Abstract
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.
Highlights
Insulin sensitivity and beta-cell function are tightly interconnected processes in the governed glucose tolerance [1,2]
Indexes for glucose tolerance assessment in the Zucker fatty rat CPMM, C-Peptide Kinetics Minimal Model; DI, Disposition Index; First phase insulin release index (FPIR), First-phase Insulin Release, i.e. Surrogate First-phase β-cell responsiveness index; GKMM, Glucose Kinetics Minimal Model; insulin sensitivity index (ISI), Surrogate Insulin sensitivity index; intravenous glucose tolerance test (IVGTT), Intravenous Glucose Tolerance Test; SI, Insulin sensitivity index derived from GKMM; second phase insulin release index (SPIR), Second-phase Insulin Release, i.e. Surrogate Second-phase β-cell responsiveness index; ZFR, Zucker Fatty Rat; Zucker lean rats (ZLR), Zucker Lean Rat
In the first formulation, we considered that first-phase secretion ends 5 minutes after glucose infusion
Summary
Insulin sensitivity and beta-cell function are tightly interconnected processes in the governed glucose tolerance [1,2]. Evaluation of quantitative indexes able to describe both phenomena is required It is commonly acknowledged, that in the presence of a reduction of insulin sensitivity, glucose tolerance is maintained into the range of normality until beta-cells are unable to secrete an increased amount of insulin compensating for such reduction [3]. Interest in the ZFR relies on the fact that it is a well-recognized genetic model of human metabolic syndrome. This strain of rat is characterized by hyperinsulinaemia, glucose intolerance and insulin resistance [4,5]
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