Adaptive Medicine 4(1): 9-14, 2012 DOI: 10.4247/AM.2012.

ABB013

Review

Adaptation of Gastrointestinal Motility to Diabetes Mellitus

Wei-Ju Huang 1 and Paulus S. Wang 2
1 2

Department of Nursing, Hsin Sheng College of Medical Care and Management, Taoyuan 325, Taiwan, Republic of China Department of Physiology, School of Medicine, National Yang Ming University, Taipei 112, Taiwan, Republic of China

Gastrointestinal (GI) motility is defined by the movement of the digestive system and the transit of the contents within it. Delayed gastric emptying indicates the symptoms included nausea and vomiting, especially in diabetes mellitus (DM). Clinically, diabetic patients may experience upper GI symptoms such as epigastric fullness, nausea and heartburn, and lower GI symptoms such as constipation, diarrhea and fecal incontinence. Insulin-dependent diabetes mellitus patients showed more delayed gastric emptying than non-insulin-dependent diabetes mellitus patients. During insulin stimulation, the GI motility is changed and accelerated. In diabetic gastroparesis, motilin, incretins (glucagon-like peptide1and glucose-dependent insulinotropic polypeptide) are also a group of GI hormones that cause an increase in the amount of insulin released from the beta cells and are discussed in the article. Ghrelin, secreted in hunger, is found chiefly from the oxyntic glands in the stomach and are often referred to as growth hormone secretagogues. It plays a much newer role in the development of metabolic syndrome as it modifies glucose as well as insulin metabolism, blood pressure levels, and adipogenesis in diabetes. The rapid gastric emptying may be due to the rising levels of ghrelin and growth hormone secretagogue receptor (GHSR) in the hypothalamus during early hyperglycemia. The duration of hyperglycemia is affected by the rising ratio of ghrelin/obestatin. Diabetic diarrea, celiac disease, as well as mechanic obstruction, were also general GI problems in hyperglycemia. Delayed gastric emptying of solids in diabetic patients with autonomic neuropathy was proven in our study, implying the gastric electrical stimulation improved the gastric motility in streptozotocin-induced diabetic rats. Clinically, prokinetic agents, including D2 receptor antagonist, motilin receptor agonists and 5-hydroxytryptamine receptor 4 receptor agonists, are generally used to improve the gastroparesis. We conclude that the mechanism between GI motility and DM may be related to the treatment of gastroparesis, the neuropathic disorders, and the roles of endocrine cell in diabetic gastroenteropathy. Further studies on the role of GHSR or some drugs for complications in clinical diabetes should be conducted. Key Words: GI motility, DM, gastroparesis, neuropathic disorders, ghrelin

Introduction
Gastrointestinal (GI) motility is defined by the movement of foods in the digestive system and the transit of the contents within it (4). The general GI motility was mainly focused on the gastric emptying or intestinal transit, sometimes the esophagus or anorectum motility was approved (1). Between meals, after all the digestible food has left the stomach, there are occasional bursts of very strong, synchronized contractions that are accompanied by opening of the pyloric sphincter muscle (22). When nerves or muscles in any portion of the digestive tract do not function with their normal strength and coordination, a person develops syndromes related to motility problems (55). The disorders of GI motility mean that it can affect the GI tract from the esophagus to the colon and rectum (4). Delayed gastric emptying (e.g. gastroparesis) indicates the symptoms including nausea and vomiting, especially in diabetes mellitus (DM) (42). This also usually has a neurological basis; the most common cause is longstanding DM (69). DM is one of the most serious metabolic diseases in the world (64). It is a disease in which the body doesnt produce or properly use insulin. Type I or insulin-dependent diabetes mellitus (IDDM) typically in childhood is an autoimmune disease which resulted from the immune systems attacking and destroying the insulin-producing beta cells in the pancreas. Type II or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes which is due to the insulin resistance of target tissue, especially in older age or obesity (64). The hyperglycemia is the appearance of both types of DM. However, some previous studies showed that the blood glucose might be normal or lower in the early stage of DM (43). The change in blood sugar concentration was considered to be a reason for the diabetic complications (43). Clinically, diabetic patients may experience upper GI symptoms such as epigastric fullness, nausea and heartburn, and lower GI symptoms such as constipation,

Corresponding author: Dr. Wei-Ju Huang, Department of Nursing, Hsin-Sheng College of Medical Care and Management, Longtan, Taoyuan 325, Taiwan, R.O.C. Tel: +886-3-4117578 ext. 561, Fax: +886-3-4117600, E-mail: amalgam32@gmail.com Received: January 28, 2011; Revised: November 8, 2011; Accepted: December 5, 2011. 2012 by The Society of Adaptive Science in Taiwan and Airiti Press Inc. ISSN : 2076-944X. http://www.sast.org.tw

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diarrhea and fecal incontinence (5). Delayed gastric emptying is a common GI problem among the majority of diabetic patients (6). Diabetic gastric dysmotility involves intrinsic neuropathy, auto-vagotomy, hyperglycemia, hormonal control, psychological factors and other medications (5).

Impacts of Diabetes to GI Motility

Disordered GI motility is an often-overlooked clinical problem (25). Delayed gastric emptying of solid and/ or liquid meal in patients with both type 1 and type 2 DM occurs in approximately 50% of these patients (24). Delayed gastric emptying is very common in patients with DM (25) and it has no direct correlation to blood sugar control, duration of the disease, and upper gastrointestinal symptoms (54). It has been well-known that the hyperglycemia induced by streptozotocin (STZ) inhibits both gastric emptying (65) and GI transit in rats, but the effect is reversed by the supplement of insulin (32). Since 1959, diabetic gastric acidity and atony has been examined in clinical, it found that gastric acidity secreted in the diabetic aged person (31, 66). A subsequent study revealed the gastric acid and blood gastrin secretion was stimulated in diabetic patients (48, 58). Furthermore, delay of gastric emptying was found in diabetic patients and rats (34, 42). It has been found that 34% of type I diabetic patients had delayed gastric emptying that correlated with female gender, increased BMI, abdominal bloating and upper abdominal pain (46). The higher blood glucose or hyperglycemia was considered to be the main reason for gastric motor dysfunction (10, 11, 20, 33). Rat small intestinal transit is independent on glucose consumption in exercise model (10). Pentagastrin induces excessive gastric acid secretion strongly in the STZ-induced rats (9). IDDM patients showed more delayed gastric emptying than NIDDM patients (38). During insulin stimulation, the GI motility was changed and accelerated (52). Gastroparesis is a common GI problem in diabetes. In diabetic gastroparesis, the gastric emptying of solids is markedly delayed (67). Based on the fact, diabetic gastroparesis and its impact on glycemia were investigated (10). A subsequent report indicated that attaining glycemic control improves gastric motility and upper abdominal symptoms in diabetic patients with gastroparesis (50). Moreover, a previous study revealed that the motilin and related compounds such as erythromycin derivatives could be useful for the treatment of disturbed gastric emptying in diabetic subjects (44). Motilin accelerates gastric emptying in diabetic gastroparesis and supports the hypothesis that erythromycins effect is mediated through motilin receptors (41). Similarly, central motilin might be involved in the regulation of gastric motility in diabetic rats (30).

With regard to the neuropathy, these conditions are thought to result from diabetic microvascular injury involving small blood vessels that supply nerves (3). Autonomic neuropathy can affect the GI system, including delayed gastric emptying, gastroparesis, nausea, bloating, and diarrhea in DM patients. Delayed gastric emptying of solids in diabetic patients with autonomic neuropathy was observed (7) while gastric electrical stimulation improved the gastric motility in STZ-induced diabetic rats (35). Immediate insulin treatment prevents gut motility alterations and loss of neurons in the ileum and colon of rats with STZ-induced diabetes (28). Collectively, our previous studies also showed treatment with atropine, muscarinic (M) 1 or M3 receptor antagonists respectively decreased the insulin-induced up-regulation of gastric emptying in DM rats (26).

The Macroscopic and Molecular Regulation in Diabetic Gastroenteropathy and Motility

Obesity and Hormone in Diabetic Gastroenteropathy Obesity may cause diabetes and dysfunctional GI motility. Obesity-induced metabolic syndrome, like DM, was widespread in clinical patients (is prevalent among clinical patients?) (64). Related to the adipocyte or cardiac problem, indeed, serum high-molecular weight adiponectin is related to early postprandial glycemic increases and gastric emptying in patients with NIDDM (27). Oesophageal motility disorders in IDDM often accompany cardiovascular autonomic neuropathy (3). Besides, incretins (glucagon-like peptide-1, GLP-1, and glucose-dependent insulinotropic polypeptide, GIP) was a common drug for diabetes. Incretins are also a group of GI hormones that cause an increase in the amount of insulin released from the beta cells of the islets of Langerhans after eating (59). Some studies demonstrated that medications that mimic or enhance the function of the endogenous incretins retard gastric emptying to enhance glycemic control, and increased circulating incretins stimulated by the delivery of nutrients to the intestine, contribute to weight loss (6). GIP and GLP-1 receptor gene expressions in pancreatic islets and in small bowel were initially high, but insulin responsiveness to stimulation of GIP and GLP-1 along with inhibition of small bowel motility indicates a preserved incretin response on motility in type II diabetes (14). Incretins may be good for sugar control and GI motility in DM initially, but have opposite effects in insulin secretion later. Interstitial Cells of Cajal (ICC) in Diabetic Gastroenteropathy ICC distributed in the GI tract control the rhythm of

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GI smooth muscle contraction, whereas gastroparesis might be due to the decrease number of ICC (60). ICC deficiency may cause functional impairment of GI tract motivation (60). Collectively, loss of ICC may be the main reason to poor intestinal motility in DM (51). Disturbed GI motility in db/db mice was related to the reduced areas of cells of ICC and expression of stem cell factor (SCF) (70). Besides, reduction of insulin and insulin-like growth factor-1 (IGF-1), plus gap junctions between ICC were damaged. These changes might be one of the mechanisms for diabetic GI dysfunction (71). Ghrelin and Diabetic Gastroenteropathy Ghrelin, secreted during hunger, was found chiefly from oxyntic glands in stomach (36) and called growth hormone (GH) secretagogues. Ghrelin plays a role in the development metabolic syndrome and modifies glucose and insulin metabolism, blood pressure levels, and adipogenesis in diabetes (57). Ghrelin also plays a physiological role in reproductive hormone secretion (63). It has been known that ghrelin changes the insulin sensitivity in children (37). Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis (15). Glucose and insulin regulate desacyl ghrelin secretion in pregnant women with diabetes. Impaired desacyl ghrelin regulation may affect energy metabolism in pregnant women with poorly controlled diabetes (18). Desacyl ghrelin and obestatin increase islet cell mass and prevent diabetes in STZ-treated newborn rats (21). The rapid gastric emptying may be due to the rising levels of ghrelin and growth hormone secretagogue receptor (GHSR) in the hypothalamus during early hyperglycemia. The duration of hyperglycemia is affected by the rising ratio of ghrelin/ obestatin (62).

Conclusion and Future Perspectives

Complications of DM, including autonomic neuropathy, GI dysmotility, gastroparesis, diabetic diarrea, celiac disease, as well as mechanic obstruction, were common problems in GI (19, 53). Clinically, prokinetic agents, including dopamine 2 (D2) receptor antagonist, motilin receptor agonists and 5-hydroxytryptamine receptor 4 (5-HT4) receptor agonists, are generally used to improve gastroparesis. Metoclopramide (primperan) is the only legal drug which can treat gastroparesis, improve the symptom and promote the gastric emptying. Based on the binding effect of 5-HT3 receptor, metoclopramide is also an antiemetic drug. Similarly, domperidone (motilium), another kind of D2 receptor antagonist, does not pass through the blood-brain

barrier and has better effect on the gastroparesis treatment (52). Levosupiride improves either the gastroparesis syndrome or blood glucose. Erythromycin, a macrolide antibiotic which acts on the motilin receptor and increases the migratory motor complex when fasting, has been used for treatment of gastroparesis (56). Furthermore, gastric electrical stimulation (GES) combined with endoscopy and surgery can contribute to severe diabetic gastroparesis, gastric emptying, and blood sugar level (49). In addition to gastroparesis, diabetic diarrea is always an unclear mechanism in DM. Recent findings revealed that abnormal intestinal transit, gut bacteria parasitism, decrease of 2-adrenergic and exocrine of pancrease might be the reasons for diabetic diarrea (35, 40). The effects of diabetes on the gastroenterology and autonomic neuropathy were not known completely. Conceivably, the correlation in hyperglycemia-induced GI dysmotility, ICC apoptosis, autoimmunity, insulin secretion, and oxidative stress will be examined (39). The loss of function in gut controlling by the adrenergic nerve was thought to be an important reason for diarrea, especially the decrease of absorption ability in water. Experiment with clonidine (2-adrenergic agonist) showed improvement of diabetic diarrea (23). The active form acylated ghrelin is a small proportion of the total ghrelin, but it plays a functional role in physiology. Several different points of view on ghrelins role in GI motility have been examined. Previous studies have shown most of them are supposed by the stimulation of GI motility (15, 61, 62). However, some opposite observation claimed that ghrelin has the inhibitory effect on GI motility (2, 29). We concluded that the acylated ghrelin might have more impact on the GI function mostly in DM, rather than desacyl ghrelin. Estradiol benzoate inhibits gastric emptying and gastrointestinal transit in ovariectomized rats via a mechanism involving CCK stimulation and CCKA receptor activation (12, 13, 68). Moreover, a previous study has shown that the effect of ghrelin depends on the release of GH and IGF-1 (8, 45). Lower serum levels of IGF-1 may be deficient in GH stimulation by ghrelin (45). However, the IGF-1, GH and ghrelin axis (GHS axis) in GI motility was unknown. GHSR exists in the hypothalamus, pituitary and stomach of rats (47). The distribution of GHSR among GI tract and the relationship between GI motility and smooth muscle contraction in diabetes remain unclear. In diabtetes, desacyl ghrelin improves glucose metabolism and preserves islet cell mass, granting a therapeutic potential in medical conditions associated with impaired beta-cell function (21). The rapid gastric emptying may be due to the rising levels of ghrelin and GHSR in the hypothalamus during early

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hyperglycemia, and the duration of hyperglycemia is affected by the rising ratio of ghrelin/obestatin (63). We concluded that the mechanism between GI motility and DM might be related to the treatment of gastroparesis, the neuropathic disorders, and the roles of endocrine cells in diabetic gastroenteropathy. Further studies should focus on the role of GHSR or some drugs in the complications of diabetes.

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Acknowledgments
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This work was supported by the grant (NSC 99-2320B-570- 001) from the National Science Council, Taiwan, R.O.C.

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