Aging per se increases the susceptibility to free fatty acid-induced insulin resistance

Abstract

Elevations in systemic free fatty acids (FFA) contribute to insulin resistance. To determine the effects of an acute elevation in FFA on insulin action with aging, we infused saline or intralipid (IL) during a hyperinsulinemic-euglycemic clamp in three groups of rats: young ad libitum-fed (YAL), old ad libitum-fed (OAL), and old on lifelong calorie restriction (OCR). The OCR group was included to distinguish between aging per se and age-related changes in body fat distribution. IL induced marked insulin resistance in both YAL and OCR, but the onset of insulin resistance was approximately two to three times more rapid in OCR as compared with YAL. In response to IL infusion, plasminogen-activating inhibitor-1 (PAI-1) expression was increased in subcutaneous fat from OAL animals. In visceral fat, a marked increase in PAI-1 and interleukin-6 expression was observed in OAL and OCR rats, but not YAL, in response to IL treatment. Thus, aging per se increases the inflammatory response to excess nutrients and vulnerability to FFA-induced insulin resistance with aging.

Figure 1.

Effect of saline (Sal) and intralipid (IL) infusion on glucose infusion rate (GIR) in (A) YAL, (B), OCR and (C) OAL rats. All rats underwent 5 hours of Sal infusion (control) or IL at a rate of 1.5 mL/h during the hyperinsulinemic clamp (3 mU/kg/min). Symbols and error bars are means ± SE (*p ≤ .05 vs Sal).

Figure 2.

Effect of saline (Sal) and intralipid (IL) infusion on glucose uptake (R_d) in (A) YAL, (B) OCR, and (C) OAL rats. Symbols and error bars are means ± SE (*p ≤ .05 vs Sal).

Figure 3.

Effect of saline (Sal) and intralipid (IL) infusion on endogenous glucose production (EGP) in (A) YAL, (B) OCR, and (C) OAL rats. Symbols and error bars are means ± SE (*p ≤ .05 vs Sal).

Figure 4.

Effect of saline (Sal) and intralipid (IL) infusion on gene expression of adipokines from visceral fat in YAL, OCR, and OAL rats during a hyperinsulinemic clamp including (A) angiotensinogen (AT), (B) resistin, (C) leptin, (D) tumor necrosis factor-α (TNFα), (E) plasminogen-activating inhibitor-1 (PAI-1), (F) interleukin (IL)-6, and (G) IL-18. All values were normalized to the expression of the housekeeping gene beta-2 microglobulin. Macrophage content as a percentage of stromal vascular cells in 1 g of visceral fat was assessed by flow cytometry and is shown in panel (H). Data are means ± SE. Different letters denote a significant difference between groups in panel H (p ≤ .05). *Denotes a significant difference between IL and Sal within groups (p ≤ .05).

Figure 5.

Effect of saline (Sal) and intralipid (IL) infusion on gene expression of adipokines from subcutaneous fat in YAL, OCR, and OAL rats during a hyperinsulinemic clamp, including (A) angiotensinogen (AT), (B) resistin, (C) leptin, (D) tumor necrosis factor-α (TNFα), (E) plasminogen-activating inhibitor-1 (PAI-1), (F) interleukin (IL)-6, and (G) IL-18. All values were normalized to the expression of the housekeeping gene beta-2 microglobulin Macrophage content as a percentage of stromal vascular cells in 1 g of SC fat was assessed by FACS is shown in panel (H). Data are means ± SE. Different letters denote a significant difference between groups (p < .05). *Denotes a significant difference between IL and Sal within groups (p ≤ .05).