Lower Insulin Clearance Parallels a Reduced Insulin Sensitivity in Obese Youths and Is Associated With a Decline in β-Cell Function Over Time

Abstract

We examined the relationship between insulin clearance, insulin sensitivity, and β-cell function and the longitudinal effect of insulin clearance on β-cell function in lean and obese insulin-sensitive and insulin-resistant adolescents. A hyperinsulinemic-euglycemic and a hyperglycemic clamp were performed in 110 youths to quantify hepatic and peripheral clearance, insulin sensitivity, and β-cell function (disposition index, DI_h-clamp). Participants underwent an oral glucose tolerance test at baseline and after 2 years to assess glucose tolerance and oral β-cell function (oDI_cpep) and were sorted into four groups (lean and obese normal glucose tolerance, insulin sensitive, insulin resistant, and impaired glucose tolerance). Insulin sensitivity was defined based on the median of insulin stimulated glucose disposal (M) measured during the hyperinsulinemic-euglycemic clamp. Lean and obese insulin-sensitive participants did not differ with respect to hepatic and peripheral clearance or for insulin sensitivity. Insulin sensitivity was linearly correlated with whole-body insulin clearance. Hepatic insulin extraction at baseline acted as an independent determinant of β-cell function at follow-up. The decline in insulin sensitivity, even in the absence of an impairment of glucose tolerance, is associated with lowering of hepatic insulin clearance in obese youth, which in turn may contribute to the decline in β-cell function over time.

Figure 1

Outline of the insulin clearance model (hepatic plasma flow 0.576 L/m²). CL_WB is calculated for constant ISR (with infusion = 0) as the ratio of insulin delivery to plasma insulin concentration (CL_WB = ISR/P). IV, intravenous.

Figure 2

Glucose and insulin profiles during hyperinsulinemic-euglycemic clamp (A and B), ISR at baseline and during the test (C), glucose and insulin during the hyperglycemic clamp (D and E), and ACPRg and steady-state C-peptide (F). Data are reported as the median and interquartile range (25th, 75th). **Indicates statistical significance.

Figure 3

CL_WB (A) and hepatic (B) and extrahepatic (C) insulin clearance. Data are reported as the median and interquartile range (25th, 75th). **Indicates statistical significance.

Figure 4

Correlation analysis between CL_WB and M (A) and ISR (B). Data are reported as median and interquartile range (25th, 75th).

Figure 5

oDI_cpep at follow-up in the low and high CL_WB groups. Low and high insulin clearance are defined as those with a CL_WB at or below the median CL_WB (low clearance) or above the median (high clearance). Data are reported as the median and interquartile range (25th, 75th). **Indicates statistical significance.