Using new methods (1-9), we and others have studied directly the binding of many polypeptide hormones to specific receptors on cells (10). The specificity of binding correlates well with the biological activity of the hormone. Typically, binding is rapid saturable, and reversible (e.g., Fig. 1) and represented as a simple biomolecular reaction, hormone + receptor T4 hormone-receptor complex. Recently, Archer, GoldfRne, Iahn, and others have found that the concentration of insulin receptors per cell fluctuates in response to altered conditions in vivo (11-23). Fasting or hypophysectomy is followed by an increase in the concentration of insulin receptors per cell (20, 22) associated with the hypoinsulinemia and the supernormal sensitivity to injected insulin that characterize these states; the increase in receptor concentration per cell correlates with increased sensitivity to insulin in vitro (20). Conversely, obesity or glucocorticoid excess, states that are characterized by chronic hyperinsulinemia and insulin resistance, are associated with large decrements in insulin receptors but not of other hormone receptors (11,13,14,21). The loss of receptors is similar in liver, fat, and lymphocytes. Appropriate treatment of the obesity or of the glucocorticoid excess ameliorates the hyperinsulinemia and insulin resistance at the same time that the receptor concentration is restored (15,16,22). In contrast to chronic hyperinsulinemia, acute elevation (up to 1 hr) in plasma insulin in all cases had no effect on the concentration of insulin receptors (11, 13, 14).In the present study we reproduce this phenomenon in vitro. Cultured lymphocytes that are exposed to chronic eleva-

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The current classification system presents challenges to the diagnosis and treatment of patients with diabetes mellitus (DM), in part due to its conflicting and confounding definitions of type 1 DM, type 2 DM, and latent autoimmune diabetes of adults (LADA). The current schema also lacks a foundation that readily incorporates advances in our understanding of the disease and its treatment. For appropriate and coherent therapy, we propose an alternate classification system. The β-cell–centric classification of DM is a new approach that obviates the inherent and unintended confusions of the current system. The β-cell–centric model presupposes that all DM originates from a final common denominator—the abnormal pancreatic β-cell. It recognizes that interactions between genetically predisposed β-cells with a number of factors, including insulin resistance (IR), susceptibility to environmental influences, and immune dysregulation/inflammation, lead to the range of hyperglycemic phenotypes within the spectrum of DM. Individually or in concert, and often self-perpetuating, these factors contribute to β-cell stress, dysfunction, or loss through at least 11 distinct pathways. Available, yet underutilized, treatments provide rational choices for personalized therapies that target the individual mediating pathways of hyperglycemia at work in any given patient, without the risk of drug-related hypoglycemia or weight gain or imposing further burden on the β-cells. This article issues an urgent call for the review of the current DM classification system toward the consensus on a new, more useful system.