Comparison between surrogate indexes of insulin sensitivity/resistance and hyperinsulinemic euglycemic clamp estimates in rats

Abstract

The hyperinsulinemic euglycemic glucose clamp, the reference standard for measuring insulin sensitivity in humans and animals, is labor intensive and technically demanding. A number of simple surrogate indexes of insulin sensitivity/resistance have been developed and validated primarily for use in large human studies. These same surrogates are also frequently used in rodent studies. However, in general, these indexes have not been rigorously evaluated in animals. In a recent validation study in mice, we demonstrated that surrogates have a weaker correlation with glucose clamp estimates of insulin sensitivity/resistance than in humans. This may be due to increased technical difficulties in mice and/or intrinsic differences between human and rodent physiology. To help distinguish among these possibilities, in the present study, using data from rats substantially larger than mice, we compared the clamp glucose infusion rate (GIR) with surrogate indexes, including QUICKI, HOMA, 1/HOMA, log (HOMA), and 1/fasting insulin. All surrogates were modestly correlated with GIR (r ϭ 0.34 -0.40). Calibration analyses of surrogates adjusted for body weight demonstrated similar predictive accuracy for GIR among all surrogates. We conclude that linear correlations of surrogate indexes with clamp estimates and predictive accuracy of surrogate indexes in rats are similar to those in mice (but not as substantial as in humans). This additional rat study (taken with the previous mouse study) suggests that application of surrogate insulin sensitivity indexes developed for humans may not be appropriate for determining primary outcomes in rodent studies due to intrinsic differences in metabolic physiology. However, use of surrogates may be appropriate in rodents, where feasibility of clamps is an obstacle and measurement of insulin sensitivity is a secondary outcome. glucose clamp; calibration model; quantitative insulin-sensitivity check index INSULIN RESISTANCE IS TYPICALLY DEFINED as decreased sensitivity and/or responsiveness to metabolic actions of insulin (19). This cardinal feature of diabetes, obesity, and dyslipidemias is also a prominent component of cardiovascular diseases, including hypertension, coronary heart disease, and atherosclerosis (6, 26). Rodent models of metabolic diseases and their cardiovascular complications are useful for elucidating underlying pathophysiology and for evaluating novel therapeutic approaches (5, 12, 22). The ability to efficiently and accurately quantify insulin sensitivity/resistance is an essential aspect of ascertaining the metabolic phenotype of rodent models of human diseases and their response to therapeutic interventions. In both humans and animals, the reference standard method for directly quantifying insulin sensitivity/resistance is the hyperinsulinemic euglycemic glucose clamp (19). This is a technically demanding, time-consuming procedure that is not feasible to apply in large studies. Therefore, more tractable surrogate indexes of insulin sensitivity/resistance have been developed ...

Glucagon secretion after metabolic surgery in diabetic rodents

“…Insulin sensitivity was assessed by a mathematical model (quantitative insulin sensitivity check index) calculating the reciprocal index of the sum of logarithms for fasting plasma glucose (mg/dl) and fasting plasma insulin (mU/ml)O (1/(log(G 0 )Clog(I 0 ))) as described elsewhere (Katz et al 2000, Muniyappa et al 2009). The area under the curve (AUC) was calculated for postprandial insulin and glucagon secretion using the trapezoidal method.…”

Hyperglycemia induced by tacrolimus and sirolimus is reversible in normal sprague–dawley rats

“…Intra-assay variations were 3.5 and 3.9%, and interassay variations were 2.7 and 5.0%, for tacrolimus and sirolimus, respectively. Insulin resistance was evaluated with the homeostasis model assessment of insulin resistance (HOMA-IR; fasting glucose (mmol/l) 9 fasting insulin (lu/l)/22.5) [30].…”

Homeostastic Model Assessment and Insulin Sensitivity/Resistance

“…Largely, they correlate with more detailed indices of S I (clamp, IVGTT) (11)(12)(13)(14) and in some longitudinal studies (15,16), but less so in others (17), and not as well in some populations such as African American men (18) and Asian-Indian men that include a preponderance of lean diabetic patients (19). In animal models, mice (20) and rats (21) do not do so well with HOMA, but rhesus monkeys do better (22). Clearly, there is some diversity.…”