Context: Major depressive disorder has been consistently identified in patients with type 2 diabetes. Despite its high prevalence and clinical effect, the neurobiological substrates underlying depression in patients with diabetes remain largely unknown. Objective: To examine the biophysical integrity of proteins in critical white and gray matter regions in patients with type 2 diabetes and major depression to understand the pathophysiology of depression in diabetes. Design: A cross-sectional, magnetization transfer study using magnetic resonance imaging. Regions examined included the anterior cingulate, corpus callosum, frontal and occipital white matter, and the caudate and lenticular nuclei. Setting: A tertiary care university hospital. Participants: We studied 1.6 patients diagnosed with type 2 diabetes and major depression, 22 patients diagnosed with diabetes without depression (diabetic controis), and 30 controls without diabetes or major depression (healthy controls). Main Outcome Measures: Magnetization transfer ratios, a measure of the biophysical structure of proteins in the gray and white matter. Results: Magnetization transfer ratios were significantly lower bilaterally in the head of the caudate nucleus in the group with diabetes and depression compared with the other 2 groups (P < .001). Diabetic, controls had values between the depressed diabetic and healthy control groups. There were no significant differences in. magnetization transfer ratios between groups in the other regions examined. Conclusions: These data indicate that there is an important subcortical biophysical component to depression in patients with type 2 diabetes. This finding has broad implications for the neuronal circuitry underlying mood disorders. © 2009 American Medical Association. All rights reserved.