Obesity and type 2 diabetes (T2D) are growing health problems associated with a loss of insulin sensitivity. Both conditions arise from a long-term energy imbalance, and frequently, lifestyle measures can be useful in its prevention, including physical activity and a healthy diet. Pancreatic β-cells are determinant nutrient sensors that participate in energetic homeostasis needs. However, when pancreatic β-cells are incapable of secreting enough insulin to counteract the reduced sensitivity, the pathology evolves to an insulin resistance condition. The primary nutrient that stimulates insulin secretion is glucose, but also, there are multiple dietary and hormonal factors influencing that response. Many studies of the physiology of β-cells have highlighted the importance of glucose, fructose, amino acids, and free fatty acids on insulin secretion. The present review summarizes recent research on how β-cells respond to the most abundant nutrients that influence insulin secretion. Taken together, understand the subjacent mechanisms of each nutrient on β-cells can help to unravel the effects of mixed variables and complexity in the context of β-cell pathology.