Simple fasting methods to assess insulin sensitivity in childhood

The 'gold standard' techniques used to measure insulin sensitivity in children are the hyperinsulinaemic-euglycaemic clamp and Bergman's minimal model. Although precise, these techniques are complex, invasive and time consuming. Alternative indirect measures of insulin sensitivity have been developed that utilize fasting glucose and insulin data in algorithms or computer programs. These methods include homeostatic model assessment (HOMA), the quantitative insulin sensitivity check index (QUICKI) and the glucose to insulin ratio (G:I). Each of these three fasting techniques has been developed and validated in adults, with little or no validation in children. Increasingly, HOMA and QUICKI are being used in childhood studies to assess insulin sensitivity. In a group of 79 pre-pubertal children, we found that the correlation between the minimal model and RHOMA (r = -0.4) was no better than that between the minimal model and fasting insulin (r = 0.4), with an even weaker correlation between the minimal model and QUICKI (r = 0.2). In addition, neither HOMA nor QUICKI were able to detect a reduction in insulin sensitivity with obesity or during growth hormone therapy, unlike the minimal model. In children with normal glucose levels, neither HOMA nor QUICKI was superior to fasting insulin. Validation of the derivation formulae for these methods in children is needed before they are more widely used. The potential benefits of these simple fasting techniques is that they are useful in large field studies. However, if the study groups are small or longitudinal changes in insulin sensitivity are sought, more precise techniques such as the clamp or minimal model should be used.     

Prematurity and insulin sensitivity

Premature infants of low and extremely low birth weight represent a challenge for neonatal intensive care units and paediatricians. These neonates may be at increased risk of insulin resistance and diabetes perinatally and during childhood. During the first week of postnatal life, infants born prematurely are at risk of abnormalities in glucose homeostasis. Additionally, there are major differences in their glucose/insulin homeostasis compared with infants born at term. Preterm infants are at risk of hypoglycaemia, due to decreases in deposits of glycogen and fat that occur during the third trimester, and also to transient hyperinsulinaemia. Hyperglycaemia may also be observed in preterm infants during the perinatal period. These infants are unable to suppress glucose production within a large range of glucose and insulin concentrations, insulin secretory response is inappropriate, insulin processing is immature and there is an increased ratio of the glucose transporters Glut-1/Glut-2 in fetal tissues, which limits sensitivity and hepatocyte reaction to increments in glucose/insulin concentration during hyperglycaemia. In addition, increased concentrations of tumour necrosis factor alpha present in intrauterine growth retardation (IUGR) and induce insulin resistance. It has been proposed that the reduced insulin sensitivity may result from adaptation to an adverse in utero environment during a critical period of development. We have investigated postnatal insulin resistance in 60 children born with very low birth weight and either small for gestational age or at an appropriate size for gestational age. This study showed that IUGR, rather than low birth weight itself, was associated with increased fasting insulin levels. As poor fetal growth may be associated with the development of obesity, type 2 diabetes and the metabolic syndrome in later life, it is important that we continue to increase our understanding of the effects of IUGR on postnatal growth and metabolism.     

Enhanced sensitivity for the determination of selenium by INAA

A working analytical procedure for selenium determinations by INAA, using γ spectrometry with a germanium well-type detector, is presented. The spectral line at 400.7 keV is employed, enhanced with the effect of energy summing in true coincidence of cascade photons. The main advantage of the method is high efficiency and reliable, interference-free results; potential drawbacks are increases in input count rate and pile-up losses, decrease in resolution, and sensitivity to errors in sample-to-detector geometry. The procedure is applied to certification analysis of reference materials, large-area biomonitoring by oak leave samples, and determination of separated proteins.     

Zinc and insulin sensitivity

Many studies have shown that zinc deficiency could decrease the response to insulin. In genetically diabetic animals, a low zinc status has been observed, contrary to induced diabetic animals. The zinc status of human patients depends on the type of diabetes and the age. Zinc supplementation seems to have beneficial effects on glucose homeostasis. However, the mechanism of insulin resistance secondary to zinc depletion is yet unclear. More studies are therefore necessary to document better zinc metabolism in diabetes mellitus, and the antioxidant activity of zinc on the insulin receptor and the glucose transporter.     

OGTT-derived measures of insulin sensitivity are confounded by factors other than insulin sensitivity itself

Insulin resistance is an important risk factor for diabetes and other diseases. It has been important to estimate insulin resistance in epidemiological and genetic studies involving significant number of individuals. Complex and invasive protocols are impractical. Therefore, insulin sensitivity indices based on the oral glucose-tolerance test (OGTT) have been introduced. The aim of the present study was to assess the accuracy with which OGTT-derived indices would reflect changes in insulin sensitivity in the face of changes in other factors, such as rate of glucose absorption and/or B-cell function. A computer model was employed to predict excursions of plasma glucose and insulin after a 75-g oral glucose load. The model was then used to predict changes in these excursions, which would be observed with altered insulin resistance, with alterations in beta-cell sensitivity to glucose and/or alterations in glucose absorption rates. Published indices of insulin sensitivity could then be calculated from the predicted curves, to ask whether changes in beta-cell function or glucose absorptions rates might be misinterpreted (using the indices) as changes in insulin sensitivity. The model accurately represented OGTT data for a normal glucose tolerant subject, closely matching published data. Imposed 50% reductions or increases in insulin sensitivity alone in the model were reflected in only small changes in OGTT-derived insulin sensitivity values. More important, imposed alterations in beta-cell sensitivity and glucose absorption without simulated changes in insulin sensitivity did change insulin sensitivity indices. These results indicate that caution is required for the interpretation of differences in OGTT-derived values of insulin sensitivity, because variation in factors other than insulin sensitivity per se appear to have the greatest effects on indices calculated from the OGTT alone.     

Role of 17beta-estradiol administration on insulin sensitivity in the rat: implications for the insulin receptor

The role of 17beta-estradiol in the early steps of insulin action is only partially known, although its effect on glucose homeostasis has been reported. In this paper, we attempt to prove the influence of 17beta-estradiol on the insulin receptor of ovariectomized rats treated with different hormonal doses. Our results show that high doses of estradiol impair insulin sensitivity while low doses improve it. We think that these results are the consequence of changes at a molecular level, because high doses of estradiol produced lower expression of the insulin receptor gene, lower content of this receptor in target tissues, and lower phosphorylation of insulin receptor in these tissues. However, low doses of estradiol seem to produce just the opposite. The possible existence of consensus response elements in the insulin receptor gene promoter to estradiol could be controlling the expression of this gene, this control being dose and timing dependent. Moreover, we cannot discard a possible effect of estradiol on the activity of protein tyrosine phosphatases, and therefore, on the activity of the insulin receptor. These new findings improve knowledge about the possible risk for insulin resistance in women taking oral contraceptives or receiving hormonal replacement therapy around the menopause, but could also open the door towards the possible utilization of 17beta-estradiol in some diabetes cases.     

A NARX modeling-based approach for evaluation of insulin sensitivity

Evaluation of insulin sensitivity is of prime importance in the clinical investigation of glucose related diseases. This paper deals with a novel model-based technique for the evaluation of an index for insulin sensitivity. A set of nonlinear autoregressive models are identified from the clinical test data of normal subjects. The two-stage identification procedure involves proper structure selection for approximating the input–output data followed by estimating the parameters of the polynomial model. The models obtained are analyzed to derive an index for insulin sensitivity by determining the effect of insulin on glucose utilization. A median bootstraped correlation (sampling with replacement) of 0.97 with 90% confidence interval of [0.92 0.98], is obtained between the indexes of the proposed model and the widely used minimal model. The proposed model is able to achieve a good fitting performance on the validation dataset. The results also suggest that for representing the dynamics of insulin action on glucose disposal, the proposed model overcomes some of the well known limitations of the minimal model, and thus gives a better representation of insulin sensitivity.     

Glucose, insulin and somatostatin infusion for the determination of insulin resistance in liver cirrhosis

Twelve patients with liver cirrhosis and ten normal subjects were studied. Using a constant intravneous infusion of glucose, insulin and somatostatin over 2 1/2 hours we determined the stteady state plasma glucose level (SSPG) in order to measure insulin resistance. The results demonstrated that the cirrhotic patients were insulin resistant compared to normals and that plasma glucagon does not account for the insulin resistance in these patients.