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
Updated: 5 hours 42 min ago

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

Thu, 01/28/2016 - 16:38
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Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates.

Nat Biotechnol. 2016 Jan 25;

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

Abstract
The foreign body response is an immune-mediated reaction that can lead to the failure of implanted medical devices and discomfort for the recipient. There is a critical need for biomaterials that overcome this key challenge in the development of medical devices. Here we use a combinatorial approach for covalent chemical modification to generate a large library of variants of one of the most widely used hydrogel biomaterials, alginate. We evaluated the materials in vivo and identified three triazole-containing analogs that substantially reduce foreign body reactions in both rodents and, for at least 6 months, in non-human primates. The distribution of the triazole modification creates a unique hydrogel surface that inhibits recognition by macrophages and fibrous deposition. In addition to the utility of the compounds reported here, our approach may enable the discovery of other materials that mitigate the foreign body response.

PMID: 26807527 [PubMed - as supplied by publisher]

The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the β-Cell-Centric Classification Schema.

Mon, 01/25/2016 - 13:26
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The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the β-Cell-Centric Classification Schema.

Diabetes Care. 2016 Feb;39(2):179-86

Authors: Schwartz SS, Epstein S, Corkey BE, Grant SF, Gavin JR, Aguilar RB

Abstract
The current classification system presents challenges to the diagnosis and treatment of patients with diabetes mellitus (DM), in part due to its conflicting and confounding definitions of type 1 DM, type 2 DM, and latent autoimmune diabetes of adults (LADA). The current schema also lacks a foundation that readily incorporates advances in our understanding of the disease and its treatment. For appropriate and coherent therapy, we propose an alternate classification system. The β-cell-centric classification of DM is a new approach that obviates the inherent and unintended confusions of the current system. The β-cell-centric model presupposes that all DM originates from a final common denominator-the abnormal pancreatic β-cell. It recognizes that interactions between genetically predisposed β-cells with a number of factors, including insulin resistance (IR), susceptibility to environmental influences, and immune dysregulation/inflammation, lead to the range of hyperglycemic phenotypes within the spectrum of DM. Individually or in concert, and often self-perpetuating, these factors contribute to β-cell stress, dysfunction, or loss through at least 11 distinct pathways. Available, yet underutilized, treatments provide rational choices for personalized therapies that target the individual mediating pathways of hyperglycemia at work in any given patient, without the risk of drug-related hypoglycemia or weight gain or imposing further burden on the β-cells. This article issues an urgent call for the review of the current DM classification system toward the consensus on a new, more useful system.

PMID: 26798148 [PubMed - in process]

Transcriptional Regulation of X-Box-Binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4α (HNF4α) is Vital to Beta-Cell Function.

Mon, 01/25/2016 - 13:26
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Transcriptional Regulation of X-Box-Binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4α (HNF4α) is Vital to Beta-Cell Function.

J Biol Chem. 2016 Jan 20;

Authors: Moore BD, Jin RU, Lo H, Jung M, Wang H, Battle MA, Wollheim CB, Urano F, Mills JC

Abstract
The transcription factor, X-box Binding Protein-One (XBP1), controls the development and maintenance of the endoplasmic reticulum (ER) in multiple secretory cell lineages. We show here that Hepatocyte Nuclear Factor 4-alpha (HNF4α) directly induces XBP1 expression. Mutations in HNF4α cause Mature-Onset Diabetes of the Young I (MODYI), a subset of diabetes characterized by diminished GSIS. In mouse models, cell lines, and ex vivo islets, using dominant negative and human-disease-allele point mutants or knockout and knockdown models, we show that disruption of HNF4α caused decreased expression of XBP1 and reduced cellular ER networks. GSIS depends on ER Ca2+ signaling; we show that diminished XBP1 and/or HNF4α in β-cells led to impaired ER Ca2+ homeostasis. Restoring XBP1 expression was sufficient to completely rescue GSIS in HNF4α-deficient β-cells. Our findings uncover a transcriptional relationship between HNF4α and Xbp1 with potentially broader implications about MODYI and the importance of transcription factor signaling in the regulation of secretion.

PMID: 26792861 [PubMed - as supplied by publisher]

Thymoquinone, a bioactive component of Nigella sativa, normalizes insulin secretion from pancreatic β-cells under glucose overload via regulation of malonyl-CoA.

Fri, 01/22/2016 - 11:42
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Thymoquinone, a bioactive component of Nigella sativa, normalizes insulin secretion from pancreatic β-cells under glucose overload via regulation of malonyl-CoA.

Am J Physiol Endocrinol Metab. 2016 Jan 19;:ajpendo.00250.2015

Authors: Gray JP, Zayasbazan Burgos D, Yuan T, Seeram N, Rebar R, Follmer R, Heart EA

Abstract
Thymoquinone (2-Isopropyl-5-methylbenzo-1,4-quinone) is a major bioactive component of Nigella sativa, a plant used in traditional medicine to treat variety of symptoms, including elevated blood glucose levels in type 2 diabetic patients. Normalization of elevated blood glucose depends on both glucose disposal by peripheral tissues, and glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. We employed clonal β-cells and rodent islets to investigate the effects of Thymoquinone (TQ) and Nigella sativa extracts (NSEs) on GSIS and cataplerotic metabolic pathways implicated in the GSIS regulation. TQ and NSE regulated NAD(P)H/NAD(P)(+) ratios via a redox cycling mechanism. TQ content was positively correlated with the degree of redox cycling activity of NSE extracts, suggesting that TQ is a major component engaged in mediating NSE-dependent redox cycling. Both acute and chronic exposure to TQ and NSE enhanced GSIS and were associated with the ability of TQ and NSE to increase the ATP/ADP ratio. Furthermore, TQ ameliorated the impairment of GSIS following chronic exposure of β-cells to glucose overload (GO). This protective action was associated with the TQ-dependent normalization of chronic accumulation of malonyl CoA, and elevation of acetyl CoA carboxylase (ACC), fatty acid synthase (FAS) and fatty acid binding proteins (FABPs) following chronic glucose overload. Together these data suggest that TQ modulates the β-cell redox circuitry, and enhances the sensitivity of β-cell metabolic pathways to glucose and GSIS under both normal conditions and hyperglycemia. This action is associated with the ability of TQ to regulate carbohydrate-to-lipid flux via downregulation of acetyl-CoA carboxylase (ACC) and malonyl-CoA.

PMID: 26786775 [PubMed - as supplied by publisher]

Harnessing immune cells to enhance β-cell mass in type 1 diabetes.

Wed, 01/13/2016 - 07:38

Harnessing immune cells to enhance β-cell mass in type 1 diabetes.

J Investig Med. 2016 Jan;64(1):14-20

Authors: Dirice E, Kulkarni RN

Abstract
Type 1 diabetes is characterized by early β-cell loss leading to insulin dependence in virtually all patients with the disease in order to maintain glucose homeostasis. Most studies over the past few decades have focused on limiting the autoimmune attack on the β cells. However, emerging data from patients with long-standing diabetes who continue to harbor functional insulin-producing cells in their diseased pancreas have prompted scientists to examine whether proliferation of existing β cells can be enhanced to promote better glycemic control. In support of this concept, several studies indicate that mononuclear cells that infiltrate the islets have the capacity to trigger proliferation of islet cells including β cells. These observations indicate the exciting possibility of identifying those mononuclear cell types and their soluble factors and harnessing their ability to promote β-cell growth concomitant with autoimmune therapy to prevent the onset and/or halt the progression of the disease.

PMID: 26755809 [PubMed - in process]

Identification of a mammalian glycerol-3-phosphate phosphatase: Role in metabolism and signaling in pancreatic β-cells and hepatocytes.

Wed, 01/13/2016 - 07:38

Identification of a mammalian glycerol-3-phosphate phosphatase: Role in metabolism and signaling in pancreatic β-cells and hepatocytes.

Proc Natl Acad Sci U S A. 2016 Jan 11;

Authors: Mugabo Y, Zhao S, Seifried A, Gezzar S, Al-Mass A, Zhang D, Lamontagne J, Attane C, Poursharifi P, Iglesias J, Joly E, Peyot ML, Gohla A, Madiraju SR, Prentki M

Abstract
Obesity, and the associated disturbed glycerolipid/fatty acid (GL/FA) cycle, contribute to insulin resistance, islet β-cell failure, and type 2 diabetes. Flux through the GL/FA cycle is regulated by the availability of glycerol-3-phosphate (Gro3P) and fatty acyl-CoA. We describe here a mammalian Gro3P phosphatase (G3PP), which was not known to exist in mammalian cells, that can directly hydrolyze Gro3P to glycerol. We identified that mammalian phosphoglycolate phosphatase, with an uncertain function, acts in fact as a G3PP. We found that G3PP, by controlling Gro3P levels, regulates glycolysis and glucose oxidation, cellular redox and ATP production, gluconeogenesis, glycerolipid synthesis, and fatty acid oxidation in pancreatic islet β-cells and hepatocytes, and that glucose stimulated insulin secretion and the response to metabolic stress, e.g., glucolipotoxicity, in β-cells. In vivo overexpression of G3PP in rat liver lowers body weight gain and hepatic glucose production from glycerol and elevates plasma HDL levels. G3PP is expressed at various levels in different tissues, and its expression varies according to the nutritional state in some tissues. As Gro3P lies at the crossroads of glucose, lipid, and energy metabolism, control of its availability by G3PP adds a key level of metabolic regulation in mammalian cells, and G3PP offers a potential target for type 2 diabetes and cardiometabolic disorders.

PMID: 26755581 [PubMed - as supplied by publisher]

Wolfram Syndrome: Diagnosis, Management, and Treatment.

Sun, 01/10/2016 - 03:00
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Wolfram Syndrome: Diagnosis, Management, and Treatment.

Curr Diab Rep. 2016 Jan;16(1):6

Authors: Urano F

Abstract
Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, diabetes insipidus, optic nerve atrophy, hearing loss, and neurodegeneration. Although there are currently no effective treatments that can delay or reverse the progression of Wolfram syndrome, the use of careful clinical monitoring and supportive care can help relieve the suffering of patients and improve their quality of life. The prognosis of this syndrome is currently poor, and many patients die prematurely with severe neurological disabilities, raising the urgency for developing novel treatments for Wolfram syndrome. In this article, we describe natural history and etiology, provide recommendations for diagnosis and clinical management, and introduce new treatments for Wolfram syndrome.

PMID: 26742931 [PubMed - in process]

Modeling analysis of inositol 1,4,5-trisphosphate receptor-mediated Ca2+ mobilization under the control of glucagon-like peptide-1 in mouse pancreatic β-cells.

Sun, 01/10/2016 - 03:00
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Modeling analysis of inositol 1,4,5-trisphosphate receptor-mediated Ca2+ mobilization under the control of glucagon-like peptide-1 in mouse pancreatic β-cells.

Am J Physiol Cell Physiol. 2015 Nov 25;:ajpcell.00234.2015

Authors: Takeda Y, Shimayoshi T, Holz GG, Noma A

Abstract
GLP-1 is an intestinally derived blood glucose-lowering hormone that potentiates glucose-stimulated insulin secretion from pancreatic β-cells. This secretagogue action of GLP-1 is explained, at least in part, by its ability to stimulate cAMP production so that cAMP may facilitate the release of Ca(2+) from IP3 receptor (IP3R)-regulated Ca(2+) stores. However, a quantitative model has yet to be provided that explains the molecular mechanisms and dynamic processes linking GLP-1-stimulated cAMP production to Ca(2+) mobilization. Here, we performed simulation studies to investigate how GLP-1 alters the abilities of Ca(2+) and IP3 to act as co-agonists at IP3R Ca(2+) release channels. A new dynamic model was constructed based on the Kaftan model, which demonstrates dual steady state allosteric regulation of the IP3R by Ca(2+) and IP3. Data obtained from β-cells were then analyzed to understand how GLP-1 facilitates IP3R-mediated Ca(2+) mobilization when UV flash photolysis is used to uncage Ca(2+) and IP3 intracellularly. When the dynamic model for IP3R activation was incorporated into a minimal cell model, the Ca(2+) transients and oscillations induced by GLP-1 were successfully reconstructed. Simulation studies indicated that transient and oscillatory responses to GLP-1 were produced by sequential positive and negative feedback regulation due to fast activation and slow inhibition of the IP3R by Ca(2+). The slow rate of Ca(2+)-dependent inhibition was revealed to provide a remarkable contribution to the time course of the decay of cytosolic Ca(2+) transients. It also served to drive and pace Ca(2+) oscillations that are significant when evaluating how GLP-1 stimulates insulin secretion.

PMID: 26741144 [PubMed - as supplied by publisher]

Simultaneous determination of α-, β- and γ-hexabromocyclododecane diastereoisomers in water samples by isotope dilution mass spectrometry using (81)Br-labeled analogs.

Sun, 01/10/2016 - 03:00
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Simultaneous determination of α-, β- and γ-hexabromocyclododecane diastereoisomers in water samples by isotope dilution mass spectrometry using (81)Br-labeled analogs.

J Chromatogr A. 2015 Dec 17;

Authors: Somoano-Blanco L, Rodriguez-Gonzalez P, Centineo G, Fonseca SG, Garcia Alonso JI

Abstract
This work describes the synthesis, characterization and application of three (81)Br-labeled diastereosiomers of hexabromocyclododecane (HBCD) for the accurate and precise determination of α-, β- and γ-HBCD in water samples by isotope dilution mass spectrometry. The synthesis of the labeled analogs was carried out by bromination of cis, trans, trans-1,5,9-cyclododecatriene with (81)Br-enriched bromine. After isolation and purification by semipreparative HPLC, each diastereoisomer was characterized in terms of concentration and isotopic enrichment. Then, they were added to the samples to simultaneously quantify the three HBCD diastereoisomers in a single LC-MS/MS injection without resorting to a methodological calibration graph. The results obtained here demonstrate that the use of (81)Br-labeled analogs provides accurate and precise determinations of α-, β- and γ-HBCD in real water samples. The limits of quantification obtained in real samples for α-, β- and γ-HBCD were 0.022, 0.073 and 0.015ngL(-1), respectively, significantly lower than those required by the European Directive 2013/39/EC.

PMID: 26739916 [PubMed - as supplied by publisher]

Islet-cell biology in 2015: Understanding secretion, ageing and death in β cells.

Thu, 01/07/2016 - 01:19
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Islet-cell biology in 2015: Understanding secretion, ageing and death in β cells.

Nat Rev Endocrinol. 2016 Jan 4;

Authors: Weir GC

PMID: 26729035 [PubMed - as supplied by publisher]

The y6 receptor suppresses bone resorption and stimulates bone formation in mice via a suprachiasmatic nucleus relay.

Mon, 01/04/2016 - 00:09
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The y6 receptor suppresses bone resorption and stimulates bone formation in mice via a suprachiasmatic nucleus relay.

Bone. 2015 Dec 22;

Authors: Khor EC, Yulyaningsih E, Driessler F, Kovaĉić N, Wee NK, Kulkarni RN, Lee NJ, Enriquez RF, Xu J, Zhang L, Herzog H, Baldock PA

Abstract
The neuropeptide Y system is known to play an important role in the regulation of bone homeostasis and while the functions of its major receptors, Y1R and Y2R, in this process have become clearer, the contributions of other Y-receptors, like the y6 receptor (y6R), are unknown. Y6R expression is restricted to the suprachiasmatic nucleus (SCN) of the hypothalamus, an area known to regulate circadian rhythms, and the testis. Here we show that lack of y6R signalling, results in significant reduction in bone mass, but no changes in bone length. Male and female y6R knockout (KO) mice display reduced cortical and cancellous bone volume in axial and appendicular bones. Mechanistically, the reduction in cancellous bone is the result of an uncoupling of bone remodelling, leading to an increase in osteoclast surface and number, and a reduction in osteoblast number, osteoid surface, mineralizing surface and bone formation rate. y6R KO mice displayed increased numbers of osteoclast precursors and produced greater numbers of osteoclasts in RANKL-treated cultures. They also produced fewer CFU-ALP osteoblast precursors in the marrow and showed reduced mineralization in primary osteoblastic cultures, as well as reduced expression for the osteoblast lineage marker, alkaline phosphatase, in bone isolates. The almost exclusive location of y6Rs in the hypothalamus suggests a critical role of central neuronal pathways controlling this uncoupling of bone remodelling which is in line with known actions or other Y-receptors in the brain. In conclusion, y6R signalling is required for maintenance of bone mass, with loss of y6R uncoupling bone remodelling and resulting in a negative bone balance. This study expands the scope of hypothalamic regulation of bone, highlighting the importance for neural/endocrine coordination and their marked effect upon skeletal homeostasis.

PMID: 26721736 [PubMed - as supplied by publisher]

The ATF6 pathway of the ER stress response contributes to enhanced viability in glioblastoma.

Thu, 12/31/2015 - 20:42

The ATF6 pathway of the ER stress response contributes to enhanced viability in glioblastoma.

Oncotarget. 2015 Dec 21;

Authors: Dadey DY, Kapoor V, Khudanyan A, Urano F, Kim AH, Thotala D, Hallahan DE

Abstract
Therapeutic resistance is a major barrier to improvement of outcomes for patients with glioblastoma. The endoplasmic reticulum stress response (ERSR) has been identified as a contributor to chemoresistance in glioblastoma; however the contributions of the ERSR to radioresistance have not been characterized. In this study we found that radiation can induce ER stress and downstream signaling associated with the ERSR. Induction of ER stress appears to be linked to changes in ROS balance secondary to irradiation. Furthermore, we observed global induction of genes downstream of the ERSR in irradiated glioblastoma. Knockdown of ATF6, a regulator of the ERSR, was sufficient to enhance radiation induced cell death. Also, we found that activation of ATF6 contributes to the radiation-induced upregulation of glucose regulated protein 78 (GRP78) and NOTCH1. Our results reveal ATF6 as a potential therapeutic target to enhance the efficacy of radiation therapy.

PMID: 26716508 [PubMed - as supplied by publisher]

SerpinB1 Promotes Pancreatic β Cell Proliferation.

Fri, 12/25/2015 - 16:48

SerpinB1 Promotes Pancreatic β Cell Proliferation.

Cell Metab. 2015 Dec 14;

Authors: El Ouaamari A, Dirice E, Gedeon N, Hu J, Zhou JY, Shirakawa J, Hou L, Goodman J, Karampelias C, Qiang G, Boucher J, Martinez R, Gritsenko MA, De Jesus DF, Kahraman S, Bhatt S, Smith RD, Beer HD, Jungtrakoon P, Gong Y, Goldfine AB, Liew CW, Doria A, Andersson O, Qian WJ, Remold-O'Donnell E, Kulkarni RN

Abstract
Although compensatory islet hyperplasia in response to insulin resistance is a recognized feature in diabetes, the factor(s) that promote β cell proliferation have been elusive. We previously reported that the liver is a source for such factors in the liver insulin receptor knockout (LIRKO) mouse, an insulin resistance model that manifests islet hyperplasia. Using proteomics we show that serpinB1, a protease inhibitor, which is abundant in the hepatocyte secretome and sera derived from LIRKO mice, is the liver-derived secretory protein that regulates β cell proliferation in humans, mice, and zebrafish. Small-molecule compounds, that partially mimic serpinB1 effects of inhibiting elastase activity, enhanced proliferation of β cells, and mice lacking serpinB1 exhibit attenuated β cell compensation in response to insulin resistance. Finally, SerpinB1 treatment of islets modulated proteins in growth/survival pathways. Together, these data implicate serpinB1 as an endogenous protein that can potentially be harnessed to enhance functional β cell mass in patients with diabetes.

PMID: 26701651 [PubMed - as supplied by publisher]

Hyperglycaemia attenuates in vivo reprogramming of pancreatic exocrine cells to beta cells in mice.

Fri, 12/25/2015 - 16:48

Hyperglycaemia attenuates in vivo reprogramming of pancreatic exocrine cells to beta cells in mice.

Diabetologia. 2015 Dec 23;

Authors: Cavelti-Weder C, Li W, Zumsteg A, Stemann-Andersen M, Zhang Y, Yamada T, Wang M, Lu J, Jermendy A, Bee YM, Bonner-Weir S, Weir GC, Zhou Q

Abstract
AIMS/HYPOTHESIS: Reprogramming of pancreatic exocrine to insulin-producing cells by viral delivery of the genes encoding transcription factors neurogenin-3 (Ngn3), pancreas/duodenum homeobox protein 1 (Pdx1) and MafA is an efficient method for reversing diabetes in murine models. The variables that modulate reprogramming success are currently ill-defined.
METHODS: Here, we assess the impact of glycaemia on in vivo reprogramming in a mouse model of streptozotocin-induced beta cell ablation, using subsequent islet transplantation or insulin pellet implantation for creation of groups with differing levels of glycaemia before viral delivery of transcription factors.
RESULTS: We observed that hyperglycaemia significantly impaired reprogramming of exocrine to insulin-producing cells in their quantity, differentiation status and function. With hyperglycaemia, the reprogramming of acinar towards beta cells was less complete. Moreover, inflammatory tissue changes within the exocrine pancreas including macrophage accumulation were found, which may represent the tissue's response to clear the pancreas from insufficiently reprogrammed cells.
CONCLUSIONS/INTERPRETATION: Our findings shed light on normoglycaemia as a prerequisite for optimal reprogramming success in a diabetes model, which might be important in other tissue engineering approaches and disease models, potentially facilitating their translational applications.

PMID: 26693711 [PubMed - as supplied by publisher]

Dual reporter-β-cell specific male transgenic rats for the analysis of β-cell functional mass and enrichment by flow cytometry.

Sat, 12/19/2015 - 14:02
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Dual reporter-β-cell specific male transgenic rats for the analysis of β-cell functional mass and enrichment by flow cytometry.

Endocrinology. 2015 Dec 15;:en20151550

Authors: Ghislain J, Fontés G, Tremblay C, Kebede MA, Poitout V

Abstract
Mouse β-cell specific reporter lines have played a key role in diabetes research. Although the rat provides several advantages, its use has lagged behind the mouse due to the relative paucity of genetic models. In this report we describe the generation and characterization of transgenic rats expressing a Renilla luciferase (RLuc)-enhanced yellow fluorescent protein (YFP) fusion under control of a 9 kb genomic fragment from the rat ins2 gene (RIP7-RLuc-YFP). Analysis of RLuc luminescence and YFP fluorescence revealed that reporter expression is restricted to β cells in the adult rat. Physiological characteristics including body weight, fat and lean mass, fasting and fed glucose levels, glucose and insulin tolerance and β-cell mass were similar between two RIP7-RLuc-YFP lines and wild-type (WT) littermates. Glucose-induced insulin secretion in isolated islets was indistinguishable from controls in one of the lines, whereas surprisingly, insulin secretion was defective in the second line. Consequently, subsequent studies were limited to the former line. We asked whether transgene activity was responsive to glucose as shown previously for the ins2 gene. Exposing islets ex vivo to high glucose (16.7 mM) or in vivo infusion of glucose for 24 h increased luciferase activity in islets whereas the fraction of YFP-positive β-cells following glucose infusion was unchanged. Finally, we showed that fluorescence-activated cell sorting of YFP-positive islet cells can be used to enrich for β cells. Overall this transgenic line will enable for the first time the application of both fluorescence and bioluminescence/luminescence-based approaches for the study of rat β cells.

PMID: 26671180 [PubMed - as supplied by publisher]

Beta cell glucose sensitivity is linked to insulin/glucagon bihormonal cells in non-diabetic humans.

Thu, 12/10/2015 - 12:17

Beta cell glucose sensitivity is linked to insulin/glucagon bihormonal cells in non-diabetic humans.

J Clin Endocrinol Metab. 2015 Dec 9;:jc20152802

Authors: Mezza T, Sorice GP, Conte C, Sun VA, Cefalo CM, Moffa S, Pontecorvi A, Mari A, Kulkarni RN, Giaccari A

Abstract
CONTEXT: Insulin resistance impacts virtually all tissues, including pancreatic β cells. Individuals with insulin resistance, but without diabetes, exhibit an increased islet size due to an elevated number of both β and α cells. Neogenesis from duct cells and trans-differentiation of α cells have been postulated to contribute to the β-cell compensatory response to insulin resistance.
OBJECTIVE: To explore parameters that could potentially predict altered islet morphology.
METHODS: We investigated 16 non-diabetic subjects by a 2-h hyperglycemic clamp to evaluate β-cell secretory function. We analyzed pancreas samples obtained during pancreatoduodenectomy in the same patients to examine glucagon, insulin double+ cells to assess islet morphology.
RESULTS: Among all the functional in vivo parameters of insulin secretion that were explored (basal, first phase and total secretion, glucose-sensitivity, arginine-stimulated insulin secretion), β-cell glucose sensitivity was unique in exhibiting a significant correlation with both islet size and alpha-beta double+ islet cells.
CONCLUSIONS: Our data suggest that poor β-cell glucose sensitivity is linked to islet trans-differentiation, possibly from α cells to β cells, in an attempt to cope with higher demands for insulin secretion. Understanding the mechanism(s) that underlies the adaptive response of the islet cells to insulin resistance is a potential approach to design tools to enhance functional β-cell mass for diabetes therapy.

PMID: 26649619 [PubMed - as supplied by publisher]

PGC-1 coactivators in β-cells regulate lipid metabolism and are essential for insulin secretion coupled to fatty acids.

Fri, 12/04/2015 - 08:53
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PGC-1 coactivators in β-cells regulate lipid metabolism and are essential for insulin secretion coupled to fatty acids.

Mol Metab. 2015 Nov;4(11):811-822

Authors: Oropeza D, Jouvet N, Bouyakdan K, Perron G, Ringuette LJ, Philipson LH, Kiss RS, Poitout V, Alquier T, Estall JL

Abstract
OBJECTIVES: Peroxisome proliferator-activated receptor γ coactivator 1 (PPARGCA1, PGC-1) transcriptional coactivators control gene programs important for nutrient metabolism. Islets of type 2 diabetic subjects have reduced PGC-1α expression and this is associated with decreased insulin secretion, yet little is known about why this occurs or what role it plays in the development of diabetes. Our goal was to delineate the role and importance of PGC-1 proteins to β-cell function and energy homeostasis.
METHODS: We investigated how nutrient signals regulate coactivator expression in islets and the metabolic consequences of reduced PGC-1α and PGC-1β in primary and cultured β-cells. Mice with inducible β-cell specific double knockout of Pgc-1α/Pgc-1β (βPgc-1 KO) were created to determine the physiological impact of reduced Pgc1 expression on glucose homeostasis.
RESULTS: Pgc-1α and Pgc-1β expression was increased in primary mouse and human islets by acute glucose and palmitate exposure. Surprisingly, PGC-1 proteins were dispensable for the maintenance of mitochondrial mass, gene expression, and oxygen consumption in response to glucose in adult β-cells. However, islets and mice with an inducible, β-cell-specific PGC-1 knockout had decreased insulin secretion due in large part to loss of the potentiating effect of fatty acids. Consistent with an essential role for PGC-1 in lipid metabolism, β-cells with reduced PGC-1s accumulated acyl-glycerols and PGC-1s controlled expression of key enzymes in lipolysis and the glycerolipid/free fatty acid cycle.
CONCLUSIONS: These data highlight the importance of PGC-1s in coupling β-cell lipid metabolism to promote efficient insulin secretion.

PMID: 26629405 [PubMed - as supplied by publisher]

Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcino-Embryonic Antigen-related Cell Adhesion Molecule 2.

Sun, 11/22/2015 - 01:53
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Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcino-Embryonic Antigen-related Cell Adhesion Molecule 2.

J Biol Chem. 2015 Nov 19;

Authors: Ghanem SS, Heinrich G, Lester SG, Pfeiffer V, Bhattacharya S, Patel PR, DeAngelis AM, Dai T, Ramakrishnan SK, Smiley ZN, Jung DY, Lee Y, Kitamura T, Ergun S, Kulkarni RN, Kim JK, Giovannucci DR, Najjar SM

Abstract
Carcinoembryonic antigen-related cell adhesion molecule 2 (CEACAM2) regulates food intake as demonstrated by hyperphagia in mice with Ceacam2 null mutation (Cc2-/-). The current studies investigated whether CEACAM2 also regulates insulin secretion. Ceacam2 deletion caused an increase in beta cell secretory function, as assessed by hyperglycemic clamp analysis, without affecting insulin response. Although CEACAM2 is expressed in pancreatic islets predominantly in non-beta cells, basal plasma levels of insulin, glucagon and somatostatin, islet areas, and glucose-induced insulin secretion in pooled Cc2-/- islets were all normal. Consistent with immunofluorescence analysis showing CEACAM2 expression in distal intestinal villi, Cc2-/- mice exhibited a higher release of oral glucose-mediated GLP-1, an incretin that potentiates insulin secretion in response to glucose. Compared to wild type, Cc2-/- mice also showed a higher insulin excursion during oral glucose tolerance test. Pretreating with exendin (9-39), a GLP-1 receptor antagonist, suppressed the effect of Ceacam2 deletion on glucose-induced insulin secretion. Moreover, GLP-1 release into the medium of GLUTag entero-endocrine cells was increased with siRNA-mediated Ceacam2 downregulation in parallel to increase in Ca2+ entry through L-type voltage-dependent Ca2+ channels. Thus, CEACAM2 regulates insulin secretion, at least in part, by a GLP-1 mediated mechanism, independent of confounding metabolic factors.

PMID: 26586918 [PubMed - as supplied by publisher]

The brain in bone and fuel metabolism.

Mon, 11/09/2015 - 17:15
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The brain in bone and fuel metabolism.

Bone. 2015 Nov 3;

Authors: Wee NK, Kulkarni RN, Horsnell H, Baldock PA

Abstract
Obesity and osteoporosis have become major public health challenges worldwide. The brain is well established as a pivotal regulator of energy homeostasis, appetite and fuel metabolism. However, there is now clear evidence for regulation between the brain and bone. Similarly, evidence also indicates that the involvement of brain in bone and adipose regulation is both related and interdependent.The hypothalamus, with its semi-permeable blood brain barrier, is one of the most powerful regulatory regions within the body, integrating and relaying signals not only from peripheral tissues but also from within the brain itself. Two main neuronal populations within the arcuate nucleus of the hypothalamus regulate energy homeostasis: The orexigenic, appetite-stimulating neurons that co-express neuropeptide Y and agouti-related peptide and the anorexigenic, appetite-suppressing neurons that co-express proopiomelanocortin and cocaine- and amphetamine related transcript. From within the arcuate, these four neuropeptides encompass some of the most powerful control of energy homeostasis in the entire body. Moreover, they also regulate skeletal homeostasis, identifying a co-ordination network linking the processes of bone and energy homeostasis. Excitingly, the number of central neuropeptides and neural factors known to regulate bone and energy homeostasis continues to grow, with cannabinoid receptors and semaphorins also involved in bone homeostasis. These neuronal pathways represent a growing area of research that is identifying novel regulatory axes between the brain and the bone, and links with other homeostatic networks; thereby revealing a far more complex, and interdependent bone biology than previously envisioned. This review examines the current understanding of the central regulation of bone and energy metabolism.

PMID: 26545334 [PubMed - as supplied by publisher]

Compensatory Response by Late Embryonic Tubular Epithelium to the Reduction in Pancreatic Progenitors.

Fri, 11/06/2015 - 15:03
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Compensatory Response by Late Embryonic Tubular Epithelium to the Reduction in Pancreatic Progenitors.

PLoS One. 2015;10(11):e0142286

Authors: Nishimura W, Kapoor A, El Khattabi I, Jin W, Yasuda K, Bonner-Weir S, Sharma A

Abstract
Early in pancreatic development, epithelial cells of pancreatic buds function as primary multipotent progenitor cells (1°MPC) that specify all three pancreatic cell lineages, i.e., endocrine, acinar and duct. Bipotent "Trunk" progenitors derived from 1°MPC are implicated in directly regulating the specification of endocrine progenitors. It is unclear if this specification process is initiated in the 1°MPC where some 1°MPC become competent for later specification of endocrine progenitors. Previously we reported that in Pdx1tTA/+;tetOMafA (bigenic) mice inducing expression of transcription factor MafA in Pdx1-expressing (Pdx1+) cells throughout embryonic development inhibited the proliferation and differentiation of 1°MPC cells, resulting in reduced pancreatic mass and endocrine cells by embryonic day (E) 17.5. Induction of the transgene only until E12.5 in Pdx1+ 1°MPC was sufficient for this inhibition of endocrine cells and pancreatic mass at E17.5. However, by birth (P0), as we now report, such bigenic pups had significantly increased pancreatic and endocrine volumes with endocrine clusters containing all pancreatic endocrine cell types. The increase in endocrine cells resulted from a higher proliferation of tubular epithelial cells expressing the progenitor marker Glut2 in E17.5 bigenic embryos and increased number of Neurog3-expressing cells at E19.5. A BrdU-labeling study demonstrated that inhibiting proliferation of 1°MPC by forced MafA-expression did not lead to retention of those progenitors in E17.5 tubular epithelium. Our data suggest that the forced MafA expression in the 1°MPC inhibits their competency to specify endocrine progenitors only until E17.5, and after that compensatory proliferation of tubular epithelium gives rise to a distinct pool of endocrine progenitors. Thus, these bigenic mice provide a novel way to characterize the competency of 1°MPC for their ability to specify endocrine progenitors, a critical limitation in our understanding of endocrine differentiation.

PMID: 26540252 [PubMed - as supplied by publisher]

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