Objective: This study aimed to investigate the relationship between insulin resistance and markers of neuronal viability and energy metabolism, as well as the additive effects of overweight or obesity, in individuals with type 2 diabetes mellitus (T2DM). Methods: Using 1H-magnetic resonance spectroscopy, prefrontal N-acetyl aspartate (NAA) and creatine levels, markers for neuronal viability and energy metabolism, respectively, were measured in 50 adults with overweight or obesity and T2DM (T2DM-O; aged 49.0 ± 7.4 years; 50% female), 50 adults with normal weight and T2DM (T2DM-N), and 50 healthy adults with normal weight (healthy-control [HC] group) matched for age and sex. The homeostatic model assessment for insulin resistance levels were calculated to assess insulin resistance. Results: Prefrontal NAA levels were lower in the T2DM-O group relative to the HC group (t = −2.51, P = 0.013). Higher insulin resistance was associated with lower prefrontal NAA levels in the T2DM-O group (t = −2.21, P = 0.032) but not in the T2DM-N group (t = −0.72, P = 0.48). Prefrontal creatine levels did not differ across the three groups. Conclusions: Overweight and obesity might contribute to T2DM-related neuronal viability deficits and could be the key links that connect insulin resistance to the decreased neuronal viability in the human diabetic brain.