Fig 1.
A conceptual framework that views insulin hypersecretion as the upstream of insulin resistance and the development of T2D.
Different from the view that hyperinsulinemia is the downstream of insulin resistance, it proposes that hyperinsulinemia results from the hyperresponsive beta-cells to hostile environment, and insulin resistance is an adaptive mechanism protecting critical tissues from insulin-induced metabolic stress [13].
Table 1.
Parameter values for the undisturbed glucose-insulin regulatory model and obesity-related diabetes model.
Fig 2.
Dynamics of glucose, insulin and functional beta-cell mass level for patient A with severe obesity (X approaches 1 progressively).
This figure depicts the impact of severe obesity on the glucose regulatory system. The pathogenic factor X initially overstimulates the beta-cell function of this patient. The insulin level exceeds 25 μU/ml after day 2631, which represents the onset of hyperinsulinemia. However, at this time, the glucose level is 102 mg/dl, which is close to normal. As X continuously increases, the functional beta-cell mass keeps rising before day 6089 and then decreases afterwards. Correspondingly, the insulin level retains increasing before day 7015 and then descends. The hyperinsulinemic stage ends after day 9373 and insulin deficiency gradually occurs afterwards. In the hyperinsulinemic stage, patient A experiences some fluctuations in the glucose levels. The glucose level exceeds the threshold of diabetic stage on day 6063, yet decreasing for a while after reaching the level 151 mg/dl on day 7134. Subsequent to the appearance of beta-cell failure and insulin deficiency, a sharp rise of the glucose level occurs, transitioning patient A to overt diabetes.
Fig 3.
Comparison of the insulin sensitivity and GIβ dynamics using C(I) and C(I, X) in the model.
The function C(I, X) is chosen to be , where C(I) is given in model (1). The other parameters maintain the same as in Fig 2. Graph (a) shows the time evolution of the insulin sensitivity C(I) in the dashed curve and C(I, X) in the solid curve. Graphs (b), (c), and (d) exhibit the corresponding GIβ dynamics under the two insulin sensitivity functions.
Fig 4.
Dynamics of glucose, insulin and functional beta-cell mass level for patient A with mild obesity (X approaches 0.17 progressively).
This figure describes the impact of the controlled obesity-related factor on the alleviation of diabetes. In contrast to the occurrence of beta-cell failure and subsequent insulin deficiency in Fig 2, hyperinsulinemia would occur to patient A on day 15460 and stay in the remainder of the life of this patient with undamaged pancreatic function. The glucose levels can be controlled below 125 mg/dl before day 20053, indicating a deferral of 38 years to develop diabetes compared with the condition in Fig 2. In addition, a moderate glycemic level, less than 130 mg/dl, can be maintained in the later life of this patient.
Fig 5.
Altered dynamics of glucose, insulin and functional beta-cell mass level for patient A after taking the Roux-en-Y gastric bypass surgery.
The patient is assumed to take the surgery on day 9300 and the obesity-related factor X is postulated to decrease exponentially to zero in approximately a week. The GIβ dynamics with taking the Roux-en-Y surgery are plotted in solid curves and the dashed curves represent the expected GIβ trajectories without taking the intervention. The solid curves are zoomed in to show the variations of the GIβ levels during the week after surgery. All of the other parameters here remain the same as those in Fig 2, except for those in the equation of X. Graph (a) illustrates that in contrast to the upsurge of glucose level after day 9300 without any intervention, the glucose levels are reduced to 100 mg/dl following surgery for one week. Graph (b) and (c) demonstrate the bariatric surgery can promptly halt the occurrence of beta-cell failure and insulin deficiency. Normal levels of insulin can be maintained after the first week.
Fig 6.
Dynamics of glucose, insulin and functional beta-cell mass for patient B with severe obesity (X approaches 1 progressively).
Patient B is assumed to have a lower insulin resistance level and less beta-cell hyperresponsiveness to the obesity-related factor than patient A does. Graph (b) shows the hyperinsulinemic stage of patient B lasts for 15.2 years, which is 3.3 years shorter than patient A does in Fig 2. The maximal insulin level he would develop is 39 μU/ml, which is 27.6 μU/ml lower than the highest level that patient A attains. During this hyperinsulinemic stage, the glucose levels can be well controlled beneath 111.6 mg/dl. Additionally, patient B would not step into the diabetic stage until day 9676, which is 11.5 years later than patient A does.
Fig 7.
Dynamics of glucose, insulin and functional beta-cell mass level for patient B with mild obesity (X approaches 0.17 progressively).
In this case, the factor X can only increase the glucose level to 104.8 mg/dl and the elevation is counteracted afterward by an upsurge of insulin. The insulin level remains moderately high after day 11010, driven by the continual hyperresponsiveness of beta-cells to the pathogenic risk. At the end, the glucose concentration of patient B can stay stable at a euglycemic level with 96.8 mg/dl.
Fig 8.
Obesity-related diabetes model fit to plasma glucose data for Pima Indian #1–#6.
Overall, the glucose levels of these patients were steadily trending upwards.
Fig 9.
Obesity-related diabetes model fit to plasma glucose data for Pima Indian #7–#9.
These data exhibit waveringly trends before the outbreak.
Fig 10.
Obesity-related diabetes model fit to plasma glucose data with large fluctuations for Pima Indian #10 and #11.
Table 2.
Parameter values of the best fits of the obesity-related diabetes model to the glucose data of Pima Indian #1-#11.