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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." beta-Cell responsivity indexes (dynamic, Phi(d); static, Phi(s); and global, Phi(oral)) 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 Phi(d), Phi(s), and Phi(oral) 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 beta-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.

The evolution with ageing of insulin resistance, body weight (BW) and mean arterial pressure (MAP) was studied in a group of Zucker fatty rats (ZFRs, n = 22), between 7 and 16 weeks of age, compared with an age-matched control group of Zucker lean rats (ZLRs, n = 22). The minimal model of glucose kinetics was applied to estimate glucose effectiveness, S(G), and insulin sensitivity, S(I), from insulinaemia and glycaemia measured during a 70 min intravenous glucose tolerance test. No correlation was found between S(G) and age in both ZFR and ZLR groups. No significant changes in mean S(G) between the two groups indicated no alteration of glucose-mediated glucose disposal. Estimates of S(I) from individual ZFRs were independent of age and, on average, showed 83% reduction (P < 0.001) compared with the ZLR group. Despite the lack of alteration of S(I) with age, the ZFR group showed an age-related increase of MAP, which correlated with increasing BW (r = 0.71 and P < 0.001). These results support the hypothesis that in our ZFRs, as a suitable genetic model of obesity and hypertension, insulin resistance is fully established at the age of 7 weeks and remains practically unaltered until at least the sixteenth week. An age-related increase in arterial pressure, observed in this strain, relates more properly to increasing BW, rather than insulin resistance. Development of hypertension with increasing age and BW may result from an enhanced insulin-mediated activity of the sympathetic nervous system, as observed in our previously reported study.

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 (DeltaMAP) and HR (DeltaHR) elicited by electrical stimulation of the sciatic nerve (5-s trains of 100 pulses, 0.5-ms pulse duration, 100- to 400-microA pulse intensity) were significantly higher (ANOVA, P<0.05) in ZFR at each level of stimulus intensity. Regression analysis showed a linear increase in DeltaMAP and DeltaHR 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.

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.

Background: This study examined the relative role of age and hypertension in deterioration of insulin-dependent (insulin sensitivity, S(I)) and insulin-independent (glucose effectiveness, S(G)) actions on glucose tolerance., Methods: We applied the minimal model of glucose kinetics to estimate S(I) and S(G) indexes from insulinemia and glycemia data detected during a frequently sampled intravenous glucose tolerance test performed in 21 normoglycemic subjects who were not affected by the metabolic syndrome (MS): seven young normotensive subjects (YN; mean age 29.3 +/- 1.5 years), six elderly normotensive subjects (EN; mean age 57.0 +/- 3.4 years) and eight elderly hypertensive patients (EH; mean age 62.1 +/- 2.1 years)., Results: Both normotensive subject groups (YN and EN) showed no significant difference in S(I) estimates despite significantly different age, whereas a significant reduction was evident in the EH patients compared with these groups. Mean estimates of S(G) showed no significant difference in elderly subject groups (EN and EH), irrespective of hypertension, whereas a significant increase was evident in the YN (analysis of variance followed by Scheffé test, P < .05)., Conclusions: Our study demonstrates that, in the absence of MS: 1) insulin sensitivity in normotensive subjects is independent of age; b) hypertension is associated with insulin resistance in elderly subjects; and c) age is a primary predictor of deterioration in glucose effectiveness, independent of hypertension.

For the assessment of glucose tolerance from IVGTT data in Zucker rat, minimal model methodology is reliable but time- and money-consuming. This study aimed to validate for the first time in Zucker rat, simple surrogate indexes of insulin sensitivity and secretion against the glucose-minimal-model insulin sensitivity index (SI) and against first- (Φ1) and second-phase (Φ2) β-cell responsiveness indexes provided by C-peptide minimal model. Validation of the surrogate insulin sensitivity index (ISI) and of two sets of coupled insulin-based indexes for insulin secretion, differing from the cut-off point between phases (FPIR3-SPIR3, t = 3 min and FPIR5-SPIR5, t = 5 min), was carried out in a population of ten Zucker fatty rats (ZFR) and ten Zucker lean rats (ZLR). Considering the whole rat population (ZLR+ZFR), ISI showed a significant strong correlation with SI (Spearman’s correlation coefficient, r = 0.88; P<0.001). Both FPIR3 and FPIR5 showed a significant (P<0.001) strong correlation with Φ1 (r = 0.76 and r = 0.75, respectively). Both SPIR3 and SPIR5 showed a significant (P<0.001) strong correlation with Φ2 (r = 0.85 and r = 0.83, respectively). ISI is able to detect (P<0.001) the well-recognized reduction in insulin sensitivity in ZFRs, compared to ZLRs. The insulin-based indexes of insulin secretion are able to detect in ZFRs (P<0.001) the compensatory increase of first- and second-phase secretion, associated to the insulin-resistant state. The ability of the surrogate indexes in describing glucose tolerance in the ZFRs was confirmed by the Disposition Index analysis. The model-based validation performed in the present study supports the utilization of low-cost, insulin-based indexes for the assessment of glucose tolerance in Zucker rat, reliable animal model of human metabolic syndrome. [ABSTRACT FROM AUTHOR]

A C-peptide-based assessment of β-cell function was performed here in the Zucker fatty rat, a suitable animal model of human metabolic syndrome. To this aim, a 90-min intravenous glucose tolerance test (IVGTT) was performed in seven Zucker fatty rats (ZFR), 7-to-9week-old, and seven age-matched Zucker lean rats (ZLR). The minimal model of C-peptide (CPMM), originally introduced for humans, was adapted to Zucker rats and then applied to interpret IVGTT data. For a comprehensive evaluation of glucose tolerance in ZFR, CPMM was applied in combination with the minimal model of glucose kinetics (GKMM). Our results showed that the present CPMM-based interpretation of data is able to: 1) provide a suitable fit of C-Peptide data; 2) achieve a satisfactory estimation of parameters of interest 3) quantify both insulin secretion by estimating the time course of pre-hepatic secretion rate, SR(t), and total insulin secretion, TIS, and pancreatic sensitivity by means of three specific indexes of β-cell responsiveness to glucose stimulus (first-phase, Ф1, second-phase, Ф2, and steady-state, Фss, never assessed in Zucker rats before; 4) detect the significant enhancement of insulin secretion in the ZFR, in face of a severe insulin-resistant state, previously observed only using a purely experimental approach. Thus, the methodology presented here represents a reliable tool to assess β-cell function in the Zucker rat, and opens new possibilities for the quantification of further processes involved in glucose homeostasis such as the hepatic insulin degradation. [ABSTRACT FROM AUTHOR]

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]