OBJECTIVE-The hypothalamus plays a critical role in the regulation of energy balance and fuel flux. Glucose ingestion inhibits hypothalamic neuronal activity in healthy humans. We hypothesized that hypothalamic neuronal activity in response to an oral glucose load would be altered in patients with type 2 diabetes.RESEARCH DESIGN AND METHODS-In this randomized, single blind, case-control study, 7 type 2 diabetic men (BMI 27.9 Ϯ 2.0 kg/m 2 ) and 10 age-matched healthy men (BMI 26.1 Ϯ 3.2 kg/m 2 ) were scanned twice for 38 min on separate days using functional magnetic resonance imaging. After 8 min, they ingested either a glucose solution (75 g in 300 ml water) or water (300 ml).RESULTS-Glucose ingestion resulted in a prolonged significant blood oxygen level-dependent signal decrease in the upper and lower hypothalamus in healthy subjects but not in diabetic patients.CONCLUSIONS-Glucose ingestion fails to inhibit hypothalamic neuronal activity in patients with type 2 diabetes. Failure of neural circuits to properly adapt to nutrient ingestion may contribute to metabolic imbalance in type 2 diabetic patients.