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We have previously presented a proposal for a new, beta-cell centric classification of diabetes based on a consilience of genetic, metabolic, and clinical research that have accrued since the current classification was instituted. It recognizes that the beta-cell is THE core defect in all patients with diabetes. Differences in the genetics (and epigenetics), insulin resistance, environment and inflammation/immune characteristics resulting in the damage to the beta-cell in each individual will determine the phenotypic presentation of hyperglycemia and allow for a patient-centric, precision-medicine therapeutic approach, part of which we labeled ‘the Egregious Eleven’. We now recognize the same pathophysiologic mechanisms that account for damage to the beta-cells govern the susceptibility of the cells involved in the complications and other conditions ‘tied to’ diabetes to damage by the abnormal metabolic environment that typifies beta-cell dysfunction and ‘fuel excess’. This abnormal metabolic environment is typified by oxidative stress which alters metabolic pathways (a la Brownlee’s Hypothesis model), alterations in gene expression, epigenetics, and inflammation. This allows us to understand the varied risk of developing complications of diabetes, including malignancies, dementia, NASH, psoriasis with similar levels of glycemic control; how non-glycemic effects of some medications for diabetes result in marked complication risk modification; and the value treating co-morbidities of diabetes in modifying complication risk. Principles we outlined in using ‘the Egregious Eleven’ model- use agents that preserve beta-cell function, treat with least number of agents that treat most number of mechanisms of hyperglycemia- can be extended to use those agents, in combination, that also engender weight loss, decrease CV outcomes and have real or potential benefits in cancers related to diabetes, dementia risk, NASH, psoriasis. This approach allows for a more accurate assessment of each patient’s disease and effecting true precision medicine Schwartz, S, et al, Diabetes Care 2016, 39:179–186. Schwartz SS, et al Trends Endocrinol Metab. 2017;28(9):645–655.

journal of the endocrine society

MON-618 A Framework for Understanding and Managing ‘The Diabetes Syndrome’: A Unified Pathophysiologic Approaching the Context of the Beta-Cell Classification of Diabetes