Molecular Mechanisms of β-Cell Dysfunction and Insulin Resistance in Type 2Diabetes Mellitus

Abstract

Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder
characterized by chronic hyperglycemia resulting from the progressive
interplay between insulin resistance and pancreatic β-cell dysfunction. The
global prevalence of T2DM continues to rise dramatically, representing a
major public health burden associated with cardiovascular disease,
nephropathy, neuropathy, retinopathy, and metabolic complications.
Although insulin resistance initially develops in peripheral tissues including
skeletal muscle, liver, and adipose tissue, progressive β-cell failure
ultimately determines disease onset and long-term glycemic deterioration.
Increasing evidence indicates that chronic inflammation, mitochondrial
dysfunction, oxidative stress, glucolipotoxicity, endoplasmic reticulum
stress, epigenetic remodeling, and immune-metabolic dysregulation
collectively contribute to β-cell exhaustion and impaired insulin signaling.
Advances in transcriptomics, metabolomics, single-cell sequencing, and
multi-omics technologies have substantially improved the understanding
of molecular heterogeneity and disease progression in T2DM.
Furthermore, emerging studies reveal that β-cell dedifferentiation,
impaired autophagy, altered gut microbiota, and chronic metaflammation
play central roles in metabolic dysfunction and insulin resistance. Novel
therapeutic strategies targeting inflammatory pathways, mitochondrial
homeostasis, incretin signaling, cellular senescence, and epigenetic
regulation are increasingly being explored for precision diabetes
management. This review discusses the molecular mechanisms underlying
β-cell dysfunction and insulin resistance in T2DM, emphasizing
inflammatory remodeling, metabolic stress responses, and emerging
translational opportunities for personalized therapeutic intervention.