This study investigates the relationship between skeletal muscle triglyceride (mTG) levels and insulin action in humans. The researchers assessed 38 nondiabetic male Pima Indians using a euglycemic clamp to measure insulin sensitivity at physiological and supraphysiological insulin levels. mTG was determined in vastus lateralis muscles obtained by percutaneous biopsy. The results showed a significant negative correlation between mTG and insulin sensitivity at both physiological and supraphysiological insulin levels, as well as nonoxidative glucose disposal. However, mTG was not related to measures of adiposity. Multiple regression analyses revealed that mTG was independently associated with measures of insulin resistance, while obesity measures were related to insulin resistance independent of mTG. The findings suggest that local supplies of triglycerides in skeletal muscle, similar to animal models, strongly influence insulin sensitivity and may play a crucial role in understanding insulin resistance.This study investigates the relationship between skeletal muscle triglyceride (mTG) levels and insulin action in humans. The researchers assessed 38 nondiabetic male Pima Indians using a euglycemic clamp to measure insulin sensitivity at physiological and supraphysiological insulin levels. mTG was determined in vastus lateralis muscles obtained by percutaneous biopsy. The results showed a significant negative correlation between mTG and insulin sensitivity at both physiological and supraphysiological insulin levels, as well as nonoxidative glucose disposal. However, mTG was not related to measures of adiposity. Multiple regression analyses revealed that mTG was independently associated with measures of insulin resistance, while obesity measures were related to insulin resistance independent of mTG. The findings suggest that local supplies of triglycerides in skeletal muscle, similar to animal models, strongly influence insulin sensitivity and may play a crucial role in understanding insulin resistance.