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β-cell dysfunction is a well-known feature of type 2 diabetes mellitus. In particular, it has been shown that defects in 1st phase insulin secretion play a fundamental role in the natural history of the disease. In this review, we highlight the clinical relevance of 1st phase impairment, focusing on its connection with post meal hyperglycemia and diabetic complications; we further evaluate possible therapeutic strategies aimed at improving β-cell secretory machinery and providing a durable control of the disease. In conclusion, we discuss the clinical relevance of C-Peptide sampling in detecting secretory defects.