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

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.

• Authors: Markus M Lindroos, Kari Majamaa, Andrea Tura, Andrea Mari, Kari K Kalliokoski, Markku T Taittonen, Patricia Iozzo, Pirjo Nuutila
• Journal: Diabetes (Diabetes) Vol. 58 Issue 3 Pg. 543-9 (Mar 2009) ISSN: 1939-327X [Electronic] United States
• PMID: 19073775 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Mitochondrial
• Fluorine Radioisotopes
• Hypoglycemic Agents
• Insulin
• Fluorodeoxyglucose F18
• Guanine
• Adenine

Topics

• Adenine
• Adult
• DNA, Mitochondrial (genetics)
• Diabetes Mellitus (genetics, physiopathology)
• Female
• Fluorine Radioisotopes
• Fluorodeoxyglucose F18 (pharmacokinetics)
• Glucose Clamp Technique
• Guanine
• Humans
• Hypoglycemic Agents (therapeutic use)
• Insulin (physiology, therapeutic use)
• Insulin-Secreting Cells (physiology)
• Islets of Langerhans (physiopathology)
• Male
• Middle Aged
• Muscle, Skeletal (physiology, physiopathology)
• Polymorphism, Single Nucleotide
• Positron-Emission Tomography
• Reference Values