Type 2 diabetes is a growing epidemic that has been accompanied by a similarly drastic increase in obesity. Its occurrence is associated with [beta]-cell dysfunction, decreased [beta]-cell mass, and insulin and leptin resistance. An increasing body of evidence suggests that endoplasmic reticulum (ER) stress may play an important role in the development of diabetes. The accumulation of terminally misfolded proteins in the ER results in ER stress if the folding capacity and degradation within the ER is insufficient. In this condition of disequilibrium, the unfolded protein response (UPR) is activated to restore ER homeostasis. The mouse and human suppressor-enhancer-lin12-1-like (Sel1L) gene encodes a structurally complex protein with high expression in the adult pancreas and central nervous system. Evidence from in vitro studies and lower organisms implicates SEL1L as a crucial factor in endoplasmic reticulum-associated degradation (ERAD) of unfolded or misfolded proteins, a pathway of the UPR. However, the physiological role of SEL1L in the whole organism remains elusive. The Long lab has generated the first mouse model featuring the global deletion of Sel1L. Mice homozygous for this hypomorphic allele are early embryonic lethal. Our embryological and in vitro data indicated that the absence of Sel1L led to changes in organelle morphology, the initiation of apoptotic pathways, decreased cell viability, and defective cellular degradation. Due to the embryonic lethality of the homozygous Sel1L mutant mice, the viable heterozygote (Sel1L+/-) mice were used to understand the contribution of ERAD to the development of obesity-induced diabetes. We found that mice heterozygous for Sel1L are predisposed to high-fat diet-induced hyperglycermia, glucose intolerance, reduced [beta]-cell mass, and impaired insulin secretion in comparison to wild-type mice. Finally, to further investigate the tissue-specific roles of SEL1L, we generated mice with the conditional deletion of Se1lL in [beta]-cells and hypothalamic neurons. Mice with RIP-Cre-mediated deletion of Sel1L (mutant) showed elevated blood glucose levels in comparison to control mice by 2 weeks of age. Additionally, mutant mice exhibit progressive glucose intolerance and severely defective glucose-stimulated insulin secretion. In adulthood, mutant mice develop hyperphagic obesity and peripheral leptin and insulin resistance. Altogether, these deviances in glucose and energy homeostasis at the level of the [beta]-cell and hypothalamic neuron, respectively, are attributed to ER stress in the absence of SEL1L. These data collectively provide compelling evidence for the causal role of ER stress in the manifestation of Type 2 diabetes.