Effects of hyperglycaemia on small intestinal and anorectal motor function in humans

Abstract

This thesis presents studies which relate to the effects of changes in the blood glucose concentration on the organisation and control of motility in the small intestine and anorectum. The motor mechanisms by which acute hyperglycaemia slows small intestinal transit in healthy humans were investigated. Hyperglycaemia (blood glucose concentration -15mmol/l) stimulated phase III activity, but there was overall suppression of small intestinal pressure waves' when compared to euglycaemia- These results indicate that marked hyperglycaemia has major effects on small intestinal motility in normal subjects. The observed suppression of small intestinal motility provides a possible mechanism for the slowing of small intestinal transit during hyperglycaemia. Among the candidate mechanisms mediating the effects of hyperglycaemia on small intestinal motility is modification of tonic inhibition mediated by enteric nerves containing nitric oxide, The effects of a specific inhibitor of nitric oxide (NO) synthase, NG-monomethyl-L-arginine (L-NMMA), on small intestinal motor activity, were evaluated in healthy human volunteers. Administration of L-NMMA was associated with stimulation of small intestinal phase III activity and a reduction in the duration of phase I activity. These results indicate that NO mechanisms are involved in the initiation of small intestinal phase III activity- Disordered defaecation occurs commonly in patients with diabetes mellitus and is associated with heterogenous anorectal motor and sensory dysfunctions' These abnormalities may potentially be due to hyperglycaemia, rather than irreversible neural dysfunction. In healthy humans, measurements of anorectal motility and sensation were performed, during euglycaemia (4mmol/l) and hyperglycaemia (8mmol/l and 12mmol/l). At a blood glucose concentration of 12mmol/l the number of spontaneous internal anal sphincter relaxations was greater and the strength of the external anal sphincter less when compared to euglycaemia. The threshold for perception of rectal balloon distension was lower at a blood glucose of 12mmol/l when compared to 4mmol/l. These observations demonstrate that acute changes in the blood glucose concentration affect both the smooth and striated muscle of the anal sphincter, as well as rectal sensation, and suggest that hyperglycaemia may contribute to incontinence in patients with diabetes mellitus. Autonomic nervous system dysfunction occurs frequently in patients with diabetes mellitus and is associated with disordered gastrointestinal motor function. The possibility that the blood glucose concentration may affect cardiovascular autonomic (parasympathetic and sympathetic) function was evaluated in healthy human volunteers by performing paired studies during euglycaemia and hyperglycaemia (∼15mmol/l). Hyperglycaemia was associated with changes in cardiovascular parasympathetic function. This observation indicates that acute changes in the blood glucose concentration affect cardiovascular autonomic function, which may be important in mediating the effects of hyperglycaemia on gastrointestinal motor function. The studies reported in this thesis provide new insights into the control of gastrointestinal motility in healthy humans and effects of changes in the blood glucose concentration. The latter observations are likely to be relevant to an understanding of gastrointestinal motor function in patients with diabetes mellitus.