The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the β-Cell-Centric Classification Schema

Abstract

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.

Figure 1

Qualitative illustration of the spectrum of factors associated with different forms of DM, including the variable age at onset, lack of obesity, metabolic syndrome, genetic associations, different forms of immune changes, C-peptide secretion, and the need for insulin therapy. T1DM, type 1 DM; T2DM, type 2 diabetes. Adapted with permission from Leslie et al. (1).

Figure 2

Genetic determinants influence IR (whether centrally or peripherally induced), loss of β-cell function and mass, environmental triggers (such as viruses, endocrine disruptors, food advanced glycosylation end products, gut biome), and immune modulation and inflammation. Singly or, more commonly, in various combinations, these factors converge on the genetically susceptible β-cell, impinge on β-cell function and biology, and orchestrate the shift from normoglycemia to hyperglycemia. As this process takes place regardless of subtype of DM, the dysfunctional β-cell is the final common denominator in all DM.

Figure 3

β-Cell–centric construct: the egregious eleven. Dysfunction of the β-cells is the final common denominator in DM. A: Eleven currently known mediating pathways of hyperglycemia are shown. Many of these contribute to β-cell dysfunction (liver, muscle, adipose tissue [shown in red to depict additional association with IR], brain, colon/biome, and immune dysregulation/inflammation [shown in blue]), and others result from β-cell dysfunction through downstream effects (reduced insulin, decreased incretin effect, α-cell defect, stomach/small intestine via reduced amylin, and kidney [shown in green]). B: Current targeted therapies for each of the current mediating pathways of hyperglycemia. GLP-1, glucagon-like peptide 1; QR, quick release.