Diabetes Spectrum
Volume 13 Number , 2000, Page 11
Feature Article/ Bernstein

The Diabetic Stomach: Management Strategies for Clinicians and Patients

Gerald Bernstein, MD


Abstract

Delayed gastric emptying, or gastroparesis, represents the far end of the spectrum of dysmotility disorders collectively referred to as diabetic gastropathy or the diabetic stomach. The diabetic stomach is a manifestation of diabetic autonomic neuropathy. It is characterized by potentially debilitating gastrointestinal symptoms and can also interfere with glucoregulation by contributing to a vicious cycle of delayed emptying of food or oral medications. The result may be late glycemic peaks followed by hyperglycemia and further delays in gastric emptying, or by hypoglycemia secondary to retention of food in the stomach. The goal of treatment of diabetic gastropathy is not only to prevent morbidity by controlling gastrointestinal manifestations, but also to enhance glucoregulation and, thus, better control the basic diabetic process. Herein, strategies are proposed for controlling symptoms and improving glycemic control in patients with manifestations of the diabetic stomach.


Delayed gastric emptying, or gastroparesis, is a well-known problem in patients with diabetes mellitus.1-5 It is at the far end of the spectrum of motility disorders collectively referred to as diabetic gastropathy or the diabetic stomach.

Although often believed to be more common in patients with type 1 diabetes, it is actually also quite common in patients with type 2 diabetes. In one study of diabetic patients receiving oral hypoglycemic therapy, 30% were found to have delayed emptying of solids.6

A substantial proportion of patients with either type 1 or type 2 diabetes mellitus have scintigraphic evidence of delayed gastric emptying of radiolabeled solid meals, which may or may not manifest in clinical symptoms.2,6,7 Conversely, many patents may have symptoms such as nausea, vomiting, early satiety, bloating, and abdominal discomfort or pain and yet have normal gastric emptying.

Diabetic gastropathy is thought to be a manifestation of autonomic neuropathy. The underlying cause of diabetic neuropathy, as well as other complications of diabetes, is hyperglycemia.8 While the entire gastrointestinal tract may be affected by autonomic neuropathy, we have a growing awareness of the role of the diabetic stomach in particular as the locus of a vicious cycle of delayed gastric emptying, poor glycemic regulation, and ascending hyperglycemia.6,9,10

The purpose of this brief review is to focus attention on the importance of early intervention in the development of diabetic gastropathy in order to prevent the debilitating symptoms associated with it and to improve quality of life.

PATHWAYS OF DIABETIC AUTONOMIC NEUROPATHY
The pathophysiology of the neuropathic complications of diabetes follows one of at least two pathways. The first is nonenzymatic glycosylation, which occurs when a persistently elevated blood glucose level results in the excessive glycosylation of proteins such as hemoglobin, other circulating molecules, and cellular structures.8 This leads to the development of advanced glycosylation end products, impairing the normal function of tissues including collagen and basement membranes of cells and capillaries.

The second pathway is enhanced activity of the polyol pathway, in which glucose is converted to sorbitol via the enzyme aldose reductase. This results in a decrease in tissue myoinositol, with far-reaching effects throughout the nervous system. As the integrity of cellular information, including the sodium-potassium ATPase system, is disrupted, nerve conduction velocity is diminished and the anatomy of nerve fibers is altered.11

Diabetic neuropathy can impair function anywhere in the nervous system. In the gastrointestinal tract, it causes, in effect, an autovagotomy.12 In addition, hyperglycemia results in cellular anatomic disruption throughout the gastrointestinal tract, but especially in the stomach. Nerve cells may swell with the loss of myelinated fibers, and smooth muscle cells may become rounded and hyalinized. In the stomach, motility may be reduced in the antrum and proximal stomach. There may also be pylorospasm.

Hyperglycemia also has secretory effects in the stomach, including decreased secretion of hydrochloric acid.13 The net result of these changes is a reduction in effective emptying, starting first with indigestible solids, then progressing to digestible solids, and eventually to liquids.14 The myoelectric and neuroanatomic consequences of hyperglycemia may be accentuated by abnormal secretion of various hormones, including glucagon, gastrin, cholecystokinin, and gastric inhibitory peptide in patients with diabetes.3

CLINICAL IMPACT OF DIABETIC GASTROPATHY
Gastropathy may result in a variety of potentially disabling upper gastrointestinal symptoms, among them postprandial nausea with or without vomiting, early satiety, anorexia, distention, and abdominal discomfort or pain. However, some diabetic patients with impaired gastric motility are asymptomatic.4 Also, some patients may experience these symptoms without an established delay in gastric emptying. This situation may be the earliest stage of the disease process of autonomic neuropathy; the first evidence of gastroparesis may be poor glucoregulation.

Gastropathy can contribute to bezoar formation and intestinal obstruction, ulcer development, acute gastric dilatation during ketoacidosis or after endoscopy, incapacitating vomiting, respiratory aspiration, and dehydration.3 In addition to impairing quality of life and compromising nutrition, gastropathy can wreak havoc on attempts to control blood glucose through insulin administration timed to meals.

Gastropathy may further retard the entry of oral medications, including hypoglycemics and pancreatic enzymes, into the bloodstream.15 Erratic absorption of nutrients and medications may result in misleading blood glucose readings, and significant hyperglycemia may occur if blood glucose levels rise out of proportion with the expected effects of insulin.3 On the other hand, slow absorption of food may lead to hypoglycemia. The toxic effect of hyperglycemia may acutely aggravate the gastropathy,9,16,17 possibly by reducing activity of both nerve and muscle.

Gastropathy may be underrecognized in clinical practice because the symptoms, if present, are nonspecific. Furthermore, the degree of gastropathy correlates poorly with the severity of gastrointestinal symptoms or with other evidence of peripheral neuropathy.3,5 The reverse is also true: dyspeptic symptoms do not confer a diagnosis of gastropathy in every diabetic patient.

RECOGNITION OF DIABETIC GASTROPATHY
When talking with patients with diabetes at their regular clinic or office visits or at a visit for any health reason, a review of their overall status should be routine. In a modern approach to diabetes management, which focuses on the whole patient and reviews general well-being in addition to glucose control, diabetes health care providers should always include questions to stimulate discussion of gastrointestinal symptoms or changes. Most patients do not know that gastrointestinal symptoms or signs may be related to their diabetes, and so may not mention gastrointestinal complaints or experiences during a routine review of their condition, particularly if the symptoms are not severe. Health care professionals must ask specific questions to elicit relevant information (Table 1).

Table 1. Questions to Elicit Information About
Gastrointestinal Symptoms


   Have you had any changes in appetite recently?
   Do you feel full before you've eaten much?
   Have you been having unexplained nausea?
   Have  you had unexplained vomiting, especially in the morning,
        of undigested food?
   Have you had bloating?
   Have you had heartburn?
   Have you had any abdominal cramping or pain?
   Have you been having trouble controlling your blood glucose?
   Have you gained or lost any weight recently?
   Have you experienced diarrhea or constipation recently?
.

Unusual answers or unresponsive behavior should be followed up as diligently as positive responses. Positive responses might be, "I've been feeling a little nauseous after I eat" or, "I think I've had the stomach flu for a few weeks" or, "I seem to be losing weight without trying."

The Asymptomatic Patient
As discussed earlier, hypomotility, manifested in the stomach as delayed emptying, may interfere with the absorption of oral medications and can lead to further hyperglycemia, which in turn may promote greater autonomic nerve damage in the digestive system and continue the cycle until damage is demonstrable and symptoms are evident. It has also been shown that acute elevations in blood glucose can lead to alterations in the functional capacity of all tissues (glucose toxicity).

Initially, however, symptoms may not be evident, or symptoms compatible with gastropathy may in fact indicate a different disorder, such as chronic cholecystitis or gastro-esophageal reflux. Early treatment of asymptomatic gastropathy may forestall further progression of this neuropathic condition and its direct and indirect consequences.

If a patient with diabetes has lost control of his or her glucose management for no apparent reason and has no gastrointestinal symptoms, it is nevertheless important to evaluate the possible causes for a digestive or absorption problem that could be upsetting the glycemic balance. This includes investigating the possibility of delayed gastric emptying due to a variety of causes (Table 2). A differential diagnosis algorithm should be followed to determine whether the patient has early or asymptomatic diabetic gastropathy that is interfering with a previously effective treatment regimen.

Table 2. Causes of Delayed
Gastric Emptying*


   Diffuse gastrointestinal motility disorder
   Connective tissue disease (e.g., scleroderma)
   Electrolyte imbalance (calcium, magnesium, Potassium)
   Postgastric surgery
   Idiopathic
   Infiltrative disorders (amyloidosis, lymphoma)
   Medication-induced
   •   Amylin
   •   Octerotide
   •   Tranquilizers
   •   Antidepressants
   •   Anticholinergic agents
   •   Opiates
   •   Ganglion-blocking agents
   •   Calcium-blocking agents
   •   Beta-adrenergic agonists
   •   Vincristine
   •   Aluminum hydroxie antacids
   •   Levodopa
   •   Digoxin (includes nausea; effect of gastric emptying unclear)
   Neuromuscular (polymyositis or dermatomyositis)
   Metabolic (diabetes mellitus, thyroid disease, renal insuffiency,
      adrenal insufficiency)

   *Gastric and small-bowel obstruction must first be ruled out
   in patients with gastroparesis, nausea, and vomiting.
.

Differential Diagnosis
When taking a patient history, clinicians should question the patient carefully about all associated gastrointestinal symptoms and ascertain the duration, severity, and precise nature of each symptom. A careful review of the patient's glucose control is essential. This may be accomplished by measuring glycosylated hemoglobin (HbA1c), which will provide an accurate long-term (23 months) appraisal of the patient's average blood glucose level.

Although diabetic gastropathy is most common in patients with long-standing insulin-dependent diabetes, it also occurs in patients who do not require insulin and in those in whom diabetes has been only recently diagnosed. It should be noted, however, that many patients with type 2 diabetes may have had the condition for many years before diagnosis.

Diabetic gastropathy is frequently associated with other diabetic complications, such as retinopathy, peripheral neuropathy, and nephropathy. Thus, it can be helpful to determine the degree of neuropathy in other systems.

Other components of the medical history include a careful drug history to rule out use of narcotics, tricyclic antidepressants, anticholinergics, and other agents that can slow gastric motility as listed in Table 2.

Physical Examination
A complete physical examination should include a focus on malnutrition, obstruction, and the presence of a succussion splash. Succussion is a diagnostic procedure that involves shaking the body to identify the presence of liquid and air in a body cavity. A splash is elicited when body fluid is present, in this case in the stomach.

Laboratory Testing
In ruling out nondiabetic causes or exacerbations of gastropathy, complete blood count, chemistry profile, electrolytes, and glucose testing should be performed, as well as thyroid evaluations.

If the cause of gastropathy is not clear, or if either the laboratory or physical examination results are suspicious, the next step in diagnosis is an upper gastrointestinal series or endoscopy to rule out mechanical obstruction of the duodenum, small bowel, or stomach. If the findings of these procedures are positive, the next step is to treat the cause of the obstruction. However, if bezoars—solid balls formed in the digestive tract—are found, gastropathy should not be ruled out. These obstructions may be the result of delayed gastric emptying. Bezoars may contain vegetable matter, sometimes mixed with hair, or incompletely digested or undigested food that has not been passed on through the alimentary system.

Patients with diabetes may have gastropathy concomitant with another condition that causes suspicious signs and symptoms. Among these are obstruction by an ulcer or neoplastic overgrowth. Also, mechanical obstruction can be caused by pyloric stenosis, prepyloric ulcer, scarring from prior ulcers, chronic ulcer disease, or neoplasia. Other conditions that might produce a similar symptom complex include nonulcer dyspepsia, irritable bowel syndrome, and gastritis from Helicobacter pylori.

If x-ray and endoscopy reveal no obstruction, the next step is a gastric emptying scan. The test is usually interpreted as percent of emptying at a specific time after ingestion or in the time to 50% emptying. However, delayed emptying is not the definitive diagnosis of gastropathy, but only of gastroparesis, the final stage of the process. A patient may have symptoms of gastroparesis indicating a motility disorder without delayed emptying.

TREATMENT APPROACHES
The two aspects of diabetes that are most consistently affected by gastropathy are glucose regulation (by either diet or medication) and quality of life, which may be threatened by a whole new set of limitations and rules. Excellent control of blood glucose may improve the symptoms of diabetic gastropathy. It will also minimize the effects of glucose toxicity as well as forestall further damage to autonomic nerves of the gastrointestinal tract.

Therapy may include use of agents to promote gastric emptying, facilitating glucose regulation. Controlling diabetes is important to protect autonomic nerves from ongoing damage caused by high blood glucose levels. However, when severe autonomic nerve disease is present, tight blood glucose control may be counterproductive. When long-term diabetes is present, patients may not be able to detect the usual signs of hypoglycemia, such as tingling around the mouth or tachycardia. In such circumstances, it may be preferable to be more lax in controlling blood glucose since the development of unrecognized hypoglycemia can be fatal.

Nonpharmacological Measures
Patients who have symptomatic gastropathy do best on diets low in fiber and including small, frequent meals. Caloric intake should be monitored and, if inadequate, can be augmented with high-calorie liquid supplements. Because liquids are emptied more readily than solids, liquid supplements are better tolerated than normal, or even smaller, meals. Patients may consume the majority of their calories as liquid supplements until gastropathy can be brought under control.

Clinicians can help patients accept new eating patterns, such as liberalizing the amount of starch, sugar, and easily digested carbohydrates. Patients can learn flexible insulin regimens that allow them to adjust insulin to the meal and cover carbohydrates, which are more easily digested than foods that delay gastric emptying, such as high-fiber foods, fats, and high-protein foods.

Smoking is known to delay gastric emptying. It is essential for a wide variety of health reasons to urge patients who smoke to stop. Have on hand information about local smoking cessation programs.

Exercise can be beneficial for patients with diabetic gastropathy. In addition to conferring the well-known benefits of helping to control weight and improve circulation, it may actually reduce the risk of delayed emptying by normalizing blood glucose. Patients should be advised to avoid exercise during periods of poor metabolic control, however, because blood glucose may actually rise rather than fall.

Patients and the therapeutic team should identify a blood glucose range that is as near to normal as possible while avoiding excessive hypoglycemia, such as a premeal blood glucose level of 100140 mg/dl. The relation between elevated blood glucose levels and gastropathy symptoms should be pointed out and emphasized.

Help patients to identify postprandial blood glucose levels that mark appropriate and inappropriate glucose concentration. Use these data to understand meal digestion and the time of medication for meal coverage. Plan frequent blood glucose monitoring before and after eating. Determine a goal range for HbA1c levels.

Pharmacological Therapy
The only agent currently approved for gastroparesis in the United States is metoclopramide. Unfortunately, the clinical value of this dopamine antagonist is limited by its potential adverse effects in the central nervous system (CNS), including extrapyramidal symptoms such as tardive dyskinesia.18,19 Other prokinetic agents that have been investigated in the management of diabetic gastroparesis include motilin agonists (e.g., erythromycin), acetylcholine-releasing agents (e.g., cisapride), and the peripherally acting dopamine antagonist domperidone.3,20,21 Because of its low potential for CNS adverse effects, domperidone shows particular promise as an alternative to metoclopramide.

A summary of the treatment approaches for gastropathy can be found in Table 3.

Table 3. Treatment of Gastropathy


   Treatment of the underlying disease process, if possible
   Smoking cessation
   Exercise
   Dietary therapy
      Hydration
      Small, frequent meals
      Liquid feedings (often better tolerated)
      Avoidance of fatty foods, fiber, indigestible solids
   Pharmacological therapy
      Anti-emetics
      Prokinetics
.

 

SUMMARY
Recognition of the diabetic stomach as the locus of a syndrome relating directly to glucoregulation points to the importance of prevention of the continuous cycle of gastroparesis and hyperglycemia. As we learn more about the gastrointestinal complications of diabetes, we should be able to achieve better control of glycemia while simultaneously ameliorating the symptomatic manifestations of gastrointestinal neuropathy.


References
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2Horowitz M, Edelbroek M, Fraser R, Maddox A, Wishart J: Disordered gastric motor function in diabetes mellitus: recent insights into prevalence, pathophysiology, clinical relevance, and treatment. Scand J Gastroenterol 26:673-84, 1991.

3Kinsley BT, Gramm HF, Rolla AR: Diabetic gastroparesis: a review. J Diabetic Complic 564:207-17, 1991.

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6Horowitz M, Harding PE, Maddox AF, Wishart JM, Akkermans LLMA, Chatterton BE, Shearman DJC: Gastric and oesophageal emptying in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 32:151-59, 1989.

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11Greene DA, Lattimer SA, Sima AAF: Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications. N Engl J Med 316:599-606, 1987.

12Feldman M, Corbett DB, Ramsey EJ, Walsh JH, Richardson CT: Abnormal gastric function in longstanding, insulin-dependent diabetic patients. Gastroenterol 77:12-17, 1979.

13Angervall L, Dotevall G, Lehmann K-E: The gastric mucosa in diabetes mellitus: a functional and histopathological study. Acta Med Scand 169:339-49, 1961.

14Chaudhuri TK, Fink S: Gastric emptying in human disease states. Am J Gastroenterol 86:533-38, 1991.

15Groop LC, DeFronzo RA, Luzi L, Melander A: Hyperglycaemia and absorption of sulphonylurea drugs. Lancet 7:129-30, 1989.

16MacGregor IL, Gueller R, Watts HD, Meyer JH: The effect of hyperglycemia on gastric emptying in man. Gastroenterology 70:190-96, 1976.

17Fraser RJ, Horowitz M, Dent J: Hyperglycemia stimulates pyloric motility in normal subjects. Gut 32:475-78, 1991.

18Albibi R, McCallum RW: Metoclopramide: pharmacology and clinical application. Ann Intern Med 98:86-95, 1983.

19Allan SG: Antiemetics. Gastroenterol Clin North Am 21:597-611, 1992.

20Reynolds JC: Prokinetic agents: a key in the future of gastroenterology. Gastroenterol Clin North Am 18:437-57, 1989.

21McCallum RW: Clinical pharmacology forum: motility agents and the gastrointestinal tract. Am J Med Sci 312:19-26, 1996.


Acknowledgment
Funding for this work was provided in part by Janssen Pharmaceutica, Titusville, N. J.


Gerald Bernstein, MD, is an associate clinical professor of medicine at the Albert Einstein College of Medicine, in Bronx, NY, and director of the Diabetes Management Program at Beth Israel Medical Center in New York. He is past president of the American Diabetes Association.

Note of disclosure: Dr. Bernstein has been a paid consultant to Janssen Pharmaceutica.


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