C-Peptide-based assessment of insulin secretion in the Zucker Fatty rat: a modelistic study

Abstract

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-9 week-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, Ф(1), second-phase, Ф(2), and steady-state, Ф(ss), 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.

Fig 1. Time course of plasma glucose (G(t), panel A) insulin (I(t), panel B) and C-peptide (CP(t), panel C) concentrations during 90-min IVGTT in our ZFR group (n = 7, closed circles) and ZLR group (n = 7, open circles).

Values are mean ± SE.

Fig 2. IVGTT-based mean (±SE) values of model predicted: whole-body insulin sensitivity (S _I, panel A); first-phase β-cell responsiveness to glucose stimulus (Φ ₁, panel B); second-phase β-cell responsiveness to glucose stimulus (Φ ₂, panel C) and total insulin secretion, for unit of distribution volume (TIS, panel D) in ZLR (open bar) and ZFR (shaded bar) groups.

Measure units are: 10^-4·dL·kg^-1·min^-1/(μU·mL^-1) for S _I; (pmol/L C-peptide)/(mmol/L glucose) for Φ ₁; 10^-1·min^-2·(pmol/L C-peptide)/(mmol/L glucose) for Φ ₂; and 10³·pmol/L for TIS. * p<0.001 and ** p<0.05 in comparing ZFR and ZLR groups.

Fig 3. Mean (±SD) weighted residual over all our fourteen Zucker rats (7 ZFRs and 7 ZLRs) provided by fitting the CPMM output to C-peptide data.

Fig 4. Time course of above steady-state insulin secretion rate, SR(t), during 90-min IVGTT in our ZFR group (n = 7, closed circles) and ZLR group (n = 7, open circles).

Values are mean ± SE.