Abstract
BACKGROUND & SCOPE OF REVIEW: Diabetes mellitus encompasses a spectrum of metabolic disorders characterized by hyperglycemia. The currently most replicated phenotypic clustering approach, introduced by Ahlqvist et al. and validated by Zaharia et al., identified subtypes based on clinical presentation and underlying pathophysiology. This classification aims at predicting complication risk and enabling targeted therapies. Our review explores shared and distinct mechanisms driving complications, focusing on cardiovascular disease and metabolic dysfunction-associated steatotic liver disease (MASLD), both strongly linked to insulin resistance. We also summarize treatment strategies targeting both conditions and outline mechanisms specific to the development of diabetic foot syndrome, exemplifying the continuum from localized to systemic complications. METHODS: We conducted a narrative review of human and translational studies, focusing on mechanisms and treatments across the above phenotype-based diabetes subtypes, given their reproducibility across populations. MAIN RESULTS: Diabetes is a multisystem disorder involving a cascade of metabolic disturbances. These include mitochondrial adaptations in key metabolically active tissues contributing to systemic and tissue-specific insulin resistance. Inflammation, inadequate immune responses, oxidative stress, and genetic and environmental factors shape the development of comorbidities whose prevalence varies across subtypes. The interplay between MASLD and diabetes forms a vicious cycle of metabolic abnormalities. Novel treatments show promise in both liver and glycemic endpoints. CONCLUSION: Phenotype-based diabetes subtypes exhibit distinct underlying pathophysiological mechanisms which shape the development of complications, with insulin resistance serving as the central link. Targeting these pathways can pave the way for personalized diabetes therapies.