Aberrant hepatic glycogenolysis and elevated insulin clearance can lead to major glucose irregularities in type 2 diabetes: insights from system identification.

Complex interactions obscure the behavior of the glucose regulation processes as a system, hampering advances in diabetes care. We synthesized the current understandings of pancreatic hormones, glucose transporters, and glycogen metabolism into a model structure of biochemical reactions and mass transport. The model structure was then used as a soft sensor or filter to computationally extract system characteristics (model coefficients) from experimental measurements. Changes in coefficient values were analyzed to observe system differences among non-obese (n=18), obese (n=18), and type 2 diabetic (n=16) individuals under three conditions: none, morning, and post-dinner exercise. The model structure captures the major kinetics in blood glucose, insulin, and glucagon and the extracted coefficient values revealed metabolic differences and impairments. Relative to the non-obese group, the obese group showed impaired glucagon clearance (47% reduction) and reduced insulin sensitivity for glycogenesis, while the diabetic group exhibited elevated glucagon sensitivity (2.4-fold increase) and an aberrant effect of glycogen on glycogenolysis, which was associated with dysregulated hepatic glucose production and rising glucose during fasting. Parameter sensitivity analysis identified insulin clearance as a dominant factor in endogenous glucose production and fasting glucose level. Exercise effects varied: post-dinner exercise enhanced hepatic glycogen synthesis and hepatic sensitivity to glucose in non-obese individuals, while morning exercise improved muscle glucose uptake in the groups with obesity and type 2 diabetes. Derivation of the model structure and its application as a soft sensor elucidate the complex metabolic interactions underlying diabetes and provide a method to generate hypothesis for future research.