hosts. The operons encoding genes of structural components of the secretion machinery and associated virulence factors are all under the control of the AraC-type transcriptional activator protein, ExsA. ExsA belongs to a unique subfamily of AraC-proteins that is regulated through protein-protein contacts rather than small molecule ligands. Prior to infection, ExsA is inhibited through a direct interaction with the anti-activator ExsD. To activate ExsA upon host cell contact this interaction is disrupted by the anti-antiactivator protein ExsC. Here we report the crystal structure of the regulatory domainmore » of ExsA, which is known to mediate ExsA dimerization as well as ExsD binding. The crystal structure suggests two models for the ExsA dimer. Both models confirmed the previously shown involvement of helix α-3 in ExsA dimerization but one also suggest a role for helix α-2. These structural data are supported by the observation that a mutation in α-2 greatly diminished the ability of ExsA to activate transcription in vitro. Lastly, additional in vitro transcription studies revealed that a conserved pocket, used by AraC and the related ToxT protein for the binding of small molecule regulators, although present in ExsA is not involved in binding of ExsD.« less

  5. Hepatitis B virus nuclear export elements: RNA stem-loop α and β, key parts of the HBV post-transcriptional regulatory element.

    PubMed

    Lim, Chun Shen; Brown, Chris M

    2016-09-01

    Many viruses contain RNA elements that modulate splicing and/or promote nuclear export of their RNAs. The RNAs of the major human pathogen, hepatitis B virus (HBV) contain a large (~600 bases) composite cis-acting 'post-transcriptional regulatory element' (PRE). This element promotes expression from these naturally intronless transcripts. Indeed, the related woodchuck hepadnavirus PRE (WPRE) is used to enhance expression in gene therapy and other expression vectors. These PRE are likely to act through a combination of mechanisms, including promotion of RNA nuclear export. Functional components of both the HBV PRE and WPRE are 2 conserved RNA cis-acting stem-loop (SL) structures, SLα and SLβ. They are within the coding regions of polymerase (P) gene, and both P and X genes, respectively. Based on previous studies using mutagenesis and/or nuclear magnetic resonance (NMR), here we propose 2 covariance models for SLα and SLβ. The model for the 30-nucleotide SLα contains a G-bulge and a CNGG(U) apical loop of which the first and the fourth loop residues form a CG pair and the fifth loop residue is bulged out, as observed in the NMR structure. The model for the 23-nucleotide SLβ contains a 7-base-pair stem and a 9-nucleotide loop. Comparison of the models with other RNA structural elements, as well as similarity searches of human transcriptome and viral genomes demonstrate that SLα and SLβ are specific to HBV transcripts. However, they are well conserved among the hepadnaviruses of non-human primates, the woodchuck and ground squirrel. PMID:27031749

  6. Clinical utility of insulin and insulin analogs

    PubMed Central

    Sanlioglu, Ahter D.; Altunbas, Hasan Ali; Balci, Mustafa Kemal; Griffith, Thomas S.; Sanlioglu, Salih

    2013-01-01

    Diabetes is a pandemic disease characterized by autoimmune, genetic and metabolic abnormalities. While insulin deficiency manifested as hyperglycemia is a common sequel of both Type-1 and Type-2 diabetes (T1DM and T2DM), it does not result from a single genetic defect—rather insulin deficiency results from the functional loss of pancreatic β cells due to multifactorial mechanisms. Since pancreatic β cells of patients with T1DM are destroyed by autoimmune reaction, these patients require daily insulin injections. Insulin resistance followed by β cell dysfunction and β cell loss is the characteristics of T2DM. Therefore, most patients with T2DM will require insulin treatment due to eventual loss of insulin secretion. Despite the evidence of early insulin treatment lowering macrovascular (coronary artery disease, peripheral arterial disease and stroke) and microvascular (diabetic nephropathy, neuropathy and retinopathy) complications of T2DM, controversy exists among physicians on how to initiate and intensify insulin therapy. The slow acting nature of regular human insulin makes its use ineffective in counteracting postprandial hyperglycemia. Instead, recombinant insulin analogs have been generated with a variable degree of specificity and action. Due to the metabolic variability among individuals, optimum blood glucose management is a formidable task to accomplish despite the presence of novel insulin analogs. In this article, we present a recent update on insulin analog structure and function with an overview of the evidence on the various insulin regimens clinically used to treat diabetes. PMID:23584214

  7. Concentrated insulins: the new basal insulins

    PubMed Central

    Lamos, Elizabeth M; Younk, Lisa M; Davis, Stephen N

    2016-01-01

    Introduction Insulin therapy plays a critical role in the treatment of type 1 and type 2 diabetes mellitus. However, there is still a need to find basal insulins with 24-hour coverage and reduced risk of hypoglycemia. Additionally, with increasing obesity and insulin resistance, the ability to provide clinically necessary high doses of insulin at low volume is also needed. Areas covered This review highlights the published reports of the pharmacokinetic (PK) and glucodynamic properties of concentrated insulins: Humulin-R U500, insulin degludec U200, and insulin glargine U300, describes the clinical efficacy, risk of hypoglycemic, and metabolic changes observed, and finally, discusses observations about the complexity of introducing a new generation of concentrated insulins to the therapeutic market. Conclusion Humulin-R U500 has a similar onset but longer duration of action compared with U100 regular insulin. Insulin glargine U300 has differential PK/pharmacodynamic effects when compared with insulin glargine U100. In noninferiority studies, glycemic control with degludec U200 and glargine U300 is similar to insulin glargine U100 and nocturnal hypoglycemia is reduced. Concentrated formulations appear to behave as separate molecular entities when compared with earlier U100 insulin analog compounds. In the review of available published data, newer concentrated basal insulins may offer an advantage in terms of reduced intraindividual variability as well as reducing the injection burden in individuals requiring high-dose and large volume insulin therapy. Understanding the PK and pharmacodynamic properties of this new generation of insulins is critical to safe dosing, dispensing, and administration. PMID:27022271

  8. A large-scale, in vivo transcription factor screen defines bivalent chromatin as a key property of regulatory factors mediating Drosophila wing development

    PubMed Central

    Schertel, Claus; Albarca, Monica; Rockel-Bauer, Claudia; Kelley, Nicholas W.; Bischof, Johannes; Hens, Korneel

    2015-01-01

    Transcription factors (TFs) are key regulators of cell fate. The estimated 755 genes that encode DNA binding domain-containing proteins comprise ∼5% of all Drosophila genes. However, the majority has remained uncharacterized so far due to the lack of proper genetic tools. We generated 594 site-directed transgenic Drosophila lines that contain integrations of individual UAS-TF constructs to facilitate spatiotemporally controlled misexpression in vivo. All transgenes were expressed in the developing wing, and two-thirds induced specific phenotypic defects. In vivo knockdown of the same genes yielded a phenotype for 50%, with both methods indicating a great potential for misexpression to characterize novel functions in wing growth, patterning, and development. Thus, our UAS-TF library provides an important addition to the genetic toolbox of Drosophila research, enabling the identification of several novel wing development-related TFs. In parallel, we established the chromatin landscape of wing imaginal discs by ChIP-seq analyses of five chromatin marks and RNA Pol II. Subsequent clustering revealed six distinct chromatin states, with two clusters showing enrichment for both active and repressive marks. TFs that carry such “bivalent” chromatin are highly enriched for causing misexpression phenotypes in the wing, and analysis of existing expression data shows that these TFs tend to be differentially expressed across the wing disc. Thus, bivalently marked chromatin can be used as a marker for spatially regulated TFs that are functionally relevant in a developing tissue. PMID:25568052

  9. Insulin Granule Biogenesis, Trafficking and Exocytosis

    PubMed Central

    Hou, June Chunqiu; Min, Le; Pessin, Jeffrey E.

    2015-01-01

    increased production of ATP, closure of the ATP-sensitive potassium channel and cellular depolarization. In turn, this opens voltage-dependent calcium channels allowing increased influx of extracellular calcium. Calcium is thought to bind to members of the fusion regulatory proteins synaptogamin that functionally repressors the fusion inhibitory protein complexin. Both complexin and synaptogamin interact as well as several other regulatory proteins interact with the core fusion machinery composed of the Q- or t-SNARE proteins syntaxin 1 and SNAP25 in the plasmamembrane that assembles with the R- or v-SNARE protein VAMP2 in insulin granules. In this chapter we will review the current progress of insulin granule biogenesis, sorting, trafficking, exocytosis and signaling pathways that comprise the molecular basis of glucose-dependent insulin secretion. PMID:19251047

  10. History of gestational diabetes, insulin resistance and coronary risk.

    PubMed

    Davis, C L; Gutt, M; Llabre, M M; Marks, J B; O'Sullivan, M J; Potter, J E; Landel, J L; Kumar, M; Schneiderman, N; Gellman, M; Skyler, J S

    1999-01-01

    The purpose of this study was to examine characteristics associated with the insulin metabolic syndrome, including insulin resistance, abnormal glucose tolerance, dyslipidemia, obesity, and elevated blood pressure, among women who have experienced gestational diabetes. 39 nondiabetic, young (20-42 years), postpartum (3-18 months) white women were recruited from obstetrical clinics. Twenty-one women had a history of gestational diabetes; 18 had uncomplicated pregnancies. Multivariate analyses revealed a significant difference between groups in insulin resistance (M, measured by euglycemic clamp) and insulin levels (from an oral glucose tolerance test), with insulin resistance showing a statistically stronger difference than insulin levels. Groups also differed significantly when compared on a set of variables associated with insulin metabolic syndrome: glucose tolerance, triglycerides, blood pressure, and body-mass index. Using insulin resistance as a covariate eliminated these group differences, suggesting that insulin resistance is the key factor underlying insulin metabolic syndrome. The higher risk of later developing type 2 diabetes and hypertension in women who have a history of gestational diabetes is explicable by their poorer profile on variables associated with insulin metabolic syndrome, and appears to be attributable to insulin resistance. Thus, insulin resistance appears to distinguish young women at risk for cardiovascular disease. PMID:10616862

  11. Islet Neogenesis Associated Protein (INGAP) induces the differentiation of an adult human pancreatic ductal cell line into insulin-expressing cells through stepwise activation of key transcription factors for embryonic beta cell development.

    PubMed

    Assouline-Thomas, Béatrice; Ellis, Daniel; Petropavlovskaia, Maria; Makhlin, Julia; Ding, Jieping; Rosenberg, Lawrence

    2015-01-01

    Regeneration of β-cells in diabetic patients is an important goal of diabetes research. Islet Neogenesis Associated Protein (INGAP) was discovered in the partially duct-obstructed hamster pancreas. Its bioactive fragment, pentadecapeptide 104-118 (INGAP-P), has been shown to reverse diabetes in animal models and to improve glucose homeostasis in patients with diabetes in clinical trials. Further development of INGAP as a therapy for diabetes requires identification of target cells in the pancreas and characterization of the mechanisms of action. We hypothesized that adult human pancreatic ductal cells retain morphogenetic plasticity and can be induced by INGAP to undergo endocrine differentiation. To test this hypothesis, we treated the normal human pancreatic ductal cell line (HPDE) with either INGAP-P or full-length recombinant protein (rINGAP) for short-term periods. Our data show that this single drug treatment induces both proliferation and transdifferentiation of HPDE cells, the latter being characterized by the rapid sequential activation of endocrine developmental transcription factors Pdx-1, Ngn3, NeuroD, IA-1, and MafA and subsequently the expression of insulin at both the mRNA and the protein levels. After 7 days, C-peptide was detected in the supernatant of INGAP-treated cells, reflecting their ability to secrete insulin. The magnitude of differentiation was enhanced by embedding the cells in Matrigel, which led to islet-like cluster formation. The islet-like clusters cells stained positive for nuclear Pdx-1 and Glut 2 proteins, and were expressing Insulin mRNA. These new data suggest that human adult pancreatic ductal cells retain morphogenetic plasticity and demonstrate that a short exposure to INGAP triggers their differentiation into insulin-expressing cells in vitro. In the context of the urgent search for a regenerative and/or cellular therapy for diabetes, these results make INGAP a promising therapeutic candidate. PMID:26558987

  12. A PPARγ-Bnip3 Axis Couples Adipose Mitochondrial Fusion-Fission Balance to Systemic Insulin Sensitivity.

    PubMed

    Tol, Marc J; Ottenhoff, Roelof; van Eijk, Marco; Zelcer, Noam; Aten, Jan; Houten, Sander M; Geerts, Dirk; van Roomen, Cindy; Bierlaagh, Marlou C; Scheij, Saskia; Hoeksema, Marten A; Aerts, Johannes M; Bogan, Jonathan S; Dorn, Gerald W; Argmann, Carmen A; Verhoeven, Arthur J

    2016-09-01

    Aberrant mitochondrial fission plays a pivotal role in the pathogenesis of skeletal muscle insulin resistance. However, fusion-fission dynamics are physiologically regulated by inherent tissue-specific and nutrient-sensitive processes that may have distinct or even opposing effects with respect to insulin sensitivity. Based on a combination of mouse population genetics and functional in vitro assays, we describe here a regulatory circuit in which peroxisome proliferator-activated receptor γ (PPARγ), the adipocyte master regulator and receptor for the thiazolidinedione class of antidiabetic drugs, controls mitochondrial network fragmentation through transcriptional induction of Bnip3. Short hairpin RNA-mediated knockdown of Bnip3 in cultured adipocytes shifts the balance toward mitochondrial elongation, leading to compromised respiratory capacity, heightened fatty acid β-oxidation-associated mitochondrial reactive oxygen species generation, insulin resistance, and reduced triacylglycerol storage. Notably, the selective fission/Drp1 inhibitor Mdivi-1 mimics the effects of Bnip3 knockdown on adipose mitochondrial bioenergetics and glucose disposal. We further show that Bnip3 is reciprocally regulated in white and brown fat depots of diet-induced obesity and leptin-deficient ob/ob mouse models. Finally, Bnip3(-/-) mice trade reduced adiposity for increased liver steatosis and develop aggravated systemic insulin resistance in response to high-fat feeding. Together, our data outline Bnip3 as a key effector of PPARγ-mediated adipose mitochondrial network fragmentation, improving insulin sensitivity and limiting oxidative stress. PMID:27325287

  13. Is insulin signaling molecules misguided in diabetes for ubiquitin-proteasome mediated degradation?

    PubMed

    Balasubramanyam, Muthuswamy; Sampathkumar, Rangasamy; Mohan, Viswanathan

    2005-07-01

    Recent mining of the human and mouse genomes, use of yeast genetics, and detailed analyses of several biochemical pathways, have resulted in the identification of many new roles for ubiquitin-proteasome mediated degradation of proteins. In the context of last year's award of Noble Prize (Chemistry) work, the ubiquitin and ubiquitin-like modifications are increasingly recognized as key regulatory events in health and disease. Although the ATP-dependent ubiquitin-proteasome system has evolved as premier cellular proteolytic machinery, dysregulation of this system by several different mechanisms leads to inappropriate degradation of specific proteins and pathological consequences. While aberrations in the ubiquitin-proteasome pathway have been implicated in certain malignancies and neurodegenerative disorders, recent studies indicate a role for this system in the pathogenesis of diabetes and its complications. Inappropriate degradation of insulin signaling molecules such as insulin receptor substrates (IRS-1 and IRS-2) has been demonstrated in experimental diabetes, mediated in part through the up-regulation of suppressors of cytokine signaling (SOCS). It appears that altered ubiquitin-proteasome system might be one of the molecular mechanisms of insulin resistance in many pathological situations. Drugs that modulate the SOCS action and/or proteasomal degradation of proteins could become novel agents for the treatment of insulin resistance and Type 2 diabetes. PMID:16335791

  14. Insulin receptor alternative splicing is regulated by insulin signaling and modulates beta cell survival

    PubMed Central

    Malakar, Pushkar; Chartarifsky, Lital; Hija, Ayat; Leibowitz, Gil; Glaser, Benjamin; Dor, Yuval; Karni, Rotem

    2016-01-01

    Type 2 Diabetes (T2DM) affects more than 300 million people worldwide. One of the hallmarks of T2DM is peripheral insulin resistance, in part due to unproductive insulin signaling through the insulin receptor. The insulin receptor (INSR) exists as two isoforms, INSR-A and INSR-B, which results from skipping or inclusion of exon 11 respectively. What determines the relative abundance of the different insulin receptor splice variants is unknown. Moreover, it is not yet clear what the physiological roles of each of the isoforms are in normal and diseased beta cells. In this study, we show that insulin induces INSR exon 11 inclusion in pancreatic beta cells in both human and mouse. This occurs through activation of the Ras-MAPK/ERK signaling pathway and up-regulation of the splicing factor SRSF1. Induction of exon 11 skipping by a splice-site competitive antisense oligonucleotide inhibited the MAPK-ERK signaling pathway downstream of the insulin receptor, sensitizing the pancreatic β-cell line MIN6 to stress-induced apoptosis and lipotoxicity. These results assign to insulin a regulatory role in INSR alternative splicing through the Ras-MAPK/ERK signaling pathway. We suggest that in beta cells, INSR-B has a protective role, while INSR-A expression sensitizes beta cells to programmed cell death. PMID:27526875

  15. Insulin pumps.

    PubMed

    Pickup, J

    2011-02-01

    The last year has seen a continued uptake of insulin pump therapy in most countries. The USA is still a leader in pump use, with probably some 40% of type 1 diabetic patients on continuous subcutaneous insulin infusion (CSII), but the large variation in usage within Europe remains, with relatively high use (> 15%) in, for example, Norway, Austria, Germany and Sweden and low use (< 5%) in Spain, the UK, Finland and Portugal. There is much speculation on the factors responsible for this variation, and the possibilities include physician attitudes to CSII and knowledge about its benefits and indications for its use (and inappropriate beliefs about dangers), the availability of reimbursement from insurance companies or funding from national health services, the availability of sufficient diabetes nurse educators and dietitians trained in pump procedures, and clear referral pathways for the pump candidate from general practitioner or general hospital to specialist pump centre. There are now several comprehensive national guidelines on CSII use (see ATTD Yearbook 2009) but more work needs to be done in unifying uptake and ensuring all those who can benefit do so. Technology developments recently include increasing use of pumps with continuous glucose monitoring (CGM) connectivity (see elsewhere in this volume) and the emergence of numerous manufacturers developing so-called 'patch pumps', often for the type 2 diabetes market. Interestingly, the evidence base for CSII in this group is not well established, and for this reason the selected papers on CSII in this section include several in this area. The use of CSII in diabetic pregnancy is a long-established practice, in spite of the lack of evidence that it is superior to multiple daily injections (MDI), and few randomised controlled trials have been done in recent years. Several papers in this field this year continue the debate about the usefulness of CSII in diabetic pregnancy and are reviewed here. It is pleasing

  16. Mice Lacking the p43 Mitochondrial T3 Receptor Become Glucose Intolerant and Insulin Resistant during Aging

    PubMed Central

    Bertrand, Christelle; Blanchet, Emilie; Pessemesse, Laurence; Annicotte, Jean Sébastien; Feillet-Coudray, Christine; Chabi, Béatrice; Levin, Jonathan; Fajas, Lluis; Cabello, Gérard; Wrutniak-Cabello, Chantal; Casas, François

    2013-01-01

    Thyroid hormones (TH) play an important regulatory role in energy expenditure regulation and are key regulators of mitochondrial activity. We have previously identified a mitochondrial triiodothyronine (T3) receptor (p43) which acts as a mitochondrial transcription factor of the organelle genome, which leads in vitro and in vivo, to a stimulation of mitochondrial biogenesis. Recently, we generated mice carrying a specific p43 invalidation. At 2 months of age, we reported that p43 depletion in mice induced a major defect in insulin secretion both in vivo and in isolated pancreatic islets, and a loss of glucose-stimulated insulin secretion. The present study was designed to determine whether p43 invalidation influences life expectancy and modulates blood glucose and insulin levels as well as glucose tolerance or insulin sensitivity during aging. We report that from 4 months old onwards, mice lacking p43 are leaner than wild-type mice. p43−/− mice also have a moderate reduction of life expectancy compared to wild type. We found no difference in blood glucose levels, excepted at 24 months old where p43−/− mice showed a strong hyperglycemia in fasting conditions compared to controls animals. However, the loss of glucose-stimulated insulin secretion was maintained whatever the age of mice lacking p43. If up to 12 months old, glucose tolerance remained unchanged, beyond this age p43−/− mice became increasingly glucose intolerant. In addition, if up to 12 months old p43 deficient animals were more sensitive to insulin, after this age we observed a loss of this capacity, culminating in 24 months old mice with a decreased sensitivity to the hormone. In conclusion, we demonstrated that during aging the depletion of the mitochondrial T3 receptor p43 in mice progressively induced an increased glycemia in the fasted state, glucose intolerance and an insulin-resistance several features of type-2 diabetes. PMID:24098680

  17. Ligand-independent activation of peroxisome proliferator-activated receptor-gamma by insulin and C-peptide in kidney proximal tubular cells: dependent on phosphatidylinositol 3-kinase activity.

    PubMed

    Al-Rasheed, Nawal M; Chana, Ravinder S; Baines, Richard J; Willars, Gary B; Brunskill, Nigel J

    2004-11-26

    Peroxisome proliferator-activated receptor gamma (PPARgamma) has key roles in the regulation of adipogenesis, inflammation, and lipid and glucose metabolism. C-peptide is believed to be inert and without appreciable biological functions. Recent studies suggest that C-peptide possesses multiple functions. The present study investigated the effects of insulin and C-peptide on PPARgamma transcriptional activity in opossum kidney proximal tubular cells. Both insulin and C-peptide induced a concentration-dependent stimulation of PPARgamma transcriptional activity. Both agents substantially augmented thiazolidinedione-stimulated PPARgamma transcriptional activity. Neither insulin nor C-peptide had any effect on the expression levels of PPARgamma. GW9662, a PPARgamma antagonist, blocked PPARgamma activation by thiazolidinediones but had no effect on either insulin- or C-peptide-stimulated PPARgamma transcriptional activity. Co-transfection of opossum kidney cells with dominant negative mitogen-activated protein kinase kinase significantly depressed basal PPARgamma transcriptional activity but had no effect on that induced by either insulin or C-peptide. Both insulin- and C-peptide-stimulated PPARgamma transcriptional activity were attenuated by wortmannin and by expression of a dominant negative phosphatidylinositol (PI) 3-kinase p85 regulatory subunit. In addition PI 3-kinase-dependent phosphorylation of PPARgamma was observed after stimulation by C-peptide or insulin. C-peptide effects but not insulin on PPARgamma transcriptional activity were abolished by pertussis toxin pretreatment. Finally both C-peptide and insulin positively control the expression of the PPARgamma-regulated CD36 scavenger receptor in human THP-1 monocytes. We concluded that insulin and C-peptide can stimulate PPARgamma activity in a ligand-independent fashion and that this effect is mediated by PI 3-kinase. These results support a new and potentially important physiological role for C-peptide in

  18. Human insulin genome sequence map, biochemical structure of insulin for recombinant DNA insulin.

    PubMed

    Chakraborty, Chiranjib; Mungantiwar, Ashish A

    2003-08-01

    Insulin is a essential molecule for type I diabetes that is marketed by very few companies. It is the first molecule, which was made by recombinant technology; but the commercialization process is very difficult. Knowledge about biochemical structure of insulin and human insulin genome sequence map is pivotal to large scale manufacturing of recombinant DNA Insulin. This paper reviews human insulin genome sequence map, the amino acid sequence of porcine insulin, crystal structure of porcine insulin, insulin monomer, aggregation surfaces of insulin, conformational variation in the insulin monomer, insulin X-ray structures for recombinant DNA technology in the synthesis of human insulin in Escherichia coli. PMID:12769691

  19. Use of insulin in diabetes: a century of treatment.

    PubMed

    Shahani, Savita; Shahani, Lokesh

    2015-12-01

    Insulin is a key player in the control of hyperglycaemia for patients with type 1 diabetes mellitus and selected patients with type 2 diabetes mellitus. There have been many advances in insulin drug delivery from its first administration as a crude pancreatic extract till today. The traditional and most predictable method for administration of insulin is by subcutaneous injection. Currently available insulin delivery systems include insulin syringes, infusion pumps, jet injectors, and pens. The major drawback of insulin therapy is its invasive nature. Non-invasive delivery of insulin has long been a major goal for the treatment of diabetes mellitus. Although there have been improvements in insulin therapy since it was first conceived, it is still far from mimicking the physiological secretion of pancreatic β-cells, and research to find new insulin formulations and new routes of administration continues. This article reviews the emerging technologies, including insulin inhalers, insulin buccal spray, insulin pill, islet cell transplant, and stem cell therapy, as treatment options for diabetes mellitus. PMID:26554270

  20. The neuropilin-like protein ESDN regulates insulin signaling and sensitivity.

    PubMed

    Li, Xuan; Jung, Jae-Joon; Nie, Lei; Razavian, Mahmoud; Zhang, Jiasheng; Samuel, Varman; Sadeghi, Mehran M

    2016-05-01

    Insulin effects on cell metabolism, growth, and survival are mediated by its binding to, and activation of, insulin receptor. With increasing prevalence of insulin resistance and diabetes there is considerable interest in identifying novel regulators of insulin signal transduction. The transmembrane protein endothelial and smooth muscle cell-derived neuropilin-like protein (ESDN) is a novel regulator of vascular remodeling and angiogenesis. Here, we investigate a potential role of ESDN in insulin signaling, demonstrating that Esdn gene deletion promotes insulin-induced vascular smooth muscle cell proliferation and migration. This is associated with enhanced protein kinase B and mitogen-activated protein kinase activation as well as insulin receptor phosphorylation. Likewise, insulin signaling in the liver, muscle, and adipose tissue is enhanced in Esdn(-/-) mice, and these animals exhibit improved insulin sensitivity and glucose homeostasis in vivo. The effect of ESDN on insulin signaling is traced back to its interaction with insulin receptor, which alters the receptor interaction with regulatory adaptor protein-E3 ubiquitin ligase pairs, adaptor protein with pleckstrin homology and Src homology 2 domain-c-Cbl and growth factor receptor bound protein 10-neuronal precursor cell-expressed developmentally downregulated 4. In conclusion, our findings establish ESDN as an inhibitor of insulin receptor signal transduction through a novel regulatory mechanism. Loss of ESDN potentiates insulin's metabolic and mitotic effects and provides insights into a novel therapeutic avenue. PMID:26921437

  1. Curcuma longa polyphenols improve insulin-mediated lipid accumulation and attenuate proinflammatory response of 3T3-L1 adipose cells during oxidative stress through regulation of key adipokines and antioxidant enzymes.

    PubMed

    Septembre-Malaterre, Axelle; Le Sage, Fanny; Hatia, Sarah; Catan, Aurélie; Janci, Laurent; Gonthier, Marie-Paule

    2016-07-01

    Plant polyphenols may exert beneficial action against obesity-related oxidative stress and inflammation which promote insulin resistance. This study evaluated the effect of polyphenols extracted from French Curcuma longa on 3T3-L1 adipose cells exposed to H2 O2 -mediated oxidative stress. We found that Curcuma longa extract exhibited high amounts of curcuminoids identified as curcumin, demethoxycurcumin, and bisdemethoxycurcumin, which exerted free radical-scavenging activities. Curcuma longa polyphenols improved insulin-mediated lipid accumulation and upregulated peroxisome proliferator-activated receptor-gamma gene expression and adiponectin secretion which decreased in H2 O2 -treated cells. Curcuminoids attenuated H2 O2 -enhanced production of pro-inflammatory molecules such as interleukin-6, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and nuclear factor κappa B. Moreover, they reduced intracellular levels of reactive oxygen species elevated by H2 O2 and modulated the expression of genes encoding superoxide dismutase and catalase antioxidant enzymes. Collectively, these findings highlight that Curcuma longa polyphenols protect adipose cells against oxidative stress and may improve obesity-related metabolic disorders. © 2016 BioFactors, 42(4):418-430, 2016. PMID:27094023

  2. Misadventures in insulin therapy: are you at risk?

    PubMed Central

    Grissinger, Matthew; Lease, Michael

    2003-01-01

    About dollar 1 out of every dollar 7 spent on health care is related to diabetes mellitus, a leading cause of blindness and kidney failure and a strong risk factor for heart disease. Prevalence of the disease has increased by a third among adults in general in the last decade, but intensive therapy has been shown to delay the onset and slow the progression of diabetes-related complications. While insulin therapy remains key in the management of type 1 diabetes, many patients with type 2, or insulin-resistant, diabetes encounter insulin administration errors that compromise the quality of insulin delivery. Insulin errors are a major, but modifiable, barrier to dosing accuracy and optimal diabetes control for many patients. Future trends to combat the problem include increased use of insulin inhalers and smaller doses of rapid- or short-acting insulin to supplement longer-acting injections. PMID:12653373

  3. Misadventures in insulin therapy: are you at risk?

    PubMed

    Grissinger, Matthew; Lease, Michael

    2003-02-01

    About dollar 1 out of every dollar 7 spent on health care is related to diabetes mellitus, a leading cause of blindness and kidney failure and a strong risk factor for heart disease. Prevalence of the disease has increased by a third among adults in general in the last decade, but intensive therapy has been shown to delay the onset and slow the progression of diabetes-related complications. While insulin therapy remains key in the management of type 1 diabetes, many patients with type 2, or insulin-resistant, diabetes encounter insulin administration errors that compromise the quality of insulin delivery. Insulin errors are a major, but modifiable, barrier to dosing accuracy and optimal diabetes control for many patients. Future trends to combat the problem include increased use of insulin inhalers and smaller doses of rapid- or short-acting insulin to supplement longer-acting injections. PMID:12653373

  4. Application of network construction to estimate functional changes to insulin receptor substrates 1 and 2 in Huh7 cells following infection with the hepatitis C virus

    PubMed Central

    Liu, Jingkun; Wang, Linbang; Wang, Wenjun; Li, Yaping; Jia, Xiaoli; Zhai, Song; Shi, Juan; Dang, Shuangsuo

    2016-01-01

    Hepatitis C virus (HCV) is closely associated with insulin resistance (IS), acting primarily by interfering with insulin signaling pathways, increasing cytokine-mediated (tumor necrosis factor α, interleukin 6) inflammatory responses and enhancing oxidative stress. In the insulin signaling pathways, the insulin receptor substrate (IRS) is one of the key regulatory factors. The present study constructed gene regulatory sub-networks specific for IRS1 and IRS2 in Huh7 cells and HCV-infected Huh7 (HCV-Huh7) cells using linear programming and a decomposition algorithm, and investigated the possible mechanisms underlying the function of IRS1/2 in HCV-induced IS in Huh7 cells. All data were obtained from GSE20948 of the Gene Expression Omnibus database from the National Center for Biotechnology Information. Genes which were significantly differentially expressed between Huh7 and HCV-Huh7 cells were analyzed using the significance analysis of microarray algorithm. The top 50 genes, including IRS1/2, were used as target genes to determine the gene regulatory networks and next the sub-networks of IRS1 and IRS2 in HCV-Huh7 and Huh7 cells using Gene Regulatory Network Inference Tool, an algorithm based on linear programming and the decomposition process. The IRS1/2 sub-networks were divided into upstream/downstream groups and activation/suppression clusters, and were further analyzed using Molecule Annotation System 3.0 and Database for Annotation, Visualization, and Integrated Discovery software, two online platforms for enrichment and clustering analysis and visualization. The results indicated that in Huh7 cells, the downstream network of IRS2 is more complex than that of IRS1, indicating that the insulin metabolism in Huh7 cells may be primarily mediated by IRS2. In HCV-Huh7 cells, the downstream pathway of IRS2 is blocked, suggesting that this may be the underlying mechanism in HCV infection that leads to insulin resistance. The present findings add a further dimension

  5. Giving an insulin injection

    MedlinePlus

    ... room temperature for a month. Gather your supplies: insulin, needles, syringes, alcohol wipes, and a container for used needles ... the plunger to get the right dose of insulin into the syringe. Check the syringe for air bubbles. If there ...

  6. High-mix insulins

    PubMed Central

    Kalra, Sanjay; Farooqi, Mohammad Hamed; El-Houni, Ali E.

    2015-01-01

    Premix insulins are commonly used insulin preparations, which are available in varying ratios of different molecules. These drugs contain one short- or rapid-acting, and one intermediate- or long-acting insulin. High-mix insulins are mixtures of insulins that contain 50% or more than 50% of short-acting insulin. This review describes the clinical pharmacology of high-mix insulins, including data from randomized controlled trials. It suggests various ways, in which high-mix insulin can be used, including once daily, twice daily, thrice daily, hetero-mix, and reverse regimes. The authors provide a rational framework to help diabetes care professionals, identify indications for pragmatic high-mix use. PMID:26425485

  7. Insulin pump (image)

    MedlinePlus

    The catheter at the end of the insulin pump is inserted through a needle into the abdominal ... with diabetes. Dosage instructions are entered into the pump's small computer and the appropriate amount of insulin ...

  8. Adherence to Insulin Therapy.

    PubMed

    Sarbacker, G Blair; Urteaga, Elizabeth M

    2016-08-01

    IN BRIEF Six million people with diabetes use insulin either alone or in combination with an oral medication. Many barriers exist that lead to poor adherence with insulin. However, there is an underwhelming amount of data on interventions to address these barriers and improve insulin adherence. Until pharmacological advancements create easier, more acceptable insulin regimens, it is imperative to involve patients in shared decision-making. PMID:27574371

  9. Plasma BDNF Is Reduced among Middle-Aged and Elderly Women with Impaired Insulin Function: Evidence of a Compensatory Mechanism

    ERIC Educational Resources Information Center

    Arentoft, Alyssa; Sweat, Victoria; Starr, Vanessa; Oliver, Stephen; Hassenstab, Jason; Bruehl, Hannah; Tirsi, Aziz; Javier, Elizabeth; McHugh, Pauline F.; Convit, Antonio

    2009-01-01

    Brain-derived neurotrophic factor (BDNF) plays a regulatory role in neuronal differentiation and synaptic plasticity and has been linked to glucose regulation and cognition. Associations among plasma BDNF, cognition, and insulin function were explored. Forty-one participants with impaired insulin function (IIF), ranging from insulin resistance to…

  10. Insulin therapy in pregnancy.

    PubMed

    Kalra, Sanjay; Jawad, Fatema

    2016-09-01

    Insulin is the mainstay of pharmacotherapy in pregnancy complicated by diabetes. This review covers the various insulin regimes and preparations, explaining how to use them, and decide appropriate doses in pregnancy. It approaches insulin treatment from a patient - centred, as well as physician and obstetrician friendly viewpoint, providing pragmatic guidance for management of diabetes in pregnancy. PMID:27582152

  11. A prospective evaluation of the influence of three bariatric procedures on insulin resistance improvement. Should the extent of undiluted bile transit be considered a key postoperative factor altering glucose metabolism?

    PubMed Central

    Proczko, Monika; Wiśniewski, Piotr; Stankiewicz, Marta; Gill, Derek; Śledziński, Zbigniew

    2015-01-01

    Introduction Insulin resistance (IR), the essential step in development of type 2 diabetes mellitus (T2DM), resolves quickly after bariatric surgery, but the effectiveness depends on the type of the procedure. Although the long-term influence on IR improvement is well documented, the mechanisms of the ultra-fast response after restrictive and bypass procedures require explanation. Aim To determine IR evolution from the initial preparative period to 6 months after the operation, exposing the rapid postoperative response while comparing the 3 bariatric methods, with the belief that the metabolic effect may be correlated with anatomical combinations. Material and methods From January to December, 2013, a cohort of severely obese, insulin resistant individuals recruited to the prospective study underwent laparoscopic sleeve gastrectomy (SG-30), Roux-en-Y gastric bypass (RYGB-30) and one-anastomosis gastric bypass (OAGB-30). Main laboratory parameters of glucose metabolism were evaluated in fasting patients preoperatively, 4 days and 1, 3 and 6 months after surgery. Results Within the whole observation period the most significant improvement in homeostasis model assessment for IR (HOMA-IR) was observed in the first 4 days after each operation. The decrease of HOMA-IR was higher (p < 0.0001) in gastric bypass groups than in patients after SG (–41%). The difference between bypass groups favors OAGB over RYGB (63 vs. –56%, p = 0.0489). Conclusions Among all bariatric management factors, operation type is the most important in IR improvement. The significant difference in response after SG vs. RYGB and OAGB supports the concept of metabolic competence of duodeno-jejunal exclusion. Altered bile flow after duodeno-jejunal exclusion may be responsible for enhanced glucose metabolism improvement. PMID:26240621

  12. Insulin Degludec (rDNA Origin) Injection

    MedlinePlus

    ... man-made version of human insulin. Insulin degludec works by replacing the insulin that is normally produced ... insulin label to make sure you received the right type of insulin from the pharmacy.Insulin degludec ...

  13. Oral Insulin Reloaded

    PubMed Central

    Heinemann, Lutz; Plum-Mörschel, Leona

    2014-01-01

    Optimal coverage of insulin needs is the paramount aim of insulin replacement therapy in patients with diabetes mellitus. To apply insulin without breaking the skin barrier by a needle and/or to allow a more physiological provision of insulin are the main reasons triggering the continuous search for alternative routes of insulin administration. Despite numerous attempts over the past 9 decades to develop an insulin pill, no insulin for oral dosing is commercially available. By way of a structured approach, we aim to provide a systematic update on the most recent developments toward an orally available insulin formulation with a clear focus on data from clinical-experimental and clinical studies. Thirteen companies that claim to be working on oral insulin formulations were identified. However, only 6 of these companies published new clinical trial results within the past 5 years. Interestingly, these clinical data reports make up a mere 4% of the considerably high total number of publications on the development of oral insulin formulations within this time period. While this picture clearly reflects the rising research interest in orally bioavailable insulin formulations, it also highlights the fact that the lion’s share of research efforts is still allocated to the preclinical stages. PMID:24876606

  14. Cardiovascular Action of Insulin in Health and Disease: Endothelial L-Arginine Transport and Cardiac Voltage-Dependent Potassium Channels

    PubMed Central

    Dubó, Sebastián; Gallegos, David; Cabrera, Lissette; Sobrevia, Luis; Zúñiga, Leandro; González, Marcelo

    2016-01-01

    Impairment of insulin signaling on diabetes mellitus has been related to cardiovascular dysfunction, heart failure, and sudden death. In human endothelium, cationic amino acid transporter 1 (hCAT-1) is related to the synthesis of nitric oxide (NO) and insulin has a vascular effect in endothelial cells through a signaling pathway that involves increases in hCAT-1 expression and L-arginine transport. This mechanism is disrupted in diabetes, a phenomenon potentiated by excessive accumulation of reactive oxygen species (ROS), which contribute to lower availability of NO and endothelial dysfunction. On the other hand, electrical remodeling in cardiomyocytes is considered a key factor in heart failure progression associated to diabetes mellitus. This generates a challenge to understand the specific role of insulin and the pathways involved in cardiac function. Studies on isolated mammalian cardiomyocytes have shown prolongated action potential in ventricular repolarization phase that produces a long QT interval, which is well explained by attenuation in the repolarizing potassium currents in cardiac ventricles. Impaired insulin signaling causes specific changes in these currents, such a decrease amplitude of the transient outward K+ (Ito) and the ultra-rapid delayed rectifier (IKur) currents where, together, a reduction of mRNA and protein expression levels of α-subunits (Ito, fast; Kv 4.2 and IKs; Kv 1.5) or β-subunits (KChIP2 and MiRP) of K+ channels involved in these currents in a MAPK mediated pathway process have been described. These results support the hypothesis that lack of insulin signaling can produce an abnormal repolarization in cardiomyocytes. Furthermore, the arrhythmogenic potential due to reduced Ito current can contribute to an increase in the incidence of sudden death in heart failure. This review aims to show, based on pathophysiological models, the regulatory function that would have insulin in vascular system and in cardiac electrophysiology. PMID

  15. Cardiovascular Action of Insulin in Health and Disease: Endothelial L-Arginine Transport and Cardiac Voltage-Dependent Potassium Channels.

    PubMed

    Dubó, Sebastián; Gallegos, David; Cabrera, Lissette; Sobrevia, Luis; Zúñiga, Leandro; González, Marcelo

    2016-01-01

    Impairment of insulin signaling on diabetes mellitus has been related to cardiovascular dysfunction, heart failure, and sudden death. In human endothelium, cationic amino acid transporter 1 (hCAT-1) is related to the synthesis of nitric oxide (NO) and insulin has a vascular effect in endothelial cells through a signaling pathway that involves increases in hCAT-1 expression and L-arginine transport. This mechanism is disrupted in diabetes, a phenomenon potentiated by excessive accumulation of reactive oxygen species (ROS), which contribute to lower availability of NO and endothelial dysfunction. On the other hand, electrical remodeling in cardiomyocytes is considered a key factor in heart failure progression associated to diabetes mellitus. This generates a challenge to understand the specific role of insulin and the pathways involved in cardiac function. Studies on isolated mammalian cardiomyocytes have shown prolongated action potential in ventricular repolarization phase that produces a long QT interval, which is well explained by attenuation in the repolarizing potassium currents in cardiac ventricles. Impaired insulin signaling causes specific changes in these currents, such a decrease amplitude of the transient outward K(+) (Ito) and the ultra-rapid delayed rectifier (IKur) currents where, together, a reduction of mRNA and protein expression levels of α-subunits (Ito, fast; Kv 4.2 and IKs; Kv 1.5) or β-subunits (KChIP2 and MiRP) of K(+) channels involved in these currents in a MAPK mediated pathway process have been described. These results support the hypothesis that lack of insulin signaling can produce an abnormal repolarization in cardiomyocytes. Furthermore, the arrhythmogenic potential due to reduced Ito current can contribute to an increase in the incidence of sudden death in heart failure. This review aims to show, based on pathophysiological models, the regulatory function that would have insulin in vascular system and in cardiac electrophysiology

  16. Evidence-based clinical use of insulin premixtures.

    PubMed

    Tambascia, Marcos Antônio; Nery, Márcia; Gross, Jorge Luiz; Ermetice, Mariana Narbot; de Oliveira, Carolina Piras

    2013-01-01

    Brazil is expected to have 19.6 million patients with diabetes by the year 2030. A key concept in the treatment of type 2 diabetes mellitus (T2DM) is establishing individualized glycemic goals based on each patient's clinical characteristics, which impact the choice of antihyperglycemic therapy. Targets for glycemic control, including fasting blood glucose, postprandial blood glucose, and glycated hemoglobin (A1C), are often not reached solely with antihyperglycemic therapy, and insulin therapy is often required. Basal insulin is considered an initial strategy; however, premixed insulins are convenient and are equally or more effective, especially for patients who require both basal and prandial control but desire a more simplified strategy involving fewer daily injections than a basal-bolus regimen. Most physicians are reluctant to transition patients to insulin treatment due to inappropriate assumptions and insufficient information. We conducted a nonsystematic review in PubMed and identified the most relevant and recently published articles that compared the use of premixed insulin versus basal insulin analogues used alone or in combination with rapid-acting insulin analogues before meals in patients with T2DM. These studies suggest that premixed insulin analogues are equally or more effective in reducing A1C compared to basal insulin analogues alone in spite of the small increase in the risk of nonsevere hypoglycemic events and nonclinically significant weight gain. Premixed insulin analogues can be used in insulin-naïve patients, in patients already on basal insulin therapy, and those using basal-bolus therapy who are noncompliant with blood glucose self-monitoring and titration of multiple insulin doses. We additionally provide practical aspects related to titration for the specific premixed insulin analogue formulations commercially available in Brazil. PMID:24011173

  17. Molecular Basis of Catalytic Chamber-assisted Unfolding and Cleavage of Human Insulin by Human Insulin-degrading Enzyme

    SciTech Connect

    Manolopoulou, Marika; Guo, Qing; Malito, Enrico; Schilling, Alexander B.; Tang, Wei-Jen

    2009-06-02

    Insulin is a hormone vital for glucose homeostasis, and insulin-degrading enzyme (IDE) plays a key role in its clearance. IDE exhibits a remarkable specificity to degrade insulin without breaking the disulfide bonds that hold the insulin A and B chains together. Using Fourier transform ion cyclotron resonance (FTICR) mass spectrometry to obtain high mass accuracy, and electron capture dissociation (ECD) to selectively break the disulfide bonds in gas phase fragmentation, we determined the cleavage sites and composition of human insulin fragments generated by human IDE. Our time-dependent analysis of IDE-digested insulin fragments reveals that IDE is highly processive in its initial cleavage at the middle of both the insulin A and B chains. This ensures that IDE effectively splits insulin into inactive N- and C-terminal halves without breaking the disulfide bonds. To understand the molecular basis of the recognition and unfolding of insulin by IDE, we determined a 2.6-A resolution insulin-bound IDE structure. Our structure reveals that IDE forms an enclosed catalytic chamber that completely engulfs and intimately interacts with a partially unfolded insulin molecule. This structure also highlights how the unique size, shape, charge distribution, and exosite of the IDE catalytic chamber contribute to its high affinity ( approximately 100 nm) for insulin. In addition, this structure shows how IDE utilizes the interaction of its exosite with the N terminus of the insulin A chain as well as other properties of the catalytic chamber to guide the unfolding of insulin and allowing for the processive cleavages.

  18. Genetic variation in insulin-induced kinase signaling

    PubMed Central

    Wang, Isabel Xiaorong; Ramrattan, Girish; Cheung, Vivian G

    2015-01-01

    Individual differences in sensitivity to insulin contribute to disease susceptibility including diabetes and metabolic syndrome. Cellular responses to insulin are well studied. However, which steps in these response pathways differ across individuals remains largely unknown. Such knowledge is needed to guide more precise therapeutic interventions. Here, we studied insulin response and found extensive individual variation in the activation of key signaling factors, including ERK whose induction differs by more than 20-fold among our subjects. This variation in kinase activity is propagated to differences in downstream gene expression response to insulin. By genetic analysis, we identified cis-acting DNA variants that influence signaling response, which in turn affects downstream changes in gene expression and cellular phenotypes, such as protein translation and cell proliferation. These findings show that polymorphic differences in signal transduction contribute to individual variation in insulin response, and suggest kinase modulators as promising therapeutics for diseases characterized by insulin resistance. PMID:26202599

  19. Insulin: its Role in the Central Control of Reproduction

    PubMed Central

    Sliwowska, Joanna H.; Fergani, Chrysanthi; Gawałek, Monika; Skowronska, Bogda; Fichna, Piotr; Lehman, Michael N.

    2014-01-01

    Insulin has long been recognized as a key regulator of energy homeostasis via its actions at the level of the brain, but in addition, plays a role in regulating neural control of reproduction. In this review, we consider and compare evidence from animal models demonstrating a role for insulin for physiological control of reproduction by effects on GnRH/LH secretion. We also review the role that insulin plays in prenatal programming of adult reproduction, and consider specific candidate neurons in the adult hypothalamus by which insulin may act to regulate reproductive function. Finally, we review clinical evidence of the role that insulin may play in adult human fertility and reproductive disorders. Overall, while insulin appears to have a significant impact on reproductive neuroendocrine function, there are many unanswered questions regarding its precise sites and mechanisms of action, and their impact on developing and adult reproductive neuroendocrine function. PMID:24874777

  20. Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance.

    PubMed

    Tuncman, Gürol; Hirosumi, Jiro; Solinas, Giovanni; Chang, Lufen; Karin, Michael; Hotamisligil, Gökhan S

    2006-07-11

    The c-Jun N-terminal kinases (JNKs) are key regulators of inflammation and interfere with insulin action in cultured cells and whole animals. Obesity increases total JNK activity, and JNK1, but not JNK2, deficiency results in reduced adiposity and improved insulin sensitivity. Interestingly, a higher-than-normal level of JNK activation is observed in Jnk2(-/-) mice, particularly in the liver, indicating an interaction between the isoforms that might have masked the metabolic activity of JNK2 in isolated mutant mice. To address the role of the JNK2 isoform in metabolic homeostasis, we intercrossed Jnk1(-/-) and Jnk2(-/-) mice and examined body weight and glucose metabolism in the resulting mutant allele combinations. Among all of the viable genotypes examined, we observed only reduced body weight and increased insulin sensitivity in Jnk1(-/-) and Jnk1(+/-)Jnk2(-/-) mice. These two groups of mice also exhibited reduced total JNK activity and cytokine expression in liver tissue compared with all other genotypes examined. These data indicate that the JNK2 isoform is also involved in metabolic regulation, but its function is not obvious when JNK1 is fully expressed because of regulatory crosstalk between the two isoforms. PMID:16818881

  1. Aberrant insulin signaling in Alzheimer's disease: current knowledge

    PubMed Central

    Bedse, Gaurav; Di Domenico, Fabio; Serviddio, Gaetano; Cassano, Tommaso

    2015-01-01

    Alzheimer's disease (AD) is the most common form of dementia affecting elderly people. AD is a multifaceted pathology characterized by accumulation of extracellular neuritic plaques, intracellular neurofibrillary tangles (NFTs) and neuronal loss mainly in the cortex and hippocampus. AD etiology appears to be linked to a multitude of mechanisms that have not been yet completely elucidated. For long time, it was considered that insulin signaling has only peripheral actions but now it is widely accepted that insulin has neuromodulatory actions in the brain. Insulin signaling is involved in numerous brain functions including cognition and memory that are impaired in AD. Recent studies suggest that AD may be linked to brain insulin resistance and patients with diabetes have an increased risk of developing AD compared to healthy individuals. Indeed insulin resistance, increased inflammation and impaired metabolism are key pathological features of both AD and diabetes. However, the precise mechanisms involved in the development of AD in patients with diabetes are not yet fully understood. In this review we will discuss the role played by aberrant brain insulin signaling in AD. In detail, we will focus on the role of insulin signaling in the deposition of neuritic plaques and intracellular NFTs. Considering that insulin mitigates beta-amyloid deposition and phosphorylation of tau, pharmacological strategies restoring brain insulin signaling, such as intranasal delivery of insulin, could have significant therapeutic potential in AD treatment. PMID:26136647

  2. PGC-1α Integrates Insulin Signaling, Mitochondrial Regulation, and Bioenergetic Function in Skeletal Muscle*S⃞

    PubMed Central

    Pagel-Langenickel, Ines; Bao, Jianjun; Joseph, Joshua J.; Schwartz, Daniel R.; Mantell, Benjamin S.; Xu, Xiuli; Raghavachari, Nalini; Sack, Michael N.

    2008-01-01

    The pathophysiology underlying mitochondrial dysfunction in insulin-resistant skeletal muscle is incompletely characterized. To further delineate this we investigated the interaction between insulin signaling, mitochondrial regulation, and function in C2C12 myotubes and in skeletal muscle. In myotubes elevated insulin and glucose disrupt insulin signaling, mitochondrial biogenesis, and mitochondrial bioenergetics. The insulin-sensitizing thiazolidinedione pioglitazone restores these perturbations in parallel with induction of the mitochondrial biogenesis regulator PGC-1α. Overexpression of PGC-1α rescues insulin signaling and mitochondrial bioenergetics, and its silencing concordantly disrupts insulin signaling and mitochondrial bioenergetics. In primary skeletal myoblasts pioglitazone also up-regulates PGC-1α expression and restores the insulin-resistant mitochondrial bioenergetic profile. In parallel, pioglitazone up-regulates PGC-1α in db/db mouse skeletal muscle. Interestingly, the small interfering RNA knockdown of the insulin receptor in C2C12 myotubes down-regulates PGC-1α and attenuates mitochondrial bioenergetics. Concordantly, mitochondrial bioenergetics are blunted in insulin receptor knock-out mouse-derived skeletal myoblasts. Taken together these data demonstrate that elevated glucose and insulin impairs and pioglitazone restores skeletal myotube insulin signaling, mitochondrial regulation, and bioenergetics. Pioglitazone functions in part via the induction of PGC-1α. Moreover, PGC-1α is identified as a bidirectional regulatory link integrating insulin-signaling and mitochondrial homeostasis in skeletal muscle. PMID:18579525

  3. Flexibility in insulin prescription

    PubMed Central

    Kalra, Sanjay; Gupta, Yashdeep; Unnikrishnan, Ambika Gopalakrishnan

    2016-01-01

    This communication explores the concept of flexibility, a propos insulin preparations and insulin regimes used in the management of type 2 diabetes. The flexibility of an insulin regime or preparation is defined as their ability to be injected at variable times, with variable injection-meal time gaps, in a dose frequency and quantum determined by shared decision making, with a minimal requirement of glucose monitoring and health professional consultation, with no compromise on safety, efficiency and tolerability. The relative flexibility of various basal, prandial and dual action insulins, as well as intensive regimes, is compared. The biopsychosocial model of health is used to assess the utility of different insulins while encouraging a philosophy of flexible insulin usage. PMID:27186563

  4. Flexibility in insulin prescription.

    PubMed

    Kalra, Sanjay; Gupta, Yashdeep; Unnikrishnan, Ambika Gopalakrishnan

    2016-01-01

    This communication explores the concept of flexibility, a propos insulin preparations and insulin regimes used in the management of type 2 diabetes. The flexibility of an insulin regime or preparation is defined as their ability to be injected at variable times, with variable injection-meal time gaps, in a dose frequency and quantum determined by shared decision making, with a minimal requirement of glucose monitoring and health professional consultation, with no compromise on safety, efficiency and tolerability. The relative flexibility of various basal, prandial and dual action insulins, as well as intensive regimes, is compared. The biopsychosocial model of health is used to assess the utility of different insulins while encouraging a philosophy of flexible insulin usage. PMID:27186563

  5. Magnetite nanoparticle interactions with insulin amyloid fibrils.

    PubMed

    Chen, Yun-Wen; Chang, Chiung-Wen; Hung, Huey-Shan; Kung, Mei-Lang; Yeh, Bi-Wen; Hsieh, Shuchen

    2016-10-14

    Accumulation of amyloid fibrils is one of the likely key factors leading to the development of Alzheimer's disease and other amyloidosis associated diseases. Magnetic nanoparticles (NPs) have been developed as promising medical materials for many medical applications. In this study, we have explored the effects of Fe3O4 NPs on the fibrillogenesis process of insulin fibrils. When Fe3O4 NPs were co-incubated with insulin, Fe3O4 NPs had no effect on the structural transformation into amyloid-like fibrils but had higher affinity toward insulin fibrils. We demonstrated that the zeta potential of insulin fibrils and Fe3O4 NPs were both positive, suggesting the binding forces between Fe3O4 NPs and insulin fibrils were van der Waals forces but not surface charge. Moreover, a different amount of Fe3O4 NPs added had no effect on secondary structural changes of insulin fibrils. These results propose the potential use of Fe3O4 NPs as therapeutic agents against diseases related to protein aggregation or contrast agents for magnetic resonance imaging. PMID:27585675

  6. Flexibility in the insulin receptor ectodomain enables docking of insulin in crystallographic conformation observed in a hormone-bound microreceptor.

    PubMed

    Vashisth, Harish

    2014-01-01

    Insulin binding to the insulin receptor (IR) is the first key step in initiating downstream signaling cascades for glucose homeostasis in higher organisms. The molecular details of insulin recognition by IR are not yet completely understood, but a picture of hormone/receptor interactions at one of the epitopes (Site 1) is beginning to emerge from recent structural evidence. However, insulin-bound structures of truncated IR suggest that crystallographic conformation of insulin cannot be accommodated in the full IR ectodomain due to steric overlap of insulin with the first two type III fibronectin domains (F1 and F2), which are contributed to the insulin binding-pocket by the second subunit in the IR homodimer. A conformational change in the F1-F2 pair has thus been suggested. In this work, we present an all-atom structural model of complex of insulin and the IR ectodomain, where no structural overlap of insulin with the receptor domains (F1 and F2) is observed. This structural model was arrived at by flexibly fitting parts of our earlier insulin/IR all-atom model into the simulated density maps of crystallized constructs combined with conformational sampling from apo-IR solution conformations. Importantly, our experimentally-consistent model helps rationalize yet unresolved Site. PMID:25309993

  7. Insulin structure and function.

    PubMed

    Mayer, John P; Zhang, Faming; DiMarchi, Richard D

    2007-01-01

    Throughout much of the last century insulin served a central role in the advancement of peptide chemistry, pharmacology, cell signaling and structural biology. These discoveries have provided a steadily improved quantity and quality of life for those afflicted with diabetes. The collective work serves as a foundation for the development of insulin analogs and mimetics capable of providing more tailored therapy. Advancements in patient care have been paced by breakthroughs in core technologies, such as semisynthesis, high performance chromatography, rDNA-biosynthesis and formulation sciences. How the structural and conformational dynamics of this endocrine hormone elicit its biological response remains a vigorous area of study. Numerous insulin analogs have served to coordinate structural biology and biochemical signaling to provide a first level understanding of insulin action. The introduction of broad chemical diversity to the study of insulin has been limited by the inefficiency in total chemical synthesis, and the inherent limitations in rDNA-biosynthesis and semisynthetic approaches. The goals of continued investigation remain the delivery of insulin therapy where glycemic control is more precise and hypoglycemic liability is minimized. Additional objectives for medicinal chemists are the identification of superagonists and insulins more suitable for non-injectable delivery. The historical advancements in the synthesis of insulin analogs by multiple methods is reviewed with the specific structural elements of critical importance being highlighted. The functional refinement of this hormone as directed to improved patient care with insulin analogs of more precise pharmacology is reported. PMID:17410596

  8. MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels.

    PubMed

    Nagarajan, Arvindhan; Petersen, Max C; Nasiri, Ali R; Butrico, Gina; Fung, Annie; Ruan, Hai-Bin; Kursawe, Romy; Caprio, Sonia; Thibodeau, Jacques; Bourgeois-Daigneault, Marie-Claude; Sun, Lisha; Gao, Guangping; Bhanot, Sanjay; Jurczak, Michael J; Green, Michael R; Shulman, Gerald I; Wajapeyee, Narendra

    2016-01-01

    Insulin resistance is a key driver of type 2 diabetes (T2D) and is characterized by defective insulin receptor (INSR) signalling. Although surface INSR downregulation is a well-established contributor to insulin resistance, the underlying molecular mechanisms remain obscure. Here we show that the E3 ubiquitin ligase MARCH1 impairs cellular insulin action by degrading cell surface INSR. Using a large-scale RNA interference screen, we identify MARCH1 as a negative regulator of INSR signalling. March1 loss-of-function enhances, and March1 overexpression impairs, hepatic insulin sensitivity in mice. MARCH1 ubiquitinates INSR to decrease cell surface INSR levels, but unlike other INSR ubiquitin ligases, MARCH1 acts in the basal state rather than after insulin stimulation. Thus, MARCH1 may help set the basal gain of insulin signalling. MARCH1 expression is increased in white adipose tissue of obese humans, suggesting that MARCH1 contributes to the pathophysiology of T2D and could be a new therapeutic target. PMID:27577745

  9. Alternative Devices for Taking Insulin

    MedlinePlus

    ... pumps contain enough insulin for several days. An infusion set carries insulin from the pump to the ... tube or needle inserted under the skin. Disposable infusion sets are used with insulin pumps to deliver ...

  10. Anti-insulin antibody test

    MedlinePlus

    Insulin antibodies - serum; Insulin Ab test ... Normally, there are no antibodies against insulin in your blood. Normal value ranges may vary slightly among different laboratories. Some labs use different measurements or ...

  11. Application of network construction to estimate functional changes to insulin receptor substrates 1 and 2 in Huh7 cells following infection with the hepatitis C virus.

    PubMed

    Liu, Jingkun; Wang, Linbang; Wang, Wenjun; Li, Yaping; Jia, Xiaoli; Zhai, Song; Shi, Juan; Dang, Shuangsuo

    2016-09-01

    Hepatitis C virus (HCV) is closely associated with insulin resistance (IS), acting primarily by interfering with insulin signaling pathways, increasing cytokine-mediated (tumor necrosis factor α, interleukin 6) inflammatory responses and enhancing oxidative stress. In the insulin signaling pathways, the insulin receptor substrate (IRS) is one of the key regulatory factors. The present study constructed gene regulatory sub‑networks specific for IRS1 and IRS2 in Huh7 cells and HCV‑infected Huh7 (HCV‑Huh7) cells using linear programming and a decomposition algorithm, and investigated the possible mechanisms underlying the function of IRS1/2 in HCV‑induced IS in Huh7 cells. All data were obtained from GSE20948 of the Gene Expression Omnibus database from the National Center for Biotechnology Information. Genes which were significantly differentially expressed between Huh7 and HCV‑Huh7 cells were analyzed using the significance analysis of microarray algorithm. The top 50 genes, including IRS1/2, were used as target genes to determine the gene regulatory networks and next the sub‑networks of IRS1 and IRS2 in HCV‑Huh7 and Huh7 cells using Gene Regulatory Network Inference Tool, an algorithm based on linear programming and the decomposition process. The IRS1/2 sub‑networks were divided into upstream/downstream groups and activation/suppression clusters, and were further analyzed using Molecule Annotation System 3.0 and Database for Annotation, Visualization, and Integrated Discovery software, two online platforms for enrichment and clustering analysis and visualization. The results indicated that in Huh7 cells, the downstream network of IRS2 is more complex than that of IRS1, indicating that the insulin metabolism in Huh7 cells may be primarily mediated by IRS2. In HCV‑Huh7 cells, the downstream pathway of IRS2 is blocked, suggesting that this may be the underlying mechanism in HCV infection that leads to insulin resistance. The present

  12. Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus

    PubMed Central

    Atkin, Stephen; Javed, Zeeshan; Fulcher, Gregory

    2015-01-01

    Patients with type 2 diabetes mellitus require insulin as disease progresses to attain or maintain glycaemic targets. Basal insulin is commonly prescribed initially, alone or with one or more rapid-acting prandial insulin doses, to limit mealtime glucose excursions (a basal–bolus regimen). Both patients and physicians must balance the advantages of improved glycaemic control with the risk of hypoglycaemia and increasing regimen complexity. The rapid-acting insulin analogues (insulin aspart, insulin lispro and insulin glulisine) all have similar pharmacokinetic and pharmacodynamic characteristics and clinical efficacy/safety profiles. However, there are important differences in the pharmacokinetic and pharmacodynamic profiles of basal insulins (insulin glargine, insulin detemir and insulin degludec). Insulin degludec is an ultra-long-acting insulin analogue with a flat and stable glucose-lowering profile, a duration of action exceeding 30 h and less inter-patient variation in glucose-lowering effect than insulin glargine. In particular, the chemical properties of insulin degludec have allowed the development of a soluble co-formulation with prandial insulin aspart (insulin degludec/insulin aspart) that provides basal insulin coverage for at least 24 h with additional mealtime insulin for one or two meals depending on dose frequency. Pharmacokinetic and pharmacodynamic studies have shown that the distinct, long basal glucose-lowering action of insulin degludec and the prandial glucose-lowering effect of insulin aspart are maintained in the co-formulation. Evidence from pivotal phase III clinical trials indicates that insulin degludec/insulin aspart translate into sustained glycaemic control with less hypoglycaemia and the potential for a simpler insulin regimen with fewer daily injections. PMID:26568812

  13. Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus.

    PubMed

    Atkin, Stephen; Javed, Zeeshan; Fulcher, Gregory

    2015-11-01

    Patients with type 2 diabetes mellitus require insulin as disease progresses to attain or maintain glycaemic targets. Basal insulin is commonly prescribed initially, alone or with one or more rapid-acting prandial insulin doses, to limit mealtime glucose excursions (a basal-bolus regimen). Both patients and physicians must balance the advantages of improved glycaemic control with the risk of hypoglycaemia and increasing regimen complexity. The rapid-acting insulin analogues (insulin aspart, insulin lispro and insulin glulisine) all have similar pharmacokinetic and pharmacodynamic characteristics and clinical efficacy/safety profiles. However, there are important differences in the pharmacokinetic and pharmacodynamic profiles of basal insulins (insulin glargine, insulin detemir and insulin degludec). Insulin degludec is an ultra-long-acting insulin analogue with a flat and stable glucose-lowering profile, a duration of action exceeding 30 h and less inter-patient variation in glucose-lowering effect than insulin glargine. In particular, the chemical properties of insulin degludec have allowed the development of a soluble co-formulation with prandial insulin aspart (insulin degludec/insulin aspart) that provides basal insulin coverage for at least 24 h with additional mealtime insulin for one or two meals depending on dose frequency. Pharmacokinetic and pharmacodynamic studies have shown that the distinct, long basal glucose-lowering action of insulin degludec and the prandial glucose-lowering effect of insulin aspart are maintained in the co-formulation. Evidence from pivotal phase III clinical trials indicates that insulin degludec/insulin aspart translate into sustained glycaemic control with less hypoglycaemia and the potential for a simpler insulin regimen with fewer daily injections. PMID:26568812

  14. Regulatory mechanisms of immune tolerance in type 1 diabetes and their failures.

    PubMed

    Kuhn, Chantal; Besançon, Alix; Lemoine, Sébastien; You, Sylvaine; Marquet, Cindy; Candon, Sophie; Chatenoud, Lucienne

    2016-07-01

    In this brief review we propose to discuss salient data showing the importance of immune regulatory mechanisms, and in particular of Treg, for the control of pathogenic anti-β-cell response in autoimmune diabetes. Disease progression that culminates with the massive destruction of insulin-secreting β-cells and advent of hyperglycemia and glycosuria tightly correlates with a functional deficit in immune regulation. Better dissection of the cellular and molecular mechanisms through which the immune system normally sustains tolerance to "self", and which become defective when autoimmune aggression is overt, is the only direct and robust way to learn how to harness these effectively, so as to restore immune tolerance in patients with insulin-dependent type 1 diabetes. No doubt that regulatory T cells are a privileged mechanism underlying this self-tolerance in the periphery. The discovery of the key role of the transcription factor FoxP3, represented the cornerstone leading to the great advances in the field we are witnessing today. Type 1 diabetes is certainly one of the prototypic T cell-mediated autoimmune diseases where immune regulatory mechanisms relying on specialized subsets of T cells have been the most thoroughly analyzed from the fundamental point of view and also largely exploited in a translational therapeutic perspective. PMID:27216249

  15. Computational modeling and analysis of insulin induced eukaryotic translation initiation.

    PubMed

    Lequieu, Joshua; Chakrabarti, Anirikh; Nayak, Satyaprakash; Varner, Jeffrey D

    2011-11-01

    Insulin, the primary hormone regulating the level of glucose in the bloodstream, modulates a variety of cellular and enzymatic processes in normal and diseased cells. Insulin signals are processed by a complex network of biochemical interactions which ultimately induce gene expression programs or other processes such as translation initiation. Surprisingly, despite the wealth of literature on insulin signaling, the relative importance of the components linking insulin with translation initiation remains unclear. We addressed this question by developing and interrogating a family of mathematical models of insulin induced translation initiation. The insulin network was modeled using mass-action kinetics within an ordinary differential equation (ODE) framework. A family of model parameters was estimated, starting from an initial best fit parameter set, using 24 experimental data sets taken from literature. The residual between model simulations and each of the experimental constraints were simultaneously minimized using multiobjective optimization. Interrogation of the model population, using sensitivity and robustness analysis, identified an insulin-dependent switch that controlled translation initiation. Our analysis suggested that without insulin, a balance between the pro-initiation activity of the GTP-binding protein Rheb and anti-initiation activity of PTEN controlled basal initiation. On the other hand, in the presence of insulin a combination of PI3K and Rheb activity controlled inducible initiation, where PI3K was only critical in the presence of insulin. Other well known regulatory mechanisms governing insulin action, for example IRS-1 negative feedback, modulated the relative importance of PI3K and Rheb but did not fundamentally change the signal flow. PMID:22102801

  16. Intranasal Insulin Improves Age-Related Cognitive Deficits and Reverses Electrophysiological Correlates of Brain Aging.

    PubMed

    Maimaiti, Shaniya; Anderson, Katie L; DeMoll, Chris; Brewer, Lawrence D; Rauh, Benjamin A; Gant, John C; Blalock, Eric M; Porter, Nada M; Thibault, Olivier

    2016-01-01

    Peripheral insulin resistance is a key component of metabolic syndrome associated with obesity, dyslipidemia, hypertension, and type 2 diabetes. While the impact of insulin resistance is well recognized in the periphery, it is also becoming apparent in the brain. Recent studies suggest that insulin resistance may be a factor in brain aging and Alzheimer's disease (AD) whereby intranasal insulin therapy, which delivers insulin to the brain, improves cognition and memory in AD patients. Here, we tested a clinically relevant delivery method to determine the impact of two forms of insulin, short-acting insulin lispro (Humalog) or long-acting insulin detemir (Levemir), on cognitive functions in aged F344 rats. We also explored insulin effects on the Ca(2+)-dependent hippocampal afterhyperpolarization (AHP), a well-characterized neurophysiological marker of aging which is increased in the aged, memory impaired animal. Low-dose intranasal insulin improved memory recall in aged animals such that their performance was similar to that seen in younger animals. Further, because ex vivo insulin also reduced the AHP, our results suggest that the AHP may be a novel cellular target of insulin in the brain, and improved cognitive performance following intranasal insulin therapy may be the result of insulin actions on the AHP. PMID:25659889

  17. Protein Crystal Bovine Insulin

    NASA Technical Reports Server (NTRS)

    1991-01-01

    The comparison of protein crystal, Bovine Insulin space-grown (left) and earth-grown (right). Facilitates the incorporation of glucose into cells. In diabetics, there is either a decrease in or complete lack of insulin, thereby leading to several harmful complications. Principal Investigator is Larry DeLucas.

  18. Devices for insulin administration.

    PubMed

    Selam, J L; Charles, M A

    1990-09-01

    There is a significant need for revised, safe, and more effective insulin-delivery methods than subcutaneous injections in the treatment of both type I (insulin-dependent) and type II (non-insulin-dependent) diabetes. The aim of this review is to describe the rationale and methods for better use of injection and infusion devices for intensive insulin therapy and to describe results of animal and human research that will lead to an implantable artificial pancreas. Injection devices, e.g., jet injectors, insulin pens, and access ports, cannot be considered as a major breakthrough in the quest for improved control, although they may improve the patient's comfort. External pumps have benefits over multiple injections and conventional insulin therapy only in specific subgroups of patients, e.g., those with recurrent severe hypoglycemia, but only when used by experienced personnel. The external artificial pancreas (Biostator) is also to be used by experienced personnel for limited clinical and research applications, e.g., surgery of the diabetic patient. The development of an implantable version of the artificial pancreas is linked to progress in the field of reliable long-duration glucose sensors. Finally, programmable implantable insulin pumps, used as an open-loop delivery system, are the most promising alternative to intensive subcutaneous insulin strategies in the short term, although clear evidence of improved safety and efficacy remains to be documented. PMID:2226111

  19. Insulin use: preventable errors.

    PubMed

    2014-01-01

    Insulin is vital for patients with type 1 diabetes and useful for certain patients with type 2 diabetes. The serious consequences of insulin-related medication errors are overdose, resulting in severe hypoglycaemia, causing seizures, coma and even death; or underdose, resulting in hyperglycaemia and sometimes ketoacidosis. Errors associated with the preparation and administration of insulin are often reported, both outside and inside the hospital setting. These errors are preventable. By analysing reports from organisations devoted to medication error prevention and from poison control centres, as well as a few studies and detailed case reports of medication errors, various types of error associated with insulin use have been identified, especially in the hospital setting. Generally, patients know more about the practicalities of their insulin treatment than healthcare professionals with intermittent involvement. Medication errors involving insulin can occur at each step of the medication-use process: prescribing, data entry, preparation, dispensing and administration. When prescribing insulin, wrong-dose errors have been caused by the use of abbreviations, especially "U" instead of the word "units" (often resulting in a 10-fold overdose because the "U" is read as a zero), or by failing to write the drug's name correctly or in full. In electronic prescribing, the sheer number of insulin products is a source of confusion and, ultimately, wrong-dose errors, and often overdose. Prescribing, dispensing or administration software is rarely compatible with insulin prescriptions in which the dose is adjusted on the basis of the patient's subsequent capillary blood glucose readings, and can therefore generate errors. When preparing and dispensing insulin, a tuberculin syringe is sometimes used instead of an insulin syringe, leading to overdose. Other errors arise from confusion created by similar packaging, between different insulin products or between insulin and other

  20. Insulin Resistance of Puberty.

    PubMed

    Kelsey, Megan M; Zeitler, Philip S

    2016-07-01

    Puberty is a time of considerable metabolic and hormonal change. Notably, puberty is associated with a marked decrease in insulin sensitivity, on par with that seen during pregnancy. In otherwise healthy youth, there is a nadir in insulin sensitivity in mid-puberty, and then it recovers at puberty completion. However, there is evidence that insulin resistance (IR) does not resolve in youth who are obese going into puberty and may result in increased cardiometabolic risk. Little is known about the underlying pathophysiology of IR in puberty, and how it might contribute to increased disease risk (e.g., type 2 diabetes). In this review, we have outlined what is known about the IR in puberty in terms of pattern, potential underlying mechanisms and other mediating factors. We also outline other potentially related metabolic changes that occur during puberty, and effects of underlying insulin resistant states (e.g., obesity) on pubertal changes in insulin sensitivity. PMID:27179965

  1. Is it dietary insulin?

    PubMed

    Vaarala, Outi

    2006-10-01

    In humans the primary trigger of insulin-specific immunity is a modified self-antigen, that is, dietary bovine insulin, which breaks neonatal tolerance to self-insulin. The immune response induced by bovine insulin spreads to react with human insulin. This primary immune response induced in the gut immune system is regulated by the mechanisms of oral tolerance. Genetic factors and environmental factors, such as the gut microflora, breast milk-derived factors, and enteral infections, control the development of oral tolerance. The age of host modifies the immune response to oral antigens because the permeability of the gut decreases with age and mucosal immune response, such as IgA response, develops with age. The factors that control the function of the gut immune system may either be protective from autoimmunity by supporting tolerance, or they may induce autoimmunity by abating tolerance to dietary insulin. There is accumulating evidence that the intestinal immune system is aberrant in children with type 1 diabetes (T1D). Intestinal immune activation and increased gut permeability are associated with T1D. These aberrancies may be responsible for the impaired control of tolerance to dietary insulin. Later in life, factors that activate insulin-specific immune cells derived from the gut may switch the response toward cytotoxic immunity. Viruses, which infect beta cells, may release autoantigens and potentiate their presentation by an infection-associated "danger signal." This kind of secondary immunization may cause functional changes in the dietary insulin primed immune cells, and lead to the infiltration of insulin-reactive T cells to the pancreatic islets. PMID:17130578

  2. Fasting and Systemic Insulin Signaling Regulate Phosphorylation of Brain Proteins That Modulate Cell Morphology and Link to Neurological Disorders.

    PubMed

    Li, Min; Quan, Chao; Toth, Rachel; Campbell, David G; MacKintosh, Carol; Wang, Hong Yu; Chen, Shuai

    2015-12-11

    Diabetes is strongly associated with cognitive decline, but the molecular reasons are unknown. We found that fasting and peripheral insulin promote phosphorylation and dephosphorylation, respectively, of specific residues on brain proteins including cytoskeletal regulators such as slit-robo GTPase-activating protein 3 (srGAP3) and microtubule affinity-regulating protein kinases (MARKs), in which deficiency or dysregulation is linked to neurological disorders. Fasting activates protein kinase A (PKA) but not PKB/Akt signaling in the brain, and PKA can phosphorylate the purified srGAP3. The phosphorylation of srGAP3 and MARKs were increased when PKA signaling was activated in primary neurons. Knockdown of PKA decreased the phosphorylation of srGAP3. Furthermore, WAVE1, a protein kinase A-anchoring protein, formed a complex with srGAP3 and PKA in the brain of fasted mice to facilitate the phosphorylation of srGAP3 by PKA. Although brain cells have insulin receptors, our findings are inconsistent with the down-regulation of phosphorylation of target proteins being mediated by insulin signaling within the brain. Rather, our findings infer that systemic insulin, through a yet unknown mechanism, inhibits PKA or protein kinase(s) with similar specificity and/or activates an unknown phosphatase in the brain. Ser(858) of srGAP3 was identified as a key regulatory residue in which phosphorylation by PKA enhanced the GAP activity of srGAP3 toward its substrate, Rac1, in cells, thereby inhibiting the action of this GTPase in cytoskeletal regulation. Our findings reveal novel mechanisms linking peripheral insulin sensitivity with cytoskeletal remodeling in neurons, which may help to explain the association of diabetes with neurological disorders such as Alzheimer disease. PMID:26499801

  3. Florida Keys

    NASA Technical Reports Server (NTRS)

    2002-01-01

    The Florida Keys are a chain of islands, islets and reefs extending from Virginia Key to the Dry Tortugas for about 309 kilometers (192 miles). The keys are chiefly limestone and coral formations. The larger islands of the group are Key West (with its airport), Key Largo, Sugarloaf Key, and Boca Chica Key. A causeway extends from the mainland to Key West.

    This image was acquired on October 28, 2001, by the Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) on NASA's Terra satellite. With its 14 spectral bands from the visible to the thermal infrared wavelength region, and its high spatial resolution of 15 to 90 meters (about 50 to 300 feet), ASTER images Earth to map and monitor the changing surface of our planet.

    ASTER is one of five Earth-observing instruments launched December 18, 1999, on NASA's Terra satellite. The instrument was built by Japan's Ministry of Economy, Trade and Industry. A joint U.S./Japan science team is responsible for validation and calibration of the instrument and the data products.

    The broad spectral coverage and high spectral resolution of ASTER will provide scientists in numerous disciplines with critical information for surface mapping, and monitoring of dynamic conditions and temporal change. Example applications are: monitoring glacial advances and retreats; monitoring potentially active volcanoes; identifying crop stress; determining cloud morphology and physical properties; wetlands evaluation; thermal pollution monitoring; coral reef degradation; surface temperature mapping of soils and geology; and measuring surface heat balance.

    Dr. Anne Kahle at NASA's Jet Propulsion Laboratory, Pasadena, Calif., is the U.S. Science team leader; Bjorn Eng of JPL is the project manager. The Terra mission is part of NASA's Earth Science Enterprise, a long- term research effort to understand and protect our home planet. Through the study of Earth, NASA will help to provide sound science to policy and economic

  4. Drosophila insulin degrading enzyme and rat skeletal muscle insulin protease cleave insulin at similar sites

    SciTech Connect

    Duckworth, W.C.; Garcia, J.V.; Liepnieks, J.J.; Hamel, F.G.; Hermodson, M.A.; Frank, B.H.; Rosner, M.R. )

    1989-03-21

    Insulin degradation is an integral part of the cellular action of insulin. Recent evidence suggests that the enzyme insulin protease is involved in the degradation of insulin in mammalian tissues. Drosophila, which has insulin-like hormones and insulin receptor homologues, also expresses an insulin degrading enzyme with properties that are very similar to those of mammalian insulin protease. In the present study, the insulin cleavage products generated by the Drosophila insulin degrading enzyme were identified and compared with the products generated by the mammalian insulin protease. Both purified enzymes were incubated with porcine insulin specifically labeled with {sup 125}I on either the A19 or B26 position, and the degradation products were analyzed by HPLC before and after sulfitolysis. Isolation and sequencing of the cleavage products indicated that both enzymes cleave the A chain of intact insulin at identical sites between residues A13 and A14 and A14 and A15. These results demonstrate that all the insulin cleavage sites generated by the Drosopohila insulin degrading enzyme are shared in common with the mammalian insulin protease. These data support the hypothesis that there is evolutionary conservation of the insulin degrading enzyme and further suggest that this enzyme plays an important role in cellular function.

  5. Tagging insulin in microgravity

    NASA Technical Reports Server (NTRS)

    Dobeck, Michael; Nelson, Ronald S.

    1992-01-01

    Knowing the exact subcellular sites of action of insulin in the body has the potential to give basic science investigators a basis from which a cause and cure for this disease can be approached. The goal of this project is to create a test reagent that can be used to visualize these subcellular sites. The unique microgravity environment of the Shuttle will allow the creation of a reagent that has the possibility of elucidating the subcellular sites of action of insulin. Several techniques have been used in an attempt to isolate the sites of action of items such as insulin. One of these is autoradiography in which the test item is obtained from animals fed radioactive materials. What is clearly needed is to visualize individual insulin molecules at their sites of action. The insulin tagging process to be used on G-399 involves the conjugation of insulin molecules with ferritin molecules to create a reagent that will be used back on Earth in an attempt to elucidate the sites of action of insulin.

  6. Technosphere inhaled insulin (Afrezza).

    PubMed

    Rendell, M

    2014-12-01

    Technosphere® insulin uses a unique carrier -fumaryl diketopiperazine (FDKP)- which adsorbs insulin to form microparticles to permit delivery to the alveoli by inhalation. Toxicity studies have been entirely negative. The pulmonary absorption of insulin is very rapid, and the disappearance time is shorter than for subcutaneously delivered rapid-acting insulins. As a result, after inhalation, there is a rapid drop in glucose levels which subsequently return to normal in a shorter time than after subcutaneous insulin administration. Consequently, there is a lower incidence of hypoglycemic reactions. Pulmonary function studies have shown a small, reversible decrease in FEV1, and pulmonary imaging studies have shown no adverse effect. The inhalation of Technosphere insulin can produce a cough in up to 27% of patients. The cough has resulted in discontinuance in as many as 9% of users. Technosphere insulin has been approved for use in type 1 and type 2 diabetes. Long-term studies of pulmonary safety and surveillance for malignancy will be performed in the future. Studies to assess the optimal time dosing regimen are needed. PMID:25588086

  7. [Alleged suicide by insulin].

    PubMed

    Birngruber, Christoph G; Krüll, Ralf; Dettmeyer, Reinhard; Verhoff, Marcel A

    2015-01-01

    A 26-year-old man, who was on probation, was found dead in his home by his mother. Insulin vials and 2 insulin pens, which the man's stepfather (an insulin-dependent diabetic) had been missing for over a week, were found next to the deceased. The circumstances suggested suicide by an injected insulin overdose. At the time of the autopsy, the corpse showed already marked signs of autolysis. Clinical chemical tests confirmed the injection of insulin, but indicated hyperglycemia at the time of death. Toxicological analyses revealed that the man had consumed amphetamine, cannabinoids, and tramadol in the recent past. Histological examination finally revealed extensive bronchopneumonia as the cause of death. The most plausible explanation for the results of the autopsy and the additional examinations was an injection of insulin as a failed attempt of self-treatment. It is conceivable that the man had discovered by a rapid test that he was a diabetic, but had decided not to go to a doctor to avoid disclosure of parole violation due to continued drug abuse. He may have misinterpreted the symptoms caused by his worsening bronchitis and the developing bronchopneumonia as symptoms of a diabetic metabolic status and may have felt compelled to treat himself with insulin. PMID:26419091

  8. Key Nutrients.

    ERIC Educational Resources Information Center

    Federal Extension Service (USDA), Washington, DC.

    Lessons written to help trainer agents prepare aides for work with families in the Food and Nutrition Program are presented in this booklet. The key nutrients discussed in the 10 lessons are protein, carbohydrates, fat, calcium, iron, iodine, and Vitamins A, B, C, and D. the format of each lesson is as follows: Purpose, Presentation, Application…

  9. Insulin and the law.

    PubMed

    Marks, Vincent

    2015-11-01

    Hypoglycaemia, if it can be proved, may be used as a defence against almost any criminal charge provided it can be established that the perpetrator was in a state of neuroglycopenic (hypoglycaemic) automatism at the time of the offence. Hypoglycaemia produced by exogenous insulin can also be used as a suicidal or homicidal weapon. This paper discusses some of the pitfalls confronting the investigator of suspected insulin misuse including problems arising from the increasing prevalence of insulin analogues and the unreliability of immunoassays for their detection and measurement in the forensic context. PMID:26092979

  10. Insulin glulisine: insulin receptor signaling characteristics in vivo.

    PubMed

    Hennige, Anita M; Lehmann, Rainer; Weigert, Cora; Moeschel, Klaus; Schäuble, Myriam; Metzinger, Elisabeth; Lammers, Reiner; Häring, Hans-Ulrich

    2005-02-01

    In recent years, recombinant DNA technology has been used to design insulin molecules that overcome the limitations of regular insulin in mealtime supplementation. However, safety issues have been raised with these alternatives, as the alteration of the three-dimensional structure may alter the interaction with the insulin and/or IGF-I receptors and therefore lead to the activation of alternate metabolic as well as mitogenic signaling pathways. It is therefore essential to carefully study acute and long-term effects in a preclinical state, as insulin therapy is meant to be a lifelong treatment. In this study, we determined in vivo the insulin receptor signaling characteristics activated by insulin glulisine (Lys(B3), Glu(B29)) at the level of insulin receptor phosphorylation, insulin receptor substrate phosphorylation, and downstream signaling elements such as phosphatidylinositol (PI) 3-kinase, AKT, and mitogen-activated protein kinase. C57BL/6 mice were injected with insulin glulisine or regular insulin and Western blot analysis was performed for liver and muscle tissue. The extent and time course of insulin receptor phosphorylation and activation of downstream signaling elements after insulin glulisine treatment was similar to that of human regular insulin in vivo. Moreover, insulin signaling in hypothalamic tissue determined by PI 3-kinase activity was comparable. Therefore, insulin glulisine may be a useful tool for diabetes treatment. PMID:15677493

  11. Age-Dependent Labeling and Imaging of Insulin Secretory Granules

    PubMed Central

    Ivanova, Anna; Kalaidzidis, Yannis; Dirkx, Ronald; Sarov, Mihail; Gerlach, Michael; Schroth-Diez, Britta; Müller, Andreas; Liu, Yanmei; Andree, Cordula; Mulligan, Bernard; Münster, Carla; Kurth, Thomas; Bickle, Marc; Speier, Stephan; Anastassiadis, Konstantinos; Solimena, Michele

    2013-01-01

    Insulin is stored within the secretory granules of pancreatic β-cells, and impairment of its release is the hallmark of type 2 diabetes. Preferential exocytosis of newly synthesized insulin suggests that granule aging is a key factor influencing insulin secretion. Here, we illustrate a technology that enables the study of granule aging in insulinoma cells and β-cells of knock-in mice through the conditional and unequivocal labeling of insulin fused to the SNAP tag. This approach, which overcomes the limits encountered with previous strategies based on radiolabeling or fluorescence timer proteins, allowed us to formally demonstrate the preferential release of newly synthesized insulin and reveal that the motility of cortical granules significantly changes over time. Exploitation of this approach may enable the identification of molecular signatures associated with granule aging and unravel possible alterations of granule turnover in diabetic β-cells. Furthermore, the method is of general interest for the study of membrane traffic and aging. PMID:23929935

  12. Age-dependent labeling and imaging of insulin secretory granules.

    PubMed

    Ivanova, Anna; Kalaidzidis, Yannis; Dirkx, Ronald; Sarov, Mihail; Gerlach, Michael; Schroth-Diez, Britta; Müller, Andreas; Liu, Yanmei; Andree, Cordula; Mulligan, Bernard; Münster, Carla; Kurth, Thomas; Bickle, Marc; Speier, Stephan; Anastassiadis, Konstantinos; Solimena, Michele

    2013-11-01

    Insulin is stored within the secretory granules of pancreatic β-cells, and impairment of its release is the hallmark of type 2 diabetes. Preferential exocytosis of newly synthesized insulin suggests that granule aging is a key factor influencing insulin secretion. Here, we illustrate a technology that enables the study of granule aging in insulinoma cells and β-cells of knock-in mice through the conditional and unequivocal labeling of insulin fused to the SNAP tag. This approach, which overcomes the limits encountered with previous strategies based on radiolabeling or fluorescence timer proteins, allowed us to formally demonstrate the preferential release of newly synthesized insulin and reveal that the motility of cortical granules significantly changes over time. Exploitation of this approach may enable the identification of molecular signatures associated with granule aging and unravel possible alterations of granule turnover in diabetic β-cells. Furthermore, the method is of general interest for the study of membrane traffic and aging. PMID:23929935

  13. Regulation of the insulin-like growth factor system by insulin in burn patients.

    PubMed

    Lang, C H; Fan, J; Frost, R A; Gelato, M C; Sakurai, Y; Herndon, D N; Wolfe, R R

    1996-07-01

    The aim of the present investigation was to determine whether there is a net uptake of insulin-like growth factor I (IGF-I) or IGF-binding proteins (IGFBPs) by the leg after burn injury and to elucidate the regulatory role of insulin exerted on this system under in vivo conditions in burn patients. Studies were performed on nine patients after burn injury (approximately 60% body surface area). Each patient was studied twice during a continuous infusion of a carbohydrate-rich enteral diet. Blood was collected simultaneously from the femoral artery and vein for the measurement of various elements of the IGF system after 7 days of enteral diet alone (basal period) and after 7 days of the enteral diet plus the infusion of insulin (insulin period). Data from these patients were compared to values in age-matched fed healthy volunteers. During the basal period, burn patients demonstrated a significant reduction in the venous concentration of IGF-I and an increase in both IGFBP-1 and -2 compared to control values. Insulin produced a significant 15% increase in the IGF-I concentration in burn patients, but decreased the circulating levels of IGFBP-1 by 50%. The IGF-I and IGFBP-1 concentrations at the end of the insulin period were still significantly different from those in control subjects. Burn patients also exhibited a marked reduction in intact IGFBP-3 and the acid-labile subunit under basal conditions, and these alterations were not reversed by insulin. Under basal conditions, all burn patients had a positive arterio-venous (A-V) difference for IGF-I across the leg. The A-V difference was increased 50% in response to insulin. The net uptake of IGF-I by the leg was 2.4 micrograms/min under basal conditions, and as leg blood flow also tended to increase in response to insulin, IGF-I uptake was elevated more than 3-fold during the insulin period. No A-V difference across the leg was detected for IGFBP-1, -2, or -3 in burn patients. In conclusion, burn injury in humans

  14. Measuring phospholipase D activity in insulin-secreting pancreatic beta-cells and insulin-responsive muscle cells and adipocytes.

    PubMed

    Cazzolli, Rosanna; Huang, Ping; Teng, Shuzhi; Hughes, William E

    2009-01-01

    Phospholipase D (PLD) is an enzyme producing phosphatidic acid and choline through hydrolysis of phosphatidylcholine. The enzyme has been identified as a member of a variety of signal transduction cascades and as a key regulator of numerous intracellular vesicle trafficking processes. A role for PLD in regulating glucose homeostasis is emerging as the enzyme has recently been identified in events regulating exocytosis of insulin from pancreatic beta-cells and also in insulin-stimulated glucose uptake through controlling GLUT4 vesicle exocytosis in muscle and adipose tissue. We present methodologies for assessing cellular PLD activity in secretagogue-stimulated insulin-secreting pancreatic beta-cells and also insulin-stimulated adipocyte and muscle cells, two of the principal insulin-responsive cell types controlling blood glucose levels. PMID:19160674

  15. Insulin Attenuates Beta-Amyloid-Associated Insulin/Akt/EAAT Signaling Perturbations in Human Astrocytes.

    PubMed

    Han, Xiaojuan; Yang, Liling; Du, Heng; Sun, Qinjian; Wang, Xiang; Cong, Lin; Liu, Xiaohui; Yin, Ling; Li, Shan; Du, Yifeng

    2016-08-01

    The excitatory amino acid transporters 1 and 2 (EAAT1 and EAAT2), mostly located on astrocytes, are the main mediators for glutamate clearance in humans. Malfunctions of these transporters may lead to excessive glutamate accumulation and subsequent excitotoxicity to neurons, which has been implicated in many kinds of neurodegenerative disorders including Alzheimer's disease (AD). Yet, the specific mechanism of the glutamate system dysregulation remains vague. To explore whether the insulin/protein kinase B (Akt)/EAAT signaling in human astrocytes could be disturbed by beta-amyloid protein (Aβ) and be protected by insulin, we incubated HA-1800 cells with varying concentrations of Aβ1-42 oligomers and insulin. Then the alterations of several key substrates in this signal transduction pathway were determined. Our results showed that expressions of insulin receptor, phospho-insulin receptor, phospho-protein kinase B, phospho-mammalian target of rapamycin, and EAAT1 and EAAT2 were decreased by the Aβ1-42 oligomers in a dose-dependent manner (p < 0.05) and this trend could be recovered by insulin treatment (p < 0.05). However, the expressions of total Akt and mTOR were invariant (p > 0.05), and the mRNA levels of EAAT1 and EAAT2 were also unchanged (p > 0.05). Taken together, this study indicates that Aβ1-42 oligomers could cause disturbances in insulin/Akt/EAAT signaling in astrocytes, which might be responsible for AD onset and progression. Additionally, insulin can exert protective functions to the brain by modulating protein modifications or expressions. PMID:26358886

  16. All about Insulin Resistance

    MedlinePlus

    ... news is that cutting calories, being active, and losing weight can reverse insulin resistance and lower your ... you’ll lose weight. Studies have shown that losing even 7% of your weight, may help. For ...

  17. Insulin Delivery System

    NASA Technical Reports Server (NTRS)

    1988-01-01

    When Programmable Implantable Medication System (PIMS) is implanted in human body, it delivers precise programmed amounts of insulin over long periods of time. Mini-Med Technologies has been refining the Technologies since initial development at APL. The size of a hockey puck, and encased in titanium shell, PIMS holds about 2 1/2 teaspoons of insulin at a programmed basal rate. If a change in measured blood sugar level dictates a different dose, the patient can vary the amount of insulin delivered by holding a small radio transceiver over the implanted system and dialing in a specific program held in the PIMS computer memory. Insulin refills are accomplished approximately 4 times a year by hypodermic needle.

  18. Insulin Resistance and Prediabetes

    MedlinePlus

    ... sleep apnea; and cigarette smoking. [ Top ] Does sleep matter? Yes. Studies show that untreated sleep problems, especially ... a severe form of insulin resistance may have dark patches of skin, usually on the back of ...

  19. Insulin Lispro Injection

    MedlinePlus

    ... a solution (liquid) and a suspension (liquid with particles that will settle on standing) to inject subcutaneously ( ... if it is colored, cloudy, or contains solid particles. If you are using insulin lispro suspension, the ...

  20. Insulin Human Inhalation

    MedlinePlus

    ... inhalation comes as a powder to inhale by mouth using a special inhaler. It is usually used ... to your doctor.Before you use your insulin oral inhaler the first time, read the written instructions ...

  1. Moving toward the ideal insulin for insulin pumps.

    PubMed

    Cengiz, Eda; Bode, Bruce; Van Name, Michelle; Tamborlane, William V

    2016-01-01

    Advances in insulin formulations have been important for diabetes management and achieving optimal glycemic control. Rapid-acting insulin analogs provide a faster time-action profile than regular insulin and are approved for use in pumps. However, the need remains for therapy to deliver a more physiologic insulin profile. New insulin formulations and delivery methods are in development, with the aim of accelerating insulin absorption to accomplish ultra-fast-acting insulin time-action profiles. Furthermore, the integration of continuous glucose monitoring with insulin pump therapy enables on-going adjustment of insulin delivery to optimize glycemic control throughout the day and night. These technological and pharmacological advances are likely to facilitate the development of closed-loop pump systems (i.e., artificial pancreas), and improve glycemic control and quality of life for patients with diabetes. PMID:26560137

  2. Insulin allergy treated with human insulin (recombinant DNA).

    PubMed

    De Leeuw, I; Delvigne, C; Bekaert, J

    1982-01-01

    Two insulin-dependent diabetic subjects treated with pork and beef insulin during a period of 6 mo developed severe local reactions. Both patients had an important allergic history (asthma, urticaria, drug reactions, rhinitis). Skin-testing revealed type I allergy to beef and pork insulin. Specific IgE-insulin binding was demonstrated with both insulins. After negative skin testing with NPH Lilly human insulin (recombinant DNA), treatment was started with this compound and remained successful during a period of 6-9 mo. In one patient a local reaction occurred when regular human insulin (recombinant DNA) was added to NPH in order to obtain better control. Skin testing with regular human insulin was positive, but not with NPH human insulin alone. The mechanism of this phenomenon remains unsolved. PMID:6765530

  3. Skeletal Muscle Insulin Resistance and Absence of Inflammation Characterize Insulin-Resistant Grade I Obese Women

    PubMed Central

    Bourret, Annick; Lambert, Karen; Birot, Olivier; Fédou, Christine; Dupuy, Anne-Marie; Cristol, Jean-Paul; Sutra, Thibault; Molinari, Nicolas; Maimoun, Laurent; Mariano-Goulart, Denis; Galtier, Florence; Avignon, Antoine; Stanke-Labesque, Françoise; Mercier, Jacques; Sultan, Ariane; Bisbal, Catherine

    2016-01-01

    Context Obesity is associated with insulin-resistance (IR), the key feature of type 2 diabetes. Although chronic low-grade inflammation has been identified as a central effector of IR development, it has never been investigated simultaneously at systemic level and locally in skeletal muscle and adipose tissue in obese humans characterized for their insulin sensitivity. Objectives We compared metabolic parameters and inflammation at systemic and tissue levels in normal-weight and obese subjects with different insulin sensitivity to better understand the mechanisms involved in IR development. Methods 30 post-menopausal women were classified as normal-weight insulin-sensitive (controls, CT) and obese (grade I) insulin-sensitive (OIS) or insulin-resistant (OIR) according to their body mass index and homeostasis model assessment of IR index. They underwent a hyperinsulinemic-euglycemic clamp, blood sampling, skeletal muscle and subcutaneous adipose tissue biopsies, an activity questionnaire and a self-administrated dietary recall. We analyzed insulin sensitivity, inflammation and IR-related parameters at the systemic level. In tissues, insulin response was assessed by P-Akt/Akt expression and inflammation by macrophage infiltration as well as cytokines and IκBα expression. Results Systemic levels of lipids, adipokines, inflammatory cytokines, and lipopolysaccharides were equivalent between OIS and OIR subjects. In subcutaneous adipose tissue, the number of anti-inflammatory macrophages was higher in OIR than in CT and OIS and was associated with higher IL-6 level. Insulin induced Akt phosphorylation to the same extent in CT, OIS and OIR. In skeletal muscle, we could not detect any inflammation even though IκBα expression was lower in OIR compared to CT. However, while P-Akt/Akt level increased following insulin stimulation in CT and OIS, it remained unchanged in OIR. Conclusion Our results show that systemic IR occurs without any change in systemic and tissues

  4. Treatment of insulin resistance: straight from the gut.

    PubMed

    Zhang, Xueli; Zheng, Xiao; Yuan, Yang

    2016-08-01

    Insulin resistance (IR) is a key pathological hallmark of obesity and type 2 diabetes. Emerging evidence has uncovered the gastrointestinal (GI) system as a previously overlooked player in fine-tuning systemic glucose homeostasis and insulin responses, which involved a complex inter-organ crosstalk through metabolic, endocrine, immune and neural mechanisms. These facts raise the intriguing possibility to explore the GI system as a new territory for IR intervention and glycemic control. Here we provide an overview of recent findings illustrating GI signals in the control of systemic insulin sensitivity and glucose homeostasis, and discuss the therapeutic prospects of exploiting the GI mechanisms to reverse IR and treat metabolic diseases. PMID:27326909

  5. Complementation analysis demonstrates that insulin cross-links both alpha subunits in a truncated insulin receptor dimer.

    PubMed

    Chan, Shu Jin; Nakagawa, Satoe; Steiner, Donald F

    2007-05-01

    The insulin receptor is a homodimer composed of two alphabeta half receptors. Scanning mutagenesis studies have identified key residues important for insulin binding in the L1 domain (amino acids 1-150) and C-terminal region (amino acids 704-719) of the alpha subunit. However, it has not been shown whether insulin interacts with these two sites within the same alpha chain or whether it cross-links a site from each alpha subunit in the dimer to achieve high affinity binding. Here we have tested the contralateral binding mechanism by analyzing truncated insulin receptor dimers (midi-hIRs) that contain complementary mutations in each alpha subunit. Midi-hIRs containing Ala(14), Ala(64), or Gly(714) mutations were fused with Myc or FLAG epitopes at the C terminus and were expressed separately by transient transfection. Immunoblots showed that R14A+FLAG, F64A+FLAG, and F714G+Myc mutant midi-hIRs were expressed in the medium but insulin binding activity was not detected. However, after co-transfection with R14A+FLAG/F714G+Myc or F64A+FLAG/F714G+Myc, hybrid dimers were obtained with a marked increase in insulin binding activity. Competitive displacement assays revealed that the hybrid mutant receptors bound insulin with the same affinity as wild type and also displayed curvilinear Scatchard plots. In addition, when hybrid mutant midi-hIR was covalently cross-linked with (125)I(A14)-insulin and reduced, radiolabeled monomer was immunoprecipitated only with anti-FLAG, demonstrating that insulin was bound asymmetrically. These results demonstrate that a single insulin molecule can contact both alpha subunits in the insulin receptor dimer during high affinity binding and this property may be an important feature for receptor signaling. PMID:17339314

  6. The core to regulatory reform

    SciTech Connect

    Partridge, J.W. Jr.

    1993-06-15

    Federal Energy Regulatory Commission (FERC) Orders 436, 500, and 636, the Clean Air Act Amendments of 1990, Public Utility Holding Company Act reform, and the 1992 Energy Policy Act all can have significant effects on an LDC's operations. Such changes in an LDC's environments must be balanced by changes within the utility, its marketplace, and its state regulatory environment. The question is where to start. For Columbia Gas Distribution Cos., based in Columbus, OH, the new operating foundation begins with each employee. Internal strength is critical in designing initiatives that meet the needs of the marketplace and are well-received by regulators. Employees must understand not only the regulatory environment in which the LDC operates, but also how their work contributes to a positive regulatory relationship. To achieve this, Columbia initiated the COntinuing Regulatory Education program, or CORE, in 1991. CORE is a regulatory-focused, information-initiative program coordinated by Columbia's Regulatory Policy, Planning, and Government Affairs Department. The CORE programs can take many forms, such as emerging issue discussions, dialogues with regulators and key parties, updates on regulatory fillings, regulatory policy meetings, and formal training classes. The speakers and discussion facilitators can range from human resource department trainers to senior officers, from regulatory department staff members to external experts, or from state commissioners to executives from other LDCs. The goals of CORE initiatives are to: Support a professional level of regulatory expertise through employee participation in well-developed regulatory programs presented by credible experts. Encourage a constructive state regulatory environment founded on communication and cooperation. CORE achieves these goals via five program levels: introductory basics, advanced learning, professional expertise, crossfunctional dialogues, and external idea exchanges.

  7. Insulin pump therapy in pregnancy.

    PubMed

    Kesavadev, Jothydev

    2016-09-01

    Control of blood glucose during pregnancy is difficult because of wide variations, ongoing hormonal changes and mood swings. The need for multiple injections, pain at the injection site, regular monitoring and skillful handling of the syringes/pen further makes insulin therapy inconvenient. Insulin pump is gaining popularity in pregnancy because it mimics the insulin delivery of a healthy human pancreas. Multiple guidelines have also recommended the use of insulin pump in pregnancy to maintain the glycaemic control. The pump can release small doses of insulin continuously (basal), or a bolus dose close to mealtime to control the spike in blood glucose after a meal and the newer devices can shut down insulin delivery before the occurrence of hypoglycaemia. Pump insulin of choice is rapid acting analogue insulin. This review underscores the role of insulin pump in pregnancy, their usage, advantages and disadvantages in the light of existing literature and clinic experience. PMID:27582150

  8. Ultrastructure of the liver microcirculation influences hepatic and systemic insulin activity and provides a mechanism for age-related insulin resistance.

    PubMed

    Mohamad, Mashani; Mitchell, Sarah Jayne; Wu, Lindsay Edward; White, Melanie Yvonne; Cordwell, Stuart James; Mach, John; Solon-Biet, Samantha Marie; Boyer, Dawn; Nines, Dawn; Das, Abhirup; Catherine Li, Shi-Yun; Warren, Alessandra; Hilmer, Sarah Nicole; Fraser, Robin; Sinclair, David Andrew; Simpson, Stephen James; de Cabo, Rafael; Le Couteur, David George; Cogger, Victoria Carroll

    2016-08-01

    While age-related insulin resistance and hyperinsulinemia are usually considered to be secondary to changes in muscle, the liver also plays a key role in whole-body insulin handling and its role in age-related changes in insulin homeostasis is largely unknown. Here, we show that patent pores called 'fenestrations' are essential for insulin transfer across the liver sinusoidal endothelium and that age-related loss of fenestrations causes an impaired insulin clearance and hyperinsulinemia, induces hepatic insulin resistance, impairs hepatic insulin signaling, and deranges glucose homeostasis. To further define the role of fenestrations in hepatic insulin signaling without any of the long-term adaptive responses that occur with aging, we induced acute defenestration using poloxamer 407 (P407), and this replicated many of the age-related changes in hepatic glucose and insulin handling. Loss of fenestrations in the liver sinusoidal endothelium is a hallmark of aging that has previously been shown to cause deficits in hepatic drug and lipoprotein metabolism and now insulin. Liver defenestration thus provides a new mechanism that potentially contributes to age-related insulin resistance. PMID:27095270

  9. Insulin signaling controls neurotransmission via the 4eBP-dependent modification of the exocytotic machinery.

    PubMed

    Mahoney, Rebekah Elizabeth; Azpurua, Jorge; Eaton, Benjamin A

    2016-01-01

    Altered insulin signaling has been linked to widespread nervous system dysfunction including cognitive dysfunction, neuropathy and susceptibility to neurodegenerative disease. However, knowledge of the cellular mechanisms underlying the effects of insulin on neuronal function is incomplete. Here, we show that cell autonomous insulin signaling within the Drosophila CM9 motor neuron regulates the release of neurotransmitter via alteration of the synaptic vesicle fusion machinery. This effect of insulin utilizes the FOXO-dependent regulation of the thor gene, which encodes the Drosophila homologue of the eif-4e binding protein (4eBP). A critical target of this regulatory mechanism is Complexin, a synaptic protein known to regulate synaptic vesicle exocytosis. We find that the amounts of Complexin protein observed at the synapse is regulated by insulin and genetic manipulations of Complexin levels support the model that increased synaptic Complexin reduces neurotransmission in response to insulin signaling. PMID:27525480

  10. Influence of anti-insulin antibodies on insulin immunoassays in the autoimmune insulin syndrome.

    PubMed

    Casesnoves, A; Mauri, M; Dominguez, J R; Alfayate, R; Picó, A M

    1998-11-01

    The autoimmune insulin syndrome (AIS) is a rare, benign syndrome characterized by hyperinsulinaemia and hypoglycaemia associated with the presence of autoantibodies to insulin in patients who have not been treated with insulin. We report here the case of a 52-year-old patient with recurrent attacks of severe postprandial hypoglycaemia and we also present the effect of anti-insulin antibodies on insulin immunoassays. The patient was submitted to the following diagnostic tests: 5-h oral glucose tolerance test (OGTT), a prolonged 72-h fast and an insulin tolerance test (ITT). Serum glucose, total and free insulin, C-peptide, proinsulin, insulin antibodies and other autoantibodies were measured. Insulin concentrations were measured by two methods: a double antibody radioimmunoassay (RIA) and an immunoradiometric assay (IRMA). Insulin concentration measured by RIA was extremely high in the OGTT and 72-h fast. In contrast, insulin concentrations measured by IRMA were between 120 and 888 pmol/L in the OGTT and between 37 and 133 pmol/L during the 72-h fast. Fasting free-insulin concentrations measured by RIA were between 2224 and 2669 pmol/L, whereas free-insulin concentrations measured by IRMA ranged between 93 and 237 pmol/L. Total insulin concentrations measured by RIA and IRMA were 57,615 and 94,021 pmol/L, respectively. The C-peptide concentrations were moderately high in the three tests. Serum insulin antibody concentrations were extremely high (62-71%), compared with less than 3% in normal serum samples. In conclusion, the high insulin concentrations measured by RIA were caused by insulin autoantibodies. However, insulin concentrations measured by IRMA were not influenced by them. We conclude that IRMA is the more accurate method for measuring insulin concentrations in such cases. PMID:9838991

  11. Depth keying

    NASA Astrophysics Data System (ADS)

    Gvili, Ronen; Kaplan, Amir; Ofek, Eyal; Yahav, Giora

    2003-05-01

    We present a new solution to the known problem of video keying in a natural environment. We segment foreground objects from background objects using their relative distance from the camera, which makes it possible to do away with the use of color for keying. To do so, we developed and built a novel depth video camera, capable of producing RGB and D signals, where D stands for the distance to each pixel. The new RGBD camera enables the creation of a whole new gallery of effects and applications such as multi-layer background substitutions. This new modality makes the production of real time mixed reality video possible, as well as post-production manipulation of recorded video. We address the problem of color spill -- in which the color of the foreground object is mixed, along its boundary, with the background color. This problem prevents an accurate separation of the foreground object from its background, and it is most visible when compositing the foreground objects to a new background. Most existing techniques are limited to the use of a constant background color. We offer a novel general approach to the problem with enabling the use of the natural background, based upon the D channel generated by the camera.

  12. An insulin signaling feedback loop regulates pancreas progenitor cell differentiation during islet development and regeneration.

    PubMed

    Ye, Lihua; Robertson, Morgan A; Mastracci, Teresa L; Anderson, Ryan M

    2016-01-15

    As one of the key nutrient sensors, insulin signaling plays an important role in integrating environmental energy cues with organism growth. In adult organisms, relative insufficiency of insulin signaling induces compensatory expansion of insulin-secreting pancreatic beta (β) cells. However, little is known about how insulin signaling feedback might influence neogenesis of β cells during embryonic development. Using genetic approaches and a unique cell transplantation system in developing zebrafish, we have uncovered a novel role for insulin signaling in the negative regulation of pancreatic progenitor cell differentiation. Blocking insulin signaling in the pancreatic progenitors hastened the expression of the essential β cell genes insulin and pdx1, and promoted β cell fate at the expense of alpha cell fate. In addition, loss of insulin signaling promoted β cell regeneration and destabilization of alpha cell character. These data indicate that insulin signaling constitutes a tunable mechanism for β cell compensatory plasticity during early development. Moreover, using a novel blastomere-to-larva transplantation strategy, we found that loss of insulin signaling in endoderm-committed blastomeres drove their differentiation into β cells. Furthermore, the extent of this differentiation was dependent on the function of the β cell mass in the host. Altogether, our results indicate that modulation of insulin signaling will be crucial for the development of β cell restoration therapies for diabetics; further clarification of the mechanisms of insulin signaling in β cell progenitors will reveal therapeutic targets for both in vivo and in vitro β cell generation. PMID:26658317

  13. An insulin signaling feedback loop regulates pancreas progenitor cell differentiation during islet development and regeneration

    PubMed Central

    Ye, Lihua; Robertson, Morgan A.; Mastracci, Teresa L.; Anderson, Ryan M.

    2016-01-01

    As one of the key nutrient sensors, insulin signaling plays an important role in integrating environmental energy cues with organism growth. In adult organisms, relative insufficiency of insulin signaling induces compensatory expansion of insulin-secreting pancreatic beta (β) cells. However, little is known about how insulin signaling feedback might influence neogenesis of β cells during embryonic development. Using genetic approaches and a unique cell transplantation system in developing zebrafish, we have uncovered a novel role for insulin signaling in the negative regulation of pancreatic progenitor cell differentiation. Blocking insulin signaling in the pancreatic progenitors hastened the expression of the essential β cell genes insulin and pdx1, and promoted β cell fate at the expense of alpha cell fate. In addition, loss of insulin signaling promoted β cell regeneration and destabilization of alpha cell character. These data indicate that insulin signaling constitutes a tunable mechanism for β cell compensatory plasticity during early development. Moreover, using a novel blastomere-to-larva transplantation strategy, we found that loss of insulin signaling in endoderm-committed blastomeres drove their differentiation into β cells. Furthermore, the extent of this differentiation was dependent on the function of the β cell mass in the host. Altogether, our results indicate that modulation of insulin signaling will be crucial for the development of β cell restoration therapies for diabetics; further clarification of the mechanisms of insulin signaling in β cell progenitors will reveal therapeutic targets for both in vivo and in vitro β cell generation. PMID:26658317

  14. [Reflections of a clinician on the switch from human to analogue insulin treatment].

    PubMed

    Deák, László

    2012-10-01

    The development of insulin therapy has not been stopped since the manufacturing of human insulin, because better mimic of physiological insulin response made it necessary to modify the human insulin molecule in order to create rapidly absorbing insulin analogues and 24-hour acting basal insulin analogues. Clinical observations indicate that the complete switch from human basal-bolus therapy to insulin analogues means not only "unit-for-unit" switch but it represents a transfer to an insulin therapy with different basal/bolus ratio as a result of different pharmacokinetic and pharmacodynamic properties of insulin and the level of insulin resistance of the patient. With reference to a case-history, the author presents his experience on a switch from human insulin to insulin analogue. Furthermore, the author summarizes data obtained from a few cases reported in international literature which draw the attention to the fact that the basal/bolus ratio should be adjusted individually, which may be the key for the success in the therapy in these cases. PMID:23022882

  15. Depression and Insulin Resistance

    PubMed Central

    Pearson, Sue; Schmidt, Mike; Patton, George; Dwyer, Terry; Blizzard, Leigh; Otahal, Petr; Venn, Alison

    2010-01-01

    OBJECTIVE To examine the association between depressive disorder and insulin resistance in a sample of young adults using the Composite International Diagnostic Interview to ascertain depression status. RESEARCH DESIGN AND METHODS Cross-sectional data were collected from 1,732 participants aged between 26 and 36 years. Insulin resistance was derived from blood chemistry measures of fasting insulin and glucose using the homeostasis model assessment method. Those identified with mild, moderate, or severe depression were classified as having depressive disorder. RESULTS The 12-month prevalence of depressive disorder was 5.4% among men and 11.7% among women. In unadjusted models mean insulin resistance was 17.2% (95% CI 0.7–36.0%, P = 0.04) higher in men and 11.4% (1.5–22.0%, P = 0.02) higher in women with depressive disorder. After adjustment for behavioral and dietary factors, the increased level of insulin resistance associated with depressive disorder was 13.2% (−3.1 to 32.3%, P = 0.12) in men and 6.1% (−4.1 to 17.4%, P = 0.25) in women. Waist circumference was identified as a mediator in the relationship between depression and insulin resistance, reducing the β coefficient in the fully adjusted models in men by 38% and in women by 42%. CONCLUSIONS A positive association was found between depressive disorder and insulin resistance in this population-based sample of young adult men and women. The association seemed to be mediated partially by waist circumference. PMID:20185745

  16. Molecular Mechanisms of Insulin Secretion and Insulin Action.

    ERIC Educational Resources Information Center

    Flatt, Peter R.; Bailey, Clifford J.

    1991-01-01

    Information and current ideas on the factors regulating insulin secretion, the mechanisms underlying the secretion and biological actions of insulin, and the main characteristics of diabetes mellitus are presented. (Author)

  17. New Insulins and New Aspects in Insulin Delivery.

    PubMed

    Woo, Vincent C

    2015-08-01

    The major abnormality in both type 1 and type 2 diabetes is insulin deficiency. The methods of replacing insulin have improved throughout the decades, but hypoglycemia is still the limiting factor for many individuals with diabetes, and it prevents them from achieving ideal glycemic targets. New insulin and newer delivery systems are being developed that can improve some of the limitations of current insulins or make the delivery of insulins more acceptable for some patients. Extending the duration of action of basal insulins and shortening the peak of fast-acting insulins may have advantages for individuals with diabetes. Different delivery systems may make insulin more acceptable to patients and may have other advantages, which may aid in attaining better glycemic control. PMID:26233724

  18. Quantitation of Insulin Analogues in Serum Using Immunoaffinity Extraction, Liquid Chromatography, and Tandem Mass Spectrometry.

    PubMed

    Van Der Gugten, J Grace; Wong, Sophia; Holmes, Daniel T

    2016-01-01

    Insulin analysis is used in combination with glucose, C-peptide, beta-hydroxybutyrate, and proinsulin determination for the investigation of adult hypoglycemia. The most common cause is the administration of too much insulin or insulin secretagogue to a diabetic patient or inadequate caloric intake after administration of either. Occasionally there is a question as to whether hypoglycemia has been caused by an exogenous insulin-whether by accident, intent, or even malicious intent. While traditionally this was confirmed by a low or undetectable C-peptide in a hypoglycemic specimen, this finding is not entirely specific and would also be expected in the context of impaired counter-regulatory response, fatty acid oxidation defects, and liver failure-though beta-hydroxybutyrate levels can lend diagnostic clarity. For this reason, insulin is often requested. However, popular automated chemiluminescent immunoassays for insulin have distinctly heterogeneous performance in detecting analogue synthetic insulins with cross-reactivities ranging from near 0 % to greater than 100 %. The ability to detect synthetic insulins is vendor-specific and varies between insulin products. Liquid Chromatography and Tandem Mass Spectrometry (LC-MS/MS) offers a means to circumvent these analytical issues and both quantify synthetic insulins and identify the specific type. We present an immunoaffinity extraction and LC-MS/MS method capable of independent identification and quantitation of native sequence insulins (endogenous, Insulin Regular, Insulin NPH), and analogues Glargine, Lispro, Detemir, and Aspart with an analytical sensitivity for endogenous insulin of between 1 and 2 μU/mL in patient serum samples. PMID:26602124

  19. Insulin Aspart (rDNA Origin) Injection

    MedlinePlus

    ... unless it is used in an external insulin pump. In patients with type 2 diabetes, insulin aspart ... also can be used with an external insulin pump. Before using insulin aspart in a pump system, ...

  20. Insulin Detemir (rDNA Origin) Injection

    MedlinePlus

    ... man-made version of human insulin. Insulin detemir works by replacing the insulin that is normally produced ... using an insulin pen, always remove the needle right after you inject your dose. Dispose of needles ...

  1. Development of insulin delivery systems.

    PubMed

    Siddiqui, N I; Siddiqui, Ni; Rahman, S; Nessa, A

    2008-01-01

    Delivery system of insulin is vital for its acceptance and adherence to therapy for achieving the glycemic targets. Enormous developments have occurred in the delivery system of insulin during the last twenty years and each improvement was aimed at two common goals: patients convenience and better glycemic control. Till to date, the various insulin delivery systems are: syringes/vials, injection aids, jet injectors, transmucosal delivery, transdermal delivery, external insulin infusion pump, implantable insulin pumps, insulin pens and insulin inhalers. Syringe/vial is the oldest and conventional method, still widely used and relatively cheaper. Modern plastic syringes are disposable, light weight with microfine needle for patients convenience and comfort. Oral route could be the most acceptable and viable, if the barriers can be overcome and under extensive trial. Insulin pen device is an important milestone in the delivery system of insulin as it is convenient, discrete, painless, attractive, portable with flexible life style and improved quality of life. More than 80% of European diabetic patients are using insulin pen. Future digital pen will have better memory option, blood glucose monitoring system, insulin dose calculator etc. Insulin infusion pump is a good option for the children, busy patients with flexible lifestyle and those who want to avoid multiple daily injections. Pulmonary route of insulin delivery is a promising, effective, non-invasive and acceptable alternative method. Exubera, the world first insulin inhaler was approved by FDA in 28 January 2006. But due to certain limitations, it has been withdrawn from the market in October 2007. The main concern of inhaled insulin are: long term pulmonary safety issues, cost effectiveness and user friendly device. In future, more acceptable and cost effective insulin inhaler will be introduced. Newer avenues are under extensive trial for better future insulin delivery systems. PMID:18285745

  2. Molecular Basis of Catalytic Chamber-assisted Unfolding and Cleavage of Human Insulin by Human Insulin-degrading Enzyme*S⃞

    PubMed Central

    Manolopoulou, Marika; Guo, Qing; Malito, Enrico; Schilling, Alexander B.; Tang, Wei-Jen

    2009-01-01

    Insulin is a hormone vital for glucose homeostasis, and insulin-degrading enzyme (IDE) plays a key role in its clearance. IDE exhibits a remarkable specificity to degrade insulin without breaking the disulfide bonds that hold the insulin A and B chains together. Using Fourier transform ion cyclotron resonance (FTICR) mass spectrometry to obtain high mass accuracy, and electron capture dissociation (ECD) to selectively break the disulfide bonds in gas phase fragmentation, we determined the cleavage sites and composition of human insulin fragments generated by human IDE. Our time-dependent analysis of IDE-digested insulin fragments reveals that IDE is highly processive in its initial cleavage at the middle of both the insulin A and B chains. This ensures that IDE effectively splits insulin into inactive N- and C-terminal halves without breaking the disulfide bonds. To understand the molecular basis of the recognition and unfolding of insulin by IDE, we determined a 2.6-Å resolution insulin-bound IDE structure. Our structure reveals that IDE forms an enclosed catalytic chamber that completely engulfs and intimately interacts with a partially unfolded insulin molecule. This structure also highlights how the unique size, shape, charge distribution, and exosite of the IDE catalytic chamber contribute to its high affinity (∼100 nm) for insulin. In addition, this structure shows how IDE utilizes the interaction of its exosite with the N terminus of the insulin A chain as well as other properties of the catalytic chamber to guide the unfolding of insulin and allowing for the processive cleavages. PMID:19321446

  3. Ovarian tumors secreting insulin.

    PubMed

    Battocchio, Marialberta; Zatelli, Maria Chiara; Chiarelli, Silvia; Trento, Mariangela; Ambrosio, Maria Rosaria; Pasquali, Claudio; De Carlo, Eugenio; Dassie, Francesca; Mioni, Roberto; Rebellato, Andrea; Fallo, Francesco; Degli Uberti, Ettore; Martini, Chiara; Vettor, Roberto; Maffei, Pietro

    2015-08-01

    Combined ovarian germ cell and neuroendocrine tumors are rare. Only few cases of hyperinsulinism due to ovarian ectopic secretion have been hypothesized in the literature. An ovarian tumor was diagnosed in a 76-year-old woman, referred to our department for recurrent hypoglycemia with hyperinsulinism. In vivo tests, in particular fasting test, rapid calcium infusion test, and Octreotide test were performed. Ectopic hyperinsulinemic hypoglycemia was demonstrated in vivo and hypoglycemia disappeared after hysteroadnexectomy. Histological exam revealed an ovarian germ cell tumor with neuroendocrine and Yolk sac differentiation, while immunostaining showed insulin positivity in neuroendocrine cells. A cell culture was obtained by tumoral cells, testing Everolimus, and Pasireotide. Insulin was detected in cell culture medium and Everolimus and Pasireotide demonstrated their potentiality in reducing insulin secretion, more than controlling cell viability. Nine cases of hyperinsulinism due to ovarian ectopic secretion reported in literature have been reviewed. These data confirm the ovarian tissue potentiality to induce hyperinsulinemic hypoglycemic syndrome after neoplastic transformation. PMID:25896552

  4. Acetoacetylation of insulin

    PubMed Central

    Lindsay, D. G.; Shall, S.

    1969-01-01

    Insulin was treated with diketen at pH6·9. The reaction mixture was resolved into four components by DEAE-Sephadex chromatography. The first component was unchanged insulin. The second and third components were shown by end-group analysis to be substituted on phenylalanine B-1 and glycine A-1 respectively. The fourth component was disubstituted on both phenylalanine B-1 and glycine A-1. The ∈-amino group of lysine B-29 was not involved in the reaction at low reagent concentrations. The purity of these derivatives was checked by their electrophoretic behaviour and by measurement of the rate of their reaction with trinitrobenzenesulphonic acid. The hormonal activity of the derivatives was determined. The effect of the modifications on the hormonal activity and the tertiary structure of insulin is discussed. ImagesFig. 10. PMID:5353531

  5. Insulin and carbohydrate dysregulation.

    PubMed

    Gelato, Marie C

    2003-04-01

    Patients with human immunodeficiency virus receiving highly active antiretroviral therapy (HAART) may experience abnormal body composition changes as well as metabolic abnormalities, including dyslipidemia, increases in triglycerides, low high-density lipoprotein cholesterol levels, and abnormal carbohydrate metabolism, ranging from insulin resistance with and without glucose intolerance to frank diabetes. Whether the body composition changes (i.e., increased visceral adiposity and fat wasting in the peripheral tissues) are linked to abnormalities in carbohydrate metabolism is unclear. The use of HAART with and without therapy with protease inhibitors (PIs) is related to carbohydrate abnormalities and changes in body composition. Regimens that include PIs appear to have a higher incidence of insulin resistance (up to 90%) and diabetes mellitus (up to 40%). The etiology of these abnormalities is not well understood; what is known about insulin and carbohydrate dysregulation with HAART is discussed. PMID:12652377

  6. Insulin C-peptide test

    MedlinePlus

    C-peptide ... the test depends on the reason for the C-peptide measurement. Ask your health care provider if ... C-peptide is measured to tell the difference between insulin produced by the body and insulin injected ...

  7. Alternative Devices for Taking Insulin

    MedlinePlus

    ... continuous glucose monitoring (CGM) system an insulin delivery system a computer program that adjusts insulin delivery based on changes in glucose levels CGM systems approved by the U.S. Food and Drug Administration ( ...

  8. Reduced insulin/insulin-like growth factor signaling decreases translation in Drosophila and mice

    PubMed Central

    Essers, Paul; Tain, Luke S.; Nespital, Tobias; Goncalves, Joana; Froehlich, Jenny; Partridge, Linda

    2016-01-01

    Down-regulation of insulin/insulin-like growth factor signaling (IIS) can increase lifespan in C. elegans, Drosophila and mice. In C. elegans, reduced IIS results in down-regulation of translation, which itself can extend lifespan. However, the effect of reduced IIS on translation has yet to be determined in other multicellular organisms. Using two long-lived IIS models, namely Drosophila lacking three insulin-like peptides (dilp2-3,5−/−) and mice lacking insulin receptor substrate 1 (Irs1−/−), and two independent translation assays, polysome profiling and radiolabeled amino acid incorporation, we show that reduced IIS lowers translation in these organisms. In Drosophila, reduced IIS decreased polysome levels in fat body and gut, but reduced the rate of protein synthesis only in the fat body. Reduced IIS in mice decreased protein synthesis rate only in skeletal muscle, without reducing polysomes in any tissue. This lowered translation in muscle was independent of Irs1 loss in the muscle itself, but a secondary effect of Irs1 loss in the liver. In conclusion, down-regulation of translation is an evolutionarily conserved response to reduced IIS, but the tissues in which it occurs can vary between organisms. Furthermore, the mechanisms underlying lowered translation may differ in mice, possibly associated with the complexity of the regulatory processes. PMID:27452396

  9. Reduced insulin/insulin-like growth factor signaling decreases translation in Drosophila and mice.

    PubMed

    Essers, Paul; Tain, Luke S; Nespital, Tobias; Goncalves, Joana; Froehlich, Jenny; Partridge, Linda

    2016-01-01

    Down-regulation of insulin/insulin-like growth factor signaling (IIS) can increase lifespan in C. elegans, Drosophila and mice. In C. elegans, reduced IIS results in down-regulation of translation, which itself can extend lifespan. However, the effect of reduced IIS on translation has yet to be determined in other multicellular organisms. Using two long-lived IIS models, namely Drosophila lacking three insulin-like peptides (dilp2-3,5(-/-)) and mice lacking insulin receptor substrate 1 (Irs1(-/-)), and two independent translation assays, polysome profiling and radiolabeled amino acid incorporation, we show that reduced IIS lowers translation in these organisms. In Drosophila, reduced IIS decreased polysome levels in fat body and gut, but reduced the rate of protein synthesis only in the fat body. Reduced IIS in mice decreased protein synthesis rate only in skeletal muscle, without reducing polysomes in any tissue. This lowered translation in muscle was independent of Irs1 loss in the muscle itself, but a secondary effect of Irs1 loss in the liver. In conclusion, down-regulation of translation is an evolutionarily conserved response to reduced IIS, but the tissues in which it occurs can vary between organisms. Furthermore, the mechanisms underlying lowered translation may differ in mice, possibly associated with the complexity of the regulatory processes. PMID:27452396

  10. A Hazard Analysis for a Generic Insulin Infusion Pump

    PubMed Central

    Zhang, Yi; Jones, Paul L.; Jetley, Raoul

    2010-01-01

    Background Researchers at the Food and Drug Administration (FDA)/Center for Device and Radiological Health/Office of Science and Engineering Laboratories have been exploring the concept of model-based engineering as a means for improving the quality of medical device software. Insulin pumps were chosen as a research subject because their design provides the desired degree of research complexity and these types of devices present an ongoing regulatory challenge. Methods Insulin pump hazards and their contributing factors are considered in the context of a highly abstract generic insulin infusion pump (GIIP) model. Hazards were identified by consulting with manufacturers, pump users, and clinicians; by reviewing national and international standards and adverse event reports collected by the FDA; and from workshops sponsored by Diabetes Technology Society. This information has been consolidated in tabular form to facilitate further community analysis and discussion. Results A generic insulin infusion pump model architecture has been established. A fairly comprehensive hazard analysis document, corresponding to the GIIP model, is presented in this article. Conclusions We believe that this work represents the genesis of an insulin pump safety reference standard upon which future insulin pump designs can be based to help ensure a basic level of safety. More interaction with the diabetes community is needed to assure the quality of this safety modeling process. PMID:20307387

  11. Insulin formulations--a review.

    PubMed

    Gualandi-Signorini, A M; Giorgi, G

    2001-01-01

    Although the improvement on insulin therapy since it was first conceived, it is still far from mimicking physiological secretion of pancreatic b-cells and research to find new insulin formulations and new routes of administration continues. Human biosynthetic insulin (rapid-acting, intermediate-acting and long-acting), produced by recombinant DNA technique, is currently available. The pharmacokinetic profile of rapid-acting insulin (regular) does not adequately reproduce the physiological post-prandial insulin response. This has led to the development of molecular analogues with slight modifications that prevent the spontaneous polymerisation underlying delayed absorption. Fast-acting analogues such as Lyspro and Aspart can be injected immediately before the meal, inducing a very fast and substantial peak of insulin, similar to that produced by b-cells, but have the disadvantage of short duration of action. For this reason, and because of the difficulty of obtaining sufficient basal insulin concentrations to control preprandial blood glucose levels with current long-acting insulins, analogues known as Glargine and Detemir have been synthesized. They have virtually no plasma peak and acts for about 24 h. These characteristics make it ideal to cover basal insulin requirement. With insulin analogues, it also seems possible to overcome the problem of intra- and inter-individual variability in absorption after subcutaneous injection. This variability is directly proportional to the duration of insulin action. Research into new routes of administration has led to production of inhaled insulin powder, soon to become commercially available. Insulin is absorbed through the lung alveoli. Trials to evaluate efficacy and toleration have shown that inhaled insulin has a similar kinetic profile to the fast-acting injected analogue and can therefore be used for mealtime requirement, combined with a single daily injection of long-acting insulin. Oral insulin is currently being

  12. Oral Insulin and Buccal Insulin: A Critical Reappraisal

    PubMed Central

    Heinemann, Lutz; Jacques, Yves

    2009-01-01

    Despite the availability of modern insulin injection devices with needles that are so sharp and thin that practically no injection pain takes place, it is still the dream of patients with diabetes to, for example, swallow a tablet with insulin. This is not associated with any pain and would allow more discretion. Therefore, availability of oral insulin would not only ease insulin therapy, it would certainly increase compliance. However, despite numerous attempts to develop such a “tablet” in the past 85 years, still no oral insulin is commercially available. Buccal insulin is currently in the last stages of clinical development by one company and might become available in the United States and Europe in the coming years (it is already on the market in some other countries). The aim of this review is to critically describe the different approaches that are currently under development. Optimal coverage of prandial insulin requirements is the aim with both routes of insulin administration (at least with most approaches). The speed of onset of metabolic effect seen with some oral insulin approaches is rapid, but absorption appears to be lower when the tablet is taken immediately prior to a meal. With all approaches, considerable amounts of insulin have to be applied in order to induce therapeutically relevant increases in the metabolic effect because of the low relative biopotency of buccal insulin. Unfortunately, the number of publications about clinical–experimental and clinical studies is surprisingly low. In addition, there is no study published in which the variability of the metabolic effect induced (with and without a meal) was studied adequately. In summary, after the failure of inhaled insulin, oral insulin and buccal insulin are hot candidates to come to the market as the next alternative routes of insulin administration. PMID:20144297

  13. Role of Osteocyte-derived Insulin-Like Growth Factor I in Developmental Growth, Modeling, Remodeling, and Regeneration of the Bone

    PubMed Central

    Sheng, Matilda H. C.; Lau, K. H. William

    2014-01-01

    The osteocyte has long been considered to be the primary mechanosensory cell in the bone. Recent evidence has emerged that the osteocyte is also a key regulator of various bone and mineral metabolism and that its regulatory effects are in part mediated through locally produced osteocyte-derived factors, such as sclerostin, receptor activator of nuclear factor-kappa B ligand (RANKL), and fibroblast growth factor (FGF)-23. Osteocytes secrete large amounts of insulin-like growth factor (IGF)-I in bone. Although IGF-I produced locally by other bone cells, such as osteoblasts and chondrocytes, has been shown to play important regulatory roles in bone turnover and developmental bone growth, the functional role of osteocyte-derived IGF-I in the bone and mineral metabolism has not been investigated and remains unclear. However, results of recent studies in osteocyte Igf1 conditional knockout transgenic mice have suggested potential regulatory roles of osteocyte-derived IGF-I in various aspects of bone and mineral metabolism. In this review, evidence supporting a regulatory role for osteocyte-derived IGF-I in the osteogenic response to mechanical loading, the developmental bone growth, the bone response to dietary calcium depletion and repletion, and in fracture repair is discussed. A potential coordinated regulatory relationship between the effect of osteocyte-derived IGF-I on bone size and the internal organ size is also proposed. PMID:24707466

  14. Biosimilar insulins: how similar is similar?

    PubMed

    Heinemann, Lutz; Hompesch, Marcus

    2011-05-01

    Biosimilar insulins (BIs) are viewed as commercially attractive products by a number of companies. In order to obtain approval in the European Union or the United States, where there is not a single BI currently on the market, a manufacturer needs to demonstrate that a given BI has a safety and efficacy profile that is similar to that of the "original" insulin formulation that is already on the market. As trivial as this may appear at first glance, it is not trivial at all for a good number of reasons that will be discussed in this commentary. As with protein manufacturing, modifications in the structure of the insulin molecule can take place (which can have serious consequences for the biological effects induced), so a rigid and careful assessment is absolutely necessary. The example of Marvel's failed application with the European Medicines Agency provides insights into the regulatory and clinical challenges surrounding the matter of BI. Although a challenging BI approval process might be regarded as a hurdle to keep companies out of certain markets, it is fair to say that the potential safety and efficacy issues surrounding BI are substantial and relevant and do warrant a careful and evidence-driven approval process. PMID:21722590

  15. Role of reduced insulin-stimulated bone blood flow in the pathogenesis of metabolic insulin resistance and diabetic bone fragility.

    PubMed

    Hinton, Pamela S

    2016-08-01

    Worldwide, 387 million adults live with type 2 diabetes (T2D) and an additional 205 million cases are projected by 2035. Because T2D has numerous complications, there is significant morbidity and mortality associated with the disease. Identification of early events in the pathogenesis of insulin resistance and T2D might lead to more effective treatments that would mitigate health and monetary costs. Here, we present our hypothesis that impaired bone blood flow is an early event in the pathogenesis of whole-body metabolic insulin resistance that ultimately leads to T2D. Two recent developments in different fields form the basis for this hypothesis. First, reduced vascular function has been identified as an early event in the development of T2D. In particular, before the onset of tissue or whole body metabolic insulin resistance, insulin-stimulated, endothelium-mediated skeletal muscle blood flow is impaired. Insulin resistance of the vascular endothelium reduces delivery of insulin and glucose to skeletal muscle, which leads to tissue and whole-body metabolic insulin resistance. Second is the paradigm-shifting discovery that the skeleton has an endocrine function that is essential for maintenance of whole-body glucose homeostasis. Specifically, in response to insulin signaling, osteoblasts secret osteocalcin, which stimulates pancreatic insulin production and enhances insulin sensitivity in skeletal muscle, adipose, and liver. Furthermore, the skeleton is not metabolically inert, but contributes to whole-body glucose utilization, consuming 20% that of skeletal muscle and 50% that of white adipose tissue. Without insulin signaling or without osteocalcin activity, experimental animals become hyperglycemic and insulin resistant. Currently, it is not known if insulin-stimulated, endothelium-mediated blood flow to bone plays a role in the development of whole body metabolic insulin resistance. We hypothesize that it is a key, early event. Microvascular dysfunction is a

  16. Cinnamon, glucose and insulin sensitivity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Compounds found in cinnamon not only improve the function of insulin but also function as antioxidants and may be anti-inflammatory. This is very important since insulin function, antioxidant status, and inflammatory response are closely linked; with decreased insulin sensitivity there is also decr...

  17. Phosphoinositides: Key modulators of energy metabolism☆

    PubMed Central

    Bridges, Dave; Saltiel, Alan R.

    2014-01-01

    Phosphoinositides are key players in many trafficking and signaling pathways. Recent advances regarding the synthesis, location and functions of these lipids have dramatically improved our understanding of how and when these lipids are generated and what their roles are in animal physiology. In particular, phosphoinositides play a central role in insulin signaling, and manipulation of PtdIns(3,4,5)P3 levels in particular, may be an important potential therapeutic target for the alleviation of insulin resistance associated with obesity and the metabolic syndrome. In this article we review the metabolism, regulation and functional roles of phosphoinositides in insulin signaling and the regulation of energy metabolism. This article is part of a Special Issue entitled Phosphoinositides. PMID:25463477

  18. An update on the treatment of type 1 and type 2 diabetes mellitus: focus on insulin detemir, a long-acting human insulin analog

    PubMed Central

    Raslova, Katarina

    2010-01-01

    Basal insulin analogs are used to minimize unpredictable processes of NPH insulin. Modification of the human insulin molecule results in a slower distribution to peripheral target tissues, a longer duration of action with stable concentrations and thus a lower rate of hypoglycemia. Insulin detemir is a basal insulin analog that provides effective therapeutic options for patients with type 1 and type 2 diabetes. For glycemic control, no significant differences were found in HbA1c levels compared with NPH and insulin glargine. It is comparable with insulin glargine in significantly reducing rates of all types of hypoglycemia. Clinical studies have demonstrated that detemir is responsible for significantly lower within-subject variability and no or less weight gain than NPH insulin and glargine. Recent pharmacodynamic studies have shown that detemir can be used once daily in many patients with diabetes. Together with patient-friendly injection devices and dose adjustments, it provides a treatment option with the potential to lower the key barriers of adherence to insulin therapy in type 2 diabetes. Recent guidelines for treatment of type 2 diabetes suggest starting intensive therapy of hyperglycemia at an early stage of diabetes and recommend therapeutic options that provide the possibility of reaching HbA1c goals individually, with a low risk of hypoglycemia or other adverse effects of treatment. The properties of insulin detemir match these requirements. PMID:20539842

  19. Insulin resistance in the liver: Deficiency or excess of insulin?

    PubMed Central

    Bazotte, Roberto B; Silva, Lorena G; Schiavon, Fabiana PM

    2014-01-01

    In insulin-resistant states (obesity, pre-diabetes, and type 2 diabetes), hepatic production of glucose and lipid synthesis are heightened in concert, implying that insulin deficiency and insulin excess coexists in this setting. The fact that insulin may be inadequate or excessive at any one point in differing organs and tissues has many biologic ramifications. In this context the concept of metabolic compartmentalization in the liver is offered herein as one perspective of this paradox. In particular, we focus on the hypothesis that insulin resistance accentuates differences in periportal and perivenous hepatocytes, namely periportal glucose production and perivenous lipid synthesis. Subsequently, excessive production of glucose and accumulation of lipids could be expected in the livers of patients with obesity and insulin resistance. Overall, in this review, we provide our integrative perspective regarding how excessive production of glucose in periportal hepatocytes and accumulation of lipids in perivenous hepatocytes interact in insulin resistant states. PMID:25486190

  20. JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity.

    PubMed

    Solinas, Giovanni; Vilcu, Cristian; Neels, Jaap G; Bandyopadhyay, Gautam K; Luo, Jun-Li; Naugler, Willscott; Grivennikov, Sergei; Wynshaw-Boris, Anthony; Scadeng, Miriam; Olefsky, Jerrold M; Karin, Michael

    2007-11-01

    Obesity-induced insulin resistance is a major factor in the etiology of type 2 diabetes, and Jun kinases (JNKs) are key negative regulators of insulin sensitivity in the obese state. Activation of JNKs (mainly JNK1) in insulin target cells results in phosphorylation of insulin receptor substrates (IRSs) at serine and threonine residues that inhibit insulin signaling. JNK1 activation is also required for accumulation of visceral fat. Here we used reciprocal adoptive transfer experiments to determine whether JNK1 in myeloid cells, such as macrophages, also contributes to insulin resistance and central adiposity. Our results show that deletion of Jnk1 in the nonhematopoietic compartment protects mice from high-fat diet (HFD)-induced insulin resistance, in part through decreased adiposity. By contrast, Jnk1 removal from hematopoietic cells has no effect on adiposity but confers protection against HFD-induced insulin resistance by decreasing obesity-induced inflammation. PMID:17983584

  1. [Insulin therapy of diabetes].

    PubMed

    Lechleitner, Monika; Roden, Michael; Weitgasser, Raimund; Ludvik, Bernhard; Fasching, Peter; Hoppichler, Friedrich; Kautzky-Willer, Alexandra; Schernthaner, Guntram; Prager, Rudolf; Wascher, Thomas C

    2016-04-01

    Hyperglycemia contributes to morbidity and mortality in patients with diabetes. Thus, reaching treatment targets with regard to control of glycemia is a central goal in the therapy of diabetic patients. The present article represents the recommendations of the Austrian Diabetes Association for the practical use of insulin according to current scientific evidence and clinical studies. PMID:27052221

  2. Insulin Resistance and Prediabetes

    MedlinePlus

    ... to be used in most health care providers' offices. The clamp is a research tool used by scientists to learn more about glucose metabolism. Research has shown that if blood tests indicate prediabetes, insulin ... care provider's office or commercial facility and sending the sample to ...

  3. Genetics of Insulin Resistance and the Metabolic Syndrome.

    PubMed

    Brown, Audrey E; Walker, Mark

    2016-08-01

    Insulin resistance and the metabolic syndrome are complex metabolic traits and key risk factors for the development of cardiovascular disease. They result from the interplay of environmental and genetic factors but the full extent of the genetic background to these conditions remains incomplete. Large-scale genome-wide association studies have helped advance the identification of common genetic variation associated with insulin resistance and the metabolic syndrome, and more recently, exome sequencing has allowed the identification of rare variants associated with the pathogenesis of these conditions. Many variants associated with insulin resistance are directly involved in glucose metabolism; however, functional studies are required to assess the contribution of other variants to the development of insulin resistance. Many genetic variants involved in the pathogenesis of the metabolic syndrome are associated with lipid metabolism. PMID:27312935

  4. Leptin, Insulin, and Cinnamon Polyphenols Attenuate Glial Swelling and Mitochondrial Dysfunction in Ischemic Injury

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity is a major risk factor for stroke, and tissue injury following a stroke may be more severe in the obese. A key feature of obesity is increased serum levels of obesity-related hormones including leptin and insulin, indicating a state of resistance to these hormones. Insulin resistance is gen...

  5. Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chronic low-grade inflammation is a hallmark of obesity and thought to contribute to the development of obesity-related insulin resistance. Toll-like receptor 4 (Tlr4) is a key mediator of pro-inflammatory responses. Mice lacking Tlr4s are protected from diet-induced insulin resistance and inflammat...

  6. Central GLP-2 enhances hepatic insulin sensitivity via activating PI3K signaling in POMC neurons

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Glucagon-like peptides (GLP-1/GLP-2) are coproduced and highlighted as key modulators to improve glucose homeostasis and insulin sensitivity after bariatric surgery. However, it is unknown if CNS GLP-2 plays any physiological role in the control of glucose homeostasis and insulin sensitivity. We sho...

  7. Selective Insulin Resistance in Adipocytes*

    PubMed Central

    Tan, Shi-Xiong; Fisher-Wellman, Kelsey H.; Fazakerley, Daniel J.; Ng, Yvonne; Pant, Himani; Li, Jia; Meoli, Christopher C.; Coster, Adelle C. F.; Stöckli, Jacqueline; James, David E.

    2015-01-01

    Aside from glucose metabolism, insulin regulates a variety of pathways in peripheral tissues. Under insulin-resistant conditions, it is well known that insulin-stimulated glucose uptake is impaired, and many studies attribute this to a defect in Akt signaling. Here we make use of several insulin resistance models, including insulin-resistant 3T3-L1 adipocytes and fat explants prepared from high fat-fed C57BL/6J and ob/ob mice, to comprehensively distinguish defective from unaffected aspects of insulin signaling and its downstream consequences in adipocytes. Defective regulation of glucose uptake was observed in all models of insulin resistance, whereas other major actions of insulin such as protein synthesis and anti-lipolysis were normal. This defect corresponded to a reduction in the maximum response to insulin. The pattern of change observed for phosphorylation in the Akt pathway was inconsistent with a simple defect at the level of Akt. The only Akt substrate that showed consistently reduced phosphorylation was the RabGAP AS160 that regulates GLUT4 translocation. We conclude that insulin resistance in adipose tissue is highly selective for glucose metabolism and likely involves a defect in one of the components regulating GLUT4 translocation to the cell surface in response to insulin. PMID:25720492

  8. Adipocyte lipolysis and insulin resistance.

    PubMed

    Morigny, Pauline; Houssier, Marianne; Mouisel, Etienne; Langin, Dominique

    2016-06-01

    Obesity-induced insulin resistance is a major risk factor for the development of type 2 diabetes. Basal fat cell lipolysis (i.e., fat cell triacylglycerol breakdown into fatty acids and glycerol in the absence of stimulatory factors) is elevated during obesity and is closely associated with insulin resistance. Inhibition of adipocyte lipolysis may therefore be a promising therapeutic strategy for treating insulin resistance and preventing obesity-associated type 2 diabetes. In this review, we explore the relationship between adipose lipolysis and insulin sensitivity. After providing an overview of the components of fat cell lipolytic machinery, we describe the hypotheses that may support the causality between lipolysis and insulin resistance. Excessive circulating fatty acids may ectopically accumulate in insulin-sensitive tissues and impair insulin action. Increased basal lipolysis may also modify the secretory profile of adipose tissue, influencing whole body insulin sensitivity. Finally, excessive fatty acid release may also worsen adipose tissue inflammation, a well-known parameter contributing to insulin resistance. Partial genetic or pharmacologic inhibition of fat cell lipases in mice as well as short term clinical trials using antilipolytic drugs in humans support the benefit of fat cell lipolysis inhibition on systemic insulin sensitivity and glucose metabolism, which occurs without an increase of fat mass. Modulation of fatty acid fluxes and, putatively, of fat cell secretory pattern may explain the amelioration of insulin sensitivity whereas changes in adipose tissue immune response do not seem involved. PMID:26542285

  9. Transdermal Insulin Delivery Using Microdermabrasion

    PubMed Central

    Andrews, Samantha; Lee, Jeong Woo; Choi, Seong-O

    2011-01-01

    Purpose Transdermal insulin delivery is an attractive needle-free alternative to subcutaneous injection conventionally used to treat diabetes. However, skin’s barrier properties prevent insulin permeation at useful levels. Methods We investigated whether microdermabrasion can selectively remove skin’s surface layers to increase skin permeability as a method to administer insulin to diabetic rats. We further assessed the relative roles of stratum corneum and viable epidermis as barriers to insulin delivery. Results Pretreatment of skin with microdermabrasion to selectively remove stratum corneum did not have a significant effect on insulin delivery or reduction in blood glucose level (BGL). Removal of full epidermis by microdermabrasion significantly reduced BGL, similar to the positive control involving subcutaneous injection of 0.1U insulin. Significant pharmacokinetic differences between microdermabrasion and subcutaneous injection were faster time to peak insulin concentration after injection and larger peak insulin concentration and area-under-the-curve after microdermabrasion. Conclusions Microdermabrasion can increase skin permeability to insulin at levels sufficient to reduce BGL. Viable epidermis is a barrier to insulin delivery such that removal of full epidermis enables significantly more insulin delivery than removal of stratum corneum alone. PMID:21499837

  10. Evidence against extrapancreatic insulin synthesis.

    PubMed Central

    Eng, J; Yalow, R S

    1981-01-01

    Labeled and unlabeled insulin in acid/ethanol tissue extracts can be concentrated up to 100-fold by using a hydrophobic adsorption technique. After adsorption to and elution from an octadecylsilyl silica column, insulin is recovered in yields greater than 75%. By using this method of concentration, insulin in brain tissues of three of four fed rats and one rabbit was found to be less than 20% of plasma concentration. The kidney is the only extrapancreatic organ in which insulin is observed to be markedly above plasma levels. Porcine-insulin-like material was not detectable in guinea pig tissues (less than 0.02 ng/g). It is concluded that insulin is not synthesized in brain or other extrapancreatic tissues and that other mammalian insulins are not found in guinea pig tissues. PMID:6270683

  11. Insulin degludec for diabetes mellitus.

    PubMed

    2013-07-01

    Over the last few years there has been a steady increase in the number of prescriptions dispensed in primary care for intermediate and long-acting insulin analogues and a reduction in prescriptions for biphasic isophane insulin. For example, in England, the volume of intermediate and long-acting insulin analogues in general practice has risen from approximately 650,000 prescriptions per quarter in 2007 to over 850,000 per quarter in 2012.(1) ▾Insulin degludec (Tresiba, Novo Nordisk) is a new long acting basal insulin analogue for the management of diabetes mellitus in adults.(2) Two strengths of insulin degludec (100 units/mL and 200 units/mL) were launched in the UK in February 2013. Here we discuss evidence for the effectiveness and safety of insulin degludec. PMID:23842634

  12. [Current concept of insulin therapy intensification, and the role of human regular insulin and rapid-acting insulin analogs in insulin treatment].

    PubMed

    Hamaguchi, Tomoya; Sadahiro, Katsuhiko; Satoh, Tomomi

    2015-03-01

    The evolution of insulin therapy from animal insulin to recombinant human regular insulin has improved diabetes treatment. Generating of rapid-acting insulin analogs, mimicking physiologic insulin action enables us to provide better control of post-prandial glucose level and lower incidence of hypoglycemia compared with human regular insulin. These rapid-acting insulin analogs show lower susceptibility of insulin precipitation and catheter occlusions, and are suitable for insulin pump therapy of continuous subcutaneous insulin infusion. Insulin lispro and insulin aspart are also applicable for diabetic patients with pregnancy, requiring excellent glycemic control. In some studies, stepwise addition of prandial insulin, as well as full basal-bolus regimen can improve glycemic control with less hypoglycemia. Treatment intensification with rapid-acting insulin analogs may offer a proper method to reach glycemic goals. PMID:25812371

  13. Basal insulin delivery reduction for exercise in type 1 diabetes: finding the sweet spot.

    PubMed

    Thabit, Hood; Leelarathna, Lalantha

    2016-08-01

    Exercise poses significant challenges to glucose management in type 1 diabetes. In spite of careful planning and manipulation of subcutaneous insulin administration, increased risk of hypoglycaemia and glycaemic variability during and after exercise may occur as a result of inherent delays in insulin action and impaired counter-regulatory hormone responses. Various strategies to mitigate this issue have been advocated in clinical practice, including ingestion of supplementary carbohydrate prior to exercise, reducing background and pre-meal insulin bolus and performing bouts of resistance/high intensity exercise before aerobic exercise. Insulin pump therapy, considered the most physiological form of insulin replacement for type 1 diabetes allows modulation of basal insulin delivery before, during and after exercise. However uncertainty remains regarding the optimal strategy to reduce basal insulin delivery and its efficacy. In this issue of Diabetologia, McAuley and colleagues (DOI: 10.1007/s00125-016-3981-9 ) report on the impact of a 50% reduction of basal insulin delivery before, during and after moderate-intensity aerobic exercise. Results from this study may contribute to a better understanding of the effects of basal insulin delivery manipulation and may aid in devising therapeutic approaches for glucose management during exercise. PMID:27287376

  14. Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer's disease intervention.

    PubMed

    Zhao, Lixia; Teter, Bruce; Morihara, Takashi; Lim, Giselle P; Ambegaokar, Surendra S; Ubeda, Oliver J; Frautschy, Sally A; Cole, Greg M

    2004-12-01

    Insulin-degrading enzyme (IDE) is one of the proteins that has been demonstrated to play a key role in degrading beta-amyloid (Abeta) monomer in vitro and in vivo, raising the possibility of upregulating IDE as an approach to reduce Abeta. Little is known, however, about the cellular and molecular regulation of IDE protein. Because one of the main functions of IDE is to degrade insulin, we hypothesized that there is a negative feedback mechanism whereby stimulation of insulin receptor-mediated signaling upregulates IDE to prevent chronic activation of the pathway. We show that treatment of primary hippocampal neurons with insulin increased IDE protein levels by approximately 25%. Insulin treatment also led to phosphatidylinositol-3 (PI3) kinase activation evidenced by Akt phosphorylation, which was blocked by PI3 kinase inhibitors, wortmannin and LY 294002. Inhibition of PI3 kinase abolished the IDE upregulation by insulin, indicating a cause-effect relationship between insulin signaling and IDE upregulation. Further support for this link was provided by the findings that deficient insulin signaling (decreased PI3 kinase subunit P85) was correlated with reduced IDE in Alzheimer's disease (AD) brains and in Tg2576 Swedish amyloid precursor protein transgenic mice fed a safflower oil-enriched ("Bad") diet used to accelerate pathogenesis. Consistent with IDE function in the degradation of Abeta monomer, the IDE decrease in the Bad diet-fed Tg2576 mice was associated with increased Abeta monomer levels. These in vitro and in vivo analyses validate the use of enhanced CNS insulin signaling as a potential strategy for AD intervention to correct the IDE defects occurring in AD. PMID:15590928

  15. Effects of food restriction and insulin treatment on (Ca2+ + Mg2+)-ATPase response to insulin in kidney basolateral membranes of noninsulin-dependent diabetic rats.

    PubMed

    Levy, J; Grunberger, G; Karl, I; Gavin, J R

    1990-01-01

    Insulin increases (Ca2+ + Mg2+)-ATPase activity in cell membranes of normal rats but fails to do so in membranes of non-insulin-dependent diabetic (NIDD) rats. The loss of regulatory effect of the hormone on the enzyme might contribute to the insulin resistance observed in the NIDD animals. To further test this hypothesis, the effects of insulin treatment and acute food restriction on the ability of insulin to regulate the ATPase activity in kidney basolateral membranes (BLM) of NIDD rats were studied. Although insulin levels in NIDD and control rats were similar, plasma glucose was higher in the NIDD rats (18.3 +/- 1.5 v 19.3 +/- 1.7 microU/mL and 236 +/- 32 v 145 +/- 3 mg/dL, respectively). Insulin treatment (2 U/100 g), which increased plasma insulin in the NIDD rats (47.8 +/- 11.5 microU/mL; P less than .05), did not decrease their glucose (221 +/- 25 mg/dL). Higher insulin dose (4 U/100 g) decreased glucose level in the NIDD rats (73 +/- 3 mg/dL; P less than .001) but increased their plasma insulin 10-fold (202.5 +/- 52.5 microU/mL). Acute food restriction decreased glucose levels in the NIDD rats to levels seen in controls (135 +/- 3 mg/dL), while their insulin decreased by half (8.5 +/- 1.0 microU/mL; P less than .05). Basal (Ca2+ + Mg2+)-ATPase activity in BLM of all diabetic rats was higher than in controls (P less than .05). None of the treatments reversed this defect.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2136760

  16. Understanding Genetic Heterogeneity in Type 2 Diabetes by Delineating Physiological Phenotypes: SIRT1 and its Gene Network in Impaired Insulin Secretion.

    PubMed

    Ali, Shafat; Nafis, Shazia; Kalaiarasan, Ponnusamy; Rai, Ekta; Sharma, Swarkar; Bamezai, Rameshwar N

    2016-01-01

    Type 2 diabetes (T2D) is a chronic metabolic disease which shows an exponential increase in all parts of the world. However, the disease is controllable by early detection and modified lifestyle. A series of factors have been associated with the pathogenesis of diabetes, and genes are considered to play a critical role. The individual risk of developing T2D is determined by an altered genetic background of the en-zymes involved in several metabolism-related biological mechanisms, including glucose homeostasis, insulin metab-olism, the glucose and ion transporters involved in glucose uptake, transcription factors, signaling intermediates of insulin signaling pathways, insulin production and secretion, pancreatic tissue development, and apoptosis. However, many candidate genes have shown heterogeneity of associations with the disease in different populations. A possible approach to resolving this complexity and under-standing genetic heterogeneity is to delineate the physiological phenotypes one by one as studying them in combination may cause discrepancies in association studies. A systems biology approach involving regulatory proteins, transcription factors, and microRNAs is one way to understand and identify key factors in complex diseases such as T2D. Our earlier studies have screened more than 100 single nucleotide polymorphisms (SNPs) belonging to more than 60 globally known T2D candidate genes in the Indian population. We observed that genes invariably involved in the activity of pancreatic β-cells provide susceptibility to type 2 diabetes (T2D). Encouraged by these results, we attempted to delineate in this review one of the commonest physiological phenotypes in T2D, namely impaired insulin secretion, as the cause of hyperglycemia. This review is also intended to explain the genetic basis of the pathophysiology of insulin secretion in the context of variations in the SIRT1 gene, a major switch that modulates insulin secretion, and a set of other genes such

  17. Insulin analog with additional disulfide bond has increased stability and preserved activity.

    PubMed

    Vinther, Tine N; Norrman, Mathias; Ribel, Ulla; Huus, Kasper; Schlein, Morten; Steensgaard, Dorte B; Pedersen, Thomas Å; Pettersson, Ingrid; Ludvigsen, Svend; Kjeldsen, Thomas; Jensen, Knud J; Hubálek, František

    2013-03-01

    Insulin is a key hormone controlling glucose homeostasis. All known vertebrate insulin analogs have a classical structure with three 100% conserved disulfide bonds that are essential for structural stability and thus the function of insulin. It might be hypothesized that an additional disulfide bond may enhance insulin structural stability which would be highly desirable in a pharmaceutical use. To address this hypothesis, we designed insulin with an additional interchain disulfide bond in positions A10/B4 based on Cα-Cα distances, solvent exposure, and side-chain orientation in human insulin (HI) structure. This insulin analog had increased affinity for the insulin receptor and apparently augmented glucodynamic potency in a normal rat model compared with HI. Addition of the disulfide bond also resulted in a 34.6°C increase in melting temperature and prevented insulin fibril formation under high physical stress even though the C-terminus of the B-chain thought to be directly involved in fibril formation was not modified. Importantly, this analog was capable of forming hexamer upon Zn addition as typical for wild-type insulin and its crystal structure showed only minor deviations from the classical insulin structure. Furthermore, the additional disulfide bond prevented this insulin analog from adopting the R-state conformation and thus showing that the R-state conformation is not a prerequisite for binding to insulin receptor as previously suggested. In summary, this is the first example of an insulin analog featuring a fourth disulfide bond with increased structural stability and retained function. PMID:23281053

  18. Dopamine-mediated autocrine inhibitory circuit regulating human insulin secretion in vitro.

    PubMed

    Simpson, Norman; Maffei, Antonella; Freeby, Matthew; Burroughs, Steven; Freyberg, Zachary; Javitch, Jonathan; Leibel, Rudolph L; Harris, Paul E

    2012-10-01

    We describe a negative feedback autocrine regulatory circuit for glucose-stimulated insulin secretion in purified human islets in vitro. Using chronoamperometry and in vitro glucose-stimulated insulin secretion measurements, evidence is provided that dopamine (DA), which is loaded into insulin-containing secretory granules by vesicular monoamine transporter type 2 in human β-cells, is released in response to glucose stimulation. DA then acts as a negative regulator of insulin secretion via its action on D2R, which are also expressed on β-cells. We found that antagonism of receptors participating in islet DA signaling generally drive increased glucose-stimulated insulin secretion. These in vitro observations may represent correlates of the in vivo metabolic changes associated with the use of atypical antipsychotics, such as increased adiposity. PMID:22915827

  19. Dopamine-Mediated Autocrine Inhibitory Circuit Regulating Human Insulin Secretion in Vitro

    PubMed Central

    Simpson, Norman; Maffei, Antonella; Freeby, Matthew; Burroughs, Steven; Freyberg, Zachary; Javitch, Jonathan; Leibel, Rudolph L.

    2012-01-01

    We describe a negative feedback autocrine regulatory circuit for glucose-stimulated insulin secretion in purified human islets in vitro. Using chronoamperometry and in vitro glucose-stimulated insulin secretion measurements, evidence is provided that dopamine (DA), which is loaded into insulin-containing secretory granules by vesicular monoamine transporter type 2 in human β-cells, is released in response to glucose stimulation. DA then acts as a negative regulator of insulin secretion via its action on D2R, which are also expressed on β-cells. We found that antagonism of receptors participating in islet DA signaling generally drive increased glucose-stimulated insulin secretion. These in vitro observations may represent correlates of the in vivo metabolic changes associated with the use of atypical antipsychotics, such as increased adiposity. PMID:22915827

  20. Insulin receptor in Drosophila melanogaster

    SciTech Connect

    Petruzzelli, L.; Herrera, R.; Rosen, O.

    1986-05-01

    A specific, high affinity insulin receptor is present in both adult Drosophila and in Drosophila embryos. Wheat germ lectin-enriched extracts of detergent-solubilized membranes from embryos and adults bind insulin with a K/sub d/ of 15 nM. Binding is specific for insulin; micromolar concentrations of proinsulin, IGFI, and IGFII are required to displace bound /sup 125/I-insulin. Insulin-dependent protein tyrosine kinase activity appears during embryogenesis. It is evident between 6 and 12 hours of development, peaks between 12 and 18 hours and falls in the adult. During 0-6 hours of embryogenesis, and in the adult, a specific protein band (Mr = 135,000) is crosslinked to /sup 125/I-insulin. During 6-12 and 12-18 hours of embryogenesis stages in which insulin-dependent protein tyrosine kinase is high, an additional band (Mr = 100,000) becomes crosslinked to /sup 125/I-insulin. Isolation and DNA sequence analysis of genomic clones encoding the Drosophila insulin receptor will be presented as will the characterization of insulin receptor mRNA's during development.

  1. Variability of NPH Insulin Preparations

    PubMed Central

    Belmonte, M. M.; Colle, E.; deBelle, R.; Murthy, D. Y. N.

    1971-01-01

    In 1968-69 certain juvenile diabetics receiving NPH insulin began having pre-breakfast glucosuria and mid-morning hypoglycemic reactions. A mail survey of our clinic population and a study done at the Quebec camp for diabetic children in 1969 revealed that certain lot numbers were associated with poor control and that a change to new lot numbers or alternate insulin preparations resulted in better control. “Suspect” insulin preparations and non-suspect insulins were given to newly diagnosed diabetics, and plasma insulin and glucose levels were measured over a 24-hour period. The data confirmed that the “suspect” insulins were causing early hypoglycemia and failing to control hyperglycemia during the latter hours of the 24-hour period. The lower glucose levels were associated with higher plasma insulin levels. The “suspect” insulins were further found to have elevated levels of free insulin in the supernatant fluid. The requirements for quality control of modified insulin preparations are reviewed and suggestions are offered for their improvement. PMID:5539004

  2. Pitfalls of Insulin Pump Clocks

    PubMed Central

    Reed, Amy J.

    2014-01-01

    The objective was to raise awareness about the importance of ensuring that insulin pumps internal clocks are set up correctly at all times. This is a very important safety issue because all commercially available insulin pumps are not GPS-enabled (though this is controversial), nor equipped with automatically adjusting internal clocks. Special attention is paid to how basal and bolus dose errors can be introduced by daylight savings time changes, travel across time zones, and am-pm clock errors. Correct setting of insulin pump internal clock is crucial for appropriate insulin delivery. A comprehensive literature review is provided, as are illustrative cases. Incorrect setting can potentially result in incorrect insulin delivery, with potential harmful consequences, if too much or too little insulin is delivered. Daylight saving time changes may not significantly affect basal insulin delivery, given the triviality of the time difference. However, bolus insulin doses can be dramatically affected. Such problems may occur when pump wearers have large variations in their insulin to carb ratio, especially if they forget to change their pump clock in the spring. More worrisome than daylight saving time change is the am-pm clock setting. If this setting is set up incorrectly, both basal rates and bolus doses will be affected. Appropriate insulin delivery through insulin pumps requires correct correlation between dose settings and internal clock time settings. Because insulin pumps are not GPS-enabled or automatically time-adjusting, extra caution should be practiced by patients to ensure correct time settings at all times. Clinicians and diabetes educators should verify the date/time of insulin pumps during patients’ visits, and should remind their patients to always verify these settings. PMID:25355713

  3. Insulin self-association and the relationship to pharmacokinetics and pharmacodynamics.

    PubMed

    DeFelippis, M R; Chance, R E; Frank, B H

    2001-01-01

    The treatment of type 1 diabetes requires multiple, daily injections of insulin. While many improvements involving formulation adjustments have been made in an attempt to optimize therapy, clinical experience indicates that the commercially available insulin preparations used for treatment have significant limitations. One principal deficiency relates to poor simulation of the physiological insulin secretion pattern, making achieving normalization of blood glucose concentrations difficult. Endogenous insulin secretion in nondiabetic subjects is characterized by a pulsatile profile that displays multiple, meal-stimulated phases and low basal concentrations between meals and overnight. Optimal diabetes therapy, therefore, requires insulin preparations that display a rapid onset of action with corresponding rapid clearance to provide for meal ingestion as well as preparations that can maintain a sustained, peakless profile for basal requirements. Recent efforts in pharmaceutical research have used the concept of rational-based design of the insulin molecule in an attempt to produce preparations that display more ideal pharmacological profiles. Using detailed structural information obtained from X-ray crystallographic studies to guide design strategies and exploit the nonrestrictive synthetic capabilities of recombinant DNA technology, researchers have prepared a number of insulin analogs that display a reduced propensity towards self-association. Clinical evaluations have shown that these so called "monomeric" analogs better mimic the meal-stimulated pharmacokinetics of insulin secretion observed in nondiabetics. Two monomeric insulin analog preparations have successfully obtained regulatory approval and are now commercially available. Efforts to produce optimized basal-acting insulin analogs have lagged behind. While some of these analogs have been engineered using recombinant DNA technology, design strategies in many cases exploit physicochemical properties of

  4. Fatty acid-induced NLRP3-PYCARD inflammasome activation interferes with insulin signaling

    PubMed Central

    Wen, Haitao; Gris, Denis; Lei, Yu; Jha, Sushmita; Zhang, Lu; Huang, Max Tze-Han; Brickey, Willie June; Ting, Jenny P.-Y.

    2014-01-01

    High-fat diet (HFD) and inflammation are key contributors to insulin resistance and type 2 diabetes (T2D). Interleukin (IL)-1β plays a role in insulin resistance; yet, how IL-1β is induced by fatty acid with HFD, and how this alters insulin signaling is unclear. We show that the saturated fatty acid, palmitate, but not unsaturated oleate, induces the activation of NLRP3-PYCARD inflammasome, causing caspase-1, IL-1β, and IL-18 production. This involves mitochondrial reactive oxygen species and the AMP-activated protein kinase and ULK1 autophagy signaling cascade. Inflammasome activation in hematopoietic cells impairs insulin signaling in several target tissues to reduce glucose tolerance and insulin sensitivity. Furthermore, IL-1β affects insulin sensitivity via TNF-independent and dependent pathways. These findings provide insights into the association of inflammation, diet and T2D. PMID:21478880

  5. Effect of acute and chronic insulin administrations on major factors involved in the control of muscle protein turnover in rainbow trout (Oncorhynchus mykiss).

    PubMed

    Seiliez, Iban; Panserat, Stéphane; Skiba-Cassy, Sandrine; Polakof, Sergio

    2011-07-01

    In this study, the effect of acute and chronic insulin treatments on major factors involved in the control of muscle protein turnover were investigated in rainbow trout (Oncorhynchus mykiss). We found that acute but not chronic insulin administration leads to the induction of the phosphorylation of several key factors (IRS1, TOR and 4E-BP1) involved in the control of the protein synthesis and to the concomitant down-regulation of the expression of ubiquitin-proteasome-related genes (atrogin1, C2, C9) and the calpains inhibitor calpastatin. In contrast, no modification of autophagy-related gene (LC3B, gabarpl1, atg4b) expressions was observed suggesting that the mechanisms controlling this proteolytic route have diverged throughout the evolution. Overall, these results provide a possible explanation of the growth-promoting properties of insulin previously described in fish and indicate that this hormone acutely administrated is able to exert a regulatory influence on various factors associated with growth in skeletal muscle. PMID:21463630

  6. Inhibition of Src homology 2 domain-containing phosphatase 1 increases insulin sensitivity in high-fat diet-induced insulin-resistant mice.

    PubMed

    Krüger, Janine; Wellnhofer, Ernst; Meyborg, Heike; Stawowy, Philipp; Östman, Arne; Kintscher, Ulrich; Kappert, Kai

    2016-03-01

    Insulin resistance plays a crucial role in the development of type 2 diabetes. Insulin receptor signalling is antagonized and tightly controlled by protein tyrosine phosphatases (PTPs). However, the precise role of the PTP src homology 2 domain-containing phosphatase 1 (SHP-1) in insulin resistance has not been explored. Male C57BL/6J mice were fed a high-fat diet (HFD, 60% kcal from fat), to induce insulin resistance, or a low-fat diet (LFD, 10% kcal from fat) for 10 weeks. Afterwards, HFD-fed mice were pharmacologically treated with the SHP-1 (Ptpn6) inhibitor sodium stibogluconate and the broad spectrum pan-PTP inhibitor bis(maltolato)oxovanadium(IV) (BMOV). Both inhibitors ameliorated the metabolic phenotype, as evidenced by reduced body weight, improved insulin sensitivity and glucose tolerance, which was not due to altered PTP gene expression. In parallel, phosphorylation of the insulin receptor and of the insulin signalling key intermediate Akt was enhanced, and both PTP inhibitors and siRNA-mediated SHP-1 downregulation resulted in an increased glucose uptake in vitro. Finally, recombinant SHP-1 was capable of dephosphorylating the ligand-induced tyrosine-phosphorylated insulin receptor. These results indicate a central role of SHP-1 in insulin signalling during obesity, and SHP-1 inhibition as a potential therapeutic approach in metabolic diseases. PMID:27047746

  7. Regulatory aspects on nanomedicines.

    PubMed

    Sainz, Vanessa; Conniot, João; Matos, Ana I; Peres, Carina; Zupancic, Eva; Moura, Liane; Silva, Liana C; Florindo, Helena F; Gaspar, Rogério S

    2015-12-18

    Nanomedicines have been in the forefront of pharmaceutical research in the last decades, creating new challenges for research community, industry, and regulators. There is a strong demand for the fast development of scientific and technological tools to address unmet medical needs, thus improving human health care and life quality. Tremendous advances in the biomaterials and nanotechnology fields have prompted their use as promising tools to overcome important drawbacks, mostly associated to the non-specific effects of conventional therapeutic approaches. However, the wide range of application of nanomedicines demands a profound knowledge and characterization of these complex products. Their properties need to be extensively understood to avoid unpredicted effects on patients, such as potential immune reactivity. Research policy and alliances have been bringing together scientists, regulators, industry, and, more frequently in recent years, patient representatives and patient advocacy institutions. In order to successfully enhance the development of new technologies, improved strategies for research-based corporate organizations, more integrated research tools dealing with appropriate translational requirements aiming at clinical development, and proactive regulatory policies are essential in the near future. This review focuses on the most important aspects currently recognized as key factors for the regulation of nanomedicines, discussing the efforts under development by industry and regulatory agencies to promote their translation into the market. Regulatory Science aspects driving a faster and safer development of nanomedicines will be a central issue for the next years. PMID:26260323

  8. Green tea polyphenols modulate insulin secretion by inhibiting glutamate dehydrogenase.

    PubMed

    Li, Changhong; Allen, Aron; Kwagh, Jae; Doliba, Nicolai M; Qin, Wei; Najafi, Habiba; Collins, Heather W; Matschinsky, Franz M; Stanley, Charles A; Smith, Thomas J

    2006-04-14

    Insulin secretion by pancreatic beta-cells is stimulated by glucose, amino acids, and other metabolic fuels. Glutamate dehydrogenase (GDH) has been shown to play a regulatory role in this process. The importance of GDH was underscored by features of hyperinsulinemia/hyperammonemia syndrome, where a dominant mutation causes the loss of inhibition by GTP and ATP. Here we report the effects of green tea polyphenols on GDH and insulin secretion. Of the four compounds tested, epigallocatechin gallate (EGCG) and epicatechin gallate were found to inhibit GDH with nanomolar ED(50) values and were therefore found to be as potent as the physiologically important inhibitor GTP. Furthermore, we have demonstrated that EGCG inhibits BCH-stimulated insulin secretion, a process that is mediated by GDH, under conditions where GDH is no longer inhibited by high energy metabolites. EGCG does not affect glucose-stimulated insulin secretion under high energy conditions where GDH is probably fully inhibited. We have further shown that these compounds act in an allosteric manner independent of their antioxidant activity and that the beta-cell stimulatory effects are directly correlated with glutamine oxidation. These results demonstrate that EGCG, much like the activator of GDH (BCH), can facilitate dissecting the complex regulation of insulin secretion by pharmacologically modulating the effects of GDH. PMID:16476731

  9. Insulin Resistance and Muscle Metabolism in Chronic Kidney Disease

    PubMed Central

    Bailey, James L.

    2013-01-01

    Insulin resistance is a common finding in chronic kidney disease (CKD) and is manifested by mild fasting hyperglycemia and abnormal glucose tolerance testing. Circulating levels of glucocorticoids are high. In muscle, changes in the insulin signaling pathway occur. An increase in the regulatory p85 subunit of Class I phosphatidylinositol 3-Kinase enzyme leads to decreased activation of the downstream effector protein kinase B (Akt). Mechanisms promoting muscle proteolysis and atrophy are unleashed. The link of Akt to the ubiquitin proteasome pathway, a major degradation pathway in muscle, is discussed. Another factor associated with insulin resistance in CKD is angiotensin II (Ang II) which appears to induce its intracellular effects through inflammatory cytokines or reactive oxygen species. Skeletal muscle ATP is depleted and the ability of AMP-activated protein kinase (AMPK) to replenish energy stores is blocked. How this can be reversed is discussed. Interleukin-6 (IL-6) levels are elevated in CKD and impair insulin signaling at the level of IRS-1. With exercise, IL-6 levels are reduced; glucose uptake and utilization are increased. For patients with CKD, exercise may improve insulin signaling and build up muscle. Treatment strategies for preventing muscle atrophy are discussed. PMID:23431467

  10. Impaired insulin-stimulated glucose transport in ATM-deficient mouse skeletal muscle.

    PubMed

    Ching, James Kain; Spears, Larry D; Armon, Jennifer L; Renth, Allyson L; Andrisse, Stanley; Collins, Roy L; Fisher, Jonathan S

    2013-06-01

    There are reports that ataxia telangiectasia mutated (ATM) plays a role in insulin-stimulated Akt phosphorylation, although this is not the case in some cell types. Because Akt plays a key role in insulin signaling, which leads to glucose transport in skeletal muscle, the predominant tissue in insulin-stimulated glucose disposal, we examined whether insulin-stimulated Akt phosphorylation and (or) glucose transport would be decreased in skeletal muscle of mice lacking functional ATM, compared with muscle from wild-type mice. We found that in vitro insulin-stimulated Akt phosphorylation was normal in soleus muscle from mice with 1 nonfunctional allele of ATM (ATM+/-) and from mice with 2 nonfunctional alleles (ATM-/-). However, insulin did not stimulate glucose transport or the phosphorylation of AS160 in ATM-/- soleus. ATM protein level was markedly higher in wild-type extensor digitorum longus (EDL) than in wild-type soleus. In EDL from ATM-/- mice, insulin did not stimulate glucose transport. However, in contrast to findings for soleus, insulin-stimulated Akt phosphorylation was blunted in ATM-/- EDL, concomitant with a tendency for insulin-stimulated phosphatidylinositol 3-kinase activity to be decreased. Together, the findings suggest that ATM plays a role in insulin-stimulated glucose transport at the level of AS160 in muscle comprised of slow and fast oxidative-glycolytic fibers (soleus) and at the level of Akt in muscle containing fast glycolytic fibers (EDL). PMID:23724874

  11. [Intensified insulin therapy and insulin micro-pumps during pregnancy].

    PubMed

    Galuppi, V

    1994-06-01

    Before conception and during pregnancy in diabetic patients, every possible effort should be made in order to obtain a good, if not perfect, metabolic control and to warrant maternal and fetal health. Multiple daily injections are required to achieve a very strict glucose regulation in pregnant patients with insulin-dependent diabetes mellitus. The most usual intensive insulin administration patterns require 3 premeal doses of short-acting insulin and 1 (at bedtime) or 2 (one in the morning and one at bedtime) injections of intermediate or slow-acting insulin. As an alternative choice, insulin pumps allow a continuous subcutaneous infusion with short-acting insulin according to a basal rate which cover the insulin need during the night and between meals. Premeal and presnack surges of insulin are administrated by the patient herself. Home glucose monitoring must be used to adjust insulin doses. Target glucose levels every diabetic pregnant woman should try to achieve are lower than in non-pregnant women: fasting glycaemia should be below 100 mg/dl, 1 hour post-prandial value below 140 mg/dl and 2 hour post-prandial level below 120 mg/dl. The stricter the control and treatment goals are, the more frequently hypoglycaemia may occur. Hypoglycaemia may be harmful especially for patients with severe diabetic complications and may affect the fetus. Therefore, every pregnant diabetic woman should receive individualized treatment and glycaemic goals according to her clinical features, her compliance and her social and cultural background. PMID:7968932

  12. Clinical Use and Evaluation of Insulin Pens.

    PubMed

    Ginsberg, Barry H

    2016-01-01

    Insulin pens are more accurate and easier to teach than other methods of insulin delivery. They also do not suffer from the risk of mismatch of insulin concentration and type of insulin syringe. The ISO standard used to test insulin pens, however, needs to be updated to reflect their clinical use. PMID:26323484

  13. Basal insulin treatment in type 2 diabetes.

    PubMed

    Hedrington, Maka S; Pulliam, Lindsay; Davis, Stephen N

    2011-06-01

    Insulin glargine is the first 24-h recombinant DNA insulin analog introduced to the market. Substitution of glycine for asparagine and addition of two arginine residues raise the isoelectric point of insulin glargine and result in microprecipitates, delaying absorption from subcutaneous tissue. This delayed absorption result in fairly flat 24-h insulin concentration profiles with no discernible peak. Large, multicenter, randomized, controlled trials in patients with type 2 diabetes show that although NPH insulin and insulin glargine are equally effective in lowering glycosylated hemoglobin (A1c) and fasting blood glucose, there is a clear advantage of insulin glargine over NPH insulin in reducing nocturnal and overall hypoglycemia. Lower risk of hypoglycemia with glargine was also consistently demonstrated by trials comparing insulin glargine and premixed analog insulins. These studies also showed greater reduction in A1c with twice-daily premixed insulins compared with glargine, when insulin glargine was administered without mealtime insulin coverage. Insulin glargine was also compared with another insulin analog, insulin detemir. Trials showed that both insulin analogs are equally effective in lowering A1c and have comparable risk of hypoglycemia. Trials comparing insulin glargine with glucagon-like peptide-1 agonists showed comparable significant reductions in A1c with both regimens. Insulin glargine is well tolerated, has low immunogenicity, reduced risks for acute myocardial infarction, and a lower risk of hypoglycemia compared with NPH insulin in individuals with type 2 diabetes. PMID:21668335

  14. Basal Insulin Treatment in Type 2 Diabetes

    PubMed Central

    Hedrington, Maka S.; Pulliam, Lindsay

    2011-01-01

    Abstract Insulin glargine is the first 24-h recombinant DNA insulin analog introduced to the market. Substitution of glycine for asparagine and addition of two arginine residues raise the isoelectric point of insulin glargine and result in microprecipitates, delaying absorption from subcutaneous tissue. This delayed absorption result in fairly flat 24-h insulin concentration profiles with no discernible peak. Large, multicenter, randomized, controlled trials in patients with type 2 diabetes show that although NPH insulin and insulin glargine are equally effective in lowering glycosylated hemoglobin (A1c) and fasting blood glucose, there is a clear advantage of insulin glargine over NPH insulin in reducing nocturnal and overall hypoglycemia. Lower risk of hypoglycemia with glargine was also consistently demonstrated by trials comparing insulin glargine and premixed analog insulins. These studies also showed greater reduction in A1c with twice-daily premixed insulins compared with glargine, when insulin glargine was administered without mealtime insulin coverage. Insulin glargine was also compared with another insulin analog, insulin detemir. Trials showed that both insulin analogs are equally effective in lowering A1c and have comparable risk of hypoglycemia. Trials comparing insulin glargine with glucagon-like peptide-1 agonists showed comparable significant reductions in A1c with both regimens. Insulin glargine is well tolerated, has low immunogenicity, reduced risks for acute myocardial infarction, and a lower risk of hypoglycemia compared with NPH insulin in individuals with type 2 diabetes. PMID:21668335

  15. Insulin Degludec, The New Generation Basal Insulin or Just another Basal Insulin?

    PubMed

    Nasrallah, Sami N; Reynolds, L Raymond

    2012-01-01

    The advances in recombinant DNA technology have led to an improvement in the properties of currently available long-acting insulin analogs. Insulin degludec, a new generation ultra-long-acting basal insulin, currently in phase 3 clinical trials, has a promising future in clinical use. When compared to its rival basal insulin analogs, a longer duration of action and lower incidence of hypoglycemic events in both type 1 and type 2 diabetic patients has been demonstrated.1,2 Its unique mechanism of action is based on multihexamer formation after subcutaneous injection. This reportedly allows for less pharmacodynamic variability and within-subject variability than currently available insulin analogs, and a duration of action that is over 24 hours.3 The lack of proof of carcinogenicity with insulin degludec is yet another factor that would be taken into consideration when choosing the optimal basal insulin for a diabetic individual.4 A formulation of insulin degludec with insulin aspart, Insulin degludec 70%/aspart 30%, may permit improved flexibly of dosing without compromising glycemic control or safety.5. PMID:22879797

  16. TonEBP suppresses adipogenesis and insulin sensitivity by blocking epigenetic transition of PPARγ2

    PubMed Central

    Ho Lee, Jun; Hee Lee, Hwan; Jin Ye, Byeong; Lee-Kwon, Whaseon; Youn Choi, Soo; Moo Kwon, Hyug

    2015-01-01

    TonEBP is a key transcription factor in cellular adaptation to hypertonic stress, and also in macrophage activation. Since TonEBP is involved in inflammatory diseases such as rheumatoid arthritis and atherosclerosis, we asked whether TonEBP played a role in adipogenesis and insulin resistance. Here we report that TonEBP suppresses adipogenesis and insulin signaling by inhibiting expression of the key transcription factor PPARγ2. TonEBP binds to the PPARγ2 promoter and blocks the epigenetic transition of the locus which is required for the activation of the promoter. When TonEBP expression is reduced, the epigenetic transition and PPARγ2 expression are markedly increased leading to enhanced adipogenesis and insulin response while inflammation is reduced. Thus, TonEBP is an independent determinant of adipose insulin sensitivity and inflammation. TonEBP is an attractive therapeutic target for insulin resistance in lieu of PPARγ agonists. PMID:26042523

  17. Regulatory RNAs

    PubMed Central

    Vazquez-Anderson, Jorge; Contreras, Lydia M

    2013-01-01

    RNAs have many important functional properties, including that they are independently controllable and highly tunable. As a result of these advantageous properties, their use in a myriad of sophisticated devices has been widely explored. Yet, the exploitation of RNAs for synthetic applications is highly dependent on the ability to characterize the many new molecules that continue to be discovered by large-scale sequencing and high-throughput screening techniques. In this review, we present an exhaustive survey of the most recent synthetic bacterial riboswitches and small RNAs while emphasizing their virtues in gene expression management. We also explore the use of these RNA components as building blocks in the RNA synthetic biology toolbox and discuss examples of synthetic RNA components used to rewire bacterial regulatory circuitry. We anticipate that this field will expand its catalog of smart devices by mimicking and manipulating natural RNA mechanisms and functions. PMID:24356572

  18. Regulatory Physiology

    NASA Technical Reports Server (NTRS)

    Lane, Helen W.; Whitson, Peggy A.; Putcha, Lakshmi; Baker, Ellen; Smith, Scott M.; Stewart, Karen; Gretebeck, Randall; Nimmagudda, R. R.; Schoeller, Dale A.; Davis-Street, Janis

    1999-01-01

    As noted elsewhere in this report, a central goal of the Extended Duration Orbiter Medical Project (EDOMP) was to ensure that cardiovascular and muscle function were adequate to perform an emergency egress after 16 days of spaceflight. The goals of the Regulatory Physiology component of the EDOMP were to identify and subsequently ameliorate those biochemical and nutritional factors that deplete physiological reserves or increase risk for disease, and to facilitate the development of effective muscle, exercise, and cardiovascular countermeasures. The component investigations designed to meet these goals focused on biochemical and physiological aspects of nutrition and metabolism, the risk of renal (kidney) stone formation, gastrointestinal function, and sleep in space. Investigations involved both ground-based protocols to validate proposed methods and flight studies to test those methods. Two hardware tests were also completed.

  19. Regulatory Anatomy

    PubMed Central

    2015-01-01

    This article proposes the term “safety logics” to understand attempts within the European Union (EU) to harmonize member state legislation to ensure a safe and stable supply of human biological material for transplants and transfusions. With safety logics, I refer to assemblages of discourses, legal documents, technological devices, organizational structures, and work practices aimed at minimizing risk. I use this term to reorient the analytical attention with respect to safety regulation. Instead of evaluating whether safety is achieved, the point is to explore the types of “safety” produced through these logics as well as to consider the sometimes unintended consequences of such safety work. In fact, the EU rules have been giving rise to complaints from practitioners finding the directives problematic and inadequate. In this article, I explore the problems practitioners face and why they arise. In short, I expose the regulatory anatomy of the policy landscape. PMID:26139952

  20. Protein Crystal Recombinant Human Insulin

    NASA Technical Reports Server (NTRS)

    1994-01-01

    The comparison of protein crystal, Recombiant Human Insulin; space-grown (left) and earth-grown (right). On STS-60, Spacehab II indicated that space-grown crystals are larger and of greater optical clarity than their earth-grown counterparts. Recombiant Human Insulin facilitates the incorporation of glucose into cells. In diabetics, there is either a decrease in or complete lack of insulin, thereby leading to several harmful complications. Principal Investigator is Larry DeLucas.

  1. Regulatory Snapshots: integrative mining of regulatory modules from expression time series and regulatory networks.

    PubMed

    Gonçalves, Joana P; Aires, Ricardo S; Francisco, Alexandre P; Madeira, Sara C

    2012-01-01

    Explaining regulatory mechanisms is crucial to understand complex cellular responses leading to system perturbations. Some strategies reverse engineer regulatory interactions from experimental data, while others identify functional regulatory units (modules) under the assumption that biological systems yield a modular organization. Most modular studies focus on network structure and static properties, ignoring that gene regulation is largely driven by stimulus-response behavior. Expression time series are key to gain insight into dynamics, but have been insufficiently explored by current methods, which often (1) apply generic algorithms unsuited for expression analysis over time, due to inability to maintain the chronology of events or incorporate time dependency; (2) ignore local patterns, abundant in most interesting cases of transcriptional activity; (3) neglect physical binding or lack automatic association of regulators, focusing mainly on expression patterns; or (4) limit the discovery to a predefined number of modules. We propose Regulatory Snapshots, an integrative mining approach to identify regulatory modules over time by combining transcriptional control with response, while overcoming the above challenges. Temporal biclustering is first used to reveal transcriptional modules composed of genes showing coherent expression profiles over time. Personalized ranking is then applied to prioritize prominent regulators targeting the modules at each time point using a network of documented regulatory associations and the expression data. Custom graphics are finally depicted to expose the regulatory activity in a module at consecutive time points (snapshots). Regulatory Snapshots successfully unraveled modules underlying yeast response to heat shock and human epithelial-to-mesenchymal transition, based on regulations documented in the YEASTRACT and JASPAR databases, respectively, and available expression data. Regulatory players involved in functionally enriched

  2. Insulin Glulisine (rDNA origin) Injection

    MedlinePlus

    ... oral medication(s) for diabetes. Insulin glulisine is a short-acting, man-made version of human insulin. Insulin ... contraceptives (birth control pills, patches, rings, injections, or implants); octreotide (Sandostatin); oral medications for diabetes; oral steroids ...

  3. SIRT2 regulates insulin sensitivity in insulin resistant neuronal cells.

    PubMed

    Arora, Amita; Dey, Chinmoy Sankar

    2016-06-10

    Insulin resistance in brain is well-associated with pathophysiology of deficits in whole-body energy metabolism, neurodegenerative diseases etc. Among the seven sirtuins, SIRT2 is the major deacetylase expressed in brain. Inhibition of SIRT2 confers neuroprotection in case of Parkinson's disease (PD) and Huntington's disease (HD). However, the role of this sirtuin in neuronal insulin resistance is not known. In this study, we report the role of SIRT2 in regulating insulin-sensitivity in neuronal cells in vitro. Using approaches like pharmacological inhibition of SIRT2, siRNA mediated SIRT2 knockdown and over-expression of wild-type and catalytically-mutated SIRT2, we observed that downregulation of SIRT2 ameliorated the reduced activity of AKT and increased insulin-stimulated glucose uptake in insulin resistant neuro-2a cells. The data was supported by over expression of catalytically-inactive SIRT2 in insulin-resistant human SH-SY5Y neuronal cells. Data highlights a crucial role of SIRT2 in regulation of neuronal insulin sensitivity under insulin resistant condition. PMID:27163642

  4. Crystallization of Enantiomerically Pure Proteins from Quasi-Racemic Mixtures: Structure Determination by X-Ray Diffraction of Isotope-Labeled Ester Insulin and Human Insulin.

    PubMed

    Mandal, Kalyaneswar; Dhayalan, Balamurugan; Avital-Shmilovici, Michal; Tokmakoff, Andrei; Kent, Stephen B H

    2016-03-01

    As a part of a program aimed towards the study of the dynamics of human insulin-protein dimer formation using two-dimensional infrared spectroscopy, we used total chemical synthesis to prepare stable isotope labeled [(1-(13) C=(18) O)Phe(B24) )] human insulin, via [(1-(13) C=(18) O)Phe(B24) )] ester insulin as a key intermediate product that facilitates folding of the synthetic protein molecule (see preceding article). Here, we describe the crystal structure of the synthetic isotope-labeled ester insulin intermediate and the product synthetic human insulin. Additionally, we present our observations on hexamer formation with these two proteins in the absence of phenol derivatives and/or Zn metal ions. We also describe and discuss the fractional crystallization of quasi-racemic protein mixtures containing each of these two synthetic proteins. PMID:26707939

  5. S961, an insulin receptor antagonist causes hyperinsulinemia, insulin-resistance and depletion of energy stores in rats

    SciTech Connect

    Vikram, Ajit; Jena, Gopabandhu

    2010-07-23

    Research highlights: {yields}Insulin receptor antagonist S961 causes hyperglycemia, hyperinsulinemia and insulin resistance in rats. {yields}Peroxysome-proliferator-activated-receptor-gamma agonist pioglitazone improves S961 induced hyperglycemia and glucose intolerance. {yields}Long term treatment with insulin receptor antagonist S961 results in the decreased adiposity and hepatic glycogen content. {yields}Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. -- Abstract: Impairment in the insulin receptor signaling and insulin mediated effects are the key features of type 2 diabetes. Here we report that S961, a peptide insulin receptor antagonist induces hyperglycemia, hyperinsulinemia ({approx}18-fold), glucose intolerance and impairment in the insulin mediated glucose disposal in the Sprague-Dawley rats. Further, long-term S961 treatment (15 day, 10 nM/kg/day) depletes energy storage as evident from decrease in the adiposity and hepatic glycogen content. However, peroxysome-proliferator-activated-receptor-gamma (PPAR{gamma}) agonist pioglitazone significantly (P < 0.001) restored S961 induced hyperglycemia (196.73 {+-} 16.32 vs. 126.37 {+-} 27.07 mg/dl) and glucose intolerance ({approx}78%). Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. Further, results of the present study reconfirms and provide direct evidence to the crucial role of insulin receptor signaling in the glucose homeostasis and fuel metabolism.

  6. Impact of patient attitudes and beliefs to insulin therapy upon initiation, and their attitudinal changes after initiation: the DAWN Japan study.

    PubMed

    Odawara, Masato; Ishii, Hitoshi; Tajima, Naoko; Iwamoto, Yasuhiko

    2016-01-01

    Objective As a part of the Diabetes Attitudes, Wishes and Needs (DAWN) Japan study, a multi-center, questionnaire-based survey conducted between 2004 and 2005, this analysis aimed to (1) explore patients' attitudes and beliefs contributing to their decision to start insulin therapy, and (2) assess the changes in their attitudes and beliefs after actual initiation. Methods Insulin-naive patients with type 2 diabetes who were recommended to start insulin therapy (n = 149) were invited to answer a 21-item questionnaire consisting of five clusters assessing their attitudes and beliefs toward insulin therapy. The questionnaire was administered twice: first upon insulin recommendation, and then 1 month after insulin initiation for those who started and 4 months after for those who did not. Results Of 130 patients included in the analysis, 74 patients (56.9%) started insulin therapy. 'Negative image of injections' and 'Positive image toward insulin therapy' were significantly associated with patient decision to start insulin therapy (odds ratios [95% CI]: 0.49 [0.32-0.76] and 2.58 [1.51-4.42], respectively). After insulin initiation, 'Negative image of injections', 'Positive image toward insulin therapy', 'Feelings of guilt regarding diabetes self-management', and 'Negative image toward insulin therapy' decreased significantly (P < 0.001 for all). 'Social/interpersonal effects' did not change after insulin initiation. Conclusions This study demonstrated that patients who started insulin therapy were less likely to have negative images of injections and more likely to have positive images toward insulin therapy. Starting insulin therapy did not deteriorate the patient's overall impression of therapy. The key limitation is the relatively small sample size (n = 130). The results suggest that education about the benefits of insulin therapy may help patients who are not ready to initiate insulin overcome their barrier to early insulin initiation and practical

  7. PI3-kinase mutation linked to insulin and growth factor resistance in vivo.

    PubMed

    Winnay, Jonathon N; Solheim, Marie H; Dirice, Ercument; Sakaguchi, Masaji; Noh, Hye-Lim; Kang, Hee Joon; Takahashi, Hirokazu; Chudasama, Kishan K; Kim, Jason K; Molven, Anders; Kahn, C Ronald; Njølstad, Pål R

    2016-04-01

    The phosphatidylinositol 3-kinase (PI3K) signaling pathway is central to the action of insulin and many growth factors. Heterozygous mutations in the gene encoding the p85α regulatory subunit of PI3K (PIK3R1) have been identified in patients with SHORT syndrome - a disorder characterized by short stature, partial lipodystrophy, and insulin resistance. Here, we evaluated whether SHORT syndrome-associated PIK3R1 mutations account for the pathophysiology that underlies the abnormalities by generating knockin mice that are heterozygous for the Pik3r1Arg649Trp mutation, which is homologous to the mutation found in the majority of affected individuals. Similar to the patients, mutant mice exhibited a reduction in body weight and length, partial lipodystrophy, and systemic insulin resistance. These derangements were associated with a reduced capacity of insulin and other growth factors to activate PI3K in liver, muscle, and fat; marked insulin resistance in liver and fat of mutation-harboring animals; and insulin resistance in vitro in cells derived from these mice. In addition, mutant mice displayed defective insulin secretion and GLP-1 action on islets in vivo and in vitro. These data demonstrate the ability of this heterozygous mutation to alter PI3K activity in vivo and the central role of PI3K in insulin/growth factor action, adipocyte function, and glucose metabolism. PMID:26974159

  8. Initiating insulin therapy in type 2 diabetes: benefits of insulin analogs and insulin pens.

    PubMed

    Brunton, Stephen

    2008-08-01

    Despite the development of alternative therapies in recent years, insulin injections remain essential treatment for type 2 diabetes once oral therapy alone becomes inadequate. However, neither patients nor physicians are proactive enough with regard to starting insulin, despite the well-known benefits of early insulin initiation and aggressive dose titration. Barriers to starting insulin therapy are being overcome by developments in insulin and delivery device technology and are the subject of this review. A literature search spanning the last 25 years was carried out to identify publications addressing issues of insulin initiation, how insulin analogs can help overcome barriers to initiation, and the advantages of pen-type insulin delivery systems. Seventy-five publications were identified. These references illustrate that the drawbacks associated with regular exogenous human insulins (soluble and NPH) are improved with modern insulin analogs. The more rapid absorption of prandial insulin analogs compared with human insulin eliminates the need for an injection-meal-interval, increasing convenience, while basal analogs have no discernible peak in activity. Modern insulin delivery devices also have advantages over the traditional vial and syringe. Currently available insulin pens are either durable (insulin cartridge is replaceable; e.g., HumaPen, Eli Lilly [Indianapolis, IN]; NovoPen series, Novo Nordisk [Bagsvaerd, Denmark]) or disposable (prefilled; e.g., FlexPen, Novo Nordisk; SoloSTAR, sanofi-aventis [Paris, France]), with features to aid ease-of-use. These include a large dose selector, dial-up and dial-down facility, and audible clicks when selecting the dose. The potential for dosing errors is thus reduced with pen-type devices, with other benefits including a discreet appearance, ease of learning, and greater user confidence. Collectively, these features contribute to overwhelming patient preference when compared with vials and syringes. Despite the greater

  9. Down-regulation of cyclin G2 by insulin, IGF-I (insulin-like growth factor 1) and X10 (AspB10 insulin): role in mitogenesis.

    PubMed

    Svendsen, Angela M; Winge, Sofia B; Zimmermann, Maike; Lindvig, Anne B; Warzecha, Caroline B; Sajid, Waseem; Horne, Mary C; De Meyts, Pierre

    2014-01-01

    The mechanisms whereby insulin analogues may cause enhanced mitogenicity through activation of either the IR (insulin receptor) or the IGF-IR (insulin-like growth factor 1 receptor) are incompletely understood. We demonstrate that in L6 myoblasts expressing only IGF-IRs as well as in the same cells overexpressing the IR, IGF-I (insulin-like growth factor 1), insulin and X10 (AspB10 insulin) down-regulate the mRNA expression level of the cell cycle inhibitor cyclin G2, as measured by qRT-PCR (quantitative reverse transcription-PCR), and induce cell growth measured by [6-(3)H]thymidine incorporation into DNA. Western blotting showed a marked down-regulation of cyclin G2 at the protein level in both cell lines. Overexpression of cyclin G2 in the two cell lines diminished the mitogenic effect of all three ligands. The use of specific inhibitors indicated that both the MAPK (mitogen-activated protein kinase) and the PI3K (phosphoinositide 3-kinase) pathways mediate the down-regulation of Ccng2. The down-regulation of CCNG2 by the three ligands was also observed in other cell lines: MCF-7, HMEC, Saos-2, R(-)/IR and INS-1. These results indicate that regulation of cyclin G2 is a key mechanism whereby insulin, insulin analogues and IGF-I stimulate cell proliferation. PMID:24059861

  10. [The discovery of insulin].

    PubMed

    Lestradet, H

    1996-02-01

    When a medical problem is intensively studied by many teams in the world, it is frequent to see the solution found simultaneously in different countries. However that was not exactly the case concerning the extraction of a potent insulin able to cure Diabetes Mellitus. It seems necessary, seventy five years later, when passions are quenched, to reconsider the chronology of the history and put Paolesco but also Collip at the right places much before Banting and Best to whom, by a curious misinterpretation of facts, was attributed the priority of this fundamental discovery. PMID:8705382

  11. [Medication of the month. Insulin glargine (Lantus)].

    PubMed

    Scheen, A J

    2004-02-01

    Insulin glargine (Lantus) is a human insulin analogue produced by recombinant DNA technology and recently launched by Aventis. Modification of the human insulin molecule at position A21 and at the C-terminus of the B-chain results in the formation of a stable compound that is soluble at pH 4.0, but forms amorphous microprecipitates in subcutaneous tissue (pH > 7,4) from which small amounts of insulin glargine are gradually released. The plasma concentration versus time profile of insulin glargine is therefore relatively constant over 24 hours as compared to conventional human insulins, especially NPH. This allows once-daily injection as basal insulin therapy, at any moment of the clock time (but if possible at the same time from day to day). Reproducibility of plasma insulin levels is also improved with insulin glargine as compared to human NPH insulin. Insulin glargine administration should be combined to rapid insulin injections, before each meal in order to control postprandial hyperglycaemia, or with oral antidiabetic agents in type 2 diabetes. The pharmacokinetic properties of insulin glargine allow an easier titration of basal insulin dose, which should facilitate adequate blood glucose control while decreasing the risk of hypoglycaemia, especially during night time. Insulin glargine use is safe with no increased antigenicity, immunogenicity or mitogenicity reactions as compared to human insulin. Optimal use of this new insulin analogue should be integrated in a global management of the diabetic patient as well as in a new culture of insulin therapy. PMID:15112902

  12. Problems in diabetes mellitus management. Insulin resistance.

    PubMed

    Wolfsheimer, K J

    1990-12-01

    Insulin resistance is a cause for morning hyperglycemia seen in diabetic patients. Other reasons for morning hyperglycemia should be eliminated by performing an insulin response test. Once insulin resistance has been established as the cause of hyperglycemia, a step-by-step process should be used to establish the cause of the insulin resistance. Common causes of insulin resistance include hyperadrenocorticism, acromegaly, hyperthyroidism, and obesity. Hepatic disease, renal insufficiency, and sepsis are other causes of insulin resistance in practice. Less common causes include insulin antibodies, pregnancy, neoplasia, hyperandrogenism, and pheochromocytoma. If the underlying cause cannot be found or resolved, then increased doses of insulin are required to manage the hyperglycemia. PMID:2134077

  13. Aβ-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Aβ Secretion in Neural Cells.

    PubMed

    Najem, Dema; Bamji-Mirza, Michelle; Yang, Ze; Zhang, Wandong

    2016-06-01

    Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) toxicity, tau pathology, insulin resistance, neuroinflammation, and dysregulation of cholesterol homeostasis, all of which play roles in neurodegeneration. Insulin has polytrophic effects on neurons and may be at the center of these pathophysiological changes. In this study, we investigated possible relationships among insulin signaling and cholesterol biosynthesis, along with the effects of Aβ42 on these pathways in vitro. We found that neuroblastoma 2a (N2a) cells transfected with the human gene encoding amyloid-β protein precursor (AβPP) (N2a-AβPP) produced Aβ and exhibited insulin resistance by reduced p-Akt and a suppressed cholesterol-synthesis pathway following insulin treatment, and by increased phosphorylation of insulin receptor subunit-1 at serine 612 (p-IRS-S612) as compared to parental N2a cells. Treatment of human neuroblastoma SH-SY5Y cells with Aβ42 also increased p-IRS-S612, suggesting that Aβ42 is responsible for insulin resistance. The insulin resistance was alleviated when N2a-AβPP cells were treated with higher insulin concentrations. Insulin increased Aβ release from N2a-AβPP cells, by which it may promote Aβ clearance. Insulin increased cholesterol-synthesis gene expression in SH-SY5Y and N2a cells, including 24-dehydrocholesterol reductase (DHCR24) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) through sterol-regulatory element-binding protein-2 (SREBP2). While Aβ42-treated SH-SY5Y cells exhibited increased HMGCR expression and c-Jun phosphorylation as pro-inflammatory responses, they also showed down-regulation of neuro-protective/anti-inflammatory DHCR24. These results suggest that Aβ42 may cause insulin resistance, activate JNK for c-Jun phosphorylation, and lead to dysregulation of cholesterol homeostasis, and that enhancing insulin signaling may relieve the insulin-resistant phenotype and the dysregulated cholesterol-synthesis pathway to promote A

  14. Resource guide 2004. Insulin delivery.

    PubMed

    2004-01-01

    Syringes...pumps...jet infectors...pens...infusers...they all do the same basic thing--deliver insulin. These items carry insulin through the outermost layer of skin and into fatty tissue so it can be used by the body. This section will also cover injection aids, products designed to make infecting easier. PMID:14976945

  15. [Endogenous hyperlactatemia and insulin secretion].

    PubMed

    Ribes, G; Valette, G; Lignon, F; Loubatières-Mariani, M M

    1978-01-01

    In the normal anesthetized dog, the endogenous hyperlactatemia induced either by intense muscular work or by a high dose of phenformin (20 mg/kg subtucaneously) is followed by an increase in the pancreaticoduodenal insulin output. A previous perfusion of sodium dichloroacetate (50 mg/kg. h) opposes the hyperlactatemia, and reduces or suppresses the increase in insulin output. PMID:150887

  16. Insulin Signaling and Heart Failure.

    PubMed

    Riehle, Christian; Abel, E Dale

    2016-04-01

    Heart failure is associated with generalized insulin resistance. Moreover, insulin-resistant states such as type 2 diabetes mellitus and obesity increases the risk of heart failure even after adjusting for traditional risk factors. Insulin resistance or type 2 diabetes mellitus alters the systemic and neurohumoral milieu, leading to changes in metabolism and signaling pathways in the heart that may contribute to myocardial dysfunction. In addition, changes in insulin signaling within cardiomyocytes develop in the failing heart. The changes range from activation of proximal insulin signaling pathways that may contribute to adverse left ventricular remodeling and mitochondrial dysfunction to repression of distal elements of insulin signaling pathways such as forkhead box O transcriptional signaling or glucose transport, which may also impair cardiac metabolism, structure, and function. This article will review the complexities of insulin signaling within the myocardium and ways in which these pathways are altered in heart failure or in conditions associated with generalized insulin resistance. The implications of these changes for therapeutic approaches to treating or preventing heart failure will be discussed. PMID:27034277

  17. Insulin Neuroprotection and the Mechanisms

    PubMed Central

    Yu, Li-Yun; Pei, Yu

    2015-01-01

    Objective: To analyze the mechanism of neuroprotection of insulin and which blood glucose range was benefit for insulin exerting neuroprotective action. Data Sources: The study is based on the data from PubMed. Study Selection: Articles were selected with the search terms “insulin”, “blood glucose”, “neuroprotection”, “brain”, “glycogen”, “cerebral ischemia”, “neuronal necrosis”, “glutamate”, “γ-aminobutyric acid”. Results: Insulin has neuroprotection. The mechanisms include the regulation of neurotransmitter, promoting glycogen synthesis, and inhibition of neuronal necrosis and apoptosis. Insulin could play its role in neuroprotection by avoiding hypoglycemia and hyperglycemia. Conclusions: Intermittent and long-term infusion insulin may be a benefit for patients with ischemic brain damage at blood glucose 6–9 mmol/L. PMID:25836621

  18. An increase in insulin is important for the acquisition conditioned taste aversion in Lymnaea.

    PubMed

    Mita, Koichi; Yamagishi, Miki; Fujito, Yutaka; Lukowiak, Ken; Ito, Etsuro

    2014-12-01

    Conditioned taste aversion (CTA) in Lymnaea is brought about by pairing a sucrose solution (the conditioned stimulus, CS) with an electric shock (the unconditioned stimulus, US). Following repeated CS-US pairings, CTA occurs and it is consolidated into long-term memory (LTM). The best CTA is achieved, if snails are food-deprived for 1 day before training commences. With a longer period of food deprivation (5 days), learning and memory formation does not occur. It has been hypothesized that the levels of insulin in the central nervous system (CNS) are very important for CTA to occur. To test his hypothesis, we injected insulin directly into 5-day food-deprived snails. The injection of insulin, as expected, resulted in a decrease in hemolymph glucose concentration. Consistent with our hypothesis with insulin injection, learning and memory formation of CTA occurred. That is, the 'insulin spike' is more important than an increase in hemolymph glucose concentration for CTA-LTM. If we injected an insulin receptor antibody into the snails before the insulin injection, learning was formed but memory formation was not, which is consistent with our previous study. Therefore, a rise in the insulin concentration (i.e., insulin spike) in the CNS is considered to be a key determining factor in the process of CTA-LTM. PMID:25451307

  19. Stress-impaired transcription factor expression and insulin secretion in transplanted human islets

    PubMed Central

    Dai, Chunhua; Kayton, Nora S.; Shostak, Alena; Poffenberger, Greg; Cyphert, Holly A.; Aramandla, Radhika; Thompson, Courtney; Papagiannis, Ioannis G.; Shiota, Masakazu; Stafford, John M.; Greiner, Dale L.; Herrera, Pedro L.; Shultz, Leonard D.; Stein, Roland; Powers, Alvin C.

    2016-01-01

    Type 2 diabetes is characterized by insulin resistance, hyperglycemia, and progressive β cell dysfunction. Excess glucose and lipid impair β cell function in islet cell lines, cultured rodent and human islets, and in vivo rodent models. Here, we examined the mechanistic consequences of glucotoxic and lipotoxic conditions on human islets in vivo and developed and/or used 3 complementary models that allowed comparison of the effects of hyperglycemic and/or insulin-resistant metabolic stress conditions on human and mouse islets, which responded quite differently to these challenges. Hyperglycemia and/or insulin resistance impaired insulin secretion only from human islets in vivo. In human grafts, chronic insulin resistance decreased antioxidant enzyme expression and increased superoxide and amyloid formation. In human islet grafts, expression of transcription factors NKX6.1 and MAFB was decreased by chronic insulin resistance, but only MAFB decreased under chronic hyperglycemia. Knockdown of NKX6.1 or MAFB expression in a human β cell line recapitulated the insulin secretion defect seen in vivo. Contrary to rodent islet studies, neither insulin resistance nor hyperglycemia led to human β cell proliferation or apoptosis. These results demonstrate profound differences in how excess glucose or lipid influence mouse and human insulin secretion and β cell activity and show that reduced expression of key islet-enriched transcription factors is an important mediator of glucotoxicity and lipotoxicity. PMID:27064285

  20. Novel Endogenous, Insulin-Stimulated Akt2 Protein Interaction Partners in L6 Myoblasts

    PubMed Central

    Caruso, Michael; Zhang, Xiangmin; Ma, Danjun; Yang, Zhao; Qi, Yue; Yi, Zhengping

    2015-01-01

    Insulin resistance and Type 2 diabetes are marked by an aberrant response in the insulin signaling network. The phosphoinositide-dependent serine/threonine kinase, Akt2, plays a key role in insulin signaling and glucose uptake, most notably within skeletal muscle. Protein-protein interaction regulates the functional consequence of Akt2 and in turn, Akt2’s role in glucose uptake. However, only few insulin-responsive Akt2 interaction partners have been identified in skeletal muscle cells. In the present work, rat L6 myoblasts, a widely used insulin sensitive skeletal muscle cell line, were used to examine endogenous, insulin-stimulated Akt2 protein interaction partners. Akt2 co-immunoprecipitation was coupled with 1D-SDS-PAGE and fractions were analyzed by HPLC-ESI-MS/MS to reveal Akt2 protein-protein interactions. The pull-down assay displayed specificity for the Akt2 isoform; Akt1 and Akt3 unique peptides were not detected. A total of 49 were detected with a significantly increased (47) or decreased (2) association with Akt2 following insulin administration (n = 4; p<0.05). Multiple pathways were identified for the novel Akt2 interaction partners, such as the EIF2 and ubiquitination pathways. These data suggest that multiple new endogenous proteins may associate with Akt2 under basal as well as insulin-stimulated conditions, providing further insight into the insulin signaling network. Data are available via ProteomeXchange with identifier PXD002557. PMID:26465754

  1. Insulin receptor binding motif tagged with IgG4 Fc (Yiminsu) works as an insulin sensitizer to activate Akt signaling in hepatocytes.

    PubMed

    Wang, J; Zou, T; Yang, H X; Gong, Y Z; Xie, X J; Liu, H Y; Liao, D F

    2015-01-01

    Insulin resistance is a key feature of obesity and type 2 diabetes mellitus (T2DM). Interaction of insulin with the insulin receptor (IR) leads to both its auto-phosphorylation and phosphorylation of tyrosine residues on the IR substrate (IRS) proteins, initiating the activation of intracellular signaling cascades. The metabolic effects of IRS are known to be mediated through pathways involving phosphatidyl-inositol 3-kinase (PI-3K), which result in the activation of Akt signaling. The C-terminal region of the IR ectodomain is required to facilitate the conformational changes that are required for high-affinity binding to insulin. Furthermore, the CH2 and CH3 domains in the Fc fragments of immunoglobulins are responsible for their binding to the Fc receptor, which triggers transcytosis. In this study, we created a fusion peptide of the C-terminal end of the human IR ectodomain with the IgG4 Fc fragment, including an intervening polyG fragment to ensure enough space for insulin binding. We named this new peptide "Yiminsu", meaning an insulin sensitizer. The results of our analyses show that Yiminsu significantly facilitates insulin signaling via the activation of Akt in hepatocytes in a dose- and time-dependent manner. Further studies are required to determine whether Yiminsu can act as an insulin sensitizer. PMID:26345813

  2. A model integration approach linking signalling and gene-regulatory logic with kinetic metabolic models.

    PubMed

    Ryll, A; Bucher, J; Bonin, A; Bongard, S; Gonçalves, E; Saez-Rodriguez, J; Niklas, J; Klamt, S

    2014-10-01

    Systems biology has to increasingly cope with large- and multi-scale biological systems. Many successful in silico representations and simulations of various cellular modules proved mathematical modelling to be an important tool in gaining a solid understanding of biological phenomena. However, models spanning different functional layers (e.g. metabolism, signalling and gene regulation) are still scarce. Consequently, model integration methods capable of fusing different types of biological networks and various model formalisms become a key methodology to increase the scope of cellular processes covered by mathematical models. Here we propose a new integration approach to couple logical models of signalling or/and gene-regulatory networks with kinetic models of metabolic processes. The procedure ends up with an integrated dynamic model of both layers relying on differential equations. The feasibility of the approach is shown in an illustrative case study integrating a kinetic model of central metabolic pathways in hepatocytes with a Boolean logical network depicting the hormonally induced signal transduction and gene regulation events involved. In silico simulations demonstrate the integrated model to qualitatively describe the physiological switch-like behaviour of hepatocytes in response to nutritionally regulated changes in extracellular glucagon and insulin levels. A simulated failure mode scenario addressing insulin resistance furthermore illustrates the pharmacological potential of a model covering interactions between signalling, gene regulation and metabolism. PMID:25063553

  3. Opposite effects of genistein on the regulation of insulin-mediated glucose homeostasis in adipose tissue

    PubMed Central

    Wang, M; Gao, X J; Zhao, W W; Zhao, W J; Jiang, C H; Huang, F; Kou, J P; Liu, B L; Liu, K

    2013-01-01

    BACKGROUND AND PURPOSE Genistein is an isoflavone phytoestrogen found in a number of plants such as soybeans and there is accumulating evidence that it has beneficial effects on the regulation of glucose homeostasis. In this study we evaluated the effect of genistein on glucose homeostasis and its underlying mechanisms in normal and insulin-resistant conditions. EXPERIMENTAL APPROACH To induce insulin resistance, mice or differentiated 3T3-L1 adipocytes were treated with macrophage-derived conditioned medium. A glucose tolerance test was used to investigate the effect of genistein. Insulin signalling activation, glucose transporter-4 (GLUT4) translocation and AMP-activated PK (AMPK) activation were detected by Western blot analysis or elisa. KEY RESULTS Genistein impaired glucose tolerance and attenuated insulin sensitivity in normal mice by inhibiting the insulin-induced phosphorylation of insulin receptor substrate-1 (IRS1) at tyrosine residues, leading to inhibition of insulin-mediated GLUT4 translocation in adipocytes. Mac-CM, an inflammatory stimulus induced glucose intolerance accompanied by impaired insulin sensitivity; genistein reversed these changes by restoring the disturbed IRS1 function, leading to an improvement in GLUT4 translocation. In addition, genistein increased AMPK activity under both normal and inflammatory conditions; this was shown to contribute to the anti-inflammatory effect of genistein, which leads to an improvement in insulin signalling and the amelioration of insulin resistance. CONCLUSION AND IMPLICATIONS Genistein showed opposite effects on insulin sensitivity under normal and inflammatory conditions in adipose tissue and this action was derived from its negative or positive regulation of IRS1 function. Its up-regulation of AMPK activity contributes to the inhibition of inflammation implicated in insulin resistance. PMID:23763311

  4. Structural Integrity of the B24 Site in Human Insulin Is Important for Hormone Functionality*

    PubMed Central

    Žáková, Lenka; Kletvíková, Emília; Veverka, Václav; Lepšík, Martin; Watson, Christopher J.; Turkenburg, Johan P.; Jiráček, Jiří; Brzozowski, Andrzej M.

    2013-01-01

    Despite the recent first structural insight into the insulin-insulin receptor complex, the role of the C terminus of the B-chain of insulin in this assembly remains unresolved. Previous studies have suggested that this part of insulin must rearrange to reveal amino acids crucial for interaction with the receptor. The role of the invariant PheB24, one of the key residues of the hormone, in this process remains unclear. For example, the B24 site functionally tolerates substitutions to d-amino acids but not to l-amino acids. Here, we prepared and characterized a series of B24-modified insulin analogues, also determining the structures of [d-HisB24]-insulin and [HisB24]-insulin. The inactive [HisB24]-insulin molecule is remarkably rigid due to a tight accommodation of the l-His side chain in the B24 binding pocket that results in the stronger tethering of B25-B28 residues to the protein core. In contrast, the highly active [d-HisB24]-insulin is more flexible, and the reverse chirality of the B24Cα atom swayed the d-HisB24 side chain into the solvent. Furthermore, the pocket vacated by PheB24 is filled by PheB25, which mimics the PheB24 side and main chains. The B25→B24 downshift results in a subsequent downshift of TyrB26 into the B25 site and the departure of B26-B30 residues away from the insulin core. Our data indicate the importance of the aromatic l-amino acid at the B24 site and the structural invariance/integrity of this position for an effective binding of insulin to its receptor. Moreover, they also suggest limited, B25-B30 only, unfolding of the C terminus of the B-chain upon insulin activation. PMID:23447530

  5. Regulatory and quality considerations for continuous manufacturing. May 20-21, 2014 Continuous Manufacturing Symposium.

    PubMed

    Allison, Gretchen; Cain, Yanxi Tan; Cooney, Charles; Garcia, Tom; Bizjak, Tara Gooen; Holte, Oyvind; Jagota, Nirdosh; Komas, Bekki; Korakianiti, Evdokia; Kourti, Dora; Madurawe, Rapti; Morefield, Elaine; Montgomery, Frank; Nasr, Moheb; Randolph, William; Robert, Jean-Louis; Rudd, Dave; Zezza, Diane

    2015-03-01

    This paper assesses the current regulatory environment, relevant regulations and guidelines, and their impact on continuous manufacturing. It summarizes current regulatory experience and learning from both review and inspection perspectives. It outlines key regulatory aspects, including continuous manufacturing process description and control strategy in regulatory files, process validation, and key Good Manufacturing Practice (GMP) requirements. In addition, the paper identifies regulatory gaps and challenges and proposes a way forward to facilitate implementation. PMID:25830179

  6. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus

    PubMed Central

    Tangvarasittichai, Surapon

    2015-01-01

    Oxidative stress is increased in metabolic syndrome and type 2 diabetes mellitus (T2DM) and this appears to underlie the development of cardiovascular disease, T2DM and diabetic complications. Increased oxidative stress appears to be a deleterious factor leading to insulin resistance, dyslipidemia, β-cell dysfunction, impaired glucose tolerance and ultimately leading to T2DM. Chronic oxidative stress, hyperglycemia and dyslipidemia are particularly dangerous for β-cells from lowest levels of antioxidant, have high oxidative energy requirements, decrease the gene expression of key β-cell genes and induce cell death. If β-cell functioning is impaired, it results in an under production of insulin, impairs glucose stimulated insulin secretion, fasting hyperglycemia and eventually the development of T2DM. PMID:25897356

  7. Effect of adiponectin on the steroidogenic acute regulatory protein, P450 side chain cleavage enzyme and 3β-hydroxysteroid dehydrogenase gene expression, progesterone and androstenedione production by the porcine uterus during early pregnancy.

    PubMed

    Smolinska, N; Dobrzyn, K; Kiezun, M; Szeszko, K; Maleszka, A; Kaminski, T

    2016-06-01

    Adiponectin and its receptors are expressed in the human and porcine uterus and this endocrine system has important role in the regulation of reproductive processes. The expression of steroidogenic acute regulatory protein (StAR) and 3β-hydroxysteroid dehydrogenase (HSD3B1) were observed in the human and porcine uterus during the oestrous cycle and pregnancy. The de novo synthesis of steroids in the uterus might be a crucial factor for effective implantation and maintenance of pregnancy. We hypothesized that adiponectin modulates the expression of key enzymes in the synthesis of the steroids: StAR, P450 side chain cleavage enzyme (CYP11A1) and HSD3B1, as well as progesterone (P4) and androstenedione (A4) secretion by the porcine uterus. Endometrial and myometrial explants harvested from gilts (n = 5) on days 10 to 11, 12 to 13, 15 to 16 and 27 to 28 of pregnancy and on days 10 to 11 of the oestrous cycle were cultured in vitro in the presence of adiponectin (1, 10 μg/ml), adiponectin with insulin (10 ng/ml) and insulin alone (10 ng/ml). Gene expression was examined by real-time PCR, and the secretion of the steroids was determined by radioimmunoassay. The content of StAR, CYP11A1 and HSD3B1 mRNAs and the secretion of P4 and A4 was modulated by adiponectin in endometrial and myometrial tissue explants during early pregnancy and the oestrous cycle. In this action adiponectin interacted with insulin. Insulin itself also regulated the steroidogenic activity of the porcine uterus. ere we reported, for the first time, the expression of CYP11A1 genes in the porcine endometrium and myometrium. Our novel findings indicate that adiponectin affects basal and insulin-stimulated expression of key steroidogenic genes and production of steroid hormones by the porcine uterus during maternal recognition of pregnancy and implantation. PMID:27512005

  8. Pten (phosphatase and tensin homologue gene) haploinsufficiency promotes insulin hypersensitivity

    PubMed Central

    Wong, J. T.; Kim, P. T. W.; Peacock, J. W.; Yau, T. Y.; Mui, A. L.-F.; Chung, S. W.; Sossi, V.; Doudet, D.; Green, D.; Ruth, T. J.; Parsons, R.; Verchere, C. B.

    2006-01-01

    Aims/hypothesis Insulin controls glucose metabolism via multiple signalling pathways, including the phosphatidylinositol 3-kinase (PI3K) pathway in muscle and adipose tissue. The protein/lipid phosphatase Pten (phosphatase and tensin homologue deleted on chromosome 10) attenuates PI3K signalling by dephosphorylating the phosphatidylinositol 3,4,5-trisphosphate generated by PI3K. The current study was aimed at investigating the effect of haploinsufficiency for Pten on insulin-stimulated glucose uptake. Materials and methods Insulin sensitivity in Pten heterozygous (Pten+/−) mice was investigated in i.p. insulin challenge and glucose tolerance tests. Glucose uptake was monitored in vitro in primary cultures of myocytes from Pten+/− mice, and in vivo by positron emission tomography. The phosphorylation status of protein kinase B (PKB/Akt), a downstream signalling protein in the PI3K pathway, and glycogen synthase kinase 3β (GSK3β), a substrate of PKB/Akt, was determined by western immunoblotting. Results Following i.p. insulin challenge, blood glucose levels in Pten+/− mice remained depressed for up to 120 min, whereas glucose levels in wild-type mice began to recover after approximately 30 min. After glucose challenge, blood glucose returned to normal about twice as rapidly in Pten+/− mice. Enhanced glucose uptake was observed both in Pten+/− myocytes and in skeletal muscle of Pten+/− mice by PET. PKB and GSK3β phosphorylation was enhanced and prolonged in Pten+/− myocytes. Conclusions/interpretation Pten is a key negative regulator of insulin-stimulated glucose uptake in vitro and in vivo. The partial reduction of Pten due to Pten haploinsufficiency is enough to elicit enhanced insulin sensitivity and glucose tolerance in Pten+/− mice. PMID:17195063

  9. Autoantibodies to Insulin Receptor Spontaneously Develop as Anti-Idiotypes in Mice Immunized with Insulin

    NASA Astrophysics Data System (ADS)

    Shechter, Yoram; Maron, Ruth; Elias, Dana; Cohen, Irun R.

    1982-04-01

    Mice immunized with insulin developed antibodies to both insulin and the insulin receptor. The antibodies to insulin receptor displaced labeled insulin from insulin receptors and mimicked the actions of insulin in stimulating the oxidation of glucose and its incorporation into lipids, and in inhibiting lipolysis. The antibodies to insulin receptor could be blocked by or bound to the antibodies to insulin, and therefore were identified as anti-idiotypes. Thus, immunization against a hormone may activate spontaneously an idiotype-anti-idiotype network resulting in antibodies to the hormone receptor.

  10. Cell factories for insulin production.

    PubMed

    Baeshen, Nabih A; Baeshen, Mohammed N; Sheikh, Abdullah; Bora, Roop S; Ahmed, Mohamed Morsi M; Ramadan, Hassan A I; Saini, Kulvinder Singh; Redwan, Elrashdy M

    2014-01-01

    The rapid increase in the number of diabetic patients globally and exploration of alternate insulin delivery methods such as inhalation or oral route that rely on higher doses, is bound to escalate the demand for recombinant insulin in near future. Current manufacturing technologies would be unable to meet the growing demand of affordable insulin due to limitation in production capacity and high production cost. Manufacturing of therapeutic recombinant proteins require an appropriate host organism with efficient machinery for posttranslational modifications and protein refolding. Recombinant human insulin has been produced predominantly using E. coli and Saccharomyces cerevisiae for therapeutic use in human. We would focus in this review, on various approaches that can be exploited to increase the production of a biologically active insulin and its analogues in E. coli and yeast. Transgenic plants are also very attractive expression system, which can be exploited to produce insulin in large quantities for therapeutic use in human. Plant-based expression system hold tremendous potential for high-capacity production of insulin in very cost-effective manner. Very high level of expression of biologically active proinsulin in seeds or leaves with long-term stability, offers a low-cost technology for both injectable as well as oral delivery of proinsulin. PMID:25270715

  11. Leptin receptor polymorphisms interact with polyunsaturated fatty acids to augment risk of insulin resistance and metabolic syndrome in adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The leptin receptor (LEPR) is associated with insulin resistance, a key feature of metabolic syndrome (MetS). Gene-fatty acid interactions may affect MetS risk. The objective was to investigate the relationship among LEPR polymorphisms, insulin resistance, andMetSrisk and whether plasma fatty acids,...

  12. Mitotic Checkpoint Regulators Control Insulin Signaling and Metabolic Homeostasis.

    PubMed

    Choi, Eunhee; Zhang, Xiangli; Xing, Chao; Yu, Hongtao

    2016-07-28

    Insulin signaling regulates many facets of animal physiology. Its dysregulation causes diabetes and other metabolic disorders. The spindle checkpoint proteins MAD2 and BUBR1 prevent precocious chromosome segregation and suppress aneuploidy. The MAD2 inhibitory protein p31(comet) promotes checkpoint inactivation and timely chromosome segregation. Here, we show that whole-body p31(comet) knockout mice die soon after birth and have reduced hepatic glycogen. Liver-specific ablation of p31(comet) causes insulin resistance, hyperinsulinemia, glucose intolerance, and hyperglycemia and diminishes the plasma membrane localization of the insulin receptor (IR) in hepatocytes. MAD2 directly binds to IR and facilitates BUBR1-dependent recruitment of the clathrin adaptor AP2 to IR. p31(comet) blocks the MAD2-BUBR1 interaction and prevents spontaneous clathrin-mediated IR endocytosis. BUBR1 deficiency enhances insulin sensitivity in mice. BUBR1 depletion in hepatocytes or the expression of MAD2-binding-deficient IR suppresses the metabolic phenotypes of p31(comet) ablation. Our findings establish a major IR regulatory mechanism and link guardians of chromosome stability to nutrient metabolism. PMID:27374329

  13. Biologically active insulin-derived peptides.

    PubMed

    Fawcett, Janet

    2014-06-01

    Insulin has many actions within cells many of which are dependent on the cell type. For example, insulin stimulates glucose uptake in adipose tissue and skeletal muscle but not in liver. In liver glucose influx will increase as insulin stimulates the phosphorylation of glucose and eventual storage in the form of glycogen. Insulin also increases glucose oxidation, decreases glucose production, decreases lipolysis, increases protein synthesis and inhibits protein degradation in addition to others. Many actions have been related to insulin binding to its receptor and subsequent phosphorylation cascades, but insulin action on protein degradation has been shown to be linked to insulin degradation, specifically insulin degradation by the insulin-degrading enzyme (IDE). This activity has been shown to be due to an interaction of IDE with the proteasome, which is responsible for degradation of ubiquitin-tagged proteins. Smaller fragments of insulin that are produced by the action of IDE that do not bind to the insulin receptor show a small effect on protein degradation and a modest effect on mitogenesis. These small fragments do however inhibit lipolysis in a similar manner to insulin. If fragments are larger and can bind to the receptor they have been shown to increase glucose oxidation. Studies show that fragments of the insulin molecule have cellular activity, and that the varied actions of insulin are not completely controlled by insulin binding to the insulin receptor, even though the mechanisms may not be mutually exclusive. PMID:24559166

  14. The label free picomolar detection of insulin in blood serum.

    PubMed

    Xu, Mengyun; Luo, Xiliang; Davis, Jason J

    2013-01-15

    Insulin, a polypeptide hormone secreted by pancreatic cells, is a key regulator in glucose homeostasis. Its deficiency leads to insulin-dependent (type I) diabetes whereas resistance to insulin is common in type II diabetes, obesity and a range of endocrine disorders. Its determination is of considerable value, particularly in the clinical diagnosis of diabetes mellitus and the doping control of athletes. It has, additionally, been noted as a potential breast cancer marker (serum insulin levels being found to be raised in comparison to control patients). Electrochemical assays are potentially very cheap, highly sensitive, and very readily transposed to a point of care. Though there exist numerous examples of label free impedimetric or capacitative assaying of biomolecules, these are rarely demonstrated to be effective in complex biological mixtures or to be applicable to low molecular weight targets (since they operate through the interfacial displacement of water/ions and/or the steric blocking of a redox probe). We report herein an ultrasensitive electrochemical and label-free biosensor for insulin in blood serum with a clinically relevant linear range and detection limit of 1.2pM. The transducing surfaces, based on readily prepared, antibody modified, polyethylene glycol monolayer modified polycrystalline gold surfaces, respond in a highly specific and re-useable manner to the target in up to 50% blood serum. PMID:22840329

  15. Metabolic programming in the pathogenesis of insulin resistance.

    PubMed

    Devaskar, Sherin U; Thamotharan, Manikkavasagar

    2007-06-01

    This review focuses on different animal models of nutrient perturbations, inclusive of restrictive and excessive states mimicking human situations during pregnancy and lactation that cause aberrations in the offspring. These aberrations consist of diminished insulin sensitivity in the presence of defective insulin production. These phenotypic changes are due to altered peripheral tissue post-insulin receptor signaling mechanisms and pancreatic beta-islet insulin synthesis and secretion defects. While these changes during in utero or postnatal life serve as essential adaptations to overcome adverse conditions, they become maladaptive subsequently and set the stage for type 2 diabetes mellitus. Pregnancy leads to gestational diabetes with trans-generational propagation of the insulin resistant phenotype. This is in response to the metabolically aberrant maternal in utero environment, and tissue specific epigenetic perturbations that permanently alter expression of critical genes transmitted to future generations. These heritable aberrations consisting of altered DNA methylation and histone modifications remodel chromatin and affect transcription of key genes. Along with an altered in utero environment, these chromatin modifications contribute to the world-wide epidemic of type 2 diabetes mellitus, with nutrient excess dominating in developed and nutrient restriction in developing countries. PMID:17657604

  16. Reducing Plasma Membrane Sphingomyelin Increases Insulin Sensitivity ▿

    PubMed Central

    Li, Zhiqiang; Zhang, Hongqi; Liu, Jing; Liang, Chien-Ping; Li, Yan; Li, Yue; Teitelman, Gladys; Beyer, Thomas; Bui, Hai H.; Peake, David A.; Zhang, Youyan; Sanders, Phillip E.; Kuo, Ming-Shang; Park, Tae-Sik; Cao, Guoqing; Jiang, Xian-Cheng

    2011-01-01

    It has been shown that inhibition of de novo sphingolipid synthesis increases insulin sensitivity. For further exploration of the mechanism involved, we utilized two models: heterozygous serine palmitoyltransferase (SPT) subunit 2 (Sptlc2) gene knockout mice and sphingomyelin synthase 2 (Sms2) gene knockout mice. SPT is the key enzyme in sphingolipid biosynthesis, and Sptlc2 is one of its subunits. Homozygous Sptlc2-deficient mice are embryonic lethal. However, heterozygous Sptlc2-deficient mice that were viable and without major developmental defects demonstrated decreased ceramide and sphingomyelin levels in the cell plasma membranes, as well as heightened sensitivity to insulin. Moreover, these mutant mice were protected from high-fat diet-induced obesity and insulin resistance. SMS is the last enzyme for sphingomyelin biosynthesis, and SMS2 is one of its isoforms. Sms2 deficiency increased cell membrane ceramide but decreased SM levels. Sms2 deficiency also increased insulin sensitivity and ameliorated high-fat diet-induced obesity. We have concluded that Sptlc2 heterozygous deficiency- or Sms2 deficiency-mediated reduction of SM in the plasma membranes leads to an improvement in tissue and whole-body insulin sensitivity. PMID:21844222

  17. Lipid signals and insulin resistance.

    PubMed

    Zhang, Chongben; Klett, Eric L; Coleman, Rosalind A

    2013-12-01

    The metabolic syndrome, a cluster of metabolic derangements that include obesity, glucose intolerance, dyslipidemia and hypertension, is a major risk factor for cardiovascular disease. Insulin resistance has been proposed to be the common feature that links obesity to the metabolic syndrome, but the mechanism remains obscure. Although the excess content of triacylglycerol in muscle and liver is highly associated with insulin resistance in these tissues, triacylglycerol itself is not causal but merely a marker. Thus, attention has turned to the accumulation of cellular lipids known to have signaling roles. This review will discuss recent progress in understanding how glycerolipids and related lipid intermediates may impair insulin signaling. PMID:24533033

  18. Insulin Receptor Signaling in Normal and Insulin-Resistant States

    PubMed Central

    Boucher, Jérémie; Kleinridders, André; Kahn, C. Ronald

    2014-01-01

    In the wake of the worldwide increase in type-2 diabetes, a major focus of research is understanding the signaling pathways impacting this disease. Insulin signaling regulates glucose, lipid, and energy homeostasis, predominantly via action on liver, skeletal muscle, and adipose tissue. Precise modulation of this pathway is vital for adaption as the individual moves from the fed to the fasted state. The positive and negative modulators acting on different steps of the signaling pathway, as well as the diversity of protein isoform interaction, ensure a proper and coordinated biological response to insulin in different tissues. Whereas genetic mutations are causes of rare and severe insulin resistance, obesity can lead to insulin resistance through a variety of mechanisms. Understanding these pathways is essential for development of new drugs to treat diabetes, metabolic syndrome, and their complications. PMID:24384568

  19. Cutaneous allergy to human (recombinant DNA) insulin.

    PubMed

    Grammer, L C; Metzger, B E; Patterson, R

    1984-03-16

    p6 report two cases of cutaneous allergy to human (recombinant DNA) insulin. Each patient had a history of systemic allergic reactions to porcine insulin and was at least as reactive to human as to porcine insulin by end-point cutaneous titration. Both patients' insulin allergy was managed with animal insulins and both have done well. Our experience with these two patients indicates that human insulin (rDNA) should not be expected to be efficacious in all patients with systemic allergy to insulin. PMID:6366262

  20. FOXO1 is Regulated by Insulin and IGF1 in Pituitary Gonadotropes

    PubMed Central

    Skarra, Danalea V.; Thackray, Varykina G.

    2015-01-01

    The FOXO1 transcription factor is important for multiple aspects of reproductive function. We previously reported that FOXO1 functions as a repressor of gonadotropin hormone synthesis, but how FOXO1 is regulated in pituitary gonadotropes is unknown. The growth factors, insulin and insulin-like growth factor I (IGF1) function as key regulators of cell proliferation, metabolism and apoptosis in multiple cell types through the PI3K/AKT signaling pathway. In this study, we found that insulin and IGF1 signaling in gonadotropes induced FOXO1 phosphorylation through the PI3K/AKT pathway in immortalized and primary cells, resulting in FOXO1 relocation from the nucleus to the cytoplasm. Furthermore, insulin administration in vivo induced phosphorylation of FOXO1 and AKT in the pituitary. Thus, insulin and IGF1 act as negative regulators of FOXO1 activity and may serve to fine-tune gonadotropin expression. PMID:25676570

  1. Phospho-dephospho-control by insulin is mimicked by a phospho-oligosaccharide in adipocytes.

    PubMed

    Alemany, S; Mato, J M; Strålfors, P

    The mechanism of insulin action is only partly understood. At one end of the signalling chain, the structure of the insulin receptor is known in detail, and at the other end, insulin controls cellular metabolism by regulating the phosphorylation of serine and threonine residues in key target enzymes. The molecular events linking the occupied receptor to changes in target enzyme phosphorylation have remained obscure. Recently, insulin was shown to promote the hydrolysis of a phosphatidylinositol glycan with release of its polar head-group. The head group was reported to activate a high-affinity cyclic AMP-phosphodiesterase and pyruvate dehydrogenase, to inhibit catecholamine-stimulated lipolysis, and also to inhibit phospholipid methyltransferase and adenylate cyclase. We report here that in intact adipocytes this head-group faithfully copies the insulin-directed effects on the phosphorylation and dephosphorylation of target proteins of the hormone. PMID:3313056

  2. New ways of insulin delivery.

    PubMed

    Heinemann, L

    2010-02-01

    When Exubera (EXU), the first inhaled insulin formulation to make it through the clinical development process, was introduced to the market some years ago it was hoped that this would be the first in a series of novel insulin formulations applied by this route. In addition, it was hoped that inhaled insulin would pave the way for other alternative routes of insulin administration (ARIA), i.e. oral insulin, nasal insulin or transdermal insulin to mention only some of the different attempts that have been studied in the last 90 years. The failure of EXU, i.e. its withdrawal from the market due to insufficient market success, was followed by the cessation of nearly all other attempts to develop inhaled insulin formulations. Currently there is only one company (MannKind) which moves sturdily ahead with their Technosphere insulin. This company has submitted an NDA for their product recently and hopes to bring it to the market by the end of 2010 or early 2011. Even if the product is able to pass the approval hurdles in the USA and Europe, this does not guarantee that it will become a market success. Many diabetologists were sceptical about the need/advantages of inhaled insulin/EXU from the start and the introduction of this product has raised even more scepticism. Reports about 'side effects' (development of lung cancer in patients treated with EXU) of inhaled insulin are also not helpful, even if the causality of the appearance of cancer with this type of insulin therapy is not proven. One of the very negative consequences of stopping EXU are the huge financial losses to Pfizer. The managers in charge in other pharmaceutical companies and also most venture capitalists are reluctant to invest in ARIA nowadays. This in turn means that many of the small companies that try to develop new forms of insulin administration have issues when they try to find a big brother and/or sufficient financial support. Clearly the economic crisis has further aggravated this issue. One can

  3. Caveolin-2 regulation of the cell cycle in response to insulin in Hirc-B fibroblast cells

    SciTech Connect

    Kim, Sangmin; Pak, Yunbae . E-mail: ybpak@nongae.gsnu.ac.kr

    2005-04-29

    The regulatory function of caveolin-2 in cell cycle regulation by insulin was investigated in human insulin receptor-overexpressed rat 1 fibroblast (Hirc-B) cells. Insulin increased induction of the caveolin-2 gene in a time-dependent manner. Direct interaction between ERK and caveolin-2 was confirmed by immunoprecipitation and phosphorylated ERK increased the specific interaction in response to insulin. That insulin induced their nuclear co-localization over time was demonstrated by immunofluorescence microscopy. Insulin increased the S phase in the cell cycle by 6-fold. When recombinant caveolin-1 was transiently expressed, a decrease in the S phase was detected by flow-cytometry. The results indicate that the up-regulation of caveolin-2 in response to insulin activates the downstream signal cascades in the cell cycle, chiefly the increased phosphorylation of ERK, the nuclear translocation of phosphorylated ERK, and the subsequent activation of G0/G1 to S phase transition of the cell cycle. The results also suggest that DNA synthesis and the activation of the cell cycle by insulin are achieved concomitantly with an increase in the interaction between caveolin-2 and phosphorylated ERK, and the nuclear translocation of that complex. Taken together, we conclude that caveolin-2 positively regulates the insulin-induced cell cycle through activation of and direct interaction with ERK in Hirc-B cells.

  4. 10 CFR 95.18 - Key personnel.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... REGULATORY COMMISSION (CONTINUED) FACILITY SECURITY CLEARANCE AND SAFEGUARDING OF NATIONAL SECURITY INFORMATION AND RESTRICTED DATA Physical Security § 95.18 Key personnel. The senior management official and the Facility Security Officer must always be cleared to a level commensurate with the...

  5. Combining Basal Insulin Analogs with Glucagon-Like Peptide-1 Mimetics

    PubMed Central

    2011-01-01

    Abstract Basal insulin analogs are recognized as an effective method of achieving and maintaining glycemic control for patients with type 2 diabetes. However, the progressive nature of the disease means that some individuals may require additional ways to maintain their glycemic goals. Intensification in these circumstances has traditionally been achieved by the addition of short-acting insulin to cover postprandial glucose excursions that are not targeted by basal insulin. However, intensive insulin regimens are associated with a higher risk of hypoglycemia and weight gain, which can contribute to a greater burden on patients. The combination of basal insulin with a glucagon-like peptide-1 (GLP-1) mimetic is a potentially attractive solution to this problem for some patients with type 2 diabetes. GLP-1 mimetics target postprandial glucose and should complement the activity of basal insulins; they are also associated with a relatively low risk of associated hypoglycemia and moderate, but significant, weight loss. Although the combination has not been approved by regulatory authorities, preliminary evidence from mostly small-scale studies suggests that basal insulins in combination with GLP-1 mimetics do provide improvements in A1c and postprandial glucose with concomitant weight loss and no marked increase in the risk of hypoglycemia. These results are promising, but further studies are required, including comparisons with basal–bolus therapy, before the complex value of this association can be fully appreciated. PMID:21711120

  6. Bilirubin Increases Insulin Sensitivity by Regulating Cholesterol Metabolism, Adipokines and PPARγ Levels.

    PubMed

    Liu, Jinfeng; Dong, Huansheng; Zhang, Yong; Cao, Mingjun; Song, Lili; Pan, Qingjie; Bulmer, Andrew; Adams, David B; Dong, Xiao; Wang, Hongjun

    2015-01-01

    Obesity can cause insulin resistance and type 2 diabetes. Moderate elevations in bilirubin levels have anti-diabetic effects. This study is aimed at determining the mechanisms by which bilirubin treatment reduces obesity and insulin resistance in a diet-induced obesity (DIO) mouse model. DIO mice were treated with bilirubin or vehicle for 14 days. Body weights, plasma glucose, and insulin tolerance tests were performed prior to, immediately, and 7 weeks post-treatment. Serum lipid, leptin, adiponectin, insulin, total and direct bilirubin levels were measured. Expression of factors involved in adipose metabolism including sterol regulatory element-binding protein (SREBP-1), insulin receptor (IR), and PPARγ in liver were measured by RT-PCR and Western blot. Compared to controls, bilirubin-treated mice exhibited reductions in body weight, blood glucose levels, total cholesterol (TC), leptin, total and direct bilirubin, and increases in adiponectin and expression of SREBP-1, IR, and PPARγ mRNA. The improved metabolic control achieved by bilirubin-treated mice was persistent: at two months after treatment termination, bilirubin-treated DIO mice remained insulin sensitive with lower leptin and higher adiponectin levels, together with increased PPARγ expression. These results indicate that bilirubin regulates cholesterol metabolism, adipokines and PPARγ levels, which likely contribute to increased insulin sensitivity and glucose tolerance in DIO mice. PMID:26017184

  7. Insulin Augments Gonadotropin-Releasing Hormone Induction of Translation in LβT2 Cells

    PubMed Central

    Navratil, Amy M.; Song, Hyunjin; Hernandez, Jeniffer B.; Cherrington, Brian D.; Santos, Sharon J.; Low, Janine M.; Do, Minh-Ha T.; Lawson, Mark A.

    2009-01-01

    Summary The integrated signaling of insulin and gonadotropin-releasing hormone in the pituitary gonadotropes may have a profound bearing on reproductive function, although the cross-receptor signaling mechanisms are unclear. We demonstrate that the insulin receptor is constitutively localized to non-caveolar lipid raft microdomains in the pituitary gonadotrope cell line LβT2. The localization to rafts is consistent with similar localization of the GnRH receptor. Insulin receptor phosphorylation occurs in raft domains and activates the downstream signaling targets Insulin Receptor Substrate1 and Akt/Protein Kinase B. Although insulin alone does not strongly activate the extracellular signal-regulated kinase second messenger cascade, co-stimulation potentiates the phosphorylation of the extracellular signal-regulated kinase by gonadotropin-releasing hormone. The co-stimulatory effect of insulin and gonadotropin-releasing hormone is also evident in increased activation of cap-dependent translation. In contrast, co-stimulation attenuates Akt/Protein Kinase B activation. Our results show that both gonadotropin-releasing hormone and insulin are capable of mutually altering their respective regulatory signaling cascades. We suggest that this provides a mechanism to integrate neuropeptide and energy homeostatic signals to modulate reproductive function. PMID:19632296

  8. Insulin inhibits cardiac contractility by inducing a Gi-biased β2-adrenergic signaling in hearts.

    PubMed

    Fu, Qin; Xu, Bing; Liu, Yongming; Parikh, Dippal; Li, Jing; Li, Ying; Zhang, Yuan; Riehle, Christian; Zhu, Yi; Rawlings, Tenley; Shi, Qian; Clark, Richard B; Chen, Xiongwen; Abel, E Dale; Xiang, Yang K

    2014-08-01

    Insulin and adrenergic stimulation are two divergent regulatory systems that may interact under certain pathophysiological circumstances. Here, we characterized a complex consisting of insulin receptor (IR) and β2-adrenergic receptor (β2AR) in the heart. The IR/β2AR complex undergoes dynamic dissociation under diverse conditions such as Langendorff perfusions of hearts with insulin or after euglycemic-hyperinsulinemic clamps in vivo. Activation of IR with insulin induces protein kinase A (PKA) and G-protein receptor kinase 2 (GRK2) phosphorylation of the β2AR, which promotes β2AR coupling to the inhibitory G-protein, Gi. The insulin-induced phosphorylation of β2AR is dependent on IRS1 and IRS2. After insulin pretreatment, the activated β2AR-Gi signaling effectively attenuates cAMP/PKA activity after β-adrenergic stimulation in cardiomyocytes and consequently inhibits PKA phosphorylation of phospholamban and contractile responses in myocytes in vitro and in Langendorff perfused hearts. These data indicate that increased IR signaling, as occurs in hyperinsulinemic states, may directly impair βAR-regulated cardiac contractility. This β2AR-dependent IR and βAR signaling cross-talk offers a molecular basis for the broad interaction between these signaling cascades in the heart and other tissues or organs that may contribute to the pathophysiology of metabolic and cardiovascular dysfunction in insulin-resistant states. PMID:24677713

  9. Early origins of heart disease: low birth weight and the role of the insulin-like growth factor system in cardiac hypertrophy.

    PubMed

    Wang, Kimberley C W; Botting, Kimberley J; Padhee, Monalisa; Zhang, Song; McMillen, I Caroline; Suter, Catherine M; Brooks, Doug A; Morrison, Janna L

    2012-11-01

    Epidemiological studies indicate that poor growth before birth is associated with left ventricular hypertrophy and an increased risk of death from heart disease later in life. In fetal life, the insulin-like growth factor (IGF) system has been implicated in physiological growth of the heart, whereas in postnatal life IGFs can be involved in both physiological and pathological cardiac hypertrophy. A reduction in substrate supply in fetal life, resulting in chronic hypoxaemia and intrauterine growth restriction, results in increased cardiac IGF-1R, IGF-2 and IGF-2R gene expression; and there is also evidence for a role of the IGF-2 receptor in the ensuing cardiac hypertrophy. The persistent high level of cardiac IGF-2R gene expression from fetal to postnatal life may be due to epigenetic changes in key cardiac hypertrophy regulatory pathways. PMID:22774980

  10. 5α-Reductase inhibitors alter steroid metabolism and may contribute to insulin resistance, diabetes, metabolic syndrome and vascular disease: a medical hypothesis.

    PubMed

    Traish, Abdulmaged M; Guay, Andre T; Zitzmann, Michael

    2014-12-01

    5α-reductases, a unique family of enzymes with a wide host of substrates and tissue distributions, play a key role in the metabolism of androgens, progestins, mineralocorticoids and glucocorticoids. These enzymes are the rate-limiting step in the synthesis of a host of neurosteroids, which are critical for central nervous system function. Androgens and glucocorticoids modulate mitochondrial function, carbohydrate, protein and lipid metabolism and energy balance. Thus, the inhibition of these regulatory enzymes results in an imbalance in steroid metabolism and clearance rates, which leads to altered physiological processes. In this report, we advance the hypothesis that inhibition of 5α-reductases by finasteride and dutasteride alters not only steroid metabolism but also interferes with the downstream actions and signaling of these hormones. We suggest that finasteride and dutasteride inhibit 5α-reductase activities and reduce the clearance of glucocorticoids and mineralocorticoids, potentiating insulin resistance, diabetes and vascular disease. PMID:25460297

  11. Methocel-Lipid Hybrid Nanocarrier for Efficient Oral Insulin Delivery.

    PubMed

    Boushra, Mariam; Tous, Sozan; Fetih, Gihan; Xue, Hui-Yi; Tran, Ngoc T; Wong, Ho Lun

    2016-05-01

    Even with the use of double-emulsion technique for preparation, the hydrophobic nature of solid lipid nanoparticles (SLNs) limits their encapsulation efficiency (EE%) for peptides such as insulin. In this study, we hypothesize that inclusion of Methocel into SLN to form Methocel-lipid hybrid nanocarriers (MLNs) will significantly enhance insulin EE% without compromising the various characteristics of SLN favorable for oral drug delivery. Our data show that incorporation of 2% wt/wt of Methocel A15C had doubled insulin EE% (around 40%) versus conventional SLN prepared using standard double emulsion technique. MLN significantly protected the entrapped insulin against chymotrypsin degradation at gastrointestinal pH. Using intestinal epithelial cells Caco2 as a model, it was shown that MLN could be extensively taken up by Caco2 cells while demonstrating low cytotoxicity. The results indicate that MLN have preserved the key advantages of SLN (biocompatibility, low cytotoxicity, good drug protection, and good interaction with cells) while overcoming their key limitation for efficient peptide entrapment. Based on this, MLN may serve as a promising nanocarrier for oral delivery of peptides. PMID:27012226

  12. Alternative Devices for Taking Insulin

    MedlinePlus

    ... the day. Pumps can also give "bolus" doses—one-time larger doses—of insulin at meals and at times when blood glucose is too high based on the programming set by the user. Frequent blood glucose monitoring ...

  13. [Alternative routes for insulin administration].

    PubMed

    Lassmann-Vague, V

    1994-01-01

    Ideally, insulin administration should be done through portal route, with a precise kinetic. It should also lead to a reproducible biologic effect, with minimal side-effects and be acceptable for the majority of diabetic patients. Many alternative routes of insulin administration try to fulfill one or more of these criteria. Intraperitoneal route is already used with implantable pumps. It has proven safety and metabolic efficacy, particularly upon the reduction of severe hypoglycaemia. Nasal route could provide a rapid kinetic, but its long-term utilisation depends on improvement of bioavailability and studies of local toxicity. Results concerning intrabronchic insulin seem promising, but are still preliminary. In the future, the choice among these alternative routes of insulin administration will be guided by the development of a closed-loop system. PMID:8001707

  14. Central insulin signaling is attenuated by long-term insulin exposure via insulin receptor substrate-1 serine phosphorylation, proteasomal degradation, and lysosomal insulin receptor degradation.

    PubMed

    Mayer, Christopher M; Belsham, Denise D

    2010-01-01

    Central insulin signaling is critical for the prevention of insulin resistance. Hyperinsulinemia contributes to insulin resistance, but it is not yet clear whether neurons are subject to cellular insulin resistance. We used an immortalized, hypothalamic, clonal cell line, mHypoE-46, which exemplifies neuronal function and expresses the components of the insulin signaling pathway, to determine how hyperinsulinemia modifies neuronal function. Western blot analysis indicated that prolonged insulin treatment of mHypoE-46 cells attenuated insulin signaling through phospho-Akt. To understand the mechanisms involved, time-course analysis was performed. Insulin exposure for 4 and 8 h phosphorylated Akt and p70-S6 kinase (S6K1), whereas 8 and 24 h treatment decreased insulin receptor (IR) and IR substrate 1 (IRS-1) protein levels. Insulin phosphorylation of S6K1 correlated with IRS-1 ser1101 phosphorylation and the mTOR-S6K1 pathway inhibitor rapamycin prevented IRS-1 serine phosphorylation. The proteasomal inhibitor epoxomicin and the lysosomal pathway inhibitor 3-methyladenine prevented the degradation of IRS-1 and IR by insulin, respectively, and pretreatment with rapamycin, epoxomicin, or 3-methyladenine prevented attenuation of insulin signaling by long-term insulin exposure. Thus, a sustained elevation of insulin levels diminishes neuronal insulin signaling through mTOR-S6K1-mediated IRS-1 serine phosphorylation, proteasomal degradation of IRS-1 and lysosomal degradation of the IR. PMID:19887566

  15. Insulin delivery methods: Past, present and future

    PubMed Central

    Shah, Rima B.; Patel, Manhar; Maahs, David M.; Shah, Viral N.

    2016-01-01

    Many patients with advanced type 2 diabetes mellitus (T2DM) and all patients with T1DM require insulin to keep blood glucose levels in the target range. The most common route of insulin administration is subcutaneous insulin injections. There are many ways to deliver insulin subcutaneously such as vials and syringes, insulin pens, and insulin pumps. Though subcutaneous insulin delivery is the standard route of insulin administration, it is associated with injection pain, needle phobia, lipodystrophy, noncompliance and peripheral hyperinsulinemia. Therefore, the need exists for delivering insulin in a minimally invasive or noninvasive and in most physiological way. Inhaled insulin was the first approved noninvasive and alternative way to deliver insulin, but it has been withdrawn from the market. Technologies are being explored to make the noninvasive delivery of insulin possible. Some of the routes of insulin administration that are under investigation are oral, buccal, nasal, peritoneal and transdermal. This review article focuses on the past, present and future of various insulin delivery techniques. This article has focused on different possible routes of insulin administration with its advantages and limitation and possible scope for the new drug development. PMID:27014614

  16. Insulin delivery methods: Past, present and future.

    PubMed

    Shah, Rima B; Patel, Manhar; Maahs, David M; Shah, Viral N

    2016-01-01

    Many patients with advanced type 2 diabetes mellitus (T2DM) and all patients with T1DM require insulin to keep blood glucose levels in the target range. The most common route of insulin administration is subcutaneous insulin injections. There are many ways to deliver insulin subcutaneously such as vials and syringes, insulin pens, and insulin pumps. Though subcutaneous insulin delivery is the standard route of insulin administration, it is associated with injection pain, needle phobia, lipodystrophy, noncompliance and peripheral hyperinsulinemia. Therefore, the need exists for delivering insulin in a minimally invasive or noninvasive and in most physiological way. Inhaled insulin was the first approved noninvasive and alternative way to deliver insulin, but it has been withdrawn from the market. Technologies are being explored to make the noninvasive delivery of insulin possible. Some of the routes of insulin administration that are under investigation are oral, buccal, nasal, peritoneal and transdermal. This review article focuses on the past, present and future of various insulin delivery techniques. This article has focused on different possible routes of insulin administration with its advantages and limitation and possible scope for the new drug development. PMID:27014614

  17. Cardiovascular effects of basal insulins.

    PubMed

    Mannucci, Edoardo; Giannini, Stefano; Dicembrini, Ilaria

    2015-01-01

    Basal insulin is an important component of treatment for both type 1 and type 2 diabetes. One of the principal aims of treatment in patients with diabetes is the prevention of diabetic complications, including cardiovascular disease. There is some evidence, although controversial, that attainment of good glycemic control reduces long-term cardiovascular risk in both type 1 and type 2 diabetes. The aim of this review is to provide an overview of the potential cardiovascular safety of the different available preparations of basal insulin. Current basal insulin (neutral protamine Hagedorn [NPH], or isophane) and basal insulin analogs (glargine, detemir, and the more recent degludec) differ essentially by various measures of pharmacokinetic and pharmacodynamic effects in the bloodstream, presence and persistence of peak action, and within-subject variability in the glucose-lowering response. The currently available data show that basal insulin analogs have a lower risk of hypoglycemia than NPH human insulin, in both type 1 and type 2 diabetes, then excluding additional harmful effects on the cardiovascular system mediated by activation of the adrenergic system. Given that no biological rationale for a possible difference in cardiovascular effect of basal insulins has been proposed so far, available meta-analyses of publicly disclosed randomized controlled trials do not show any signal of increased risk of major cardiovascular events between the different basal insulin analogs. However, the number of available cardiovascular events in these trials is very small, preventing any clear-cut conclusion. The results of an ongoing clinical trial comparing glargine and degludec with regard to cardiovascular safety will provide definitive evidence. PMID:26203281

  18. Cardiovascular effects of basal insulins

    PubMed Central

    Mannucci, Edoardo; Giannini, Stefano; Dicembrini, Ilaria

    2015-01-01

    Basal insulin is an important component of treatment for both type 1 and type 2 diabetes. One of the principal aims of treatment in patients with diabetes is the prevention of diabetic complications, including cardiovascular disease. There is some evidence, although controversial, that attainment of good glycemic control reduces long-term cardiovascular risk in both type 1 and type 2 diabetes. The aim of this review is to provide an overview of the potential cardiovascular safety of the different available preparations of basal insulin. Current basal insulin (neutral protamine Hagedorn [NPH], or isophane) and basal insulin analogs (glargine, detemir, and the more recent degludec) differ essentially by various measures of pharmacokinetic and pharmacodynamic effects in the bloodstream, presence and persistence of peak action, and within-subject variability in the glucose-lowering response. The currently available data show that basal insulin analogs have a lower risk of hypoglycemia than NPH human insulin, in both type 1 and type 2 diabetes, then excluding additional harmful effects on the cardiovascular system mediated by activation of the adrenergic system. Given that no biological rationale for a possible difference in cardiovascular effect of basal insulins has been proposed so far, available meta-analyses of publicly disclosed randomized controlled trials do not show any signal of increased risk of major cardiovascular events between the different basal insulin analogs. However, the number of available cardiovascular events in these trials is very small, preventing any clear-cut conclusion. The results of an ongoing clinical trial comparing glargine and degludec with regard to cardiovascular safety will provide definitive evidence. PMID:26203281

  19. Modelling the regulatory system for diabetes mellitus with a threshold window

    NASA Astrophysics Data System (ADS)

    Yang, Jin; Tang, Sanyi; Cheke, Robert A.

    2015-05-01

    Piecewise (or non-smooth) glucose-insulin models with threshold windows for type 1 and type 2 diabetes mellitus are proposed and analyzed with a view to improving understanding of the glucose-insulin regulatory system. For glucose-insulin models with a single threshold, the existence and stability of regular, virtual, pseudo-equilibria and tangent points are addressed. Then the relations between regular equilibria and a pseudo-equilibrium are studied. Furthermore, the sufficient and necessary conditions for the global stability of regular equilibria and the pseudo-equilibrium are provided by using qualitative analysis techniques of non-smooth Filippov dynamic systems. Sliding bifurcations related to boundary node bifurcations were investigated with theoretical and numerical techniques, and insulin clinical therapies are discussed. For glucose-insulin models with a threshold window, the effects of glucose thresholds or the widths of threshold windows on the durations of insulin therapy and glucose infusion were addressed. The duration of the effects of an insulin injection is sensitive to the variation of thresholds. Our results indicate that blood glucose level can be maintained within a normal range using piecewise glucose-insulin models with a single threshold or a threshold window. Moreover, our findings suggest that it is critical to individualise insulin therapy for each patient separately, based on initial blood glucose levels.

  20. What options are available when considering starting insulin: premix or basal?

    PubMed

    Lavernia, Frank

    2011-06-01

    Several large studies in diabetes have shown that early initiation of intensive therapy is better for the prevention of long-term complications and suggest that patients with more advanced disease may be at increased risk of adverse cardiovascular events. Despite these findings, insulin initiation is often delayed in patients with type 2 diabetes, typically until A1C exceeds 8.5%. Barriers to the use of insulin are many, arising from both a patient and a physician perspective, and the decision to initiate insulin treatment can be influenced by cost, risk of hypoglycemia, convenience, and the potential for weight gain. Choosing when to initiate insulin and which insulin/treatment regimen to adopt in patients with type 2 diabetes is key, and the importance of tailoring treatment to the patient is widely acknowledged. However, there is currently no universal consensus on the optimal course of action. Once-daily basal insulin and twice-daily premix insulin are commonly used for insulin initiation. Relatively few studies have directly compared these starter treatment regimens, although general findings suggest that, although glycemic control appears to be similar with once-daily basal insulin and twice-daily premix, the lower hypoglycemia rates, lower weight gain, simplicity, and convenience associated with basal insulin support its first-line use as a starter insulin regimen in patients failing on oral antidiabetes agents. Variables such as age, body mass index, and bedtime or post-breakfast plasma glucose levels may alter the efficacy of the chosen treatment regimen, further supporting the need to tailor treatment to meet individual patient's requirements. PMID:21668341

  1. Role of the Transcription Factor Sox4 in Insulin Secretion and Impaired Glucose Tolerance

    PubMed Central

    Goldsworthy, Michelle; Hugill, Alison; Freeman, Helen; Horner, Emma; Shimomura, Kenju; Bogani, Debora; Pieles, Guido; Mijat, Vesna; Arkell, Ruth; Bhattacharya, Shoumo; Ashcroft, Frances M.; Cox, Roger D.

    2008-01-01

    OBJECTIVES— To identify, map, clone, and functionally validate a novel mouse model for impaired glucose tolerance and insulin secretion. RESEARCH DESIGN AND METHODS— Haploinsufficiency of the insulin receptor and associated mild insulin resistance has been used to sensitize an N-ethyl-N-nitrosourea (ENU) screen to identify novel mutations resulting in impaired glucose tolerance and diabetes. The new impaired glucose tolerance 4 (IGT4) model was selected using an intraperitoneal glucose tolerance test and inheritance of the phenotype confirmed by generation of backcross progeny. Segregation of the phenotype was correlated with genotype information to map the location of the gene and candidates sequenced for mutations. The function of the SRY-related high mobility group (HMG)-box 4 (Sox4) gene in insulin secretion was tested using another ENU allele and by small interfering RNA silencing in insulinoma cells. RESULTS— We describe two allelic autosomal dominant mutations in the highly conserved HMG box of the transcription factor Sox4. Previously associated with pancreas development, Sox4 mutations in the adult mouse result in an insulin secretory defect, which exhibits impaired glucose tolerance in association with insulin receptor+/−–induced insulin resistance. Elimination of the Sox4 transcript in INS1 and Min6 cells resulted in the abolition of glucose-stimulated insulin release similar to that observed for silencing of the key metabolic enzyme glucokinase. Intracellular calcium measurements in treated cells indicate that this defect lies downstream of the ATP-sensitive K+ channel (KATP channel) and calcium influx. CONCLUSIONS— IGT4 represents a novel digenic model of insulin resistance coupled with an insulin secretory defect. The Sox4 gene has a role in insulin secretion in the adult β-cell downstream of the KATP channel. PMID:18477811

  2. Maternal Overweight Programs Insulin and Adiponectin Signaling in the Offspring

    PubMed Central

    Shankar, Kartik; Kang, Ping; Harrell, Amanda; Zhong, Ying; Marecki, John C.; Ronis, Martin J. J.; Badger, Thomas M.

    2010-01-01

    Gestational exposure to maternal overweight (OW) influences the risk of obesity in adult life. Male offspring from OW dams gain greater body weight and fat mass and develop insulin resistance when fed high-fat diets (45% fat). In this report, we identify molecular targets of maternal OW-induced programming at postnatal d 21 before challenge with the high-fat diet. We conducted global transcriptome profiling, gene/protein expression analyses, and characterization of downstream signaling of insulin and adiponectin pathways in conjunction with endocrine and biochemical characterization. Offspring born to OW dams displayed increased serum insulin, leptin, and resistin levels (P < 0.05) at postnatal d 21 preceding changes in body composition. A lipogenic transcriptome signature in the liver, before development of obesity, was evident in OW-dam offspring. A coordinated locus of 20 sterol regulatory element-binding protein-1-regulated target genes was induced by maternal OW. Increased nuclear levels of sterol regulatory element-binding protein-1 and recruitment to the fatty acid synthase promoter were confirmed via ELISA and chromatin immunoprecipitation analyses, respectively. Higher fatty acid synthase and acetyl coenzyme A carboxylase protein and pAKT (Thr308) and phospho-insulin receptor-β were confirmed via immunoblotting. Maternal OW also attenuated AMP kinase/peroxisome proliferator-activated receptor-α signaling in the offspring liver, including transcriptional down-regulation of several peroxisome proliferator-activated receptor-α-regulated genes. Hepatic mRNA and circulating fibroblast growth factor-21 levels were significantly lower in OW-dam offspring. Furthermore, serum levels of high-molecular-weight adiponectin (P < 0.05) were decreased in OW-dam offspring. Phosphorylation of hepatic AMP-kinase (Thr172) was significantly decreased in OW-dam offspring, along with lower AdipoR1 mRNA. Our results strongly suggest that gestational exposure to maternal

  3. The regulation of reproductive neuroendocrine function by insulin and insulin-like growth factor-1 (IGF-1)

    PubMed Central

    Wolfe, Andrew; Divall, Sara; Wu, Sheng

    2014-01-01

    The mammalian reproductive hormone axis regulates gonadal steroid hormone levels and gonadal function essential for reproduction. The neuroendocrine control of the axis integrates signals from a wide array of inputs. The regulatory pathways important for mediating these inputs have been the subject of numerous studies. One class of proteins that have been shown to mediate metabolic and growth signals to the CNS includes Insulin and IGF-1. These proteins are structurally related and can exert endocrine and growth factor like action via related receptor tyrosine kinases. The role that insulin and IGF-1 play in controlling the hypothalamus and pituitary and their role in regulating puberty and nutritional control of reproduction has been studied extensively. This review summarizes the in vitro and in vivo models that have been used to study these neuroendocrine structures and the influence of these growth factors on neuroendocrine control of reproduction. PMID:24929098

  4. Cross-sectional association of dietary patterns with insulin resistance phenotypes among adults without diabets in the Framingham Offspring Study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Several studies have linked dietary patterns which derived by cluster analysis with metabolic syndrome. Insulin resistance and hyperinsulinemia are key metabolic abnormalities which drive the metabolic syndrome. However, whether dietary patterns identified by cluster analysis are also associated wi...

  5. Impaired Translocation of GLUT4 Results in Insulin Resistance of Atrophic Soleus Muscle

    PubMed Central

    Xu, Peng-Tao; Song, Zhen; Zhang, Wen-Cheng; Jiao, Bo; Yu, Zhi-Bin

    2015-01-01

    Whether or not the atrophic skeletal muscle induces insulin resistance and its mechanisms are not resolved now. The antigravity soleus muscle showed a progressive atrophy in 1-week, 2-week, and 4-week tail-suspended rats. Hyperinsulinemic-euglycemic clamp showed that the steady-state glucose infusion rate was lower in 4-week tail-suspended rats than that in the control rats. The glucose uptake rates under insulin- or contraction-stimulation were significantly decreased in 4-week unloaded soleus muscle. The key protein expressions of IRS-1, PI3K, and Akt on the insulin-dependent pathway and of AMPK, ERK, and p38 on the insulin-independent pathway were unchanged in unloaded soleus muscle. The unchanged phosphorylation of Akt and p38 suggested that the activity of two signal pathways was not altered in unloaded soleus muscle. The AS160 and GLUT4 expression on the common downstream pathway also was not changed in unloaded soleus muscle. But the GLUT4 translocation to sarcolemma was inhibited during insulin stimulation in unloaded soleus muscle. The above results suggest that hindlimb unloading in tail-suspended rat induces atrophy in antigravity soleus muscle. The impaired GLUT4 translocation to sarcolemma under insulin stimulation may mediate insulin resistance in unloaded soleus muscle and further affect the insulin sensitivity of whole body in tail-suspended rats. PMID:25713812

  6. Insulin Regulates Hepatic Triglyceride Secretion and Lipid Content via Signaling in the Brain.

    PubMed

    Scherer, Thomas; Lindtner, Claudia; O'Hare, James; Hackl, Martina; Zielinski, Elizabeth; Freudenthaler, Angelika; Baumgartner-Parzer, Sabina; Tödter, Klaus; Heeren, Joerg; Krššák, Martin; Scheja, Ludger; Fürnsinn, Clemens; Buettner, Christoph

    2016-06-01

    Hepatic steatosis is common in obesity and insulin resistance and results from a net retention of lipids in the liver. A key mechanism to prevent steatosis is to increase secretion of triglycerides (TG) packaged as VLDLs. Insulin controls nutrient partitioning via signaling through its cognate receptor in peripheral target organs such as liver, muscle, and adipose tissue and via signaling in the central nervous system (CNS) to orchestrate organ cross talk. While hepatic insulin signaling is known to suppress VLDL production from the liver, it is unknown whether brain insulin signaling independently regulates hepatic VLDL secretion. Here, we show that in conscious, unrestrained male Sprague Dawley rats the infusion of insulin into the third ventricle acutely increased hepatic TG secretion. Chronic infusion of insulin into the CNS via osmotic minipumps reduced the hepatic lipid content as assessed by noninvasive (1)H-MRS and lipid profiling independent of changes in hepatic de novo lipogenesis and food intake. In mice that lack the insulin receptor in the brain, hepatic TG secretion was reduced compared with wild-type littermate controls. These studies identify brain insulin as an important permissive factor in hepatic VLDL secretion that protects against hepatic steatosis. PMID:26861781

  7. Impaired translocation of GLUT4 results in insulin resistance of atrophic soleus muscle.

    PubMed

    Xu, Peng-Tao; Song, Zhen; Zhang, Wen-Cheng; Jiao, Bo; Yu, Zhi-Bin

    2015-01-01

    Whether or not the atrophic skeletal muscle induces insulin resistance and its mechanisms are not resolved now. The antigravity soleus muscle showed a progressive atrophy in 1-week, 2-week, and 4-week tail-suspended rats. Hyperinsulinemic-euglycemic clamp showed that the steady-state glucose infusion rate was lower in 4-week tail-suspended rats than that in the control rats. The glucose uptake rates under insulin- or contraction-stimulation were significantly decreased in 4-week unloaded soleus muscle. The key protein expressions of IRS-1, PI3K, and Akt on the insulin-dependent pathway and of AMPK, ERK, and p38 on the insulin-independent pathway were unchanged in unloaded soleus muscle. The unchanged phosphorylation of Akt and p38 suggested that the activity of two signal pathways was not altered in unloaded soleus muscle. The AS160 and GLUT4 expression on the common downstream pathway also was not changed in unloaded soleus muscle. But the GLUT4 translocation to sarcolemma was inhibited during insulin stimulation in unloaded soleus muscle. The above results suggest that hindlimb unloading in tail-suspended rat induces atrophy in antigravity soleus muscle. The impaired GLUT4 translocation to sarcolemma under insulin stimulation may mediate insulin resistance in unloaded soleus muscle and further affect the insulin sensitivity of whole body in tail-suspended rats. PMID:25713812

  8. Controlling in Vitro Insulin Amyloidosis with Stable Peptide Conjugates: A Combined Experimental and Computational Study.

    PubMed

    Mishra, Narendra Kumar; Krishna Deepak, R N V; Sankararamakrishnan, Ramasubbu; Verma, Sandeep

    2015-12-17

    Insulin aggregation, to afford amyloidogenic polypeptide fibrils, is an energetically driven, well-studied phenomenon, which presents interesting biological ramifications. These aggregates are also known to form around insulin injection sites and in diabetic patients suffering from Parkinson's disease. Such occurrences force considerable reduction in hormone activity and are often responsible for necrotic deposits in diabetic patients. Changes in physicochemical environment, such as pH, temperature, ionic strength, and mechanical agitation, affect insulin fibrillation, which also presents intrigue from the structural viewpoint. Several reports have tried to unravel underlying mechanisms concerning the aggregation process taking into account a three aromatic amino acid patch Phe(B24)-Phe(B25)-Tyr(B26) located in the C-terminal part of the B chain, identified as a key site for human insulin-receptor interaction. The present study describes design and inhibitory effects of novel peptide conjugates toward fibrillation of insulin as investigated by thioflavin T assay, circular dichroism, and AFM. Possible interaction of insulin with peptide-based fibrillation inhibitors reveals an important role of hydrophobic interactions in the inhibition process. Molecular dynamics simulation studies demonstrate that inhibitor D4 interacts with insulin residues from the helix and the C-terminal extended segment of chain B. These studies present a novel approach for the discovery of stable, peptide-based ligands as novel antiamyloidogenic agents for insulin aggregation. PMID:26569375

  9. Reversal of diet-induced obesity and insulin resistance by inducible genetic ablation of GRK2.

    PubMed

    Vila-Bedmar, Rocio; Cruces-Sande, Marta; Lucas, Elisa; Willemen, Hanneke L D M; Heijnen, Cobi J; Kavelaars, Annemieke; Mayor, Federico; Murga, Cristina

    2015-07-21

    Insulin resistance is a common feature of obesity and predisposes individuals to various prevalent pathological conditions. G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor kinase 2 (GRK2) integrates several signal transduction pathways and is emerging as a physiologically relevant inhibitor of insulin signaling. GRK2 abundance is increased in humans with metabolic syndrome and in different murine models of insulin resistance. To support GRK2 as a potential drug target in type 2 diabetes and obesity, we investigated whether lowering GRK2 abundance reversed an ongoing systemic insulin-resistant phenotype, using a mouse model of tamoxifen-induced GRK2 ablation after high-fat diet-dependent obesity and insulin resistance. Tamoxifen-triggered GRK2 deletion impeded further body weight gain, normalized fasting glycemia, improved glucose tolerance, and was associated with preserved insulin sensitivity in skeletal muscle and liver, thereby maintaining whole-body glucose homeostasis. Moreover, when continued to be fed a high-fat diet, these animals displayed reduced fat mass and smaller adipocytes, were resistant to the development of liver steatosis, and showed reduced expression of proinflammatory markers in the liver. Our results indicate that GRK2 acts as a hub to control metabolic functions in different tissues, which is key to controlling insulin resistance development in vivo. These data suggest that inhibiting GRK2 could reverse an established insulin-resistant and obese phenotype, thereby putting forward this enzyme as a potential therapeutic target linking glucose homeostasis and regulation of adiposity. PMID:26198359

  10. The contribution of visceral fat to improved insulin signaling in Ames dwarf mice.

    PubMed

    Menon, Vinal; Zhi, Xu; Hossain, Tanvir; Bartke, Andrzej; Spong, Adam; Gesing, Adam; Masternak, Michal M

    2014-06-01

    Ames dwarf (Prop1(df), df/df) mice are characterized by growth hormone (GH), prolactin, and thyrotropin deficiency, remarkable extension of longevity and increased insulin sensitivity with low levels of fasting insulin and glucose. Plasma levels of anti-inflammatory adiponectin are increased in df/df mice, while pro-inflammatory IL-6 is decreased in plasma and epididymal fat. This represents an important shift in the balance between pro- and anti-inflammatory adipokines in adipose tissue, which was not exposed to GH signals during development or adult life. To determine the role of adipose tissue in the control of insulin signaling in these long-living mutants, we examined the effects of surgical removal of visceral (epididymal and perinephric) adipose tissue. Comparison of the results obtained in df/df mice and their normal (N) siblings indicated different effects of visceral fat removal (VFR) on insulin sensitivity and glucose tolerance. The analysis of the expression of genes related to insulin signaling indicated that VFR improved insulin action in skeletal muscle in N mice. Interestingly, this surgical intervention did not improve insulin signaling in df/df mice skeletal muscle but caused suppression of the signal in subcutaneous fat. We conclude that altered profile of adipokines secreted by visceral fat of Ames dwarf mice may act as a key contributor to increased insulin sensitivity and extended longevity of these animals. PMID:24690289

  11. Identification of novel insulin mimetic drugs by quantitative total internal reflection fluorescence (TIRF) microscopy

    PubMed Central

    Lanzerstorfer, Peter; Stadlbauer, Verena; Chtcheglova, Lilia A; Haselgrübler, Renate; Borgmann, Daniela; Wruss, Jürgen; Hinterdorfer, Peter; Schröder, Klaus; Winkler, Stephan M; Höglinger, Otmar; Weghuber, Julian

    2014-01-01

    Background and Purpose Insulin stimulates the transport of glucose in target tissues by triggering the translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Resistance to insulin, the major abnormality in type 2 diabetes, results in a decreased GLUT4 translocation efficiency. Thus, special attention is being paid to search for compounds that are able to enhance this translocation process in the absence of insulin. Experimental Approach Total internal reflection fluorescence (TIRF) microscopy was applied to quantify GLUT4 translocation in highly insulin-sensitive CHO-K1 cells expressing a GLUT4-myc-GFP fusion protein. Key Results Using our approach, we demonstrated GLUT4 translocation modulatory properties of selected substances and identified novel potential insulin mimetics. An increase in the TIRF signal was found to correlate with an elevated glucose uptake. Variations in the expression level of the human insulin receptor (hInsR) showed that the insulin mimetics identified stimulate GLUT4 translocation by a mechanism that is independent of the presence of the hInsR. Conclusions and Implications Taken together, the results indicate that TIRF microscopy is an excellent tool for the quantification of GLUT4 translocation and for identifying insulin mimetic drugs. PMID:25039620

  12. Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity

    PubMed Central

    Ma, Gary S.; Lopez-Sanchez, Inmaculada; Aznar, Nicolas; Kalogriopoulos, Nicholas; Pedram, Shabnam; Midde, Krishna; Ciaraldi, Theodore P.; Henry, Robert R.; Ghosh, Pradipta

    2015-01-01

    Insulin resistance (IR) is a metabolic disorder characterized by impaired insulin signaling and cellular glucose uptake. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the sole conduit for postreceptor signaling. Here we challenge that paradigm and show that GIV/Girdin, a guanidine exchange factor (GEF) for the trimeric G protein Gαi, is another major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind InsR, IRS1, and phosphoinositide 3-kinase, GIV serves as a key hub in the immediate postreceptor level, which coordinately enhances the metabolic insulin response and glucose uptake in myotubes via its GEF function. Site-directed mutagenesis or phosphoinhibition of GIV-GEF by the fatty acid/protein kinase C-theta pathway triggers IR. Insulin sensitizers reverse phosphoinhibition of GIV and reinstate insulin sensitivity. We also provide evidence for such reversible regulation of GIV-GEF in skeletal muscles from patients with IR. Thus GIV is an essential upstream component that couples InsR to G-protein signaling to enhance the metabolic insulin response, and impairment of such coupling triggers IR. We also provide evidence that GIV-GEF serves as therapeutic target for exogenous manipulation of physiological insulin response and reversal of IR in skeletal muscles. PMID:26378251

  13. Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity.

    PubMed

    Ma, Gary S; Lopez-Sanchez, Inmaculada; Aznar, Nicolas; Kalogriopoulos, Nicholas; Pedram, Shabnam; Midde, Krishna; Ciaraldi, Theodore P; Henry, Robert R; Ghosh, Pradipta

    2015-11-15

    Insulin resistance (IR) is a metabolic disorder characterized by impaired insulin signaling and cellular glucose uptake. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the sole conduit for postreceptor signaling. Here we challenge that paradigm and show that GIV/Girdin, a guanidine exchange factor (GEF) for the trimeric G protein Gαi, is another major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind InsR, IRS1, and phosphoinositide 3-kinase, GIV serves as a key hub in the immediate postreceptor level, which coordinately enhances the metabolic insulin response and glucose uptake in myotubes via its GEF function. Site-directed mutagenesis or phosphoinhibition of GIV-GEF by the fatty acid/protein kinase C-theta pathway triggers IR. Insulin sensitizers reverse phosphoinhibition of GIV and reinstate insulin sensitivity. We also provide evidence for such reversible regulation of GIV-GEF in skeletal muscles from patients with IR. Thus GIV is an essential upstream component that couples InsR to G-protein signaling to enhance the metabolic insulin response, and impairment of such coupling triggers IR. We also provide evidence that GIV-GEF serves as therapeutic target for exogenous manipulation of physiological insulin response and reversal of IR in skeletal muscles. PMID:26378251

  14. [Oxidative stress in adipose tissue as a primary link in pathogenesis of insulin resistance].

    PubMed

    Kuzmenko, D I; Udintsev, S N; Klimentyeva, T K; Serebrov, V Yu

    2016-01-01

    Obesity is a leading risk factor of diabetes mellitus type 2, impairments of lipid metabolism and cardiovascular diseases. Dysfunctions of the accumulating weight of the visceral fat are primarily linked to pathogenesis of systemic insulin resistance. The review considers modern views about biochemical mechanisms underlying formation of oxidative stress in adipocytes at obesity, as one of key elements of impairments of their metabolism triggering formation of systemic insulin resistance. PMID:26973182

  15. Insulin therapy: going the "smarter" way.

    PubMed

    Kalra, Sanjay; Joshi, Ameya; Parmar, Girish

    2014-01-01

    Insulin pharmacology has evolved from nonhuman source based extraction of insulin, to use of recombinant technologies for human insulin production, to tailor made synthetic insulin analogues. The delivery techniques of insulin have also improved, from injections to pumps, and to pumps with sensors. However, to achieve the final goal of a closed loop insulin delivery is far from achieved. One of the researches in this direction includes synthetic smart insulins. These are systems with chemical sensors for glucose, linked to reactions that trigger glucose mediated insulin delivery. Interest in this field is high and recent publications and patents show promise. The current review tries to summarize the basic concept of smart insulin as well as cater the recent developments and patents in this direction. PMID:24975640

  16. Treatment of insulin resistance in uremia.

    PubMed

    Stefanović, V; Nesić, V; Stojimirović, B

    2003-02-01

    Insulin resistance is a characteristic feature of uremia. As long as the hyperinsulinemia adequate to overcome the insulin resistance, glucose tolerance remains normal. In patients destined to develop type 2 diabetes, the beta cell compensatory response declines, and relative, or absolute, insulin deficiency develops. At this point glucose intolerance and eventually frank type 2 diabetes occur. Insulin resistance and concomitant hyperinsulinemia are present irrespective of the type of renal disease. Several studies have confirmed that hemodialysis (HD) treatment significantly improves insulin resistance. Both CAPD and CCPD are shown to improve insulin resistance in uremic patients. Comparing the effect of PD and HD treatment, it was found that the CCPD group has significantly higher insulin sensitivity than the HD group with the CAPD group similar to HD. Treatment of calcium and phosphate disturbances, including vitamin D therapy, significantly reduces insulin resistance in uremia. Treatment with recombinant human erythropoietin (EPO) is an efficient way to increase hematocrit, to reverse cardiovascular problems and to improve insulin sensitivity. Angiotensin-converting enzyme inhibitors have been shown to improve insulin resistance, hyperinsulinemia and glucose intolerance in uremic patients. Thiazolidinediones (TZDs), the new insulin-sensitizing drugs, provide the proof that pharmacologic treatment of insulin resistance can be of enormous clinical benefit. The great potential of insulin resistance therapy illuminated by the TZDs will continue to catalyze research in this area directed toward the discovery of new insulin-sensitizing agents that work through other mechanisms. PMID:12653342

  17. Human insulin: DNA technology's first drug.

    PubMed

    The, M J

    1989-11-01

    The history, biologic activity, and immunogenicity of human insulin are described. Recombinant human insulin first entered clinical trials in humans in 1980. At that time, the A and B chains of the insulin molecule were produced separately and then combined by chemical techniques. Since 1986, a different recombinant process has been used. The human genetic coding for proinsulin is inserted into Escherichia coli cells, which are then grown by fermentation to produce proinsulin. The connecting peptide is cleaved enzymatically from proinsulin to produce human insulin. Studies indicate that there are no important differences between pork insulin and human insulin in terms of therapeutic efficacy and disposition after intravenous administration. Recombinant human insulin has a faster onset of action and lower immunogenicity than pork or beef insulin. Diabetic patients may have an improvement in glucose concentrations when their therapy is switched from animal-source insulin to human insulin. Such a change usually requires a dosage adjustment, which must be determined by a physician. Pharmacists are responsible for educating patients concerning all insulin products and for preventing patients from interchanging insulin products. The availability of human insulin as the first pharmaceutical product manufactured through recombinant DNA technology, however, has had little effect on the pharmacist's role in the care of such patients. The production of human insulin through recombinant DNA technology represents an important advance in the treatment of patients with diabetes. PMID:2690608

  18. Fumosorinone, a novel PTP1B inhibitor, activates insulin signaling in insulin-resistance HepG2 cells and shows anti-diabetic effect in diabetic KKAy mice

    SciTech Connect

    Liu, Zhi-Qin; Liu, Ting; Chen, Chuan; Li, Ming-Yan; Wang, Zi-Yu; Chen, Ruo-song; Wei, Gui-xiang; Wang, Xiao-yi; Luo, Du-Qiang

    2015-05-15

    Insulin resistance is a characteristic feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of the insulin signaling pathways, and its increased activity and expression are implicated in the pathogenesis of insulin resistance. Therefore, the inhibition of PTP1B is anticipated to become a potential therapeutic strategy to treat T2DM. Fumosorinone (FU), a new natural product isolated from insect fungi Isaria fumosorosea, was found to inhibit PTP1B activity in our previous study. Herein, the effects of FU on insulin resistance and mechanism in vitro and in vivo were investigated. FU increased the insulin-provoked glucose uptake in insulin-resistant HepG2 cells, and also reduced blood glucose and lipid levels of type 2 diabetic KKAy mice. FU decreased the expression of PTP1B both in insulin-resistant HepG2 cells and in liver tissues of diabetic KKAy mice. Furthermore, FU increased the phosphorylation of IRβ, IRS-2, Akt, GSK3β and Erk1/2 in insulin-resistant HepG2 cells, as well as the phosphorylation of IRβ, IRS-2, Akt in liver tissues of diabetic KKAy mice. These results showed that FU increased glucose uptake and improved insulin resistance by down-regulating the expression of PTP1B and activating the insulin signaling pathway, suggesting that it may possess antidiabetic properties. - Highlights: • Fumosorinone is a new PTP1B inhibitor isolated from insect pathogenic fungi. • Fumosorinone attenuated the insulin resistance both in vitro and in vivo. • Fumosorinone decreased the expression of PTP1B both in vitro and in vivo. • Fumosorinone activated the insulin signaling pathway both in vitro and in vivo.

  19. Molecular mechanisms for the control of translation by insulin.

    PubMed Central

    Proud, C G; Denton, R M

    1997-01-01

    Insulin acutely stimulates protein synthesis in mammalian cells, and this involves activation of the process of mRNA translation. mRNA translation is a complex multi-step process mediated by proteins termed translation factors. Several translation factors are regulated in response to insulin, often as a consequence of changes in their states of phosphorylation. The initiation factor eIF4E binds to the cap structure at the 5'-end of the mRNA and mediates assembly of an initiation-factor complex termed eIF4F. Assembly of this complex can be regulated by eIF4E-binding proteins (4E-BPs), which inhibit eIF4F complex assembly. Insulin induces phosphorylation of the 4E-BPs, resulting in alleviation of the inhibition. This regulatory mechanism is likely to be especially important for the control of the translation of specific mRNAs whose 5'-untranslated regions (5'-UTRs) are rich in secondary structure. Translation of another class of mRNAs, those with 5'-UTRs containing polypyrimidine tracts is also activated by insulin and this, like phosphorylation of the 4E-BPs, appears to involve the rapamycin-sensitive signalling pathway which leads to activation of the 70 kDa ribosomal protein S6 kinase (p70 S6 kinase) and the phosphorylation of the ribosomal protein S6. Overall stimulation of translation may involve activation of initiation factor eIF2B, which is required for all initiation events. This effect is dependent upon phosphatidylinositol 3-kinase and may involve the inactivation of glycogen synthase kinase-3 and consequent dephosphorylation of eIF2B, leading to its activation. Peptide-chain elongation can also be activated by insulin, and this is associated with the dephosphorylation and activation of elongation factor eEF2, probably as a consequence of the insulin-induced reduction in eEF2 kinase activity. Thus multiple signalling pathways acting on different steps in translation are involved in the activation of this process by insulin and lead both to general

  20. Patient Perspectives on Biosimilar Insulin.

    PubMed

    Wilkins, Alasdair R; Venkat, Manu V; Brown, Adam S; Dong, Jessica P; Ran, Nina A; Hirsch, James S; Close, Kelly L

    2014-01-01

    Given that a new wave of biosimilar insulins will likely enter the market in coming years, it is important to understand patient perspectives on these biosimilars. A survey (N = 3214) conducted by the market research company dQ&A, which maintains a 10 000-patient panel of people with type 1 or type 2 diabetes in roughly equal measure, investigated these perspectives. The survey asked whether patients would switch to a hypothetical less expensive biosimilar insulin that was approved by their provider. Approximately 66% of respondents reported that they would "definitely" or "likely" use a biosimilar insulin, while 17% reported that they were "unlikely" to use or would "definitely not use" such a product. Type 2 diabetes patients demonstrated slightly more willingness to use biosimilars than type 1 diabetes patients. Common patient concerns included whether biosimilars would be as effective as reference products (~650 respondents), whether side effect profiles would deviate from those of reference products (~220 respondents), and the design of the delivery device (~50 respondents). While cost savings associated with biosimilar insulins could increase patient uptake, especially among patients without health insurance (some recent estimates suggest that biosimilars will come at a substantial discount), patients may still need assurance that a cheaper price tag is not necessarily associated with substandard quality. Overall, the dQ&A survey indicates that the majority of patients are willing to consider biosimilar insulins, but manufacturers will need to work proactively to address and assuage patient concerns regarding efficacy, safety, drug administration, and other factors. PMID:24876533

  1. Oxidative Stress and Insulin Resistance

    PubMed Central

    Park, Kyong; Gross, Myron; Lee, Duk-Hee; Holvoet, Paul; Himes, John H.; Shikany, James M.; Jacobs, David R.

    2009-01-01

    OBJECTIVE Although cumulative evidence suggests that increased oxidative stress may lead to insulin resistance in vivo or in vitro, community-based studies are scarce. This study examined the longitudinal relationships of oxidative stress biomarkers with the development of insulin resistance and whether these relationships were independent of obesity in nondiabetic young adults. RESEARCH DESIGN AND METHODS Biomarkers of oxidative stress (F2-isoprostanes [F2Isop] and oxidized LDL [oxLDL]), insulin resistance (the homeostasis model assessment of insulin resistance [HOMA-IR]), and various fatness measures (BMI, waist circumference, and estimated percent fat) were obtained in a population-based observational study (Coronary Artery Risk Development in Young Adults) and its ancillary study (Young Adult Longitudinal Trends in Antioxidants) during 2000–2006. RESULTS There were substantial increases in estimated mean HOMA-IR over time. OxLDL and F2Isop showed little association with each other. Mean evolving HOMA-IR increased with increasing levels of oxidative stress markers (P < 0.001 for oxLDL and P = 0.06 for F2Isop), measured in 2000–2001. After additional adjustment for adiposity, a positive association between oxLDL and HOMA-IR was strongly evident, whereas the association between F2Isop and HOMA-IR was not. CONCLUSIONS We observed positive associations between each of two oxidative stress markers and insulin resistance. The association with oxidized LDL was independent of obesity, but that with F2Isop was not. PMID:19389821

  2. How to achieve a predictable basal insulin?

    PubMed

    Kurtzhals, P

    2005-09-01

    The development of insulin analogues over the last two decades have aimed at optimising the pharmacokinetic profile of subcutaneously injected insulin for therapeutic use in diabetes mellitus. Rapid acting analogues were successfully engineered and marketed in the late 1990's. In engineering long-acting analogues it has been a particular challenge to obtain action profiles that would be predictable from day to day in the same person. The most recent approach has been to acylate the insulin molecule with a fatty acid which provides the insulin molecule with a specific affinity for albumin. The first clinically available agent of this type is insulin detemir. Pharmacological studies have shown that reversible albumin binding will protract absorption following subcutaneous injection but still allow the insulin molecule to be recognised by the insulin receptor following dissociation from the carrier protein. Moreover, the molecular features of insulin detemir are attractive in that the molecule can be formulated as a neutral aqueous solution and does not precipitate after injection. Together with an important buffering mechanism effected by plasma albumin binding, this explains a highly significant reduction of within-subject variability of pharmacodynamic response observed in repeat isoglycaemic clamp studies where insulin detemir was compared to other basal insulin products. No safety considerations have been identified in using albumin as an insulin carrier to protract and buffer insulin action. In assessing the clinical attractiveness of insulin analogues, it is furthermore critically important to consider how the molecular modifications impact efficacy and safety. A number of pharmacological studies have shown that insulin detemir overall retains the molecular pharmacological properties of native human insulin, including a physiological balance between metabolic and mitogenic potencies. Taken together, insulin detemir provides an attractive novel approach for

  3. Insulin receptors in the mammary gland

    SciTech Connect

    Smith, D.H.

    1986-01-01

    Insulin binding studies were conducted using mammary membrane preparations to further the authors understanding of insulin's role in regulating mammary metabolism, particularly ruminant mammary metabolism. Specific objectives were to: (1) characterize insulin binding to bovine mammary microsomes and determine if the specificity and kinetics of binding indicate the presence of insulin receptors in bovine mammary gland; (2) examine and compare insulin binding by liver and mammary microsomes of the pig and dairy cow; (3) examine insulin binding to bovine milk fat globule membranes (MFGM) and evaluate this model's usefulness in assessing insulin receptor regulation in the mammary gland of the cow; (4) examine the effect of dietary fat in insulin binding by rat mammary and liver microsomes. The specificity and kinetics of /sup 125/I-insulin binding of bovine mammary microsomes indicated the presence of insulin receptors in bovine mammary gland. Bovine liver and mammary microsomes specifically bound less /sup 125/I-insulin than did the corresponding porcine microsomes, and mammary microsomes, regardless of species, specifically bound less /sup 125/I-insulin than did liver microsomes. These differences in binding suggest differences in insulin responsiveness between pigs and cattle, as well as between the liver and mammary glands.

  4. Characterization of the chicken muscle insulin receptor

    SciTech Connect

    Adamo, M.; Simon, J.; Rosebrough, R.W.; McMurtry, J.P.; Steele, N.C.; LeRoith, D.

    1987-12-01

    Insulin receptors are present in chicken skeletal muscle. Crude membrane preparations demonstrated specific /sup 125/I-insulin binding. The nonspecific binding was high (36-55% of total binding) and slightly lower affinity receptors were found than are typically observed for crude membrane insulin binding in other chicken tissues. Affinity crosslinking of /sup 125/I-insulin to crude membranes revealed insulin receptor alpha-subunits of Mr 128K, intermediate between those of liver (134K) and brain (124K). When solubilized and partially purified on wheat germ agglutinin (WGA) affinity columns, chicken muscle insulin receptors exhibited typical high affinity binding, with approximately 10(-10) M unlabeled insulin producing 50% inhibition of the specific /sup 125/I-insulin binding. WGA purified chicken muscle insulin receptors also exhibited insulin-stimulated autophosphorylation of the beta-subunit, which appeared as phosphorylated bands of 92- and 81K. Both bands were immunoprecipitated by anti-receptor antiserum (B10). WGA purified membranes also demonstrated dose-dependent insulin-stimulated phosphorylation of the exogenous substrate poly(Glu,Tyr)4:1. However, unlike chicken liver, chicken muscle insulin receptor number and tyrosine kinase activity were unaltered by 48 hr of fasting or 48 hr of fasting and 24 hr of refeeding. Thus, despite the presence of insulin receptors in chicken muscle showing normal coupling to receptor tyrosine kinase activity, nutritional alterations modulate these parameters in a tissue-specific manner in chickens.

  5. Transplacental passage of insulin complexed to antibody.

    PubMed Central

    Bauman, W A; Yalow, R S

    1981-01-01

    The passage of plasma proteins across the placental barrier in humans is known to be highly selective. Thus, free maternal insulin has been reported not to cross the normal maternofetal barrier, although insulin-binding antibodies have been detected in newborn infants whose diabetic mothers received insulin therapy. In this report we demonstrate, with the use of a human antiserum that permits distinction between human and animal insulins, that insulin in the cord blood of each of two neonates of insulin-treated diabetic mothers was, in part, animal insulin. The higher the antibody titer of the mother the greater was the total insulin in the cord plasma and the greater was the fraction that was animal insulin. In case 1 cord plasma insulin was 0.7 unit/liter, of which 10% was animal insulin; in case 2 cord plasma insulin was 3.5 units/liter, of which 25% was animal insulin. The demonstration that antigen restricted from transplacental passage can be transferred while complexed to antibody raises the question whether such fetal exposure would induce partial or total immunologic unresponsiveness subsequently if the fetus were rechallenged with the same antigen. PMID:7027265

  6. In vivo peripheral nervous system insulin signaling

    PubMed Central

    Grote, Caleb W.; Ryals, Janelle M.; Wright, Douglas E.

    2014-01-01

    Alterations in peripheral nervous system (PNS) insulin support may contribute to diabetic neuropathy (DN); yet, PNS insulin signaling is not fully defined. Here, we investigated in vivo insulin signaling in the PNS and compared the insulin-responsiveness to that of muscle, liver, and adipose. Nondiabetic mice were administered increasing doses of insulin to define a dose response relationship between insulin and Akt activation in the DRG and sciatic nerve. Resulting EC50 doses were used to characterize the PNS insulin signaling time course and make comparisons between insulin signaling in the PNS and other peripheral tissues (i.e., muscle, liver, adipose). The results demonstrate that the PNS is responsive to insulin and that differences in insulin signaling pathway activation exist between PNS compartments. At a therapeutically relevant dose, Akt was activated in the muscle, liver, and adipose at 30 minutes, correlating with the changes in blood glucose levels. Interestingly, the sciatic nerve showed a similar signaling profile as insulin-sensitive tissues, however there was not a comparable activation in the DRG or spinal cord. These results present new evidence regarding PNS insulin signaling pathways in vivo and provide a baseline for studies investigating the contribution of disrupted PNS insulin signaling to DN pathogenesis. PMID:24028189

  7. Effects of sleep restriction on glucose control and insulin secretion during diet-induced weight loss

    PubMed Central

    Nedeltcheva, A. V.; Imperial, J. G.; Penev, P. D.

    2012-01-01

    Insufficient sleep is associated with changes in glucose tolerance, insulin secretion, and insulin action. Despite widespread use of weight-loss diets for metabolic risk reduction, the effects of insufficient sleep on glucose regulation in overweight dieters are not known. To examine the consequences of recurrent sleep restriction on 24-hour blood glucose control during diet-induced weight loss, 10 overweight and obese adults (3F/7M; mean [SD] age 41 [5] y; BMI 27.4 [2.0] kg/m2) completed two 14-day treatments with hypocaloric diet and 8.5 or 5.5-h nighttime sleep opportunity in random order 7 [3] months apart. Oral and intravenous glucose tolerance test (IVGTT) data, fasting lipids and free-fatty acids (FFA), and 24-hour blood glucose, insulin, C-peptide, and counter-regulatory hormone measurements were collected after each treatment. Participants had comparable weight loss (1.0 [0.3] BMI units) during each treatment. Bedtime restriction reduced sleep by 131 [30] min/day. Recurrent sleep curtailment decreased 24-hour serum insulin concentrations (i.e. enhanced 24-hour insulin economy) without changes in oral glucose tolerance and 24-hour glucose control. This was accompanied by a decline in fasting blood glucose, increased fasting FFA which suppressed normally following glucose ingestion, and lower total and LDL cholesterol concentrations. Sleep-loss-related changes in counter-regulatory hormone secretion during the IVGTT limited the utility of the test in this study. In conclusion, sleep restriction enhanced 24-hour insulin economy without compromising glucose homeostasis in overweight individuals placed on a balanced hypocaloric diet. The changes in fasting blood glucose, insulin, lipid and FFA concentrations in sleep-restricted dieters resembled the pattern of human metabolic adaptation to reduced carbohydrate availability. PMID:22513492

  8. Hindbrain estrogen receptor-beta antagonism normalizes reproductive and counter-regulatory hormone secretion in hypoglycemic steroid-primed ovariectomized female rats.

    PubMed

    Briski, Karen P; Shrestha, Prem K

    2016-09-01

    Hindbrain dorsal vagal complex A2 noradrenergic signaling represses the pre-ovulatory luteinizing hormone (LH) surge in response to energy deficiency. Insulin-induced hypoglycemia augments A2 neuron adenosine 5'-monophosphate-activated protein kinase (AMPK) activity and estrogen receptor-beta (ERβ) expression, coincident with LH surge suppression. We hypothesized that ERβ is critical for hypoglycemia-associated patterns of LH secretion and norepinephrine (NE) activity in key reproduction-relevant forebrain structures. The neural mechanisms responsible for tight coupling of systemic energy balance and procreation remain unclear; here, we investigated whether ERβ-dependent hindbrain signals also control glucose counter-regulatory responses to hypoglycemia. Gonadal steroid-primed ovariectomized female rats were pretreated by caudal fourth ventricular administration of the ERβ antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP) or vehicle before insulin injection at LH surge onset. Western blot analysis of laser-microdissected A2 neurons revealed hypoglycemic intensification of AMPK activity and dopamine-β-hydroxylase protein expression; the latter response was attenuated by PHTPP pretreatment. PHTPP regularized LH release, but not preoptic GnRH-I precursor protein expression in insulin-injected rats, and reversed hypoglycemic stimulation of glucagon and corticosterone secretion. Hypoglycemia caused PHTPP-reversible changes in NE and prepro-kisspeptin protein content in the hypothalamic arcuate (ARH), but not anteroventral periventricular nucleus. Results provide novel evidence for ERβ-dependent caudal hindbrain regulation of LH and counter-regulatory hormone secretion during hypoglycemia. Observed inhibition of LH likely involves mechanisms at the axon terminal that impede GnRH neurotransmission. Data also show that caudal hindbrain ERβ exerts site-specific control of NE activity in forebrain projection sites during

  9. 3 CFR - Regulatory Review

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 3 The President 1 2010-01-01 2010-01-01 false Regulatory Review Presidential Documents Other Presidential Documents Memorandum of January 30, 2009 Regulatory Review Memorandum for the Heads of Executive Departments and Agencies For well over two decades, the Office of Information and Regulatory Affairs (OIRA) at the Office of Management...

  10. Treatment Approach to Patients With Severe Insulin Resistance.

    PubMed

    Church, Timothy J; Haines, Stuart T

    2016-04-01

    In Brief Patients with severe insulin resistance require >2 units/kg of body weight or 200 units/day of insulin. Yet, many patients do not achieve glycemic targets despite using very high doses of insulin. Insulin can cause weight gain, which further contributes to worsening insulin resistance. This article describes the pharmacological options for managing patients with severe insulin resistance, including the use of U-500 insulin and newer agents in combination with insulin. PMID:27092020

  11. Group key management

    SciTech Connect

    Dunigan, T.; Cao, C.

    1997-08-01

    This report describes an architecture and implementation for doing group key management over a data communications network. The architecture describes a protocol for establishing a shared encryption key among an authenticated and authorized collection of network entities. Group access requires one or more authorization certificates. The implementation includes a simple public key and certificate infrastructure. Multicast is used for some of the key management messages. An application programming interface multiplexes key management and user application messages. An implementation using the new IP security protocols is postulated. The architecture is compared with other group key management proposals, and the performance and the limitations of the implementation are described.

  12. Modular Connector Keying Concept

    NASA Technical Reports Server (NTRS)

    Ishman, Scott; Dukes, Scott; Warnica, Gary; Conrad, Guy; Senigla, Steven

    2013-01-01

    For panel-mount-type connectors, keying is usually "built-in" to the connector body, necessitating different part numbers for each key arrangement. This is costly for jobs that require small quantities. This invention was driven to provide a cost savings and to reduce documentation of individual parts. The keys are removable and configurable in up to 16 combinations. Since the key parts are separate from the connector body, a common design can be used for the plug, receptacle, and key parts. The keying can then be set at the next higher assembly.

  13. Regulatory affairs administration as regulatory policy determinant

    SciTech Connect

    Forcier, J.R.

    1984-05-10

    It is the thesis of this article that the processing of a utility company's regulation-related work, the supporting tasks and the manner in which they are completed, can and does have a significant impact on the final results or work product of the regulatory affairs function, including even, potentially, the action of the regulatory agency. The article is therefore full of practical pointers on how the interface with the regulatory authority can best be organized, managed, and carried through to the attainment of optimum results for the utility. 2 references.

  14. Pursuit of a perfect insulin.

    PubMed

    Zaykov, Alexander N; Mayer, John P; DiMarchi, Richard D

    2016-06-01

    Insulin remains indispensable in the treatment of diabetes, but its use is hampered by its narrow therapeutic index. Although advances in peptide chemistry and recombinant DNA-based macromolecule synthesis have enabled the synthesis of structurally optimized insulin analogues, the growing epidemics of obesity and diabetes have emphasized the need for diabetes therapies that are more efficacious, safe and convenient. Accordingly, a broad set of drug candidates, targeting hyperglycaemia plus other disease abnormalities, is now progressing through the clinic. The development of an insulin therapy that is responsive to glucose concentration remains an ultimate goal, with initial prototypes now reaching the proof-of-concept stage. Simultaneously, the first alternatives to injectable delivery have progressed to registration. PMID:26988411

  15. Retinoic Acid-Related Orphan Receptor γ (RORγ): A Novel Participant in the Diurnal Regulation of Hepatic Gluconeogenesis and Insulin Sensitivity

    PubMed Central

    Takeda, Yukimasa; Kang, Hong Soon; Freudenberg, Johannes; DeGraff, Laura M.; Jothi, Raja; Jetten, Anton M.

    2014-01-01

    The hepatic circadian clock plays a key role in the daily regulation of glucose metabolism, but the precise molecular mechanisms that coordinate these two biological processes are not fully understood. In this study, we identify a novel connection between the regulation of RORγ by the clock machinery and the diurnal regulation of glucose metabolic networks. We demonstrate that particularly at daytime, mice deficient in RORγ exhibit improved insulin sensitivity and glucose tolerance due to reduced hepatic gluconeogenesis. This is associated with a reduced peak expression of several glucose metabolic genes critical in the control of gluconeogenesis and glycolysis. Genome-wide cistromic profiling, promoter and mutation analysis support the concept that RORγ regulates the transcription of several glucose metabolic genes directly by binding ROREs in their promoter regulatory region. Similar observations were made in liver-specific RORγ-deficient mice suggesting that the changes in glucose homeostasis were directly related to the loss of hepatic RORγ expression. Altogether, our study shows that RORγ regulates several glucose metabolic genes downstream of the hepatic clock and identifies a novel metabolic function for RORγ in the diurnal regulation of hepatic gluconeogenesis and insulin sensitivity. The inhibition of the activation of several metabolic gene promoters by an RORγ antagonist suggests that antagonists may provide a novel strategy in the management of metabolic diseases, including type 2 diabetes. PMID:24831725

  16. Role of cardiotrophin-1 in obesity and insulin resistance

    PubMed Central

    Moreno-Aliaga, María J.; Romero-Lozano, M. Asunción; Castaño, David; Prieto, Jesús; Bustos, Matilde

    2012-01-01

    Cardiotrophin-1 (CT-1) is a member of the gp130 family of cytokines. In a recent study we examined the metabolic features of ct-1 null mice and the effects on body composition, glucose and lipid metabolism of acute and chronic administration of recombinant CT-1. Our data revealed that CT-1 is a key regulator of energy metabolism with potential applications in the treatment of obesity and the metabolic syndrome. This commentary discusses the significance of these findings in the context of other key studies in the field of obesity and insulin resistance. PMID:23700521

  17. Insulin Degludec (rDNA Origin) Injection

    MedlinePlus

    ... be used with another type of insulin (a short-acting insulin). In patients with type 2 diabetes, ... contraceptives (birth control pills, patches, rings, injections, or implants); medications for mental illness and nausea; monoamine oxidase ( ...

  18. Insulin Glargine (rDNA origin) Injection

    MedlinePlus

    ... be used with another type of insulin (a short-acting insulin). In patients with type 2 diabetes, ... therapy (birth control pills, patches, rings, injections, or implants); isoniazid (Laniazid, in Rifamate, in Rifater); lithium (Lithobid); ...

  19. Quantification of adipose tissue insulin sensitivity.

    PubMed

    Søndergaard, Esben; Jensen, Michael D

    2016-06-01

    In metabolically healthy humans, adipose tissue is exquisitely sensitive to insulin. Similar to muscle and liver, adipose tissue lipolysis is insulin resistant in adults with central obesity and type 2 diabetes. Perhaps uniquely, however, insulin resistance in adipose tissue may directly contribute to development of insulin resistance in muscle and liver because of the increased delivery of free fatty acids to those tissues. It has been hypothesized that insulin adipose tissue resistance may precede other metabolic defects in obesity and type 2 diabetes. Therefore, precise and reproducible quantification of adipose tissue insulin sensitivity, in vivo, in humans, is an important measure. Unfortunately, no consensus exists on how to determine adipose tissue insulin sensitivity. We review the methods available to quantitate adipose tissue insulin sensitivity and will discuss their strengths and weaknesses. PMID:27073214

  20. Metabolic inflammation: connecting obesity and insulin resistance.

    PubMed

    Dali-Youcef, Nassim; Mecili, Mustapha; Ricci, Roméo; Andrès, Emmanuel

    2013-05-01

    Insulin resistance is a pathological condition that arises when insulin signaling is impaired, forcing β-cells to produce more insulin in order to cope with body demands and to maintain glucose homeostasis. When the pancreas is no more able to support an appropriate insulin secretion, insulin resistance becomes decompensated and hyperglycemia is detected. One of the mechanisms leading to insulin resistance is low-grade inflammation that involves a number of protagonists such as inflammatory cytokines, lipids and their metabolites, reactive oxygen species (ROS), hypoxia and endoplasmic reticulum stress, and changes in gut microbiota profiles. We review here the molecular aspects of metabolic inflammation converging to insulin resistance and secondarily to type 2 diabetes. We also discuss the place of high-sensitivity C-reactive protein (hsCRP) in the assessment of metabolic inflammation and potential therapeutic interventions aimed to impede inflammation and therefore prevent insulin resistance. PMID:22834949

  1. Metabolism A higher power for insulin

    NASA Astrophysics Data System (ADS)

    Gribble, Fiona M.

    2005-04-01

    Glucose output from the liver is tightly regulated by insulin. But insulin holds sway over more than the liver - an unappreciated circuit in glucose control involves the opening of ion channels in the brain.

  2. Emerging Trends in Noninvasive Insulin Delivery

    PubMed Central

    Verma, Arun; Kumar, Nitin; Malviya, Rishabha; Sharma, Pramod Kumar

    2014-01-01

    This paper deals with various aspects of oral insulin delivery system. Insulin is used for the treatment of diabetes mellitus, which is characterized by the elevated glucose level (above the normal range) in the blood stream, that is, hyperglycemia. Oral route of administration of any drug is the most convenient route. Development of oral insulin is still under research. Oral insulin will cause the avoidance of pain during the injection (in subcutaneous administration), anxiety due to needle, and infections which can be developed. Different types of enzyme inhibitors, like sodium cholate, camostat, mesilate, bacitracin, leupeptin, and so forth, have been used to prevent insulin from enzymatic degradation. Subcutaneous route has been used for administration of insulin, but pain and itching at the site of administration can occur. That is why various alternative routes of insulin administration like oral route are under investigation. In this paper authors summarized advancement in insulin delivery with their formulation aspects. PMID:26556194

  3. Hypersensitivity Reaction to Insulin Glargine and Insulin Detemir in a Pediatric Patient: A Case Report.

    PubMed

    Badik, Jennifer; Chen, Jimmy; Letvak, Kira; So, Tsz-Yin

    2016-01-01

    Allergy to human insulin or its analogs is rare, but it is still a significant issue in current diabetes care. Allergic reactions can range from localized injection site reactions to generalized anaphylaxis, and they can be caused by excipients or the insulin molecules themselves. We presented a case of a 14-year-old male patient with generalized allergic reactions to insulin glargine and insulin detemir. The patient was successfully managed by being switched to a continuous subcutaneous insulin infusion with insulin aspart. Allergic reactions to insulin detemir and insulin glargine have both been well described, with insulin detemir allergy appearing to be more common. There are several potential mechanisms for insulin allergy, and immunologic characteristics vary among different insulin analogs. After confirming insulin allergy in practice, management involves treating symptoms and switching insulin preparations. This is the first documented case of allergies to both insulin glargine and insulin detemir in a pediatric patient. Exact mechanism of insulin allergy is unknown, and management strategies must be individualized for each patient. PMID:26997933

  4. Hypersensitivity Reaction to Insulin Glargine and Insulin Detemir in a Pediatric Patient: A Case Report

    PubMed Central

    Badik, Jennifer; Chen, Jimmy; Letvak, Kira

    2016-01-01

    Allergy to human insulin or its analogs is rare, but it is still a significant issue in current diabetes care. Allergic reactions can range from localized injection site reactions to generalized anaphylaxis, and they can be caused by excipients or the insulin molecules themselves. We presented a case of a 14-year-old male patient with generalized allergic reactions to insulin glargine and insulin detemir. The patient was successfully managed by being switched to a continuous subcutaneous insulin infusion with insulin aspart. Allergic reactions to insulin detemir and insulin glargine have both been well described, with insulin detemir allergy appearing to be more common. There are several potential mechanisms for insulin allergy, and immunologic characteristics vary among different insulin analogs. After confirming insulin allergy in practice, management involves treating symptoms and switching insulin preparations. This is the first documented case of allergies to both insulin glargine and insulin detemir in a pediatric patient. Exact mechanism of insulin allergy is unknown, and management strategies must be individualized for each patient. PMID:26997933

  5. Structural and Biochemical Characterization of the KRLB Region in Insulin Receptor Substrate-2

    SciTech Connect

    Wu,J.; Tseng, Y.; Xu, C.; Neubert, T.; White, M.; Hubbard, S.

    2008-01-01

    Insulin receptor substrates 1 and 2 (IRS1 and -2) are crucial adaptor proteins in mediating the metabolic and mitogenic effects of insulin and insulin-like growth factor 1. These proteins consist of a pleckstrin homology domain, a phosphotyrosine binding domain and a C-terminal region containing numerous sites of tyrosine, serine and threonine phosphorylation. Previous yeast two-hybrid studies identified a region unique to IRS2, termed the kinase regulatory-loop binding (KRLB) region, which interacts with the tyrosine kinase domain of the insulin receptor. Here we present the crystal structure of the insulin receptor kinase in complex with a 15-residue peptide from the KRLB region. In the structure, this segment of IRS2 is bound in the kinase active site with Tyr628 positioned for phosphorylation. Although Tyr628 was phosphorylated by the insulin receptor, its catalytic turnover was poor, resulting in kinase inhibition. Our studies indicate that the KRLB region functions to limit tyrosine phosphorylation of IRS2.

  6. PTPRD silencing by DNA hypermethylation decreases insulin receptor signaling and leads to type 2 diabetes.

    PubMed

    Chen, Yng-Tay; Lin, Wei-D; Liao, Wen-Lin; Lin, Ying-Ju; Chang, Jan-Gowth; Tsai, Fuu-Jen

    2015-05-30

    Genome-wide association study (GWAS) data showed that the protein tyrosine phosphatase receptor type delta (PTPRD) is associated with increased susceptibility to type 2 diabetes (T2D) in Han Chinese. A replication study indicated that PTPRD is involved in the insulin signaling pathway; however, the underlying mechanism remains unclear. We evaluated PTPRD expression in patients with T2D and controls. PTPRD expression levels were lower in patients and were correlated with the duration of the disease. Overexpression of the human insulin receptor PPARγ2 in HepG2 cells induced overexpression of PTPRD and the insulin receptor. PTPRD knockdown, using a shRNA, resulted in down-regulation of the insulin receptor. These results indicate that PTPRD activates PPARγ2 in the insulin signaling pathway. Similar results for PTPRD expression were found using a T2D mouse model. Silencing of PTPRD was caused by DNA methylation in T2D mice and patients, and correlated with DNMT1 expression. Furthermore, we showed that a DNMT1 SNP (rs78789647) was correlated with susceptibility to T2D. This study shows for the first time that DNMT1 caused PTPRD DNA hypermethylation and induced insulin signaling silencing in T2D patients. Our findings contribute to a better understanding of the crucial roles of these regulatory elements in human T2D. PMID:26079428

  7. PTPRD silencing by DNA hypermethylation decreases insulin receptor signaling and leads to type 2 diabetes

    PubMed Central

    Chen, Yng-Tay; Lin, Wei-De; Liao, Wen-Lin; Lin, Ying-Ju; Chang, Jan-Gowth; Tsai, Fuu-Jen

    2015-01-01

    Genome-wide association study (GWAS) data showed that the protein tyrosine phosphatase receptor type delta (PTPRD) is associated with increased susceptibility to type 2 diabetes (T2D) in Han Chinese. A replication study indicated that PTPRD is involved in the insulin signaling pathway; however, the underlying mechanism remains unclear. We evaluated PTPRD expression in patients with T2D and controls. PTPRD expression levels were lower in patients and were correlated with the duration of the disease. Overexpression of the human insulin receptor PPARγ2 in HepG2 cells induced overexpression of PTPRD and the insulin receptor. PTPRD knockdown, using a shRNA, resulted in down-regulation of the insulin receptor. These results indicate that PTPRD activates PPARγ2 in the insulin signaling pathway. Similar results for PTPRD expression were found using a T2D mouse model. Silencing of PTPRD was caused by DNA methylation in T2D mice and patients, and correlated with DNMT1 expression. Furthermore, we showed that a DNMT1 SNP (rs78789647) was correlated with susceptibility to T2D. This study shows for the first time that DNMT1 caused PTPRD DNA hypermethylation and induced insulin signaling silencing in T2D patients. Our findings contribute to a better understanding of the crucial roles of these regulatory elements in human T2D. PMID:26079428

  8. Insulin signaling controls neurotransmission via the 4eBP-dependent modification of the exocytotic machinery

    PubMed Central

    Mahoney, Rebekah Elizabeth; Azpurua, Jorge; Eaton, Benjamin A

    2016-01-01

    Altered insulin signaling has been linked to widespread nervous system dysfunction including cognitive dysfunction, neuropathy and susceptibility to neurodegenerative disease. However, knowledge of the cellular mechanisms underlying the effects of insulin on neuronal function is incomplete. Here, we show that cell autonomous insulin signaling within the Drosophila CM9 motor neuron regulates the release of neurotransmitter via alteration of the synaptic vesicle fusion machinery. This effect of insulin utilizes the FOXO-dependent regulation of the thor gene, which encodes the Drosophila homologue of the eif-4e binding protein (4eBP). A critical target of this regulatory mechanism is Complexin, a synaptic protein known to regulate synaptic vesicle exocytosis. We find that the amounts of Complexin protein observed at the synapse is regulated by insulin and genetic manipulations of Complexin levels support the model that increased synaptic Complexin reduces neurotransmission in response to insulin signaling. DOI: http://dx.doi.org/10.7554/eLife.16807.001 PMID:27525480

  9. Deepure Tea Improves High Fat Diet-Induced Insulin Resistance and Nonalcoholic Fatty Liver Disease

    PubMed Central

    Deng, Jing-Na; Li, Juan; Mu, Hong-Na; Liu, Yu-Ying; Wang, Ming-Xia; Pan, Chun-Shui; Fan, Jing-Yu; Ye, Fei; Han, Jing-Yan

    2015-01-01

    This study was to explore the protective effects of Deepure tea against insulin resistance and hepatic steatosis and elucidate the potential underlying molecular mechanisms. C57BL/6 mice were fed with a high fat diet (HFD) for 8 weeks to induce the metabolic syndrome. In the Deepure tea group, HFD mice were administrated with Deepure tea at 160 mg/kg/day by gavage for 14 days. The mice in HFD group received water in the same way over the same period. The age-matched C57BL/6 mice fed with standard chow were used as normal control. Compared to the mice in HFD group, mice that received Deepure tea showed significantly reduced plasma insulin and improved insulin sensitivity. Deepure tea increased the expression of insulin receptor substrate 2 (IRS-2), which plays an important role in hepatic insulin signaling pathway. Deepure tea also led to a decrease in hepatic fatty acid synthesis and lipid accumulation, which were mediated by the downregulation of sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthesis (FAS), and acetyl-CoA carboxylase (ACC) proteins that are involved in liver lipogenesis. These results suggest that Deepure tea may be effective for protecting against insulin resistance and hepatic steatosis via modulating IRS-2 and downstream signaling SREBP-1c, FAS, and ACC. PMID:26504484

  10. Insulin induction of SREBP-1c in rodent liver requires LXRα-C/EBPβ complex

    PubMed Central

    Tian, Jing; Goldstein, Joseph L.; Brown, Michael S.

    2016-01-01

    Insulin increases lipid synthesis in liver by activating transcription of the gene encoding sterol regulatory element-binding protein-1c (SREBP-1c). SREBP-1c activates the transcription of all genes necessary for fatty acid synthesis. Insulin induction of SREBP-1c requires LXRα, a nuclear receptor. Transcription of SREBP-1c also requires transcription factor C/EBPβ, but a connection between LXRα and C/EBPβ has not been made. Here we show that LXRα and C/EBPβ form a complex that can be immunoprecipitated from rat liver nuclei. Chromatin immunoprecipitation assays showed that the LXRα-C/EBPβ complex binds to the SREBP-1c promoter in a region that contains two binding sites for LXRα and is known to be required for insulin induction. Knockdown of C/EBPβ in fresh rat hepatocytes or mouse livers in vivo reduces the ability of insulin to increase SREBP-1c mRNA. The LXRα-C/EBPβ complex is bound to the SREBP-1c promoter in the absence or presence of insulin, indicating that insulin acts not by increasing the formation of this complex, but rather by activating it. PMID:27382175

  11. Novel repressor regulates insulin sensitivity through interaction with Foxo1

    PubMed Central

    Nakae, Jun; Cao, Yongheng; Hakuno, Fumihiko; Takemori, Hiroshi; Kawano, Yoshinaga; Sekioka, Risa; Abe, Takaya; Kiyonari, Hiroshi; Tanaka, Toshiya; Sakai, Juro; Takahashi, Shin-Ichiro; Itoh, Hiroshi

    2012-01-01

    Forkhead box-containing protein o (Foxo) 1 is a key transcription factor in insulin and glucose metabolism. We identified a Foxo1-CoRepressor (FCoR) protein in mouse adipose tissue that inhibits Foxo1's activity by enhancing acetylation via impairment of the interaction between Foxo1 and the deacetylase Sirt1 and via direct acetylation. FCoR is phosphorylated at Threonine 93 by catalytic subunit of protein kinase A and is translocated into nucleus, making it possible to bind to Foxo1 in both cytosol and nucleus. Knockdown of FCoR in 3T3-F442A cells enhanced expression of Foxo target and inhibited adipocyte differentiation. Overexpression of FCoR in white adipose tissue decreased expression of Foxo-target genes and adipocyte size and increased insulin sensitivity in Leprdb/db mice and in mice fed a high-fat diet. In contrast, Fcor knockout mice were lean, glucose intolerant, and had decreased insulin sensitivity that was accompanied by increased expression levels of Foxo-target genes and enlarged adipocytes. Taken together, these data suggest that FCoR is a novel repressor that regulates insulin sensitivity and energy metabolism in adipose tissue by acting to fine-tune Foxo1 activity. PMID:22510882

  12. PICK1 and ICA69 Control Insulin Granule Trafficking and Their Deficiencies Lead to Impaired Glucose Tolerance

    PubMed Central

    Kam, Chuen; Xiao, Nan; Cao, Xiaoxing; Shen, Chong; Cheng, Kenneth K. Y.; Xu, Aimin; Lee, Kwong-Man; Jiang, Liwen; Xia, Jun

    2013-01-01

    Diabetes is a metabolic disorder characterized by hyperglycemia. Insulin, which is secreted by pancreatic beta cells, is recognized as the critical regulator of blood glucose, but the molecular machinery responsible for insulin trafficking remains poorly defined. In particular, the roles of cytosolic factors that govern the formation and maturation of insulin granules are unclear. Here we report that PICK1 and ICA69, two cytosolic lipid-binding proteins, formed heteromeric BAR-domain complexes that associated with insulin granules at different stages of their maturation. PICK1-ICA69 heteromeric complexes associated with immature secretory granules near the trans-Golgi network (TGN). A brief treatment of Brefeldin A, which blocks vesicle budding from the Golgi, increased the amount of PICK1 and ICA69 at TGN. On the other hand, mature secretory granules were associated with PICK1 only, not ICA69. PICK1 deficiency in mice caused the complete loss of ICA69 and led to increased food and water intake but lower body weight. Glucose tolerance tests demonstrated that these mutant mice had high blood glucose, a consequence of insufficient insulin. Importantly, while the total insulin level was reduced in PICK1-deficient beta cells, proinsulin was increased. Lastly, ICA69 knockout mice also displayed similar phenotype as the mice deficient in PICK1. Together, our results indicate that PICK1 and ICA69 are key regulators of the formation and maturation of insulin granules. Author Summary Insulin is a key regulator of blood glucose and insufficient insulin leads to diabetes. Insulin is synthesized as proinsulin, processed in endoplasmic reticulum and Golgi, and eventually packaged into insulin granules, a type of dense core vesicles. Despite its importance, the molecular mechanisms governing the biogenesis and maturation of insulin granules are not fully understood. In this study, we identified two cytosolic proteins, PICK1 and ICA69, as important regulators of insulin granule

  13. Public Key Cryptography.

    ERIC Educational Resources Information Center

    Tapson, Frank

    1996-01-01

    Describes public key cryptography, also known as RSA, which is a system using two keys, one used to put a message into cipher and another used to decipher the message. Presents examples using small prime numbers. (MKR)

  14. A case of hypersensitivity to soluble and isophane insulins but not to insulin glargine

    PubMed Central

    Belhekar, Mahesh N.; Pai, Sarayu; Tayade, Parimal; Dalwadi, Pradip; Munshi, Renuka; Varthakavi, Prema

    2015-01-01

    Insulin is an important agent for the treatment of diabetes mellitus (DM). Allergic reactions to insulin therapy, although rare, have been evident since animal insulin became available for the treatment of DM in 1922. Hypersensitivity to insulin has considerably been reduced with the introduction of human insulin produced by recombinant deoxyribonucleic acid technology. Here, we present a case of Type 2 DM who demonstrated immediate (Type 1) hypersensitivity reaction on the sites of subcutaneous injection of soluble and isophane insulin but insulin glargine was tolerated well and provided good glycemic control. PMID:25878390

  15. A case of hypersensitivity to soluble and isophane insulins but not to insulin glargine.

    PubMed

    Belhekar, Mahesh N; Pai, Sarayu; Tayade, Parimal; Dalwadi, Pradip; Munshi, Renuka; Varthakavi, Prema

    2015-01-01

    Insulin is an important agent for the treatment of diabetes mellitus (DM). Allergic reactions to insulin therapy, although rare, have been evident since animal insulin became available for the treatment of DM in 1922. Hypersensitivity to insulin has considerably been reduced with the introduction of human insulin produced by recombinant deoxyribonucleic acid technology. Here, we present a case of Type 2 DM who demonstrated immediate (Type 1) hypersensitivity reaction on the sites of subcutaneous injection of soluble and isophane insulin but insulin glargine was tolerated well and provided good glycemic control. PMID:25878390

  16. [Chronic insulin urticaria. Therapeutic efficacy and good tolerability of human insulins].

    PubMed

    Mirouze, J; Monnier, L; Rodier, M; Balducchi, J P; Orsetti, A; Clot, J

    1982-10-23

    A case of type III (Arthus') hypersensitivity to insulin which occurred several years after insulin treatment was instituted is described. Its persistence even with highly purified insulins of bovine or porcine origin was suggestive of a direct reaction against insulin itself. The patient had no history of allergy and, contrary to most similar cases published, had not received intermittent insulin therapy. Using stimulation of lymphocyte blastogenesis, the authors were able to demonstrate the presence of specific antigen-mediated hypersensitivity to all insulins tested, including human insulins. The circulating immune complexes did not appear to be pathogenic, since the patient only had minimal retinopathy after 22 years of insulin-dependent diabetes. Human insulin was tolerated and proved effective in controlling both blood glucose levels and skin rashes in response to conventional insulins. PMID:6757860

  17. A retrospective database analysis of insulin use patterns in insulin-naïve patients with type 2 diabetes initiating basal insulin or mixtures

    PubMed Central

    Bonafede, Machaon MK; Kalsekar, Anupama; Pawaskar, Manjiri; Ruiz, Kimberly M; Torres, Amelito M; Kelly, Karen R; Curkendall, Suellen M

    2010-01-01

    Objective: To describe insulin persistence among patients with type 2 diabetes initiating insulin therapy with basal insulin or insulin mixtures and determine factors associated with nonpersistence. Research design and methods: The Thomson Reuters MarketScan® databases were used to retrospectively analyze insulin-naïve patients with type 2 diabetes by initiating insulin therapy. Insulin use was described using a variety of measures. The persistence to insulin was described using both a gap-based measure and the number of claims measure. Results: Patients in the basal insulin cohort (N = 15,255) primarily used insulin analogs (88.1%) and vial and syringe (97%). Patients in the mixture cohort (N = 2,732) were more likely to initiate on human insulin mixtures (62.5%) and vial and syringe (68.1%). Average time between insulin refills was 80 and 71 days for basal and mixture initiators, respectively. Nearly, 75% of basal insulin initiators and 65% of insulin mixture initiators had a 90-day gap in insulin prescriptions. More than half of all the patients had at least one insulin prescription per quarter. Patients initiating with insulin analogs were more likely to be persistent compared with those initiating with human insulin across both cohorts and measures of persistence (P < 0.001). Conclusion: Persistence to insulin therapy is poorer than one would anticipate, but appears to be higher in users of insulin analogs and insulin mixtures. PMID:20622915

  18. Keys to Scholarship

    ERIC Educational Resources Information Center

    Hebert, Terri

    2011-01-01

    Up ahead, a foreboding wooden door showing wear from passage of earlier travelers is spotted. As the old porch light emits a pale yellow glow, a key ring emerges from deep inside the coat pocket. Searching for just the right key, the voyager settles on one that also shows age. As the key enters its receptacle and begins to turn, a clicking noise…

  19. Work Keys USA.

    ERIC Educational Resources Information Center

    Work Keys USA, 1998

    1998-01-01

    "Work Keys" is a comprehensive program for assessing and teaching workplace skills. This serial "special issue" features 18 first-hand reports on Work Keys projects in action in states across North America. They show how the Work Keys is helping businesses and educators solve the challenge of building a world-class work force. The reports are as…

  20. Oral Insulin Delivery: How Far Are We?

    PubMed Central

    Fonte, Pedro; Araújo, Francisca; Reis, Salette; Sarmento, Bruno

    2013-01-01

    Oral delivery of insulin may significantly improve the quality of life of diabetes patients who routinely receive insulin by the subcutaneous route. In fact, compared with this administration route, oral delivery of insulin in diabetes treatment offers many advantages: higher patient compliance, rapid hepatic insulinization, and avoidance of peripheral hyperinsulinemia and other adverse effects such as possible hypoglycemia and weight gain. However, the oral delivery of insulin remains a challenge because its oral absorption is limited. The main barriers faced by insulin in the gastrointestinal tract are degradation by proteolytic enzymes and lack of transport across the intestinal epithelium. Several strategies to deliver insulin orally have been proposed, but without much clinical or commercial success. Protein encapsulation into nanoparticles is regarded as a promising alternative to administer insulin orally because they have the ability to promote insulin paracellular or transcellular transport across the intestinal mucosa. In this review, different delivery systems intended to increase the oral bioavailability of insulin will be discussed, with a special focus on nanoparticulate carrier systems, as well as the efforts that pharmaceutical companies are making to bring to the market the first oral delivery system of insulin. The toxicological and safety data of delivery systems, the clinical value and progress of oral insulin delivery, and the future prospects in this research field will be also scrutinized. PMID:23567010

  1. 21 CFR 522.1160 - Insulin.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Insulin. 522.1160 Section 522.1160 Food and Drugs..., AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS § 522.1160 Insulin. (a) Specifications—(1) Each milliliter (mL) of porcine insulin zinc suspension contains 40 international units...

  2. 21 CFR 522.1160 - Insulin.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Insulin. 522.1160 Section 522.1160 Food and Drugs..., AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS § 522.1160 Insulin. (a) Specifications—(1) Each milliliter (mL) of porcine insulin zinc suspension contains 40 international units...

  3. 21 CFR 522.1160 - Insulin.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Insulin. 522.1160 Section 522.1160 Food and Drugs..., AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS § 522.1160 Insulin. (a) Specifications—(1) Each milliliter (mL) of porcine insulin zinc suspension contains 40 international units...

  4. [Resistance to the action of insulin].

    PubMed

    Azevedo, M da S

    1993-06-01

    The author analyses the insulin and glucagon effect on glycaemia regulation. The structure of glucose transporters and insulin receptors is described in some detail. Finally the author attempts to explain the insulin resistance mechanism based on a post receptor alteration that would be advantageous in traditional nutrition, but is noxious in a western type society, due to excessive caloric intake. PMID:8368096

  5. Oral insulin delivery: how far are we?

    PubMed

    Fonte, Pedro; Araújo, Francisca; Reis, Salette; Sarmento, Bruno

    2013-01-01

    Oral delivery of insulin may significantly improve the quality of life of diabetes patients who routinely receive insulin by the subcutaneous route. In fact, compared with this administration route, oral delivery of insulin in diabetes treatment offers many advantages: higher patient compliance, rapid hepatic insulinization, and avoidance of peripheral hyperinsulinemia and other adverse effects such as possible hypoglycemia and weight gain. However, the oral delivery of insulin remains a challenge because its oral absorption is limited. The mainbarriers faced by insulin in the gastrointestinal tract are degradation by proteolytic enzymes and lack of transport across the intestinal epithelium. Several strategies to deliver insulin orally have been proposed, but without much clinical or commercial success. Protein encapsulation into nanoparticles is regarded as a promising alternative to administer insulin orally because they have the ability to promote insulin paracellular or transcellular transport across the intestinal mucosa. In this review, different delivery systems intended to increase the oral bioavailability of insulin will be discussed, with a special focus on nanoparticulate carrier systems, as well as the efforts that pharmaceutical companies are making to bring to the market the first oral delivery system of insulin. The toxicological and safety data of delivery systems, the clinical value and progress of oral insulin delivery, and the future prospects in this research field will be also scrutinized. PMID:23567010

  6. Dietary and pharmacological modification of the insulin/IGF-1 system: exploiting the full repertoire against cancer.

    PubMed

    Klement, R J; Fink, M K

    2016-01-01

    As more and more links between cancer and metabolism are discovered, new approaches to treat cancer using these mechanisms are considered. Dietary restriction of either calories or macronutrients has shown great potential in animal studies to both reduce the incidence and growth of cancer, and to act synergistically with other treatment strategies. These studies have also shown that dietary restriction simultaneously targets many of the molecular pathways that are targeted individually by anticancer drugs. The insulin/insulin-like growth factor-1 (IGF-1) system has thereby emerged as a key regulator of cancer growth pathways. Although lowering of insulin levels with diet or drugs such as metformin and diazoxide seems generally beneficial, some practitioners also utilize strategic elevations of insulin levels in combination with chemotherapeutic drugs. This indicates a broad spectrum of possibilities for modulating the insulin/IGF-1 system in cancer treatment. With a specific focus on dietary restriction, insulin administration and the insulin-lowering drug diazoxide, such modifications of the insulin/IGF-1 system are the topic of this review. Although preclinical data are promising, we point out that insulin regulation and the metabolic response to a certain diet often differ between mice and humans. Thus, the need for collecting more human data has to be emphasized. PMID:26878387

  7. Interaction between IGFBP7 and insulin: a theoretical and experimental study

    PubMed Central

    Ruan, Wenjing; Kang, Zhengzhong; Li, Youzhao; Sun, Tianyang; Wang, Lipei; Liang, Lijun; Lai, Maode; Wu, Tao

    2016-01-01

    Insulin-like growth factor binding protein 7 (IGFBP7) can bind to insulin with high affinity which inhibits the early steps of insulin action. Lack of recognition mechanism impairs our understanding of insulin regulation before it binds to insulin receptor. Here we combine computational simulations with experimental methods to investigate the interaction between IGFBP7 and insulin. Molecular dynamics simulations indicated that His200 and Arg198 in IGFBP7 were key residues. Verified by experimental data, the interaction remained strong in single mutation systems R198E and H200F but became weak in double mutation system R198E-H200F relative to that in wild-type IGFBP7. The results and methods in present study could be adopted in future research of discovery of drugs by disrupting protein–protein interactions in insulin signaling. Nevertheless, the accuracy, reproducibility, and costs of free-energy calculation are still problems that need to be addressed before computational methods can become standard binding prediction tools in discovery pipelines. PMID:27101796

  8. Interaction between IGFBP7 and insulin: a theoretical and experimental study

    NASA Astrophysics Data System (ADS)

    Ruan, Wenjing; Kang, Zhengzhong; Li, Youzhao; Sun, Tianyang; Wang, Lipei; Liang, Lijun; Lai, Maode; Wu, Tao

    2016-04-01

    Insulin-like growth factor binding protein 7 (IGFBP7) can bind to insulin with high affinity which inhibits the early steps of insulin action. Lack of recognition mechanism impairs our understanding of insulin regulation before it binds to insulin receptor. Here we combine computational simulations with experimental methods to investigate the interaction between IGFBP7 and insulin. Molecular dynamics simulations indicated that His200 and Arg198 in IGFBP7 were key residues. Verified by experimental data, the interaction remained strong in single mutation systems R198E and H200F but became weak in double mutation system R198E-H200F relative to that in wild-type IGFBP7. The results and methods in present study could be adopted in future research of discovery of drugs by disrupting protein–protein interactions in insulin signaling. Nevertheless, the accuracy, reproducibility, and costs of free-energy calculation are still problems that need to be addressed before computational methods can become standard binding prediction tools in discovery pipelines.

  9. Reduced Graphene Oxide Modified the Interdigitated Chain Electrode for an Insulin Sensor.

    PubMed

    Yagati, Ajay Kumar; Park, Jinsoo; Cho, Sungbo

    2016-01-01

    Insulin is a key regulator in glucose homeostasis and its deficiency or alternations in the human body causes various types of diabetic disorders. In this paper, we present the development of a reduced graphene oxide (rGO) modified interdigitated chain electrode (ICE) for direct capacitive detection of insulin. The impedance properties of rGO-ICE were characterized by equivalent circuit modeling. After an electrochemical deposition of rGO on ICE, the electrode was modified with self-assembled monolayers and insulin antibodies in order to achieve insulin binding reactions. The impedance spectra and capacitances were measured with respect to the concentrations of insulin and the capacitance change (ΔC) was analyzed to quantify insulin concentration. The antibody immobilized electrode showed an increment of ΔC according to the insulin concentration in human serum ranging from 1 ng/mL to 10 µg/mL. The proposed sensor is feasible for label-free and real-time measuring of the biomarker and for point-of-care diagnosis. PMID:26784202

  10. Reduced Graphene Oxide Modified the Interdigitated Chain Electrode for an Insulin Sensor

    PubMed Central

    Yagati, Ajay Kumar; Park, Jinsoo; Cho, Sungbo

    2016-01-01

    Insulin is a key regulator in glucose homeostasis and its deficiency or alternations in the human body causes various types of diabetic disorders. In this paper, we present the development of a reduced graphene oxide (rGO) modified interdigitated chain electrode (ICE) for direct capacitive detection of insulin. The impedance properties of rGO-ICE were characterized by equivalent circuit modeling. After an electrochemical deposition of rGO on ICE, the electrode was modified with self-assembled monolayers and insulin antibodies in order to achieve insulin binding reactions. The impedance spectra and capacitances were measured with respect to the concentrations of insulin and the capacitance change (ΔC) was analyzed to quantify insulin concentration. The antibody immobilized electrode showed an increment of ΔC according to the insulin concentration in human serum ranging from 1 ng/mL to 10 µg/mL. The proposed sensor is feasible for label-free and real-time measuring of the biomarker and for point-of-care diagnosis. PMID:26784202

  11. A receptor state space model of the insulin signalling system in glucose transport.

    PubMed

    Gray, Catheryn W; Coster, Adelle C F

    2015-12-01

    Insulin is a potent peptide hormone that regulates glucose levels in the blood. Insulin-sensitive cells respond to insulin stimulation with the translocation of glucose transporter 4 (GLUT4) to the plasma membrane (PM), enabling the clearance of glucose from the blood. Defects in this process can give rise to insulin resistance and ultimately diabetes. One widely cited model of insulin signalling leading to glucose transport is that of Sedaghat et al. (2002) Am. J. Physiol. Endocrinol. Metab. 283, E1084-E1101. Consisting of 20 deterministic ordinary differential equations (ODEs), it is the most comprehensive model of insulin signalling to date. However, the model possesses some major limitations, including the non-conservation of key components. In the current work, we detail mathematical and sensitivity analyses of the Sedaghat model. Based on the results of these analyses, we propose a reduced state space model of the insulin receptor subsystem. This reduced model maintains the input-output relation of the original model but is computationally more efficient, analytically tractable and resolves some of the limitations of the Sedaghat model. PMID:25673317

  12. Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cells

    PubMed Central

    Ferdaoussi, Mourad; Dai, Xiaoqing; Jensen, Mette V.; Wang, Runsheng; Peterson, Brett S.; Huang, Chao; Ilkayeva, Olga; Smith, Nancy; Miller, Nathanael; Hajmrle, Catherine; Spigelman, Aliya F.; Wright, Robert C.; Plummer, Gregory; Suzuki, Kunimasa; Mackay, James P.; van de Bunt, Martijn; Gloyn, Anna L.; Ryan, Terence E.; Norquay, Lisa D.; Brosnan, M. Julia; Trimmer, Jeff K.; Rolph, Timothy P.; Kibbey, Richard G.; Manning Fox, Jocelyn E.; Colmers, William F.; Shirihai, Orian S.; Neufer, P. Darrell; Yeh, Edward T.H.; Newgard, Christopher B.; MacDonald, Patrick E.

    2015-01-01

    Insulin secretion from β cells of the pancreatic islets of Langerhans controls metabolic homeostasis and is impaired in individuals with type 2 diabetes (T2D). Increases in blood glucose trigger insulin release by closing ATP-sensitive K+ channels, depolarizing β cells, and opening voltage-dependent Ca2+ channels to elicit insulin exocytosis. However, one or more additional pathway(s) amplify the secretory response, likely at the distal exocytotic site. The mitochondrial export of isocitrate and engagement with cytosolic isocitrate dehydrogenase (ICDc) may be one key pathway, but the mechanism linking this to insulin secretion and its role in T2D have not been defined. Here, we show that the ICDc-dependent generation of NADPH and subsequent glutathione (GSH) reduction contribute to the amplification of insulin exocytosis via sentrin/SUMO-specific protease-1 (SENP1). In human T2D and an in vitro model of human islet dysfunction, the glucose-dependent amplification of exocytosis was impaired and could be rescued by introduction of signaling intermediates from this pathway. Moreover, islet-specific Senp1 deletion in mice caused impaired glucose tolerance by reducing the amplification of insulin exocytosis. Together, our results identify a pathway that links glucose metabolism to the amplification of insulin secretion and demonstrate that restoration of this axis rescues β cell function in T2D. PMID:26389676

  13. MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling.

    PubMed

    Ahn, Byungyong; Soundarapandian, Mangala M; Sessions, Hampton; Peddibhotla, Satyamaheshwar; Roth, Gregory P; Li, Jian-Liang; Sugarman, Eliot; Koo, Ada; Malany, Siobhan; Wang, Miao; Yea, Kyungmoo; Brooks, Jeanne; Leone, Teresa C; Han, Xianlin; Vega, Rick B; Kelly, Daniel P

    2016-09-01

    Intramuscular lipid accumulation is a common manifestation of chronic caloric excess and obesity that is strongly associated with insulin resistance. The mechanistic links between lipid accumulation in myocytes and insulin resistance are not completely understood. In this work, we used a high-throughput chemical biology screen to identify a small-molecule probe, SBI-477, that coordinately inhibited triacylglyceride (TAG) synthesis and enhanced basal glucose uptake in human skeletal myocytes. We then determined that SBI-477 stimulated insulin signaling by deactivating the transcription factor MondoA, leading to reduced expression of the insulin pathway suppressors thioredoxin-interacting protein (TXNIP) and arrestin domain-containing 4 (ARRDC4). Depleting MondoA in myocytes reproduced the effects of SBI-477 on glucose uptake and myocyte lipid accumulation. Furthermore, an analog of SBI-477 suppressed TXNIP expression, reduced muscle and liver TAG levels, enhanced insulin signaling, and improved glucose tolerance in mice fed a high-fat diet. These results identify a key role for MondoA-directed programs in the coordinated control of myocyte lipid balance and insulin signaling and suggest that this pathway may have potential as a therapeutic target for insulin resistance and lipotoxicity. PMID:27500491

  14. Glucosamine induces REDD1 to suppress insulin action in retinal Müller cells.

    PubMed

    Moore, Joshua A; Miller, William P; Dennis, Michael D

    2016-05-01

    Resistance to insulin action is a key cause of diabetic complications, yet much remains unknown about the molecular mechanisms that contribute to the defect. Glucose-induced insulin resistance in peripheral tissues such as the retina is mediated in part by the hexosamine biosynthetic pathway (HBP). Glucosamine (GAM), a leading dietary supplement marketed to relieve the discomfort of osteoarthritis, is metabolized by the HBP, and in doing so bypasses the rate-limiting enzyme of the pathway. Thus, exogenous GAM consumption potentially exacerbates the resistance to insulin action observed with diabetes-induced hyperglycemia. In the present study, we evaluated the effect of GAM on insulin action in retinal Müller cells in culture. Addition of GAM to Müller cell culture repressed insulin-induced activation of the Akt/mTORC1 signaling pathway. However, the effect was not recapitulated by chemical inhibition to promote protein O-GlcNAcylation, nor was blockade of O-GlcNAcylation sufficient to prevent the effects of GAM. Instead, GAM induced ER stress and subsequent expression of the protein Regulated in DNA Damage and Development (REDD1), which was necessary for GAM to repress insulin-stimulated phosphorylation of Akt on Thr308. Overall, the findings support a model whereby GAM promotes ER stress in retinal Müller cells, resulting in elevated REDD1 expression and thus resistance to insulin action. PMID:26852666

  15. Insulin requirements in patients with diabetes and declining kidney function: differences between insulin analogues and human insulin?

    PubMed Central

    Kulozik, Felix

    2013-01-01

    Objectives: In diabetic nephropathy the decline of renal function causes modifications of the insulin and carbohydrate metabolism resulting in changed insulin requirements. The aim of the present study was to identify potential differences in the requirements of human insulin and various insulin analogues in patients with type 1 diabetes mellitus and renal dysfunction. Methods: The insulin requirements of 346 patients with type 1 diabetes mellitus under everyday life circumstances were assessed in an observational study. Simultaneously, laboratory parameters were measured and the estimated glomerular filtration rate (eGFR) was calculated using the formula by Cockcroft–Gault. Medical history and concomitant medication were recorded. The insulin requirements of long- and short-acting insulin were tested for a relationship with the eGFR and laboratory parameters. Results: The dosage of long-acting human insulin did not show any relation to eGFR. In contrast, a strong positive relation between dosage and renal function was found for insulin glargine and insulin detemir. After classification according to renal function, the insulin dosage at eGFR less than 60 ml/min was 29.7% lower in glargine-treated and 27.3% lower in detemir-treated patients compared with eGFR greater than 90 ml/min. Considering the whole range of eGFR, short-acting human insulin did not show a relation with renal function. Only after classification according to renal function was a dose reduction found for human insulin at eGFR less than 60 ml/min. In contrast, requirements of insulin lispro were significantly related to eGFR over the whole range of eGFR. At eGFR less than 60 ml/min the insulin dosage was 32.6% lower than at eGFR greater than 90 ml/min. The requirements of insulin aspart did not show any association with the eGFR. Conclusions: Patients with type 1 diabetes mellitus show different insulin requirements according to the renal function depending on the applied insulin. This finding is

  16. Regulation of the pituitary tumor transforming gene by insulin-like-growth factor-I and insulin differs between malignant and non-neoplastic astrocytes

    SciTech Connect

    Chamaon, Kathrin; Kirches, Elmar; Kanakis, Dimitrios; Braeuninger, Stefan; Dietzmann, Knut; Mawrin, Christian . E-mail: christian.mawrin@medizin.uni-magdeburg.de

    2005-05-27

    The reasons for overexpression of the oncogene pituitary tumor transforming gene (PTTG) in tumors are still not fully understood. A possible influence of the insulin-like growth factor I (Igf-I) may be of interest, since enhanced Igf-I signalling was reported in various human tumors. We examined the influence of Igf-I and insulin on PTTG expression in human astrocytoma cells in comparison to proliferating non-neoplastic rat embryonal astrocytes. PTTG mRNA expression and protein levels were increased in malignant astrocytes treated with Igf-I or insulin, whereas in rat embryonic astrocytes PTTG expression and protein levels increased only when cells were exposed to Igf-I. Enhanced transcription did not occur after treatment with inhibitors of phosphoinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK), blocking the two basic signalling pathways of Igf-I and insulin. In addition to this transcriptional regulation, both kinases directly bind to PTTG, suggesting a second regulatory route by phosphorylation. However, the interaction of endogenous PTTG with MAPK and PI3K, as well as PTTG phosphorylation were independent from Igf-I or insulin. The latter results were also found in human testis, which contains high PTTG levels as well as in nonneoplastic astrocytes. This suggest, that PI3K and MAPK signalling is involved in PTTG regulation not only in malignant astrocytomas but also in non-tumorous cells.

  17. Effects of Insulin and High Glucose on Human Meibomian Gland Epithelial Cells

    PubMed Central

    Ding, Juan; Liu, Yang; Sullivan, David A.

    2015-01-01

    Purpose Type 2 diabetes is a risk factor for meibomian gland dysfunction (MGD). We hypothesize that this diabetic impact is due, at least in part, to the effects of insulin resistance/deficiency and hyperglycemia on human meibomian gland epithelial cells (HMGECs). To begin to test this hypothesis, we examined whether insulin and high glucose influence immortalized (I) HMGECs. Methods Immortalized HMGECs were cultured in serum-containing or -free media and treated with insulin, insulin-like growth factor–1 (IGF-1), IGF-1 receptor (R) blocking antibody, and glucose or mannitol for varying time periods. Specific proteins were detected by Western blots, cell proliferation was evaluated by manual cell counting and lipids were assessed with LipidTOX and high performance thin layer chromatography. Results We found that insulin induces a dose-dependent increase in phosphatidylinositide 3-kinase/Akt (AKT) signaling in IHMGECs. This effect involves the IGF-1R, but not the insulin receptor (IR), and is associated with a stimulation of cell proliferation and neutral lipid accumulation. In contrast, high glucose exposure alters cell morphology, causes a progressive cell loss, and significantly reduces the levels of IGF-1R, phospho (p)-AKT, Foxhead box protein O1 (FOXO1), and sterol-regulatory element binding protein (SREBP-1) in IHMGECs. Conclusions Our data show that insulin stimulates, and that high glucose is toxic for, IHMGECs. These results support our hypothesis that insulin resistance/deficiency and hyperglycemia are deleterious for HMGECs and may help explain why type II diabetes is a risk factor for MGD. PMID:26658502

  18. High fasting serum insulin level due to autoantibody interference in insulin immunoassay discloses autoimmune insulin syndrome: a case report.

    PubMed

    Lamy, Pierre-Jean; Sault, Corinne; Renard, Eric

    2016-08-01

    Insulin-antibodies are a cause of misleading results in insulin immunoassays. They may also mediate deleterious blood glucose variations. A patient presented with overtiredness, recurrent episodes of sweating, dizziness and fainting fits. A fasting serum insulin assay performed on a Modular platform (Modular analytic E170, Roche Diagnostic, Meylan, France) showed a highly elevated value of 194.7 mIU/L, whereas on the same sample glucose and C-peptide levels were normal. Other immunometric insulin assays were performed, as well as antibodies anti-insulin radiobinding assay (RBA) and gel filtration chromatography (GFC). While complementary insulin assays yielded closer to normal fasting levels, the free insulin concentration assessed after PEG precipitation was 14.0 mIU/L and the RBA was positive. GFC revealed that most of the insulin was complexed with a 150 kDa molecule, corresponding to an immunoglobulin G (IgG). A high fasting serum insulin level in a patient with neuroglucopenic symptoms was related to a high insulin-antibody level, suggesting an insulin autoimmune syndrome. PMID:27492703

  19. Globular Adiponectin Enhances Muscle Insulin Action via Microvascular Recruitment and Increased Insulin Delivery

    PubMed Central

    Zhao, Lina; Chai, Weidong; Fu, Zhuo; Dong, Zhenhua; Aylor, Kevin W.; Barrett, Eugene J.; Cao, Wenhong; Liu, Zhenqi

    2014-01-01

    Rationale Adiponectin enhances insulin action and induces nitric oxide–dependent vasodilatation. Insulin delivery to muscle microcirculation and transendothelial transport are 2 discrete steps that limit insulin's action. We have shown that expansion of muscle microvascular surface area increases muscle insulin delivery and action. Objective To examine whether adiponectin modulates muscle microvascular recruitment thus insulin delivery and action in vivo. Methods and Results Overnight fasted adult male rats were studied. We determined the effects of adiponectin on muscle microvascular recruitment, using contrast-enhanced ultrasound, on insulin-mediated microvascular recruitment and whole-body glucose disposal, using contrast-enhanced ultrasound and insulin clamp, and on muscle insulin clearance and uptake with 125I-insulin. Globular adiponectin potently increased muscle microvascular blood volume without altering microvascular blood flow velocity, leading to a significantly increased microvascular blood flow. This was paralleled by a ≈30% to 40% increase in muscle insulin uptake and clearance, and ≈30% increase in insulin-stimulated whole-body glucose disposal. Inhibition of endothelial nitric oxide synthase abolished globular adiponectin-mediated muscle microvascular recruitment and insulin uptake. In cultured endothelial cells, globular adiponectin dose-dependently increased endothelial nitric oxide synthase phosphorylation but had no effect on endothelial cell internalization of insulin. Conclusions Globular adiponectin increases muscle insulin uptake by recruiting muscle microvasculature, which contributes to its insulin-sensitizing action. PMID:23459195

  20. Insulin-induced cytokine production in macrophages causes insulin resistance in hepatocytes.

    PubMed

    Manowsky, Julia; Camargo, Rodolfo Gonzalez; Kipp, Anna P; Henkel, Janin; Püschel, Gerhard P

    2016-06-01

    Overweight and obesity are associated with hyperinsulinemia, insulin resistance, and a low-grade inflammation. Although hyperinsulinemia is generally thought to result from an attempt of the β-cell to compensate for insulin resistance, there is evidence that hyperinsulinaemia itself may contribute to the development of insulin resistance and possibly the low-grade inflammation. To test this hypothesis, U937 macrophages were exposed to insulin. In these cells, insulin induced expression of the proinflammatory cytokines IL-1β, IL-8, CCL2, and OSM. The insulin-elicited induction of IL-1β was independent of the presence of endotoxin and most likely mediated by an insulin-dependent activation of NF-κB. Supernatants of the insulin-treated U937 macrophages rendered primary cultures of rat hepatocytes insulin resistant; they attenuated the insulin-dependent induction of glucokinase by 50%. The cytokines contained in the supernatants of insulin-treated U937 macrophages activated ERK1/2 and IKKβ, resulting in an inhibitory serine phosphorylation of the insulin receptor substrate. In addition, STAT3 was activated and SOCS3 induced, further contributing to the interruption of the insulin receptor signal chain in hepatocytes. These results indicate that hyperinsulinemia per se might contribute to the low-grade inflammation prevailing in overweight and obese patients and thereby promote the development of insulin resistance particularly in the liver, because the insulin concentration in the portal circulation is much higher than in all other tissues. PMID:27094035

  1. 77 FR 8004 - Fall 2011 Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-13

    ... Location Semiannual Regulatory Agenda....... www.reginfo.gov/ and Not in FR. www.regulations.gov....regulations.gov . Monthly Action Initiation List..... http://www.regulations.gov/ Not in FR. #!docketDetail;D... www.epa.gov/regdarrt/ ...... Not in FR. Retrospective Review Tracker. B. What Key Statutes...

  2. 76 FR 40118 - Spring 2011 Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-07

    .../ , http:// Not in FR www.regulations.gov , and http://www.epa.gov/lawsregs/search/regagenda.html...://www.regulations.gov/ Not in FR fdmspublic/component/ main?main=DocketDetail&d=EPA-HQ- OA-2008-0265 and... in FR B. What Are EPA's Regulatory Priorities, and What Key Principles, Statutes, and...

  3. Mitochondrial efficiency and insulin resistance.

    PubMed

    Crescenzo, Raffaella; Bianco, Francesca; Mazzoli, Arianna; Giacco, Antonia; Liverini, Giovanna; Iossa, Susanna

    2014-01-01

    Insulin resistance, "a relative impairment in the ability of insulin to exert its effects on glucose, protein and lipid metabolism in target tissues," has many detrimental effects on metabolism and is strongly correlated to deposition of lipids in non-adipose tissues. Mitochondria are the main cellular sites devoted to ATP production and fatty acid oxidation. Therefore, a role for mitochondrial dysfunction in the onset of skeletal muscle insulin resistance has been proposed and many studies have dealt with possible alteration in mitochondrial function in obesity and diabetes, both in humans and animal models. Data reporting evidence of mitochondrial dysfunction in type two diabetes mellitus are numerous, even though the issue that this reduced mitochondrial function is causal in the development of the disease is not yet solved, also because a variety of parameters have been used in the studies carried out on this subject. By assessing the alterations in mitochondrial efficiency as well as the impact of this parameter on metabolic homeostasis of skeletal muscle cells, we have obtained results that allow us to suggest that an increase in mitochondrial efficiency precedes and therefore can contribute to the development of high-fat-induced insulin resistance in skeletal muscle. PMID:25601841

  4. Nutritional Modulation of Insulin Resistance

    PubMed Central

    Weickert, Martin O.

    2012-01-01

    Insulin resistance has been proposed as the strongest single predictor for the development of Type 2 Diabetes (T2DM). Chronic oversupply of energy from food, together with inadequate physical activity, have been recognized as the most relevant factors leading to overweight, abdominal adiposity, insulin resistance, and finally T2DM. Conversely, energy reduced diets almost invariably to facilitate weight loss and reduce abdominal fat mass and insulin resistance. However, sustained weight loss is generally difficult to achieve, and distinct metabolic characteristics in patients with T2DM further compromise success. Therefore, investigating the effects of modulating the macronutrient composition of isoenergetic diets is an interesting concept that may lead to additional important insights. Metabolic effects of various different dietary concepts and strategies have been claimed, but results from randomized controlled studies and particularly from longer-term-controlled interventions in humans are often lacking. However, some of these concepts are supported by recent research, at least in animal models and short-term studies in humans. This paper provides an update of the current literature regarding the role of nutrition in the modulation of insulin resistance, which includes the discussion of weight-loss-independent metabolic effects of commonly used dietary concepts. PMID:24278690

  5. PP2A inhibition results in hepatic insulin resistance despite Akt2 activation.

    PubMed

    Galbo, Thomas; Perry, Rachel J; Nishimura, Erica; Samuel, Varman T; Quistorff, Bjørn; Shulman, Gerald I

    2013-10-01

    In the liver, insulin suppresses hepatic gluconeogenesis by activating Akt, which inactivates the key gluconeogenic transcription factor FoxO1 (Forkhead Box O1). Recent studies have implicated hyperactivity of the Akt phosphatase Protein Phosphatase 2A (PP2A) and impaired Akt signaling as a molecular defect underlying insulin resistance. We therefore hypothesized that PP2A inhibition would enhance insulin-stimulated Akt activity and decrease glucose production. PP2A inhibitors increased hepatic Akt phosphorylation and inhibited FoxO1in vitro and in vivo, and suppressed gluconeogenesis in hepatocytes. Paradoxically, PP2A inhibition exacerbated insulin resistance in vivo. This was explained by phosphorylation of both hepatic glycogen synthase (GS) (inactivation) and phosphorylase (activation) resulting in impairment of glycogen storage. Our findings underline the significance of GS and Phosphorylase as hepatic PP2A substrates and importance of glycogen metabolism in acute plasma glucose regulation. PMID:24150286

  6. Liver-derived systemic factors drive β-cell hyperplasia in insulin resistant states

    SciTech Connect

    El Ouaamari, Abdelfattah; Kawamori, Dan; Dirice, Ercument; Liew, Chong Wee; Shadrach, Jennifer L.; Hu, Jiang; Katsuta, Hitoshi; Hollister-Lock, Jennifer; Qian, Weijun; Wagers, Amy J.; Kulkarni, Rohit N.

    2013-02-21

    Integrative organ cross-talk regulates key aspects of energy homeostasis and its dysregulation may underlie metabolic disorders such as obesity and diabetes. To test the hypothesis that cross-talk between the liver and pancreatic islets modulates β-cell growth in response to insulin resistance, we used the Liver-specific Insulin Receptor Knockout (LIRKO) mouse, a unique model that exhibits dramatic islet hyperplasia. Using complementary in vivo parabiosis and transplantation assays, and in vitro islet culture approaches, we demonstrate that humoral, non-neural, non-cell autonomous factor(s) induce β-cell proliferation in LIRKO mice. Furthermore, we report that a hepatocyte-derived factor(s) stimulates mouse and human β-cell proliferation in ex vivo assays, independent of ambient glucose and insulin levels. These data implicate the liver as a critical source of β-cell growth factors in insulin resistant states.

  7. Important role of heparan sulfate in postnatal islet growth and insulin secretion

    SciTech Connect

    Takahashi, Iwao; Noguchi, Naoya; Nata, Koji; Yamada, Shuhei; Kaneiwa, Tomoyuki; Mizumoto, Shuji; Ikeda, Takayuki; Sugihara, Kazushi; Asano, Masahide; Yoshikawa, Takeo; Yamauchi, Akiyo; Shervani, Nausheen Jamal; Uruno, Akira; Kato, Ichiro; Unno, Michiaki; Sugahara, Kazuyuki; Takasawa, Shin; and others

    2009-05-22

    Heparan sulfate (HS) binds with several signaling molecules and regulates ligand-receptor interactions, playing an essential role in embryonic development. Here we showed that HS was intensively expressed in pancreatic islet {beta}-cells after 1 week of age in mice. The enzymatic removal of HS in isolated islets resulted in attenuated glucose-induced insulin secretion with a concomitant reduction in gene expression of several key components in the insulin secretion machinery. We further depleted islet HS by inactivating the exostosin tumor-like 3 gene specifically in {beta}-cells. These mice exhibited abnormal islet morphology with reduced {beta}-cell proliferation after 1 week of age and glucose intolerance due to defective insulin secretion. These results demonstrate that islet HS is involved in the regulation of postnatal islet maturation and required to ensure normal insulin secretion.

  8. The Telecommunications Regulatory Environment and Its Impact upon Distance Education.

    ERIC Educational Resources Information Center

    Wagner, Ellen D.

    1993-01-01

    Explains how the availability and cost of telecommunications services and equipment are determined through regulatory means. Highlights include distance education and training; telephone services; regulation and public policy; and key telecommunications regulatory activities, including judicial, legislative, and executive. (Contains 13…

  9. Patient Perspectives on Biosimilar Insulin

    PubMed Central

    Wilkins, Alasdair R.; Venkat, Manu V.; Brown, Adam S.; Dong, Jessica P.; Ran, Nina A.; Hirsch, James S.

    2014-01-01

    Given that a new wave of biosimilar insulins will likely enter the market in coming years, it is important to understand patient perspectives on these biosimilars. A survey (N = 3214) conducted by the market research company dQ&A, which maintains a 10 000-patient panel of people with type 1 or type 2 diabetes in roughly equal measure, investigated these perspectives. The survey asked whether patients would switch to a hypothetical less expensive biosimilar insulin that was approved by their provider. Approximately 66% of respondents reported that they would “definitely” or “likely” use a biosimilar insulin, while 17% reported that they were “unlikely” to use or would “definitely not use” such a product. Type 2 diabetes patients demonstrated slightly more willingness to use biosimilars than type 1 diabetes patients. Common patient concerns included whether biosimilars would be as effective as reference products (~650 respondents), whether side effect profiles would deviate from those of reference products (~220 respondents), and the design of the delivery device (~50 respondents). While cost savings associated with biosimilar insulins could increase patient uptake, especially among patients without health insurance (some recent estimates suggest that biosimilars will come at a substantial discount), patients may still need assurance that a cheaper price tag is not necessarily associated with substandard quality. Overall, the dQ&A survey indicates that the majority of patients are willing to consider biosimilar insulins, but manufacturers will need to work proactively to address and assuage patient concerns regarding efficacy, safety, drug administration, and other factors. PMID:24876533

  10. Understanding genetic regulatory networks

    NASA Astrophysics Data System (ADS)

    Kauffman, Stuart

    2003-04-01

    Random Boolean networks (RBM) were introduced about 35 years ago as first crude models of genetic regulatory networks. RBNs are comprised of N on-off genes, connected by a randomly assigned regulatory wiring diagram where each gene has K inputs, and each gene is controlled by a randomly assigned Boolean function. This procedure samples at random from the ensemble of all possible NK Boolean networks. The central ideas are to study the typical, or generic properties of this ensemble, and see 1) whether characteristic differences appear as K and biases in Boolean functions are introducted, and 2) whether a subclass of this ensemble has properties matching real cells. Such networks behave in an ordered or a chaotic regime, with a phase transition, "the edge of chaos" between the two regimes. Networks with continuous variables exhibit the same two regimes. Substantial evidence suggests that real cells are in the ordered regime. A key concept is that of an attractor. This is a reentrant trajectory of states of the network, called a state cycle. The central biological interpretation is that cell types are attractors. A number of properties differentiate the ordered and chaotic regimes. These include the size and number of attractors, the existence in the ordered regime of a percolating "sea" of genes frozen in the on or off state, with a remainder of isolated twinkling islands of genes, a power law distribution of avalanches of gene activity changes following perturbation to a single gene in the ordered regime versus a similar power law distribution plus a spike of enormous avalanches of gene changes in the chaotic regime, and the existence of branching pathway of "differentiation" between attractors induced by perturbations in the ordered regime. Noise is serious issue, since noise disrupts attractors. But numerical evidence suggests that attractors can be made very stable to noise, and meanwhile, metaplasias may be a biological manifestation of noise. As we learn more

  11. Selective Insulin Resistance in the Kidney

    PubMed Central

    Horita, Shoko; Nakamura, Motonobu; Suzuki, Masashi; Satoh, Nobuhiko; Suzuki, Atsushi; Seki, George

    2016-01-01

    Insulin resistance has been characterized as attenuation of insulin sensitivity at target organs and tissues, such as muscle and fat tissues and the liver. The insulin signaling cascade is divided into major pathways such as the PI3K/Akt pathway and the MAPK/MEK pathway. In insulin resistance, however, these pathways are not equally impaired. For example, in the liver, inhibition of gluconeogenesis by the insulin receptor substrate (IRS) 2 pathway is impaired, while lipogenesis by the IRS1 pathway is preserved, thus causing hyperglycemia and hyperlipidemia. It has been recently suggested that selective impairment of insulin signaling cascades in insulin resistance also occurs in the kidney. In the renal proximal tubule, insulin signaling via IRS1 is inhibited, while insulin signaling via IRS2 is preserved. Insulin signaling via IRS2 continues to stimulate sodium reabsorption in the proximal tubule and causes sodium retention, edema, and hypertension. IRS1 signaling deficiency in the proximal tubule may impair IRS1-mediated inhibition of gluconeogenesis, which could induce hyperglycemia by preserving glucose production. In the glomerulus, the impairment of IRS1 signaling deteriorates the structure and function of podocyte and endothelial cells, possibly causing diabetic nephropathy. This paper mainly describes selective insulin resistance in the kidney, focusing on the proximal tubule. PMID:27247938

  12. Transdermal delivery of insulin via microneedles.

    PubMed

    Narayan, Roger J

    2014-09-01

    Treatment of insulin-dependent diabetes mellitus, also known as Type 1 diabetes mellitus, requires delivery of exogenous insulin via injection or pump. An alternative to syringe-based subcutaneous delivery of insulin involves use of microneedles. These < 300 μm diameter, 50-900 μm long needle shaped devices may be used for intradermal delivery of insulin. Benefits associated with microneedle-based delivery of insulin include minimal training for use, painless insertion, as well as the potential to combine microneedles with sensors and drug delivery devices to create an autonomous artificial pancreas. In this review, the efforts of academic and industrial researchers over the past decade to examine the functionality of microneedles for delivery of insulin, including insulin-containing nanomaterials, via in vitro, ex vivo, and in vivo studies are considered. PMID:25992456

  13. A framework for the in vitro evaluation of cancer-relevant molecular characteristics and mitogenic potency of insulin analogues.

    PubMed

    Baricevic, Ivona; Jones, David R; Roberts, Darren L; Lutzen, Anne; Lundby, Anders; Worm, Jesper; Hansen, Bo F; Renehan, Andrew G

    2015-09-01

    Epidemiological and laboratory studies raise the possibility of a link between clinically prescribed insulin analogues and increased cancer risk. Accordingly, there is a regulatory mandate for cancer-related pre-clinical safety evaluation during insulin analogue development, but currently, there is no standardized framework for such in vitro evaluation. We tested human insulin; the super-mitogenic insulin, X10 and insulin-like growth factor I, in four cancer cell lines with a range of insulin-like growth factor-I receptor (IGF-IR)/IR (insulin receptor) ratios (HCT 116, HT-29, COLO 205 and MCF7) and related these to IGF-IR and IR expression in 17 human adenocarcinomas. All cell types were IR-A isoform dominant. We determined IGF-IR/IR signalling pathway endpoints in dose- and time-varying experiments, and performed mitogenic dose-response equivalent assays to derive EC50 values, and correlated these with IGF-IR/IR ratios. We superimposed relative EC50 values onto data from the literature in a meta-analysis. The IGF-IR/IR ratios varied from <1 to 12 in the selected cell lines; similar pattern ranges were observed in human adenocarcinomas. The three ligands demonstrated differential IR/IGF-IR and Akt phosphorylation, which correlated with cell-specific IGF-IR/IR ratios. Mitogenic profiles of X10 mimicked those for insulin-like growth factor I (IGF-I) and correlated with IGF-IR/IR ratios. The meta-analysis, adding data from five additional studies, supported the hypothesis that ligand mitogenic potency, relative to human insulin, increases with increasing cell-specific IGF-IR/IR ratio. This study established a framework for the in vitro evaluation of cancer-relevant bioassays for comparisons of insulin analogues, and specifically consolidated earlier studies that determination of the cell-specific IGF-IR/IR ratio is crucial for the interpretation of ranking relative biological activities. PMID:26026165

  14. Temporal Relationship between Diet-Induced Steatosis and Onset of Insulin/Leptin Resistance in Male Wistar Rats

    PubMed Central

    Zhang, Li; Song, Haiyan; Ge, Yingli; Ji, Guang; Yao, Zemin

    2015-01-01

    Rats fed with high-fat-high-sucrose (HFHS) diet are known to manifest metabolic syndrome including hyperinsulinemia, hyperleptinemia, hyperglycemia, diabetic dyslipidemia, and hepatic steatosis. The aim of the current study is to determine the temporal relationships between the development of hepatic steatosis and the onset of insulin and leptin resistance in hypothalamus and liver in male Wistar rats (six weeks of age) fed chow or HFHS diet for up to 8 weeks. Fasting plasma glucose, lipids/lipoproteins, insulin and leptin levels were quantified, histopathologic score of hepatic steatosis and inflammation were assessed, and the responses of common checkpoints of insulin and leptin signalling responsible for lipogenesis and gluconeogenesis were analyzed. In addition, acute insulin or leptin administration was performed at different stages of HFHS dieting to determine the responsiveness of the respective signalling pathways. Hyperinsulinemia, hyperglycemia, dyslipidemia, and increased homeostasis model assessment of basal insulin resistance occurred 1-week after HFHS dieting, coinciding with upregulation of suppressor of cytokine signalling 3 in both hypothalamus and liver. However, hepatosteatosis, accompanied with increased expression of sterol regulatory element binding protein 1c and phosphoenolpyruvate carboxykinase, did not manifest until 4- to 8-week after HFHS dieting. Lowered insulin sensitivity (shown by decreased insulin receptor substrate 1 and protein kinase B phosphorylation) occurred approximately 2 weeks prior to leptin resistance (shown by impaired signal transducer and activator of transcription 3 activation) in both the liver and hypothalamus. Acute insulin/leptin administration also demonstrated the impaired insulin or leptin signalling transduction. These data suggest that lowered insulin sensitivity and leptin resistance occurred at least 2–3 weeks earlier than the manifestation of hepatosteatosis in rats fed HFHS diet. PMID:25658428

  15. Unstructured quantum key distribution

    NASA Astrophysics Data System (ADS)

    Coles, Patrick; Metodiev, Eric; Lutkenhaus, Norbert

    Quantum key distribution (QKD) allows for communication with security guaranteed by quantum theory. The main theoretical problem in QKD is to calculate the secret key rate for a given protocol. Analytical formulas are known for protocols with a high degree of symmetry, since symmetry simplifies the analysis. However, experimental imperfections break symmetries, hence the effect of imperfections on key rates is difficult to estimate. Furthermore, it is an interesting question whether (intentionally) asymmetric protocols could outperform symmetric ones. In this work, we develop a robust numerical approach for calculating the key rate for arbitrary discrete-variable QKD protocols. Ultimately this will allow researchers to study ``unstructured'' protocols, i.e., those that lack symmetry. Our approach relies on transforming the key rate calculation to the dual optimization problem, which dramatically reduces the number of parameters and hence the calculation time. We illustrate our method by investigating some unstructured protocols for which the key rate was previously unknown.

  16. Genipin ameliorates age-related insulin resistance through inhibiting hepatic oxidative stress and mitochondrial dysfunction.

    PubMed

    Guan, Lili; Feng, Haiyan; Gong, Dezheng; Zhao, Xu; Cai, Li; Wu, Qiong; Yuan, Bo; Yang, Mei; Zhao, Jie; Zou, Yuan

    2013-12-01

    Insulin resistance (IR) increases with age and plays a key role in the pathogenesis of type 2 diabetes mellitus. Oxidative stress and mitochondrial dysfunction are supposed to be major factors leading to age-related IR. Genipin, an extract from Gardenia jasminoides Ellis fruit, has been reported to stimulate insulin secretion in pancreatic islet cells by regulating mitochondrial function. In this study, we first investigated the effects of genipin on insulin sensitivity and the potential mitochondrial mechanisms in the liver of aging rats. The rats were randomly assigned to receive intraperitoneal injections of either 25mg/kg genipin or vehicle once daily for 12days. The aging rats showed hyperinsulinemia and hyperlipidemia, and insulin resistance as examined by the decreased glucose decay constant rate during insulin tolerance test (kITT). The hepatic tissues showed steatosis and reduced glycogen content. Hepatic malondialdehyde level and mitochondrial reactive oxygen species (ROS) were higher, and levels of mitochondrial membrane potential (MMP) and ATP were lower as compared with the normal control rats. Administration of genipin ameliorated systemic and hepatic insulin resistance, alleviated hyperinsulinemia, hyperglyceridemia and hepatic steatosis, relieved hepatic oxidative stress and mitochondrial dysfunction in aging rats. Furthermore, genipin not only improved insulin sensitivity by promoting insulin-stimulated glucose consumption and glycogen synthesis, inhibited cellular ROS overproduction and alleviated the reduction of levels of MMP and ATP, but also reversed oxidative stress-associated JNK hyperactivation and reduced Akt phosphorylation in palmitate-treated L02 hepatocytes. In conclusion, genipin ameliorates age-related insulin resistance through inhibiting hepatic oxidative stress and mitochondrial dysfunction. PMID:24041487

  17. INSULIN INDUCED EPIDERMAL GROWTH FACTOR ACTIVATION IN VASCULAR SMOOTH MUSCLE CELLS IS ADAM-DEPENDENT

    PubMed Central

    Roztocil, Elisa; Nicholl, Suzanne M.; Davies, Mark G.

    2008-01-01

    Background With the rise in metabolic syndrome, understanding the role of insulin signaling within the cells of vasculature has become more important but yet remains poorly defined. The study examines the role of insulin actions on a pivotal cross-talk receptor, Epidermal Growth Factor Receptor (EGFR). EGFR is transactivated by both G-protein-coupled receptors and receptor linked tyrosine kinases and is key to many of their responses. Objective To determine the pathway of EGFR transactivation by insulin in human coronary smooth muscle cells (VSMC) Methods VSMC were cultured in vitro. Assays of EGFR phosphorylation were examined in response to insulin in the presence and absence of the plasmin inhibitors (e-aminocaproic acid and aprotinin) matrix metalloprotease (MMP) inhibitor GM6001, the ADAM (A Disintegrin And Metalloproteinase Domain) inhibitors TAPI-0 and TAPI-1, Heparin binding epidermal growth factor (HB-EGF) inhibitor, CRM197, HB-EGF inhibitory antibodies, EGF inhibitory antibodies and the EGFR inhibitor AG1478. Results Insulin induced time-dependent EGFR phosphorylation, which was inhibited by AG1478 in a concentration dependent manner. Application of the plasmin inhibitors did not block the response. EGFR phosphorylation by insulin was blocked by inhibition of MMP activity and the ligand HB-EGF. The presence of the ADAM inhibitors, TAPI-0 and TAPI-1 significantly decreased EGFR activation. EGFR phosphorylation by EGF was not interrupted by inhibition of plasmin, MMPs TAPIs, or HB-EGF. Direct blockade of the EGFR prevented activation by both insulin and EGF. Conclusion Insulin can induce transactivation of EGFR by an ADAM-mediated, HB-EGF dependent process. This is the first description of crosstalk via ADAM between insulin and EGFR in vascular SMC. Targeting a pivotal cross-talk receptor such as EGFR, which can be transactivated by both G-protein-coupled receptors and receptor tyrosine kinases is an attractive molecular target. PMID:18656632

  18. Exercise Training and Insulin Resistance: A Current Review

    PubMed Central

    Keshel, Tyler E; Coker, Robert H

    2015-01-01

    There is a general perception that increased physical activity will improve glucose homeostasis in all individuals. While this is an attractive concept, this conclusion may be overly simplistic and even misleading. The topic was reviewed extensively over 30 years ago and it was concluded that acute exercise enhances glucose uptake. However, in some cases the chronic influence of interventions utilizing exercise may have little effect on glucose metabolism. Moreover, insulin resistance often returns to near baseline levels within a couple of days following cessation of the exercise bout; leaving the overall effectiveness of the intervention in question. Since improving glucose homeostasis should be the focal endpoint of any intervention designed to mitigate the overwhelming degree of insulin resistance in individuals at risk for metabolic disease, it is essential to evaluate the key components of a successful approach. PMID:26523243

  19. An Improved PID Algorithm Based on Insulin-on-Board Estimate for Blood Glucose Control with Type 1 Diabetes

    PubMed Central

    Hu, Ruiqiang; Li, Chengwei

    2015-01-01

    Automated closed-loop insulin infusion therapy has been studied for many years. In closed-loop system, the control algorithm is the key technique of precise insulin infusion. The control algorithm needs to be designed and validated. In this paper, an improved PID algorithm based on insulin-on-board estimate is proposed and computer simulations are done using a combinational mathematical model of the dynamics of blood glucose-insulin regulation in the blood system. The simulation results demonstrate that the improved PID algorithm can perform well in different carbohydrate ingestion and different insulin sensitivity situations. Compared with the traditional PID algorithm, the control performance is improved obviously and hypoglycemia can be avoided. To verify the effectiveness of the proposed control algorithm, in silico testing is done using the UVa/Padova virtual patient software. PMID:26550021

  20. Insulin degludec and insulin degludec/insulin aspart in Ramadan: A single center experience

    PubMed Central

    Kalra, Sanjay

    2016-01-01

    This study aimed to document the utility and safety of insulin degludec (IDeg) and insulin degludec aspart (IDegAsp) in persons with type 2 diabetes, observing the Ramadan fast. An observational study was conducted at a single center, in the real world setting, on six persons who either switched to IDeg or IDegAsp a month before Ramadan or changed time of administration of IDegAsp at the onset of Ramadan, to keep the fast in a safe manner. Subjects were kept under regular monitoring and surveillance before, during, and after Ramadan, and counseled in an opposite manner. Four persons, who shifted from premixed insulin to IDegAsp, experienced a 12–18% dose reduction after 14 days. At the onset of Ramadan, the Suhur dose was reduced by 30%, and this remained unchanged during the fasting month. The Iftar dose had to be increased by 4 units. One person who shifted from neutral protamine hagedorn to IDeg demonstrated a 25% dose reduction at 20 days, without any further change in insulin requirement during Ramadan. One person who changed time of injection of IDegAsp from morning to night reported no change in dosage. No episode of major hypoglycemia was reported. IDeg and IDegAsp are effective, safe, and well-tolerated means of achieving glycemic control in persons with type 2 diabetes who wish to fast. PMID:27366727

  1. Insulin degludec and insulin degludec/insulin aspart in Ramadan: A single center experience.

    PubMed

    Kalra, Sanjay

    2016-01-01

    This study aimed to document the utility and safety of insulin degludec (IDeg) and insulin degludec aspart (IDegAsp) in persons with type 2 diabetes, observing the Ramadan fast. An observational study was conducted at a single center, in the real world setting, on six persons who either switched to IDeg or IDegAsp a month before Ramadan or changed time of administration of IDegAsp at the onset of Ramadan, to keep the fast in a safe manner. Subjects were kept under regular monitoring and surveillance before, during, and after Ramadan, and counseled in an opposite manner. Four persons, who shifted from premixed insulin to IDegAsp, experienced a 12-18% dose reduction after 14 days. At the onset of Ramadan, the Suhur dose was reduced by 30%, and this remained unchanged during the fasting month. The Iftar dose had to be increased by 4 units. One person who shifted from neutral protamine hagedorn to IDeg demonstrated a 25% dose reduction at 20 days, without any further change in insulin requirement during Ramadan. One person who changed time of injection of IDegAsp from morning to night reported no change in dosage. No episode of major hypoglycemia was reported. IDeg and IDegAsp are effective, safe, and well-tolerated means of achieving glycemic control in persons with type 2 diabetes who wish to fast. PMID:27366727

  2. Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production

    PubMed Central

    Glister, Claire; Satchell, Leanne; Bathgate, Ross A. D.; Wade, John D.; Dai, Yanzhenzi; Ivell, Richard; Anand-Ivell, Ravinder; Rodgers, Raymond J.; Knight, Philip G.

    2013-01-01

    Bone morphogenetic proteins (BMPs) are firmly implicated as intra-ovarian regulators of follicle development and steroidogenesis. Here we report a microarray analysis showing that treatment of cultured bovine theca cells (TC) with BMP6 significantly (>twofold; P < 0.01) up- or down-regulated expression of 445 genes. Insulin-like peptide 3 (INSL3) was the most heavily down-regulated gene (−43-fold) with cytochrome P450, subfamily XVII (CYP17A1) and other key steroidogenic transcripts including steroidogenic acute regulatory protein (STAR), cytochrome P450 family 11, subfamily A1 (CYP11A1) and 3 beta-hydroxysteroid dehydrogenase type 1 (HSD3B1) also down-regulated. BMP6 also reduced expression of nuclear receptor subfamily 5A1 (NR5A1) known to target the promoter regions of the aforementioned genes. Real-time PCR confirmed these findings and also revealed a marked reduction in expression of INSL3 receptor, relaxin/insulin-like family peptide receptor 2 (RXFP2). Secretion of INSL3 protein and androstenedione were also suppressed suggesting a functional link between BMP and INSL3 pathways in controlling androgen synthesis. RNAi-mediated knockdown of INSL3 reduced INSL3 mRNA (75%) and protein (94%) level and elicited a 77% reduction in CYP17A1 mRNA and 83% reduction in androstenedione secretion. Knockdown of RXFP2 also reduced CYP17A1 expression (81%) and androstenedione secretion (88%). Conversely, treatment with exogenous (human) INSL3 increased androstenedione secretion ∼twofold. The CYP17A1 inhibitor abiraterone abolished androgen secretion and reduced expression of both INSL3 and RXFP2. Collectively, these findings indicate a positive autoregulatory role for INSL3 signaling in maintaining thecal androgen production, and visa versa. Moreover, BMP6-induced suppression of thecal androgen synthesis may be mediated, at least in part, by reduced INSL3-RXFP2 signaling. PMID:23530236

  3. Structural and functional characterization of pathogenic non- synonymous genetic mutations of human insulin-degrading enzyme by in silico methods.

    PubMed

    Shaik, Noor A; Kaleemuddin, Mohammed; Banaganapalli, Babajan; Khan, Fazal; Shaik, Nazia S; Ajabnoor, Ghada; Al-Harthi, Sameer E; Bondagji, Nabeel; Al-Aama, Jumana Y; Elango, Ramu

    2014-04-01

    Insulin-degrading enzyme (IDE) is a key protease involved in degrading insulin and amyloid peptides in human body. Several non-synonymous genetic mutations of IDE gene have been recently associated with susceptibility to both diabetes and Alzheimer's diseases. However, the consequence of these mutations on the structure of IDE protein and its substrate binding characteristics is not well elucidated. The computational investigation of genetic mutation consequences on structural level of protein is recently found to be an effective alternate to traditional in vivo and in vitro approaches. Hence, by using a combination of empirical rule and support vector machine based in silico algorithms, this study was able to identify that the pathogenic nonsynonymous genetic mutations corresponding to p.I54F, p.P122T, p.T533R, p.P581A and p.Y609A have more potential role in structural and functional deviations of IDE activity. Moreover, molecular modeling and secondary structure analysis have also confirmed their impact on the stability and secondary properties of IDE protein. The molecular docking analysis of IDE with combinational substrates has revealed that peptide inhibitors compared to small non-peptide inhibitor molecules possess good inhibitory activity towards mutant IDE. This finding may pave a way to design novel potential small peptide inhibitors for mutant IDE. Additionally by un-translated region (UTR) scanning analysis, two regulatory pathogenic genetic mutations i.e., rs5786997 (3' UTR) and rs4646954 (5' UTR), which can influence the translation pattern of IDE gene through sequence alteration of upstream-Open Reading Frame and Internal Ribosome Entry Site elements were identified. Our findings are expected to help in narrowing down the number of IDE genetic variants to be screened for disease association studies and also to select better competitive inhibitors for IDE related diseases. PMID:24059301

  4. Glucose metabolism in non-diabetic and insulin-dependent diabetic subjects with end-stage renal failure.

    PubMed

    Schmitz, O

    1991-02-01

    that the uremic insulin resistance is located not only in peripheral tissues but also in the liver. At low insulin concentrations, the restraining potency of insulin on HGP seems to be decreased in uremia. Splanchnic glucose uptake is hardly affected, but is always very insensitive to insulin. The glucoregulatory function of the liver is further disturbed in uremia. Acute glucagon exposure elicits an inadequate glucose release, suggesting a coexisting resistance to glucagon. In vitro studies have shown, that the first step in the cascade of reactions initiated by insulin, namely binding to its specific receptor is normal in uremia. In addition, the activity of key enzymes such as the insulin receptor kinase and glycogen synthase have been found within normal in the uremic muscle.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:2026051

  5. The ergogenic supplement β-hydroxy-β-methylbutyrate (HMB) attenuates insulin resistance through suppressing GLUT-2 in rat liver.

    PubMed

    Sharawy, Maha H; El-Awady, Mohammed S; Megahed, Nirmeen; Gameil, Nariman M

    2016-05-01

    This study investigates the effect of the ergogenic supplement β-hydroxy-β-methylbutyrate (HMB) on insulin resistance induced by high-fructose diet (HFD) in rats. Male Sprague Dawley rats were fed 60% HFD for 12 weeks and HMB (320 mg·kg(-1)·day(-1), orally) for 4 weeks. HFD significantly increased fasting insulin, fasting glucose, glycosylated hemoglobin (HBA1C), liver glycogen content, and homeostasis model assessment of insulin resistance (HOMA-IR) index, while it decreased glucose and insulin tolerance. Furthermore, HFD significantly increased serum triglycerides (TG), low density lipoprotein cholesterol (LDL-C), and very low density lipoprotein cholesterol (VLDL-C) levels, while it significantly decreased high density lipoprotein cholesterol (HDL-C). Moreover, HFD significantly increased mRNA expression of glucose transporter type-2 (GLUT-2), the mammalian target of rapamycin (mTOR), and sterol regulatory element-binding protein-1c (SREBP-1c) but decreased peroxisome proliferator-activated receptor-alpha (PPAR-α) in liver. Aortic relaxation to acetylcholine (ACh) was impaired and histopathology showed severe hepatic steatosis. HMB significantly increased insulin tolerance and decreased fasting insulin, HOMA-IR, HBA1C, hepatic glycogen content, serum TG, LDL-C, and VLDL-C. Additionally, HMB enhanced ACh-induced relaxation, ameliorated hepatic steatosis, and decreased mRNA expression of GLUT-2. In conclusion, HMB may attenuate insulin resistance and hepatic steatosis through inhibiting GLUT-2 in liver. PMID:26871756

  6. Class III PI3K regulates organismal glucose homeostasis by providing negative feedback on hepatic insulin signalling

    PubMed Central

    Nemazanyy, Ivan; Montagnac, Guillaume; Russell, Ryan C.; Morzyglod, Lucille; Burnol, Anne-Françoise; Guan, Kun-Liang; Pende, Mario; Panasyuk, Ganna

    2015-01-01

    Defective hepatic insulin receptor (IR) signalling is a pathogenic manifestation of metabolic disorders including obesity and diabetes. The endo/lysosomal trafficking system may coordinate insulin action and nutrient homeostasis by endocytosis of IR and the autophagic control of intracellular nutrient levels. Here we show that class III PI3K—a master regulator of endocytosis, endosomal sorting and autophagy—provides negative feedback on hepatic insulin signalling. The ultraviolet radiation resistance-associated gene protein (UVRAG)-associated class III PI3K complex interacts with IR and is stimulated by insulin treatment. Acute and chronic depletion of hepatic Vps15, the regulatory subunit of class III PI3K, increases insulin sensitivity and Akt signalling, an effect that requires functional IR. This is reflected by FoxO1-dependent transcriptional defects and blunted gluconeogenesis in Vps15 mutant cells. On depletion of Vps15, the metabolic syndrome in genetic and diet-induced models of insulin resistance and diabetes is alleviated. Thus, feedback regulation of IR trafficking and function by class III PI3K may be a therapeutic target in metabolic conditions of insulin resistance. PMID:26387534

  7. Skeletal Muscle TRIB3 Mediates Glucose Toxicity in Diabetes and High- Fat Diet-Induced Insulin Resistance.

    PubMed

    Zhang, Wei; Wu, Mengrui; Kim, Teayoun; Jariwala, Ravi H; Garvey, W John; Luo, Nanlan; Kang, Minsung; Ma, Elizabeth; Tian, Ling; Steverson, Dennis; Yang, Qinglin; Fu, Yuchang; Garvey, W Timothy

    2016-08-01

    In the current study, we used muscle-specific TRIB3 overexpressing (MOE) and knockout (MKO) mice to determine whether TRIB3 mediates glucose-induced insulin resistance in diabetes and whether alterations in TRIB3 expression as a function of nutrient availability have a regulatory role in metabolism. In streptozotocin diabetic mice, TRIB3 MOE exacerbated, whereas MKO prevented, glucose-induced insulin resistance and impaired glucose oxidation and defects in insulin signal transduction compared with wild-type (WT) mice, indicating that glucose-induced insulin resistance was dependent on TRIB3. In response to a high-fat diet, TRIB3 MOE mice exhibited greater weight gain and worse insulin resistance in vivo compared with WT mice, coupled with decreased AKT phosphorylation, increased inflammation and oxidative stress, and upregulation of lipid metabolic genes coupled with downregulation of glucose metabolic genes in skeletal muscle. These effects were prevented in the TRIB3 MKO mice relative to WT mice. In conclusion, TRIB3 has a pathophysiological role in diabetes and a physiological role in metabolism. Glucose-induced insulin resistance and insulin resistance due to diet-induced obesity both depend on muscle TRIB3. Under physiological conditions, muscle TRIB3 also influences energy expenditure and substrate metabolism, indicating that the decrease and increase in muscle TRIB3 under fasting and nutrient excess, respectively, are critical for metabolic homeostasis. PMID:27207527

  8. Effect of insulin-induced hypoglycaemia on the central nervous system: evidence from experimental studies.

    PubMed

    Jensen, V F H; Bøgh, I B; Lykkesfeldt, J

    2014-03-01

    Insulin-induced hypoglycaemia (IIH) is a major acute complication in type 1 as well as in type 2 diabetes, particularly during intensive insulin therapy. The brain plays a central role in the counter-regulatory response by eliciting parasympathetic and sympathetic hormone responses to restore normoglycaemia. Brain glucose concentrations, being approximately 15-20% of the blood glucose concentration in humans, are rigorously maintained during hypoglycaemia through adaptions such as increased cerebral glucose transport, decreased cerebral glucose utilisation and, possibly, by using central nervous system glycogen as a glucose reserve. However, during sustained hypoglycaemia, the brain cannot maintain a sufficient glucose influx and, as the cerebral hypoglycaemia becomes severe, electroencephalogram changes, oxidative stress and regional neuronal death ensues. With particular focus on evidence from experimental studies on nondiabetic IIH, this review outlines the central mechanisms behind the counter-regulatory response to IIH, as well as cerebral adaption to avoid sequelae of cerebral neuroglycopaenia, including seizures and coma. PMID:24428753

  9. Designing the modern pump: engineering aspects of continuous subcutaneous insulin infusion software.

    PubMed

    Welsh, John B; Vargas, Steven; Williams, Gary; Moberg, Sheldon

    2010-06-01

    Insulin delivery systems attracted the efforts of biological, mechanical, electrical, and software engineers well before they were commercially viable. The introduction of the first commercial insulin pump in 1983 represents an enduring milestone in the history of diabetes management. Since then, pumps have become much more than motorized syringes and have assumed a central role in diabetes management by housing data on insulin delivery and glucose readings, assisting in bolus estimation, and interfacing smoothly with humans and compatible devices. Ensuring the integrity of the embedded software that controls these devices is critical to patient safety and regulatory compliance. As pumps and related devices evolve, software engineers will face challenges and opportunities in designing pumps that are safe, reliable, and feature-rich. The pumps and related systems must also satisfy end users, healthcare providers, and regulatory authorities. In particular, pumps that are combined with glucose sensors and appropriate algorithms will provide the basis for increasingly safe and precise automated insulin delivery-essential steps to developing a fully closed-loop system. PMID:20515305

  10. Identification and evolution of two insulin receptor genes involved in Tribolium castaneum development and reproduction.

    PubMed

    Sang, Ming; Li, Chengjun; Wu, Wei; Li, Bin

    2016-07-10

    The insulin and insulin-like signaling (IIS) pathway exists in a wide range of organisms from mammals to invertebrates and regulates several vital physiological functions. A phylogenetic analysis have indicated that insulin receptors have been duplicated at least twice among vertebrates, whereas only one duplication occurred in insects before the differentiation of Coleoptera, Hymenoptera, and Hemiptera. Thus, we cloned two putative insulin receptor genes, T.cas-ir1 and T.cas-ir2, from T. castaneum and determined that T.cas-ir1 is most strongly expressed during the late adult and early pupal stages, whereas T.cas-ir2 is most strongly expressed during the late larval stage. We found that larval RNAi against T.cas-ir1 and T.cas-ir2 causes 100% and 42.0% insect death, respectively, and that parental RNAi against T.cas-ir1 and T.cas-ir2 leads to 100% and 33.3% reductions in beetle fecundity, respectively. The hatching rate of ds-ir2 insects was 66.2%. Moreover, RNAi against these two genes increased the expression of the pkc, foxo, jnk, cdc42, ikk, and mekk genes but decreased erk gene expression. Despite these similarities, these two genes act via distinct regulatory pathways. These results indicate that these two receptors have functionally diverged with respect to the development and reproduction of T. castaneum, even though they retain some common regulatory signaling pathways. PMID:26923187

  11. Insulin degludec. Uncertainty over cardiovascular harms.

    PubMed

    2014-06-01

    Insulin isophane (NPH) is the standard long-acting human insulin for patients with type 1 and type 2 diabetes. Long-acting human insulin analogues are also available: insulin glargine and insulin detemir. Uncertainties remain concerning their long-term adverse effects. Insulin degludec (Tresiba, Novo Nordisk) is another long-acting human insulin analogue, also approved in the EU for patients with type 1 and type 2 diabetes. It was authorised at a concentration of 100 units per ml, like other insulins, and also at a concentration of 200 units per ml. There are no comparative data on insulin degludec 200 units per ml in patients using high doses of insulin. Insulin degludec has mainly been evaluated in ten randomised, unblinded, "non-inferiority" trials lasting 26 to 52 weeks, nine versus insulin glargine and one versus insulin detemir. Insulin degludec was administered at a fixed time each evening, or in either the morning or evening on alternate days, at varying intervals of 8 to 40 hours between doses. Efficacy in terms of HbA1c control was similar to that of the other insulin analogues administered once a day. The frequency of severe hypoglycaemia was similar in the groups treated with insulin degludec and those treated with the other insulins (10% to 12% among patients with type 1 diabetes and less than 5% in patients with type 2 diabetes). Deaths and other serious adverse events were similarly frequent in the different groups. A meta-analysis of clinical trials, carried out by the US Food and Drug Administration, suggested an increase of about 60% in the incidence of cardiovascular complications, based on a composite endpoint combining myocardial infarction, stroke and cardiovascular death. Other adverse effects observed in these trials were already known to occur with human insulin and its analogues, including weight gain, hypersensitivity reactions, reactions at the injection site, etc. The trials were too short in duration to assess long-term harms

  12. Long-term effect of insulin on glucose transport and insulin binding in cultured adipocytes from normal and obese humans with and without non-insulin-dependent diabetes.

    PubMed Central

    Sinha, M K; Taylor, L G; Pories, W J; Flickinger, E G; Meelheim, D; Atkinson, S; Sehgal, N S; Caro, J F

    1987-01-01

    We have tested the hypothesis that in vitro exposure of insulin-resistant adipocytes with insulin results in improved insulin action. A primary culture system of adipocytes from obese subjects with or without non-insulin-dependent diabetes mellitus (NIDDM) and nonobese control subjects has been developed. The adipocytes when cultured in serum-free medium do not lose their original characteristics in regard to insulin binding and glucose transport. The adipocytes from three groups were incubated with insulin (0, 10(-10) M, and 10(-7) M) for 24 h at 37 degrees C, receptor-bound insulin was dissociated, and basal and insulin (1 X 10(-11)-10(-7) M)-stimulated glucose transport and 125I-insulin binding were determined. The 24-h insulin exposure of adipocytes from control subjects decreased basal and insulin-stimulated glucose transport. The effects of 1 X 10(-7) M insulin were more pronounced than 1 X 10(-10) M insulin. Similarly, insulin exposure decreased insulin sensitivity and responsiveness of cultured adipocytes from obese and NIDDM patients. The insulin-induced reduction in insulin sensitivity and responsiveness for glucose transport in three groups were due to alterations at insulin binding and postbinding levels. In conclusion, insulin induces insulin resistance in control adipocytes and further worsens the insulin resistance of adipocytes from obese and NIDDM subjects. For insulin to improve the insulin resistance of adipocytes from NIDDM patients, either more prolonged in vitro insulin exposure and/or other hormonal factors might be required. PMID:3308958

  13. The Effects of Anti-insulin Antibodies and Cross-reactivity with Human Recombinant Insulin Analogues in the E170 Insulin Immunometric Assay

    PubMed Central

    Kim, Serim; Hur, Mina; Moon, Hee Won; Kim, Jin Q

    2011-01-01

    Background Insulin assays are affected by varying degrees of interference from anti-insulin antibodies (IAs) and by cross-reactivity with recombinant insulin analogues. We evaluated the usefulness of the E170 insulin assay by assessing IA effects and cross-reactivity with 2 analogues. Methods Sera were obtained from 59 type 2 diabetes patients receiving continuous subcutaneous insulin infusion and 18 healthy controls. Insulin levels were determined using an E170 analyzer. To investigate the effects of IAs, we performed IA radioimmunoassays, and analyzed the differences between directly measured insulin (direct insulin) and polyethylene glycol (PEG)-treated insulins (free, IA-unbound; total, IA-bound and unbound insulin). We performed in-vitro cross-reactivity tests with insulin aspart and insulin glulisine. Results In IA-positive patients, E170 free insulin levels measured using the E170 analyzer were significantly lower than the direct insulin levels. The mean value of the direct/free insulin ratio and IA-bound insulin, which were calculated as the difference between total and free insulin, increased significantly as endogenous IA levels increased. The E170 insulin assay showed low cross-reactivities with both analogues (< 0.7%). Conclusions IAs interfered with E170 insulin assay, and the extent of interference correlated with the IA levels, which may be attributable to the increase in IA-bound insulin, and not to an error in the assay. The E170 insulin assay may measure only endogenous insulin since cross-reactivity is low. Our results suggest that the measurement of free insulin after PEG pre-treatment could be useful for β cell function assessment in diabetic patients undergoing insulin therapy. PMID:21239867

  14. The Hygiene Hypothesis: An Explanation for the Increased Frequency of Insulin-Dependent Diabetes

    PubMed Central

    Bach, Jean-François; Chatenoud, Lucienne

    2012-01-01

    The steadily increasing frequency of insulin-dependent diabetes in several countries is best explained today by the decline of infections. Epidemiologic and animal data support this conclusion, which, however, requires confirmation by intervention trials in man. The mechanisms of the protective effect of infections on diabetes onset are diverse including competition for homeostatic factors and stimulation of regulatory T cells and of Toll-like receptors. These considerations might have interesting therapeutic applications for the prevention of the disease. PMID:22355800

  15. Insulin-dependent (type I) diabetes mellitus.

    PubMed Central

    Rodger, W

    1991-01-01

    Insulin-dependent (type I) diabetes mellitus is a chronic disease characterized by hyperglycemia, impaired metabolism and storage of important nutrients, evidence of autoimmunity, and long-term vascular and neurologic complications. Insulin secretory function is limited. Cell membrane binding is not primarily involved. The goal of treatment is to relieve symptoms and to achieve blood glucose levels as close to normal as possible without severe hypoglycemia. However, even with education and self-monitoring of the blood glucose level, attaining recommended target values (plasma glucose level less than 8.0 mmol/L before main meals for adults) remains difficult. Human insulin offers no advantage in glycemic control but is important in the management and prevention of immune-related clinical problems (e.g., injection-site lipoatrophy, insulin resistance and allergy) associated with the use of beef or pork insulin. Therapy with one or two injections per day of mixed short-acting or intermediate-acting insulin preparations is a compromise between convenience and the potential for achieving target plasma glucose levels. Intensive insulin therapy with multiple daily injections or continuous infusion with an insulin pump improves mean glycated hemoglobin levels; however, it increases rates of severe hypoglycemia and has not been shown to decrease the incidence of clinically significant renal, retinal or neurologic dysfunction. Future prospects include automated techniques of insulin delivery, immunosuppression to preserve endogenous insulin secretion and islet transplantation. PMID:1933705

  16. Evolving strategies for insulin delivery and therapy.

    PubMed

    Cefalu, William T

    2004-01-01

    It has now been conclusively proven that adequate control of blood glucose delays or prevents the progression of diabetic complications. In order to achieve the suggested targets for glycaemic control necessary to reduce the incidence of diabetic complications, it has been established that a more intensive insulin regimen requiring multiple insulin injections is required for patients with type 1 diabetes mellitus. For patients with type 2 diabetes, oral antidiabetic therapy is generally used initially, but given the natural history of type 2 diabetes and the need to achieve improved glycaemic control, earlier use of insulin has been promoted. However, the use of insulin in more intensive regimens for the patient with type 1 diabetes or for earlier treatment of the patient with type 2 diabetes is not routine. Many factors are responsible for this observation. Nevertheless, available device options such as insulin pens or insulin pumps are routinely available for implementation of intensive insulin therapy. However, a major limitation for advancing to intensive insulin therapy is that the only viable way to administer insulin is through injection. Delivery options that use dermal, nasal and oral approaches have been explored. The oral approach may include gastrointestinal, buccal or pulmonary uptake. Recent evidence shows that delivery of insulin via the oral cavity with uptake occurring in the pulmonary alveoli may be the most viable clinical option in the future. PMID:15161324

  17. Yeast secretory expression of insulin precursors.

    PubMed

    Kjeldsen, T

    2000-09-01

    Since the 1980s, recombinant human insulin for the treatment of diabetes mellitus has been produced using either the yeast Saccharomyces cerevisiae or the prokaryote Escherichia coli. Here, development of the insulin secretory expression system in S. cerevisiae and its subsequent optimisation is described. Expression of proinsulin in S. cerevisiae does not result in efficient secretion of proinsulin or insulin. However, expression of a cDNA encoding a proinsulin-like molecule with deletion of threonine(B30) as a fusion protein with the S. cerevisiae alpha-factor prepro-peptide (leader), followed either by replacement of the human proinsulin C-peptide with a small C-peptide (e.g. AAK), or by direct fusion of lysine(B29) to glycine(A1), results in the efficient secretion of folded single-chain proinsulin-like molecules to the culture supernatant. The secreted single-chain insulin precursor can then be purified and subsequently converted to human insulin by tryptic transpeptidation in organic aqueous medium in the presence of a threonine ester. The leader confers secretory competence to the insulin precursor, and constructed (synthetic) leaders have been developed for efficient secretory expression of the insulin precursor in the yeasts S. cerevisiae and Pichia pastories. The Kex2 endoprotease, specific for dibasic sites, cleaves the leader-insulin precursor fusion protein in the late secretory pathway and the folded insulin precursor is secreted to the culture supernatant. However, the Kex2 endoprotease processing of the pro-peptide-insulin precursor fusion protein is incomplete and a significant part of the pro-peptide-insulin precursor fusion protein is secreted to the culture supernatant in a hyperglycosylated form. A spacer peptide localised between the leader and the insulin precursor has been developed to optimise Kex2 endoprotease processing and insulin precursor fermentation yield. PMID:11030562

  18. Insulin-like activity in the retina

    SciTech Connect

    Das, A.

    1986-01-01

    A number of studies have recently demonstrated that insulin or a homologous peptide may be synthesized outside the pancreas also. The present study was designed to investigate whether insulin-like activity exists in the retina, and if it exists, whether it is due to local synthesis of insulin or a similar peptide in the retina. To determine whether the insulin-like immunoreactivity in retinal glial cells is due to binding and uptake or local synthesis of insulin, a combined approach of immunocytochemistry and in situ DNA-RNA hybridization techniques was used on cultured rat retinal glial cells. Insulin-like immunoreactivity was demonstrated in the cytoplasma of these cells. In situ hybridization studies using labeled rat insulin cDNA indicated that these cells contain the mRNA necessary for de novo synthesis of insulin or a closely homologous peptide. Since human retinal cells have, as yet, not been conveniently grown in culture, an ocular tumor cell line, human Y79 retinoblastoma was used as a model to extend these investigations. The presence of insulin-like immunoreactivity as well as insulin-specific mRNA was demonstrated in this cell line. Light microscopic autoradiography following incubation of isolated rat retinal cells with /sup 125/I-insulin showed the presence of insulin binding sites on the photoreceptors and amarcine cells. On the basis of these observations that rat retina glial cells, including Muller cells are sites of synthesis of insulin or a similar peptide, a model for the pathogenesis of dabetic retinopathy is proposed.

  19. FFA-induced hepatic insulin resistance in vivo is mediated by PKCδ, NADPH oxidase, and oxidative stress.

    PubMed

    Pereira, Sandra; Park, Edward; Mori, Yusaku; Haber, C Andrew; Han, Ping; Uchida, Toyoyoshi; Stavar, Laura; Oprescu, Andrei I; Koulajian, Khajag; Ivovic, Alexander; Yu, Zhiwen; Li, Deling; Bowman, Thomas A; Dewald, Jay; El-Benna, Jamel; Brindley, David N; Gutierrez-Juarez, Roger; Lam, Tony K T; Najjar, Sonia M; McKay, Robert A; Bhanot, Sanjay; Fantus, I George; Giacca, Adria

    2014-07-01

    Fat-induced hepatic insulin resistance plays a key role in the pathogenesis of type 2 diabetes in obese individuals. Although PKC and inflammatory pathways have been implicated in fat-induced hepatic insulin resistance, the sequence of events leading to impaired insulin signaling is unknown. We used Wistar rats to investigate whether PKCδ and oxidative stress play causal roles in this process and whether this occurs via IKKβ- and JNK-dependent pathways. Rats received a 7-h infusion of Intralipid plus heparin (IH) to elevate circulating free fatty acids (FFA). During the last 2 h of the infusion, a hyperinsulinemic-euglycemic clamp with tracer was performed to assess hepatic and peripheral insulin sensitivity. An antioxidant, N-acetyl-L-cysteine (NAC), prevented IH-induced hepatic insulin resistance in parallel with prevention of decreased IκBα content, increased JNK phosphorylation (markers of IKKβ and JNK activation, respectively), increased serine phosphorylation of IRS-1 and IRS-2, and impaired insulin signaling in the liver without affecting IH-induced hepatic PKCδ activation. Furthermore, an antisense oligonucleotide against PKCδ prevented IH-induced phosphorylation of p47(phox) (marker of NADPH oxidase activation) and hepatic insulin resistance. Apocynin, an NADPH oxidase inhibitor, prevented IH-induced hepatic and peripheral insulin resistance similarly to NAC. These results demonstrate that PKCδ, NADPH oxidase, and oxidative stress play a causal role in FFA-induced hepatic insulin resistance in vivo and suggest that the pathway of FFA-induced hepatic insulin resistance is FFA → PKCδ → NADPH oxidase and oxidative stress → IKKβ/JNK → impaired hepatic insulin signaling. PMID:24824652

  20. Involvement of mTOR in Type 2 CRF Receptor Inhibition of Insulin Signaling in Muscle Cells.

    PubMed

    Chao, Hongxia; Li, Haochen; Grande, Rebecca; Lira, Vitor; Yan, Zhen; Harris, Thurl E; Li, Chien

    2015-06-01

    Type 2 corticotropin-releasing factor receptor (CRFR2) is expressed in skeletal muscle and stimulation of the receptor has been shown to inhibit the effect of insulin on glucose uptake in muscle cells. Currently, little is known about the mechanisms underlying this process. In this study, we first showed that both in vivo and in vitro CRFR2 expression in muscle was closely correlated with insulin sensitivity, with elevated receptor levels observed in insulin resistant muscle cells. Stimulation of CRFR2 by urocortin 2 (Ucn 2), a CRFR2-selective ligand, in C2C12 myotubes greatly attenuated insulin-induced glucose uptake. The inhibitory effect of CRFR2 signaling required cAMP production and is involved the mammalian target of rapamycine pathway, as rapamycin reversed the inhibitory effect of CRFR2 stimulation on insulin-induced glucose uptake. Moreover, stimulation of CRFR2 failed to inhibit glucose uptake in muscle cells induced by platelet-derived growth factor, which, similar to insulin, signals through Akt-mediated pathway but is independently of insulin receptor substrate (IRS) proteins to promote glucose uptake. This result argues that CRFR2 signaling modulates insulin's action likely at the levels of IRS. Consistent with this notion, Ucn 2 reduced insulin-induced tyrosine phosphorylation of IRS-1, and treatment with rapamycin reversed the inhibitory effect of Ucn 2 on IRS-1 and Akt phosphorylation. In conclusion, the inhibitory effect of CRFR2 signaling on insulin action is mediated by cAMP in a mammalian target of rapamycine-dependent manner, and IRS-1 is a key nodal point where CRFR2 signaling modulates insulin-stimulated glucose uptake in muscle cells. PMID:25875045

  1. Insulin Resistance and Skin Diseases

    PubMed Central

    Napolitano, Maddalena; Megna, Matteo; Monfrecola, Giuseppe

    2015-01-01

    In medical practice, almost every clinician may encounter patients with skin disease. However, it is not always easy for physicians of all specialties to face the daily task of determining the nature and clinical implication of dermatologic manifestations. Are they confined to the skin, representing a pure dermatologic event? Or are they also markers of internal conditions relating to the patient's overall health? In this review, we will discuss the principal cutaneous conditions which have been linked to metabolic alterations. Particularly, since insulin has an important role in homeostasis and physiology of the skin, we will focus on the relationships between insulin resistance (IR) and skin diseases, analyzing strongly IR-associated conditions such as acanthosis nigricans, acne, and psoriasis, without neglecting emerging and potential scenarios as the ones represented by hidradenitis suppurativa, androgenetic alopecia, and hirsutism. PMID:25977937

  2. FDA-Approved Biosimilar Insulin

    PubMed Central

    2014-01-01

    If a biosimilar insulin is discovered postmarketing to be subpotent, superpotent, or contaminated or the contents mislabeled, it is an adulterated product and must be quarantined for removal including from a patient’s home. Adulterated products could be considered “counterfeit” since they do not meet the original standards established by the FDA. The FDA must establish a method of regularly assaying samples of biosimilar insulin drawn directly from the supply pipeline to help ensure patient safety and evaluate clinical performance. Independent groups without conflict of interest would perform confidential comparison assay. For less than 5 cents per vial/pen, manufacturers could easily support an independent, FDA-recognized, random sample program and create a functional postmarket surveillance system that better protects the public and the manufacturer from undesired outcomes. PMID:25172881

  3. Nuclear Regulatory Commission Semiannual Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-20

    ...) 2010, less the amounts appropriated from the Nuclear Waste Fund, amounts appropriated for Waste... agenda on April 26, 2010 (75 FR 21960). For this edition of the NRC's regulatory agenda, the most... publication of the last NRC semiannual agenda on April 26, 2010 (75 FR 21960). Within each group, the...

  4. NRC regulatory agenda

    SciTech Connect

    Not Available

    1991-04-01

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action or has proposed, or is considering action and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter.

  5. NRC regulatory agenda

    SciTech Connect

    Not Available

    1992-05-01

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considering action, and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter.

  6. NRC Regulatory Agenda

    SciTech Connect

    Not Available

    1991-10-01

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considering action, and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter.

  7. NRC Regulatory Agenda

    SciTech Connect

    Not Available

    1991-08-01

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action or has proposed, or is considering action and all petitions for rulemaking which have been received by the commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter.

  8. NRC regulatory agenda

    SciTech Connect

    Not Available

    1993-04-01

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considering action, and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter.

  9. NRC regulatory agenda

    SciTech Connect

    Not Available

    1990-07-01

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has proposed or is considering action and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter.

  10. Plant Regulatory Organizations

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The chapter on Plant Regulatory Organizations is part of a book titled Pest Management and Phytosanitary Trade Barriers authored by Neil Heather (Australia) and Guy Hallman. It covers the role of plant regulatory organizations from the international to state level in protecting plant health. At on...

  11. Pioglitazone Increases Whole Body Insulin Sensitivity in Obese, Insulin-Resistant Rhesus Monkeys

    PubMed Central

    Tozzo, Effie; Bhat, Gowri; Cheon, Kyeongmi; Camacho, Raul C.

    2015-01-01

    Hyperinsulinemic-euglycemic clamps are considered the "gold standard" for assessing whole body insulin sensitivity. When used in combination with tracer dilution techniques and physiological insulin concentrations, insulin sensitization can be dissected and attributed to hepatic and peripheral (primarily muscle) effects. Non-human primates (NHPs), such as rhesus monkeys, are the closest pre-clinical species to humans, and thus serve as an ideal model for testing of compound efficacy to support translation to human efficacy. We determined insulin infusion rates that resulted in high physiological insulin concentrations that elicited maximal pharmacodynamic responses during hyperinsulinemic-euglycemic clamps. These rates were then used with [U-13C]-D-glucose, to assess and document the degrees of hepatic and peripheral insulin resistance between healthy and insulin-resistant, dysmetabolic NHPs. Next, dysmetabolic NHPs were treated for 28 days with pioglitazone (3 mg/kg) and again had their insulin sensitivity assessed, illustrating a significant improvement in hepatic and peripheral insulin sensitivity. This coincided with a significant increase in insulin clearance, and normalization of circulating adiponectin. In conclusion, we have determined a physiological clamp paradigm (similar to humans) for assessing glucose turnover in NHPs. We have also demonstrated that insulin-resistant, dysmetabolic NHPs respond to the established insulin sensitizer, pioglitazone, thus confirming their use as an ideal pre-clinical translational model to assess insulin sensitizing compounds. PMID:25954816

  12. Postreceptor defects causing insulin resistance in normoinsulinemic non-insulin-dependent diabetes mellitus

    SciTech Connect

    Bolinder, J.; Ostman, J.; Arner, P.

    1982-10-01

    The mechanisms of the diminished hypoglycemic response to insulin in non-insulin-dependent diabetes mellitus (NIDDM) with normal levels of circulating plasma insulin were investigated. Specific binding of mono-/sup 125/I (Tyr A14)-insulin to isolated adipocytes and effects of insulin (5--10,000 microunits/ml) on glucose oxidation and lipolysis were determined simultaneously in subcutaneous adipose tissue of seven healthy subjects of normal weight and seven untreated NIDDM patients with normal plasma insulin levels. The two groups were matched for age, sex, and body weight. Insulin binding, measured in terms of receptor number and affinity, was normal in NIDDM, the total number of receptors averaging 350,000 per cell. Neither sensitivity nor the maximum antilipolytic effect of insulin was altered in NIDDM patients as compared with control subjects; the insulin concentration producing half the maximum effect (ED50) was 10 microunits/ml. As regards the effect of insulin on glucose oxidation, for the control subjects ED50 was 30 microunits/ml, whereas in NIDDM patients, insulin exerted no stimulatory effect. The results obtained suggest that the effect of insulin on glucose utilization in normoinsulinemic NIDDM may be diminished in spite of normal insulin binding to receptors. The resistance may be due solely to postreceptor defects, and does not involve antilipolysis.

  13. [Insulin therapy for type 1 diabetes mellitus: past and present].

    PubMed

    Pires, Antonio Carlos; Chacra, Antonio Roberto

    2008-03-01

    The discovery of insulin can be considered the milestone of diabetes mellitus history and a great achievement for its treatment. The first insulin available was the regular. Afterwards, Hagedorn added the protamine to the insulin, thus, creating the NPH insulin. In the 1950s an insulin free of protamine was synthesized: the lente insulin. With the advent of molecular biology, synthetic human insulin was synthesized using recombinant DNA technology. Most recently several types of insulin analogues were available, providing the patients with better metabolic control. Type 1 diabetes mellitus treatment includes plain substitution and individualization for short-acting plus long-acting insulin according to the physician's assistance, besides regular practice of physical activities and diet orientations. In type 1 diabetes mellitus the insulin of low variability is the best choice since basal/bolus insulin therapy or continuous subcutaneous insulin infusion pump can mimetize the physiological release of insulin by beta cells. PMID:18438537

  14. Insulin dysfunction and Tau pathology

    PubMed Central

    El Khoury, Noura B.; Gratuze, Maud; Papon, Marie-Amélie; Bretteville, Alexis; Planel, Emmanuel

    2013-01-01

    The neuropathological hallmarks of Alzheimer's disease (AD) include senile plaques of β-amyloid (Aβ) peptides (a cleavage product of the Amyloid Precursor Protein, or APP) and neurofibrillary tangles (NFT) of hyperphosphorylated Tau protein assembled in paired helical filaments (PHF). NFT pathology is important since it correlates with the degree of cognitive impairment in AD. Only a small proportion of AD is due to genetic variants, whereas the large majority of cases (~99%) is late onset and sporadic in origin. The cause of sporadic AD is likely to be multifactorial, with external factors interacting with biological or genetic susceptibilities to accelerate the manifestation of the disease. Insulin dysfunction, manifested by diabetes mellitus (DM) might be such factor, as there is extensive data from epidemiological studies suggesting that DM is associated with an increased relative risk for AD. Type 1 diabetes (T1DM) and type 2 diabetes (T2DM) are known to affect multiple cognitive functions in patients. In this context, understanding the effects of diabetes on Tau pathogenesis is important since Tau pathology show a strong relationship to dementia in AD, and to memory loss in normal aging and mild cognitive impairment. Here, we reviewed preclinical studies that link insulin dysfunction to Tau protein pathogenesis, one of the major pathological hallmarks of AD. We found more than 30 studies reporting Tau phosphorylation in a mouse or rat model of insulin dysfunction. We also payed attention to potential sources of artifacts, such as hypothermia and anesthesia, that were demonstrated to results in Tau hyperphosphorylation and could major confounding experimental factors. We found that very few studies reported the temperature of the animals, and only a handful did not use anesthesia. Overall, most published studies showed that insulin dysfunction can promote Tau hyperphosphorylation and pathology, both directly and indirectly, through hypothermia. PMID:24574966

  15. Globular adiponectin ameliorates metabolic insulin resistance via AMPK-mediated restoration of microvascular insulin responses.

    PubMed

    Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W; Barrett, Eugene J; Cao, Wenhong; Liu, Zhenqi

    2015-09-01

    Adiponectin is an adipokine with anti-inflammatory and anti-diabetic properties. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance in obesity and diabetes. Insulin resistance is present in muscle microvasculature and this may contribute to decreased insulin delivery to, and action in, muscle. In this study we examined whether adiponectin ameliorates metabolic insulin resistance by affecting muscle microvascular recruitment. We demonstrated that a high-fat diet induces vascular adiponectin and insulin resistance but globular adiponectin administration can restore vascular insulin responses and improve insulin's metabolic action via an AMPK- and nitric oxide-dependent mechanism. This suggests that globular adiponectin might have a therapeutic potential for improving insulin resistance and preventing cardiovascular complications in patients with diabetes via modulation of microvascular insulin responses. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance, and microvasculature plays a critical role in the regulation of insulin action in muscle. Here we tested whether adiponectin replenishment could improve metabolic insulin sensitivity in male rats fed a high-fat diet (HFD) via the modulation of microvascular insulin responses. Male Sprague-Dawley rats were fed either a HFD or low-fat diet (LFD) for 4 weeks. Small resistance artery myograph changes in tension, muscle microvascular recruitment and metabolic response to insulin were determined. Compared with rats fed a LFD, HFD feeding abolished the vasodilatory actions of globular adiponectin (gAd) and insulin on pre-constricted distal saphenous arteries. Pretreatment with gAd improved insulin responses in arterioles isolated from HFD rats, which was blocked by AMP-activated protein kinase (AMPK) inhibition. Similarly, HFD abolished microvascular responses to either gAd or insulin and decreased insulin-stimulated glucose disposal by

  16. Subcutaneous insulin substitution in insulin-dependent diabetes mellitus. Pharmacokinetic and pharmacodynamic studies.

    PubMed

    Olsson, P O

    1987-01-01

    Determination of free and total insulin with radioimmunoassay, after precipitation of endogenous insulin antibodies with polyethylene glycol, was evaluated. Insulin substitution in insulin-dependent diabetic patients was investigated, embracing the 24 h free insulin and glucose profiles with different regimens, the miscibility of insulin preparations, the overnight metabolic control, and bolus doses of different size with infusion pumps. In the free and total insulin assay precipitation of immunoglobulins with polyethylene glycol was almost complete and the recovery was high. Compared to immediately precipitated and assayed plasma samples at 37 degrees C, free insulin slightly decreased in immediately processed serum (20 degrees C), and also in plasma after 3 h at 20 degrees C. In stored (-20 degrees C) unprecipitated plasma samples free insulin increased after 4 weeks and also in serum samples after 26 weeks, whereas stored PEG-supernates were stable. In healthy controls a low basal insulin was found, increasing about tenfold postprandially. No morning rise in free insulin or glucose was found. The 24 h free insulin profile was strikingly unphysiological with 1 or 2 dose regimens; there was preprandial and nocturnal hyperinsulinaemia but absence of meal-related free insulin peaks. A considerable glucose rise was found after breakfast. Intensive regimens with conventional injections or infusion pumps, gave 24 h free insulin profiles that were similar to the physiological. However, the prandial peaks were retarded; and hyperinsulinaemia was shown with infusion pumps during daytime. An immediate loss of regular insulin was demonstrated after mixture with semisynthetic human lente insulin in vitro and in vivo, but not after mixture with biosynthetic human NPH insulin. The morning glucose control was similar with a bedtime injection of intermediate-acting insulin or continuous subcutaneous insulin infusion, but less hyperinsulinaemia overnight was found with the

  17. Methylated trivalent arsenicals are potent inhibitors of glucose stimulated insulin secretion by murine pancreatic islets

    SciTech Connect

    Douillet, Christelle; Currier, Jenna; Saunders, Jesse; Bodnar, Wanda M.; Matoušek, Tomáš; Stýblo, Miroslav

    2013-02-15

    Epidemiologic evidence has linked chronic exposure to inorganic arsenic (iAs) with an increased prevalence of diabetes mellitus. Laboratory studies have identified several mechanisms by which iAs can impair glucose homeostasis. We have previously shown that micromolar concentrations of arsenite (iAs{sup III}) or its methylated trivalent metabolites, methylarsonite (MAs{sup III}) and dimethylarsinite (DMAs{sup III}), inhibit the insulin-activated signal transduction pathway, resulting in insulin resistance in adipocytes. Our present study examined effects of the trivalent arsenicals on insulin secretion by intact pancreatic islets isolated from C57BL/6 mice. We found that 48-hour exposures to low subtoxic concentrations of iAs{sup III}, MAs{sup III} or DMAs{sup III} inhibited glucose-stimulated insulin secretion (GSIS), but not basal insulin secretion. MAs{sup III} and DMAs{sup III} were more potent than iAs{sup III} as GSIS inhibitors with estimated IC{sub 50} ≤ 0.1 μM. The exposures had little or no effects on insulin content of the islets or on insulin expression, suggesting that trivalent arsenicals interfere with mechanisms regulating packaging of the insulin transport vesicles or with translocation of these vesicles to the plasma membrane. Notably, the inhibition of GSIS by iAs{sup III}, MAs{sup III} or DMAs{sup III} could be reversed by a 24-hour incubation of the islets in arsenic-free medium. These results suggest that the insulin producing pancreatic β-cells are among the targets for iAs exposure and that the inhibition of GSIS by low concentrations of the methylated metabolites of iAs may be the key mechanism of iAs-induced diabetes. - Highlights: ► Trivalent arsenicals inhibit glucose stimulated insulin secretion by pancreatic islets. ► MAs{sup III} and DMAs{sup III} are more potent inhibitors than arsenite with IC{sub 50} ∼ 0.1 μM. ► The arsenicals have little or no effects on insulin expression in pancreatic islets. ► The inhibition of

  18. Three key imperatives

    SciTech Connect

    Colvin, Joe F.

    2004-06-01

    This article is an excerpt from a speech given by Joe F. Colvin, president and CEO, Nuclear Energy Institute (NEI) at NEI's Nuclear Energy Assembly on May 13, 2004 in New Orleans. Three areas were highlighted in the excerpt as critical to the industry: finalizing a regulatory framework that is safety-focused; ensuring a stable and reliable reactor fuel supply; and, finishing the job of securing an operating used fuel repository at Yucca Mountain.

  19. Altered fetal skeletal muscle nutrient metabolism following an adverse in utero environment and the modulation of later life insulin sensitivity.

    PubMed

    Dunlop, Kristyn; Cedrone, Megan; Staples, James F; Regnault, Timothy R H

    2015-01-01

    The importance of the in utero environment as a contributor to later life metabolic disease has been demonstrated in both human and animal studies. In this review, we consider how disruption of normal fetal growth may impact skeletal muscle metabolic development, ultimately leading to insulin resistance and decreased insulin sensitivity, a key precursor to later life metabolic disease. In cases of intrauterine growth restriction (IUGR) associated with hypoxia, where the fetus fails to reach its full growth potential, low birth weight (LBW) is often the outcome, and early in postnatal life, LBW individuals display modifications in the insulin-signaling pathway, a critical precursor to insulin resistance. In this review, we will present literature detailing the classical development of insulin resistance in IUGR, but also discuss how this impaired development, when challenged with a postnatal Western diet, may potentially contribute to the development of later life insulin resistance. Considering the important role of the skeletal muscle in insulin resistance pathogenesis, understanding the in utero programmed origins of skeletal muscle deficiencies in insulin sensitivity and how they may interact with an adverse postnatal environment, is an important step in highlighting potential therapeutic options for LBW offspring born of pregnancies characterized by placental insufficiency. PMID:25685986

  20. Altered Fetal Skeletal Muscle Nutrient Metabolism Following an Adverse In Utero Environment and the Modulation of Later Life Insulin Sensitivity

    PubMed Central

    Dunlop, Kristyn; Cedrone, Megan; Staples, James F.; Regnault, Timothy R.H.

    2015-01-01

    The importance of the in utero environment as a contributor to later life metabolic disease has been demonstrated in both human and animal studies. In this review, we consider how disruption of normal fetal growth may impact skeletal muscle metabolic development, ultimately leading to insulin resistance and decreased insulin sensitivity, a key precursor to later life metabolic disease. In cases of intrauterine growth restriction (IUGR) associated with hypoxia, where the fetus fails to reach its full growth potential, low birth weight (LBW) is often the outcome, and early in postnatal life, LBW individuals display modifications in the insulin-signaling pathway, a critical precursor to insulin resistance. In this review, we will present literature detailing the classical development of insulin resistance in IUGR, but also discuss how this impaired development, when challenged with a postnatal Western diet, may potentially contribute to the development of later life insulin resistance. Considering the important role of the skeletal muscle in insulin resistance pathogenesis, understanding the in utero programmed origins of skeletal muscle deficiencies in insulin sensitivity and how they may interact with an adverse postnatal environment, is an important step in highlighting potential therapeutic options for LBW offspring born of pregnancies characterized by placental insufficiency. PMID:25685986

  1. Integrin-Linked Kinase in Muscle Is Necessary for the Development of Insulin Resistance in Diet-Induced Obese Mice.

    PubMed

    Kang, Li; Mokshagundam, Shilpa; Reuter, Bradley; Lark, Daniel S; Sneddon, Claire C; Hennayake, Chandani; Williams, Ashley S; Bracy, Deanna P; James, Freyja D; Pozzi, Ambra; Zent, Roy; Wasserman, David H

    2016-06-01

    Diet-induced muscle insulin resistance is associated with expansion of extracellular matrix (ECM) components, such as collagens, and the expression of collagen-binding integrin, α2β1. Integrins transduce signals from ECM via their cytoplasmic domains, which bind to intracellular integrin-binding proteins. The integrin-linked kinase (ILK)-PINCH-parvin (IPP) complex interacts with the cytoplasmic domain of β-integrin subunits and is critical for integrin signaling. In this study we defined the role of ILK, a key component of the IPP complex, in diet-induced muscle insulin resistance. Wild-type (ILK(lox/lox)) and muscle-specific ILK-deficient (ILK(lox/lox)HSAcre) mice were fed chow or a high-fat (HF) diet for 16 weeks. Body weight was not different between ILK(lox/lox) and ILK(lox/lox)HSAcre mice. However, HF-fed ILK(lox/lox)HSAcre mice had improved muscle insulin sensitivity relative to HF-fed ILK(lox/lox) mice, as shown by increased rates of glucose infusion, glucose disappearance, and muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. Improved muscle insulin action in the HF-fed ILK(lox/lox)HSAcre mice was associated with increased insulin-stimulated phosphorylation of Akt and increased muscle capillarization. These results suggest that ILK expression in muscle is a critical component of diet-induced insulin resistance, which possibly acts by impairing insulin signaling and insulin perfusion through capillaries. PMID:27207548

  2. Optical key system

    DOEpatents

    Hagans, Karla G.; Clough, Robert E.

    2000-01-01

    An optical key system comprises a battery-operated optical key and an isolated lock that derives both its operating power and unlock signals from the correct optical key. A light emitting diode or laser diode is included within the optical key and is connected to transmit a bit-serial password. The key user physically enters either the code-to-transmit directly, or an index to a pseudorandom number code, in the key. Such person identification numbers can be retained permanently, or ephemeral. When a send button is pressed, the key transmits a beam of light modulated with the password information. The modulated beam of light is received by a corresponding optical lock with a photovoltaic cell that produces enough power from the beam of light to operate a password-screen digital logic. In one application, an acceptable password allows a two watt power laser diode to pump ignition and timing information over a fiberoptic cable into a sealed engine compartment. The receipt of a good password allows the fuel pump, spark, and starter systems to each operate. Therefore, bypassing the lock mechanism as is now routine with automobile thieves is pointless because the engine is so thoroughly disabled.

  3. Optical key system

    SciTech Connect

    Hagans, K.G.; Clough, R.E.

    2000-04-25

    An optical key system comprises a battery-operated optical key and an isolated lock that derives both its operating power and unlock signals from the correct optical key. A light emitting diode or laser diode is included within the optical key and is connected to transmit a bit-serial password. The key user physically enters either the code-to-transmit directly, or an index to a pseudorandom number code, in the key. Such person identification numbers can be retained permanently, or ephemeral. When a send button is pressed, the key transmits a beam of light modulated with the password information. The modulated beam of light is received by a corresponding optical lock with a photovoltaic cell that produces enough power from the beam of light to operate a password-screen digital logic. In one application, an acceptable password allows a two watt power laser diode to pump ignition and timing information over a fiberoptic cable into a sealed engine compartment. The receipt of a good password allows the fuel pump, spark, and starter systems to each operate. Therefore, bypassing the lock mechanism as is now routine with automobile thieves is pointless because the engine is so thoroughly disabled.

  4. Nuclear SREBP-1a causes loss of pancreatic {beta}-cells and impaired insulin secretion

    SciTech Connect

    Iwasaki, Yuko; Iwasaki, Hitoshi; Yatoh, Shigeru; Ishikawa, Mayumi; Kato, Toyonori; Matsuzaka, Takashi; Nakagawa, Yoshimi; Yahagi, Naoya; Kobayashi, Kazuto; Takahashi, Akimitsu; Suzuki, Hiroaki; Yamada, Nobuhiro; Shimano, Hitoshi

    2009-01-16

    Transgenic mice expressing nuclear sterol regulatory element-binding protein-1a under the control of the insulin promoter were generated to determine the role of SREBP-1a in pancreatic {beta}-cells. Only low expressors could be established, which exhibited mild hyperglycemia, impaired glucose tolerance, and reduced plasma insulin levels compared to C57BL/6 controls. The islets isolated from the transgenic mice were fewer and smaller, and had decreased insulin content and unaltered glucagon staining. Both glucose- and potassium-stimulated insulin secretions were decreased. The transgenic islets consistently expressed genes for fatty acids and cholesterol synthesis, resulting in accumulation of triglycerides but not cholesterol. PDX-1, {beta}{epsilon}{tau}{alpha}2, MafA, and IRS-2 were suppressed, partially explaining the loss and dysfunction of {beta}-cell mass. The transgenic mice on a high fat/high sucrose diet still exhibited impaired insulin secretion and continuous {beta}-cell growth defect. Therefore, nuclear SREBP-1a, even at a low level, strongly disrupts {beta}-cell mass and function.

  5. Decreased insulin secretion and glucose clearance in exocrine pancreas-insufficient pigs.

    PubMed

    Lozinska, Liudmyla; Weström, Björn; Prykhodko, Olena; Lindqvist, Andreas; Wierup, Nils; Ahrén, Bo; Szwiec, Katarzyna; Pierzynowski, Stefan G

    2016-01-01

    The effect of exocrine pancreatic function on the glucose-mediated insulin response and glucose utilization were studied in an exocrine pancreas-insufficient (EPI) pig model. Five 10-week-old EPI pigs after pancreatic duct ligation and 6 age-matched, non-operated control pigs were used in the study. Blood glucose, plasma insulin and C-peptide concentrations were monitored during meal (MGTT), oral (OGTT) and intravenous (IVGTT) glucose tolerance tests. Upon post-mortem examination, the pancreatic remnants of the EPI pigs showed acinar fibrotic atrophy but normal islets and β-cell morphology. The EPI pigs displayed increased fasting glucose concentrations compared with control animals (6.4 ± 0.4 versus 4.8 ± 0.1 mmol l(-1) , P < 0.0001) but unchanged insulin concentrations (2.4 ± 0.6 versus 2.1 ± 0.2 pmol l(-1) ). During the OGTT and IVGTT, the EPI pigs showed slower, impaired glucose utilization, with the disruption of a well-timed insulin response. Plasma C-peptide concentrations confirmed the delayed insulin response during the IVGTT in EPI pigs. Oral pancreatic enzyme supplementation (PES) of EPI pigs improved glucose clearance during IVGTT [AUC(glucose) 1295 ± 70 mmol l(-1) × (120 min) in EPI versus 1044 ± 32 mmol l(-1) × (120 min) in EPI + PES, P < 0.0001] without reinforcing the release of insulin [AUC(C-peptide) 14.4 ± 3.8 nmol l(-1) × (120 min) in EPI versus 6.4 ± 1.3 nmol l(-1) × (120 min) in EPI + PES, P < 0.002]. The results suggest the existence of an acino-insular axis regulatory communication. The presence of pancreatic enzymes in the gut facilitates glucose utilization in an insulin-independent manner, indicating the existence of a gut-derived pancreatic enzyme-dependent mechanism involved in peripheral glucose utilization. PMID:26663041

  6. Regulatory polymorphisms underlying complex disease traits.

    PubMed

    Knight, Julian C

    2005-02-01

    There is growing evidence that genetic variation plays an important role in the determination of individual susceptibility to complex disease traits. In contrast to coding sequence polymorphisms, where the consequences of non-synonymous variation may be resolved at the level of the protein phenotype, defining specific functional regulatory polymorphisms has proved problematic. This has arisen for a number of reasons, including difficulties with fine mapping due to linkage disequilibrium, together with a paucity of experimental tools to resolve the effects of non-coding sequence variation on gene expression. Recent studies have shown that variation in gene expression is heritable and can be mapped as a quantitative trait. Allele-specific effects on gene expression appear relatively common, typically of modest magnitude and context specific. The role of regulatory polymorphisms in determining susceptibility to a number of complex disease traits is discussed, including variation at the VNTR of INS, encoding insulin, in type 1 diabetes and polymorphism of CTLA4, encoding cytotoxic T lymphocyte antigen, in autoimmune disease. Examples where regulatory polymorphisms have been found to play a role in mongenic traits such as factor VII deficiency are discussed, and contrasted with those polymorphisms associated with ischaemic heart disease at the same gene locus. Molecular mechanisms operating in an allele-specific manner at the level of transcription are illustrated, with examples including the role of Duffy binding protein in malaria. The difficulty of resolving specific functional regulatory variants arising from linkage disequilibrium is demonstrated using a number of examples including polymorphism of CCR5, encoding CC chemokine receptor 5, and HIV-1 infection. The importance of understanding haplotypic structure to the design and interpretation of functional assays of putative regulatory variation is highlighted, together with discussion of the strategic use of

  7. Food Purchase Decision-Making Typologies of Women with Non-Insulin-Dependent Diabetes Mellitus.

    ERIC Educational Resources Information Center

    Miller, Carla; Warland, Rex; Achterberg, Cheryl

    1997-01-01

    Food selection is a key factor in the nutritional management of diabetes. Criteria that influence point-of-purchase decision making in women with non-insulin-dependent diabetes mellitus were identified. Four types of shoppers were distinguished from interviews; cluster analysis was used to confirm the analysis. Usefulness in patient education is…

  8. Use of a Small Peptide Fragment as an Inhibitor of Insulin Fibrillation Process: A Study by High and Low Resolution Spectroscopy

    PubMed Central

    Datta, Aritreyee; Parthasarathi, Krupakar; Chatterjee, Subhrangsu; Das, Kali P.; Bhunia, Anirban

    2013-01-01

    A non-toxic, nine residue peptide, NIVNVSLVK is shown to interfere with insulin fibrillation by various biophysical methods. Insulin undergoes conformational changes under certain stress conditions leading to amyloid fibrils. Fibrillation of insulin poses a problem in its long-term storage, reducing its efficacy in treating type II diabetes. The dissociation of insulin oligomer to monomer is the key step for the onset of fibrillation. The time course of insulin fibrillation at 62°C using Thioflavin T fluorescence shows an increase in the lag time from 120 min without peptide to 236 min with peptide. Transmission electron micrographs show branched insulin fibrils in its absence and less inter-fibril association in its presence. Upon incubation at 62°C and pH 2.6, insulin lost some α-helical structure as seen by Fourier transformed infra-red spectroscopy (FT-IR), but if the peptide is added, secondary structure is almost fully maintained for 3 h, though lost partially at 4 h. FT-IR spectroscopy also shows that insulin forms the cross beta structure indicative of fibrils beyond 2 h, but in the presence of the peptide, α-helix retention is seen till 4 h. Both size exclusion chromatography and dynamic light scattering show that insulin primarily exists as trimer, whose conversion to a monomer is resisted by the peptide. Saturation transfer difference nuclear magnetic resonance confirms that the hydrophobic residues in the peptide are in close contact with an insulin hydrophobic groove. Molecular dynamics simulations in conjunction with principal component analyses reveal how the peptide interrupts insulin fibrillation. In vitro hemolytic activity of the peptide showed insignificant cytotoxicity against HT1080 cells. The insulin aggregation is probed due to the inter play of two key residues, PheB24 and TyrB26 monitored from molecular dynamics simulations studies. Further new peptide based leads may be developed from this nine residue peptide. PMID:24009675

  9. Use of a small peptide fragment as an inhibitor of insulin fibrillation process: a study by high and low resolution spectroscopy.

    PubMed

    Banerjee, Victor; Kar, Rajiv K; Datta, Aritreyee; Parthasarathi, Krupakar; Chatterjee, Subhrangsu; Das, Kali P; Bhunia, Anirban

    2013-01-01

    A non-toxic, nine residue peptide, NIVNVSLVK is shown to interfere with insulin fibrillation by various biophysical methods. Insulin undergoes conformational changes under certain stress conditions leading to amyloid fibrils. Fibrillation of insulin poses a problem in its long-term storage, reducing its efficacy in treating type II diabetes. The dissociation of insulin oligomer to monomer is the key step for the onset of fibrillation. The time course of insulin fibrillation at 62°C using Thioflavin T fluorescence shows an increase in the lag time from 120 min without peptide to 236 min with peptide. Transmission electron micrographs show branched insulin fibrils in its absence and less inter-fibril association in its presence. Upon incubation at 62°C and pH 2.6, insulin lost some α-helical structure as seen by Fourier transformed infra-red spectroscopy (FT-IR), but if the peptide is added, secondary structure is almost fully maintained for 3 h, though lost partially at 4 h. FT-IR spectroscopy also shows that insulin forms the cross beta structure indicative of fibrils beyond 2 h, but in the presence of the peptide, α-helix retention is seen till 4 h. Both size exclusion chromatography and dynamic light scattering show that insulin primarily exists as trimer, whose conversion to a monomer is resisted by the peptide. Saturation transfer difference nuclear magnetic resonance confirms that the hydrophobic residues in the peptide are in close contact with an insulin hydrophobic groove. Molecular dynamics simulations in conjunction with principal component analyses reveal how the peptide interrupts insulin fibrillation. In vitro hemolytic activity of the peptide showed insignificant cytotoxicity against HT1080 cells. The insulin aggregation is probed due to the inter play of two key residues, Phe(B24) and Tyr(B26) monitored from molecular dynamics simulations studies. Further new peptide based leads may be developed from this nine residue peptide. PMID:24009675

  10. Celastrol Protects against Antimycin A-Induced Insulin Resistance in Human Skeletal Muscle Cells.

    PubMed

    Abu Bakar, Mohamad Hafizi; Cheng, Kian-Kai; Sarmidi, Mohamad Roji; Yaakob, Harisun; Huri, Hasniza Zaman

    2015-01-01

    Mitochondrial dysfunction and inflammation are widely accepted as key hallmarks of obesity-induced skeletal muscle insulin resistance. The aim of the present study was to evaluate the functional roles of an anti-inflammatory compound, celastrol, in mitochondrial dysfunction and insulin resistance induced by antimycin A (AMA) in human skeletal muscle cells. We found that celastrol treatment improved insulin-stimulated glucose uptake activity of AMA-treated cells, apparently via PI3K/Akt pathways, with significant enhancement of mitochondrial activities. Furthermore, celastrol prevent