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. Although originally designed as a longitudinal model for the progression from normal glucose tolerance through pre-diabetes to diabetes, the model can also be applied to assess insulin resistance and beta-cell function at any stage along the process by fitting data from OGTTs. The model in this form is called the Insulin Sensitivity and Secretion Model (ISS). 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. See Ref. #1 for further details. 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. This year, the International Diabetes Federation adopted the cut-off of 209 mg/dl (11.6 mM) glucose at the one-hour time point as an alternative definition of T2D. We joined a group of colleagues who have been working in this area to propose a detailed staging scheme to make best use of one hour glucose (see Ref. #1). We also worked with our colleagues from the 16-year longitudinal Korean Genetics and Epidemiology Study (KoGES) on a paper showing that one-hour glucose is an earlier marker of T2D in that cohort (see Ref. #2). Although the role of insulin resistance in the development of T2D has been studied extensively with longitudinal mathematical models, the role of excessive secretion of glucagon, which develops in parallel with insulin resistance and raises plasma glucose by increasing glucose production in the liver, has not previously been modeled longitudinally. With K25 mentee Vijaya Subramanian (Johns Hopkins) we developed such a model and found that hyperglucagonemia indeed plays a major role in pathogenesis. Interestingly, mild glucagon excess fosters enhanced beta-cell function and delays onset of T2D, but severe excess accelerates disease onset by raising glucose and hence glucotoxicity faster than the beta cells can compensate. The paper will appear in the November, 2025 issue of Diabetologia and has been selected for the "Up Front" feature that highlights five articles that merit special attention.