Mechanism of insulin-stimulated clearance of plasma nonesterified fatty acids in humans

Abstract

Insulin increases plasma nonesterified fatty acid (NEFA) clearance in humans, but whether this is independent of change in plasma NEFA appearance is currently unknown. Nine nondiabetic men (age: 28 Ϯ 3 yr, body mass index: 27.2 Ϯ 1.7 kg/m 2 ) underwent euglycemic clamps to maintain low (LINS) vs. high (HINS) physiological insulin levels for 6 h. An intravenous infusion of heparin ϩ Intralipid (HI) was performed during 4 of the 6 h of the clamps (in the last 4 h at LINS and in the first 4 h at HINS), whereas saline infusion (SAL) was administered in the remaining 2 h to modulate plasma NEFA levels independently of plasma insulin levels. Four experimental conditions were obtained in each individual: LINS with saline (LINS/SAL) and with HI infusion (LINS/HI) and HINS with saline (HINS/SAL) and with HI infusion (HINS/HI). Plasma palmitate appearance during HINS/SAL was lower than during the three other experimental conditions (P Ͻ 0.05). In contrast, plasma linoleate appearance, as expected, was increased by HI independently of insulin level (P Ͻ 0.02). Plasma palmitate clearance during HINS/SAL was higher than LINS/SAL and LINS/HI (P Ͻ 0.008), and this increase was blunted during HINS/HI. We observed a linear decrease in plasma palmitate clearance with increasing plasma NEFA appearance independent of insulin levels. Plasma NEFA levels increased exponentially with increase in plasma NEFA appearance. We conclude that insulin stimulates plasma NEFA clearance by reducing the endogenous appearance rate of NEFA. The relationship between plasma NEFA level and appearance rate is nonlinear.human; insulin action; lipid metabolism; fatty acid metabolism UNDERSTANDING THE REGULATION of plasma nonesterified fatty acid (NEFA) is very important to elucidate its potential role in the development of various pathological conditions, including type 2 diabetes (27). Prolonged experimental elevation of plasma NEFA in humans reproduces the cardinal pathophysiological features of type 2 diabetes, including reduced insulinmediated glucose utilization, impaired glucose-mediated insulin secretion, and increased endogenous glucose production (10, 36, 39). Epidemiological studies have linked elevated plasma NEFA levels to insulin resistance and type 2 diabetes (15,26,35), and reduced suppression of postprandial plasma NEFA concentration is among the earliest metabolic abnormalities seen in the natural history of type 2 diabetes (3).Insulin potently suppresses plasma NEFA appearance. It is often assumed that plasma NEFA level is an accurate reflection of plasma NEFA appearance rate in various physiological and pathophysiological conditions known to affect plasma NEFA levels through change in plasma insulin level, i.e., that plasma NEFA clearance does not change with changing levels of plasma insulin. However, this may not necessarily be the case, because insulin has been shown to stimulate NEFA transport across plasma cell membranes (6). Elevation of plasma insulin level was associated with enhanced plasma NEFA clearance in human studies durin...

Relationship between Total and High Molecular Weight Adiponectin Levels and Plasma Nonesterified Fatty Acid Tolerance during Enhanced Intravascular Triacylglycerol Lipolysis in Men

“…The choice of [U-13 C]palmitate as the NEFA tracer was based on the following: 1) palmitate, oleate, and linoleate are the most prevalent NEFA both in human plasma and in Intralipid, and they have similar plasma clearance rates in humans (14); 2) palmitate was previously used to trace total NEFA turnover in humans after oral fat intake (15,16); and 3) during iv infusion of heparin plus Intralipid infusion (HI) in humans, we have shown that NEFA appearance rates determined with [U-13 C]palmitate predict very well the rates determined using simultaneous palmitate and linoleate tracers (r ϭ 0.90; P Ͻ 0.001) (17). To quantify plasma glycerol flux as a measure of whole body TG lipolysis, a primed continuous (1.6 mol/kg; 0.11 mol/kg ⅐ min Ϫ1 ) infusion of [1,1,2,3,3-2 H 5 ]glycerol (Cambridge Isotopes Laboratories) was also administered during both protocols (18).…”

Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans

“…RaNEFA was measured using i.v. administration of [U-13 C]-palmitate during protocol B using the Steele steady-state equation, as previously described (29,35). Tissue oxidative metabolism was determined after i.v.…”

Update on adipose tissue blood flow regulation

“…ATBF after a normal meal peaks earlier than plasma TG levels (167). Similarly, lipoprotein lipase (LPL) action concomitantly with adipose tissue fat deposition occurs later (32,35). Conversely, ATBF coincides with FFA suppression (42), suggesting that increased postprandial blood flow might serve to deliver a signal, such as insulin, triggering postprandial LPL transcription in preparation for a subsequent peak in plasma TG.…”