"Hepatic Substrate Flux Rates in Type 2 Diabetes" (IMPACT)

"Non-invasive Measurement of Hepatic Substrate Flux Rates in People with Diabetes Mellitus Type 2"

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

Study Overview

• Status: Active, not recruiting
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: On Metformin; Drug: Off Metformin

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).

• Study Type: Interventional
• Enrollment (Estimated): 23
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • NRW
    • Duesseldorf, NRW, Germany, 40225
      • German Diabetes Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin - T2D; Participants with type-2 diabetes will intake metformin 1 g daily for 2 weeks	Drug: On Metformin; Oral intake of Metformin (1 g / day) for 2 weeks
Placebo Comparator: No Metformin - T2D; Participants with type-2 diabetes will pause metformin 1 g daily for 2 weeks	Drug: Off Metformin; No oral intake of Metformin (1 g / day) for 2 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	2 weeks

Collaborators and Investigators

• Sponsor: German Diabetes Center
• Collaborators: Yale University
• Investigators: Principal Investigator: Michael Roden, Prof., MD, German Diabetes Center

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2019
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: September 11, 2019
• First Submitted That Met QC Criteria: September 12, 2019
• First Posted (Actual): September 13, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 9, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: type 2 diabetes, redox shuttle, gluconeogenesis
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus, Type 2; Diabetes Mellitus; Physiological Effects of Drugs; Hypoglycemic Agents; Metformin
• Other Study ID Numbers: IMPACT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No