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Mitochondrial function in skeletal muscle in type 2 diabetes

Rasmus Rabøl  


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Accepted by: Faculty ofHealth Sciences University of Copenhagen
Defended on: January 9, 2009
Official opponents: Kurt Højlund, PhD , Kent Sahlin, dr. techn. , THomas Mandrup-Poulsen, Prof. dr. med
Tutors: Flemming Dela, Prof. dr. med , Sten Madsbad, Prof. dr. med , Thomas Almdal, dr. med

Published in the PhD Database: January 10, 2009


English abstract
Reduced skeletal muscle mitochondrial function has been proposed to lead to insulin resistance
and type 2 diabetes. It has been known for several years that oxidative capacity of skeletal muscle
is reduced in patients with type 2 diabetes compared to obese controls. The reduction in
oxidative capacity supposedly leads to the accumulation of intramyocellular lipid which inhibits
insulin signalling and causes insulin resistance.
This PhD-thesis describes the effect of different pharmacological interventions
on mitochondrial function in type 2 diabetes and describe whether mitochondrial function is
uniformly distributed to both upper and lower extremities. Furthermore, a hypothesis on the
molecular mechanism for weight gain observed with anthyperglycaemic treatment will be
presented.
Study I.
To study the role of hyperglycaemia on mitochondrial function 11 patients with type 2 diabetes
were included. The patients were studied after a period of poor glycaemic control (2-week washout of antidiabetic medication) and again after a period of optimal glycaemic control (6-week intensive insulin treatment). The insulin treatment brought the HbA1c and fruktosamin down significantly, but did not change mitochondrial respiration measured on saponin-treated skinned muscle fibers. A control group matched for age- and BMI was also included. The non-diabetic controlas had, on average, a 20% higher respiration than the patients with type 2 diabetes. This was due to a higher mitochondrial content in their muscle measured as a higher citrate synthase activity. We conclude that the reduction in mitochondrial capacity in type 2 diabetes is not due to hyperglycaemia.
Study II.
Measurements of skeletal muscle mitochondrial capacity have traditionally been carried out in
the leg musculature. We included 10 patients with type 2 diabetes and obtained muscle biopsies
from m. deltoideus and m. vastus lateralis. We compared intramuscular triglyceride,
mitochondrial respiration and citrate synthase activity between these two muscles. We also
included a control group, matched for age- and BMI. The groups had comparable VO2max. M. deltoideus and m. vastus lateralis were selected because of the similar fibertype composition of
these muscles.
When comparing mitochondrial respiration in patients with type 2 diabetes and obese
control subjects, we could only find a significant difference in the leg muscle. The arm muscle in
the patients and the controls had similar levels of respiration, and were comparable to the level of
the legs of the patients with type 2 diabetes.
We conclude that reduced mitochondrial capacity is not present in all muscle groups in type 2
diabetes, and this does not support the assumption that mitochondrial dysfunction is a
primary genetic defect in type 2 diabetes.
Study III.
In order to demonstrate a direct relationship between insulin sensitivity and mitochondrial
function we treated 12 patients with type 2 diabetes with an insulin sensitizer (rosiglitazone). All
patients had their insulin sensitivity measured, and muscle biopsies from m. vastus lateralis were
obtained at baseline and after three months therapy.
Treatment resulted in a significant improvement in insulin sensitivity, but a paradoxical,
significant decrease in mitochondrial respiration. We conclude that insulin sensitivity can be
improved without concommitant improvements in mitochondrial function in type 2 diabetes.
Study IV.
Optimal glyceamic control did not affect mitochondrial respiration in study I. However, we found
a decrease in inner mitochondrial proton leak as a result of the improved glyceamic control. Proton leak is directly correlated to energy metabolism, and we have shown that improvements in glyceamic control leads to increases in mitochondrial efficiency and a drecrease in energy metabolism. This could be one of the mechanisms explaining why patien



Danish abstract