Impaired Gastrointestinal Motility and Glycemic Control in Patients with Type 2 Diabetes

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The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 1.0 category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity.

Valid December 1, 2005- February 28, 2006. Estimated time: 1 hour

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Educational Objectives
1. To understand the pathophysiology of gastroparesis
2. To understand the impact of diabetes in gastroparesis
3. To understand the impact of gastroparesis on type 2 diabetes
4. To be able to implement management for patients with type 2 diabetes who have gastroparesis
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Diabetes affects approximately 18.2 million persons in the United States (6.3% of the population), with increased prevalence with aging, reaching a rate of 18.3% in persons 60 years and older.¹ Along with the increasing diabetes prevalence in this age group, the prevalence of upper gastrointestinal (GI) diseases is increasing among those age 65 years and older.² Although cardiovascular diseases remain the leading cause of mortality in persons with diabetes, neuropathies account for substantial morbidity and disability. Uncontrolled hyperglycemia can cause diffuse damage to peripheral nerves and small vessels in virtually every organ system, including the GI tract, where it may impair smooth muscle function. This article reviews upper GI dysfunction associated with diabetes, prevalence and pathophysiology of diabetes-related gastropathies, along with disease assessment and treatment considerations as they relate to older patients.

EPIDEMIOLOGY

A constellation of GI symptoms occurs commonly in persons with diabetes and may be caused by autonomic dysfunction, as well as by other factors. These symptoms include heartburn, nausea, vomiting of undigested food, an early feeling of fullness when eating, weight loss, abdominal bloating, erratic blood glucose levels, lack of appetite, gastroesophageal reflux, and spasms of the stomach wall.³ Between 20% and 40% of patients with diabetes develop some form of autonomic nervous system impairment.^4,5 Approximately 75% of patients with diabetes report GI symptoms.⁶

Delayed gastric emptying of solid and/or liquid nutrient meals occurs in about half of patients with longstanding (> 5 years) type 1 or type 2 diabetes compared with controls without diabetes.^7,8 There are conflicting reports in the literature regarding prevalence of GI symptoms in patients with diabetes versus the general population.^9-11 However, a large population-based survey of 15,000 adults indicated that the prevalence of all GI symptoms was greater in subjects with diabetes compared with those without diabetes.⁹ Moreover, among the subjects with diabetes there was a dose-response relationship between self-reported glycemic control and the frequency of GI symptoms (Figure 1).⁹ However, there is a relatively weak correlation between the occurrence of GI symptoms and impaired gastric emptying of solids and liquids in patients with diabetes.¹² Thus, although quantitative studies of gastric emptying indicate that as many as half of patients with longstanding diabetes suffer from delayed gastric emptying,^7,8 only 50% of these patients with measured delay in gastric emptying are symptomatic.^12,13 Complicating any analysis, many of these symptoms occur in persons with normal gastric emptying and are therefore nonspecific—except possibly bloating, vomiting, and postprandial fullness.¹⁴

NORMAL GASTROINTESTINAL EMPTYING

The physiologic functions of the stomach are controlled by autonomic and enteric nervous system activities. When food reaches the stomach, the fundus relaxes to accommodate the ingested food; this accommodation is mediated by a vagal reflex and modulated by the local production of nitric oxide and vasoactive intestinal polypeptide. Gastric contractions in the body and antrum of the stomach reduce the food particles to a size small enough to empty into the duodenum. Normally there is a lag phase of roughly 30 minutes between the entry of food into the stomach and the start of gastric emptying. The rate of gastric emptying is typically faster for liquids compared with solids, slower for higher caloric density foods, slower for fat compared with carbohydrate and protein, and slower for hyperosmolar compared with isotonic liquids. In general, gastric transit time is 1-4 hours. In the fasting state, gastric motor activity consists of four phases based on the frequency and amplitude of spontaneous gastric contractions: 1) phase I is a period with no spontaneous contractile activity; 2) phase II consists of irregular motor activity; 3) phase III consists of the “migrating motor complexes” (MMCs) of rhythmic contractions at a frequency of three cycles per minute; and 4) phase IV is a brief period of irregular contractions. The MMCs of phase III are believed to be regulated by the central nervous system via the vagus nerve, and from a physiological perspective these rhythmic contractions are important because they serve a “housekeeping” role by moving residual, undigested food through the GI tract. The MMCs depend on intrinsic electric activity of the interstitial cells of Cajal, which are located throughout the GI tract; however, the key cells responsible for regulating normal phase III activity are located between the fundus and the greater curvature of the body, an area known as the gastric pacemaker area of the stomach (Figure 2).¹⁵ The MMCs of phase III are the cause of stomach “growling” and can readily be abolished by the ingestion of food.

PATHOPHYSIOLOGY

There are a number of different causes of gastroparesis (Table I3), yet the underlying pathophysiology remains unclear. Diabetes and idiopathic etiologies, which includes acute postviral gastroparesis, are the most common.¹⁶

NERVOUS SYSTEM IMPAIRMENT OF GASTROINTESTINAL FUNCTION

Autonomic neuropathy is a common cause of gastropathies in patients with diabetes. Gastroparesis, including both symptomatic and asymptomatic gastric retention in the absence of any physical obstruction, is frequently associated with other diabetes complications such as retinopathy, nephropathy, and disorders of the peripheral autonomic nervous system, which produce anhidrosis, gustatory sweating, orthostatic hypotension, sexual dysfunction, abnormal pupillary responses, and urinary bladder dysfunction. This article focuses on upper GI dysfunction; however, the GI manifestations of autonomic dysfunction can affect the esophagus (esophageal enteropathy), stomach (gastroparesis, pylorospasm), small bowel (impaired motility or diarrhea), colon (impaired gastrocolic reflex and constipation), or rectum (sphincter abnormalities, fecal incontinence), as described in the American Diabetes Association’s technical review of diabetic autonomic neuropathy.⁵ Autonomic neuropathy affecting the GI tract is characterized by impaired gastric contractility or abnormal myoelectrical control, frequently attributable to vagal nerve dysfunction.¹⁷ Normal gastric emptying is largely dependent on vagus nerve function, which can be severely impaired in diabetes.⁵ Autonomic neuropathy and diminished vagal tone resulting in disruption of normal neuromuscular functions at the stomach wall can lead to gastric dysrhythmias, which can result in gastroparesis.¹⁸ Abnormalities in the excitatory or inhibitory enteric nerves are associated with abnormal GI sensory and motor function in diabetes.¹⁹ Motilin, a gastric peptide under vagal control, stimulates phase III motor activity of the MMC,4 and disruption of vagal nerve function is believed to result in impaired motilin release. Indeed, phase III MMCs are frequently reduced or absent in patients with diabetes, resulting in poor grinding of stomach contents and gastric retention.⁴

HYPERGLYCEMIA

It is known that hyperglycemia can cause GI motility disturbances, but there is also evidence showing that hyperglycemia can be exacerbated by delayed gastric emptying, thereby complicating management of glycemia. The stomach is the fine regulator of fuel delivery and, therefore, blood glucose levels. A number of studies have indicated that hyperglycemia impairs gastric motility both in normal individuals and in those who have diabetes. In patients with type 1 diabetes, acute induction of hyperglycemia or euglycemia using a modification of the glucose clamp procedure produced significant differences in both liquid and solid gastric emptying, including delays in both, under the condition of hyperglycemia (blood glucose, 288-360 mg/dL).²⁰ Furthermore, in subjects without diabetes, experimental induction of hyperglycemia slowed the gastric emptying rate of both solid and liquid components of a meal, apart from any osmotic effect of glucose.²¹ Mechanisms for the impact of hyperglycemia on gastric emptying include suppression of antral pressure waves, antral phase III motor activity,²² and increased pyloric contractions that cause intermittent obstruction to gastric outflow.²³ The rate of gastric emptying of a solid meal was found to be similar in patients with longstanding type 1 diabetes (mean duration, 28 ± 6 years) and sensorimotor neuropathy compared with healthy controls when blood glucose levels were tightly controlled by continuous intravenous insulin infusion 10 hours prior to and throughout the test period in the subjects with diabetes.²⁴ These results indicate that the hyperglycemia-induced functional defect in gastric emptying is correctable with insulin. Although acute changes in blood glucose clearly modify GI motor activity, the impact of chronic, long-term hyperglycemia in the etiology of GI dysfunction in persons with diabetes is less clear, and no evidence currently exists to support that the reversal of chronic hyperglycemia and poor glycemic control will directly correct gastroparesis. Although there are very limited clinical data for delayed gastric emptying in elderly individuals, two early studies demonstrated delayed gastric emptying of radiolabeled liquids in elderly patients (mean age, 77 years) relative to younger patients.^25,26

IMPACT OF DELAYED GASTRIC EMPTYING ON NUTRIENT AND DRUG ABSORPTION

Slowed gastric emptying delays the delivery of nutrients for absorption in the small intestine. For affected patients who take antihyperglycemic medications at mealtimes, the unpredictable GI transit time of the meal can result in hyperglycemia or hypoglycemia, depending on how the peak effect of the medication corresponds to the availability of nutrients. Impaired gastric emptying is caused by hyperglycemia and can lead to worsening of hyperglycemia in patients treated with oral antihyperglycemic agents, due to altered absorption of these drugs.^20,27 The resulting exacerbation of hyperglycemia may further impair GI function. The implication of this vicious circle of impaired gastric emptying and hyperglycemia is that bypassing the GI tract to deliver antihyperglycemic therapy may facilitate improvement in glycemic control, and thereby improve gastric motor function.

ASSESSMENT

The clinical features of gastroparesis in patients with diabetes include nausea, vomiting, early satiety, abdominal distention, bloating, and anorexia. Aside from obvious upper GI symptoms of dyspepsia, heartburn, nausea and vomiting, and early satiety, gastroparesis should be suspected in patients presenting with wide fluctuations in plasma glucose levels and episodes of postprandial hypoglycemia. Fluctuations in glucose levels are caused by temporal disparity between the availability and absorption of nutrients, as well as dosing of antihyperglycemic medications, effectively resulting in a fuel/insulin “mismatch.” Gastric outlet obstruction and medication-induced gastroparesis should be ruled out as the cause of delayed gastric emptying. This is particularly important in the elderly patient taking a number of medications for chronic conditions. Medications such as anticholinergic drugs (Table I) reduce GI motility and can cause upper GI symptoms or exacerbate preexisting gastroparesis. Diets high in fiber, such as those prescribed in diabetes, can lead to bezoar formation and gastric obstruction. Gastric retention of food after an 8- to 12-hour fast in the absence of any mechanical obstruction is diagnostic of gastroparesis. Assessments of patients with suspected gastroparesis (Table II) may include upper GI endoscopy or barium series to rule out structural or mucosal abnormalities.⁴ However, quantitative measures of gastric emptying alone should be interpreted with recognition of the fact that there is a relatively weak correlation between upper GI symptoms and measured gastric emptying; patients presenting with severe nausea and vomiting may have normal gastric emptying.²⁸ Conversely, 50% of patients with abnormal gastric emptying are asymptomatic. The presence of autonomic neuropathy can be established with measurement of heart rate variability.⁵ It is rare to find gastroparesis with normal heart rate variability. More selective tests of vagal function include the pancreatic polypeptide response to hyperglycemia at meal ingestion.²⁹

CLINICAL MANAGEMENT

Nutritional approaches Correction of dehydration and electrolyte imbalance is particularly important during acute exacerbation of gastroparesis, particularly when vomiting is present. Nonpharmacologic management of gastroparesis (Table III) also includes dietary modifications, such as more frequent, smaller-volume meals that are low fat and low fiber.3 Use of multivitamins and liquid caloric supplements is also recommended.³ However, parenteral nutrition support is not recommended—except in patients refractory to other approaches—because of the risks of infection and thrombosis.^3,30

During episodes of poor gastric control or ketoacidosis, it is important to use nasogastric suction until motility returns. Also, moderate exercise may be helpful in improving GI motility in many patients, although intense exercise may have a deleterious effect on motility. Pharmacologic approaches Pharmacologic therapy of gastroparesis in patients with diabetes includes the use of prokinetic agents, antiemetic medications, and eradication of bacterial overgrowth when present (Table III).

Although prokinetic agents are useful in many patients, the overall long-term efficacy of these drugs is limited. Metoclopramide and erythromycin are the only currently available Food and Drug Administration (FDA)-approved prokinetic agents in the United States. Metoclopramide is a dopamine antagonist that has both prokinetic and antiemetic properties. It also acts as a serotonin type 3 (5-HT3) receptor antagonist, a serotonin type 4 (5-HT4) receptor agonist, and a cholinergic agonist. Long-term use of metoclopramide is limited by its poor tolerability due to side effects, such as extrapyramidal effects resulting from its antidopaminergic activity in the central nervous system.

Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with metoclopramide. The prevalence of this syndrome appears to be highest among the elderly, especially elderly women. The risks and benefits associated with metoclopramide use in the elderly patient should therefore be carefully considered.³¹

Domperidone is a peripheral dopamine receptor antagonist that has a peripheral prokinetic effect.^30,31 Domperidone, while not currently approved for use in the United States, has been used in many other countries to treat gastroparesis. This agent should be used with caution in elderly patients and in those with hepatic impairment.³²

Erythromycin is a macrolide antibiotic that works by stimulating motilin receptors leading to accelerated gastric emptying in patients with gastroparesis. Erythromycin also increases the amplitude of antral contractions and improves antral-duodenal coordination.^33,34 Long-term efficacy of erythromycin is limited by the development of drug tolerance due to motilin receptor downregulation. The efficacy of erythromycin,³³ and possibly other prokinetic agents, is impaired by marked hyperglycemia, another compelling reason to restore good glycemic control as a primary therapeutic intervention.

The medications described above may act to accelerate gastric emptying; however, it is important to note that a number of commonly used medications may actually act to slow gastric emptying and cause gastroparesis (Table I). Therefore, in evaluating gastric symptoms in patients with type 2 diabetes, it is important for the physician to consider the contribution to these symptoms of other medications the patient is currently taking, as opposed to immediately making the assumption that oral antihyperglycemic therapy or insulin therapy is failing and leading to the progression of neuropathy and gastroparesis.

Because gastric emptying is dependent on nitrergic nerve function, there have been early anecdotal reports of successful control of symptoms using inhibitors of cGMP phosphodiesterase, which increases nitric oxide in the stomach. Antiemetic and other medications. Antiemetic agents such as selective serotonin 5-HT3 receptor antagonists (ondansetron, granisetron, and dolasetron) are effective in symptomatic relief of nausea and vomiting, but their high cost may limit their chronic, long-term use in the management of these symptoms in patients with gastroparesis.³⁵

Antibiotic therapy is indicated in patients with symptomatic bacterial overgrowth secondary to delayed gastric emptying and stasis. Treatment with doxycycline, metronidazole, ciprofloxacin, or rifaximin have been effective in treating bacterial overgrowth.36 New approaches to the medical management of gastroparesis in clinical development include pyloric injection of botulinum neurotoxin to promote gastric emptying by reducing pyloric tone,³⁷ a variety of 5-HT4 antagonists,³⁸ and cholecystokinin (a receptor antagonist).³⁹ In particular, serotonin receptor antagonism with tegaserod maleate may demonstrate promise and is currently being investigated. Surgical approaches Patients who fail to respond to medical therapy may be candidates for endoscopic or surgical interventions.

These treatments include placement of gastrostomy or jejunostomy tubes for maintaining nutrition, the use of gastric pacing, and, in some cases, gastrectomy as an approach for patients who fail all other treatments. Gastric electrical stimulation has been applied to the treatment of gastroparesis based on the concept that impaired myoelectrical activity in the antrum and resulting impaired antral contractility, which is regulated by electrical slow-wave activity originating in the pacemaker region of the stomach (Figure 2),¹⁵ plays a role in the underlying pathophysiology.

The clinical efficacy of gastric electrical stimulation is controversial, with evidence of reduced severity of symptoms and enhanced quality of life despite little objective demonstration of improved gastric emptying.⁴⁰

TREATMENT OF HYPERGLYCEMIA  

Improvement of glycemic control may be helpful in reversing the symptoms of dyspepsia in patients with diabetes. Achieving and maintaining glycemic control may also reverse abnormal gastric emptying.²⁰ However, monitoring 2-hour postprandial blood glucose levels may be inappropriate for patients with gastroparesis, as unpredictable gastric emptying precludes accurate assessment of this glycemic parameter. Instead, frequent glucose monitoring, including measurement of fasting blood glucose levels and aggressive intervention to produce good glycemic control, may address the origin of the problem and should be considered a priority in patient evaluation and management. Indeed, it has been proposed that hyperglycemia may be more important than neuropathy in the pathophysiology of gastroparesis in patients with diabetes.²⁴

INSULIN THERAPY 

Insulin therapy can be an effective treatment option to offset the consequences of unpredictable absorption of oral antihyperglycemic agents and nutrients. Insulin also can prevent hyperglycemia caused by the temporal disparity between absorption of food and medication. However, hypoglycemia episodes may occur when the administration of exogenous insulin and subsequent glucose lowering precedes delivery of nutrients to the small bowel for absorption. Thus, it is important to point out that the use of mealtime insulin boluses is likely to have the same limitation as prandial oral agents: the narrow window of effective glucose lowering may produce hypoglycemia if the administration is not timed to coincide with nutrient availability. Furthermore, the use of premixed insulin requires relatively strict adherence to mealtimes and assumes nutrient availability within normal timeframes to avoid hypoglycemia.

Premixed insulin, therefore, may not be the best choice for patients with variable or unpredictable gastric emptying. The addition of basal insulin therapy to an oral therapy regimen may be valuable in achieving glycemic control to resolve gastroparesis and other diabetes-related gastric motor abnormalities. Indeed, newer long-acting insulin analogs are associated with less hypoglycemia, and therefore may be appropriate in elderly patients, who may be more susceptible to hypoglycemia. Furthermore, basal insulin therapy with a 24-hour time action profile that closely mimics normal pancreatic basal secretion may improve overall glycemic control, with a lower risk of hypoglycemia.

Insulin glargine is a long-acting insulin analog that mimics physiological basal insulin secretion with no pronounced peaks in plasma insulin. Riddle et al,41 using an easy-to-follow titration algorithm targeting a fasting plasma glucose of 100 mg/dL, demonstrated that the addition of basal insulin glargine or neutral protamine Hagedorn (NPH) in patients inadequately controlled with oral antihyperglycemic agents facilitated the attainment of the A1c goal of 7.0% or lower. More patients in the insulin glargine group, however, reached this goal without an instance of documented nocturnal hypoglycemia, compared with the NPH insulin group (33.2% vs 26.7%, P < 0.05). Patients in this study ranged in age from 30 to 70 years (mean, 56 years). Use of basal insulin therapy in patients with gastropathy associated with diabetes may be a useful approach to enhancing glycemic control and alleviating gastric motor dysfunction, and therefore warrants further investigation in controlled clinical trials. Basal insulin may facilitate breaking the cycle of impaired gastric emptying that often leads to a fuel/insulin mismatch. Additionally, knowledge of the rate of gastric emptying allows one to use rapid-acting insulins, such as insulin lispro, insulin aspart, or insulin glulisine, given during the course of the meal or nearing its completion, to prevent meal-induced hyperglycemia. Finally, intensive therapy may prevent or delay the progression of neuropathy that can lead to gastroparesis.

CONCLUSION

Upper GI dysfunction, including gastroparesis, occurs commonly in patients with diabetes, particularly those with poor glycemic control. Hyperglycemia and poor glycemic control play a substantial role in gastroparesis, both as an etiologic factor and a clinical manifestation. Therapy to correct poor glycemic control is an important component in managing gastroparesis in patients with diabetes. However, oral antihyperglycemic medications are often ineffective and can contribute to swings in blood glucose levels, due to the temporal mismatch between medication and nutrient absorption. Therefore, basal insulin therapy combined with administration of rapid-acting insulin given at an appropriate time during the meal may be considered as an alternative treatment option to alleviate concerns regarding absorption and availability of oral agents to restore metabolic control.