Diabetes mellitus is a huge health burden due to decreased quality of life and the escalating cost of treatment. Obesity, insulin resistance and metabolic abnormalities in liver, adipose, and muscle are important factors in disease. Most of the gene loci recently found associated with type 2 diabetes, however, encode proteins that enable insulin production from pancreatic beta cells. Nutrients and hormones regulate not only insulin secretion but also the capacity of β cells to continue to produce insulin. During the onset of diabetes, pancreatic beta cells become unable to produce sufficient insulin to maintain blood glucose within the normal range. Among important nutrient-sensing pathways are the mitogen-activated protein kinases ERK1/2. These protein kinases are essential for nutrient-stimulated insulin gene transcription, and also contribute to reduced nutrient-induced insulin gene transcription following long term hyperglycemia and hyperglycemia combined with proinflammatory cytokines. The core ERK1/2 cascade kinases are associated with the insulin gene and we are examining how they act on the insulin gene promoter. We are also examining molecular mechanisms of action of small molecules that enhance β-cell function. These molecules stimulate insulin production by β cells, improve oral glucose tolerance of mice, and restore insulin production by human islets in long term culture. We have identified a number of changes that take place in β cells treated with these drugs, including epigenetic alterations, changes in concentrations of key transcription factors, and molecules involved in secretion. These small molecules may offer promise for future diabetic therapies.