Improved glycaemic control decreases inner mitochondrial membrane leak in type 2 diabetes.
OBJECTIVE
Several mechanisms have been targeted as culprits of weight gain during antihyperglycaemic treatment in type 2 diabetes (T2DM). These include reductions in glucosuria, increased food intake from fear of hypoglycaemia, the anabolic effect of insulin, decreased metabolic rate and increased efficiency in fuel usage. The purpose of the study was to test the hypothesis that mitochondrial efficiency increases as a result of insulin treatment in patients with type 2 diabetes.


METHODS
We included ten patients with T2DM (eight males) on oral antidiabetic treatment, median age: 51.5 years (range: 39-67) and body mass index (BMI): 30.1 +/- 1.2 kg/m2 (mean +/- s.e.). Muscle biopsies from m. vastus lateralis and m. deltoideus were obtained before and after seven weeks of intensive insulin treatment, and mitochondrial respiration was measured using high-resolution respirometry. State 3 respiration was measured with the substrates malate, pyruvate, glutamate, succinate and ADP. State 4o was measured with addition of oligomycine. An age, sex and BMI-matched control group was also included.


RESULTS
HbA1c improved significantly and the patients gained on average 3.4 +/- 0.9 kg. Before treatment, respiratory control ratios (RCRs) of the T2DM were lower than the obese controls [2.6 vs. 3.2 (p < 0.05)], but RCR returned to the levels of the control subjects during treatment. Average state 4o of arm and leg declined by 14% (p < 0.05) during insulin treatment.


CONCLUSIONS
Tight glycaemic control leads to reductions in inner mitochondrial membrane leak and increased efficiency of mitochondria. This change in mitochondrial physiology could contribute to the weight gain seen with antihyperglycaemic treatment.
Rabøl
R
R
Copenhagen Muscle Research Centre, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. rasmus.rabol@yale.edu
Højberg
P M V
PM
Almdal
T
T
Boushel
R
R
Haugaard
S B
SB
Madsbad
S
S
Dela
F
F
D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism*; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism
D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; C517652:hemoglobin A1c protein, human