Modeling Pathogenesis of Type 2 Diabetes

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

In previous reports we have described our model for T2D pathogenesis. It builds on the foundational model of Topp et al (J. Theor. Biol. 2000; 206(4):605-19), which posited that moderate but persistent increases (i.e., not daily fluctuations) in blood sugar mediate negative feedback to increase insulin secretion by increasing beta-cell mass, either by increased replication or reduced apoptosis. However, if that increase fails to occur or is inadequate to restore normal glucose homeostasis, further increases in glucose raise it to a level where it becomes toxic to beta cells. Instead of negative feedback (homeostasis), there is then positive feedback (anti-homeostasis), which causes a catastrophic loss of beta-cell mass and T2D. In addition to quantitative refinements to more accurately reflect the measured dynamics of T2D progression in humans and rodents, we included regulation of beta-cell function, in two distinct forms, in addition to mass. Data show that such changes are more rapid and more extensive than changes in mass, especially for humans, for whom beta-cell replication is very slow after adolescence. The model captures many key features of T2D progression, including the sudden deterioration of glucose control after a long period of gradual worsening (threshold behavior) and the fact that prevention is generally much easier than reversal, but drastic interventions, such as bariatric surgery and extreme caloric restriction can reverse established disease. The model has been further extended to track fasting and post-prandial glucose, rather than just average daily glucose, which is important because individuals differ in which aspect of glucose first deviates from normal. In addition, the model can be paused at any point during progression over years to simulate glucose tolerance tests, both oral (OGTT) and intravenous (IVGTT). We also used the model to investigate the hypothesis that high insulin causes insulin resistance rather than the other way around, as we assume in our model. Although there is strong evidence that hyperinsulinemia does contribute to insulin resistance, model simulations suggest that this effect by itself lead to diabetes. However, if an individual is on a pathway to T2D because of increasing insulin resistance, the incremental effect of compensatory insulin to further increase insulin resistance may be able to accelerate the progression. K25 mentee Vijaya Subramanian, Johns Hopkins University, is working on an enhanced longitudinal model that will examine the contribution of elevated glucagon secretion, which increases release of glucose from the liver, to diabetes projection. Preliminary results, presented at the ADA Scientific Sessions, are promising, and we anticipate being able to report on this next year. Although originally designed as longitudinal model for the progression from normal glucose tolerance through pre-diabetes to diabetes, we have found that the model can be applied to assess insulin resistance and beta-cell function at any stage along the process by fitting data from OGTTs. We have found that the estimates correlate and agree reasonably well with those from other widely used, but more invasive and costly approaches. One is the frequently sampled intravenous glucose tolerance test, which requires more than 20 glucose and insulin samples, which are then analyzed using the Bergman-Cobelli Minimal Model (MINMOD). Another is the hyperinsulinemic, euglycemic clamp, in which glucose is infused to maintain glucose at a fixed level in the face of simultaneous insulin infusion. This is technically challenging and takes up to four hours. OGTTs are much easier to implement and more cost-effective for large-scale clinical studies, so our model thus has the potential to enhance the value of such studies. We have also found that the disposition index, defined as the ratio of beta-cell function to insulin resistance, can be calculated from our model without the need to measure insulin, further benefiting large-scale clinical studies. A paper is in review, and a preprint has been posted in bioRxiv (doi: https://doi.org/10.1101/2023.06.16.545377). Accumulating evidence shows that glucose at the one-hour time point of an OGTT is equal to or better than the current standard using the two-hour time point. Diagnostic cut points for pre-diabetes and T2D, taking into account that glucose is generally higher at one hour, have been proposed. Most work up until now has used cross-sectional data, but simulations with our longitudinal model have suggested that one-hour glucose may cross its diagnostic thresholds earlier than two-hour glucose. We tested this with a data set provided by Dr. Clifton Bogardus of the NIDDK Phoenix Branch where a subset of the Southwestern Native Americans they have studied for decades underwent OGTTs approximately every 2 years for 6 - 10 years. We confirmed that for most individuals, the one-hour criterion was satisfied first. The median advance of 1.7 years for prediabetes and 1 year for T2D would likely provide clinically significant benefit from earlier intervention. The work has been published in Ref. #1. The model simulations showed further that for people whose risk for T2D stems from impaired insulin secretion rather than insulin resistance would benefit. We tested this with a data set provided by Dr. Christine Chan, University of Colorado Anschutz medical school, of adolescents with cystic fibrosis (CF). People with CF are at high risk cystic fibrosis related diabetes (CFRD), secondary to the pancreatic inflammation associated with CF, which damages the beta cells. We found by Kaplan-Meier survival analysis that those who had high one-hour glucose but low two-hour glucose had increased 5-year risk of T2D. Importantly, this group of high risk youth would be missed by the standard ADA guidelines for OGTTs. Among those who have at least two OGTTs during the study, we found that one-hour glucose was an earlier predictor of T2D risk. The work has been published in Ref. #2. We are also investigating the utility of one-hour OGTT glucose in a large longitudinal study in Korea, where insulin secretion is generally more limited than in European populations. Preliminary work has been presented at the ADA Scientific Sessions and the Mid-Atlantic Diabetes and Obesity Research Symposium. We anticipate being able to report on this next year.