m.3243A>G mutation in mitochondrial DNA leads to decreased insulin sensitivity in skeletal muscle and to progressive beta-cell dysfunction.
OBJECTIVE
To study insulin sensitivity and perfusion in skeletal muscle together with the beta-cell function in subjects with the m.3243A>G mutation in mitochondrial DNA, the most common cause of mitochondrial diabetes.


METHODS
We measured skeletal muscle glucose uptake and perfusion using positron emission tomography and 2-[18F]fluoro-2-deoxyglucose and [15O]H2O during euglycemic hyperinsulinemia in 15 patients with m.3243A>G. These patients included five subjects with no diabetes as defined by the oral glucose tolerance test (OGTT) (group 1), three with GHb <6.1% and newly found diabetes by OGTT (group 2), and seven with a previously diagnosed diabetes (group 3). Control subjects consisted of 13 healthy individuals who were similar to the carriers of m.3243A>G with respect to age and physical activity. Beta-cell function was assessed using the OGTT and subsequent mathematical modeling.


RESULTS
Skeletal muscle glucose uptake was significantly lower in groups 1, 2, and 3 than in the control subjects. The glucose sensitivity of beta-cells in group 1 patients was similar to that of the control subjects, whereas in group 2 and 3 patients, the glucose sensitivity was significantly lower. The insulin secretion parameters correlated strongly with the proportion of m.3243A>G mutation in muscle.


CONCLUSIONS
Our findings show that subjects with m.3243A>G are insulin resistant in skeletal muscle even when beta-cell function is not markedly impaired or glucose control compromised. We suggest that both the skeletal muscle insulin sensitivity and the beta-cell function are affected before the onset of the mitochondrial diabetes caused by the m.3243A>G mutation.
Lindroos
Markus M
MM
Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland. markus.lindroos@utu.fi
Majamaa
Kari
K
Tura
Andrea
A
Mari
Andrea
A
Kalliokoski
Kari K
KK
Taittonen
Markku T
MT
Iozzo
Patricia
P
Nuutila
Pirjo
P
D000225:Adenine; D000328:Adult; D004272:DNA, Mitochondrial / Q000235:genetics*; D003920:Diabetes Mellitus / Q000235:genetics / Q000503:physiopathology; D005260:Female; D005462:Fluorine Radioisotopes; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D015309:Glucose Clamp Technique; D006147:Guanine; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000502:physiology* / Q000627:therapeutic use; D050417:Insulin-Secreting Cells / Q000502:physiology*; D007515:Islets of Langerhans / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000502:physiology* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D049268:Positron-Emission Tomography; D012016:Reference Values
D004272:DNA, Mitochondrial; D005462:Fluorine Radioisotopes; D007004:Hypoglycemic Agents; D007328:Insulin; D019788:Fluorodeoxyglucose F18; D006147:Guanine; D000225:Adenine