Brain changes in diabetes mellitus patients with gastrointestinal symptoms

Table 1 Animal models of diabetes

Ref.	Methods	Results
Bhardwaj et al[42]	Signal transduction in brains was investigated in rats with 1-3 mo of induced diabetes	Protein kinase A and C were increased and calcium/calmodulin dependent protein kinase II decreased
Li et al[81]	Proteins were extracted from brain tissues of control rats and type 1 diabetic rats	The proteomic identification could be a useful tool for understanding of diabetic encephalopathy mechanisms
Yang et al[41]	Rats were randomized into a control and a DM group and neuron and vessel changes were examined with electron microscopy	Increasing abnormality in the neurons and blood vessels were seen that correlated to the length of diabetes
Ramos-Rodriguez et al[82]	Brain morphology was analyzed in mice	Hippocampal and cortical atrophy was found as well as cell proliferation and neurogenesis impairment

DM: Diabetes mellitus.

Table 2 Findings with quantitative sensory testing and evoked brain potentials in patients with diabetes and gastrointestinal symptoms

Ref.	Method	Results
Frøkjær et al[11]	12 healthy controls and 12 type-1 diabetes patients with proven autonomic neuropathy and severe GI symptoms had their sensitivity to stimulations in the oesophagus and duodenum assessed	A 46% increase in the somatic referred pain areas, indicating central hyper excitability. The results also indicated that the sensory nerves in the GI tract were widely affected. Furthermore it is suggested that future targets in the treatment of GI symptoms in DM patients could be based on modulation of the central nervous system excitability
Frøkjær et al[63]	14 type-1 diabetes patients with autonomic neuropathy and GI symptoms and 15 healthy volunteers had their sensitivity to electrical oesophageal and median nerve stimulations assessed by using an euglycemic-hyperinsulinemic clamp. The EPs were also collected	GI symptoms correlated with characteristics of brain potentials in the DM patients. These results indicate a change in peripheral visceral nerves as well as in the central nervous system
Frøkjær et al[47]	Evoked potentials to oesophageal and median nerve stimulations were recorded in 14 type-1 diabetes patients with GI symptoms	The study concluded that acute hyperglycaemia had no effect on the brain activation of visceral and somatic stimulations
Frøkjær et al[62]	15 healthy volunteers and 14 type-1-diabetes patients with autonomic neuropathy and related GI symptoms had their EPs recorded following painful oesophageal electrical stimulation	Evidence of altered central processing to visceral stimulation in diabetes was found. Compared to controls, the patients with diabetes had a posterior shift of the electrical sources in the anterior cingulate cortex, and additional sources close to the posterior insula and in medial frontal gyrus
Frøkjær et al[45]	Ultrasound monitored oesophageal distension was used to study 17 patients with longstanding DM and GI symptoms and 13 healthy controls	The reduced sensitivity was associated with the presence of peripheral neuropathy. This indicates a coexisting change within the visceral and somatic neuropathy
Brock et al[64]	14 type-1 diabetes patients with diabetes autonomy neuropathy and 15 healthy volunteers underwent multichannel EEG during painful electrical stimulation of the lower esophagus	Central neuroplastic changes within DM patients were found in the insular region, and it was suggested that the GI symptoms are due to the abnormal insular processing
Lelic et al[46]	Electrical stimulation of the rectum was done in 12 healthy controls and 12 type 1 diabetes patients with GI symptoms while having their EPs recorded	Changes in the cingulate-operculum brain network were found in DM patients with GI symptoms. Changes could serve as a biomarker of disturbed sensory visceral processing and GI symptoms in patients with diabetes
Brock et al[4]	15 healthy volunteers and 15 diabetes patients with GI symptoms and clinical suspicion of autonomic neuropathy were included. Electrical source analysis to painful recto-sigmoid electrostimulations was modelled	Patients with autonomic neuropathy and GI symptoms had evidence for altered brain activation and dysregulation of the central regulation of the autonomic nervous system, which could explain appearance and persistence of upper GI symptoms
Søfteland et al[48]	16 healthy controls and 20 DM patients with sensorimotor polyneuropathy had their heart rate variability and peripheral tactile thresholds recorded and underwent a cold-pressor-test	The patients in this study suffered from generalized polyneuropathy evident as autonomic neuropathy, peripheral hypoesthesia and central changes manifested as impaired conditioned pain modulation
Lelic et al[61]	EPs to electrical esophageal stimulation were achieved in 23 diabetes patients with upper GI symtoms and 27 healthy controls. Network analysis between active sources were performed	There was a reorganisation in the opercular cortex, which was correlated with GI symptoms. It was proposing that the changes in the operculo-cingulate cortex could help explain the development and maintenance of GI symptoms in diabetes patients

EPs: Evoked brain potentials; GI: Gastrointestinal; EEG: Electroencephalography; DM: Diabetes mellitus.

Table 3 Imaging findings in patients with diabetes

Ref.	Method	Results
Jongen et al[72]	MR images of 99 DM patients and 46 controls	Larger lateral ventricular volume with white matter lesion and smaller great matter volume was seen in the diabetes patients. The effect of diabetes on brain atrophy where only significant in women
Kodl et al[83]	25 type-1 diabetes patients and controls were scanned with a diffusion tensor imaging protocol	White matter microstructural deficits in patients with longstanding diabetes type-1 were found. The deficits correlated with the neurocognitive tests
Last et al[71]	Cerebral blood flow was examined in 26 diabetes patients and 25 controls using continuous arterial spin labeling imaging during baseline, CO2 rebreathing and hyperventilation	Type-2 diabetes was associated with cortical and subcortical atrophy involving frontal and temporal brain regions and with diminished vasoreactivity and regional cerebral perfusion. Uncontrolled diabetes may further contribute to hypoperfusion and atrophy
Kamiyama et al[74]	Voxel-based morphometric analysis was performed on 28 diabetes patients and 28 controls	Diabetes patients had hippocampal region atrophy and whole-brain atrophy
Northham et al[84]	MRI and IQ test were performed on 106 type-1 diabetes patients and 75 control subjects at baseline and then a 12-yr follow-up	DM subjects had lower verbal and full scale IQs, a decreased gray matter in bilateral thalami and right parahippocampal gyrus and insular cortex. White matter was decreased in bilateral parahippocampus, left temporal lobe, and middle frontal area
van Elderen et al[32]	Cognitive function test and MRI was conducted on 438 control subjects and 89 DM patients aged 70-82 yr	Elderly DM patients have accelerated progression of brain atrophy with significant consequences in cognition compared to the control subjects
Frøkjær et al[68]	MR scanning was performed in 23 controls and 26 patients with DM and GI symptoms and diffusion tensor imaging was performed	Diabetes patients had microstructural changes in brain areas involved in visceral sensory processing. This could be related to generalized DM-induced brain changes
Rosebud et al[73]	MRI on 51437 subjects including 214 with diabetes was performed	Midlife diabetes was associated with subcortical infarctions. Reduced hippocampal volume, whole brain volume and mild cognitive impairment were registered in diabetes patients
Frøkjær et al[75]	20 healthy controls and 15 patients with longstanding type 1 diabetes mellitus were scanned and cortical thickness was assessed based on a cortical segmentation method	Reduced cortical thickness of superior parietal and postcentral gyrus. No overall macrostructural brain alterations were detected, but the authors concluded that cortical thinning involving sensory related areas might be important in diabetes

MR: Magnetic resonance; MRI: Magnetic resonance imaging; GI: Gastrointestinal; IQ: Intelligence quotient; DM: Diabetes mellitus.