Recent Publications of BIIC Members

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NCBI: db=pubmed; Term=Gray JP OR Heart E OR Zarrouki B OR Corkey BE OR Bonner-Weir S OR Urano F OR Cline GW OR Sharp GW OR Holz GG OR Weir GC OR Kulkarni RN OR Tornheim K OR Kibbey RG OR Fonseca SG OR Straub SG OR Jetton TL OR Poitout V OR Prentki M
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IRS1 deficiency protects β-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation.

Fri, 07/08/2016 - 00:41

IRS1 deficiency protects β-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation.

Sci Rep. 2016;6:28177

Authors: Takatani T, Shirakawa J, Roe MW, Leech CA, Maier BF, Mirmira RG, Kulkarni RN

Abstract
Endoplasmic reticulum (ER) stress is among several pathological features that underlie β-cell failure in the development of type 1 and type 2 diabetes. Adaptor proteins in the insulin/insulin-like-growth factor-1 signaling pathways, such as insulin receptor substrate-1 (IRS1) and IRS2, differentially impact β-cell survival but the underlying mechanisms remain unclear. Here we report that β-cells deficient in IRS1 (IRS1KO) are resistant, while IRS2 deficiency (IRS2KO) makes them susceptible to ER stress-mediated apoptosis. IRS1KOs exhibited low nuclear accumulation of spliced XBP-1 due to its poor stability, in contrast to elevated accumulation in IRS2KO. The reduced nuclear accumulation in IRS1KO was due to protein instability of Xbp1 secondary to proteasomal degradation. IRS1KO also demonstrated an attenuation in their general translation status in response to ER stress revealed by polyribosomal profiling. Phosphorylation of eEF2 was dramatically increased in IRS1KO enabling the β-cells to adapt to ER stress by blocking translation. Furthermore, significantly high ER calcium (Ca(2+)) was detected in IRS1KO β-cells even upon induction of ER stress. These observations suggest that IRS1 could be a therapeutic target for β-cell protection against ER stress-mediated cell death by modulating XBP-1 stability, protein synthesis, and Ca(2+) storage in the ER.

PMID: 27378176 [PubMed - as supplied by publisher]

Synthetic small molecule GLP-1 secretagogues prepared by means of a three-component indole annulation strategy.

Fri, 07/01/2016 - 22:46

Synthetic small molecule GLP-1 secretagogues prepared by means of a three-component indole annulation strategy.

Sci Rep. 2016;6:28934

Authors: Chepurny OG, Leech CA, Tomanik M, DiPoto MC, Li H, Han X, Meng Q, Cooney RN, Wu J, Holz GG

Abstract
Rational assembly of small molecule libraries for purposes of drug discovery requires an efficient approach in which the synthesis of bioactive compounds is enabled so that numerous structurally related compounds of a similar basic formulation can be derived. Here, we describe (4 + 3) and (3 + 2) indole annulation strategies that quickly generate complex indole heterocycle libraries that contain novel cyclohepta- and cyclopenta[b]indoles, respectively. Screening of one such library comprised of these indoles identifies JWU-A021 to be an especially potent stimulator of glucagon-like peptide-1 (GLP-1) secretion in vitro. Surprisingly, JWU-A021 is also a potent stimulator of Ca(2+) influx through TRPA1 cation channels (EC50 ca. 200 nM), thereby explaining its ability to stimulate GLP-1 release. Of additional importance, the available evidence indicates that JWU-A021 is one of the most potent non-electrophilic TRPA-1 channel agonists yet to be reported in the literature.

PMID: 27352904 [PubMed - in process]

Hypophosphatemia promotes lower rates of muscle ATP synthesis.

Sat, 06/25/2016 - 22:25
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Hypophosphatemia promotes lower rates of muscle ATP synthesis.

FASEB J. 2016 Jun 23;

Authors: Pesta DH, Tsirigotis DN, Befroy DE, Caballero D, Jurczak MJ, Rahimi Y, Cline GW, Dufour S, Birkenfeld AL, Rothman DL, Carpenter TO, Insogna K, Petersen KF, Bergwitz C, Shulman GI

Abstract
Hypophosphatemia can lead to muscle weakness and respiratory and heart failure, but the mechanism is unknown. To address this question, we noninvasively assessed rates of muscle ATP synthesis in hypophosphatemic mice by using in vivo saturation transfer [(31)P]-magnetic resonance spectroscopy. By using this approach, we found that basal and insulin-stimulated rates of muscle ATP synthetic flux (VATP) and plasma inorganic phosphate (Pi) were reduced by 50% in mice with diet-induced hypophosphatemia as well as in NaPi2a knockout mice (NaPi2a(-/-)) compared with their wild-type littermate controls. Rates of VATP normalized in both hypophosphatemic groups after restoring plasma Pi concentrations. Furthermore, VATP was directly related to cellular and mitochondrial Pi uptake in L6 and RC13 rodent myocytes and isolated muscle mitochondria. Similar findings were observed in a patient with chronic hypophosphatemia as a result of a mutation in SLC34A3 who had a 50% reduction in both serum Pi content and muscle VATP After oral Pi repletion and normalization of serum Pi levels, muscle VATP completely normalized in the patient. Taken together, these data support the hypothesis that decreased muscle ATP synthesis, in part, may be caused by low blood Pi concentrations, which may explain some aspects of muscle weakness observed in patients with hypophosphatemia.-Pesta, D. H., Tsirigotis, D. N., Befroy, D. E., Caballero, D., Jurczak, M. J., Rahimi, Y., Cline, G. W., Dufour, S., Birkenfeld, A. L., Rothman, D. L., Carpenter, T. O., Insogna, K., Petersen, K. F., Bergwitz, C., Shulman, G. I. Hypophosphatemia promotes lower rates of muscle ATP synthesis.

PMID: 27338702 [PubMed - as supplied by publisher]

Is Transforming Stem Cells to Pancreatic Beta Cells Still the Holy Grail for Type 2 Diabetes?

Sun, 06/19/2016 - 21:04

Is Transforming Stem Cells to Pancreatic Beta Cells Still the Holy Grail for Type 2 Diabetes?

Curr Diab Rep. 2016 Aug;16(8):70

Authors: Kahraman S, Okawa ER, Kulkarni RN

Abstract
Diabetes is a progressive disease affecting millions of people worldwide. There are several medications and treatment options to improve the life quality of people with diabetes. One of the strategies for the treatment of diabetes could be the use of human pluripotent stem cells or induced pluripotent stem cells. The recent advances in differentiation of stem cells into insulin-secreting beta-like cells in vitro make the transplantation of the stem cell-derived beta-like cells an attractive approach for treatment of type 1 and type 2 diabetes. While stem cell-derived beta-like cells provide an unlimited cell source for beta cell replacement therapies, these cells can also be used as a platform for drug screening or modeling diseases.

PMID: 27313072 [PubMed - in process]

Corrigendum: Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates.

Fri, 06/10/2016 - 18:29
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Corrigendum: Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates.

Nat Biotechnol. 2016 Jun 9;34(6):666

Authors: Vegas AJ, Veiseh O, Doloff JC, Ma M, Tam HH, Bratlie K, Li J, Bader AR, Langan E, Olejnik K, Fenton P, Kang JW, Hollister-Locke J, Bochenek MA, Chiu A, Siebert S, Tang K, Jhunjhunwala S, Aresta-Dasilva S, Dholakia N, Thakrar R, Vietti T, Chen M, Cohen J, Siniakowicz K, Qi M, McGarrigle J, Lyle S, Harlan DM, Greiner DL, Oberholzer J, Weir GC, Langer R, Anderson DG

PMID: 27281428 [PubMed - as supplied by publisher]

Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome.

Fri, 06/10/2016 - 18:29
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Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome.

Nature. 2016 Jun 9;534(7606):213-7

Authors: Perry RJ, Peng L, Barry NA, Cline GW, Zhang D, Cardone RL, Petersen KF, Kibbey RG, Goodman AL, Shulman GI

Abstract
Obesity, insulin resistance and the metabolic syndrome are associated with changes to the gut microbiota; however, the mechanism by which modifications to the gut microbiota might lead to these conditions is unknown. Here we show that increased production of acetate by an altered gut microbiota in rodents leads to activation of the parasympathetic nervous system, which, in turn, promotes increased glucose-stimulated insulin secretion, increased ghrelin secretion, hyperphagia, obesity and related sequelae. Together, these findings identify increased acetate production resulting from a nutrient-gut microbiota interaction and subsequent parasympathetic activation as possible therapeutic targets for obesity.

PMID: 27279214 [PubMed - in process]

Identification and determination of the inulin content in the roots of the Northeast Brazilian species Pombalia calceolaria L.

Tue, 06/07/2016 - 18:11
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Identification and determination of the inulin content in the roots of the Northeast Brazilian species Pombalia calceolaria L.

Carbohydr Polym. 2016 Sep 20;149:391-8

Authors: Pontes AG, Silva KL, Fonseca SG, Soares AA, Feitosa JP, Braz-Filho R, Romero NR, Bandeira MA

Abstract
A polysaccharide was extracted from the roots of Pombalia calceolaria, a plant used in folk medicine in Northeastern Brazil, by decoction followed by precipitation with methanol, yielding a concentration of 13.0% w/w, and purification with acetone. The molar mass peak was estimated to be 4.0×10(3)Da using gel permeation chromatography (GPC). Polarized light photomicrography of histological sections revealed the presence of inulin in the cortical parenchyma. The chemical composition of inulin was identified by 1D and 2D NMR and FT-IR spectroscopy and the findings were compared with the literature. This is the first time inulin has been identified on FT-IR and NMR for the species Pombalia calceolaria.

PMID: 27261763 [PubMed - in process]

Mechanisms of doxorubicin toxicity in pancreatic β-cells.

Sat, 06/04/2016 - 16:34
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Mechanisms of doxorubicin toxicity in pancreatic β-cells.

Toxicol Sci. 2016 Jun 2;

Authors: Heart E, Karandrea S, Liang X, Balke ME, Beringer PA, Bobczynski EM, Zayas-Bazán Burgos D, Richardson T, Gray JP

Abstract
Exposure to chemotherapeutic agents has been linked to an increased risk of type 2 diabetes (T2D), a disease characterized by both the peripheral insulin resistance and impaired glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. Using the rat β-cell line INS-1 832/13 and isolated mouse pancreatic islets, we investigated the effect of the chemotherapeutic drug doxorubicin (Adriamycin) on pancreatic β-cell survival and function. Exposure of INS-1 832/13 cells to doxorubicin caused impairment of GSIS, cellular viability, an increase in cellular toxicity, as soon as 6 h post-exposure. Doxorubicin impaired plasma membrane electron transport (PMET), a pathway dependent upon reduced equivalents NADH and NADPH, but failed to redox cycle in INS-1 832/13 cells and with their lysates. While NADPH/NADP(+) content was unaffected, NADH/NAD(+) content decreased at 4 h post-exposure to doxorubicin, and was followed by a reduction in ATP content. Previous studies have demonstrated that doxorubicin functions as a topoisomerase II inhibitor via induction of DNA cross-linking, resulting in apoptosis. Doxorubicin induced the expression of mRNA for mdm2, cyclin G1, and fas while downregulating p53, and increased the melting temperature of genomic DNA, consistent with DNA damage and induction of apoptosis. Doxorubicin also induced caspase-3 and -7 activity in INS-1 832/13 cells and mouse islets; co-treatment with the pan-caspase inhibitor Z-VAD-FMK temporarily attenuated the doxorubicin-mediated loss of viability in INS-1 832/13 cells. Together, these data suggest that DNA damage, not H2O2 produced via redox cycling, is a major mechanism of doxorubicin toxicity in pancreatic β-cells.

PMID: 27255381 [PubMed - as supplied by publisher]

Differential Roles of Insulin and IGF-1 Receptors in Adipose Tissue Development and Function.

Mon, 05/23/2016 - 15:58
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Differential Roles of Insulin and IGF-1 Receptors in Adipose Tissue Development and Function.

Diabetes. 2016 May 13;

Authors: Boucher J, Softic S, El Ouaamari A, Krumpoch MT, Kleinridders A, Kulkarni RN, O'Neill BT, Kahn CR

Abstract
To determine the roles of insulin and IGF-1 action in adipose tissue we created mice lacking either the insulin receptor (IR), IGF-1 receptor (IGF1R), or both using Cre-recombinase driven by the adiponectin promoter. Mice lacking IGF1R only (F-IGFRKO) had a ∼25% reduction in white and brown adipose tissue (WAT and BAT), whereas mice lacking both IR and IGF1R (F-IR/IGFRKO) showed an almost complete absence of WAT and BAT. Interestingly, mice lacking only the IR (F-IRKO) had a 95% reduction in WAT, but a paradoxical 50% increase in BAT with accumulation of large unilocular lipid droplets. Both F-IRKO and F-IR/IGFRKO mice were unable to maintain body temperature in the cold and developed severe diabetes, ectopic lipid accumulation in liver and muscle, and pancreatic islet hyperplasia. Leptin treatment normalized blood glucose levels in both groups. Glucose levels also improved spontaneously by 1 year of age, despite sustained lipodystrophy and insulin resistance. Thus, loss of IR is sufficient to disrupt white fat formation, but not brown fat formation and/or maintenance, although it is required for normal BAT function and temperature homeostasis. IGF1R has only a modest contribution to both WAT and BAT formation and function.

PMID: 27207537 [PubMed - as supplied by publisher]

Response to 'Energy balance measurement: when something is not better than nothing'.

Fri, 05/20/2016 - 15:53
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Response to 'Energy balance measurement: when something is not better than nothing'.

Int J Obes (Lond). 2015 Jul;39(7):1175-6

Authors: Dhurandhar NV, Schoeller DA, Brown AW, Heymsfield SB, Thomas D, Sørensen TI, Speakman JR, Jeansonne M, Allison DB, Energy Balance Measurement Working Group

PMID: 25924713 [PubMed - indexed for MEDLINE]

Energy balance measurement: when something is not better than nothing.

Fri, 05/20/2016 - 15:53
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Energy balance measurement: when something is not better than nothing.

Int J Obes (Lond). 2015 Jul;39(7):1109-13

Authors: Dhurandhar NV, Schoeller D, Brown AW, Heymsfield SB, Thomas D, Sørensen TI, Speakman JR, Jeansonne M, Allison DB, Energy Balance Measurement Working Group

Abstract
Energy intake (EI) and physical activity energy expenditure (PAEE) are key modifiable determinants of energy balance, traditionally assessed by self-report despite its repeated demonstration of considerable inaccuracies. We argue here that it is time to move from the common view that self-reports of EI and PAEE are imperfect, but nevertheless deserving of use, to a view commensurate with the evidence that self-reports of EI and PAEE are so poor that they are wholly unacceptable for scientific research on EI and PAEE. While new strategies for objectively determining energy balance are in their infancy, it is unacceptable to use decidedly inaccurate instruments, which may misguide health-care policies, future research and clinical judgment. The scientific and medical communities should discontinue reliance on self-reported EI and PAEE. Researchers and sponsors should develop objective measures of energy balance.

PMID: 25394308 [PubMed - indexed for MEDLINE]

ERRγ-A New Player in β Cell Maturation.

Tue, 05/17/2016 - 15:46
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ERRγ-A New Player in β Cell Maturation.

Cell Metab. 2016 May 10;23(5):765-7

Authors: Shirakawa J, Kulkarni RN

Abstract
Glucose and hormone responsiveness of pancreatic β cells is acquired during postnatal maturation and is critical for appropriate insulin secretion. In a recent issue of Cell Metabolism, Yoshihara et al. (2016) report that estrogen-related receptor γ (ERRγ) promotes functional maturation of both mouse neonatal β cells and human iPSC-derived β-like cells.

PMID: 27166940 [PubMed - in process]

Reduced intestinal lipid absorption and body weight-independent improvements in insulin sensitivity in high-fat diet-fed Park2 knockout mice.

Tue, 05/17/2016 - 15:46
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Reduced intestinal lipid absorption and body weight-independent improvements in insulin sensitivity in high-fat diet-fed Park2 knockout mice.

Am J Physiol Endocrinol Metab. 2016 May 10;:ajpendo.00042.2016

Authors: Costa DK, Huckestein BR, Edmunds LR, Petersen MC, Nasiri A, Butrico GM, Abulizi A, Harmon DB, Lu C, Mantell BS, Hartman DJ, Camporez JG, O'Doherty RM, Cline GW, Shulman GI, Jurczak MJ

Abstract
Mitochondrial dysfunction is associated with many human diseases and results from mismatch of damage and repair over the life of the organelle. Park2 is an ubiquitin E3 ligase that regulates mitophagy, a repair mechanism that selectively degrades damaged mitochondria. Deletion of Park2 in multiple in vivo models results in susceptibility to stress-induced mitochondrial and cellular dysfunction. Surprisingly, Park2 knockout (KO) mice are protected from nutritional stress and do not develop obesity, hepatic steatosis or insulin resistance when fed high-fat diet (HFD). However, these phenomena are casually related and the physiological basis for this phenotype is unknown. We therefore undertook a series of acute HFD studies to more completely understand the physiology of Park2 KO during nutritional stress. We find that intestinal lipid absorption is impaired in Park2 KO mice as evidenced by increased fecal lipids and reduced plasma triglycerides after intragastric fat challenge. Park2 KO mice developed hepatic steatosis in response to intravenous lipid infusion, as well as during incubation of primary hepatocytes with fatty acids, suggesting that hepatic protection from nutritional stress was secondary to changes in energy balance due to altered intestinal triglyceride absorption. Park2 KO mice showed reduced adiposity after one-week HFD, as well as improved hepatic and peripheral insulin sensitivity. These studies suggest that changes in intestinal lipid absorption may play a primary role in protection from nutritional stress in Park2 KO mice by preventing HFD-induced weight gain and highlight the need for tissue-specific models to address the role of Park2 during metabolic stress.

PMID: 27166280 [PubMed - as supplied by publisher]

Trimeprazine increases IRS2 in human islets and promotes pancreatic β cell growth and function in mice.

Sun, 05/08/2016 - 14:55

Trimeprazine increases IRS2 in human islets and promotes pancreatic β cell growth and function in mice.

JCI Insight. 2016;1(3)

Authors: Kuznetsova A, Yu Y, Hollister-Lock J, Opare-Addo L, Rozzo A, Sadagurski M, Norquay L, Reed JE, El Khattabi I, Bonner-Weir S, Weir GC, Sharma A, White MF

Abstract
The capacity of pancreatic β cells to maintain glucose homeostasis during chronic physiologic and immunologic stress is important for cellular and metabolic homeostasis. Insulin receptor substrate 2 (IRS2) is a regulated adapter protein that links the insulin and IGF1 receptors to downstream signaling cascades. Since strategies to maintain or increase IRS2 expression can promote β cell growth, function, and survival, we conducted a screen to find small molecules that can increase IRS2 mRNA in isolated human pancreatic islets. We identified 77 compounds, including 15 that contained a tricyclic core. To establish the efficacy of our approach, one of the tricyclic compounds, trimeprazine tartrate, was investigated in isolated human islets and in mouse models. Trimeprazine is a first-generation antihistamine that acts as a partial agonist against the histamine H1 receptor (H1R) and other GPCRs, some of which are expressed on human islets. Trimeprazine promoted CREB phosphorylation and increased the concentration of IRS2 in islets. IRS2 was required for trimeprazine to increase nuclear Pdx1, islet mass, β cell replication and function, and glucose tolerance in mice. Moreover, trimeprazine synergized with anti-CD3 Abs to reduce the progression of diabetes in NOD mice. Finally, it increased the function of human islet transplants in streptozotocin-induced (STZ-induced) diabetic mice. Thus, trimeprazine, its analogs, or possibly other compounds that increase IRS2 in islets and β cells without adverse systemic effects might provide mechanism-based strategies to prevent the progression of diabetes.

PMID: 27152363 [PubMed - as supplied by publisher]

CMPF: A Biomarker for Type 2 Diabetes Mellitus Progression?

Mon, 05/02/2016 - 14:18
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CMPF: A Biomarker for Type 2 Diabetes Mellitus Progression?

Trends Endocrinol Metab. 2016 Apr 27;

Authors: Koppe L, Poitout V

Abstract
The factors that precipitate the transition from insulin resistance to type 2 diabetes mellitus (T2DM) remain elusive. A recent study showed that circulating levels of the furan fatty acid (FA) metabolite 3-Carboxy-4-Methyl-5-Propyl-2-Furanopropanoic Acid (CMPF) increase in individuals who progress from prediabetes to T2DM. CMPF increases oxidative stress and impairs insulin granule maturation and secretion.

PMID: 27132217 [PubMed - as supplied by publisher]

GPR119 agonist AS1269574 activates TRPA1 cation channels to stimulate GLP-1 secretion.

Sun, 04/17/2016 - 06:01
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GPR119 agonist AS1269574 activates TRPA1 cation channels to stimulate GLP-1 secretion.

Mol Endocrinol. 2016 Apr 15;:me20151306

Authors: Chepurny OG, Holz GG, Roe MW, Leech CA

Abstract
GPR119 is a G protein-coupled receptor expressed on intestinal L-cells that synthesize and secrete the blood glucose-lowering hormone glucagon-like peptide-1 (GLP-1). GPR119 agonists stimulate the release of GLP-1 from L-cells, and for this reason there is interest in their potential use as a new treatment for type 2 diabetes mellitus (T2DM). AS1269574 is one such GPR119 agonist, and it is the prototype of a series of 2,4,6 tri-substituted pyrimidines that exert positive glucoregulatory actions in mice. Here, we report the unexpected finding that AS1269574 stimulates GLP-1 release from the STC-1 intestinal cell line by directly promoting Ca(2+) influx through TRPA1 cation channels. These GPR119-independent actions of AS1269574 are inhibited by TRPA1 channel blockers (AP-18, A967079, HC030031), and are not secondary to intracellular Ca(2+) release or cAMP production. Patch clamp studies reveal that AS1269574 activates an outwardly rectifying membrane current with properties expected of TRPA1 channels. However, the TRPA1 channel-mediated action of AS1269574 to increase [Ca(2+)]i is not replicated by GPR119 agonists (AR231453, OEA) unrelated in structure to AS1269574. Using HEK-293 cells expressing recombinant rat TRPA1 channels but not GPR119, direct TRPA1 channel activating properties of AS1269574 are validated. Since we find that AS1269574 also acts in a conventional GPR119-mediated manner to stimulate proglucagon gene promoter activity in the GLUTag intestinal L-cell line, new findings reported here reveal the surprising capacity of AS1269574 to act as a "dual agonist" at two molecular targets (GPR119 / TRPA1) important to the control of L-cell function and T2DM drug discovery research.

PMID: 27082897 [PubMed - as supplied by publisher]

Executive Summary of IPITA-TTS Opinion Leaders Report on the Future of β-Cell Replacement.

Sun, 04/17/2016 - 06:01
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Executive Summary of IPITA-TTS Opinion Leaders Report on the Future of β-Cell Replacement.

Transplantation. 2016 Apr 14;

Authors: Markmann JF, Bartlett ST, Johnson P, Korsgren O, Hering BJ, Scharp D, Kay TW, Bromberg J, Odorico JS, Weir GC, Bridges N, Kandaswamy R, Stock P, Friend P, Gotoh M, Cooper DK, Park CG, OʼConnell PJ, Stabler C, Matsumoto S, Ludwig B, Choudhary P, Khovatchev B, Rickels MR, Sykes M, Wood K, Kraemer K, Hwa A, Stanley E, Ricordi C, Zimmerman M, Greenstein J, Montanya E, Otonkoski T

Abstract
The International Pancreas and Islet Transplant Association (IPITA), in conjunction with the Transplantation Society (TTS), convened a workshop to consider the future of pancreas and islet transplantation in the context of potential competing technologies that are under development, including the artificial pancreas, transplantation tolerance, xenotransplantation, encapsulation, stem cell derived beta cells, beta cell proliferation, and endogenous regeneration. Separate workgroups for each topic and then the collective group reviewed the state of the art, hurdles to application, and proposed research agenda for each therapy that would allow widespread application. Herein we present the executive summary of this workshop that focuses on obstacles to application and the research agenda to overcome them; the full length article with detailed background for each topic is published as an online supplement to Transplantation.

PMID: 27082827 [PubMed - as supplied by publisher]

Proinflammatory Cytokines Induce Endocrine Differentiation in Pancreatic Ductal Cells via STAT3-Dependent NGN3 Activation.

Sun, 04/17/2016 - 06:01
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Proinflammatory Cytokines Induce Endocrine Differentiation in Pancreatic Ductal Cells via STAT3-Dependent NGN3 Activation.

Cell Rep. 2016 Apr 6;

Authors: Valdez IA, Dirice E, Gupta MK, Shirakawa J, Teo AK, Kulkarni RN

Abstract
A major goal of diabetes research is to develop strategies that replenish pancreatic insulin-producing beta cells. One emerging strategy is to harness pancreatic plasticity-the ability of pancreatic cells to undergo cellular interconversions-a phenomenon implicated in physiological stress and pancreatic injury. Here, we investigate the effects of inflammatory cytokine stress on the differentiation potential of ductal cells in a human cell line, in mouse ductal cells by pancreatic intraductal injection, and during the progression of autoimmune diabetes in the non-obese diabetic (NOD) mouse model. We find that inflammatory cytokine insults stimulate epithelial-to-mesenchymal transition (EMT) as well as the endocrine program in human pancreatic ductal cells via STAT3-dependent NGN3 activation. Furthermore, we show that inflammatory cytokines activate ductal-to-endocrine cell reprogramming in vivo independent of hyperglycemic stress. Together, our findings provide evidence that inflammatory cytokines direct ductal-to-endocrine cell differentiation, with implications for beta cell regeneration.

PMID: 27068459 [PubMed - as supplied by publisher]

Corrigendum: Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice.

Fri, 04/08/2016 - 03:28

Corrigendum: Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice.

Nat Med. 2016 Apr 6;22(4):446

Authors: Vegas AJ, Veiseh O, G M, Millman JR, Pagliuca FW, Bader AR, Doloff JC, Li J, Chen M, Olejnik K, Tam HH, Jhunjhunwala S, Langan E, Aresta-Dasilva S, Gandham S, McGarrigle JJ, Bochenek MA, Hollister-Lock J, Oberholzer J, Greiner DL, Weir GC, Melton DA, Langer R, Anderson DG

PMID: 27050590 [PubMed - in process]

Solution Structure and Constrained Molecular Dynamics Study of Vitamin B12 Conjugates of the Anorectic Peptide PYY(3-36).

Sat, 04/02/2016 - 02:01
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Solution Structure and Constrained Molecular Dynamics Study of Vitamin B12 Conjugates of the Anorectic Peptide PYY(3-36).

ChemMedChem. 2016 Mar 30;

Authors: Henry KE, Kerwood DJ, Allis DG, Workinger JL, Bonaccorso RL, Holz GG, Roth CL, Zubieta J, Doyle RP

Abstract
Vitamin B12 -peptide conjugates have considerable therapeutic potential through improved pharmacokinetic and/or pharmacodynamic properties imparted on the peptide upon covalent attachment to vitamin B12 (B12 ). There remains a lack of structural studies investigating the effects of B12 conjugation on peptide secondary structure. Determining the solution structure of a B12 -peptide conjugate or conjugates and measuring functions of the conjugate(s) at the target peptide receptor may offer considerable insight concerning the future design of fully optimized conjugates. This methodology is especially useful in tandem with constrained molecular dynamics (MD) studies, such that predictions may be made about conjugates not yet synthesized. Focusing on two B12 conjugates of the anorectic peptide PYY(3-36), one of which was previously demonstrated to have improved food intake reduction compared with PYY(3-36), we performed NMR structural analyses and used the information to conduct MD simulations. The study provides rare structural insight into vitamin B12 conjugates and validates the fact that B12 can be conjugated to a peptide without markedly affecting peptide secondary structure.

PMID: 27027248 [PubMed - as supplied by publisher]

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