Metabolic signaling from the liver in type 2 diabetes

I hypothesize that 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.

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.