213-LB: Impact of Alpha- and Beta-Cell Dysfunction on the Longitudinal Progression to Type 2 Diabetes

T2D results from glucotoxicity-driven impairment of insulin secretion which limits compensation for increased insulin demand. Increased demand results from insulin resistance and elevated hepatic glucose production (HGP). Increased HGP can result either from insulin resistance or alpha-cell dysregulation leading to hyperglucagonemia.

Objectives: To investigate with a mathematical model whether increased HGP and progression to T2D could result from impaired glucagon secretion in addition to insulin resistance. Toward this end, we developed a realistic model of beta-cell growth, death and function and interfaced it with a previously validated model of glucose-insulin-glucagon dynamics.

Methods: A previously published model of longitudinal progression to T2D over years was extended to include glucagon dynamics. The beta cell mass/function equation was parametrized by interfacing with results from a previously published paper on modeling isoglycemic, intravenous glucose infusion tests to obtain snapshots of the metabolic state. The range of parameters observed in the cohort studied cover the gamut from normal, insulin sensitive to normal, insulin resistant to T2D patients, and was used to calibrate the model. The influence of insulin resistance and impaired glucagon secretion as they develop over time was included in the combined model to see how they impact the balance between enhanced and impaired beta-cell function and mass.

Results and Conclusion: When only insulin sensitivity was allowed to decrease, the normal subjects did not transition to T2D. This was because the glucose levels were not elevated sufficiently to upset the balance between enhancement and impairment and lead to a catastrophic decline in insulin secretion. Including time-dependent impairment of glucagon suppression, in addition to declining insulin sensitivity, was sufficient to lead to the significant imbalance required to progress to T2D diabetes. Thus, both appear to be required.