Our study has several novel findings: 1) insulin clearance is not associated with age or sex; 2) insulin sensitivity, insulin secretion, and adiposity are independently related to insulin clearance across sex, race/ethnic populations, varying states of glucose tolerance and adiposity, and family history of diabetes; and 3) insulin sensitivity, insulin secretion, and adiposity appear to explain differences in insulin clearance by race/ethnicity and glucose tolerance status.
In the fasting state, the liver clears ~40–60% of the insulin concentration in the portal blood (10
). Results from a study of intentional weight gain in men with normal weight (change in BMI from 21.8 to 23.8 kg/m2
in 15 weeks) suggest that reduced insulin clearance may be the most important compensatory mechanism for explaining the increase in basal and stimulated insulin concentrations (11
). Insulin clearance has also been described as the first compensatory mechanism to experimental fat-induced insulin resistance (1
), even though insulin clearance is not altered by acute hyperglycemia (12
). The reduction in insulin clearance enhances glucose uptake and suppress lipolysis by increasing insulin levels. Consequently, it has been hypothesized that insulin clearance is reduced in insulin-resistant states to lessen the demands on the β-cell (1
In an animal model of alloxan-induced selective decrease in β-cell mass, insulin secretion decreases in proportion to β-cell mass (13
). Insulin secretion after meal ingestion is impaired along with worsening of hepatic insulin clearance. Human studies have also shown that skeletal muscle contributes to peripheral insulin clearance (14
). Physiological hyperinsulinemia recruits skeletal muscle capillaries, but insulin clearance is reduced because of the saturation of the trans endothelial insulin transport (a rate-limiting process for insulin action) (14
). Obesity has been shown to impair microvascular recruitment (15
). The cross-sectional nature of our study precludes us from making causal inferences. However, our results suggest that there is a complex relationship between insulin secretion and insulin clearance independently of the effect of obesity and insulin sensitivity.