Mechanism-based disease progression modeling of type 2 diabetes in Goto-Kakizaki rats

Abstract

The dynamics of aging and type 2 diabetes (T2D) disease progression were investigated in normal [Wistar-Kyoto (WKY)] and diabetic [Goto-Kakizaki (GK)] rats and a mechanistic disease progression model was developed for glucose, insulin, and glycosylated hemoglobin (HbA1c) changes over time. The study included 30 WKY and 30 GK rats. Plasma glucose and insulin, blood glucose and HbA1c concentrations and hematological measurements were taken at ages 4, 8, 12, 16 and 20 weeks. A mathematical model described the development of insulin resistance (IR) and β-cell function with age/growth and diabetes progression. The model utilized transit compartments and an indirect response model to quantitate biomarker changes over time. Glucose, insulin and HbA1c concentrations in WKY rats increased to a steady-state at 8 weeks due to developmental changes. Glucose concentrations at 4 weeks in GK rats were almost twice those of controls, and increased to a steady-state after 8 weeks. Insulin concentrations at 4 weeks in GK rats were similar to controls, and then hyperinsulinemia occurred until 12-16 weeks of age indicating IR. Subsequently, insulin concentrations in GK rats declined to slightly below WKY controls due to β-cell failure. HbA1c showed a delayed increase relative to glucose. Modeling of HbA1c was complicated by age-related changes in hematology in rats. The diabetes model quantitatively described the glucose/insulin inter-regulation and HbA1c production and reflected the underlying pathogenic factors of T2D--IR and β-cell dysfunction. The model could be extended to incorporate other biomarkers and effects of various anti-diabetic drugs.

Fig. 1

Model schematic for inter-regulation of glucose, insulin and HbA1c during maturation (WKY) and T2D (GK) progression. Parameters and symbols are defined in the tables. Lines with arrows indicate conversion to or turn-over of the indicated responses. Lines ending in closed circles indicate an effect is exerted by the connected factors. Open and solid boxes differentiate stimulatory and inhibitory effects. Dashed lines depict pathways of maturation/disease progression

Fig. 2

Time course of plasma glucose (left) and insulin (right) in WKY (solid circles) and GK (open circles) rats. All observations are reported as mean ± SD. Model fittings are shown as lines

Fig. 3

Time course of MCH (a), RBC (b), Hemoglobin (c) and HbA1c (d) in WKY (solid circles) and GK (open circles) rats. All observations are reported as mean ± SD. Model fittings are shown as lines

Fig. 4

Time courses of IR (a, c), insulin secretion rate constant (b, d), and/or insulin production rate (e), and S_Glu (f) in WKY (dashed line) and GK (solid line) rats according to model estimations

Fig. 5

Simulated time courses of plasma glucose and insulin in WKY (dashed line) and GK (solid line) rats over 52 weeks of age