Metabolic signaling from the liver in type 2 diabetes

Metabolic crosstalk between liver and other tissues affects the development and outcome of Type 2 Diabetes. T2D is caused by impairments of insulin secretion by pancreatic islets, usually secondary to insulin resistance in its target tissues. The liver is the largest producer and storage facility of glucose and therefore it controls blood glucose levels but this either is deranged or not sufficient in T2D. We will determine metabolic remodeling in the liver during development of T2D and how this affects the physiological parameters of islets, fat tissue, and muscle. This will be done in db/db mice using metabolomics, transcriptomics, and lipidomics. These results will provide an overview of metabolic changes associated with T2D and from these we will select metabolites and hepatokines with potential to signal to islets, fat tissue, and muscle. We will study how these metabolites affect insulin secretion, lipid species, and gene expression using islet, adipose, and muscle cell lines, as well as human islets and mouse models. Our results will uncover how other tissues react to liver metabolites and what is the mechanism underlying this crosstalk in T2D. We will validate our results in patient samples including liver biopsies, human hepatocytes, liver organoids, and in patient stem cell derived hepatocytes. This will determine the applicability of our results to patients and guide us to design clinical trials to test novel therapeutic approaches for T2D patients.

Diabetes and fatty liver does not only affect millions of people but is also an increasing burden for our health care system and society in general. Diabetes is caused by the loss of insulin secretion of the pancreatic islets secondary to insulin resistance in its target organs. Diabetic patients often require treatment with insulin injections, which is less than perfect due to insulin resistance and other side effects. It is puzzling that approximately 50% of diabetes patients also develop a fatty liver. The liver is the largest organ of our body and both produces and stores glucose/sugar. Therefore, it is conceivable that the liver plays a major role in diabetes. My hypothesis is that the liver sends and receives signals during the development of diabetes that affect the physiology of a number of organs in our body. This could mean that diabetes is not just a disease caused by defects in the pancreatic islets and insulin resistance but that the liver metabolome is remodeled, which then leads to changes in several organs collectively causing the morbidities of diabetes. Therefore, we need to consider “out-of-the-box” approaches for the treatment of diabetes.
Our approach is to map all the signals that the liver receives or sends using state-of-the-art methods in a mouse model for diabetes. Applying bioinformatics to analyse the results, we will identify signaling molecules/metabolites that are exchanging information between the liver and other organs. These metabolites will be tested for their effects on cell lines originating from pancreatic islets, fat tissue, and muscles. In addition, we will use mouse models to investigate how the signals from the liver affect the physiology of organs and how this leads to the disease in the liver, pancreatic islets, and also other organs. These experiments will tell us how distant organs react to liver metabolites and what are the mechanisms of metabolic crosstalk in diabetes. We will then validate our results in liver biopsies, human liver cells, liver organoids, and patient stem cell derived liver cells. These approaches will tell us whether our data applies also to patients suffering from diabetes or a fatty liver. Our main long-term goal is to help patients and therefore to develop new cures. These novel therapeutic approaches can then be tested in clinical trials. Our work will focus on the liver while considering distal organs, rather than focusing on the pancreatic islets. Therefore, we will uncover a signaling network connecting several organs, which is the cause of the defects seen in diabetes.