Characterization of human induced pluripotent stem cell (iPSC)-derived hepatocytes from insulin-resistant subjects

• Grant number: 14/25370-8
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: March 01, 2015
• End date: February 29, 2016
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Everardo Magalhães Carneiro
• Grantee: Thiago Martins Batista
• Supervisor: C. Ronald Kahn
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: Harvard University, Boston, United States

Abstract

Insulin resistance links obesity, Type 2 Diabetes Mellitus (T2D) and metabolic syndrome. Both environmental factors (e.g. overnutrition and low physical activity) and genetic inheritance are key determinants of insulin resistance. Studies in fibroblasts and lymphoblasts from patients with rare genetically determined forms of insulin resistance provided valuable information regarding insulin action in health and disease. However, the specific cellular phenotype in metabolically relevant tissues from insulin resistant subjects remains largely unknown. The reprogramming of differentiated cells into induced Pluripotent Stem Cells (iPSCs) and their conversion into all three germ layer-derived tissues created a new and promising platform for the study of complex human diseases, such as T2D. Recently, the Kahn Lab (Host Laboratory) described the conversion of skin fibroblasts into iPSCs from individuals with mutation in the insulin receptor gene (IR-Mut). Insulin signaling, cell growth and proliferation were largely impaired in IR-Mut iPSCs. Moreover, global gene profiling revealed different expression patterns in response to the IR-Mut genotype between fibroblasts and iPSCs, suggesting that genotypic alterations may lead to different phenotypes according to the cellular context. Therefore, this proposal is aimed at extending these findings by converting the IR-Mut iPSCs into liver cells for study of insulin signaling, cell growth, proliferation, gene profiling and regulation of glucose output. Thus, the study of iPSC-derived hepatocytes shall give important insights into the outcomes of insulin resistance upon liver function. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BATISTA, THIAGO M.; GARCIA-MARTIN, RUBEN; CAI, WEIKANG; KONISHI, MASAHIRO; O'NEILL, BRIAN T.; SAKAGUCHI, MASAJI; KIM, JONG HUN; JUNG, DAE YOUNG; KIM, JASON K.; KAHN, C. RONALD. Multi-dimensional Transcriptional Remodeling by Physiological Insulin In Vivo. CELL REPORTS, v. 26, n. 12, p. 3429+, MAR 19 2019. (14/25370-8)

BATISTA, THIAGO M.; JAYAVELU, ASHOK KUMAR; ALBRECHTSEN, NICOLAI J. WEWER; IOVINO, SALVATORE; LEBASTCHI, JASMIN; PAN, HUI; DREYFUSS, JONATHAN M.; KROOK, ANNA; ZIERATH, JULEEN R.; MANN, MATTHIAS; et al. A Cell-Autonomous Signature of Dysregulated Protein Phosphorylation Underlies Muscle Insulin Resistance in Type 2 Diabetes. Cell Metabolism, v. 32, n. 5, p. 844+, NOV 3 2020. (14/25370-8)

CAI, WEIKANG; ZHANG, XUEMEI; BATISTA, THIAGO M.; GARCIA-MARTIN, RUBEN; SOFTIC, SAMIR; WANG, GUOXIAO; RAMIREZ, ALFRED K.; KONISHI, MASAHIRO; O'NEILL, BRIAN T.; KIM, JONG HUN; et al. Peripheral Insulin Regulates a Broad Network of Gene Expression in Hypothalamus, Hippocampus, and Nucleus Accumbens. Diabetes, v. 70, n. 8, p. 1857-1873, AUG 2021. (14/25370-8)