tance contributes to the pathophysiology of diabetes and is a hallmark of obesity, metabolic syndrome, and many cardiovascular diseases. Therefore, quantifying insulin sensitivity/resistance in humans and animal models is of great importance for epidemiological studies, clinical and basic science investigations, and eventual use in clinical practice. Direct and indirect methods of varying complexity are currently employed for these purposes. Some methods rely on steady-state analysis of glucose and insulin, whereas others rely on dynamic testing. Each of these methods has distinct advantages and limitations. Thus, optimal choice and employment of a specific method depends on the nature of the studies being performed. Established direct methods for measuring insulin sensitivity in vivo are relatively complex. The hyperinsulinemic euglycemic glucose clamp and the insulin suppression test directly assess insulin-mediated glucose utilization under steady-state conditions that are both labor and time intensive. A slightly less complex indirect method relies on minimal model analysis of a frequently sampled intravenous glucose tolerance test. Finally, simple surrogate indexes for insulin sensitivity/ resistance are available (e.g., QUICKI, HOMA, 1/insulin, Matusda index) that are derived from blood insulin and glucose concentrations under fasting conditions (steady state) or after an oral glucose load (dynamic). In particular, the quantitative insulin sensitivity check index (QUICKI) has been validated extensively against the reference standard glucose clamp method. QUICKI is a simple, robust, accurate, reproducible method that appropriately predicts changes in insulin sensitivity after therapeutic interventions as well as the onset of diabetes. In this Frontiers article, we highlight merits, limitations, and appropriate use of current in vivo measures of insulin sensitivity/resistance. glucose clamp; quantitative insulin sensitivity check index; minimal model; homeostatis model assessment INSULIN IS AN ESSENTIAL PEPTIDE HORMONE whose metabolic actions maintain whole body glucose homeostasis and promote efficient glucose utilization (3). Insulin stimulates increased glucose disposal in skeletal muscle and adipose tissue, whereas it inhibits gluconeogenesis in liver to help regulate glucose homeostasis. In addition to these classical insulin target tissues, there are many other important physiological targets of insulin, including the brain, pancreatic ␤-cells, heart, and vascular endothelium, that help to coordinate and couple metabolic and cardiovascular homeostasis under healthy conditions (3,54,72,79). Insulin has concentration-dependent saturable actions to increase whole body glucose disposal. The maximal effect of insulin defines "insulin responsiveness," whereas the insulin concentration required for a half-maximal response defines "insulin sensitivity" (Fig. 1A).Insulin resistance is typically defined as decreased sensitivity or responsiveness to metabolic actions of insulin, such as insulin-mediated glucose d...

Insulin resistance contributes to the pathophysiology of diabetes, obesity, and their cardiovascular complications. Mouse models of these human diseases are useful for gaining insight into pathophysiological mechanisms. The reference standard for measuring insulin sensitivity in both humans and animals is the euglycemic glucose clamp. Many studies have compared surrogate indexes of insulin sensitivity and resistance with glucose clamp estimates in humans. However, regulation of metabolic physiology in humans and rodents differs and comparisons between surrogate indexes and the glucose clamp have not been directly evaluated in rodents previously. Therefore, in the present study, we compared glucose clamp-derived measures of insulin sensitivity (GIR and SI(Clamp)) with surrogate indexes, including quantitative insulin-sensitivity check index (QUICKI), homeostasis model assessment (HOMA), 1/HOMA, log(HOMA), and 1/fasting insulin, using data from 87 mice with a wide range of insulin sensitivities. We evaluated simple linear correlations and performed calibration model analyses to evaluate the predictive accuracy of each surrogate. All surrogate indexes tested were modestly correlated with both GIR and SI(Clamp). However, a stronger correlation between body weight per se and both GIR and SI(Clamp) was noted. Calibration analyses of surrogate indexes adjusted for body weight demonstrated improved predictive accuracy for GIR [e.g., R = 0.68, for QUICKI and log(HOMA)]. We conclude that linear correlations of surrogate indexes with clamp data and predictive accuracy of surrogate indexes in mice are not as substantial as in humans. This may reflect intrinsic differences between human and rodent physiology as well as increased technical difficulties in performing glucose clamps in mice.

Objectives: To investigate the clinical outcome of patients treated with chronic deep brain stimulation (DBS) of the centromedian nucleus (CM) for refractory epilepsy and to determine the location of active contacts. Methods: The outcome of CM stimulation was evaluated as percent seizure reduction compared to the baseline 3 months. To establish the location of active contacts, 27 leads were studied in 14 patients with refractory epilepsy. An analysis was conducted to reveal whether any coordinates of the center of the active contacts predicted percent seizure reduction. Results: With an average follow-up of 18.2 ± 5.6 months, the mean percent seizure reduction (n = 14) was 68 ± 22.4% (25-100%). Eleven of the 14 patients (78.6%) achieved >50% improvement in seizure frequency. Specifically, all 4 patients (100%) with generalized epilepsy (Lennox-Gastaut syndrome) and 7 of 10 patients (70%) with multilobar epilepsy showed >50% reduction in seizure frequency. The mean coordinates of the center of the active contact were located in the superior part of the anterior ventrolateral CM. The calculated coordinates of laterality from midline (x), anterior-posterior (y) and height (z) from the posterior commissure did not correlate with seizure outcome measured by percent seizure reduction. However, the locations of active contacts used during chronic CM stimulation in multilobar epilepsy were identified more dorsal to those used in generalized epilepsy. Conclusions: Chronic CM stimulation is a safe and effective means in the treatment of refractory epilepsy.

We investigated the cutoff values of surrogate of insulin resistance for diagnosing metabolic syndrome in Korean adults. The data from 976 non-diabetic individuals (484 men and 492 women) aged 30-79 yr were analyzed. We determined the odds ratios for the prevalence of metabolic syndrome according to the quartiles of fasting insulin, homeostasis model for insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI) as independent variables, while adjusting for age, sex, and body mass index. The cutoff values of fasting insulin, HOMA-IR, and QUICKI were estimated by the areas under the receiver-operating characteristic (ROC) curves. The cutoff points for defining insulin resistance are a fasting insulin level of 12.94 µU/mL, HOMA-IR=3.04 as the 75th percentile value, and QUICKI=0.32 as the 25th percentile value. Compared with the lowest quartile, the adjusted odds ratios for the prevalence of metabolic syndrome in the highest quartiles of fasting insulin, HOMA-IR, and QUICKI were 1.95 (1.26-3.01), 2.27 (1.45-3.56), and 2.27 (1.45-3.56), respectively. The respective cutoff values for fasting serum insulin, HOMA-IR, and QUICKI by ROC analysis were 10.57 µU/mL (sensitivity 58.5%, specificity 66.8%), 2.34 (sensitivity 62.8%, specificity 65.7%), and 0.33 (sensitivity 61.2%, specificity 66.8%). Fasting insulin, HOMA-IR, and QUICKI can be used as surrogate measures of insulin resistance in Korean non-diabetic adults.

SummaryObjective ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare and unusual cause of Cushing's syndrome, characterized by bilateral nodular adrenocortical hyperplasia and hypersecretion of cortisol. Familial AIMAH has rarely been reported. Recently, the aberrant expression of adrenal receptors for various ligands in AIMAH patients has become important in explaining the pathogenesis of AIMAH. In this study, we present the cases of two sisters who were affected with AIMAH. Patients and Measurements Two sisters, aged 46 and 58, respectively, at the time of diagnosis, were found to have Cushing's syndrome due to AIMAH. We performed provocation tests with various materials and reverse transcription polymerase chain reaction (RT-PCR) with their resected adrenal tissues to examine the hyperresponsiveness to steroidogenesis and the overexpression of related receptors, respectively. Results Provocation tests in vivo indicated that arginine vasopressin (AVP) promoted cortisol secretion through vasopressin V1a as well as V1b and V2 receptors. RT-PCR analysis revealed an abnormal cDNA expression of vasopressin V1b and V2 receptors, none of which is known to be normally expressed in the adrenal glands. Conclusion The expression of ectopic vasopressin V1b and V2 receptors may be involved in the aetiology of AIMAH, at least in the case of the sibling patients presented here.