SSTR1 is found on the majority of human pancreatic beta cells, however, its role in insulin secretion has yet to be elucidated. In this study, we used the SSTR1 knockout mouse model to examine the role of SSTR1 in insulin secretion and glucose homeostasis in mice. Despite the reported effect of SSTR1 in inhibiting growth hormone secretion, SSTR1-/- mice had significantly reduced body weight with growth retardation. Perfusion of isolated mouse pancreata at 3 months of age demonstrated a significant increase in insulin secretion in SSTR1-/- mice compared with that of WT controls. We also found that at 3 months of age, SSTR1-/- mice had significantly decreased levels of systemic insulin secretion and were glucose intolerant. However, SSTR1 gene-ablated mice had a much higher rate of insulin clearance compared to WT mice at the same age. When challenged at 12 months of age, we found SSTR1-/- mice had increased glucose tolerance with exaggerated increase of insulin levels at the end of the experiment. Immunochemical analysis showed that the pancreatic islets of SSTR1-/- mice had significantly decreased levels of somatostatin staining and a significant decrease of SSTR5 expression. These results demonstrate that SSTR1 plays an important role in the regulation of insulin secretion in the endocrine pancreas in mice.