Type 2 Diabetes
Conditions
Keywords
type 2 diabetes, redox shuttle, gluconeogenesis
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).
Interventions
DRUGOn Metformin
Oral intake of Metformin (1 g / day) for 2 weeks
DRUGOff Metformin
No oral intake of Metformin (1 g / day) for 2 weeks
Sponsors
Yale University
German Diabetes Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hepatic gluconeogenic flux (U-13C-lactate tracer) (mg/min) | 2 weeks | 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. |
| Hepatic gluconeogenic flux (glycerol tracer) (mg/min) | 2 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Endogenous glucose production (mg/min/kg BW) | 2 weeks | 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. |
| Hepatic mitochondrial oxidative flux (mg/min) | 2 weeks | 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. |
| Hepatic gammaATP (mmol/L) | 2 weeks | 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. |
| Hepatic lipid content (%) | 2 weeks | Hepatic fat \[%\] content will be assessed in people with T2D with and without metformin treatment by employing specific 1H- magnetic resonance spectroscopy. |
Countries
Germany
Outcome results
None listed