Inhibition Of Adipose Tissue Lipolysis Increases Intramuscular Lipid Use In Type 2 Diabetes Patients

Abstract

Numerous studies have reported the association between elevated plasma free fatty acid (FFA) concentrations, intramyocellular triacylglycerol (IMTG) accumulation and the development of insulin resistance. Excess IMTG accretion is the result of an imbalance between FFA uptake, IMTG deposition and its subsequent mobilisation and/or oxidation. Recent data indicate that this imbalance, and not the actual size or distribution of the IMTG pool, is responsible for the development of insulin resistance. Therefore, the turnover of the IMTG pool should form a major therapeutic target in the prevention and treatment of skeletal muscle insulin resistance. PURPOSE To investigate the consequences of adipose tissue lipolytic inhibition on skeletal muscle substrate use. METHODS Ten type 2 diabetes patients were studied at rest, during exercise and subsequent recovery under normal, fasting conditions (CON) and following administration of a nicotinic acid analogue (LFA). Continuous [U-13C]palmitate and [6,6-2H2]glucose infusions were applied to quantify plasma FFA and glucose oxidation rates, and to estimate intramyocellular lipid and glycogen use. Muscle biopsies were collected before and after exercise to determine net changes in fibre type specific lipid and glycogen content. RESULTS In the LFA trial, plasma FFA rate of appearance was effectively reduced, resulting in 2–5 fold lower plasma FFA concentrations (P<0.001). Plasma FFA oxidation rates were substantially reduced at rest, during exercise and recovery in the LFA trial, which was compensated by an increase in both IMTG and endogenous carbohydrate use. Plasma glucose disposal rates did not differ between trials. During exercise, IMTG use averaged 0.18 ± 0.05 vs 0.08 ± 0.03 g/min in the LFA and CON trial, respectively (P<0.01). In accordance to these tracer data, a greater net decline in type I and type II muscle fiber lipid content was observed following exercise in the LFA vs the CON trial (P<0.05). CONCLUSION This study shows that plasma FFA availability regulates IMTG use and introduces adipose tissue lipolytic inhibition as a means to augment IMTG use in type 2 diabetes patients. The latter seems to represent an effective strategy to improve whole-body insulin sensitivity.