Jan Tack, Florencia Carbone; Alessandra Rotondo


Curr Opin Gastroenterol. 2015;31(6):499-505. 

In This Article



The mechanisms through which gastric motor control processes are affected in diabetic and idiopathic gastroparesis are incompletely elucidated. Autoimmunity is a key feature in the pathogenesis of type 1 diabetes, but may also be involved in type 2 diabetes as shown by the presence of autoantibodies. Singla et al.[16] report antiglutamic acid decarboxylase but no antiislet cell or antiinsulin antibodies in six (five type 1 diabetes) out of 16 diabetic gastroparesis patients (12 with type 1 diabetes). There was no association with severity of symptoms or delay in gastric emptying, suggesting, therefore, that autoantibodies are probably not key factors in the pathogenesis of diabetic gastroparesis.

Glycemic Control in Type 2 Diabetes

Altered glycemic control has been implicated in the pathogenesis of dysmotility in diabetes,[17,18] and this is the basis to recommend improved glycemic control for treating diabetic gastroparesis.[2,3] Bharucha et al.[19] studied the impact of improved glycemic control on gastric emptying rate in 30 patients with poorly controlled type 2 diabetes (glycosylated hemoglobin levels >9%). Baseline gastric emptying was abnormal in two-thirds of the patients (delayed in 14, rapid in six), and higher fasting glucose was associated with more rapid emptying. Patients were randomized to a repeat emptying test one week later with administration of saline or insulin. Although insulin improved glycemia, gastric emptying rate did not differ from the saline group. All patients underwent 6 months intensive diabetes therapy, which significantly improved glycosylated hemoglobin levels but not gastric emptying. These findings argue, at least in type 2 diabetes, against the widely held belief that better glycemic control will improve gastric emptying. However, as the patients in this study did not report major gastrointestinal symptoms, the implications for treatment of gastroparesis symptoms remain unclear.[19]

Neuropathy and Glycemic Control in Type 1 Diabetes

Softeland et al.[20] studied gastric emptying (using radiopaque markers), rectal multimodal sensitivity (heat, mechanical distension, and electrical stimulation), and autonomic cardiac innervation in 20 diabetic patients with gastroparesis symptoms and 16 healthy controls. Delayed gastric emptying was found in 60% of the patients, and this was inversely associated with symptoms of nausea and vomiting (i.e., less symptoms with more delayed emptying). Compared with controls, patients were hyposensitive to thermal, mechanical, and electrical rectal stimulation, and showed signs of autonomic neuropathy (reduced heart-rate variability). Rectal thermal hyposensitivity was correlated to gastric retention and to reduced heart-rate variability. These observations indicate that diabetic patients have a widespread neuropathy, involving both autonomic and sensory neuropathy, and including visceral hyposensitivity.[20]

Bharucha et al.[21] also studied a cohort of type 1 diabetes patients who were enrolled in multicenter long-term follow-up studies of effects of improved glycemic control. Seventy four type 1 diabetes patients from seven centers, with a diabetes history of more than 400 months, underwent gastric emptying testing, and results were correlated to parameters of glycemic control, diabetes complications, and gastrointestinal symptom questionnaires. Delayed emptying was present in 47% and, in multivariate analysis, this was associated with the presence of retinopathy, the duration of diabetes, and glycosylated hemoglobin levels before and during the follow-up study. Gastrointestinal symptom scores, assessed with PAGI-SYM and GCSI questionnaires,[12,14] did not differ between normal or delayed emptying.[21] This study shows that long-term poor glycemic control is a risk factor for the development of gastroparesis, and was associated with increased prevalence of other diabetic complications, but the impact on gastrointestinal symptoms is limited.[21]

Interstitial Cells of Cajal and Macrophages

The studies discussed above have focused on functional changes at the organ level in diabetic gastroparesis. Histological studies utilizing gastric resection specimens show alterations of myenteric neurons, a low-grade inflammatory infiltrate and, most consistently, loss of interstitial cells of Cajal (ICC) in human gastroparesis.[22] Recent studies in mice models of type 1 diabetes demonstrate a protective effect of CD206-positive heme oxygenase-1 expressing M2 macrophages against the development of gastroparesis.[23] Bernard et al.[24] studied transmural gastric corpus biopsies from diabetic patients with and without gastroparesis, idiopathic gastroparesis patients, and controls (n = 10 age-matched females each). The number of ICCs was significantly lower in idiopathic and diabetic gastroparesis specimens. The number of CD45-positive immune cells, CD206-positive macrophages, and inducible nitric oxide synthase-positive cells did not differ significantly between groups, but a significant correlation was found between the number of CD206-positive macrophages and ICC in diabetic patients with or without gastroparesis. These observations confirm the finding of ICC depletion in gastroparesis, and suggest that, similar to mice, CD206-positive cells may serve a protective role in preserving ICC. Other pathways may be involved in idiopathic gastroparesis.[24]