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Two new formulations, respectively denominated INT_M1 and INT_M2, of an integrated mathematical model to describe the glycemic and insulinemic responses to a 75g oral glucose tolerance test (OGTT) are proposed and compared. The INT_M1 assumes a single compartment for the intestine and the derivative of a power exponential function for the gastric emptying rate, while, in the INT_M2, a nonlinear three-compartment system model is adopted to produce a more realistic, multiphase gastric emptying rate. Both models were implemented in a Matlab-based, two-step procedure for estimation of seven adjustable coefficients characterizing the gastric emptying rate and the incretin, insulin and glucose kinetics. Model behaviour was tested vs. mean plasma glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucose and insulin measurements from two different laboratories, where glycemic profiles observed during a 75g OGTT were matched in healthy subjects (HC1- and HC2-group, respectively) by means of an isoglycemic intravenous glucose (I-IVG) infusion. Under the hypothesis of an additive effect of GLP-1 and GIP on insulin potentiation, our results demonstrated a substantial equivalence of the two models in matching the data. Model parameter estimates showed to be suitable markers of differences observed in the OGTT and matched I-IVG responses from the HC1-group compared to the HC2-group. Model implementation in our two-step parameter estimation procedure enhances the possibility of a prospective application for individualization of the incretin effect in a single subject, when his/her data are plugged in. [ABSTRACT FROM AUTHOR]

Based on glucose kinetics minimal model (GKMM) interpretation of frequently sampled intravenous glucose tolerance test (FSIGTT), the aim was to broaden the characterization of insulin-mediated glucose disposal in hypertension by aid of a dynamic insulin sensitivity index, $$ S_{\text{I}}^{\text{D}} $$, and the related efficiency, $$ \eta = S_{\text{I}}^{\text{D}} /S_{\text{I}} , $$ of the metabolic system to convert the maximal individual response capacity, measured by S, into an effective insulin control on glucose. The C-peptide minimal model (CPMM) was used to interpret the role of β-cell function. Plasma glucose, insulin, and C-peptide concentrations were measured, during a 5-h FSIGTT, in eighteen normoglycemic individuals: ten hypertensive patients (H-group) and eight normotensive subjects (N-group) with no metabolic syndrome. Compared to our N-group, the H-group showed a significant ( P < 0.05) reduction of both S (56%) and $$ S_{\text{I}}^{\text{D}} $$ (50%), no significant change of η, a significant increase of both the first-phase β-cell responsiveness to glucose (105%) and total insulin secretion (55%), and no significant change in disposition indexes, defined as the product of insulin sensitivity (either S and $$ S_{\text{I}}^{\text{D}} $$) and β-cell responsiveness. These findings suggest that, in spite of no change of efficiency, insulin resistance in normoglycemic hypertensive patients is primarily compensated by an increase in first-phase insulin secretion to preserve glucose tolerance to intravenous glucose load. [ABSTRACT FROM AUTHOR]

Abstract: Relationship between insulin action and secretion was analyzed in 10 hypertensive patients (H group; 5 male, 5 female; 56.9 ± 2.5 years) compared with 10 normotensive subjects (N group; 5 male, 5 female; 51.7 ± 3.7 years; P > .05) matched for age, sex, and body mass index. All participants (normoglycemic, nonobese, and not affected by metabolic syndrome) underwent a 5-hour, 22-sample, oral (75 g) glucose tolerance test. Insulin sensitivity was quantified by quantitative insulin sensitivity check index and an insulin sensitivity index computed by minimal-model–based “integral equation.” β-Cell responsivity indexes (dynamic, Φd; static, Φs; and global, Φoral) were estimated by C-peptide oral minimal model. Compared with the N group, our H group featured no significant difference (P > .05) in fasting glycemia, significant (P < .02) increase in plasma insulin (93%) and C-peptide (53%) concentrations, and significant (P < .01) reduction in both quantitative insulin sensitivity check index (10%) and insulin sensitivity index (68%). No significant variations of mean Φd, Φs, and Φoral were observed across the 2 groups in response to glucose challenge. Thus, insulin sensitivity deterioration in hypertension was not mirrored by a reciprocal change in β-cell responsivity. Nevertheless, our H group featured a 143% (P < .005) increase in the area under the curve of circulating insulin and a 34% (P < .01) reduction in the ratio between the area under C-peptide curve and the area under the curve of circulating insulin. These results support the hypothesis that decreased insulin clearance in hypertensive patients, not affected by metabolic syndrome, is a further regulatory mechanism, in addition to increased insulin secretion, to compensate for insulin resistance. [Copyright &y& Elsevier]

Somatosympathetic reflexes were studied in young hyperinsulinemic, insulin-resistant (Zucker fatty) rats (ZFR) and a related control (Zucker lean) strain (ZLR). Glucose metabolism was characterized by minimal model analysis of intravenous glucose tolerance test data. Seven-week-old ZFR (n = 18) and ZLR (n = 17) were studied under pentobarbital anesthesia. Mean body weight and plasma glucose and insulin concentration were significantly greater (P < 0.05) in ZFR than in ZLR, whereas basal values of mean arterial pressure (MAP) and heart rate (HR) were not significantly different. Increments of MAP (ΔMAP) and HR (AHR) elicited by electrical stimulation of the sciatic nerve (5-s trains of 100 pulses, 0.5-ms pulse duration, 100- to 400-μA pulse intensity) were significantly higher (ANOVA, P < 0.05) in ZFR at each level of stimulus intensity. Regression analysis showed a linear increase in ΔMAP and AHR with increasing sciatic nerve stimulus intensity. Pressor responses to phenylephrine after ganglionic blockade demonstrated that vascular reactivity to adrenergic stimulation is not increased in ZFR compared with ZLR. Thus this factor does not contribute to enhancement of somatosympathetic reflexes observed in this strain. Insulin sensitivity in ZFR was one-fourth (P < 0.05) that in ZLR. These results suggest that stronger sympathetic nervous reactivity in ZFR is associated with a severe insulin-resistant state before the onset of hypertension and support the hypothesis that insulin-mediated stimulation of the sympathetic nervous system is involved in the development of cardiovascular diseases related to alterations of glucose metabolism. [ABSTRACT FROM AUTHOR]

Abstract: Four methods reported in the literature for evaluation of insulin sensitivity indexes from oral glucose tolerance tests (OGTTs) were analyzed and compared in order to test their ability to discriminate the insulin-resistant state in hypertension. To this aim, 15 normoglycemic subjects, not affected by metabolic syndrome, underwent a 22-sample, 300-minute OGTT. Eight subjects were normotensive (mean age, 47.0 ± 4.2 years) and 7 were hypertensive (mean age, 53.6 ± 1.6 years). The following insulin sensitivity indexes were computed and compared: (a) 2 indexes, ISIE22/300 and ISIE8/180, provided by an integral equation (IE) method applied to the full OGTT and to a reduced 8-sample, 180-minute data subset, respectively; (b) 2 indexes, ISOGIS180 and ISOGIS120, computed by the oral glucose, insulin sensitivity (OGIS) method, which only requires 3 blood samples taken within 180 and 120 minutes, respectively; (c) an index, ISISI, which considers fasting and mean insulinemia and glycemia measured during a 5-sample, 120-minute OGTT; and (d) an index, ISMCR, which considers body mass index and requires 2 blood samples taken within 120 minutes. Except the ISOGIS180, all other indexes were able to detect a significant reduction (unpaired Student t test, P < .05) of insulin sensitivity in our hypertensive group compared with the normotensive group. Failure of ISOGIS180 was explained by the fact that this index did not capture the information portrayed by the peak of insulinemia in hypertensive patients, which occurred around the 90th minute. Intraclass correlation coefficients higher than 0.89 demonstrated a substantial agreement between ISIE22/300 and ISIE8/180 indexes. These are the only indexes characterized by units of measure consistent with the definition of insulin sensitivity as the ability of insulin to enhance glucose effectiveness. [Copyright &y& Elsevier]

Abstract: Role of hepatic insulin degradation in modulating insulin delivery to peripheral circulation, in insulin-resistant hypertensive patients, is not yet fully understood. This issue was investigated here by a novel application to hypertension of a previously proposed minimal modelling of insulin and C-peptide data, using population values for insulin and C-peptide kinetics parameters. Data, from frequently sampled intravenous glucose tolerance test (FSIGTT), were analysed in ten normoglycemic, hypertensive patients (H-group), compared with eight normoglycemic, normotensive subjects (N-group), matched for age, gender and body mass index. Minimal modelling of C-peptide and insulin data provided β-cell responsiveness to glucose perturbation (first, Φ 1, second, Φ 2, and basal, Φ b , phase), insulin secretion rate, ISR(t) and total pre-hepatic insulin secretion, TIS, as well as insulin delivery rate, IDR(t), and total insulin delivery, TID, into plasma, over 5-h test. Instantaneous normalized hepatic insulin degradation rate was computed as HIDR(t)=1−[IDR(t)/ISR(t)]. In our H-group, insulin sensitivity, S I , assessed by minimal model of glucose kinetics, showed a 56% reduction, which confirmed deterioration of insulin action in hypertension. This was associated with significant increase in Φ 1 (105%), TIS (55%) and TID (62%). No significant alterations were observed in other characteristic parameters of secretion and hepatic degradation of insulin, such that no significant difference was observed in HIDR(t) between our H and N groups. In conclusion, an increase of first phase and total insulin secretion occurring, in our H-group, in the presence of no alteration of hepatic insulin degradation, resulted in up-regulation of total insulin delivered to plasma (TID) for insulin-resistance compensation. [Copyright &y& Elsevier]