Diabetes: Many Faces of the Disease | EK18

Feb 1, 2021 ‐ Feb 3, 2021



Sessions

Groundbreaking technique for the prevention of pancreatic beta cells dysfunction

Feb 1, 2021 12:00am ‐ Feb 1, 2021 12:00am

Identification: EK18-eposter-feyisa-mulugeta

Groundbreaking technique for the prevention of pancreatic beta cells dysfunction Beta cells which are located in the pancreatic islets secrete insulin hormone which control blood sugar (glucose) level. Pancreatic beta cells dysfunction which is commonly caused by autoimmune disease is the leading cause of type I diabetes. Co-delivery of artificial beta cells and immunosuppressive agent into healthy individual can prevent autoimmune disease of the natural pancreatic beta cells which leads to type I diabetes. Repeated exposure of our immune system to artificial beta cells in the presence of immunosuppressive agent can halt autoimmune reaction to natural pancreatic beta cells. To sum up, training our immune system to recognize pancreatic beta cells as ‘self’ can be beneficial for the prevention of type I diabetes. Author: Mulugeta Feyisa, DVM Ethiopian Agricultural Transformation Agency

Speaker(s):

Investigating the Metabolic role of PTEN in Parasympathetic Phox2B neurons

Feb 1, 2021 12:00am ‐ Feb 1, 2021 12:00am

Identification: EK18-eposter-li-yuzhe

Investigating the Metabolic role of PTEN in Parasympathetic Phox2B neurons Title: Investigating the Metabolic role of PTEN in Parasympathetic Phox2B neurons Authors: Y Li1,2, J Rapps1,2, E Tahiri2, M Woo1,2,3 1University of Toronto, Institute of Medical Science 2Toronto General Hospital Research Institute 3Division of Endocrinology and Metabolism, Department of Medicine, UHN/SHS, University of Toronto Background: Insulin resistance and deficiency are two critical factors that contribute to the development of type 2 diabetes (T2D). One major negative regulator of insulin signalling is phosphatase and tensin homolog (PTEN) which antagonizes the insulin-mediated phosphoinositol 3-kinase pathway, the main enzymatic pathway that is activated in response to insulin. We and others have shown that loss of Pten in multiple tissues leads to improved systemic insulin sensitivity and glucose tolerance, suggesting that selective targeting of Pten may protect against T2D. Previously, our lab has shown that selective Pten knockout (KO) in rat insulin-2 (RIP2) promoter expressing neurons resulted in the activation of cholinergic anti-inflammatory reflex and improved peripheral insulin sensitivity (Wang et al Nat Med). As RIP2 promoter is expressed non-specifically in the brain, we proceeded to investigate the essential role of PTEN exclusively in parasympathetic cholinergic paired like homeobox 2B (Phox2B) neurons in the dorsal vagal complex. Approach and Results: To assess the metabolic effects of PTEN in Phox2B neurons, we generated Phox2B-PTEN KO mice using the Cre-Loxp system. Phox2B-PTEN KO mice and wildtype (WT) littermate controls were subsequently fed with a high fat diet (HFD) consisting of 60% fat content for 3 months from 6 weeks of age, and in vivo intra-peritoneal insulin and glucose tolerance tests were performed to assess glucose homeostasis. Notably, we found that deletion of PTEN in Phox2B neurons resulted in improved glucose tolerance and insulin sensitivity when compared to WT littermate controls following 3 months of HFD and gained less weight. Phox2B-PTEN KO mice had decreased liver weights and liver histological sections stained with hematoxylin and eosin or oil-red-o showed decreased liver lipid droplets. Liver triglyceride content was also decreased in Phox2B-PTEN KO mice compared to WT controls. qPCR performed on liver samples of Phox2B-PTEN KO mice showed increased expression of anti-inflammatory and decreased expression of lipogenic, fibrotic and inflammatory genes compared to controls. Phox2B-PTEN KO mice also had significantly reduced visceral white adipose tissue (vWAT) mass and histological sections revealed decreased adipocyte size and increased number compared to WT controls. qPCR analysis on vWAT samples from Phox2B-PTEN mice showed increased expression of lipolytic and adipogenesis genes with a decrease in leptin gene expression. To assess for potential mechanism by which Phox2B-PTEN KO mice were metabolically protected, we tested the role of acetylcholine by injecting mecamylamine (MEC) IP, to antagonize nicotinic receptor to ablate the effects of peripheral acetylcholine. Interestingly, MEC abolished the protective effects observed in Phox2B-PTEN KO mice including the improved insulin sensitivity, low weight gain on HFD, and decreased adiposity. Furthermore, MEC abolished the differences in gene expression of vWAT samples of Phox2B-PTEN KO mice. Similarly, vagotomy performed on Phox2B-PTEN KO mice ablated their protective metabolic effects compared to sham group. Conclusion: Our results suggest that Pten in PHOX2B neurons have a critical role in regulating energy and glucose homeostasis with alterations in liver and adipose fat content as well as inflammation. Thus, PTEN in the PNS may have an important role in regulating peripheral insulin sensitivity and inflammation.

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Novel Dyrk1A inhibitors as a potential therapeutic agents

Feb 1, 2021 12:00am ‐ Feb 1, 2021 12:00am

Identification: EK18-EPOSTER-BARZOWSKA-AGATA

Novel Dyrk1A inhibitors as a potential therapeutic agents Novel Dyrk1A inhibitors as a potential therapeutic agents Agata Barzowska, Barbara Pucelik, Alex Matsuda, Anna Czarna Jagiellonian University, Małopolska Centre of Biotechnology, Gronostajowa 7A, 30-387, Kraków, Poland Small molecules targeting protein kinases are among the best tools for advanced therapy. They allow us to understand the mechanisms of disease. In recent years, the role of DYRK1A kinase in beta-cell proliferation and its possible use as a therapeutic target in the treatment of diabetes has been demonstrated [1]. Consequently, novel compounds dedicated to this kinase are being sought. The inhibitors under investigation are potential regulatory agents that restore pancreatic β-cell mass, secretory, and organ regulatory functions. Moreover, patient-derived induced pluripotent stem cells (iPSCs) allow screening for various diseases and facilitate the discovery of new drugs [2,3]. The optimal inhibitor will restore the blood glucose levels and provide the conditions necessary for the growth and function of the host and new beta cells derived from iPSCs. The presented study proved that tested inhibitors increase the beta-cell proliferation, homing, engraftment, and thus regulate the blood glucose levels. The functionality of pancreatic islets derived from iPSC was also confirmed after treatment with selected inhibitors. Islets were isolated from BALB/c mice, and insulin secretion was determined after treatment with the tested compounds. The NCN financed this work within the grant no 2019/34/E/NZ1/00467 [1] Wang P, Alvarez-Perez J-C, Felsenfeld DP, et al. A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat Med. 2015;21:383–388. [2] Pagliuca FW, Millman JR, Gürtler M, et al. Generation of functional human pancreatic β cells in vitro. Cell. 2014;159:428–439. [3] Russ HA, Parent AV, Ringler JJ, et al. Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro. EMBO J. 2015;34:1759–1772.

Speaker(s):

Human islet microtissues as an in vitro and in vivo model system for diabetes

Feb 1, 2021 12:00am ‐ Feb 1, 2021 12:00am

Identification: EK18-eposter-mir-coll-joan

Human islet microtissues as an in vitro and in vivo model system for diabetes Joan Mir-Coll1, Tilo Moede2, Meike Paschen2, Aparna Neelakandhan1, Ismael Valladolid-Acebes2, Barbara Leibiger2, Adelinn Biernath1, Carina Ämmälä3, Ingo B. Leibiger2, Burcak Yesildag1 and Per-Olof Berggren2 1 InSphero AG, Wagistrasse 27a, 8952 Schlieren, Switzerland; joan.mir@insphero.com; aparna.neelakandhan@insphero.com; adelinn.biernath@insphero.com; burcak.yesildag@insphero.com. 2 The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska Sjukhuset L1:03, 17176 Stockholm, Sweden; tilo.moede@ki.se; paschen.meike@gmail.com; ismael.valladolid.acebes@ki.se; barbara.leibiger@ki.se; ingo.leibiger@ki.se; per-olof.berggren@ki.se. 3 Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, 431 38 Mölndal, Gothenburg, Sweden; carina.ammala@astrazeneca.com. Loss of pancreatic β-cell function is a critical event in the pathophysiology of type 2 diabetes. However, studies of its underlying mechanisms as well as the discovery of novel targets and therapies have been hindered due to limitations in available experimental models. In this study we exploited the stable viability and function of standardized human islet microtissues to develop a disease-relevant, scalable, and reproducible model of β-cell dysfunction by exposing them to long-term glucotoxicity and glucolipotoxicity. Moreover, by establishing a method for highly-efficient and homogeneous viral transduction, we were able to monitor the loss of functional β-cell mass in vivo by transplanting reporter human islet microtissues into the anterior chamber of the eye of immune-deficient mice exposed to a diabetogenic diet for 12 weeks. This newly developed in vitro model as well as the described in vivo methodology represent a new set of tools that will facilitate the study of β-cell failure in type 2 diabetes and could accelerate the discovery of novel therapeutic agents.

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Novel genetic regulators of body fat distribution in humans, HCK, ITPRIPL2, and ZMIZ2 uncovered using network modeling approaches

Feb 1, 2021 12:00am ‐ Feb 1, 2021 12:00am

Identification: EK18-EPOSTER-REED-JORDAN

Novel genetic regulators of body fat distribution in humans, HCK, ITPRIPL2, and ZMIZ2 uncovered using network modeling approaches Reed, JN, Civelek, M University of Virginia, Center for Public Health Genomics Body fat distribution (BFD) is a complex trait that describes the non-uniform storage of fat in various adipose tissue depots. Excess fat storage in the abdominal region is a well-established risk factor for Type II Diabetes (T2D) and contributes to higher rates of hospitalization and death. The comparative storage between abdominal and gluteofemoral depots is approximated in large studies by the waist-to-hip ratio adjusted for body mass index (WHRadjBMI), a metric that is independent of overall adiposity and is a more significant disease risk indicator than BMI. While genome-wide association studies (GWAS) have uncovered novel loci and genes associated with WHRadjBMI, a majority of these genes are understudied, and the link between gene expression and fat storage remains largely unknown. Our objective was to identify novel genes that regulate BFD using systems biology approaches. We modeled gene-gene interactions on a large scale by creating directed networks from a curated gene set of ~7,000 putative BFD-related genes. We used adipose tissue gene expression data from 3 independent cohorts ranging from n = 434 to n = 663 males and females to create 3 independent networks. Because of the unique structure of these networks, we could mathematically calculate genes whose expression regulates the expression of many others in the network. We then chose genes whose expression was highly correlated with WHRadjBMI and whose expression regulated BFD genes identified in GWAS in the network. We determined HCK, ITPRIPL2, and ZMIZ2 regulate genes identified in BFD GWAS in 2 out of 3 independent network models. HCK, ITPRIPL2, and ZMIZ2 may play an important role in the differential fat storage in adipose tissue that contributes to overall BFD. In future studies, we will manipulate the expression of these genes in adipocytes using a modified CRISPR system to study their role in adipocyte function and fat storage.

Speaker(s):

Circulating Trimethylamine N-Oxide is associated with increased risk of cardiovascular mortality in type 2 diabetes: Results from a Dutch Diabetes Cohort.

Feb 1, 2021 12:00am ‐ Feb 1, 2021 12:00am

Identification: EK18-eposter-flores-guerrero-jose

Circulating Trimethylamine N-Oxide is associated with increased risk of cardiovascular mortality in type 2 diabetes: Results from a Dutch Diabetes Cohort. Authors and Affiliations Jose L. Flores-Guerrero1, Peter R. van Dijk2,3, Margery A. Connelly4, Erwin Garcia4, Henk J.G. Bilo5, Gerjan Navis1, Robin P.F. Dullaart2, Stephan J.L. Bakker1 1 Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 2 Department of Internal Medicine, Division of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 3 Diabetes Centre, Isala, Zwolle, The Netherlands. 4 Laboratory Corporation of America Holdings (LabCorp), Morrisville, North Carolina, USA. 5 Faculty of Medical Sciences, University of Groningen, Groningen, The Netherlands. Correspondence: j.l.flores.guerrero@umcg.nl Abstract. Background. Trimethylamine N-oxide (TMAO), a gut microbiome–derived metabolite, has been proposed as a risk factor for cardiovascular (CV) disease and mortality in the general population. Furthermore, it has been proposed that branched chain amino acids (BCAA) concentrations are affected by microbiota, as well. The association of TMAO with CV mortality in Type 2 Diabetes (T2D) and its determinants remain unclear. Therefore, the objective of our study was to investigate the association of plasma TMAO concentrations with CV mortality in individuals with T2D and to evaluate the association between BCAA and TMAO. Methods. Data of 595 participants from the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) cohort were analysed. Plasma TMAO and BCAA were measured by nuclear magnetic resonance spectroscopy. The risk of CV mortality was estimated using multivariable-adjusted Cox proportional hazards regression models. Results. During a median follow-up of 10 years, 180 participants died, of which 113 from CV disease. In Cox regression analyses, adjusted for age, sex, systolic blood pressure, T2D duration, macrovascular complications, smoking, total cholesterol, HDL cholesterol, triglycerides, BCAAs and albuminuria TMAO was independently associated with CV mortality: HR 2.09 [1.21; 3.60], p = 0.008 (for the highest compared to the lowest tertile of the TMAO distribution). The same was true for analyses with TMAO as continuous variable: HR 1.38 [1.11; 1.70], p = 0.003 (per SD increase). In contrast, BCAAs were not independently associated with increased CV mortality. Conclusions. Higher plasma concentrations of TMAO but not BCAAs are independently associated with an increased risk of CV mortality in individuals with T2D, independent of clinical and biochemical risk markers. Key Words— Trimethylamine-N-oxide; TMAO; Branched Chain Amino Acids; BCAA; Cardiovascular mortality; Bayesian methods

Speaker(s):

Evaluation of the antidiabetic properties of Gongronema latifolium leaves extract-loaded solid lipid microparticles

Feb 1, 2021 12:00am ‐ Feb 1, 2021 12:00am

Identification: EK18-EPOSTER-CHIME-SALOME

Evaluation of the antidiabetic properties of Gongronema latifolium leaves extract-loaded solid lipid microparticles Salome A. Chime, Ph.D1,*; Paschal U. Ugwoke, B. Pharm.1; Anthony A. Attama, Prof. of Pharmaceutics 2 1Department of Pharmaceutical Technology and Industrial Pharmacy;2 Department of Pharmaceutics, University of Nigeria, Nsukka 410001, Nigeria. Context: Gongronema latifolium Benth Hook, (Asclepiadaceae) is a tropical rainforest plant primarily used in traditional folk medicine in the treatment of malaria, diabetes, hypertension, and as laxative. Aim: To study the antidiabetic properties of Gongronema latifolium-loaded solid lipid microparticles (SLMs). Materials and Methods: The methanolic extract of Gongronema latifolium leaves were obtained and formulated into SLMs using lipid matrix comprising of fat from Capra hircus and Phospholipon® 90H. The SLMs were characterised in vitro by determining the particle size and morphology, pH stability studies and encapsulation efficiency EE%. Also the antidiabetic properties of the Gongronema latifolium-loaded SLMs were studied in alloxan-induced diabetic rats. Results and discussion: The results show that particle size of G. latifolium-loaded SLMs were within acceptable range for SLMs. Highest EE% of 68 % was obtained for SLMs containing 5 % G. latifolium (batch F3). The formulations remained stable with insignificant pH reduction over time (p < 0.05). Gongronema latifolium-loaded SLMs had mean percentage reduction in blood glucose of 76 % at 2 h, 42.3 % at 8 h and 24.4 % at 12 h, while the group that received the reference-glibenclamide had 82.6, 61.7 and 46.7 % at 2, 8 and 12 h respectively after oral administration of all samples. Gongronema latifolium-loaded SLMs had blood glucose reduction significantly higher than the pure extract and the glibenclamide (p < 0.05) at the concentrations used. Conclusion: Gongronema latifolium-loaded SLMs exhibited good hypoglycemic effect and could be used for the treatment of diabetes.

Speaker(s):
  • Salome A. Chime, PhD, Department of Pharmaceutical Technology and Industrial Pharmacy, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Nigeria

Peripheral and Central Faces of Hepatic Insulin Resistance

Feb 1, 2021 10:00am ‐ Feb 1, 2021 10:40am

Identification: ek17-ek18-esym-session-White-Morris

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[Joint Session] Welcome Remarks and Keynote Address

Feb 1, 2021 10:00am ‐ Feb 1, 2021 10:40am

Identification: _ek17-ek18-esym-session-keynote

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[Joint Session] Gut Instincts: Influence of the Intestine on Glucose Homeostasis

Feb 1, 2021 10:40am ‐ Feb 1, 2021 12:50pm

Identification: _ek17-ek18-esym-session-instincts

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