OBJECTIVE: To evaluate the effect of combination therapy with pioglitazone and glucagon-like peptide (GLP)-1 in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Eight patients with type 2 diabetes (BMI 32.7 +/- 1.3 kg/m(2) and fasting plasma glucose 13.5 +/- 1.2 mmol/l) underwent four different treatment regimens in random order: saline therapy, monotherapy with continuous subcutaneous infusion of GLP-1 (4.8 pmol x kg(-1) x min(-1)), monotherapy with pioglitazone (30-mg tablet of Actos), and combination therapy with GLP-1 and pioglitazone. The observation period was 48 h. End points were plasma levels of glucose, insulin, glucagon, free fatty acids (FFAs), and sensation of appetite. RESULTS: Fasting plasma glucose decreased from 13.5 +/- 1.2 mmol/l (saline) to 11.7 +/- 1.2 (GLP-1) and 11.5 +/- 1.2 (pioglitazone) and further decreased to 9.9 +/- 1.0 (combination) (P < 0.001). Eight-hour mean plasma glucose levels were reduced from 13.7 +/- 1.1 mmol/l (saline) to 10.6 +/- 1.0 (GLP-1) and 12.0 +/- 1.2 (pioglitazone) and were further reduced to 9.5 +/- 0.8 (combination) (P < 0.0001). Insulin levels increased during monotherapy with GLP-1 compared with monotherapy with pioglitazone (P < 0.01). Glucagon levels were reduced in GLP-1 and combination therapy compared with saline and monotherapy with pioglitazone (P < 0.01). FFAs during breakfast (area under the curve, 0-3 h) were reduced in combination therapy compared with saline (P = 0.03). Sensation of appetite was reduced during monotherapy with GLP-1 and combination therapy (P < 0.05). CONCLUSIONS: GLP-1 and pioglitazone show an additive glucose-lowering effect. A combination of the two agents may, therefore, be a valuable therapeutic approach for the treatment of type 2 diabetes.