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 43 min ago

Dynamic development of the pancreas from birth to adulthood.

Wed, 03/23/2016 - 23:09

Dynamic development of the pancreas from birth to adulthood.

Ups J Med Sci. 2016 Mar 21;:1-4

Authors: Bonner-Weir S, Aguayo-Mazzucato C, Weir GC

Abstract
After birth the endocrine pancreas continues its development, a complex process that involves both the maturation of islet cells and a marked expansion of their numbers. New beta cells are formed both by duplication of pre-existing cells and by new differentiation (neogenesis) across the first postnatal weeks, with the result of beta cells of different stages of maturation even after weaning. Improving our understanding of this period of beta cell expansion could provide valuable therapeutic insights.

PMID: 26998806 [PubMed - as supplied by publisher]

Direct Reprogramming for Pancreatic Beta-Cells Using Key Developmental Genes.

Wed, 03/23/2016 - 23:09

Direct Reprogramming for Pancreatic Beta-Cells Using Key Developmental Genes.

Curr Pathobiol Rep. 2015 Mar 1;3(1):57-65

Authors: Cavelti-Weder C, Li W, Zumsteg A, Stemann M, Yamada T, Bonner-Weir S, Weir G, Zhou Q

Abstract
Direct reprogramming is a promising approach for regenerative medicine whereby one cell type is directly converted into another without going through a multipotent or pluripotent stage. This reprogramming approach has been extensively explored for the generation of functional insulin-secreting cells from non-beta-cells with the aim of developing novel cell therapies for the treatment of people with diabetes lacking sufficient endogenous beta-cells. A common approach for such conversion studies is the introduction of key regulators that are important in controlling beta-cell development and maintenance. In this review, we will summarize the recent advances in the field of beta-cell reprogramming and discuss the challenges of creating functional and long-lasting beta-cells.

PMID: 26998407 [PubMed - as supplied by publisher]

α/β-Hydrolase Domain 6 Deletion Induces Adipose Browning and Prevents Obesity and Type 2 Diabetes.

Wed, 03/23/2016 - 23:09

α/β-Hydrolase Domain 6 Deletion Induces Adipose Browning and Prevents Obesity and Type 2 Diabetes.

Cell Rep. 2016 Mar 15;

Authors: Zhao S, Mugabo Y, Ballentine G, Attane C, Iglesias J, Poursharifi P, Zhang D, Nguyen TA, Erb H, Prentki R, Peyot ML, Joly E, Tobin S, Fulton S, Brown JM, Madiraju SR, Prentki M

Abstract
Suppression of α/β-domain hydrolase-6 (ABHD6), a monoacylglycerol (MAG) hydrolase, promotes glucose-stimulated insulin secretion by pancreatic β cells. We report here that high-fat-diet-fed ABHD6-KO mice show modestly reduced food intake, decreased body weight gain and glycemia, improved glucose tolerance and insulin sensitivity, and enhanced locomotor activity. ABHD6-KO mice also show increased energy expenditure, cold-induced thermogenesis, brown adipose UCP1 expression, fatty acid oxidation, and white adipose browning. Adipose browning and cold-induced thermogenesis are replicated by the ABHD6 inhibitor WWL70 and by antisense oligonucleotides targeting ABHD6. Our evidence suggests that one mechanism by which the lipolysis derived 1-MAG signals intrinsic and cell-autonomous adipose browning is via PPARα and PPARγ activation, and that ABHD6 regulates adipose browning by controlling signal competent 1-MAG levels. Thus, ABHD6 regulates energy homeostasis, brown adipose function, and white adipose browning and is a potential therapeutic target for obesity and type 2 diabetes.

PMID: 26997277 [PubMed - as supplied by publisher]

FoxO1 Deacetylation Decreases Fatty Acid Oxidation in beta-cells and Sustains Insulin Secretion in Diabetes.

Sun, 03/20/2016 - 21:31

FoxO1 Deacetylation Decreases Fatty Acid Oxidation in beta-cells and Sustains Insulin Secretion in Diabetes.

J Biol Chem. 2016 Mar 16;

Authors: Kim-Muller JY, Kim YJ, Fan J, Zhao S, Banks AS, Prentki M, Accili D

Abstract
Pancreatic lower case Greek beta-cell dysfunction contributes to onset and progression of type 2 diabetes. In this state β-cells become metabolically inflexible, losing the ability to select between carbohydrates and lipids as substrates for mitochondrial oxidation. These changes lead to lower case Greek beta-cell dedifferentiation. We have proposed that FoxO proteins are activated through deacetylation-dependent nuclear translocation to forestall the progression of these abnormalities. However, how deacetylated FoxO exert their actions remains unclear. To address this question, we analyzed islet function in mice homozygous for knock-in alleles encoding deacetylated FoxO1 (6KR). Islets expressing 6KR mutant FoxO1 have enhanced insulin secretion in vivo and ex vivo, and decreased fatty acid oxidation ex vivo. Remarkably, the gene expression signature associated with FoxO1 deacetylation differs from wild-type by only ~2% of the > 4,000 genes regulated in response to re-feeding. But this narrow swath includes key genes required for lower case Greek beta-cell identity, lipid metabolism, and mitochondrial fatty acid and solute transport. The data support the notion that deacetylated FoxO1 protects lower case Greek beta-cell function by limiting mitochondrial lipid utilization, and raise the possibility that inhibition of fatty acid oxidation in lower case Greek beta-cells is beneficial to diabetes treatment.

PMID: 26984405 [PubMed - as supplied by publisher]

The Hypoglycemic Phenotype is Islet Cell-Autonomous in Short-chain Hydroxyacyl-CoA Dehydrogenase (SCHAD) Deficient Mice.

Fri, 03/11/2016 - 16:49
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The Hypoglycemic Phenotype is Islet Cell-Autonomous in Short-chain Hydroxyacyl-CoA Dehydrogenase (SCHAD) Deficient Mice.

Diabetes. 2016 Mar 7;

Authors: Molven A, Hollister-Lock J, Hu J, Martinez R, Njølstad PR, Liew CW, Weir G, Kulkarni RN

Abstract
Congenital hyperinsulinism of infancy (CHI) can be caused by inactivating mutations in the gene encoding short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), a ubiquitously expressed enzyme involved in fatty acid oxidation. The hypersecretion of insulin may be explained by a loss of interaction between SCHAD and glutamate dehydrogenase in the pancreatic beta-cells. However, in affected individuals there is also a general accumulation of metabolites specific for the enzymatic defect. It remains to be explored whether hypoglycemia in SCHAD-CHI can be uncoupled from the systemic effect on fatty acid oxidation. We therefore transplanted islets from global SCHAD knock-out (SCHADKO) mice into mice with streptozotocin-induced diabetes. Following transplantation, SCHADKO islet recipients exhibited significantly lower random and fasting blood glucose compared with mice transplanted with normal islets or non-diabetic, non-transplanted controls. Furthermore, intraperitoneal glucose tolerance was improved in animals receiving SCHADKO islets compared with those receiving normal islets. Graft beta-cell proliferation and apoptosis rates were similar in the two transplantation groups. We conclude that hypoglycemia in SCHAD-CHI is islet cell-autonomous.

PMID: 26953163 [PubMed - as supplied by publisher]

Inhibition of DYRK1A stimulates human beta-cell proliferation.

Fri, 03/11/2016 - 16:49
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Inhibition of DYRK1A stimulates human beta-cell proliferation.

Diabetes. 2016 Mar 7;

Authors: Dirice E, Walpita D, Vetere A, Meier BC, Kahraman S, Hu J, Dančík V, Burns SM, Gilbert TJ, Olson DE, Clemons PA, Kulkarni RN, Wagner BK

Abstract
Restoring functional beta-cell mass is an important therapeutic goal for both type 1 and type 2 diabetes (1). While proliferation of existing beta cells is the primary means of beta-cell replacement in rodents (2), it is unclear whether a similar principle applies to humans as human beta cells are remarkably resistant to stimulation of division (3, 4). Here, we show that 5-iodotubercidin (5-IT), an annotated adenosine kinase inhibitor previously reported to increase proliferation in rodent and porcine islets (5), strongly and selectively increases human beta-cell proliferation in vitro and in vivo. Remarkably, 5-IT also increased glucose-dependent insulin secretion after prolonged treatment. Kinome profiling revealed 5-IT to be a potent and selective inhibitor of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) and cell division cycle (CDC)-like (CLK) kinase families. Induction of beta-cell proliferation by either 5-IT or harmine, another natural-product DYRK1A inhibitor, was suppressed by co-incubation with the calcineurin inhibitor FK506, suggesting involvement of DYRK1A and NFAT signaling. Gene-expression profiling in whole islets treated with 5-IT revealed induction of proliferation- and cell cycle-related genes, suggesting that true proliferation is induced by 5-IT. Furthermore, 5-IT promotes beta-cell proliferation in human islets grafted under the kidney capsule of NOD-scid IL2Rg(null) mice. These results point to inhibition of DYRK1A as a therapeutic strategy to increase human beta-cell proliferation.

PMID: 26953159 [PubMed - as supplied by publisher]

Mesencephalic Astrocyte-Derived Neurotrophic Factor as a Urine Biomarker for Endoplasmic Reticulum Stress-Related Kidney Diseases.

Sat, 03/05/2016 - 13:40
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Mesencephalic Astrocyte-Derived Neurotrophic Factor as a Urine Biomarker for Endoplasmic Reticulum Stress-Related Kidney Diseases.

J Am Soc Nephrol. 2016 Mar 3;

Authors: Kim Y, Lee H, Manson SR, Lindahl M, Evans B, Miner JH, Urano F, Chen YM

Abstract
Endoplasmic reticulum (ER) stress and disrupted proteostasis contribute to the pathogenesis of a variety of glomerular and tubular diseases. Thus, it is imperative to develop noninvasive biomarkers for detecting ER stress in podocytes or tubular cells in the incipient stage of disease, when a kidney biopsy is not yet clinically indicated. Mesencephalic astrocyte-derived neurotrophic factor (MANF) localizes to the ER lumen and is secreted in response to ER stress in several cell types. Here, using mouse models of human nephrotic syndrome caused by mutant laminin β2 protein-induced podocyte ER stress and AKI triggered by tunicamycin- or ischemia-reperfusion-induced tubular ER stress, we examined MANF as a potential urine biomarker for detecting ER stress in podocytes or renal tubular cells. ER stress upregulated MANF expression in podocytes and tubular cells. Notably, urinary MANF excretion concurrent with podocyte or tubular cell ER stress preceded clinical or histologic manifestations of the corresponding disease. Thus, MANF can potentially serve as a urine diagnostic or prognostic biomarker in ER stress-related kidney diseases to help stratify disease risk, predict disease progression, monitor treatment response, and identify subgroups of patients who can be treated with ER stress modulators in a highly targeted manner.

PMID: 26940092 [PubMed - as supplied by publisher]

Inhibition of TGF-beta signaling promotes human pancreatic beta cell replication.

Sat, 03/05/2016 - 13:40
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Inhibition of TGF-beta signaling promotes human pancreatic beta cell replication.

Diabetes. 2016 Mar 2;

Authors: Dhawan S, Dirice E, Kulkarni RN, Bhushan A

Abstract
Diabetes is associated with loss of functional pancreatic beta cells and restoration of beta cells is a major goal for regenerative therapies. Endogenous regeneration of beta cells via beta cell replication has the potential to restore cellular mass, however pharmacologic agents that promote regeneration or expansion of endogenous beta cells have been elusive. The regenerative capacity of beta cells declines rapidly with age, due to accumulation of p16(INK4a), resulting in limited capacity for adult endocrine pancreas regeneration. Here, we show that TGF beta signaling via Smad3 integrates with the trithorax complex to activate and maintain Ink4a expression to prevent beta cell replication. Importantly, inhibition of TGF-beta signaling can result in repression of the Ink4a/Arf locus resulting in increased beta cell replication in adult mice. Furthermore, small molecule inhibitors of the TGF-beta pathway promote beta cell replication in human islets transplanted into NOD-scid IL2Rgnull (NSG) mice. These data reveal a novel role for TGF beta signaling in the regulation of the Ink4a/Arf locus and highlight the l potential of using small molecule inhibitors of TGF-beta signaling to promote human beta cell replication.

PMID: 26936960 [PubMed - as supplied by publisher]

Poly-dipeptides encoded by the C9ORF72 repeats block global protein translation.

Sat, 03/05/2016 - 13:40
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Poly-dipeptides encoded by the C9ORF72 repeats block global protein translation.

Hum Mol Genet. 2016 Feb 29;

Authors: Kanekura K, Yagi T, Cammack AJ, Mahadevan J, Kuroda M, Harms MB, Miller TM, Urano F

Abstract
The expansion of the GGGGCC hexanucleotide repeat in the non-coding region of the Chromosome 9 open reading frame 72 (C9orf72) gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophc lateral sclerosis (ALS). This genetic alteration leads to the accumulation of five types of poly-dipeptides translated from the GGGGCC hexanucleotide repeat. Among these, poly-PR and poly-GR peptides are known to be neurotoxic. However, the mechanisms of neurotoxicity associated with these poly-dipeptides are not clear. A proteomics approach identified a number of interacting proteins with poly-PR peptide, including mRNA binding proteins, ribosomal proteins, translation initiation factors, and translation elongation factors. Immunostaining of brain sections from patients with C9orf72 ALS showed that poly-GR was colocalized with a mRNA binding protein, hnRNP A1. In vitro translation assays showed that poly-PR and poly-GR peptides made insoluble complexes with mRNA, restrained the access of translation factors to mRNA, and blocked protein translation. Our results demonstrate that impaired protein translation mediated by poly-PR and poly-GR peptides plays a role in neurotoxicity and reveal that the pathways altered by the poly-dipeptides-mRNA complexes are potential therapeutic targets for treatment of C9orf72 FTD/ALS.

PMID: 26931465 [PubMed - as supplied by publisher]

Adaptive Preconditioning in Neurological Diseases - Therapeutic Insights from Proteostatic Perturbations.

Wed, 03/02/2016 - 12:28
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Adaptive Preconditioning in Neurological Diseases - Therapeutic Insights from Proteostatic Perturbations.

Brain Res. 2016 Feb 25;

Authors: Mollereau B, Rzechorzek NM, Roussel BD, Sedru M, Van den Brink D, Bailly-Maitre B, Palladino F, Medinas DB, Domingos PM, Hunot S, Chandran S, Birman S, Baron T, Vivien D, Duarte CB, Ryoo HD, Steller H, Urano F, Chevet E, Kroemer G, Ciechanover A, Calabrese EJ, Kaufman RJ, Hetz C

Abstract
In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a 'proteostasis network' and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge - the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson´s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses - and the molecular pathways they recruit - might be exploited for therapeutic gain.

PMID: 26923166 [PubMed - as supplied by publisher]

Selective cognitive and psychiatric manifestations in Wolfram Syndrome.

Wed, 03/02/2016 - 12:28
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Selective cognitive and psychiatric manifestations in Wolfram Syndrome.

Orphanet J Rare Dis. 2015;10:66

Authors: Bischoff AN, Reiersen AM, Buttlaire A, Al-Lozi A, Doty T, Marshall BA, Hershey T, Washington University Wolfram Syndrome Research Group

Abstract
BACKGROUND: Wolfram Syndrome (WFS) is known to involve diabetes mellitus, diabetes insipidus, optic nerve atrophy, vision loss, hearing impairment, motor abnormalities, and neurodegeneration, but has been less clearly linked to cognitive, sleep, and psychiatric abnormalities. We sought to determine whether these abnormalities are present in children, adolescents, and young adults with WFS compared to age- and gender-matched individuals with and without type 1 diabetes using standardized measures.
METHODS: Individuals with genetically-confirmed WFS (n = 19, ages 7-27) were compared to age- and gender- equivalent groups of individuals with type 1 diabetes (T1DM; n = 25), and non-diabetic healthy controls (HC: n = 25). Cognitive performance across multiple domains (verbal intelligence, spatial reasoning, memory, attention, smell identification) was assessed using standardized tests. Standardized self- and parent-report questionnaires on psychiatric symptoms and sleep disturbances were acquired from all groups and an unstructured psychiatric interview was performed within only the WFS group.
RESULTS: The three groups were similar demographically (age, gender, ethnicity, parental IQ). WFS and T1DM had similar duration of diabetes but T1DM had higher HbA1C levels than WFS and as expected both groups had higher levels than HC. The WFS group was impaired on smell identification and reported sleep quality, but was not impaired in any other cognitive or self-reported psychiatric domain. In fact, the WFS group performed better than the other two groups on selected memory and attention tasks. However, based upon a clinical evaluation of only WFS patients, we found that psychiatric and behavioral problems were present and consisted primarily of anxiety and hypersomnolence.
CONCLUSIONS: This study found that cognitive performance and psychological health were relatively preserved WFS patients, while smell and sleep abnormalities manifested in many of the WFS patients. These findings contradict past case and retrospective reports indicating significant cognitive and psychiatric impairment in WFS. While many of these patients were diagnosed with anxiety and hypersomnolence, self-reported measures of psychiatric symptoms indicated that the symptoms were not of grave concern to the patients. It may be that cognitive and psychiatric issues become more prominent later in life and/or in later stages of the disease, but this requires standardized assessment and larger samples to determine. In the relatively early stages of WFS, smell and sleep-related symptoms may be useful biomarkers of disease and should be monitored longitudinally to determine if they are good markers of progression as well.
TRIAL REGISTRATION: Current Clinicaltrials.gov Trial NCT02455414 .

PMID: 26025012 [PubMed - indexed for MEDLINE]

α/β-Hydrolase domain-6 and saturated long chain monoacylglycerol regulate insulin secretion promoted by both fuel and non-fuel stimuli.

Sun, 02/28/2016 - 12:09
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α/β-Hydrolase domain-6 and saturated long chain monoacylglycerol regulate insulin secretion promoted by both fuel and non-fuel stimuli.

Mol Metab. 2015 Dec;4(12):940-50

Authors: Zhao S, Poursharifi P, Mugabo Y, Levens EJ, Vivot K, Attane C, Iglesias J, Peyot ML, Joly E, Madiraju SR, Prentki M

Abstract
OBJECTIVE: α/β-Hydrolase domain-6 (ABHD6) is a newly identified monoacylglycerol (MAG) lipase. We recently reported that it negatively regulates glucose stimulated insulin secretion (GSIS) in the β cells by hydrolyzing lipolysis-derived MAG that acts as a metabolic coupling factor and signaling molecule via exocytotic regulator Munc13-1. Whether ABHD6 and MAG play a role in response to all classes of insulin secretagogues, in particular various fuel and non-fuel stimuli, is unknown.
METHODS: Insulin secretion in response to various classes of secretagogues, exogenous MAG and pharmacological agents was measured in islets of mice deficient in ABHD6 specifically in the β cell (BKO). Islet perifusion experiments and determinations of glucose and fatty acid metabolism, cytosolic Ca(2+) and MAG species levels were carried out.
RESULTS: Deletion of ABHD6 potentiated insulin secretion in response to the fuels glutamine plus leucine and α-ketoisocaproate and to the non-fuel stimuli glucagon-like peptide 1, carbamylcholine and elevated KCl. Fatty acids amplified GSIS in control and BKO mice to the same extent. Exogenous 1-MAG amplified insulin secretion in response to fuel and non-fuel stimuli. MAG hydrolysis activity was greatly reduced in BKO islets without changes in total diacylglycerol and triacylglycerol lipase activity. ABHD6 deletion induced insulin secretion independently from KATP channels and did not alter the glucose induced rise in intracellular Ca(2+). Perifusion studies showed elevated insulin secretion during second phase of GSIS in BKO islets that was not due to altered cytosolic Ca(2+) signaling or because of changes in glucose and fatty acid metabolism. Glucose increased islet saturated long chain 1-MAG species and ABHD6 deletion caused accumulation of these 1-MAG species at both low and elevated glucose.
CONCLUSION: ABHD6 regulates insulin secretion in response to fuel stimuli at large and some non-fuel stimuli by controlling long chain saturated 1-MAG levels that synergize with other signaling pathways for secretion.

PMID: 26909310 [PubMed]

Central agonism of GPR120 acutely inhibits food intake and food reward and chronically suppresses anxiety-like behaviour in mice.

Mon, 02/22/2016 - 08:30
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Central agonism of GPR120 acutely inhibits food intake and food reward and chronically suppresses anxiety-like behaviour in mice.

Int J Neuropsychopharmacol. 2016 Feb 17;

Authors: Auguste S, Fisette A, Fernandes MF, Hryhorczuk C, Poitout V, Alquier T, Fulton S

Abstract
BACKGROUND: GPR120 (FFAR4) is a G-protein coupled receptor implicated in the development of obesity and the anti-inflammatory and insulin-sensitizing effects of omega-3 (ω-3) polyunsaturated fatty acids (PUFA). Increasing central ω-3 PUFA levels has been shown to have both anorectic and anxiolytic actions. Despite the strong clinical interest in GPR120 its role in the brain is largely unknown, and thus we sought to determine the impact of central GPR120 pharmacological activation on energy balance, food reward and anxiety-like behaviour.
METHODS: Male C57Bl6 mice with intracerebroventricular cannulae received a single injection (0.1 or 1μM) or continuous 2-week infusion (1μM/day; mini-pump) of a GPR120 agonist or vehicle. Free-feeding intake, operant lever-pressing for palatable food, energy expenditure (indirect calorimetry) and body weight were measured. GPR120 mRNA expression was measured in pertinent brain areas. Anxiety-like behavior was assessed in the elevated-plus maze and open field test.
RESULTS: GPR120 agonist injections substantially reduced chow intake during four hours post-injection, suppressed the rewarding effects of high-fat/sugar food, and blunted approach-avoidance behavior in the open field. Conversely, prolonged central GPR120 agonist infusions reduced anxiety-like behaviour in the elevated-plus maze and open field, yet failed to affect free-feeding intake, energy expenditure and body weight on a high-fat diet.
CONCLUSION: Acute reductions in food intake and food reward suggest that GPR120 could mediate the effects of central ω-3 PUFA to inhibit appetite. The anxiolytic effect elicited by GPR120 agonist infusions favors the testing of compounds that can enter the brain to activate GPR120 for the mitigation of anxiety.

PMID: 26888796 [PubMed - as supplied by publisher]

Neuroimaging evidence of deficient axon myelination in Wolfram syndrome.

Mon, 02/22/2016 - 08:30
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Neuroimaging evidence of deficient axon myelination in Wolfram syndrome.

Sci Rep. 2016;6:21167

Authors: Lugar HM, Koller JM, Rutlin J, Marshall BA, Kanekura K, Urano F, Bischoff AN, Shimony JS, Hershey T, Washington University Wolfram Syndrome Research Study Group

Abstract
Wolfram syndrome is a rare autosomal recessive genetic disease characterized by insulin dependent diabetes and vision, hearing and brain abnormalities which generally emerge in childhood. Mutations in the WFS1 gene predispose cells to endoplasmic reticulum stress-mediated apoptosis and may induce myelin degradation in neuronal cell models. However, in vivo evidence of this phenomenon in humans is lacking. White matter microstructure and regional volumes were measured using magnetic resonance imaging in children and young adults with Wolfram syndrome (n = 21) and healthy and diabetic controls (n = 50). Wolfram patients had lower fractional anisotropy and higher radial diffusivity in major white matter tracts and lower volume in the basilar (ventral) pons, cerebellar white matter and visual cortex. Correlations were found between key brain findings and overall neurological symptoms. This pattern of findings suggests that reduction in myelin is a primary neuropathological feature of Wolfram syndrome. Endoplasmic reticulum stress-related dysfunction in Wolfram syndrome may interact with the development of myelin or promote degeneration of myelin during the progression of the disease. These measures may provide objective indices of Wolfram syndrome pathophysiology that will be useful in unraveling the underlying mechanisms and in testing the impact of treatments on the brain.

PMID: 26888576 [PubMed - in process]

Early Developmental Perturbations in a Human Stem Cell Model of MODY5/HNF1B Pancreatic Hypoplasia.

Fri, 02/19/2016 - 05:47
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Early Developmental Perturbations in a Human Stem Cell Model of MODY5/HNF1B Pancreatic Hypoplasia.

Stem Cell Reports. 2016 Feb 8;

Authors: Teo AK, Lau HH, Valdez IA, Dirice E, Tjora E, Raeder H, Kulkarni RN

Abstract
Patients with an HNF1B(S148L/+) mutation (MODY5) typically exhibit pancreatic hypoplasia. However, the molecular mechanisms are unknown due to inaccessibility of patient material and because mouse models do not fully recapitulate MODY5. Here, we differentiated MODY5 human-induced pluripotent stem cells (hiPSCs) into pancreatic progenitors, and show that the HNF1B(S148L/+) mutation causes a compensatory increase in several pancreatic transcription factors, and surprisingly, a decrease in PAX6 pancreatic gene expression. The lack of suppression of PDX1, PTF1A, GATA4, and GATA6 indicates that MODY5-mediated pancreatic hypoplasia is mechanistically independent. Overexpression studies demonstrate that a compensatory increase in PDX1 gene expression is due to mutant HNF1B(S148L/+) but not wild-type HNF1B or HNF1A. Furthermore, HNF1B does not appear to directly regulate PAX6 gene expression necessary for glucose tolerance. Our results demonstrate compensatory mechanisms in the pancreatic transcription factor network due to mutant HNF1B(S148L/+) protein. Thus, patients typically develop MODY5 but not neonatal diabetes despite exhibiting pancreatic hypoplasia.

PMID: 26876668 [PubMed - as supplied by publisher]

Fibroblast Growth Factor 21 (FGF21) Protects against High Fat Diet Induced Inflammation and Islet Hyperplasia in Pancreas.

Tue, 02/16/2016 - 05:37
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Fibroblast Growth Factor 21 (FGF21) Protects against High Fat Diet Induced Inflammation and Islet Hyperplasia in Pancreas.

PLoS One. 2016;11(2):e0148252

Authors: Singhal G, Fisher FM, Chee MJ, Tan TG, El Ouaamari A, Adams AC, Najarian R, Kulkarni RN, Benoist C, Flier JS, Maratos-Flier E

Abstract
Fibroblast growth factor 21 (FGF21) is an important endocrine metabolic regulator expressed in multiple tissues including liver and adipose tissue. Although highest levels of expression are in pancreas, little is known about the function of FGF21 in this tissue. In order to understand the physiology of FGF21 in the pancreas, we analyzed its expression and regulation in both acinar and islet tissues. We found that acinar tissue express 20-fold higher levels than that observed in islets. We also observed that pancreatic FGF21 is nutritionally regulated; a marked reduction in FGF21 expression was noted with fasting while obesity is associated with 3-4 fold higher expression. Acinar and islet cells are targets of FGF21, which when systemically administered, leads to phosphorylation of the downstream target ERK 1/2 in about half of acinar cells and a small subset of islet cells. Chronic, systemic FGF21 infusion down-regulates its own expression in the pancreas. Mice lacking FGF21 develop significant islet hyperplasia and periductal lymphocytic inflammation when fed with a high fat obesogenic diet. Inflammatory infiltrates consist of TCRb+ Thy1+ T lymphocytes with increased levels of Foxp3+ regulatory T cells. Increased levels of inflammatory cells were coupled with elevated expression of cytokines such as TNFα, IFNγ and IL1β. We conclude that FGF21 acts to limit islet hyperplasia and may also prevent pancreatic inflammation.

PMID: 26872145 [PubMed - as supplied by publisher]

Inhibition of Monoacylglycerol Lipase Activity Decreases Glucose-Stimulated Insulin Secretion in INS-1 (832/13) Cells and Rat Islets.

Tue, 02/16/2016 - 05:37
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Inhibition of Monoacylglycerol Lipase Activity Decreases Glucose-Stimulated Insulin Secretion in INS-1 (832/13) Cells and Rat Islets.

PLoS One. 2016;11(2):e0149008

Authors: Berdan CA, Erion KA, Burritt NE, Corkey BE, Deeney JT

Abstract
Lipid signals derived from lipolysis and membrane phospholipids play an important role in glucose-stimulated insulin secretion (GSIS), though the exact secondary signals remain unclear. Previous reports have documented a stimulatory role of exogenously added mono-acyl-glycerol (MAG) on insulin secretion from cultured β-cells and islets. In this report we have determined effects of increasing intracellular MAG in the β-cell by inhibiting mono-acyl-glycerol lipase (MGL) activity, which catalyzes the final step in triacylglycerol breakdown, namely the hydrolysis of MAG to glycerol and free fatty acid (FA). To determine the role of MGL in GSIS, we used three different pharmacological agents (JZL184, MJN110 and URB602). All three inhibited GSIS and depolarization-induced insulin secretion in INS-1 (832/13). JZL184 significantly inhibited both GSIS and depolarization-induced insulin secretion in rat islets. JZL184 significantly decreased lipolysis and increased both mono- and diacyglycerol species in INS-1 cells. Analysis of the kinetics of GSIS showed that inhibition was greater during the sustained phase of secretion. A similar pattern was observed in the response of Ca2+ to glucose and depolarization but to a lesser degree suggesting that altered Ca2+ handling alone could not explain the reduction in insulin secretion. In addition, a significant reduction in long chain-CoA (LC-CoA) was observed in INS-1 cells at both basal and stimulatory glucose following inhibition of MGL. Our data implicate an important role for MGL in insulin secretion.

PMID: 26867016 [PubMed - in process]

Report from IPITA-TTS Opinion Leaders Meeting on the Future of β-Cell Replacement.

Sat, 02/06/2016 - 23:20
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Report from IPITA-TTS Opinion Leaders Meeting on the Future of β-Cell Replacement.

Transplantation. 2016 Feb;100 Suppl 2:S1-S44

Authors: Bartlett ST, Markmann JF, 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 P, Stabler C, Matsumoto S, Ludwig B, Choudhary P, Kovatchev B, Rickels MR, Sykes M, Wood K, Kraemer K, Hwa A, Stanley E, Ricordi C, Zimmerman M, Greenstein J, Montanya E, Otonkoski T

PMID: 26840096 [PubMed - in process]

Prader-Willi Critical Region, a Non-Translated, Imprinted Central Regulator of Bone Mass: Possible Role in Skeletal Abnormalities in Prader-Willi Syndrome.

Sun, 01/31/2016 - 19:47
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Prader-Willi Critical Region, a Non-Translated, Imprinted Central Regulator of Bone Mass: Possible Role in Skeletal Abnormalities in Prader-Willi Syndrome.

PLoS One. 2016;11(1):e0148155

Authors: Khor EC, Fanshawe B, Qi Y, Zolotukhin S, Kulkarni RN, Enriquez RF, Purtell L, Lee NJ, Wee NK, Croucher PI, Campbell L, Herzog H, Baldock PA

Abstract
Prader-Willi Syndrome (PWS), a maternally imprinted disorder and leading cause of obesity, is characterised by insatiable appetite, poor muscle development, cognitive impairment, endocrine disturbance, short stature and osteoporosis. A number of causative loci have been located within the imprinted Prader-Willi Critical Region (PWCR), including a set of small non-translated nucleolar RNA's (snoRNA). Recently, micro-deletions in humans identified the snoRNA Snord116 as a critical contributor to the development of PWS exhibiting many of the classical symptoms of PWS. Here we show that loss of the PWCR which includes Snord116 in mice leads to a reduced bone mass phenotype, similar to that observed in humans. Consistent with reduced stature in PWS, PWCR KO mice showed delayed skeletal development, with shorter femurs and vertebrae, reduced bone size and mass in both sexes. The reduction in bone mass in PWCR KO mice was associated with deficiencies in cortical bone volume and cortical mineral apposition rate, with no change in cancellous bone. Importantly, while the length difference was corrected in aged mice, consistent with continued growth in rodents, reduced cortical bone formation was still evident, indicating continued osteoblastic suppression by loss of PWCR expression in skeletally mature mice. Interestingly, deletion of this region included deletion of the exclusively brain expressed Snord116 cluster and resulted in an upregulation in expression of both NPY and POMC mRNA in the arcuate nucleus. Importantly, the selective deletion of the PWCR only in NPY expressing neurons replicated the bone phenotype of PWCR KO mice. Taken together, PWCR deletion in mice, and specifically in NPY neurons, recapitulates the short stature and low BMD and aspects of the hormonal imbalance of PWS individuals. Moreover, it demonstrates for the first time, that a region encoding non-translated RNAs, expressed solely within the brain, can regulate bone mass in health and disease.

PMID: 26824232 [PubMed - as supplied by publisher]

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

Thu, 01/28/2016 - 16:38
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Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice.

Nat Med. 2016 Jan 25;

Authors: Vegas AJ, Veiseh O, Gürtler 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

Abstract
The transplantation of glucose-responsive, insulin-producing cells offers the potential for restoring glycemic control in individuals with diabetes. Pancreas transplantation and the infusion of cadaveric islets are currently implemented clinically, but these approaches are limited by the adverse effects of immunosuppressive therapy over the lifetime of the recipient and the limited supply of donor tissue. The latter concern may be addressed by recently described glucose-responsive mature beta cells that are derived from human embryonic stem cells (referred to as SC-β cells), which may represent an unlimited source of human cells for pancreas replacement therapy. Strategies to address the immunosuppression concerns include immunoisolation of insulin-producing cells with porous biomaterials that function as an immune barrier. However, clinical implementation has been challenging because of host immune responses to the implant materials. Here we report the first long-term glycemic correction of a diabetic, immunocompetent animal model using human SC-β cells. SC-β cells were encapsulated with alginate derivatives capable of mitigating foreign-body responses in vivo and implanted into the intraperitoneal space of C57BL/6J mice treated with streptozotocin, which is an animal model for chemically induced type 1 diabetes. These implants induced glycemic correction without any immunosuppression until their removal at 174 d after implantation. Human C-peptide concentrations and in vivo glucose responsiveness demonstrated therapeutically relevant glycemic control. Implants retrieved after 174 d contained viable insulin-producing cells.

PMID: 26808346 [PubMed - as supplied by publisher]

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