Our findings provide compelling evidence that, despite increased mechanical loading and independent of lean mass, adipose tissue is not beneficial to bone structure.

Suppression of hepatic glucose output (HGO) has been shown to be primarily mediated by peripheral rather than portal insulin concentrations; however, the mechanism by which peripheral insulin suppresses HGO has not yet been determined. Previous findings by our group indicated a strong correlation between free fatty acids (FFA) and HGO, suggesting that insulin suppression of HGO is mediated via suppression of lipolysis. To directly test the hypothesis that insulin suppression of HGO is causally linked to the suppression of adipose tissue lipolysis, we performed euglycemic-hyperinsulinemic glucose clamps in conscious dogs ( n ϭ 8) in which FFA were either allowed to fall or were prevented from falling with Liposyn plus heparin infusion (LI; 0.

We found that visceral and sc fat have opposite effects on the appendicular skeleton; whereas sc fat is beneficial to bone structure and strength, visceral fat serves as an unique pathogenic fat depot.

The in vivo effect of elevated free fatty acids (FFA) on β-cell function in humans remains extremely controversial. We examined, in healthy young men, the acute (90 min) and chronic (48 h) effects of an approximately twofold elevation of plasma FFA vs. control on glucose-stimulated insulin secretion (GSIS). GSIS was studied in response to a graded intravenous glucose infusion (peak plasma glucose, ∼10 mmol/l, n = 8) and a two-step hyperglycemic clamp (10 and 20 mmol/l, n = 8). In the acute studies, GSIS was significantly higher, insulin sensitivity index (SI) was lower, and disposition index (DI = insulin sensitivity × insulin secretion) was unchanged with elevated FFA vs. control [2-step clamp: DI = 8.9 ± 1.4 × 10−3l2 ⋅ kg−1 ⋅ min−2in control vs. 10.0 ± 1.9 × 10−3l2 ⋅ kg−1 ⋅ min−2with high FFA, P = nonsignificant (NS)]. In the chronic studies, there was no difference in absolute GSIS between control and high FFA studies, but there was a reduction in SI and a loss of the expected compensatory increase in insulin secretion as assessed by the DI (2-step clamp: DI = 10.0 ± 1.2 × 10−3l2 ⋅ kg−1 ⋅ min−2in control vs. 6.1 ± 0.7 × 10−3l2 ⋅ kg−1 ⋅ min−2with high FFA, P = 0.01). In summary, 1) acute and chronic FFA elevation induces insulin resistance; 2) with acute FFA elevation, this insulin resistance is precisely countered by an FFA-induced increase in insulin secretion, such that DI does not change; and 3) chronic FFA elevation disables this β-cell compensation.

Central adiposity is highly correlated with insulin resistance, which is an important risk factor for type 2 diabetes and other chronic diseases. However, in normal individuals, central adiposity can be tolerated for many years without development of impaired glucose tolerance or diabetes. Here we examine longitudinally the mechanisms by which glucose tolerance can be maintained in the face of substantial insulin resistance. Normal dogs were fed a diet enriched with moderate amounts of fat (2 g · kg -1 · day -1 ), similar to that seen in modern "cafeteria" diets, and the time course of metabolic changes in these animals was examined over 12 weeks. Trunk adiposity as assessed by magnetic resonance imaging increased from 12 to 19%, but body weight remained unchanged. Insulin sensitivity (S I ) as determined by frequently sampled intravenous glucose tolerance tests was measured over a 12-week period. S I decreased 35% by week 1 and remained impaired for the entire 12 weeks. Intravenous glucose tolerance was reduced transiently for 1 week, recovered to baseline, and then again began to decline after 8 weeks. Firstphase insulin response began to increase after week 2, peaked by week 6 (190% of basal), and then declined. The increase in insulin response was due partially to enhanced ␤-cell function (22%) but due also to añ 50% reduction in insulin clearance. This compensation by insulin clearance was also confirmed with insulin clamps performed in fat-fed versus control dogs. The present study confirms the ability of the normal individual to compensate for fat-induced insulin resistance by enhanced insulin response, such that the product of insulin sensitivity ؋ secretion is little changed. However, the compensation is due as much to reduced insulin clearance as increased ␤-cell sensitivity to glucose. Reduced hepatic extraction of insulin may be the first line of defense providing a higher proportion of secreted insulin to the periphery and sparing the ␤-cells during compensation for the insulin-resistant state. Diabetes 49:2116-2125, 2000 T here is abundant evidence that diabetes and obesity are increasing in the U.S. population (1-3). Because adiposity is related to insulin resistance (4-6), and insulin resistance is a risk factor for type 2 diabetes and cardiovascular disease, a consensus has emerged that increased adiposity is responsible for the increased incidence of type 2 diabetes and its associated morbidity (metabolic syndrome or syndrome X [7]). In addition, evidence has accumulated indicating that visceral adiposity in particular is associated with insulin resistance and the metabolic syndrome (8,9).Despite overwhelming evidence demonstrating association between insulin resistance, visceral adiposity, and metabolic risk, there is little evidence directly demonstrating that central adiposity in fact causes insulin resistance. In addition, there is little understanding of the mechanisms underlying the relationship among visceral adiposity, insulin resistance, and risk.To examine the acute effects of adiposi...