Physiologically, autophagy is a major protective mechanism of β-cells from apoptosis, through can reserve normal β- cell mass and inhibit the progression of β-cells destruction. Beta-cell mass can be affected by differentiation from progenitors and de-differentiation as well as self-renewal and apoptosis. Shred evidence indicated that hypoglycemic drugs can induce β-cell proliferation capacity and neogenesis via autophagy stimulation. However, prolonged use of selective hypoglycemic drugs has induced pancreatitis besides several other factors that contribute to β-cell destruction and apoptosis initiation. Interestingly, some nonhypoglycemic medications possess the same effects on β-cells but depending on the combination of these drugs and the duration of exposure to β-cells. The paper comprehensively illustrates the role of the hypoglycemic drugs on the insulin-producing cells and the pathogeneses of β-cell destruction in type 2 diabetes mellitus, in addition to the regulation mechanisms of β-cells division in norm and pathology. The grasping of the hypoglycemic drug’s role in beta-cell is clinically crucial to evaluate novel therapeutic targets such as new signaling pathways. The present paper addresses a new strategy for diabetes mellitus management via targeting specific autophagy inducer factors (transcription factors, genes, lipid molecules, etc.).