Adam R. Stinchcombe

Insulin, a key hormone in the regulation of glucose homoeostasis, is secreted by pancreatic β ‐cells in response to elevated glucose levels. Insulin is released in a biphasic manner in response to glucose metabolism in β ‐cells. The first phase of insulin secretion is triggered by an increase in the ATP:ADP ratio; the second phase occurs in response to both a rise in ATP:ADP and other key metabolic signals, including a rise in the NADPH:NADP + ratio. Experimental evidence indicates that pyruvate‐cycling pathways play an important role in the elevation of the NADPH:NADP + ratio in response to glucose. The authors developed a kinetic model for the tricarboxylic acid cycle and pyruvate cycling pathways. The authors successfully validated the model against experimental observations and performed a sensitivity analysis to identify key regulatory interactions in the system. The model predicts that the dicarboxylate carrier and the pyruvate transporter are the most important regulators of pyruvate cycling and NADPH production. In contrast, the analysis showed that variation in the pyruvate carboxylase flux was compensated by a response in the activity of mitochondrial isocitrate dehydrogenase (ICD m ) resulting in minimal effect on overall pyruvate cycling flux. The model predictions suggest starting points for further experimental investigation, as well as potential drug targets for the treatment of type 2 diabetes.

Mathematical models have been used extensively in chronobiology to explore characteristics of biological clocks. In particular, for human circadian studies, the Kronauer model has been modified multiple times to describe rhythm production and responses to sensory input. This phenomenological model comprises a single set of parameters which can simulate circadian responses in humans under a variety of environmental conditions. However, corresponding models for nocturnal rodents commonly used in circadian rhythm studies are not available and may require new parameter values for different species and even strains. Moreover, due to a considerable variation in experimental data collected from mice of the same strain, within and across laboratories, a range of valid parameters is essential. This study develops a Kronauer-like model for mice by re-fitting relevant parameters to published phase response curve and period data using total least squares. Local parameter sensitivity analysis and parameter distributions determine the parameter ranges that give a near-identical model and data distribution of periods. However, the model required further parameter adjustments to match characteristics of other mouse strains, implying that the model itself detects changes in the core processes of rhythm generation and control. The model is a useful tool to understand and interpret future mouse circadian clock experiments.