A novel fast-slow model of diabetes progression: Insights into mechanisms of response to the interventions in the Diabetes Prevention Program

Abstract

Several models for the long-term development of T2DM already exist, focusing on the dynamics of the interaction between glycemia, insulinemia and β-cell mass. Current models consider representative (fasting or daily average) glycemia and insulinemia as characterizing the compensation state of the subject at some instant in slow time. This implies that only these representative levels can be followed through time and that the role of fast glycemic oscillations is neglected. An improved model (DPM15) for the long-term progression of T2DM is proposed, introducing separate peripheral and hepatic (liver and kidney) insulin actions. The DPM15 model no longer uses near-equilibrium approximation to separate fast and slow time scales, but rather describes, at each step in slow time, a complete day in the life of the virtual subject in fast time. The model can thus represent both fasting and postprandial glycemic levels and describe the effect of interventions acting on insulin-enhanced tissue glucose disposal or on insulin-inhibited hepatic glucose output, as well as on insulin secretion and β-cell replicating ability. The model can simulate long-term variations of commonly used clinical indices (HOMA-B, HOMA-IR, insulinogenic index) as well as of Oral Glucose Tolerance or Euglycemic Hyperinsulinemic Clamp test results. The model has been calibrated against observational data from the Diabetes Prevention Program study: it shows good adaptation to observations as a function of very plausible values of the parameters describing the effect of such interventions as Placebo, Intensive LifeStyle and Metformin administration.

Type 2 Diabetes: One Disease, Many Pathways

“…The study in (24) found that it was necessary to assume that the efficacy of treatment wanes with time in order to fit the data from lifestyle and drug interventions in the DPP. Here we have shown that even if the efficacy of treatment is maintained, the intrinsic dynamics of progressive beta-cell dysfunction can cause treatment to fail.…”

“…The normal homeostatic negative feedback is converted to positive feedback, leading to deterioration in glucose tolerance and culminating in diabetes. This fundamental concept has been incorporated into other models that broadly agree but emphasize different details (23, 24, 35, 38, 43, 79). Notably, the model of (38) was shown to be able to account for the progression of fasting hyperglycemia and T2D observed in the Diabetes Prevention Program (DPP)(45).…”

“…See (24) for further comment on the models cited here and other models, and see (54) for a perspective on modeling T2D.…”

“…The initial wave of mechanistic longitudinal models simulated fasting or average daily glucose and were therefore unable to describe post-prandial responses or responses to glucose challenges such as OGTTs and IVGTTs. A recent model (24) added the capability of following daily and post-challenge glucose variations and was fit to OGTT data from the DPP. It also introduced a distinction between peripheral and hepatic insulin resistance in order to account for the effects of drug and lifestyle interventions on these parameters.…”

Type 2 diabetes: one disease, many pathways

“…The normal homeostatic negative feedback is converted to positive feedback, leading to deterioration in glucose tolerance and culminating in diabetes. This fundamental concept has been incorporated into other models that broadly agree but emphasize different details (23,24,35,38,43,79). Notably, the model of Ref.…”