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Androgen excess in pancreatic β cells and neurons predisposes female mice to type 2 diabetes.
Navarro G, Allard C, Morford JJ, Xu W, Liu S, Molinas AJ, Butcher SM, Fine NH, Blandino-Rosano M, Sure VN, Yu S, Zhang R, Münzberg H, Jacobson DA, Katakam PV, Hodson DJ, Bernal-Mizrachi E, Zsombok A, Mauvais-Jarvis F
(2018) JCI Insight 3:
MeSH Terms: Androgens, Animals, Diabetes Mellitus, Type 2, Diet, Western, Dihydrotestosterone, Female, Glucose, Humans, Hyperinsulinism, Hypothalamus, Insulin Resistance, Insulin-Secreting Cells, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Neurons, Receptors, Androgen, Streptozocin
Show Abstract · Added June 28, 2018
Androgen excess predisposes women to type 2 diabetes (T2D), but the mechanism of this is poorly understood. We report that female mice fed a Western diet and exposed to chronic androgen excess using dihydrotestosterone (DHT) exhibit hyperinsulinemia and insulin resistance associated with secondary pancreatic β cell failure, leading to hyperglycemia. These abnormalities are not observed in mice lacking the androgen receptor (AR) in β cells and partially in neurons of the mediobasal hypothalamus (MBH) as well as in mice lacking AR selectively in neurons. Accordingly, i.c.v. infusion of DHT produces hyperinsulinemia and insulin resistance in female WT mice. We observe that acute DHT produces insulin hypersecretion in response to glucose in cultured female mouse and human pancreatic islets in an AR-dependent manner via a cAMP- and mTOR-dependent pathway. Acute DHT exposure increases mitochondrial respiration and oxygen consumption in female cultured islets. As a result, chronic DHT exposure in vivo promotes islet oxidative damage and susceptibility to additional stress induced by streptozotocin via AR in β cells. This study suggests that excess androgen predisposes female mice to T2D following AR activation in neurons, producing peripheral insulin resistance, and in pancreatic β cells, promoting insulin hypersecretion, oxidative injury, and secondary β cell failure.
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19 MeSH Terms
A specific phosphorylation regulates the protective role of αA-crystallin in diabetes.
Ruebsam A, Dulle JE, Myers AM, Sakrikar D, Green KM, Khan NW, Schey K, Fort PE
(2018) JCI Insight 3:
MeSH Terms: Aged, Animals, Cell Line, Crystallins, Diabetes Mellitus, Experimental, Diabetic Retinopathy, Electroretinography, Ependymoglial Cells, Female, Humans, Male, Mice, Mice, Knockout, Neurons, Phosphorylation, Rats, Rats, Sprague-Dawley, Recombinant Proteins, Retina, Streptozocin, Transfection, alpha-Crystallin A Chain, alpha-Crystallin B Chain
Show Abstract · Added April 3, 2018
Neurodegeneration is a central aspect of the early stages of diabetic retinopathy, the primary ocular complication associated with diabetes. While progress has been made to improve the vascular perturbations associated with diabetic retinopathy, there are still no treatment options to counteract the neuroretinal degeneration associated with diabetes. Our previous work suggested that the molecular chaperones α-crystallins could be involved in the pathophysiology of diabetic retinopathy; however, the role and regulation of α-crystallins remained unknown. In the present study, we demonstrated the neuroprotective role of αA-crystallin during diabetes and its regulation by its phosphorylation on residue 148. We further characterized the dual role of αA-crystallin in neurons and glia, its essential role for neuronal survival, and its direct dependence on phosphorylation on this residue. These findings support further evaluation of αA-crystallin as a treatment option to promote neuron survival in diabetic retinopathy and neurodegenerative diseases in general.
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23 MeSH Terms
Imbalance between HDAC and HAT activities drives aberrant STAT1/MyD88 expression in macrophages from type 1 diabetic mice.
Filgueiras LR, Brandt SL, Ramalho TR, Jancar S, Serezani CH
(2017) J Diabetes Complications 31: 334-339
MeSH Terms: Acetylation, Animals, Bone Marrow Cells, Cells, Cultured, Diabetes Mellitus, Type 1, Enzyme Inhibitors, Epigenesis, Genetic, Gene Expression Regulation, Glucose, Histone Acetyltransferases, Histone Deacetylases, Histones, Macrophages, Macrophages, Peritoneal, Male, Mice, Inbred C57BL, Myeloid Differentiation Factor 88, Osmolar Concentration, Promoter Regions, Genetic, Protein Processing, Post-Translational, STAT1 Transcription Factor, Streptozocin
Show Abstract · Added May 4, 2017
AIMS - To investigate the hypothesis that alteration in histone acetylation/deacetylation triggers aberrant STAT1/MyD88 expression in macrophages from diabetics. Increased STAT1/MyD88 expression is correlated with sterile inflammation in type 1 diabetic (T1D) mice.
METHODS - To induce diabetes, we injected low-doses of streptozotocin in C57BL/6 mice. Peritoneal or bone marrow-differentiated macrophages were cultured in 5mM (low) or 25mM (high glucose). ChIP analysis of macrophages from nondiabetic or diabetic mice was performed to determine acetylation of lysine 9 in histone H3 in MyD88 and STAT1 promoter regions. Macrophages from diabetic mice were treated with the histone acetyltransferase inhibitor anacardic acid (AA), followed by determination of mRNA expression by qPCR.
RESULTS - Increased STAT1 and MyD88 expression in macrophages from diabetic but not naive mice cultured in low glucose persisted for up to 6days. Macrophages from diabetic mice exhibited increased activity of histone acetyltransferases (HAT) and decreased histone deacetylases (HDAC) activity. We detected increased H3K9Ac binding to Stat1/Myd88 promoters in macrophages from T1D mice and AA in vitro treatment reduced STAT1 and MyD88 mRNA expression.
CONCLUSIONS/INTERPRETATION - These results indicate that histone acetylation drives elevated Stat1/Myd88 expression in macrophages from diabetic mice, and this mechanism may be involved in sterile inflammation and diabetes comorbidities.
Copyright © 2016 Elsevier Inc. All rights reserved.
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22 MeSH Terms
Loss of tumour suppressor PTEN expression in renal injury initiates SMAD3- and p53-dependent fibrotic responses.
Samarakoon R, Helo S, Dobberfuhl AD, Khakoo NS, Falke L, Overstreet JM, Goldschmeding R, Higgins PJ
(2015) J Pathol 236: 421-32
MeSH Terms: Animals, Apoptosis, Aristolochic Acids, Cell Cycle Checkpoints, Cell Line, Cell Proliferation, Disease Models, Animal, Enzyme Inhibitors, Fibrosis, Gene Expression Regulation, Humans, Kidney Diseases, Kidney Tubules, Male, Mice, Inbred C57BL, PTEN Phosphohydrolase, Plasminogen Activator Inhibitor 1, RNA Interference, Signal Transduction, Smad3 Protein, Streptozocin, Transfection, Transforming Growth Factor beta1, Tumor Suppressor Protein p53, Ureteral Obstruction
Show Abstract · Added April 19, 2016
Deregulation of the tumour suppressor PTEN occurs in lung and skin fibrosis and diabetic and ischaemic renal injury. However, the potential role of PTEN and associated mechanisms in the progression of kidney fibrosis is unknown. Tubular and interstitial PTEN expression was dramatically decreased in several models of renal injury, including aristolochic acid nephropathy (AAN), streptozotocin (STZ)-mediated injury and ureteral unilateral obstruction (UUO), correlating with Akt, p53 and SMAD3 activation and fibrosis. Stable silencing of PTEN in HK-2 human tubular epithelial cells induced dedifferentiation and CTGF, PAI-1, vimentin, α-SMA and fibronectin expression, compared to HK-2 cells expressing control shRNA. Furthermore, PTEN knockdown stimulated Akt, SMAD3 and p53(Ser15) phosphorylation, with an accompanying decrease in population density and an increase in epithelial G1 cell cycle arrest. SMAD3 or p53 gene silencing or pharmacological blockade partially suppressed fibrotic gene expression and relieved growth inhibition orchestrated by deficiency or inhibition of PTEN. Similarly, shRNA suppression of PAI-1 rescued the PTEN loss-associated epithelial proliferative arrest. Moreover, TGFβ1-initiated fibrotic gene expression is further enhanced by PTEN depletion. Combined TGFβ1 treatment and PTEN silencing potentiated epithelial cell death via p53-dependent pathways. Thus, PTEN loss initiates tubular dysfunction via SMAD3- and p53-mediated fibrotic gene induction, with accompanying PAI-1-dependent proliferative arrest, and cooperates with TGFβ1 to induce the expression of profibrotic genes and tubular apoptosis.
Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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25 MeSH Terms
Activated FoxM1 attenuates streptozotocin-mediated β-cell death.
Golson ML, Maulis MF, Dunn JC, Poffenberger G, Schug J, Kaestner KH, Gannon MA
(2014) Mol Endocrinol 28: 1435-47
MeSH Terms: Animals, Cell Cycle, Cell Death, Cell Proliferation, Cell Survival, Diabetes Mellitus, Female, Forkhead Box Protein M1, Forkhead Transcription Factors, Immune System, Insulin-Secreting Cells, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Regeneration, Sequence Analysis, RNA, Streptozocin
Show Abstract · Added November 25, 2014
The forkhead box transcription factor FoxM1, a positive regulator of the cell cycle, is required for β-cell mass expansion postnatally, during pregnancy, and after partial pancreatectomy. Up-regulation of full-length FoxM1, however, is unable to stimulate increases in β-cell mass in unstressed mice or after partial pancreatectomy, probably due to the lack of posttranslational activation. We hypothesized that expression of an activated form of FoxM1 could aid in recovery after β-cell injury. We therefore derived transgenic mice that inducibly express an activated version of FoxM1 in β-cells (RIP-rtTA;TetO-hemagglutinin (HA)-Foxm1(Δ)(NRD) mice). This N-terminally truncated form of FoxM1 bypasses 2 posttranslational controls: exposure of the forkhead DNA binding domain and targeted proteasomal degradation. Transgenic mice were subjected to streptozotocin (STZ)-induced β-cell ablation to test whether activated FoxM1 can promote β-cell regeneration. Mice expressing HA-FoxM1(ΔNRD) displayed decreased ad libitum-fed blood glucose and increased β-cell mass. β-Cell proliferation was actually decreased in RIP-rtTA:TetO-HA-Foxm1(NRD) mice compared with that in RIP-rtTA mice 7 days after STZ treatment. Unexpectedly, β-cell death was decreased 2 days after STZ treatment. RNA sequencing analysis indicated that activated FoxM1 alters the expression of extracellular matrix and immune cell gene profiles, which may protect against STZ-mediated death. These studies highlight a previously underappreciated role for FoxM1 in promoting β-cell survival.
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18 MeSH Terms
Adult duct-lining cells can reprogram into β-like cells able to counter repeated cycles of toxin-induced diabetes.
Al-Hasani K, Pfeifer A, Courtney M, Ben-Othman N, Gjernes E, Vieira A, Druelle N, Avolio F, Ravassard P, Leuckx G, Lacas-Gervais S, Ambrosetti D, Benizri E, Hecksher-Sorensen J, Gounon P, Ferrer J, Gradwohl G, Heimberg H, Mansouri A, Collombat P
(2013) Dev Cell 26: 86-100
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Blood Glucose, Cell Differentiation, Cell Lineage, Cell Movement, Cellular Reprogramming, Diabetes Mellitus, Experimental, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Glucagon-Secreting Cells, Homeodomain Proteins, Hypertrophy, Insulin-Secreting Cells, Mice, Nerve Tissue Proteins, Paired Box Transcription Factors, Pancreatic Ducts, Streptozocin
Show Abstract · Added August 14, 2013
It was recently demonstrated that embryonic glucagon-producing cells in the pancreas can regenerate and convert into insulin-producing β-like cells through the constitutive/ectopic expression of the Pax4 gene. However, whether α cells in adult mice display the same plasticity is unknown. Similarly, the mechanisms underlying such reprogramming remain unclear. We now demonstrate that the misexpression of Pax4 in glucagon(+) cells age-independently induces their conversion into β-like cells and their glucagon shortage-mediated replacement, resulting in islet hypertrophy and in an unexpected islet neogenesis. Combining several lineage-tracing approaches, we show that, upon Pax4-mediated α-to-β-like cell conversion, pancreatic duct-lining precursor cells are continuously mobilized, re-express the developmental gene Ngn3, and successively adopt a glucagon(+) and a β-like cell identity through a mechanism involving the reawakening of the epithelial-to-mesenchymal transition. Importantly, these processes can repeatedly regenerate the whole β cell mass and thereby reverse several rounds of toxin-induced diabetes, providing perspectives to design therapeutic regenerative strategies.
Copyright © 2013 Elsevier Inc. All rights reserved.
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19 MeSH Terms
Identification of cross-species shared transcriptional networks of diabetic nephropathy in human and mouse glomeruli.
Hodgin JB, Nair V, Zhang H, Randolph A, Harris RC, Nelson RG, Weil EJ, Cavalcoli JD, Patel JM, Brosius FC, Kretzler M
(2013) Diabetes 62: 299-308
MeSH Terms: Adult, Animals, Diabetes Mellitus, Experimental, Diabetic Nephropathies, Gene Regulatory Networks, Humans, Janus Kinases, Kidney Glomerulus, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Middle Aged, Real-Time Polymerase Chain Reaction, STAT Transcription Factors, Species Specificity, Streptozocin
Show Abstract · Added January 28, 2014
Murine models are valuable instruments in defining the pathogenesis of diabetic nephropathy (DN), but they only partially recapitulate disease manifestations of human DN, limiting their utility. To define the molecular similarities and differences between human and murine DN, we performed a cross-species comparison of glomerular transcriptional networks. Glomerular gene expression was profiled in patients with early type 2 DN and in three mouse models (streptozotocin DBA/2, C57BLKS db/db, and eNOS-deficient C57BLKS db/db mice). Species-specific transcriptional networks were generated and compared with a novel network-matching algorithm. Three shared human-mouse cross-species glomerular transcriptional networks containing 143 (Human-DBA STZ), 97 (Human-BKS db/db), and 162 (Human-BKS eNOS(-/-) db/db) gene nodes were generated. Shared nodes across all networks reflected established pathogenic mechanisms of diabetes complications, such as elements of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and vascular endothelial growth factor receptor (VEGFR) signaling pathways. In addition, novel pathways not previously associated with DN and cross-species gene nodes and pathways unique to each of the human-mouse networks were discovered. The human-mouse shared glomerular transcriptional networks will assist DN researchers in selecting mouse models most relevant to the human disease process of interest. Moreover, they will allow identification of new pathways shared between mice and humans.
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16 MeSH Terms
Generation of functional insulin-producing cells in the gut by Foxo1 ablation.
Talchai C, Xuan S, Kitamura T, DePinho RA, Accili D
(2012) Nat Genet 44: 406-12, S1
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, C-Peptide, Cell Differentiation, Diabetes Mellitus, Experimental, Enteroendocrine Cells, Forkhead Box Protein O1, Forkhead Transcription Factors, Gastrointestinal Tract, Glucose, Hyperglycemia, Insulin, Insulin Secretion, Insulin-Secreting Cells, Mice, Mice, Transgenic, Nerve Tissue Proteins, Neuroendocrine Cells, Stem Cells, Streptozocin, Sulfonylurea Compounds, Wnt Signaling Pathway
Show Abstract · Added April 13, 2012
Restoration of regulated insulin secretion is the ultimate goal of therapy for type 1 diabetes. Here, we show that, unexpectedly, somatic ablation of Foxo1 in Neurog3(+) enteroendocrine progenitor cells gives rise to gut insulin-positive (Ins(+)) cells that express markers of mature β cells and secrete bioactive insulin as well as C-peptide in response to glucose and sulfonylureas. Lineage tracing experiments showed that gut Ins(+) cells arise cell autonomously from Foxo1-deficient cells. Inducible Foxo1 ablation in adult mice also resulted in the generation of gut Ins(+) cells. Following ablation by the β-cell toxin streptozotocin, gut Ins(+) cells regenerate and produce insulin, reversing hyperglycemia in mice. The data indicate that Neurog3(+) enteroendocrine progenitors require active Foxo1 to prevent differentiation into Ins(+) cells. Foxo1 ablation in gut epithelium may provide an approach to restore insulin production in type 1 diabetes.
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22 MeSH Terms
Reversal of type 1 diabetes in mice by brown adipose tissue transplant.
Gunawardana SC, Piston DW
(2012) Diabetes 61: 674-82
MeSH Terms: Adipose Tissue, Brown, Animals, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Female, Glucose, Homeostasis, Insulin, Interleukin-6, Ion Channels, Mice, Mice, Inbred C57BL, Mitochondrial Proteins, Receptor, Insulin, Streptozocin, Tumor Necrosis Factor-alpha, Uncoupling Protein 1, Weight Gain
Show Abstract · Added December 5, 2013
Current therapies for type 1 diabetes (T1D) involve insulin replacement or transplantation of insulin-secreting tissue, both of which suffer from numerous limitations and complications. Here, we show that subcutaneous transplants of embryonic brown adipose tissue (BAT) can correct T1D in streptozotocin-treated mice (both immune competent and immune deficient) with severely impaired glucose tolerance and significant loss of adipose tissue. BAT transplants result in euglycemia, normalized glucose tolerance, reduced tissue inflammation, and reversal of clinical diabetes markers such as polyuria, polydipsia, and polyphagia. These effects are independent of insulin but correlate with recovery of the animals' white adipose tissue. BAT transplants lead to significant increases in adiponectin and leptin, but with levels that are static and not responsive to glucose. Pharmacological blockade of the insulin receptor in BAT transplant mice leads to impaired glucose tolerance, similar to what is seen in nondiabetic animals, indicating that insulin receptor activity plays a role in the reversal of diabetes. One possible candidate for activating the insulin receptor is IGF-1, whose levels are also significantly elevated in BAT transplant mice. Thus, we propose that the combined action of multiple adipokines establishes a new equilibrium in the animal that allows for chronic glycemic control without insulin.
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18 MeSH Terms
Central insulin resistance and synaptic dysfunction in intracerebroventricular-streptozotocin injected rodents.
Shonesy BC, Thiruchelvam K, Parameshwaran K, Rahman EA, Karuppagounder SS, Huggins KW, Pinkert CA, Amin R, Dhanasekaran M, Suppiramaniam V
(2012) Neurobiol Aging 33: 430.e5-18
MeSH Terms: Alzheimer Disease, Animals, Brain, Humans, Injections, Intraventricular, Insulin Resistance, Long-Term Potentiation, Male, Rats, Rats, Wistar, Receptors, Glutamate, Streptozocin, Synapses, Synaptic Transmission
Show Abstract · Added July 2, 2013
To better understand the role of insulin signaling in the development of Alzheimer's disease (AD), we utilized an animal model (intracerebroventricular injection of streptozotocin-ic-streptozotocin (STZ)) that displays insulin resistance only in the brain and exhibits AD pathology. In this model, deficits in hippocampal synaptic transmission and long-term potentiation (LTP) were observed. The decline in LTP correlated with decreased expression of NMDAR subunits NR2A and NR2B. The deficits in LTP were accompanied by changes in the expression and function of synaptic AMPARs. In ic-STZ animals, an alteration in integrin-linked kinase (ILK)-glycogen synthase kinase 3 beta (GSK-3-β) signaling was identified (p < 0.05). Similarly, there was decreased expression (p < 0.05) of brain derived neurotropic factor (BDNF) and stargazin, an AMPAR auxiliary subunit; both are required for driving AMPA receptors to the surface of the postsynaptic membrane. Our data illustrate that altered ILK-GSK-3β signaling due to impaired insulin signaling may decrease the trafficking and function of postsynaptic glutamate receptors; thereby, leading to synaptic deficits contributing to memory loss.
Copyright © 2012 Elsevier Inc. All rights reserved.
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14 MeSH Terms