Hyperbolic relationship between insulin secretion and sensitivity on oral glucose tolerance test

The utility of the disposition index as a measure of beta-cell compensatory capacity rests on the established hyperbolic relationship between its component insulin secretion and sensitivity measures as derived from the intravenous glucose tolerance test (IVGTT). If one is to derive an analogous measure of beta-cell compensation from the oral glucose tolerance test (OGTT), it is thus necessary to first establish the existence of this hyperbolic relationship between OGTT-based measures of insulin secretion and insulin sensitivity. In this context, we tested five OGTT-based measures of secretion (insulinogenic index, Stumvoll first phase, Stumvoll second phase, ratio of total area-under-the-insulin-curve to area-under-the-glucose-curve (AUC(ins/gluc)), and incremental AUC(ins/gluc)) with two measures of sensitivity (Matsuda index and 1/Homeostasis Model of Assessment for insulin resistance (HOMA-IR)). Using a model of log(secretion measure) = constant + beta x log(sensitivity measure), a hyperbolic relationship can be established if beta is approximately equal to -1, with 95% confidence interval (CI) excluding 0. In 277 women with normal glucose tolerance (NGT), the pairing of total AUC(ins/gluc) and Matsuda index was the only combination that satisfied these criteria (beta = -0.99, 95% CI (-1.66, -0.33)). This pairing also satisfied hyperbolic criteria in 53 women with impaired glucose tolerance (IGT) (beta = -1.02, (-1.72, -0.32)). In a separate data set, this pairing yielded distinct hyperbolae for NGT (n = 245) (beta = -0.99, (-1.67, -0.32)), IGT (n = 116) (beta = -1.18, (-1.84, -0.53)), and diabetes (n = 43) (beta = -1.37, (-2.46, -0.29)). Moreover, the product of AUC(ins/gluc) and Matsuda index progressively decreased from NGT (212) to IGT (193) to diabetes (104) (P < 0.001), consistent with declining beta-cell function. In summary, a hyperbolic relationship can be demonstrated between OGTT-derived AUC(ins/gluc) and Matsuda index across a range of glucose tolerance. Based on these findings, the product of these two indices emerges as a potential OGTT-based measure of beta-cell function.     

Measurement of selective effect of insulin on glucose disposal from labeled glucose oral test minimal model

The oral glucose minimal model (OMM) measures insulin sensitivity (S(I)) and the glucose rate of appearance (R(a)) of ingested glucose in the presence of physiological changes of insulin and glucose concentrations. However, S(I) of OMM measures the overall effect of insulin on glucose utilization and glucose production. In this study we show that, by adding a tracer to the oral dose, e.g., of a meal, and by using the labeled version of OMM, OMM* to interpret the data, one can measure the selective effect of insulin on glucose disposal, S(I)*. Eighty-eight individuals underwent both a triple-tracer meal with the tracer-to-tracee clamp technique, providing a model-independent reference of the R(a) of ingested glucose (R(a meal)(ref)) and an insulin-modified labeled intravenous glucose tolerance test (IVGTT*). We show that OMM* provides not only a reliable means of tracing the R(a) of ingested glucose (R(a meal)) but also accurately measures S(I)*. We do so by comparing OMM* R(a meal) with the model-independent R(a meal)(ref) provided by the tracer-to-tracee clamp technique, while OMM* S(I)* is compared with both S(I)(* ref), obtained by using as known input R(a meal)(ref), and with S(I)* measured during IVGTT*.     

Caffeine ingestion elevates plasma insulin response in humans during an oral glucose tolerance test

We tested the hypothesis that caffeine ingestion results in an exaggerated response in blood glucose and (or) insulin during an oral glucose tolerance test (OGTT). Young, fit adult males (n = 18) underwent 2 OGTT. The subjects ingested caffeine (5 mg/kg) or placebo (double blind) and 1 h later ingested 75 g of dextrose. There were no differences between the fasted levels of serum insulin, C peptide, blood glucose, or lactate and there were no differences within or between trials in these measures prior to the OGTT. Following the OGTT, all of these parameters increased (P < or = 0.05) for the duration of the OGTT. Caffeine ingestion resulted in an increase (P < or = 0.05) in serum fatty acids, glycerol, and plasma epinephrine prior to the OGTT. During the OGTT, these parameters decreased to match those of the placebo trial. In the caffeine trial the serum insulin and C peptide concentrations were significantly greater (P < or = 0.001) than for placebo for the last 90 min of the OGTT and the area under the curve (AUC) for both measures were 60 and 37% greater (P < or = 0.001), respectively. This prolonged, increased elevation in insulin did not result in a lower blood glucose level; in fact, the AUC for blood glucose was 24% greater (P = 0.20) in the caffeine treatment group. The data support our hypothesis that caffeine ingestion results in a greater increase in insulin concentration during an OGTT. This, together with a trend towards a greater rather than a more modest response in blood glucose, suggests that caffeine ingestion may have resulted in insulin resistance.     

Plasma glucose and insulin responses to oral and intravenous glucose in cold-exposed humans

Although glucose tolerance and skeletal muscle glucose uptake are markedly improved by cold exposure in animals, little is known about such responses in humans. This study used two variations of a glucose tolerance test (GTT) to investigate changes in carbohydrate metabolism in healthy males during nude exposure to cold. In experiment 1, an oral GTT was performed in the cold and in the warm (3 h at 10 or 29 degrees C). To bypass the gastrointestinal tract, and to suppress hepatic glucose output, a second experiment was carried out as described above, using an intravenous GTT. Even though cold exposure raised metabolic rate greater than 2.5 times, plasma glucose and insulin responses to an oral GTT remained unaltered. In contrast, cold exposure reduced the entire plasma glucose profile as a function of time during the intravenous GTT (P less than 0.05), as plasma glucose was returned to basal levels within 1 h in comparison to a full 2 h in the warm, despite low insulin levels. The results of the intravenous GTT demonstrate that even with low insulin levels, carbohydrate metabolism is increased in cold-exposed males. This effect could be masked in the oral GTT by gastrointestinal factors and a high hepatic glucose output. Cold exposure may enhance insulin sensitivity and/or responsiveness for glucose uptake, mainly in shivering skeletal muscles.     

A missing sugar prevents glucose entry: a new twist on insulin secretion

The signaling pathway that regulates glucose-stimulated insulin secretion depends on glucose metabolism, which is itself controlled by glucokinase. In a recent issue of Cell, show that altering N-glycosylation of the GLUT2 glucose transporter prevents its anchoring and retention at the cell surface; this impairs glucose uptake and insulin secretion.     

Comparative changes with age of the fasting response in circulating ketone bodies, glucose and insulin and oral glucose tolerance test in the rat

1. Body weight loss in 48 hr fasted rats decreased with age. 2. Blood glucose and plasma RIA-insulin levels correlated negatively and positively respectively with body weight in fed rats. Fasting produced a greater fall in blood glucose and a smaller decrease in RIA-insulin in young than in old rats. 3. Blood ketone bodies correlated negatively with body weight after 48 hr fasting. 4. In oral glucose tolerance tests, blood glucose rose more in adult and old rats than in prepuberals when both fed and fasted. RIA-insulin levels rose more in prepuberals than in older rats when fed but not when fasted. 5. Changes in body composition and reduced insulin sensitivity with age are discussed.     

Reference values for 75 g oral glucose tolerance test in pregnancy

A 75 g oral glucose tolerance test was performed in 212 pregnant women with no predisposing factors suggesting glucose intolerance to establish the normal pattern of glucose metabolism in pregnancy. Reference values for the test were established for the middle of pregnancy (14-20 weeks, n=43) and late pregnancy (28-37 weeks, n=168). One woman was excluded because she had diabetes that required treatment with insulin. There were statistically significant differences between the two groups for samples taken both one and two hours after the glucose load. Reference ranges for the interpretation of the glucose tolerance test in pregnancy should therefore take account of the period of gestation.Arbitrary upper limits of normal (represented by the 97·5 centile) two hours after a 75 g oral glucose load are proposed at 7·5 and 9·6 mmol/l for the second and third trimesters, respectively.     

Minimal model estimation of glucose absorption and insulin sensitivity from oral test: validation with a tracer method

Measuring insulin sensitivity during the physiological milieu of oral glucose perturbation, e.g., a meal or an oral glucose tolerance test, would be extremely valuable but difficult since the rate of appearance of absorbed glucose is unknown. The reference method is a tracer two-step one: first, the rate of appearance of glucose (R(a meal)(ref)) is reconstructed by employing the tracer-to-tracee ratio clamp technique with two tracers and a model of non-steady-state glucose kinetics; next, this R(a meal)(ref) is used as the known input of a model describing insulin action on glucose kinetics to estimate insulin sensitivity (SI(ref)). Recently, a nontracer method based on the oral minimal model (OMM) has been proposed to estimate simultaneously the above quantities, denoted R(a meal) and SI, respectively, from plasma glucose and insulin concentrations measured after an oral glucose perturbation. This last method has obvious advantages over the tracer method, but its domain of validity has never been assessed against a reference method. It is thus important to establish whether or not the "nontracer" R(a meal) and SI compare well with the "tracer" R(a meal)(ref) and SI(ref). We do this comparison on a database of 88 subjects, and it is very satisfactory: R(a meal) profiles agree well with the R(a meal)(ref) and correlation of SI(ref) with SI is r = 0.86 (P < 0.0001). We conclude that OMM candidates as a reliable tool to measure both the rate of glucose absorption and insulin sensitivity from oral glucose tests without employing tracers.     

Comparison between the oral glucose tolerance test and the glucose infusion test in the characterization of protodiabetes]

Within 3 days the 2-hour glucose infusion test (GIT) and the 50gm oral glucose tolerance test (oGTT) were performed in 113 normal weight and 33 obese persons suspected to protodiabetes and in 14 control subjects respectively. The results are compared with criteria from a group of healthy persons without any heredity of diabetes worked out in our laboratory. In about 66 per cent of the investigated subjects a concordance between both tests could observed in carbohydrate tolerance. Abnormal results were found more frequently after the oral glucose application. From these finding it was concluded a higher sensitivity of the oGTT. On the other hand followup studies of the disagreed diagnosis have shown that in 91 per cent the test results of the GIT were reproduced. The insulin secretion pattern agreed in 70 per cent between both tests. Whereas the insulin secretion pattern during the oGTT does not allowed to differ between the groups using the glucose infusion test we were able to observe a significant diminished hormone release in the initial as well as in the late phases, if the carbohydrate tolerance was pathologically. Summarizing the results we concluded that the GIT is characterized by a good reproducibility and a higher diagnostic importance than the 50 gm oGTT.     

Beta-endorphin, insulin, ACTH and cortisol plasma levels during oral glucose tolerance test in obesity after weight loss

In order to clarify a possible relationship between opioid peptides and glucose homeostasis in obesity we studied Beta-Endorphin (B-Ep), ACTH, cortisol and insulin plasma levels in response to an oral glucose tolerance test (OGTT) in 8 subjects after a hypocaloric diet for 90 days. We obtained through this treatment a weight loss superior to 30% of the initial weight excess (WE) compared with ideal body weight. Moreover, we compared the obtained results with our preliminary study that was performed with the same protocol but without caloric restriction. B-Ep was measured by RIA after silicic acid extraction and G75 Sephadex column chromatography. ACTH, insulin and cortisol were measured directly on plasma by an RIA method. Basal and during OGTT-induced levels of glucose, insulin, ACTH and cortisol decreased in comparison with the values obtained before diet. Conversely, B-Ep remained higher than normal both in the basal condition and during OGTT, and showed values consistently similar to those before diet. These data show that hyperinsulinemia is corrected by weight loss, while hyperbetaendorphinemia remains unchanged. Accordingly, it can be suggested that no direct relationship occurs between hyper-B-Ep-hyper-IRI in obesity. A further insight into the role of hyper-B-Ep in obesity is, thus, necessary, assuming as hypothesis that the increase in B-Ep may be a cause and not a corollary of the polymorphic aspects of obesity.