PANcreatic-DERived factor (PANDER, FAM3B) is a novel protein that is highly expressed within the endocrine pancreas and to a lesser degree in other tissues. Under glucose stimulation, PANDER is co-secreted with insulin from the β-cell. Despite prior creation and characterization of acute hepatic PANDER animal models, the physiologic function remains to be elucidated from pancreas-secreted PANDER. To determine this, in this study, a transgenic mouse exclusively overexpressing PANDER from the endocrine pancreas was generated. PANDER was selectively expressed by the pancreatic-duodenal homeobox-1 (PDX1) promoter. The PANDER transgenic (PANTG) mice were metabolically and proteomically characterized to evaluate effects on glucose homeostasis, insulin sensitivity, and lipid metabolism. Fasting glucose, insulin and C-peptide levels were elevated in the PANTG compared with matched WT mice. Younger PANTG mice also displayed glucose intolerance in the absence of peripheral insulin sensitivity. Hyperinsulinemic–euglycemic clamp studies revealed that hepatic glucose production and insulin resistance were significantly increased in the PANTG with no difference in either glucose infusion rate or rate of disappearance. Fasting glucagon, corticosterones, resistin and leptin levels were also similar between PANTG and WT. Stable isotope labeling of amino acids in cell culture revealed increased gluconeogenic and lipogenic proteomic profiles within the liver of the PANTG with phosphoenol-pyruvate carboxykinase demonstrating a 3.5-fold increase in expression. This was matched with increased hepatic triglyceride content and decreased p-AMPK and p-acetyl coenzyme A carboxylase-1 signaling in the PANTG. Overall, our findings support a role of pancreatic β-cell-secreted PANDER in the regulation of hepatic insulin and lipogenenic signaling with subsequent impact on overall glycemia.