Clinical trial NCT04088851: "Hepatic Substrate Flux Rates in Type 2 Diabetes"
Official title: "Non-invasive Measurement of Hepatic Substrate Flux Rates in People with Diabetes Mellitus Type 2"
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Type 2 Diabetes
Keywords: type 2 diabetes, redox shuttle, gluconeogenesis
Lead sponsor: German Diabetes Center
Sponsor class: OTHER
Collaborators: name: Yale University
First posted: 2019-09-13
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: Investigation of the effects of redox shuttle inhibition by metformin on gluconeogenic flux rates of lactate and glycerol in humans with type 2 diabetes

Detailed description: Type 2 diabetes (T2D) is characterized by insulin resistance and relative insulin deficiency leading to hyperglycemia. Enhanced endogenous glucose production during fasting is a key feature of hepatic insulin resistance and a major contributor to deterioration of glycemia. Metformin reduces fasting gluconeogenesis (GNG); the underlying mechanisms are still not fully understood, but involve the inhibition of complexes of the electron transport chain and thus the redox shuttle.

The investigators have previously provided evidence for abnormal hepatic ATP synthesis and mitochondrial efficiency in T2D, but it remains unknown, how and which substrate fluxes account for excessive GNG in T2D. For this reason, this proposal aims at investigating hepatic glucose and energy fluxes in T2D with focus on gluconeogenic contribution of lactate and glycerol to hepatic mitochondrial substrate flux, mitochondrial ATP synthase flux and the activity of the redox shuttle, also after metformin intake, by using a novel combination of positional isotopomer nuclear magnetic resonance (NMR) analysis (PINTA) with multinuclei magnetic resonance spectroscopy (MRS).

Eligibility criteria: Inclusion criteria:

* type 2 diabetes (duration \<7 years),
* age (18-75 years)
* BMI \<40 kg/m2
* HbA1c 6-15%

Exclusion criteria:

* uncontrolled hyperglycaemia (\>340 mg/dl)
* diabetes types other than type 2 diabetes (ADA criteria)
* thiazolidinedione use during the preceding 6 months
* clinically relevant angiopathy, restrictive or obstructive lung diseases
* other acute or chronic diseases including wounds and the use of pharmacological agents known to affect insulin sensitivity, lipid metabolism or immunological function.

Primary outcomes:
measure: Hepatic gluconeogenic flux (U-13C-lactate tracer) (mg/min)
timeFrame: 2 weeks
measure: Hepatic gluconeogenic flux (glycerol tracer) (mg/min)
timeFrame: 2 weeks
Secondary outcomes:
measure: Endogenous glucose production (mg/min/kg BW)
timeFrame: 2 weeks
measure: Hepatic mitochondrial oxidative flux (mg/min)
timeFrame: 2 weeks
measure: Hepatic gammaATP (mmol/L)
timeFrame: 2 weeks
measure: Hepatic lipid content (%)
timeFrame: 2 weeks
Other outcomes:
Locations:
city: Duesseldorf
country: Germany
facility: German Diabetes Center
state: NRW
Study officials:
affiliation: German Diabetes Center
name: Michael Roden, Prof., MD
role: PRINCIPAL_INVESTIGATOR
References: