High Incomplete Skeletal Muscle Fatty Acid Oxidation Explains Low Muscle Insulin Sensitivity in Poorly Controlled T2D

Area of Science:

• Metabolic diseases
• Endocrinology
• Skeletal muscle physiology

Background:

• Type 2 diabetes (T2D) affects nearly half of patients with poor glycemic control (HbA1c ≥ 7%).
• Worsening glycemic control mechanisms in T2D are not fully understood.
• Reduced skeletal muscle mitochondrial respiratory capacity is linked to insulin resistance and T2D development.

Purpose of the Study:

• To investigate differences in skeletal muscle insulin sensitivity (SI) between well-controlled T2D (WCD) and poorly controlled T2D (PCD) patients.
• To determine if these SI differences are associated with variations in mitochondrial respiratory function.

Main Methods:

• Measured vastus lateralis muscle mitochondrial respiration, content, enzyme activity, and fatty acid oxidation (FAO).
• Calculated SI and acute insulin response to glucose (AIRg) using MINMOD analysis from glucose and insulin data.
• Utilized a modified, frequently sampled, intravenous glucose tolerance test.

Main Results:

• PCD patients exhibited lower SI and AIRg compared to WCD patients.
• Incomplete FAO was higher in PCD patients and correlated with lower SI and higher HbA1c.
• Hydroxyacyl-coenzyme A dehydrogenase expression and activity were elevated in PCD patients, but maximal mitochondrial respiration and content did not differ.

Conclusions:

• Elevated skeletal muscle incomplete FAO in poorly controlled T2D is attributed to increased beta-oxidation.
• This incomplete FAO is associated with diminished muscle insulin sensitivity, contributing to worsening glycemic control in T2D.