Introduction and Hypothesis: Insulin and c-peptide are co-secreted in a 1:1 ratio, but cleared from the blood by different mechanisms. Insulin is cleared by the liver (t1/2 ∼ 4 min), while c-peptide is cleared by the kidney (t1/2∼ 40 min). Thus, differences between steady-state serum insulin and c-peptide may reflect subject-to-subject variation in liver and/or kidney clearance rates.

Specific Aim: In lieu of direct measures of clearance, the aim was to examine the association of insulin/c-peptide residuals with markers of liver and kidney function. Associations were analyzed using cross-sectional data from the 1999-2000 U.S. National Health and Nutrition Examination Survey.

Methods: The inclusion criterion was age ≥ 12, and the exclusion criteria were diabetes, pregnancy, fasting < 8 h, serum creatinine > 2, or missing insulin or c-peptide values, yielding 2,417 subjects. Insulin residuals were calculated as the difference between observed Ln insulin and the predicted value from the regression line for Ln insulin vs. Ln c-peptide.

Results: Insulin residuals were positively correlated with insulin levels (r=0.55, p<0.0001). After adjusting for serum creatinine (kidney function), the association of insulin residuals with other markers was assessed using multiple linear regression. Positive associations were observed with ALT, LDH, CRP and urinary NTx/creatinine, as well as Hispanic ethnicity. Negative associations were observed with age, male gender, white and black race, total serum protein and bilirubin.

Conclusion: Insulin residuals, adjusted for creatinine, are associated with markers of liver dysfunction, inflammation, bone resorption and race/ethnicity. The hepatic clearance rate of insulin is known to be affected by some of these factors. Higher insulin residuals presumably reflect slower hepatic insulin clearance, which promotes hyperinsulinemia. Insulin residuals could be a simple surrogate for assessing differences in insulin clearance. Further studies are warranted.


C. Perkins: None. E. Campbell: None. D.P. Cistola: None.


National Institutes of Health (R21HL143030)

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at