"Hepatic Substrate Flux Rates in Type 2 Diabetes"

N/AActive Not RecruitingNCT04088851

German Diabetes Center23 enrolled

Overview

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

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Conditions

Type 2 Diabetes

Interventions

On MetforminDRUG

Oral intake of Metformin (1 g / day) for 2 weeks

Off MetforminDRUG

No oral intake of Metformin (1 g / day) for 2 weeks

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Locations (1)

German Diabetes Center

Düsseldorf, North Rhine-Westphalia, Germany

Outcomes

Primary Outcomes

Hepatic gluconeogenic flux (U-13C-lactate tracer) (mg/min)

Hepatic gluconeogenic flux rates from lactate \[mg/min\] in humans with T2D w/wo metformin treatment will be measured by specific tracer metabolism and turnover of the substrates.

Time frame: 2 weeks

Hepatic gluconeogenic flux (glycerol tracer) (mg/min)

Hepatic gluconeogenic flux rates from glycerol \[mg/min\] in humans with T2D w/wo metformin treatment will be measured by specific tracer metabolism and turnover of the substrates.

Time frame: 2 weeks

Secondary Outcomes

Endogenous glucose production (mg/min/kg BW)

Endogenous glucose production (mg/min/kg BW) in humans with T2D w/wo metformin treatment will be measured by specific tracer metabolism and turnover of the substrates.

Time frame: 2 weeks

Hepatic mitochondrial oxidative flux (mg/min)

Hepatic mitochondrial oxidative flux (mg/min) in humans with T2D w/wo metformin treatment will be measured by specific tracer metabolism and turnover of the substrates.

Time frame: 2 weeks

Hepatic gammaATP (mmol/L)

Hepatic energy \[ATP mmol/l\] content will be assessed in people with T2D with and without metformin treatment by employing specific 31P- magnetic resonance spectroscopy.

Time frame: 2 weeks

Hepatic lipid content (%)

Hepatic fat \[%\] content will be assessed in people with T2D with and without metformin treatment by employing specific 1H- magnetic resonance spectroscopy.

Time frame: 2 weeks

Data from ClinicalTrials.gov

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