Subjects With Early-Onset Type 2 Diabetes Show Defective Activation of the Skeletal Muscle PGC-1α/Mitofusin-2 Regulatory Pathway in Response to Physical Activity

Objective: Type 2 diabetes is associated with insulin resistance and skeletal muscle mitochondrial dysfunction. We have found that subjects with early-onset type 2 diabetes show incapacity to increase Vo2max in response to chronic exercise. This suggests a defect in muscle mitochondrial response to exercise. Here, we have explored the nature of the mechanisms involved. Research design and methods: Muscle biopsies were collected from young type 2 diabetic subjects and obese control subjects before and after acute or chronic exercise protocols, and the expression of genes and/or proteins relevant to mitochondrial function was measured. In particular, the regulatory pathway peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha/mitofusin-2 (Mfn2) was analyzed. Results: At baseline, subjects with diabetes showed reduced expression (by 26%) of the mitochondrial fusion protein Mfn2 and a 39% reduction of the alpha-subunit of ATP synthase. Porin expression was unchanged, consistent with normal mitochondrial mass. Chronic exercise led to a 2.8-fold increase in Mfn2, as well as increases in porin, and the alpha-subunit of ATP synthase in muscle from control subjects. However, Mfn2 was unchanged after chronic exercise in individuals with diabetes, whereas porin and alpha-subunit of ATP synthase were increased. Acute exercise caused a fourfold increase in PGC-1alpha expression in muscle from control subjects but not in subjects with diabetes. Conclusions: Our results demonstrate alterations in the regulatory pathway that controls PGC-1alpha expression and induction of Mfn2 in muscle from patients with early-onset type 2 diabetes. Patients with early-onset type 2 diabetes display abnormalities in the exercise-dependent pathway that regulates the expression of PGC-1alpha and Mfn2.</p

Correction: Prevalence of Cutaneous Leishmaniasis in Districts of High and Low Endemicity in Mali.

[This corrects the article DOI: 10.1371/journal.pntd.0005141.]

Prevalence of LST positivity by age group and by study districts.

<p>Prevalence of LST positivity by age group and by study districts.</p

Images representative of active CL cases diagnosed during the study.

<p><b>A</b>: Ulcero-crusted lesion of CL (3 to 4 cm diameter) on the forearm of 8 years old girl from the village of Nafadji. <b>B</b>: Ulcerated nodule of CL (1.5 cm diameter) of the left forearm of 10 years old girl from the village of Nafadji. <b>C</b>: Superinfected and crusted lesion of CL of the right forearm of a 3 years old girl from the village of Guemou. Please note the dry and erythematous halo with an eczematization of the lesion. <b>D</b>: Ulcerated lesion of CL with black crusted lesion (covered by a local traditional powder) of leg of a 2 years boy from the village of Nafadji. <b>E</b>: Ulcerated nodule of CL of the right knee of a 13 years old boy from the village of Tinkare.</p

Map of Mali showing the study sites in different districts.

<p>Map of Mali showing the study sites in different districts.</p

Optical density (OD) of antibodies against sand fly saliva measured by ELISA.

<p>A) Antibody levels in tested subjects from the 6 study villages. Sample size is shown in brackets. B) Overall antibody levels in leishmanin positive (LST+) and negative (LST-) study subjects. CTL, non-endemic controls from US healthy volunteers not exposed to <i>Leishmania</i>.</p