Blunted rise in brain glucose levels during hyperglycemia in adults with obesity and T2DM

Abstract

In rodent models, obesity and hyperglycemia alter cerebral glucose metabolism and glucose transport into the brain, resulting in disordered cerebral function as well as inappropriate responses to homeostatic and hedonic inputs. Whether similar findings are seen in the human brain remains unclear. In this study, 25 participants (9 healthy participants; 10 obese nondiabetic participants; and 6 poorly controlled, insulin- and metformin-treated type 2 diabetes mellitus (T2DM) participants) underwent 1H magnetic resonance spectroscopy scanning in the occipital lobe to measure the change in intracerebral glucose levels during a 2-hour hyperglycemic clamp (glucose ~220 mg/dl). The change in intracerebral glucose was significantly different across groups after controlling for age and sex, despite similar plasma glucose levels at baseline and during hyperglycemia. Compared with lean participants, brain glucose increments were lower in participants with obesity and T2DM. Furthermore, the change in brain glucose correlated inversely with plasma free fatty acid (FFA) levels during hyperglycemia. These data suggest that obesity and poorly controlled T2DM progressively diminish brain glucose responses to hyperglycemia, which has important implications for understanding not only the altered feeding behavior, but also the adverse neurocognitive consequences associated with obesity and T2DM.

Figure 1. Plasma and intracerebral glucose levels.

(A) Mean plasma glucose levels over time. Mixed-effects regression model controlling for age and sex, P = 0.09. (B) Mean change in plasma glucose (between time 60–120 minutes). P = 0.83 across groups. (C) Mean change in intracerebral glucose concentrations over time. Mixed-effects regression model controlling for age and sex, P = 0.0001. (D) Mean change in intracerebral glucose concentrations (between times 60–120 minutes). ANOVA was used to determine statistical differences among the three groups followed by Fisher’s least significant difference test for pairwise comparisons. All subjects (lean, n = 9; obese, n = 10; T2DM, n = 6) were included in analysis. Data represent mean ± SEM.

Figure 2. Relationships between plasma free fatty acids and intracerebral glucose.

(A) Free fatty acid (FFA) levels at the end of the study (120 minutes). ANOVA followed by Fisher’s least significant difference test for pairwise comparisons. Data represent mean ± SEM. (B) FFA levels were log transformed and correlated using a Spearman’s correlation with average brain glucose levels at steady state (time 60–120 minutes). Of note, 11 participants (3 obese and 8 lean) had FFA levels below the detection limits of the assay.

Figure 3. Relationships between intracerebral glucose and hunger, fullness, and satiety ratings.

Intracerebral glucose levels and hunger (A), fullness (B), and satiety (C) ratings taken immediately after scanning. Intracerebral glucose levels were correlated using Pearson’s correlation with hunger, satiety, and fullness ratings.

Figure 4. Spectral processing for intracerebral glucose.

An example using one representative lean subject of how an individual time point is calculated for change in brain glucose levels using difference spectra. The blue spectrum was obtained at baseline, and the red spectrum was obtained 10 minutes later. The black spectrum underneath is the difference between the red and blue spectra. The green spectrum represents a glucose reference spectrum obtained under in vivo conditions of temperature 37°C, pH 7.4, and ionic strength of 150 mM.