FIG. 1.

Progress of type 2 diabetes development from the β-cells point of view. Scheme shows a tentative sequence of events affecting pancreatic islet β-cells during type 2 diabetes progression. Hypothetical initial stimuli of overfeeding may shift the β-cell identity checking, thus transforming β-cells to a prediabetic state, in which they promote hypothetical stress signals causing partial insulin resistance of periphery besides the compensatory responses. The latter may include the excessive insulin expression leading to UPR and ER stress. The resulting mild oxidative stress accelerates into the intensive oxidative stress due to the subsequently ongoing lipotoxicity and glucotoxicity, while causing impaired GSIS and dysfunction to the other modes of insulin secretion. Resulting further turn of such a pathological spiral includes severely affected β-cell identity checking, causing the impaired INS gene expression, altered transcriptome, and β-cell dedifferentiation and transdifferentiation, which further deterioriate GSIS and the other modes of insulin secretion. At the final stage, systemic inflammation and islet inflammation can affect β-cell so to initiate apoptosis or other forms of cell death. ER, endoplasmic reticulum; GSIS, glucose-stimulated insulin secretion; UPR, unfolded protein response.