Assessing Insulin Secretion by Modeling in Multiple-Meal Tests

We developed a mathematical model of the glucose control of insulin secretion capable of quantifying β-cell function from a physiological meal test. The model includes a static control, i.e., a secretion component that is a function of plasma glucose concentration (the dose-response function), and a dynamic control, i.e., a secretion component that is proportional to the positive values of the glucose concentration derivative. Furthermore, the dose-response function is assumed to be modulated by a time-varying potentiation factor. To test the model, nine nondiabetic control subjects and nine type 2 diabetic patients received three standardized mixed meals over a period of 14–15 h. Blood samples were drawn for the measurement of glucose, insulin, and C-peptide concentration. The dose-response function, the parameter of the dynamic control, and the potentiation factor were determined by fitting the model to glucose and C-peptide concentrations. In diabetic patients, the dose-response function was shifted to the right (glucose concentration at a reference insulin secretion of 300 pmol · min−1 · m−2 was 11.7 ± 1.1 vs. 7.2 ± 0.7 mmol/l; P < 0.05), and decreased in slope (53 ± 15 vs. 148 ± 38 pmol · min−1 · m−2 · mmol−1 · l; P < 0.05) and the parameter of the dynamic control was decreased (220 ± 67 vs. 908 ± 276 pmol · m−2 · mmol−1 · l; P < 0.05) compared with the nondiabetic control subjects. Furthermore, potentiation was markedly blunted and delayed: maximum potentiation was observed at the first meal in normal subjects and at the second meal (about 4 h later) in diabetic subjects; the mean time for the potentiation factor was higher (7.1 ± 0.2 vs. 5.9 ± 0.2 h; P < 0.01), and the size of potentiation was reduced (2.6 ± 0.5 vs. 7.2 ± 1.5 fold increase; P < 0.005). In conclusion, our model of insulin secretion extracts multiple indexes of β-cell function from a physiological meal test. Use of the model in patients with type 2 diabetes retrieves known defects in insulin secretion but also uncovers new facets of β-cell dysfunction

Electroimpedance Spectroscopy for the Measurement of the Dielectric Properties of Sodium Chloride Solutions at Different Glucose Concentrations

We investigated possible variations of impedance values in samples of sodium chloride solution (sodium chloride 0.9%) with glucose at different concentrations, ranging from 5000 to around 75 mg/dL. The sodium chloride solution (either saline physiological solution) was chosen since it has similarities to blood but no cell components, which may be confounding factors in this study. Special focus was on the effect of stirring and of temperature variations on the impedance spectrum of samples at different glucose concentrations. We found that variations in glucose concentration directly affect the impedance modulus of the sample both in static conditions and in dynamic conditions due to stirring, as well as at both room temperature and at increased temperature. In fact, even if the impedance variations were often small (around 3-4 mΩper mg/dL), they were usually clearly measurable. These findings may be the basis for possible development of a new approach, based on impedance technology, for the noninvasive monitoring of glycaemia

Electroimpedance Spectroscopy for the Measurement of the Dielectric Properties of Sodium Chloride Solutions at Different Glucose Concentrations

We investigated possible variations of impedance values in samples of sodium chloride solution (sodium chloride 0.9%) with glucose at different concentrations, ranging from 5000 to around 75 mg/dL. The sodium chloride solution (either saline physiological solution) was chosen since it has similarities to blood but no cell components, which may be confounding factors in this study. Special focus was on the effect of stirring and of temperature variations on the impedance spectrum of samples at different glucose concentrations. We found that variations in glucose concentration directly affect the impedance modulus of the sample both in static conditions and in dynamic conditions due to stirring, as well as at both room temperature and at increased temperature. In fact, even if the impedance variations were often small (around 3-4 mΩ per mg/dL), they were usually clearly measurable. These findings may be the basis for possible development of a new approach, based on impedance technology, for the noninvasive monitoring of glycaemia

A Low Frequency Electromagnetic Sensor for Indirect Measurement of Glucose Concentration: In Vitro Experiments in Different Conductive Solutions

In recent years there has been considerable interest in the study of glucose-induced dielectric property variations of human tissues as a possible approach for non-invasive glycaemia monitoring. We have developed an electromagnetic sensor, and we tested in vitro its ability to estimate variations in glucose concentration of different solutions with similarities to blood (sodium chloride and Ringer-lactate solutions), differing though in the lack of any cellular components. The sensor was able to detect the effect of glucose variations over a wide range of concentrations (∼78–5,000 mg/dL), with a sensitivity of ∼0.22 mV/(mg/dL). Our proposed system may thus be useful in a new approach for non-invasive and non-contact glucose monitoring

Gait symmetry and regularity in transfemoral amputees assessed by trunk accelerations

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to evaluate a method based on a single accelerometer for the assessment of gait symmetry and regularity in subjects wearing lower limb prostheses.</p> <p>Methods</p> <p>Ten transfemoral amputees and ten healthy control subjects were studied. For the purpose of this study, subjects wore a triaxial accelerometer on their thorax, and foot insoles. Subjects were asked to walk straight ahead for 70 m at their natural speed, and at a lower and faster speed. Indices of step and stride regularity (Ad1 and Ad2, respectively) were obtained by the autocorrelation coefficients computed from the three acceleration components. Step and stride durations were calculated from the plantar pressure data and were used to compute two reference indices (SI1 and SI2) for step and stride regularity.</p> <p>Results</p> <p>Regression analysis showed that both Ad1 well correlates with SI1 (<it>R</it>²up to 0.74), and Ad2 well correlates with SI2 (<it>R</it>²up to 0.52). A ROC analysis showed that Ad1 and Ad2 has generally a good sensitivity and specificity in classifying amputee's walking trial, as having a normal or a pathologic step or stride regularity as defined by means of the reference indices SI1 and SI2. In particular, the antero-posterior component of Ad1 and the vertical component of Ad2 had a sensitivity of 90.6% and 87.2%, and a specificity of 92.3% and 81.8%, respectively.</p> <p>Conclusions</p> <p>The use of a simple accelerometer, whose components can be analyzed by the autocorrelation function method, is adequate for the assessment of gait symmetry and regularity in transfemoral amputees.</p

Recommended number of strides for automatic assessment of gait symmetry and regularity in above-knee amputees by means of accelerometry and autocorrelation analysis

<p>Abstract</p> <p>Background</p> <p>Symmetry and regularity of gait are essential outcomes of gait retraining programs, especially in lower-limb amputees. This study aims presenting an algorithm to automatically compute symmetry and regularity indices, and assessing the minimum number of strides for appropriate evaluation of gait symmetry and regularity through autocorrelation of acceleration signals.</p> <p>Methods</p> <p>Ten transfemoral amputees (AMP) and ten control subjects (CTRL) were studied. Subjects wore an accelerometer and were asked to walk for 70 m at their natural speed (twice). Reference values of step and stride regularity indices (Ad1 and Ad2) were obtained by autocorrelation analysis of the vertical and antero-posterior acceleration signals, excluding initial and final strides. The Ad1 and Ad2 coefficients were then computed at different stages by analyzing increasing portions of the signals (considering both the signals cleaned by initial and final strides, and the whole signals). At each stage, the difference between Ad1 and Ad2 values and the corresponding reference values were compared with the minimum detectable difference, MDD, of the index. If that difference was less than MDD, it was assumed that the portion of signal used in the analysis was of sufficient length to allow reliable estimation of the autocorrelation coefficient.</p> <p>Results</p> <p>All Ad1 and Ad2 indices were lower in AMP than in CTRL (P < 0.0001). Excluding initial and final strides from the analysis, the minimum number of strides needed for reliable computation of step symmetry and stride regularity was about 2.2 and 3.5, respectively. Analyzing the whole signals, the minimum number of strides increased to about 15 and 20, respectively.</p> <p>Conclusions</p> <p>Without the need to identify and eliminate the phases of gait initiation and termination, twenty strides can provide a reasonable amount of information to reliably estimate gait regularity in transfemoral amputees.</p

The Impact of Low-dose Gliclazide on the Incretin Effect and Indices of Beta-cell Function

AIMS/HYPOTHESIS: Studies in permanent neonatal diabetes suggest that sulphonylureas lower blood glucose without causing hypoglycemia, in part by augmenting the incretin effect. This mechanism has not previously been attributed to sulphonylureas in patients with type 2 diabetes (T2DM). We therefore aimed to evaluate the impact of low-dose gliclazide on beta-cell function and incretin action in patients with T2DM. METHODS: Paired oral glucose tolerance tests and isoglycemic infusions were performed to evaluate the difference in the classical incretin effect in the presence and absence of low-dose gliclazide in 16 subjects with T2DM (hemoglobin A1c < 64 mmol/mol, 8.0%) treated with diet or metformin monotherapy. Beta-cell function modeling was undertaken to describe the relationship between insulin secretion and glucose concentration. RESULTS: A single dose of 20 mg gliclazide reduced mean glucose during the oral glucose tolerance test from 12.01 ± 0.56 to 10.82 ± 0.5mmol/l [P = 0.0006; mean ± standard error of the mean (SEM)]. The classical incretin effect was augmented by 20 mg gliclazide, from 35.5% (lower quartile 27.3, upper quartile 61.2) to 54.99% (34.8, 72.8; P = 0.049). Gliclazide increased beta-cell glucose sensitivity by 46% [control 22.61 ± 3.94, gliclazide 33.11 ± 7.83 (P = 0.01)] as well as late-phase incretin potentiation [control 0.92 ± 0.05, gliclazide 1.285 ± 0.14 (P = 0.038)]. CONCLUSIONS/INTERPRETATION: Low-dose gliclazide reduces plasma glucose in response to oral glucose load, with concomitant augmentation of the classical incretin effect. Beta-cell modeling shows that low plasma concentrations of gliclazide potentiate late-phase insulin secretion and increase glucose sensitivity by 50%. Further studies are merited to explore whether low-dose gliclazide, by enhancing incretin action, could effectively lower blood glucose without risk of hypoglycemia

A Plant-Based Dietary Intervention Improves Beta-Cell Function and Insulin Resistance in Overweight Adults: A 16-Week Randomized Clinical Trial.

The aim of this study was to test the effect of a plant-based dietary intervention on beta-cell function in overweight adults with no history of diabetes. Participants (n = 75) were randomized to follow a low-fat plant-based diet (n = 38) or to make no diet changes (n = 37) for 16 weeks. At baseline and 16 weeks, beta-cell function was quantified with a mathematical model. Using a standard meal test, insulin secretory rate was calculated by C-peptide deconvolution. The Homeostasis Model Assessment (HOMA-IR) index was used to assess insulin resistance while fasting. A marked increase in meal-stimulated insulin secretion was observed in the intervention group compared with controls (interaction between group and time, Gxt, p \u3c 0.001). HOMA-IR index fell significantly (p \u3c 0.001) in the intervention group (treatment effect −1.0 (95% CI, −1.2 to −0.8); Gxt, p = 0.004). Changes in HOMA-IR correlated positively with changes in body mass index (BMI) and visceral fat volume (r = 0.34; p = 0.009 and r = 0.42; p = 0.001, respectively). The latter remained significant after adjustment for changes in BMI (r = 0.41; p = 0.002). Changes in glucose-induced insulin secretion correlated negatively with BMI changes (r = −0.25; p = 0.04), but not with changes in visceral fat. Beta-cell function and insulin sensitivity were significantly improved through a low-fat plant-based diet in overweight adult

Mathematical Model of Glucagon Kinetics for the Assessment of Insulin-Mediated Glucagon Inhibition During an Oral Glucose Tolerance Test

none6siGlucagon is secreted from the pancreatic alpha cells and plays an important role in the maintenance of glucose homeostasis, by interacting with insulin. The plasma glucose levels determine whether glucagon secretion or insulin secretion is activated or inhibited. Despite its relevance, some aspects of glucagon secretion and kinetics remain unclear. To gain insight into this, we aimed to develop a mathematical model of the glucagon kinetics during an oral glucose tolerance test, which is sufficiently simple to be used in the clinical practice. The proposed model included two first-order differential equations -one describing glucagon and the other describing C-peptide in a compartment remote from plasma - and yielded a parameter of possible clinical relevance (i.e., SGLUCA(t), glucagon-inhibition sensitivity to glucose-induced insulin secretion). Model was validated on mean glucagon data derived from the scientific literature, yielding values for SGLUCA(t) ranging from -15.03 to 2.75 (ng of glucagon·nmol of C-peptide-1). A further validation on a total of 100 virtual subjects provided reliable results (mean residuals between -1.5 and 1.5 ng·L-1) and a negative significant linear correlation (r = -0.74, p < 0.0001, 95% CI: -0.82 - -0.64) between SGLUCA(t) and the ratio between the areas under the curve of suprabasal remote C-peptide and glucagon. Model reliability was also proven by the ability to capture different patterns in glucagon kinetics. In conclusion, the proposed model reliably reproduces glucagon kinetics and is characterized by sufficient simplicity to be possibly used in the clinical practice, for the estimation in the single individual of some glucagon-related parameters.openMorettini, Micaela; Burattini, Laura; Göbl, Christian; Pacini, Giovanni; Ahrén, Bo; Tura, AndreaMorettini, Micaela; Burattini, Laura; Göbl, Christian; Pacini, Giovanni; Ahrén, Bo; Tura, Andre

Mathematical model of insulin kinetics accounting for the amino acids effect during a mixed meal tolerance test

Amino acids (AAs) are well known to be involved in the regulation of glucose metabolism and, in particular, of insulin secretion. However, the effects of different AAs on insulin release and kinetics have not been completely elucidated. The aim of this study was to propose a mathematical model that includes the effect of AAs on insulin kinetics during a mixed meal tolerance test. To this aim, five different models were proposed and compared. Validation was performed using average data, derived from the scientific literature, regarding subjects with normal glucose tolerance (CNT) and with type 2 diabetes (T2D). From the average data of the CNT and T2D people, data for two virtual populations (100 for each group) were generated for further model validation. Among the five proposed models, a simple model including one first-order differential equation showed the best results in terms of model performance (best compromise between model structure parsimony, estimated parameters plausibility, and data fit accuracy). With regard to the contribution of AAs to insulin appearance/disappearance (kAA model parameter), model analysis of the average data from the literature yielded 0.0247 (confidence interval, CI: 0.0168 - 0.0325) and -0.0048 (CI: -0.0281 - 0.0185) μU·ml-1/(μmol·l-1·min), for CNT and T2D, respectively. This suggests a positive effect of AAs on insulin secretion in CNT, and negligible effect in T2D. In conclusion, a simple model, including single first-order differential equation, may help to describe the possible AAs effects on insulin kinetics during a physiological metabolic test, and provide parameters that can be assessed in the single individuals