Historically, the lion’s share of attention in the pancreatic islet field is turned to pancreatic beta cells. They are the only cell in our body capable of releasing meaningful levels of insulin, which is essential for life. Pancreatic islets contain several endocrine cell types that coordinate to maintain blood glucose homeostasis including pancreatic alpha cells that make glucagon and delta cells that produce somatostatin (SST). Yet, only beta cells cause disease when lost to autoimmune-mediated destruction in type 1 diabetes or dysfunction secondary to various forms of metabolic dysregulation in type 2 diabetes. While beta and alpha cells are thought to be the main drivers of glucose homeostasis through insulin and glucagon secretion respectively, alpha cell ablation is surprisingly without major consequences. The physiological role of pancreatic delta cells remains to be established. When we remove local SST signaling within the islet or ablate delta cells, we observe a sustained decrease in the glycemic set point. This coincides with a decreased glucose threshold for insulin response from beta cells, leading to increased insulin secretion to the same glucose challenge. In contrast, alpha cell ablation had no effect on glycemic set point. Collectively, these data establish the physiological role of delta cells in determining the glycemic set point through their interaction with β cells. These findings also demonstrate that local inhibition of beta cells by delta cells restrains insulin secretion but will not block it in the face of robust nutrient stimulation. Clearly that level of feedback inhibition is of measurable physiological importance. Whether recapitulating this natural feedback inhibition in stem cell-derived beta cell-like cells is necessary, and how to rank it in relation to other challenges that are still being met in securing a regenerative diabetes cure is an outstanding question.