Since the discovery of insulin and its introduction as treatment for diabetes in 1922, the survival rate of patients with diabetes has risen dramatically (Jervell, 1996). However, with the aging of the diabetic population, it has become clear that diabetes affects several organ systems, including the gastrointestinal (GI) system (Locke, 1995). Consequently, complications rates from diabetes are also increasing. Gastrointestinal symptoms such as nausea, vomiting, heartburn, abdominal pain, diarrhea, constipation, fecal incontinence and feeling of incomplete defecation are often encountered in patients with diabetes (Camilleri, 1996; Nompleggi et al., 1989; Schvarcz et al., 1996; Spångéus et al., 1999). In studies of this phenomena, the prevalence of such symptoms varied from 22.1% to 76% (Enck et al., 1994; Feldman and Schiller, 1983).

Diabetic gastroenteropathy is a clinically serious condition. In addition to morbidity, it can also seriously hamper metabolic control, which in turn increases the risk of hyper- and hypoglycemia. Furthermore, poorly controlled blood glucose levels increase the risk of microvascular complications--such as retinopathy, nephropathy and neuropathy--and macrovascular complications, with increased risk of myocardial infarction, stroke and limb amputation. In extreme cases, GI symptoms can cause malnutrition (Nompleggi et al., 1989), which, together with the disturbed immune defense seen in diabetes, may lead to severe intercurrent infections.

Gastrointestinal symptoms in patients with diabetes are attributed to disturbed gastrointestinal motility (Abrahamsson, 1995; Koch, 1999). Such dysmotility in patients with diabetes is believed to result from autonomic neuropathy and/or hyperglycemia (Björnsson et al., 1994; Koch, 1999). In clinically based studies, the frequency of GI dysfunction is much higher than the reported rates of autonomic neuropathy (Bucceri et al., 2002). In one study of 114 patients with type 1 and type 2 diabetes, GI disorders were not significantly associated with autonomic neuropathy (Clouse and Lustman, 1989). Whereas acute hyperglycemia is correlated with gastrointestinal dysmotility in patients with diabetes (Björnsson et al., 1994; Koch, 1999), chronic hyperglycemia is not (El-Salhy and Sitohy, 2001; Merio et al., 1997). The neuroendocrine system of the gut secretes peptides/amines that are regulators of GI motility, and researchers believe that a disturbance of this regulatory system could be involved in the pathogenesis of GI complications in diabetes (El-Salhy, 2002).

In addition to GI complaints, patients with diabetes whose metabolic control has been successfully regulated begin to exhibit fluctuating blood glucose levels that are difficult to regulate. Currently, there are no means to correct autonomic neuropathy in patients with diabetes. Normoglycemia is already an objective that the patient and physician are endeavoring to achieve. This leaves the gut neuroendocrine system disorders as a possible target for treatment of diabetic gastroenteropathy.

Changes in gut motility may result in small bowel bacterial overgrowth and bile acid malabsorption. Moreover, celiac sprue is overrepresented in these patients (Valdovinos et al., 1993; von der Ohe, 1995). These conditions should be excluded by performing hydrogen breath tests and a 75Se-homocholic acid taurine (SeHCAT) test, as well as gastroscopy with duodenal biopsies and/or measuring serum antigliadin antibodies.

Gastrointestinal motility can be assessed by scintigraphic measurement of gastric emptying, of colonic transit by use of radio-opaque markers and manometry of various segments of the GI tract. In most cases, anamnesis, gastric emptying and colonic transit tests will suffice to establish a diagnosis.

Apart from treatment for symptoms, there are few drugs that can be used to regulate gut motility. The treatment of diabetes gastroenteropathy has been covered in a comprehensive review (Koch, 1999). The following is a summary of our experience at University Hospital in Umeå, Sweden.

Erythromycin. Erythromycin, a motilin receptor agonist, has been used with good results in patients with diabetes with slow gastric emptying, nausea and vomiting (Camilleri, 1996; Koch, 1999). However, the effect of erythromycin subsides with time, and, after three to four weeks, it is completely ineffective (Camilleri, 1996). Moreover, the drug cannot be used for long-term treatment as it causes abdominal pain, a common side effect with the doses given to patients with diabetes (Koch, 1999).

It was assumed that the erythromycin dose regularly given was high, leading to the development of resistance in the motilin receptors. In order to verify this assumption, we tested a low dose of erythromycin in patients with diabetes. We treated 11 patients with type 1 diabetes with 40 mg erythromycin ethylsuccinate 15 minutes before meals, three times daily. These patients were nine females and two males (mean age=45 years; range=28 to 78 years) whose diabetes duration ranged between 13 and 48 years (median=22.5 years). Ten patients had organ complications, and all were suffering from GI disorders. The patients were followed for seven to 33 (median=14) months. None complained of abdominal pain. This erythromycin regimen afforded sustained relief from nausea and vomiting. Furthermore, it improved gastric emptying and glycemic control. Surprisingly, other symptoms, such as diarrhea and constipation, disappeared. At the dosage given, erythromycin seemed to stimulate intestinal motility, as had been reported for motilin at physiological concentrations (Christofides and Bloom, 1981; Poitras, 1994). One may speculate that improved gastric emptying would allow the postprandial glucose peak in the blood to correspond to the peak injected insulin, achieving better glycemic regulation. Good metabolic control would further improve gastric emptying, as hyperglycemia has been shown to impair gastric emptying (Björnsson et al., 1994; Eliasson et al., 1995).

Serotonin receptor agonists. Serotonin (5-HT) cells have been reported to be abnormal in the GI tracts of patients with diabetes (El-Salhy, 2002; El-Salhy and Sitohy, 2001). Two specific 5-HT₄ receptor agonists, prucalopride and tegaserod (Zelnorm), that accelerate colonic transit have been developed (Spiller, 2002). Prucalopride is more selective for the 5-HT₄ receptors and does not affect gastric or small bowel transit (Bouras et al., 1999; Poen et al., 1999). Tegaserod accelerates both gastric emptying and small bowel transit (Degen et al., 2001). We have tested an oral dose of tegaserod 6 mg bid in our clinic in patients with diabetes complaining of constipation, nausea and vomiting. The outcome seems promising, but evaluation of this treatment is not yet ready.

Dietary modification. Diet modification as a form of treatment for diabetic gastroenteropathy has been described in detail elsewhere (Koch, 1999). At our clinic, we have tested a regimen of six light meals as recommended by Koch. This relieved the GI symptoms and improved metabolic control. We have not yet carried out a scientific evaluation of this treatment. Synthesis and release of gut neuroendocrine signal substances are regulated not only by the amount of ingested food, but also by its composition. Dietary modifications can be, therefore, a very effective way to regulate the synthesis and release of neuroendocrine signal substances of the gut in patients with diabetes and gastroenteropathy.

The author's work reported in this review was supported by grants from Bengt Ihre's Foundation; Sahlberg's Foundation; the Faculty of Medicine, Umeå University Research Funds Foundation; and the Julin's Foundation.

Dr. El-Salhy is professor in gastroenterology and hepatology and senior consultant gastroenterologist and internist in the department of medicine at University Hospital in Umeå, Sweden.

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Overview of Diabetic Gastroenteropathy