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Neurog3-Independent Methylation Is the Earliest Detectable Mark Distinguishing Pancreatic Progenitor Identity.
Liu J, Banerjee A, Herring CA, Attalla J, Hu R, Xu Y, Shao Q, Simmons AJ, Dadi PK, Wang S, Jacobson DA, Liu B, Hodges E, Lau KS, Gu G
(2019) Dev Cell 48: 49-63.e7
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Lineage, Endocrine Cells, Homeodomain Proteins, Insulin-Secreting Cells, Islets of Langerhans, Mice, Nerve Tissue Proteins, Organogenesis, Pancreas, Transcription Factors
Show Abstract · Added February 6, 2019
In the developing pancreas, transient Neurog3-expressing progenitors give rise to four major islet cell types: α, β, δ, and γ; when and how the Neurog3 cells choose cell fate is unknown. Using single-cell RNA-seq, trajectory analysis, and combinatorial lineage tracing, we showed here that the Neurog3 cells co-expressing Myt1 (i.e., Myt1Neurog3) were biased toward β cell fate, while those not simultaneously expressing Myt1 (Myt1Neurog3) favored α fate. Myt1 manipulation only marginally affected α versus β cell specification, suggesting Myt1 as a marker but not determinant for islet-cell-type specification. The Myt1Neurog3 cells displayed higher Dnmt1 expression and enhancer methylation at Arx, an α-fate-promoting gene. Inhibiting Dnmts in pancreatic progenitors promoted α cell specification, while Dnmt1 overexpression or Arx enhancer hypermethylation favored β cell production. Moreover, the pancreatic progenitors contained distinct Arx enhancer methylation states without transcriptionally definable sub-populations, a phenotype independent of Neurog3 activity. These data suggest that Neurog3-independent methylation on fate-determining gene enhancers specifies distinct endocrine-cell programs.
Published by Elsevier Inc.
1 Communities
1 Members
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13 MeSH Terms
A Call for Improved Reporting of Human Islet Characteristics in Research Articles.
Poitout V, Satin LS, Kahn SE, Stoffers DA, Marchetti P, Gannon M, Verchere CB, Herold KC, Myers MG, Marshall SM
(2019) Diabetes 68: 239-240
MeSH Terms: Humans, Islets of Langerhans, Islets of Langerhans Transplantation
Added April 15, 2019
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3 MeSH Terms
A call for improved reporting of human islet characteristics in research articles.
Poitout V, Satin LS, Kahn SE, Stoffers DA, Marchetti P, Gannon M, Verchere CB, Herold KC, Myers MG, Marshall SM
(2019) Diabetologia 62: 209-211
MeSH Terms: Humans, Islets of Langerhans, Islets of Langerhans Transplantation
Added April 15, 2019
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MeSH Terms
Pancreatic islet-autonomous insulin and smoothened-mediated signalling modulate identity changes of glucagon α-cells.
Cigliola V, Ghila L, Thorel F, van Gurp L, Baronnier D, Oropeza D, Gupta S, Miyatsuka T, Kaneto H, Magnuson MA, Osipovich AB, Sander M, Wright CEV, Thomas MK, Furuyama K, Chera S, Herrera PL
(2018) Nat Cell Biol 20: 1267-1277
MeSH Terms: Animals, Cell Differentiation, Cell Plasticity, Cell Proliferation, Female, Glucagon-Secreting Cells, Insulin, Insulin-Secreting Cells, Islets of Langerhans, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, SCID, Mice, Transgenic, Signal Transduction, Smoothened Receptor
Show Abstract · Added November 6, 2018
The mechanisms that restrict regeneration and maintain cell identity following injury are poorly characterized in higher vertebrates. Following β-cell loss, 1-2% of the glucagon-producing α-cells spontaneously engage in insulin production in mice. Here we explore the mechanisms inhibiting α-cell plasticity. We show that adaptive α-cell identity changes are constrained by intra-islet insulin- and Smoothened-mediated signalling, among others. The combination of β-cell loss or insulin-signalling inhibition, with Smoothened inactivation in α- or δ-cells, stimulates insulin production in more α-cells. These findings suggest that the removal of constitutive 'brake signals' is crucial to neutralize the refractoriness to adaptive cell-fate changes. It appears that the maintenance of cell identity is an active process mediated by repressive signals, which are released by neighbouring cells and curb an intrinsic trend of differentiated cells to change.
2 Communities
2 Members
1 Resources
16 MeSH Terms
Identical and Nonidentical Twins: Risk and Factors Involved in Development of Islet Autoimmunity and Type 1 Diabetes.
Triolo TM, Fouts A, Pyle L, Yu L, Gottlieb PA, Steck AK, Type 1 Diabetes TrialNet Study Group
(2019) Diabetes Care 42: 192-199
MeSH Terms: Adolescent, Adult, Autoantibodies, Autoimmunity, Child, Child, Preschool, Diabetes Mellitus, Type 1, Disease Progression, Diseases in Twins, Environment, Female, Genetic Predisposition to Disease, Glutamate Decarboxylase, Humans, Insulin, Islets of Langerhans, Male, Mass Screening, Risk Factors, Seroepidemiologic Studies, Siblings, Twins, Twins, Dizygotic, Twins, Monozygotic, Young Adult
Show Abstract · Added August 15, 2018
OBJECTIVE - There are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings.
RESEARCH DESIGN AND METHODS - Subjects from the TrialNet Pathway to Prevention Study ( = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A], and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years.
RESULTS - At screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all < 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all ≤ 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody-positive, 13% for single autoantibody-positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody-positive, 12% for single autoantibody-positive, and 0.5% for initially autoantibody-negative subjects.
CONCLUSIONS - Risk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody-positive identical twins and multiple autoantibody-positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins.
© 2018 by the American Diabetes Association.
0 Communities
2 Members
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25 MeSH Terms
A Type 1 Diabetes Genetic Risk Score Predicts Progression of Islet Autoimmunity and Development of Type 1 Diabetes in Individuals at Risk.
Redondo MJ, Geyer S, Steck AK, Sharp S, Wentworth JM, Weedon MN, Antinozzi P, Sosenko J, Atkinson M, Pugliese A, Oram RA, Type 1 Diabetes TrialNet Study Group
(2018) Diabetes Care 41: 1887-1894
MeSH Terms: Adolescent, Adult, Autoantibodies, Autoimmunity, Child, Child, Preschool, Diabetes Complications, Diabetes Mellitus, Type 1, Disease Progression, Female, Genetic Predisposition to Disease, Genotype, HLA-DQ Antigens, Humans, Infant, Islets of Langerhans, Male, Middle Aged, Polymorphism, Single Nucleotide, Prognosis, Risk Factors, Young Adult
Show Abstract · Added July 23, 2018
OBJECTIVE - We tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals.
RESEARCH DESIGN AND METHODS - We studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients' relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2-51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial-Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables.
RESULTS - Higher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio [HR] 1.29 for a 0.05 increase, 95% CI 1.06-1.6; = 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS >0.295, 95% CI 1.47-3.51; = 0.0002).
CONCLUSIONS - The T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives.
© 2018 by the American Diabetes Association.
0 Communities
1 Members
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22 MeSH Terms
Sex differences underlying pancreatic islet biology and its dysfunction.
Gannon M, Kulkarni RN, Tse HM, Mauvais-Jarvis F
(2018) Mol Metab 15: 82-91
MeSH Terms: Animals, Diabetes Mellitus, Gonadal Hormones, Humans, Islets of Langerhans, Sex Characteristics
Show Abstract · Added April 15, 2019
BACKGROUND - The sex of an individual affects glucose homeostasis and the pathophysiology, incidence, and prevalence of diabetes as well as the response to therapy.
SCOPE OF THE REVIEW - This review focuses on clinical and experimental sex differences in islet cell biology and dysfunction during development and in adulthood in human and animal models. We discuss sex differences in β-cell and α-cell function, heterogeneity, and dysfunction. We cover sex differences in communication between gonads and islets and islet-cell immune interactions. Finally, we discuss sex differences in β-cell programming by nutrition and other environmental factors during pregnancy.
MAJOR CONCLUSIONS - Important sex differences exist in islet cell function and susceptibility to failure. These differences represent sex-related biological factors that can be harnessed for gender-based prevention of and therapy for diabetes.
Published by Elsevier GmbH.
0 Communities
1 Members
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6 MeSH Terms
Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability.
Kropp PA, Dunn JC, Carboneau BA, Stoffers DA, Gannon M
(2018) Am J Physiol Endocrinol Metab 314: E308-E321
MeSH Terms: Adaptation, Physiological, Animals, Animals, Newborn, Cell Differentiation, Cells, Cultured, Diet, High-Fat, Gene Expression Regulation, Developmental, Glucose, Hepatocyte Nuclear Factor 6, Homeodomain Proteins, Insulin-Secreting Cells, Islets of Langerhans, Male, Mice, Mice, Transgenic, Multipotent Stem Cells, Organogenesis, Trans-Activators
Show Abstract · Added April 15, 2019
The transcription factors pancreatic and duodenal homeobox 1 (Pdx1) and onecut1 (Oc1) are coexpressed in multipotent pancreatic progenitors (MPCs), but their expression patterns diverge in hormone-expressing cells, with Oc1 expression being extinguished in the endocrine lineage and Pdx1 being maintained at high levels in β-cells. We previously demonstrated that cooperative function of these two factors in MPCs is necessary for proper specification and differentiation of pancreatic endocrine cells. In those studies, we observed a persistent decrease in expression of the β-cell maturity factor MafA. We therefore hypothesized that Pdx1 and Oc1 cooperativity in MPCs impacts postnatal β-cell maturation and function. Here our model of Pdx1-Oc1 double heterozygosity was used to investigate the impact of haploinsufficiency for both of these factors on postnatal β-cell maturation, function, and adaptability. Examining mice at postnatal day (P) 14, we observed alterations in pancreatic insulin content in both Pdx1 heterozygotes and double heterozygotes. Gene expression analysis at this age revealed significantly decreased expression of many genes important for glucose-stimulated insulin secretion (e.g., Glut2, Pcsk1/2, Abcc8) exclusively in double heterozygotes. Analysis of P14 islets revealed an increase in the number of mixed islets in double heterozygotes. We predicted that double-heterozygous β-cells would have an impaired ability to respond to stress. Indeed, we observed that β-cell proliferation fails to increase in double heterozygotes in response to either high-fat diet or placental lactogen. We thus report here the importance of cooperation between regulatory factors early in development for postnatal islet maturation and adaptability.
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MeSH Terms
Cytokine-mediated changes in K channel activity promotes an adaptive Ca response that sustains β-cell insulin secretion during inflammation.
Dickerson MT, Bogart AM, Altman MK, Milian SC, Jordan KL, Dadi PK, Jacobson DA
(2018) Sci Rep 8: 1158
MeSH Terms: Adult, Animals, Calcium, Female, Gene Expression Regulation, Glucose, Humans, Insulin, Insulin Secretion, Insulin-Secreting Cells, Interferon-gamma, Interleukin-1beta, Ion Transport, Islets of Langerhans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Potassium, Potassium Channels, Tandem Pore Domain, Primary Cell Culture, RNA, Messenger, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Tissue Culture Techniques, Tumor Necrosis Factor-alpha
Show Abstract · Added February 7, 2018
Cytokines present during low-grade inflammation contribute to β-cell dysfunction and diabetes. Cytokine signaling disrupts β-cell glucose-stimulated Ca influx (GSCI) and endoplasmic reticulum (ER) Ca ([Ca]) handling, leading to diminished glucose-stimulated insulin secretion (GSIS). However, cytokine-mediated changes in ion channel activity that alter β-cell Ca handling remain unknown. Here we investigated the role of K currents in cytokine-mediated β-cell dysfunction. K currents, which control the termination of intracellular Ca ([Ca]) oscillations, were reduced following cytokine exposure. As a consequence, [Ca] and electrical oscillations were accelerated. Cytokine exposure also increased basal islet [Ca] and decreased GSCI. The effect of cytokines on TALK-1 K currents were also examined as TALK-1 mediates K by facilitating [Ca] release. Cytokine exposure decreased KCNK16 transcript abundance and associated TALK-1 protein expression, increasing [Ca] storage while maintaining 2 phase GSCI and GSIS. This adaptive Ca response was absent in TALK-1 KO islets, which exhibited decreased 2 phase GSCI and diminished GSIS. These findings suggest that K and TALK-1 currents play important roles in altered β-cell Ca handling and electrical activity during low-grade inflammation. These results also reveal that a cytokine-mediated reduction in TALK-1 serves an acute protective role in β-cells by facilitating increased Ca content to maintain GSIS.
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25 MeSH Terms
Mouse pancreatic islet macrophages use locally released ATP to monitor beta cell activity.
Weitz JR, Makhmutova M, Almaça J, Stertmann J, Aamodt K, Brissova M, Speier S, Rodriguez-Diaz R, Caicedo A
(2018) Diabetologia 61: 182-192
MeSH Terms: Adenosine Triphosphate, Animals, Insulin, Insulin-Secreting Cells, Islets of Langerhans, Macrophages, Mice, Pancreas
Show Abstract · Added March 21, 2018
AIMS/HYPOTHESIS - Tissue-resident macrophages sense the microenvironment and respond by producing signals that act locally to maintain a stable tissue state. It is now known that pancreatic islets contain their own unique resident macrophages, which have been shown to promote proliferation of the insulin-secreting beta cell. However, it is unclear how beta cells communicate with islet-resident macrophages. Here we hypothesised that islet macrophages sense changes in islet activity by detecting signals derived from beta cells.
METHODS - To investigate how islet-resident macrophages respond to cues from the microenvironment, we generated mice expressing a genetically encoded Ca indicator in myeloid cells. We produced living pancreatic slices from these mice and used them to monitor macrophage responses to stimulation of acinar, neural and endocrine cells.
RESULTS - Islet-resident macrophages expressed functional purinergic receptors, making them exquisite sensors of interstitial ATP levels. Indeed, islet-resident macrophages responded selectively to ATP released locally from beta cells that were physiologically activated with high levels of glucose. Because ATP is co-released with insulin and is exclusively secreted by beta cells, the activation of purinergic receptors on resident macrophages facilitates their awareness of beta cell secretory activity.
CONCLUSIONS/INTERPRETATION - Our results indicate that islet macrophages detect ATP as a proxy signal for the activation state of beta cells. Sensing beta cell activity may allow macrophages to adjust the secretion of factors to promote a stable islet composition and size.
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8 MeSH Terms