Transgenic mice expressing nuclear sterol regulatory element-binding protein-1a I a under the control of the insulin promoter were generated to determine the role of SREBP-la in pancreatic beta-cells. Only low expressors could be established, which exhibited mild hyperglycemia, impaired glucose tolerance, and reduced plasma insulin levels compared to C57BL/G controls. The islets isolated from the transgenic mice were fewer and smaller, and had decreased insulin content and unaltered glucagon staining. Both glucose- and potassium-stimulated insulin secretions were decreased. The transgenic islets consistently expressed genes for fatty acids and cholesterol synthesis, resulting in accumulation of triglycerides but not cholesterol. PDX-1, BETA2, MafA, and IRS-2 were suppressed, partially explaining the loss and dysfunction of beta-cell.mass. The transgenic mice on a high fat/high Sucrose diet still exhibited impaired insulin secretion and continuous P-cell growth defect. Therefore, nuclear SREBP-la, even at a low level, strongly disrupts p-cell mass and function. (C) 2008 Elsevier Inc. All rights reserved.