Both type 1 and type 2 diabetes have been associated with reduced performance on multiple domains of cognitive function and with structural abnormalities in the brain. With an aging population and a growing epidemic of diabetes, central nervous system–related complications of diabetes are expected to rise and could have challenging future public health implications. In this review, we will discuss the brain structural and functional changes that have been associated with type 1 and type 2 diabetes. Diabetes duration and glycemic control may play important roles in the development of cognitive impairment in diabetes, but the exact underlying pathophysiological mechanisms causing these changes in cognition and structure are not well understood. Future research is needed to better understand the natural history and the underlying mechanisms, as well as to identify risk factors that predict who is at greatest risk of developing cognitive impairment. This information will lead to the development of new strategies to minimize the impact of diabetes on cognitive function.

To date, functional ¹H NMR spectroscopy has been utilized to report the time courses of few metabolites, primarily lactate. Benefiting from the sensitivity offered by ultra-high magnetic field (7 T), the concentrations of 17 metabolites were measured in the human visual cortex during two paradigms of visual stimulation lasting 5.3 and 10.6 mins. Significant concentration changes of approximately 0.2 μmol/g were observed for several metabolites: lactate increased by 23% ± 5% ( P < 0.0005), glutamate increased by 3% ± 1% ( P < 0.01), whereas aspartate decreased by 15% ± 6% ( P < 0.05). Glucose concentration also manifested a tendency to decrease during activation periods. The lactate concentration reached the new steady-state level within the first minute of activation and came back to baseline only after the stimulus ended. The changes of the concentration of metabolites implied a rise in oxidative metabolism to a new steady-state level during activation and indicated that amino-acid homeostasis is affected by physiological stimulation, likely because of an increased flux through the malate—aspartate shuttle.

Several laboratories have consistently reported small concentration changes in lactate, glutamate, aspartate, and glucose in the human cortex during prolonged stimuli. However, whether such changes correlate with blood oxygenation level—dependent functional magnetic resonance imaging (BOLD-fMRI) signals have not been determined. The present study aimed at characterizing the relationship between metabolite concentrations and BOLD-fMRI signals during a block-designed paradigm of visual stimulation. Functional magnetic resonance spectroscopy (fMRS) and fMRI data were acquired from 12 volunteers. A short echo-time semi-LASER localization sequence optimized for 7 Tesla was used to achieve full signal-intensity MRS data. The group analysis confirmed that during stimulation lactate and glutamate increased by 0.26±0.06 μmol/g (∼30%) and 0.28±0.03 μmol/g (∼3%), respectively, while aspartate and glucose decreased by 0.20±0.04 μmol/g (∼5%) and 0.19±0.03 μmol/g (∼16%), respectively. The single-subject analysis revealed that BOLD-fMRI signals were positively correlated with glutamate and lactate concentration changes. The results show a linear relationship between metabolic and BOLD responses in the presence of strong excitatory sensory inputs, and support the notion that increased functional energy demands are sustained by oxidative metabolism. In addition, BOLD signals were inversely correlated with baseline γ-aminobutyric acid concentration. Finally, we discussed the critical importance of taking into account linewidth effects on metabolite quantification in fMRS paradigms.

Functional magnetic resonance spectroscopy (fMRS) allows the non‐invasive measurement of metabolite concentrations in the human brain, including changes induced by variations in neurotransmission activity. However, the limited spatial and temporal resolution of fMRS does not allow specific measurements of metabolites in different cell types. Thus, the analysis of fMRS data in the context of compartmentalized metabolism requires the formulation and application of mathematical models. In the present study we utilized the mathematical model introduced by Simpson et al. (2007) to gain insights into compartmentalized metabolism in vivo from the fMRS data obtained in humans at ultra high magnetic field by Mangia et al. (2007a). This model simulates brain glucose and lactate levels in a theoretical cortical slice. Using experimentally determined concentrations and catalytic activities for the respective transporter proteins, we calculate inflow and export of glucose and lactate in endothelium, astrocytes, and neurons. We then vary neuronal and astrocytic glucose and lactate utilization capacities until close correspondence is observed between in vivo and simulated glucose and lactate levels. The results of the simulations indicate that, when literature values of glucose transport capacity are utilized, the fMRS data are consistent with export of lactate by neurons and import of lactate by astrocytes, a mechanism that can be referred to as a neuron‐to‐astrocyte lactate shuttle. A shuttle of lactate from astrocytes to neurons could be simulated, but this required the astrocytic glucose transport capacity to be increased by 12‐fold, and required that neurons not respond to activation with increased glycolysis, two conditions that are not supported by current literature.

Unraveling the energy metabolism and the hemodynamic outcomes of excitatory and inhibitory neuronal activity is critical not only for our basic understanding of overall brain function, but also for the understanding of many brain disorders. Methodologies of magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) are powerful tools for the noninvasive investigation of brain metabolism and physiology. However, the temporal and spatial resolution of in vivo MRS and MRI is not suitable to provide direct evidence for hypotheses that involve metabolic compartmentalization between different cell types, or to untangle the complex neuronal microcircuitry, which results in changes of electrical activity. This review aims at describing how the current models of brain metabolism, mainly built on the basis of in vitro evidence, relate to experimental findings recently obtained in vivo by ¹H MRS, ¹³C MRS, and MRI. The hypotheses related to the role of different metabolic substrates, the metabolic neuron—glia interactions, along with the available theoretical predictions of the energy budget of neurotransmission will be discussed. In addition, the cellular and network mechanisms that characterize different types of increased and suppressed neuronal activity will be considered within the sensitivity-constraints of MRS and MRI.