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

Markus M Lindroos, Kari Majamaa, Andrea Tura, Andrea Mari, Kari K Kalliokoski, Markku T Taittonen, Patricia Iozzo, Pirjo Nuutila, Markus M Lindroos, Kari Majamaa, Andrea Tura, Andrea Mari, Kari K Kalliokoski, Markku T Taittonen, Patricia Iozzo, Pirjo Nuutila

Abstract

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.

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). 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.

Figures

FIG. 1.
FIG. 1.
OGTT in patients with the m.3243A>G mutation. A: Glucose concentration. B: C-peptide concentration. C: Insulin concentration. ○, control subjects. Patients with m.3243A>G mutation: •, group 1; ▴, group 2; and ×, group 3. A–C: *P < 0.05 vs. healthy subjects, at respective time points.
FIG. 2.
FIG. 2.
Rate sensitivity and glucose sensitivity of the β-cells during OGTT. A: Rate sensitivity is the insulin secretion response to the pace of increase in plasma glucose. Control subjects, □. Patients with m.3243A>G mutation: , group 1; , group 2; and ▪, group 3. The apparently high rate sensitivity in group 1 is partly due to the higher insulin sensitivity in the control subjects, because rate sensitivity tends to be inversely correlated with insulin sensitivity (see Table 2 for respective disposition index). B: Glucose sensitivity is the insulin dose-response function to absolute glucose level during OGTT.
FIG. 3.
FIG. 3.
Skeletal muscle and whole-body glucose uptake. A: Skeletal muscle insulin-stimulated glucose uptake. B: Correlation between skeletal muscle and whole-body glucose uptake (M value) in all groups (for linear correlation r = 0.78–0.99 and P < 0.007). ○, control subjects. Patients with m.3243A>G mutation: •, group 1; ▴, group 2; and ×, group 3.
FIG. 4.
FIG. 4.
Perfusion and glucose extraction in skeletal muscle. A: Skeletal muscle blood flow per tissue weight. B: Glucose extraction; glucose uptake per blood flow in skeletal muscle.
FIG. 5.
FIG. 5.
β-Cell function and m.3243A>G heteroplasmy. There was an inverse relationship between dynamic insulin secretion parameters and m.3243A>G heteroplasmy. The AUCI/AUCG as a function of m.3243A>G heteroplasmy in skeletal muscle (r = −0.83; P = 0.001).

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