The ectoenzyme, PC-1, is an insulin receptor (IR) inhibitor that is elevated in cells and tissues of humans with type 2 diabetes (T2D). While we have recently shown that acute PC-1 overexpression in liver causes insulin resistance and glucose intolerance in mice (3), the chronic effects of PC-1 overexpression on plasma glucose levels are unknown. Herein we produced transgenic mice overexpressing the potent q allele of human PC-1 in muscle and liver. Compared to controls, these mice had 2-3 fold elevations of PC-1 content in liver and 5-10 fold elevations in muscle. In the fed state the PC-1 animals had 100 mg/dl higher glucose levels, and six-fold higher insulin levels when compared to controls. During glucose tolerance tests, these PC-1 animals had peak glucose levels that were over 150 mg % higher than controls. In vivo uptake of 2 deoxy-D-glucose in muscle during insulin infusion was decreased in the PC-1 animals. These in vivo data support the concept therefore that PC-1 plays a role in insulin resistance and hyperglycemia, and suggest that animals with overexpression of human PC-1 in liver and muscle may be important models to investigate diabetes mellitus.