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Prevailing insulin resistance and the resultant hyperglycemia elicits a compensatory response from pancreatic islet beta cells (β-cells) that involves increases in β-cell function and β-cell mass. However, the sustained metabolic stress eventually leads to β-cell failure characterized by severe β-cell dysfunction and progressive loss of β-cell mass. Whereas, β-cell dysfunction is relatively well understood at the mechanistic level, the avenues leading to loss of β-cell mass are less clear with reduced proliferation, dedifferentiation, and apoptosis all potential mechanisms. Butler and colleagues documented increased β-cell apoptosis in pancreas from lean and obese human Type 2 diabetes (T2D) subjects, with no changes in rates of β-cell replication or neogenesis, strongly suggesting a role for apoptosis in β-cell failure. Here, we describe a permissive role for TGF-β/Smad3 in β-cell apoptosis. Human islets undergoing β-cell apoptosis release increased levels of TGF-β1 ligand and phosphorylation levels of TGF-β’s chief transcription factor, Smad3, are increased in human T2D islets suggestive of an autocrine role for TGF-β/Smad3 signaling in β-cell apoptosis. Smad3 phosphorylation is similarly increased in diabetic mouse islets undergoing β-cell apoptosis. In mice, β-cell-specific activation of Smad3 promotes apoptosis and loss of β-cell mass in association with β-cell dysfunction, glucose intolerance, and diabetes. In contrast, inactive Smad3 protects from apoptosis and preserves β-cell mass while improving β-cell function and glucose tolerance. At the molecular level, Smad3 associates with Foxo1 to propagate TGF-β-dependent β-cell apoptosis. Indeed, genetic or pharmacologic inhibition of TGF-β/Smad3 signals or knocking down Foxo1 protects from β-cell apoptosis. These findings reveal the importance of TGF-β/Smad3 in promoting β-cell apoptosis and demonstrate the therapeutic potential of TGF-β/Smad3 antagonism to restore β-cell mass lost in diabetes.

Rationale: We recently demonstrated that the Metabesity factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1-CoREST complex but its expression pattern and function in adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues. Methods: HMG20A expression profile was assessed by quantitative PCR (QT-PCR), Western blotting and/or immunofluorescence in: 1) the hypothalamus of mice exposed or not to either a high-fat diet or a high-fat high-sucrose regimen, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals and 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate. RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A. Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-Treated astrocytes. The impact of ORY100. An Inhibitor Of The LSD1-CoREST Complex, On Hmg20a Expression, Reactive Astrogliosis And Glucose Metabolism Was Evaluated In Vitro And In Vivo In High-Fat High-Sucrose Fed Mice. Results: We Show That Hmg20a Is Predominantly Expressed In Hypothalamic Astrocytes, The Main Nutrient-Sensing Cell Type Of The Brain. Hmg20a Expression Was Upregulated In Diet-Induced Obesity And Glucose Intolerant Mice, Correlating With Increased Transcript Levels Of Gfap And Il1b Indicative Of Inflammation And Reactive Astrogliosis. Hmg20a Transcript Levels Were Also Increased In Adipose Tissue Of Obese Non-Diabetic Individuals As Compared To Obese Diabetic Patients. Hmg20a Silencing In Astrocytes Resulted In Repression Of Inflammatory, Cholesterol Biogenesis And Epithelial-To-Mesenchymal Transition Pathways Which Are Hallmarks Of Reactive Astrogliosis. Accordingly, Hmg20a Depleted Astrocytes Exhibited Reduced Mitochondrial Bioenergetics And Increased Susceptibility To Apoptosis. Neuron Viability Was Also Hindered In HMG20A-Depleted Astrocyte-Derived Conditioned Media. Ory1001 Treatment Rescued Expression Of Reactive Astrogliosis-Linked Genes In Hmg20a Ablated Astrocytes While Enhancing Cell Surface Area, Gfap Intensity And Stat3 Expression In Healthy Astrocytes, Mimicking The Effect Of Hmg20a. Furthermore, Ory1001 Treatment Protected Against Obesity-Associated Glucose Intolerance In Mice Correlating With A Regression Of Hypothalamic Hmg20a Expression, Indicative Of Reactive Astrogliosis Attenuation With Improved Health Status. Conclusion: Hmg20a Coordinates The Astrocyte Polarization State. Under Physiological Pressure Such As Obesity And Insulin Resistance That Induces Low Grade Inflammation, Hmg20a Expression Is Increased To Induce Reactive Astrogliosis In An Attempt To Preserve The Neuronal Network And Re-Establish Glucose Homeostasis. Nonetheless, A Chronic Metabesity State Or Functional Mutations Will Result In Lower Levels Of Hmg20a, Failure To Promote Reactive Astrogliosis And Increase Susceptibility Of Neurons To Stress-Induced Apoptosis. Such Effects Could Be Reversed By Ory1001 Treatment Both In Vitro And In Vivo, Paving The Way For A New Therapeutic Approach For Type 2 Diabetes Mellitus., The authors are supported by grants from the Consejería de Salud, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía (PI-0727-2010 and PI-0001-2020 to B.R.G.; PI-0085-2013 to P.I.L.; PI-0006-2016 to E.F.M.; PI-0574-2012 to S.Y.R.Z; PI-0247-2016 to F.J.B.S.), the Consejería de Economía, Innovación y Ciencia (P10.CTS.6359 to B.R.G.; CTS.8081 to E.G.F.), the Ministerio de Economía y Competitividad co-funded by Fondos FEDER (PI10/00871, PI13/00593 and BFU2017-83588-P to B.R.G.; PRE2018-084907 to M.E.M.V.G.; PI13/00309; PI17/01004 to F.J.B.S.; BFU2014-5343-P to J.C.R.; and AGL2017-86927-R to F.M.), Vencer el Cancer (B.R.G), DiabetesCero (B.R.G.) and the Juvenile Diabetes Research Foundation (17-2013-372 and 2-SRA-2019-837-S-B to B.R.G.). E.F.M. was a recipient of a Juan de la Cierva Incorporación Fellowship from the Ministerio de Economía y Competitividad (IJCI-2015-26238). S.Y.R.Z is a recipient of a postdoctoral fellowship from Consejería de Salud, Junta de Andalucía (RH-0070-2013). L.L.N. is supported by a Consejeria de Economia, Conocimiento, Empresas y Universidad postdoctoral fellowship (DOC_00652). F.J.B.S. and E.G.F. are recipients of "Nicolás Monardes" research contracts from Consejería de Salud Junta de Andalucía, (C-0070-2012 and C-0031-2016). A.M.M. is supported by CPII19/00023 and PI18/01590 from the Instituto de Salud Carlos III co-funded by Fondos FEDER. CIBERDEM is an initiative of the Instituto de Salud Carlos III. V.C. is supported by a AECC investigator award.

Cobo-Vuilleumier, Nadia et al., Type 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function. Liver receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive organs, and protects pancreatic islets against apoptosis. Here, we show that BL001, a small LRH-1 agonist, impedes hyperglycemia progression and the immune-dependent inflammation of pancreas in murine models of T1DM, and beta cell apoptosis in islets of type 2 diabetic patients, while increasing beta cell mass and insulin secretion. Thus, we suggest that LRH-1 agonism favors a dialogue between immune and islet cells, which could be druggable to protect against diabetes mellitus., This work was funded by grants from the Juvenile Diabetes Research Foundation (17-2013-372 to B.R.G.), the Consejeria de Salud, Fundacion Publica Andaluza Progreso y Salud, Junta de Andalucia (PI-0727-2010 to B.R.G. and P10CTS6505 to B.S.), Consejeria de Economia, Innovacion y Ciencia (P10.CTS.6359 to B.R.G.), the Ministerio de Economia y Competidividad co-funded by Fondos FEDER (PI10/00871, PI13/00593, and BFU2017-83588-P to B.R.G.; PI14/01015, RD12/0019/0028, and RD16/0011/0034 to B.S.; PI16/00259 to A.H.) and Deutsche Forschungsgemeinschaft (GRK-1789 ´CEMMA´ and DFG SCHI-505/6-1 to R.S.). Special thanks to the families of the DiabetesCero Foundation that graciously supported this work (to B.R.G.). A.M.M. is a recipient of a Miguel Servet grant (CP14/00105) from the Instituto de Salud Carlos III co-funded by Fondos FEDER whereas E.F.M. is a recipient of a Juan de la Cierva Fellowship. I.G.H.G. is supported by a fellowship from Amarna Therapeutics. In some instances, human islets were procured through the European Consortium for Islet Transplantation funded by Juvenile Diabetes Research Foundation (3-RSC-2016-162-I-X).

Journal Article; Pancreatic beta-cell apoptosis is known to participate in the beta-cell destruction process that occurs in diabetes. It has been described that high glucose level induces a hyperfunctional status which could provoke apoptosis. This phenomenon is known as glucotoxicity and has been proposed that it can play a role in type 1 diabetes mellitus pathogenesis. In this study we develop an experimental design to sensitize pancreatic islet cells by high glucose to streptozotocin (STZ) and proinflammatory cytokines [interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma]-induced apoptosis. This method is appropriate for subsequent quantification of apoptotic islet cells stained with Tdt-mediated dUTP Nick-End Labeling (TUNEL) and protein expression assays by Western Blotting (WB). Yes