"The Role of the Liver for Interorgan Metabolic Crosstalk in Type 2 Diabetes"

WP 1: Working hypothesis: The gluconeogenic flux rates from pyruvate (lactate, alanine) and glycerol are higher in patients with T2D compared to the healthy control group. WP2: Working Hypothesis: The gluconeogenic flux rates of lactate and glycerol are reduced in patients with T2D by acute inhibition of the redox shuttle.

Type 2 diabetes (T2D) is characterized by insulin resistance and inadequate insulin secretion leading to hyperglycemia. Current concepts indicate that insulin resistant adipose tissue releases metabolites, which stimulate hepatic gluconeogenesis (GNG), lipid deposition and secretion. Failure of compensation by ß cell function will favour muscle insulin resistance and fasting/postprandial hyperglycemia. The investigators have previously provided evidence for abnormal ATP synthesis and mitochondrial efficiency, but it remains unknown, how and which substrate fluxes account for excessive GNG in T2D. For this reason, the main objective of this project is to adress the multi-system challenges of T2D, by examining interorgan metabolic crosstalk with an emphasis on liver as orchestrator of interorgan substrate fluxes and driver of the transition from normo- to hyperglycemia. This proposal aims at investigating hepatic glucose and energy flux in T2D with focus on gluconeogenic contribution of lactate to hepatic mitochondrial substrate flux, the activity of the redox shuttle and mitochondrial ATP synthase flux, also after inhibition by metformin by using a novel combination of positional isotopomer nuclear magnetic resonance (NMR) analysis (PINTA) with multinuclei magnetic resonance spectroscopy (MRS).

The gluconeogenic flux rates from pyruvate (lactate, alanine) and glycerol are higher in patients with T2D compared to the healthy control group.

The present study tests the hypothesis that the GDP redox-shuttle is overactive and responsible for excessive GNG in human T2D what could be enhanced by adipocines secreted from inflammed adipose tissue in obese. It is a randomized controlled trial investigating liver energy metabolism in patients with T2D with and without inhibition of redox shuttle in patients with T2D and compared to a healthy control group (age- and BMI corrected). Patients and healthy controls are included prospectively. The combination of PINTA method and MRS determines the flux rates of pyruvate (lactate and alanine) and glycerol as well as gluconeogenesis and glycogenolysis. In addition, acute cellular changes after acute inhibition of the redox shuttle are investigated.

Inclusion Criteria: T2D + metformin therapy healthy volunteers Exclusion Criteria: no metformin therapy