In previous reports we have described our model for T2D pathogenesis. It builds on the foundational model (Topp et al, J. Theor. Biol. 2000; 206(4):605-19), which posited that moderate but persistent increases 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, there is then positive feedback, 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 deviates first 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 have applied the model to extract better information from OGTTs, with a particular focus on whether glucose at the 1-hour time point (1hG) is an equivalent or superior predictor to the current standard, 2-hour glucose (2hG), of future T2D or other aspects of metabolic health. Our collaborator Dr. Michael Bergman (NYU Langone) has been a leader in an international effort, including a petition to the American Diabetes Association, to establish a threshold of 1hG of 155 mg/dl for pre-diabetes. Simulations with our model suggested that 1hG would cross its proposed threshold before 2hG crosses its established threshold of 140 mg/dl. In collaboration with Dr. Clifton Bogardus (NIDDK), we obtained a unique historical longitudinal data set in which 52 participants from their studies of Pima Indians had multiple (3 -11) OGTTs over an average follow-up of 7.2 years. We found that 1hG crossed its threshold almost 2 years earlier than 2hG, which could be clinically important in this population, which experiences rapid diabetes onset and progression. The results were presented in poster form at the 2019 Scientific Sessions of the American Diabetes Association, and a paper is in preparation. We are studying the utility of 1hG vs. 2hG using a cross-sectional data set of African immigrants living in the US together with Drs. Sumner and Chung (NIDDK). We found that 1hG above 155 mg/dl, in individuals who would be classified with normal glucose tolerance by current criteria, was associated with higher insulin resistance and poorer beta-cell function than in people with 1hG below 155 mg/dl. A paper is in review. We are also following up this idea in a data set from adolescent patients with cystic fibrosis-related diabetes (CFRD) in collaboration with Dr. Christine Chan (UC Colorado Anschutz Medical Campus). We expect the results to be of particular clinical importance in this group because 1hG is more associated with beta-cell dysfunction than 2hG, as shown in a number of clinical studies and confirmed by model simulations. Related to this, we assisted a study of Drs. Sumner and Chung investigating whether hemoglobin A1c could be used as an alternative to OGTT in people of African descent. A1c offers advantages especially in resource-poor environments, such as parts of Africa, because it does not require the patient to be fasting and requires only one blood draw. However, results may be unreliable in individuals with nutritional deficiencies, anemia or variant hemoglobin, such as sickle cell trait, all of which are common in Africa. To circumvent these difficulties, we studied a cohort of African immigrants living in America, who were nutritionally replete and not anemic. Most important, we found that even in those who did not have variant hemoglobin, A1c was not effective at detecting diabetes or pre-diabetes (reference # 1 below). In another modeling approach, we have worked with Drs. Sumner and Chung to evaluate why non-diabetic and pre-diabetic African-American women have higher insulin levels in spite of lower glucose levels. Using published models from the Bergman lab (Cedars Sinai Medical Center, Los Angeles), and the Cobelli lab (University of Padova, Italy), we have shown that the higher insulin results from reduced insulin clearance by the liver rather than increased insulin secretion from the beta cells (reference # 2 below). Further study will be needed to determine whether the higher insulin levels or higher clearance rates contribute to the elevated T2D risk of African Americans, or whether the increased risk is in spite of higher insulin.
