Gastrointestinal motility and glycemic control in diabetes: the chicken and the egg revisited?

Abstract

Upper gastrointestinal dysfunction occurs frequently in diabetes and potentially contributes to both abdominal symptoms and impaired glycemic control; conversely, variations in blood glucose concentration reversibly affect gut motility in humans. In this issue of the JCI, Anitha et al. report apoptosis of rodent enteric neurons under hyperglycemic conditions, both in vitro and in vivo, associated with impaired PI3K activity and preventable by glial cell line-derived neurotrophic factor. These observations add to recent insights gained from animal models regarding the etiology of diabetic gastrointestinal dysfunction, but investigators must strive to translate animal data to human diabetes.

Figure 1

The pathogenesis of gastrointestinal dysfunction in a diabetic mouse model, as proposed by Anitha et al. (18). Mice that are hyperglycemic as a result of STZ-induced diabetes have apoptosis of enteric neurons in the myenteric plexus, associated with delayed gastric emptying and rapid intestinal transit when compared with control mice. Activity of the PI3K/Akt pathway is decreased in the diabetic mice, which implies an impairment of retrograde axonal transport of neurotropic factors. Both neuronal apoptosis and disordered gastrointestinal motility are prevented in mice that overexpress GDNF.