Decoding inflammation to target hybrid diabetes phenotypes

With the escalating global epidemic of overweight and obesity worldwide, metabolic abnormalities (i.e., central obesity, insulin resistance, dyslipidemia and hypertension) are raising in patients with type 1 diabetes (T1D). On the other hand, data are emerging on the detection of autoimmune markers in obese individuals previously diagnosed with type 2 diabetes (T2D). These overlapping immune-metabolic features, characterizing hybrid phenotypes of diabetes such as double diabetes (DD) and latent autoimmune diabetes in adults (LADA), add a new layer of complexity in the diabetes spectrum and increase the risk of diabetes-related complications and mortality. Low-grade chronic inflammation is thought to play a pivotal role in the pathogenesis of DD and LADA and may represent a major driver in β-cell dysfunction and metabolic dysregulation. However, the literature on the topic is still limited, as well as the availability of specific therapeutic clinical approaches. This review aims to summarize current evidence on inflammatory and immune-metabolic biomarkers for early detection and identification of DD and LADA as compared to other types of diabetes. Novel diagnostic strategies, including genomics, miRNomics, metabolomics and microbiomics analysis, together with therapeutic options targeting metabolic and inflammatory pathways will be also explored. Challenges, including disease heterogeneity will be discussed alongside future directions, emphasizing the need for personalized medicine and longitudinal studies to shed more light on this overlooked hybrid phenotypes of diabetes.