Normal postprandial nonesterified fatty acid uptake in muscles despite increased circulating fatty acids in type 2 diabetes

OBJECTIVE

Postprandial plasma nonesterified fatty acid (NEFA) appearance is increased in type 2 diabetes. Our objective was to determine whether skeletal muscle uptake of plasma NEFA is abnormal during the postprandial state in type 2 diabetes.

RESEARCH DESIGN AND METHODS

Thigh muscle blood flow and oxidative metabolism indexes and NEFA uptake were determined using positron emission tomography coupled with computed tomography (PET/CT) with [¹¹C]acetate and 14(R,S)-[¹⁸F]fluoro-6-thia-heptadecanoic acid (¹⁸FTHA) in seven healthy control subjects (CON) and seven subjects with type 2 diabetes during continuous oral intake of a liquid meal to achieve steady postprandial NEFA levels with insulin infusion to maintain similar plasma glucose levels in both groups.

RESULTS

In the postprandial state, plasma NEFA level was higher in type 2 diabetic subjects versus CON (P < 0.01), whereas plasma glucose was at the same level in both groups. Muscle NEFA fractional extraction and blood flow index levels were 56% (P < 0.05) and 24% (P = 0.27) lower in type 2 diabetes, respectively. However, muscle NEFA uptake was similar to that of CON (quadriceps femoris [QF] 1.47 ± 0.23 vs. 1.37 ± 0.24 nmol ⋅ g⁻¹ ⋅ min⁻¹, P = 0.77; biceps femoris [BF] 1.54 ± 0.26 vs. 1.46 ± 0.28 nmol ⋅ g⁻¹ ⋅ min⁻¹, P = 0.85). Muscle oxidative metabolism was similar in both groups. Muscle NEFA fractional extraction and blood flow index were strongly and positively correlated (r = 0.79, P < 0.005).

CONCLUSIONS

Postprandial muscle NEFA uptake is normal despite elevated systemic NEFA levels and acute normalization of plasma glucose in type 2 diabetes. Lower postprandial muscle blood flow with resulting reduction in muscle NEFA fractional extraction may explain this phenomenon.Increased intramyocellular triglyceride (IMTG) level correlates with impaired insulin sensitivity in obese insulin-resistant subjects and subjects with type 2 diabetes (1). Experimental elevation of plasma nonesterified fatty acid (NEFA) in humans using intravenous lipid infusion was associated with rapid deposition of IMTG associated with the development of insulin resistance within 4 h (2). Similarly, high-fat diet for 3 days in healthy volunteers induced IMTG accumulation associated with impaired insulin sensitivity (3). It has been demonstrated that subjects with type 2 diabetes have increased postprandial IMTG deposition (4), but the mechanisms leading to this phenomenon have not been elucidated. Impaired muscle fatty acid oxidation has been shown during fasting and during exercise in obese insulin-resistant subjects and subjects with type 2 diabetes (5–7). However, impaired muscle NEFA oxidation was associated with impaired NEFA uptake in the later studies, and suppression of muscle fatty acid oxidation by insulin was reduced in insulin-resistant individuals (5). During similar intravenous fat load, NEFA levels were higher in subjects with impaired glucose tolerance, a phenomenon that is significantly correlated with lipid-induced insulin resistance and impaired β-cell function in vivo (8). We demonstrated that this “impaired NEFA tolerance” during intravenous fat load is associated with increased whole-body palmitate oxidation in offspring of parents with type 2 diabetes (9). Recently, we showed that subjects with type 2 diabetes have increased postprandial NEFA appearance and whole-body oxidation rates without or with acute correction of hyperglycemia using intravenous insulin infusion to clamp glucose level (10).The aim of the current study was to determine whether postprandial NEFA uptake in thigh skeletal muscles is increased in men with established but well-controlled type 2 diabetes compared with healthy men without a family history of type 2 diabetes. Our hypothesis was that increased postprandial NEFA appearance is associated with increased NEFA uptake in thigh skeletal muscle of men with type 2 diabetes. Our study design also allowed us, as a secondary objective, to determine postprandial leg subcutaneous adipose tissue NEFA uptake that may be a potential mechanism for increased postprandial plasma NEFA levels in type 2 diabetes.