Insulin Resistance in Human iPS Cells Reduces Mitochondrial Size and Function

Area of Science:

• Cellular Metabolism
• Mitochondrial Biology
• Diabetes Pathophysiology

Background:

• Insulin resistance is a precursor to type 2 diabetes (T2D).
• Mitochondrial dysfunction is linked to T2D.
• The causal link between insulin resistance and mitochondrial dysfunction requires clarification.

Purpose of the Study:

• To investigate the cause-effect relationship between insulin resistance and mitochondrial dysfunction.
• To compare mitochondrial metabolism in insulin-resistant cells versus healthy controls.

Main Methods:

• Utilized induced pluripotent stem cells (iPSC) from healthy individuals and patients with insulin receptor mutations.
• Assessed mitochondrial number, size, oxidative function (citrate synthase activity, spare respiratory capacity), glycolytic enzyme expression, lactate production, ADP/ATP ratio, AMPK activity, and catalase activity.

Main Results:

• Insulin-resistant iPSC exhibited increased mitochondrial number but decreased size.
• Impaired mitochondrial oxidative function, reduced spare respiratory capacity, and increased lactate production were observed.
• Elevated ADP/ATP ratio and AMPK activity indicated cellular energetic stress.
• Reduced catalase activity and increased susceptibility to oxidative stress were noted.

Conclusions:

• Insulin resistance can directly cause mitochondrial dysfunction.
• This dysfunction is characterized by altered mitochondrial morphology, reduced oxidative capacity, and impaired energy production.
• These findings highlight a critical mechanism linking insulin resistance to diabetes pathophysiology.