The m.3243A>G mutation in mitochondrial DNA leads to decreased insulin sensitivity in skeletal muscle and to progressive β-cell dysfunction

Abstract

Objective: To study insulin sensitivity and perfusion in skeletal muscle together with the β-cell function in subjects with the m.3243A>G mutation in mitochondrial DNA, the most common cause of mitochondrial diabetes.

Research Design and 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). Controls consisted of 13 healthy subjects that were similar to the carriers of m.3243A>G with respect to age and physical activity. β-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 controls. The glucose sensitivity of β-cells in group 1 patients was similar to that of the controls, 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 the β-cell function is not markedly impaired or glucose control compromised. We suggest that both the skeletal muscle insulin sensitivity and the β-cell function are affected before the onset of the mitochondrial diabetes caused by the m.3243A>G mutation.