Pathogenesis of Obesity and Type 2 Diabetes
Obesity is a major risk factor for type 2 diabetes and is associated with metabolic dysfunction in multiple organs, including the pancreas and liver. Type 2 diabetes develops when insulin-sensitive tissues become resistant to insulin and pancreatic β cells progressively lose their ability to produce sufficient insulin to maintain normal blood glucose levels.
At the same time, metabolic stress promotes liver dysfunction, contributing to impaired glucose and lipid metabolism that further accelerates disease progression.
Metformin remains the recommended first-line therapy to improve insulin sensitivity, while GLP-1 receptor agonists such as semaglutide have transformed the treatment of obesity and type 2 diabetes by promoting weight loss and improving glycaemic control. Despite these advances, many patients continue to experience progressive β-cell dysfunction and metabolic complications, highlighting the need for new therapeutic approaches.
Group Leader, Esteban Gurzov, Ph.D.
Research Interests
The role of JAK-STAT signalling in obesity.
The JAK–STAT signalling pathway is a critical regulator of cellular responses to hormones, cytokines, and inflammatory signals and plays an important role in maintaining metabolic homeostasis. Increasing evidence indicates that dysregulated JAK–STAT activity contributes to obesity-associated metabolic dysfunction by altering key processes such as inflammation, insulin sensitivity, β-cell survival, and liver metabolism. Changes in STAT transcription factor activity within metabolic tissues have been implicated in the development of insulin resistance, impaired pancreatic β-cell function, and progression towards type 2 diabetes.
Our research aims to define how specific components of the JAK–STAT pathway regulate metabolic physiology and contribute to disease progression. Using human stem cell-derived metabolic models, including insulin-producing β-cells and albumin-positive hepatocytes, combined with CRISPR-based gene editing and advanced metabolic phenotyping, we investigate the direct consequences of altered JAK–STAT signalling in human cells.
Building on our expertise in human disease modelling, we aim to uncover how individual JAK–STAT pathway components influence processes such as hepatic homeostasis, energy balance, food intake regulation, inflammation, and β-cell dysfunction. These studies will provide new insights into the molecular basis of obesity-associated diabetes and identify potential therapeutic targets to restore metabolic health. (Figure adapted from Gurzov EN et al., FEBS Journal, 2016)
Mapping cellular metabolism using single-cell technologies
Traditional bulk tissue approaches often overlook cellular heterogeneity, limiting our understanding of disease progression. Advances in single-cell RNA sequencing, spatial transcriptomics, and multi-omics technologies now enable high-resolution analysis of pancreatic and hepatic cell populations, revealing disease-associated cellular states and molecular pathways involved in insulin resistance, inflammation, β-cell failure, and metabolic dysfunction.
Our laboratory combines single-cell approaches with human stem cell-derived β-cells and hepatocytes, CRISPR-based gene editing, and advanced metabolic imaging technologies to investigate mechanisms linking obesity to diabetes. Genetically encoded fluorescent biosensors allow real-time monitoring of metabolic processes, including glycolysis, mitochondrial function, lipid metabolism, and cellular stress responses, providing dynamic insights into how pancreatic and liver cells adapt to metabolic stress.
By integrating computational analyses with functional validation, we aim to identify causal mechanisms underlying β-cell dysfunction, hepatic steatosis, and impaired glucose and lipid metabolism. These approaches will enable the discovery of novel therapeutic targets to preserve insulin-producing cells, restore liver metabolic homeostasis, and prevent the progression of obesity-associated type 2 diabetes. (Figure adapted from Pérez Chávez I, Gilglioni EH et al., TEM, 2026)
Selected Publications
Schaschkow A, Pang L, Vandenbempt V, Elvira B, Litwak SA, Vekeriotaite B, Maillard E, Vermeersch M, Paula FM, Pinget M, Perez-Morga D, Gough DJ, Gurzov EN. STAT3 regulates mitochondrial gene expression in pancreatic β-cells and its deficiency induces glucose intolerance in obesity. Diabetes 70(9):2026-2041, 2021
Gurzov EN, Ke PC, Ahlgren U, Garcia Ribeiro RS, Gotthardt M. Novel Strategies to Protect and Visualize Pancreatic β Cells in Diabetes. Trends Endocrinol Metab 31(12):905-917, 2020
Litwak SA, Pang L, Galic S, Igoillo-Esteve M, Stanley WJ, Turatsinze J-V, Loh K, Thomas HE, Sharma A, Trepo E, Moreno C, Gough DJ, Eizirik DL, de Haan JB, Gurzov EN JNK activation of BIM promotes hepatic oxidative stress, steatosis and insulin resistance in obesity. Diabetes 66:2973 -2986, 2017
Gurzov EN, Stanley WJ, Pappas EG, Thomas HE, Gough DJ. The JAK/STAT Pathway in Obesity and Diabetes. FEBS J 283:3002-3015, 2016
Litwak SA, Stanley WJ, Pappas EG, Wali JA, Selck C, Strasser A, Thomas HE, Gurzov EN. p53-upregulated modulator of apoptosis (PUMA)-deficiency affects leptin levels but does not improve glucose homeostasis in obesity. Sci Rep 6:23802, 2016
Gurzov EN, Wang B, Pilkington EH, Chen P, Kakinen A, Stanley WJ, Litwak SA, Davis TP, Ding F, Ke PC. Inhibition of hIAPP Amyloid Aggregation and Pancreatic beta cell Toxicity by OH-terminated PAMAM Dendrimer. Small 12:1615-1626, 2016
Gurzov EN, Stanley WJ, Brodnicki TC, Thomas HE. Protein tyrosine phosphatases: molecular switches in metabolism and diabetes. Trends Endocrinol Metab 26:30-39, 2015
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