CALORIC RESTRICTION REVERSES HEPATIC INSULIN-RESISTANCE IN AGING RATSBY DECREASING VISCERAL FAT

Hyperinsulinemia and increased visceral/abdominal fat (VF) are common features of human aging. To examine the relationships among VF, periph eral, and hepatic insulin sensitivity, we studied 4- and 18-mo-old mal e Sprague-Dawley rats (n = 42) fed ad libitum (4 AL and 18 AL) or mode rately calorie restricted (18 CR) up to 18 mo of age, Total fat mass ( FM) and VF were decreased in 18 CR to approximately one-third of that of 18 AL (P < 0.001), while lean body mass (LBM) was unchanged, Most i mportant, 18 CR had more FM (65 +/- 6 vs. 45 +/- 6 g) but less VF (7.8 +/- 0.6 vs. 12.3 +/- 3.3 g) compared with 4 AL (P < 0.01 for both). T hus, the effects of variable VF on HIS could be assessed, independent of FM and age. Marked hepatic insulin resistance ensued with aging (18 AL) and CR restored hepatic insulin sensitivity to the levels of youn g rats, while peripheral insulin sensitivity remained unchanged (by in sulin clamp of 18 mU/kg/min), In fact, the rates of insulin infusion r equired to maintain basal hepatic glucose production in the presence o f pancreatic clamp were 0.75 +/- 0.10, 1.41 +/- 0.13, and 0.51 +/- 0.1 2 mU/kg.min, in 4 AL, 18 AL, and 18 CR, respectively (P < 0.01 between all groups), and in 18 CR rats infused with insulin at similar rates as in the 18 AL (1.4 mU/kg/min) hepatic glucose production was decreas ed by 32% (P < 0.005). Furthermore, when 18 CR rats were fed AL for 14 d, VF rapidly and selectively increased and severe hepatic insulin re sistance was induced, We propose that in this animal model the age-ass ociated decrease in hepatic (rather than peripheral) insulin action is the major determinant of fasting hyperinsulinemia and that increased visceral adiposity plays the major role in inducing hepatic insulin re sistance. Thus, interventions designed to prevent the accumulation of VF are likely to represent an effective mean to improve carbohydrate m etabolism in aging.