OBJECTIVE -To validate fasting indices of insulin sensitivity and secretion in a diverse pediatric population against gold standard estimates from euglycemic and hyperglycemic clamps. RESEARCH DESIGN AND METHODS-A total of 31 children (mean BMI 25.1 Ϯ 4.9 kg/m 2 , mean age 8.7 Ϯ 1.4 years, 15 girls and 16 boys, 12 black and 19 white) underwent euglycemic and hyperglycemic clamps 2-6 weeks apart to derive insulin sensitivity indices (SI Eug clamp and SI Hyper clamp ). Fasting samples were used to derive the homeostasis model assessment of insulin resistance index (HOMA-IR), HOMA of percent ␤-cell function (HOMA-B%), quantitative insulin sensitivity check index (QUICKI), insulinogenic index, antilipolytic insulin sensitivity index (ISI-FFA), and C-peptide-to-insulin ratio.RESULTS -The QUICKI correlated best with SI Eug clamp (r ϭ 0.69, P Ͻ 0.05) and had greater correlations to SI Eug clamp than did either SI Hyper clamp (r ϭ 0.45, P Ͻ 0.05) or the HOMA-IR (r ϭ Ϫ0.51, P Ͻ 0.05). Both fasting insulin and the insulinogenic index correlated well with first-and steady-phase insulin secretion (r's from 0.79 to 0.86, P Ͻ 0.05). HOMA-B% was not as highly correlated (r ϭ 0.69 -0.72, P Ͻ 0.05). Fasting C-peptide-to-insulin ratio was not significantly correlated with clamp-derived metabolic clearance rate of insulin. ISI-FFA was not correlated with the degree of free fatty acid suppression obtained from the clamps.CONCLUSIONS -The QUICKI, fasting insulin, and the insulinogenic index all closely correlate with corresponding clamp-derived indices of insulin sensitivity and secretion in this diverse pediatric cohort. These results, if replicated in similarly diverse populations, suggest that estimates based on fasting samples can be used to rank order insulin secretion and sensitivity in pediatric cohorts. Diabetes Care 25:2081-2087, 2002O besity and type 2 diabetes are diseases that have assumed considerable public health importance in the 21st century in both developed and developing countries (1-3). The increased prevalence of both these conditions in children adds an added dimension of seriousness to these modern day epidemics (4). Since insulin resistance appears central to the development of the metabolic syndrome X (1,5), accurate quantification of insulin's in vivo action, secretion, and disposal is necessary. While a combination of hyperglycemic and euglycemic-hyperinsulinemic clamp studies supplies the gold standard for quantifying these parameters (6), clamp studies are expensive and difficult tests to perform and require highly trained personnel. The difficulties with obtaining sequential clamp studies are even more pronounced for young children who may have more difficulty with clamp procedure requirements.For the purpose of epidemiologic studies, several indices based on fasting blood that estimate insulin sensitivity, secretion, and disposal have been developed for adults. The homeostasis model assessment of insulin resistance index (HOMA-IR), the HOMA of percent ␤-cell function (HOMA-B%), the insulinogenic index...

Several mech s of posttranscriptional gene regulation are involved in regulation of the expression of essential proteins of iron metabolism. Coordinate regulation of ferritin and transferrin receptor expression is produced by binding of a cytosolic protein, the iron-responsive element binding protein (IRE-BP) to specific stem-oop structures present in target RNAs. The affinity of this protein for its cognate RNA is regulated by the cell in response to changes in iron availability. The IRE-BP demonstrates a striking level of amino acid sequence identity to the iron-sulfur (Fe-S) protein mitochondrial aconitase. Moreover, the recombinant IRE-BP has aconitase function. The lability of the Fe-S cluster in mitochondrial aconitase has led us to propose that the mechnism by which iron levels are sensed by the IRE-BP involves changes in an Fe-S cluster in the IRE-BP. In this study, we demonstrate that procedures aimed at altering the IRE-BP Fe-S cluster in vitro reciprocally alter the RNA binding and aconitase activity of the IRE-BP. The changes in the RNA big of the protein produced in vitro appear to match the previously described alterations of the protein in response to iron availability in the cell. Furthermore, iron manipulation ofcells correlates with the activation or inactivation of the IRE-BP aoitas activity. The results are consistent with a model for the ponslatonal regulation of the IRE-BP in which the Fe-S cluster is altered in response to the availability of intracellular iron and this, in turn, regulates the RNA-binding activity.

Post-transcriptional regulation of genes important in iron metabolism, ferritin and the transferrin receptor (TfR), is achieved through regulated binding of a cytosolic protein, the iron-responsive element binding protein (IRE-BP), to RNA stem-loop motifs known as iron-responsive elements (IREs). Binding of the IRE-BP represses ferritin translation and represses degradation of the TfR mRNA. The IRE-BP senses iron levels and accordingly modifies binding to IREs through a novel sensing mechanism. An iron-sulfur cluster of the IRE-BP reversibly binds iron; when cytosolic iron levels are depleted, the cluster becomes depleted of iron and the IRE-BP acquires the capacity to bind IREs. When cytosolic iron levels are replete, the IRE-BP loses RNA binding capacity, but acquires enzymatic activity as a functional aconitase. RNA binding and aconitase activity are mutually exclusive activities of the IRE-BP, and the state of the iron-sulfur cluster determines how the IRE-BP will function.