Insulin Clearance and the Incidence of Type 2 Diabetes in Hispanics and African Americans: The IRAS Family Study

OBJECTIVE

We aimed to identify factors that are independently associated with the metabolic clearance rate of insulin (MCRI) and to examine the association of MCRI with incident type 2 diabetes in nondiabetic Hispanics and African Americans.

RESEARCH DESIGN AND METHODS

We investigated 1,116 participants in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study with baseline examinations from 2000 to 2002 and follow-up examinations from 2005 to 2006. Insulin sensitivity (S_I), acute insulin response (AIR), and MCRI were determined at baseline from frequently sampled intravenous glucose tolerance tests. MCRI was calculated as the ratio of the insulin dose over the incremental area under the curve of insulin. Incident diabetes was defined as fasting glucose ≥126 mg/dL or antidiabetic medication use by self-report.

RESULTS

We observed that S_I and HDL cholesterol were independent positive correlates of MCRI, whereas fasting insulin, fasting glucose, subcutaneous adipose tissue, visceral adipose tissue, and AIR were independent negative correlates (all P < 0.05) at baseline. After 5 years of follow-up, 71 (6.4%) participants developed type 2 diabetes. Lower MCRI was associated with a higher risk of incident diabetes after adjusting for demographics, lifestyle factors, HDL cholesterol, indexes of obesity and adiposity, and insulin secretion (odds ratio 2.01 95% CI 1.30–3.10], P = 0.0064, per one-SD decrease in log_e-transformed MCRI).

CONCLUSIONS

Our data showed that lower MCRI predicts the incidence of type 2 diabetes.Insulin clearance is an integral component of insulin metabolism, as it regulates the cellular response to the hormone by decreasing insulin availability and mediates certain aspects of insulin action (1). The liver is the primary site of insulin clearance. Approximately 80% of endogenous insulin is removed by the liver, and the remainder is cleared by the kidneys and muscles (2). Clearance rates for insulin decrease in glucose intolerance (3), obesity (4), in particular abdominal obesity (5), hypertension (6), hepatic cirrhosis (7), and nonalcoholic fatty liver disease (8).Although the plasma concentration of insulin is largely determined by its rate of secretion and clearance, existing evidence suggests that increased insulin resistance is associated with reduced insulin clearance (9–12). Reduced insulin clearance has important physiological functions; for example, animal models have shown that decreased insulin clearance serves as a compensatory mechanism to preserve β-cell function and to maintain peripheral insulin levels in the states of insulin resistance (13,14). In addition, insulin clearance has been found to be a highly heritable trait in Mexican Americans, and specific haplotypes in the AMPD1 gene were associated with variation in insulin clearance (15).Despite its potential role in the etiology of diabetes, little is known about the factors that are independently associated with decreased insulin clearance. In addition, no previous study has investigated whether decreased insulin clearance predicts the risk of type 2 diabetes. In this study, we aimed to identify demographic and metabolic factors that are independently associated with the metabolic clearance rate of insulin (MCRI), and to examine its association with the 5-year risk of incident type 2 diabetes, using the data from a large, well-characterized cohort of Hispanics and African Americans with direct measurements of insulin metabolism (secretion, sensitivity, and clearance) and adipose tissue (visceral and subcutaneous) in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study.