Diabetic autonomic neuropathy affects symptom generation and brain-gut axis

Abstract

Objective: Long-term diabetes leads to severe peripheral, autonomous, and central neuropathy in combination with clinical gastrointestinal symptoms. The brain-gut axis thus expresses a neurophysiological profile, and heart rate variability (HRV) can be correlated with clinical gastrointestinal symptoms.

Research design and methods: Fifteen healthy volunteers and 15 diabetic patients (12 with type 1 diabetes) with severe gastrointestinal symptoms and clinical suspicion of autonomic neuropathy were included. Psychophysics and evoked brain potentials were assessed after painful rectosigmoid electrostimulations, and brain activity was modeled by brain electrical source analysis. Self-reported gastrointestinal symptoms (per the Patient Assessment of Upper Gastrointestinal Disorder Severity Symptom Index) and quality of life (SF-36 Short Form Survey) were collected.

Results: Diabetic patients had autonomous neuropathy, evidenced by decreased electrocardiographic R-R interval (P = 0.03) and lower HRV (P = 0.008). Patients were less sensitive to painful stimulation (P = 0.007), had prolonged latencies of evoked potentials (P ≤ 0.001), and showed diminished amplitude of the N2-P2 component in evoked potentials (P = 0.01). There was a caudoanterior shift of the insular brain source (P = 0.01) and an anterior shift of the cingulate generator (P = 0.01). Insular source location was associated with HRV assessments (all P < 0.02), and the shift (expressed in mm) correlated negatively with physical health (P < 0.001) and positively with nausea (P = 0.03) and postprandial fullness (P = 0.03). Cingulate source shift was correlated negatively with physical health (P = 0.005) and positively with postprandial fullness (P ≤ 0.001).

Conclusions: This study provides evidence for interaction between autonomic neuropathy and peripheral nervous degeneration, as well as changes in dipole sources in diabetic patients with gastrointestinal symptoms. The findings may lead to improved treatment modalities targeting pharmacological neuroprotection or neuromodulation.

Figure 1

A: Sensory profile at visual analog scale ratings of 1 (sensory detection threshold), 3 (moderate sensation), 5 (pain detection threshold), and 7 (moderate pain) in response to electrical stimulation of the rectosigmoid junction. Patients (gray) in general tolerate higher stimulation intensities than do healthy controls (black). B: EPs to rectosigmoid stimulation in representative subjects from each group (healthy volunteers in black and diabetic patients in gray) recorded at the central site on the scalp (Cz electrode). Prolonged latencies and reduced peak-to-peak amplitudes in the diabetic patient group indicate abnormal interoception. C: Localization of dipolar brain sources evoked by painful stimulations of the rectosigmoid in patients (red) and healthy volunteers (blue). The average of the individual Talairach coordinates deriving from the individual brain sources was projected to a standardized magnetic resonance image. The localization of the insular and cingulate dipole showed significant differences between the two groups.

Figure 2

Altered brain activation is displayed in diabetic patients with autonomic neuropathy and gastrointestinal symptoms. Top left: Negative association between physical health score (SF-36) and altered insular activity after electrical stimulation of the rectosigmoid assessed as the Euclidian dipole shift. This means that increased caudoanterior insular reorganization was associated with inferior physical health experience. Bottom left: Positive association between reorganized insular activity (dipole shift) and nausea. Top right: Positive association between physical health score (SF-36) and the altered cingulate activity assessed as the Euclidian dipole shift. This means that increased anterior cingulate activity was associated with better physical health. Bottom right: Negative correlation between reorganized cingulate activity and postprandial fullness, meaning that the more anteriorly the cingulate activity is reorganized, the less complaints of postprandial fullness.