Type 2 diabetes mellitus is the most common form of diabetes. Both genetic and environmental factors affect insulin resistance and beta cell dysfunction, which are the two major pathophysiologic abnormalities of type 2 diabetes. Recently we have investigated the 10 year trajectory of insulin secretion and insulin resistance in the development of type 2 diabetes in Korean patients and observed that Koreans are more likely to have impairment in insulin secretion compared to westerners. We are investigating the mechanisms and therapeutic targets of insulin resistance with special interest in PPAR-ν, which is known as the master switch of adipogenesis and in SENP2, which seems to play a critical role in metabolic regulation by de-SUMOylation of key metabolic transcription factors. Regarding beta cell dysfunction, we are trying to clarify its mechanisms, by exploring the autophagy, endoplasmic reticulum stress, and cytosolic calcium homeostasis. Stem cell differentiation to insulin producing cell is investigated as novel therapy to overcome beta cell dysfunction. A recent study showed that the gastrointestinal endocrine system plays an important role in maintaining glucose homeostasis. We are also searching for genetic factors of type 2 diabetes and its related complications using genome-wide approach including whole exome sequencing. Through these efforts we believe we can change the therapeutic paradigm of diabetes in the near future.