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Nutrition and diabetes.pdf

Tan Attila, M.D. and Timothy R. Koch, M.D. CONTENTS
Physiological Basis for Gastric Smooth-Muscle Activity . 428 Pathophysiology of Diabetic Gastropathy. 429 Perspectives on Evaluation of Gastric Emptying. 431 Contemporary Methods for Evaluation of Gastric Emptying . 432A.
Scintigraphic Assessment of Gastric Emptying . 433 Evaluation of Patients with Suspected Diabetic Gastropathy . 435 Treatment Strategies in Diabetic Gastropathy . 436A.
Nutrition and Diabetes: Pathophysiology and Management I. INTRODUCTION
Diabetes mellitus, with an estimated prevalence of 3 percent to 10 percent of thepopulation, is the fourth leading cause of death in the U.S. This disease complexcan affect almost every organ system, including the gastrointestinal tract. Patho-physiologic changes involving the gut can be related to either acute hyperglycemiaor chronic changes resulting from neuropathic or myopathic processes. This chap-ter will focus on the pathophysiology, diagnosis, and management of diabeticgastropathy. The clinical presentation of diabetic gastropathy is not specific and may overlap with both structural disorders and functional dyspepsia. Nausea, vomiting, bloating,early satiety, postprandial fullness, and upper-abdominal discomfort are the mostcommon presenting symptoms.1 Abdominal pain, which is likely due to gastricdistension or retension, may be an important component of the overall symptoma-tology.2 Interestingly, symptoms do not correlate well with gastric-emptying rate;therefore, an improvement in the gastric-emptying rate does not always result insymptomatic improvement, or vice versa. II. PHYSIOLOGICAL BASIS FOR GASTRIC
SMOOTH-MUSCLE ACTIVITY
Gastrointestinal-contractile activity is regulated by smooth-muscle electromechani-cal properties.3 Gastric smooth muscle, similar to other smooth muscle, is charac-terized by a voltage-tension curve. In this relationship, depolarization of smooth-muscle cell membrane results in increased smooth-muscle tonic contraction. Slowwaves, the basic gastric smooth-muscle electrical event, are periodic, regular depo-larizations from the cell’s resting membrane potential.4 A slow wave follows a setsequence during changes in resting membrane potential: initially, a rapid upstrokedepolarization, a partial repolarization, a sustained plateau potential, and then com-plete repolarization to the resting membrane potential. This chain of events is largelythe result of activation and deactivation of calcium channels and calcium-dependentpotassium channels. Only slow waves exceeding a threshold depolarization willresult in an action potential leading to smooth-muscle contraction. The basic rhythmic activity of gastric smooth-muscle cells is thought to originate from the interstitial cells of Cajal, which are located in the greater curvature at thejunction of proximal and distal stomach.5–8 Interstitial cells of Cajal are foundthroughout the gastrointestinal tract. Both extrinsic nerves innervating the stomachand the intrinsic gastric nervous system are in constant interaction with the interstitialcells of Cajal, and thus may modulate relaxation and contraction of gastric smoothmuscle. The regional variation of the relationship between electrical activity andtension development is the result of a proximal-to-distal gradient in cell resting-membrane potentials from –48 mV in the fundus to –75 mV in the pylorus.6,9 Thisdifference is likely related to differences in the density of calcium-dependent potas-sium channels, since a chemical voltage clamp involving different concentrations ofpotassium chloride can change both the resting-membrane potential and the toniccontraction of smooth muscle obtained from different regions of the stomach.10 This Pathophysiology and Management of Diabetic Gastropathy relationship has been suggested to be the electrical basis for contraction and relax-ation in canine gastric smooth muscle.10 This relationship may aid in understandingthe varying mechanical functions of different gastric compartments, as well as thepropagation of slow waves in an organized fashion from the proximal body to thepylorus. In human stomach, gastric pacemakers generate rhythmic depolarizations at a frequency of three cycles per minute, resulting in circular muscle contractions.6,11Abnormal rhythms of gastric myoelectrical activity, termed gastric dysrhythmias,originate from abnormal or ectopic gastric pacemakers. A suggested classificationsystem includes a definition for tachygastria (> 6 cycles/min), bradygastria (< 3cycles/min), bradytachyarrythmia, or absent activity.12, 13 III. PATHOPHYSIOLOGY OF
DIABETIC GASTROPATHY
In this chapter, we will address the pathophysiology, symptoms, and treatment options in patients with diabetic gastropathy. Potential pathophysiological abnor-malities include: gastric dysrrhythmias,14–16 antral hypomotility,17 pylorospasm,18 andgastroparesis.14,19 There are several potential mechanisms to explain altered gastric physiology in patients with diabetes mellitus (Table 23.1). Almost 50 percent of diabetic patientshave some form of neuropathy, such as peripheral, autonomic, proximal, or focalneuropathy, but gastrointestinal symptoms are not seen in all of these patients.20Although the pathophysiology of diabetic neuropathy has not been clearly deter-mined, the highest rates of diabetic neuropathy have been seen among patients withlong-standing disease, especially in those patients with poor glycemic control.20,21Although autonomic dysfunction, particularly vagal neuropathy,17,22–23 has been tra-ditionally regarded as the likely origin for diabetic gastropathy, morphologic abnor-malities of the vagus nerve or gastric myenteric plexus in patients with diabetesmellitus have not been routinely identified using conventional histology.24 Neurop-athies, such as axonopathy in sympathetic nerves25 and ultrastructural and morpho-metric changes in parasympathetic nerves,26 have been described in animal modelsof diabetes mellitus.27,28 A decrease in the interstitial cells of Cajal, decreasedinhibitory neurotransmitter systems containing neuronal nitric-oxide synthase, vaso-active intestinal peptide, or tyrosine hydroxylase immunopositive nerve fibers, and TABLE 23.1
Potential Pathophysiologic
Mechanisms for Diabetic
Gastropathy

Nutrition and Diabetes: Pathophysiology and Management TABLE 23.2
Effects of Hyperglycemia on Upper
Gastrointestinal Function

Decreased Lower Esophageal Sphincter Tonic Contraction increased levels of excitatory neurochemical and substance P have been observedin the gut of long-standing diabetic patients.29 Further research examining theneuropathic aspects of diabetic gastropathy is needed to better define this potentialpathophysiological feature. There is a complex relationship between glycemic control and upper-gastrointes- tinal function. Postprandial glucose levels both determine and are determined by thedelivery rate of nutrients from the stomach to the small intestine. Studies in bothhealthy individuals and diabetic individuals have revealed that hyperglycemia canaffect gastrointestinal function (Table 23.2). It has been previously shown thathyperglycemia can induce: 1) delayed gastric emptying;30–34 2) rapid gastric empty-ing;35 3) gastric myoelectrical disturbances;36 4) inhibition of migrating motor com-plexes; 5) inhibition of antral motility;37 6) pyloric contractions;38 7) inhibition ofgallbladder contractions and small-intestinal transit;39,40 8) altered esophageal motil-ity; and 9) decreased lower esophageal sphincter pressure.41 Normalization of blood-glucose levels in diabetic patients has been shown to improve gastric-emptying times.33 Previous studies have shown that secretion of thepancreatic hormone, human Pancreatic Polypeptide (hPP), is regulated by vagal-nerve input. Hyperglycemia can reduce hPP secretion, as well as gastric secretoryand plasma hPP responses to modified sham feeding in humans; these findingssupport the notion of impaired vagal-cholinergic activity during hyperglycemia.42,43Very low plasma levels of hPP have been reported in diabetic patients with cardiacautonomic neuropathy and delayed gastric emptying.44 In support of this concept,patients with poorly controlled diabetes mellitus have an increased perception ofupper-gastrointestinal symptoms, such as nausea, fullness, early satiety, and upper-abdominal pain.45–47 The exact mechanisms by which hyperglycemia leads to dis-turbances in gastric motility has not been fully delineated. Unfortunately, much of the available information on the effects of blood-glucose concentration on upper-gastrointestinal motor and sensory function has been obser-vational. Available data on potential mechanisms that may mediate these effects aresparse. Major neurochemicals involved in the regulation of gastrointestinal motor Pathophysiology and Management of Diabetic Gastropathy function include nitric oxide (NO),48–50 vagally mediated cholinergic input, and vaso-vagal reflexes.51,52 In animal studies utilizing diabetic rats, there is evidence support-ing the presence of impaired NO-synthase expression in the gastric myentericplexus.53 Delayed gastric emptying can be reversed by restoration of neuronal NO-synthase expression through addition of insulin or addition of the phosphodiesteraseinhibitor sildenafil, which increases NO signaling.54 As an additional possible mechanism, impaired antioxidant status, which is associated with accelerated liquid gastric emptying,55 has been noted in individualswith impaired glucose tolerance and diabetes.56 However, a potential associationwith delayed gastric emptying has not yet been delineated. Defective cholinergic neuromuscular transmission in the myenteric plexus,57 impaired release of vasoactive intestinal polypepetide and calcitonin gene-relatedpeptide during stimulation of enteric nerves,58 and impaired NO-mediated relaxationof the duodenum59 have been observed in diabetic rats. Indomethacin, a prostaglan-din-synthesis inhibitor, reverses gastric dysrhythmia induced by hyperglycemia.60Additional studies are needed to examine the effects of neurohumoral and cellularmechanisms, and to elucidate the effects of abnormal glucose homeostasis on gas-trointestinal motor and sensory function. Although animal studies provide insight as to the mechanisms of diabetic gas- tropathy, we should be very careful in extrapolating this information into humandisease. These observations suggest that the effect of glucose homeostasis on thegastrointestinal system is multifactorial, and more work is required to explore thepathophysiology of this common problem. In addition to the pathophysiologicaleffects of glucose homeostasis on gastrointestinal motility, factors that modulate therate of gastric emptying must be taken into consideration, such as volume, acidity,osmolarity, nutrient density, fat content, ileal fat, colonic/rectal distention, and useof medications.
IV. SYMPTOMS OF DIABETIC GASTROPATHY
Although gastrointestinal symptoms are common among diabetic patients seen indiabetic clinics,62 the prevalence of most gastrointestinal-tract symptoms is similarin persons in the community without diabetes mellitus.63 In subspecialty clinics, 76percent of diabetic patients who participated in a survey had one or more gastrointes-tinal symptoms (Table 23.3), including constipation, diarrhea, fecal incontinence,and upper-abdominal symptoms, including nausea and vomiting.62 These patientsare not immune to the presence of functional gastrointestinal symptoms, perhapsleading to an overestimation of symptom prevalence.
V. PERSPECTIVES ON EVALUATION OF
GASTRIC EMPTYING
Beaumont made the earliest comments on the rates of gastric emptying in the early19th century during his observations utilizing a patient with a traumatic gastricfistula.63 Von Luebe performed the first definitive gastric-emptying study by a single Nutrition and Diabetes: Pathophysiology and Management TABLE 23.3
Clinical Presentation
for Patients with
Diabetic Gastropathy

gastric aspiration seven hours after liquid-meal ingestion.64 Rehfuss introducedrepeated sampling of gastric contents at regular intervals.65 Hunt and Spurrell usedan aspiration technique to measure the volume of a residual test solution and theconcentration of a marker that was believed to estimate the amount emptied.66 To overcome the need for repeated gastric intubation, George described a method using double-sampling of the stomach contents.67 A marker was administered fol-lowing the initial sampling of a test meal. The marker concentration in the subsequentsampling allowed calculation of the remaining gastric volume, and the chlorideconcentration of the sample enabled determination of the rate of gastric secretion.
Recovery of a gastric marker from the duodenum, with the help of duodenal andgastric intubation through a triple lumen assembly, allowed measurement of gastricemptying. In addition, distal-duodenal sampling allowed measurement of pancreaticand biliary secretions.68 The first gastric x-ray studies concentrated on gastric motility rather than eval- uation of gastric-emptying time.69,70 Subsequent x-ray contrast studies examined theemptying of liquid barium sulfate or a radiopaque meal. With these techniques, onlycomplete gastric-emptying time of radiopaque material could be calculated, becausethe volume and density of gastric residual barium could not be determined radio-graphically. Dissociation of barium into liquid phase allowed assessment of onlyliquid emptying in tests using solid meals impregnated with barium granules.71Comparison of a barium test meal with scintigraphic gastric emptying did not reveala correlation between the magnitude of retained barium at six hours and the half-time, as well as percentage of gastric isotope remaining at six hours after ingestionof a test meal.72 Therefore, results from these two tests are not comparable.
VI. CONTEMPORARY METHODS FOR EVALUATION
OF GASTRIC EMPTYING
The presence of multiple methods to evaluate gastric emptying is an indication ofthe absence of a precise and widely available technique (namely, a gold standard).
Different techniques have limitations that need to be overcome. The followingsection critically analyzes and summarizes contemporary methods used for theassessment of gastric emptying of solids.
Pathophysiology and Management of Diabetic Gastropathy A. UPPER-GASTROINTESTINAL X-RAY SERIES
Since radiocontrast material is not a physiological meal and residual gastric bariumcan not be quantitatively measured, unless there is significant prolongation of gastricemptying, an upper-gastrointestinal X-ray series is not sufficiently sensitive to com-ment on gastric emptying. The primary role of these X-ray studies is to exclude asignificant mucosal abnormality or a gastric-outlet obstruction.
B. SCINTIGRAPHIC ASSESSMENT OF GASTRIC EMPTYING
This test is sensitive, quantitative, noninvasive, easy to perform, and a physiologicmethod. Therefore, this test is currently considered to be the gold standard for theassessment of gastric emptying in research and clinical practice. The technique isbased on the measurement of the disappearance of a radioisotope from the gastricregion during scintigraphic scanning. Evaluation of gastric emptying of solids is amore sensitive technique, since gastric emptying of liquids is usually preserved evenin the presence of abnormal solid gastric emptying. Gastric emptying of liquids canbe clinically useful if the presence of rapid gastric emptying, termed dumpingsyndrome, is suspected. There are important, basic points that alter the sensitivity and specificity of scintigraphic gastric-emptying studies.73 First, radioisotope marker should effec-tively bind to substrate, be nonabsorbable, be resistant to a wide range of pH, andbe stable during the procedure. All studies should contain the same meal volume,composition, and caloric content. A standard patient position should be preservedto prevent variations due to the effect of posture. Appropriate corrections for radio-isotope decay, three-dimensional motion of intragastric material, penetration, atten-uation, and scattering must also be considered. The use of a variety of radioisotopes, meals, and separate protocols by individual hospital centers impede the comparison of gastric-emptying studies from differentinstitutions. Most major centers use either technetium99-labeled scrambled egg orchicken liver. Simplified standardized scintigraphic gastric-emptying protocols havebeen studied in order to establish normal gastric-emptying values, as well as toscreen patients with suspected gastric dysmotility.74,75 In these studies, one-halfemptying time of a gastric radioisotope (t ) is a commonly assessed parameter. Unfortunately, scintigraphic gastric-emptying studies do not provide information with regards to the etiology and pathophysiology of gastric dysmotility. There isfrequently no direct correlation between gastric-emptying time, patient symptoms,and their response to therapy.76 C. TRACER METHODS
These methods are based on the assumption that measurement of the appearance ofa marker substance either in the blood or in expired air can serve as an indirectestimation of gastric emptying. Gastric emptying should be the rate-limiting step inthe appearance of a marker substance either in the blood or in expired air. Specifi-cally, the amount of gastric content that enters the duodenum should directly correlatewith the amount that is absorbed and appeared in the blood or expired air. It is Nutrition and Diabetes: Pathophysiology and Management assumed that the absorption, transport, and metabolism of a marker are constantboth interindividually and intraindividually. Mucosal diseases that alter absorption,pancreatic diseases, hepatic diseases, and pulmonary diseases, as well as hemody-namic variations, can alter the accuracy of these studies.
Paracetamol,77 C13-octanoic acid,78–82 and C13-acetate have been used as markers in these tracer studies.83 In contrast to scintigraphic studies, the absence of ionizingradiation in C13 breath tests enables the safe evaluation of children and pregnantwomen. Tracer methods can be used in centers without gamma camera, in physician’soffices, or at a patient’s hospital bedside. These tests are considered as test choicein certain centers in Europe, but are not widely used at this time in the U.S.
D. ULTRASONOGRAPHY
Real-time ultrasonographic evaluation of gastric emptying is based upon the mea-surement of changes in the cross-sectional area of the antrum in response to a testmeal.84–86 The return of antral area and volume to the fasting baseline are consideredto mark the final emptying time. Gastric-contraction frequency can also be measuredby ultrasonography.87 Ultrasonography has been suggested to be equivalent to anda valid alternative to the use of scintigraphy.88,89 The main advantages of this methodare that it is noninvasive, widely available, and there is absence of ionizing radiation.
This makes ultrasonography suitable for repeated examinations. However, it is time-consuming, operator dependent, and difficult to perform in obese patients. It is alsodifficult to perform this test in the presence of excessive abdominal gas, it generallymeasures liquid gastric emptying, and it is not suitable for patients following partialgastrectomy.
E. MAGNETIC RESONANCE IMAGING (MRI)
This noninvasive, radiation-free technique is very promising for providing informa-tion on gastric emptying, anatomical morphology, and gastric secretion.90,91 Improve-ments in MRI technology could allow the study of gastric motility.92,93 The cost andavailability of MRI presently limit its clinical utility. F. ELECTROGASTROGRAPHY (EGG)
EGG is a noninvasive method for the recording of gastric myoelectrical activity byplacing electrodes on the anterior abdominal wall.95 The correlation between thecutaneous EGG recordings and myoelectrical activity recorded from gastric serosalelectrodes has been previously validated.96–98 Important parameters that can beobtained with the use of EGG include different frequency components and relativepower change.99 Normal gastric slow-wave frequency is considered to range betweentwo and four cycles per minute. Conditions below this range are termed bradygastria,and above this range are termed tachygastria, or, as a general term, gastric arrhyth-mia. The relative power change corresponds to the gastric-contractile strength. Sincegastric myoelectric activity is only one of many factors that alter gastric emptying,the correlation between EGG and gastric emptying is variable.100–103 According to arecent expert consensus opinion, the positive predictive value of an abnormal EGG Pathophysiology and Management of Diabetic Gastropathy FIGURE 23.1 Suggested evaluation of suspected diabetic gastropathya. Modified from sug-
gestions of Hasler, WL and Chey, WD, Gastroenterology, 125, 1860, 2003.
to predict delayed gastric emptying averages 65 percent, while the accuracy of anormal EGG to predict normal gastric emptying averages 75 percent.104 Gastricdysrhythmias rather than gastric retension may be a better prognosticator of upper-gastrointestinal symptoms.105 Therefore, EGG may be a complementary study ratherthan a replacement for standard gastric-emptying studies. Further studies are neededto clarify the potential role for and indications for performance of EGG.
VII. EVALUATION OF PATIENTS WITH SUSPECTED
DIABETIC GASTROPATHY
Suggestions for the potential evaluation of patients with suspected diabetic gastrop-athy are outlined in Figure 23.1.
Major historical features can include a history of long-standing, insulin-dependent diabetes mellitus or a prior history of peptic-ulcer disease. The patient may have knowndiabetic nephropathy or diabetic retinopathy, which could support a diagnosis of gutautonomic neuropathy. A history of migraine headaches could support the presenceof cyclical-vomiting syndrome. Suggestive gastrointestinal symptoms of diabetic gas-tropathy may include nausea, emesis, weight loss, history of dehydration, or earlysatiety. It is quite important to try to elicit the potential use of medications that canalter gastric emptying, including use of over-the-counter, nonsteroidal, antiinflamma-tory drugs or antihistamines, or prescription narcotics or anticholinergic compounds,such as antispasmotics. Nonsteroidal, antiinflammatory drug use may be detected bya serum platelet aggregation assay. Use of narcotics may be detected by urine screening.
In young individuals, bulimia must be considered. Nutrition and Diabetes: Pathophysiology and Management On physical examination, potential evidence for a peripheral neuropathy (stock- ing, glove) should be sought. Examination of the extremities includes looking forevidence of sclerodactyly. Upon examination of the abdomen, percussion in theupper abdomen or shaking the upper abdomen may confirm the presence of asuccussion splash. It can be helpful to perform auscultation of the abdomen duringpercussion of the upper abdomen, which is designed to elicit a splashing sound dueto the presence of air and fluid in the stomach. Normally, less than 200 ml of fluidis present in the stomach following an overnight fast.
Laboratory testing should include examination for potential thyroid dysfunction, hypokalemia, chronic renal failure, or hypercalcemia. Upper endoscopy is preferredin order to exclude ulcer disease or an obstruction at the pylorus or proximalduodenum. In the absence of obstruction, solid-meal gastric-emptying studies byscintigraphy are more readily available to look for evidence of delayed gastricemptying.
VIII. TREATMENT STRATEGIES IN DIABETIC
GASTROPATHY
A. INTRODUCTION
The medical management of diabetic gastric disorders is challenging and maybecome frustrating for both clinicians and their patients. Present management prin-ciples include dietary and supportive care, optimizing care of an underlying etiology,and symptomatic relief. Medicines that alter gastrointestinal motility, such as anti-cholinergic medications and opiate agonists, should be avoided. Patients who do notrespond to dietary and lifestyle modifications, improved glycemic control, and phar-macologic agents may be candidates for endoscopic or surgical intervention forsymptomatic and supportive management. B. DIETARY AND SUPPORTIVE THERAPY
Dietary modifications, such as use of low-residue, low-lipid, high-liquid-contentmeals in small but frequent portions may decrease bezoar formation, improve symp-toms and prevent malnutrition, dehydration, and electrolyte imbalances. Somepatients may benefit from a gastroparesis diet.106 Enteral feeding can permit adequatenutritional support and hydration in those patients who do not tolerate oral intake.
Parenteral nutrition is reserved for patients in whom enteral feeding is not possible.
C. OPTIMIZING GLYCEMIC CONTROL
Hyperglycemia may cause antral hypomotility and pyloric contractions,107 affect gastricmotility,108 and impair the efficacy of prokinetic agents.109,110 Gastric-emptying disor-ders may result in erratic glycemic control due to variability of glucose availability orabsorption. Optimizing glycemic control may improve gastric dysmotility and patientsymptoms. It is not presently clear whether improved nutrition alters patient symptomsvia a mechanism that could include increased tissue levels of antioxidants.
Pathophysiology and Management of Diabetic Gastropathy D. METOCLOPRAMIDE
Metoclopromide, the only Food and Drug Administration-approved agent for thetreatment of gastroparesis, has both prokinetic and antiemetic effects through itsantidopaminergic, 5-HT3 antagonist, and 5-HT4 agonist properties.106 Its prokineticeffects are limited to the upper-gastrointestinal tract. The usual oral dose rangesfrom 5 mg to 20 mg before meals and at bedtime, and is best provided in syrupform if gastroparesis is suspected. It can also be given to patients intravenously orsubcutaneously if there is intolerance to oral intake. Although metoclopramideprovides symptomatic relief and accelerates gastric emptying,111–113 its prokineticeffects are not sustained over a long period of time.114 It appears that its symptomaticrelief may be due to its central antiemetic properties rather than being related to itsprokinetic effects. Contrary to early studies, a more recent publication did not showany symptomatic, prokinetic benefit over use of a placebo.115 Numerous adverse events affect up to 20 percent of patients, including devel- opment of acute dystonic reactions, extrapyramidal effects, drowsiness, fatigue,lassitude, restlessness, akathisia, irritability, elevation of serum prolactin level, Par-kinson-like symptom profile, and tardive dyskinesia (which may be irreversible afterthe discontinuation of the drug).113,116–118 The poor side-effect profile and inconsistentefficacy on gastric emptying may limit the long-term use of metoclopramide inpatients with diabetic gastropathy and gastric retention.
E. ERYTHROMYCIN
Erythromycin is a macrolide antibiotic that has prokinetic properties through itspresumed activation of motilin receptors.119 This agent may increase the amplitudeand frequency of antral contractions, as well as initiation of gastric phase threecontractions of the migrating motor complex.120–121 There is a motilin-receptor gra-dient in mammalian gastrointestinal tract, with the highest concentrations identifiedin the upper-gastrointestinal tract.122 Administration of erythromycin has beenreported to improve solid and liquid gastric emptying in diabetic, postvagotomy, andidiopathic gastroparesis.123–127 Intravenous doses in acute treatment range between1 to 3 mg/kg every eight hours. The commonly used oral doses are between 50 to250 mg/kg every six to eight hours. Although the optimal dosing and route ofadministration has not yet been resolved, oral regimen does not appear to be aseffective as intravenous administration.128 Unfortunately, the long-term efficacy oferythromycin has been unsatisfactory and may include the risks of long-term anti-biotic use.129 Adverse events induced by erythromycin include abdominal pain,cramping, nausea, and vomiting.
F. CISAPRIDE
Cisapride, a prokinetic agent with a mixed 5-HT3 antagonist and 5-HT4 agonistactivity, has been extensively evaluated in those patients with gastrointestinal dys-motility and gastroesophageal-reflux disease. Its effects on gastric emptying arelikely due to stimulation and coordination of antral-pyloro-duodenal motility andpossibly due to changes in gastric-outlet resistance.130–135 Although cisparide has Nutrition and Diabetes: Pathophysiology and Management been shown to accelerate gastric emptying in multiple studies, the correlationbetween improved gastric emptying and control of patient symptoms has remainedless convincing.136–139 Reports of arrythmias and sudden death related to prolongationof the QT interval resulted in significant restrictions on the routine use of cisapridein the United States.140–142 Most of these adverse events occurred in the context ofconcomitant systemic diseases or drugs that could prolong cisapride metabolism.
G. DOMPERIDONE
Domperidone, similar to metoclopromide, is an agent with both prokinetic andantiemetic properties related to its peripheral dopamine 2 receptor antagonist activ-ity; this agent blocks dopamine’s inhibitory effects on smooth muscle.143 Domperi-done is not available routinely in the United States, but it is available in Canada. Itsantiemetic property is due to its antidopaminergic action on the central chemore-ceptor trigger zone. Unlike metoclopromide, this agent does not cross theblood–brain barrier; therefore, adverse central nervous system side effects are lesslikely.144,145 Domperidone has been shown to improve liquid and solid gastricemptying and symptoms during the acute treatment of patients with diabetic gastro-paresis.144,146 The long-term treatment effects on gastric emptying and symptomshave been variable.146–148 Side effects of domperidone are related to elevated serumprolactin levels, headache, diarrhea, somnolence, and abdominal pain.143 H. TEGASEROD
Tegaserod is a serotonergic (5-HT4) receptor partial agonist and has been approvedby the FDA for treatment of women with constipation-predominant irritable-bowelsyndrome.149 Although it increases orocecal transit time with preliminary promisingresults on gastric emptying, further studies are needed to determine its role in themanagement of gastroparesis.150–152 Use of tegaserod has been associated in routinemedical care with the development of diarrhea, and possibly ischemic colitis.
I. REFRACTORY GASTROPATHY
Some patients with refractory diabetic gastropathy undergo repeated hospitalizationsfor dehydration, develop protein-calorie malnutrition, or require frequent outpatientencounters. Frequent hospitalizations and outpatient encounters for refractory nausea,vomiting, and dehydration can be major burdens to health-care costs, as well as to thepatient’s quality of life. Acceptable management of these difficult problems in refrac-tory patients has been developed in medical centers that utilize a team approach.
Management decisions can include input from an endocrinologist, a gastroenterologist,a nutritionist, a therapeutic radiologist, and a gastrointestinal surgeon. Therapeutic options that utilize pharmacologic agents are limited for the treat- ment of refractory gastroparesis. Surgically or endoscopically placed gastro-jejunalor jejunal feeding tubes provide nutrition and rehydration by using a defined formuladiet or elemental diet, and permit delivery of medications in a patient with a poorlyemptying stomach. A gastrostomy or jejunostomy port allows simultaneous decom-pression of a dilated stomach or small intestine.153,154 Unfortunately, it is extremely Pathophysiology and Management of Diabetic Gastropathy difficult and time-consuming to maintain gastrojejunostomy tubes that have beenplaced by therapeutic endoscopy. These devices are best managed in specializedcenters that have extensive experience in their utilization and limitations. The useof total parenteral nutrition can be considered, especially in those patients with ageneralized gastrointestinal motility disorder. Total parenteral nutrition should bereserved for those individuals who have not responded clinically during the use ofan elemental diet. Data on the long-term effects of parenteral and enteral nutritionand micronutrients on diabetic gastroparesis is lacking. Early data appears promising in specialty centers that have studied an external- stimulation device with temporary electrodes to pace the stomach.155–157 These stud-ies have shown improvement in symptoms and gastric emptying. Although thesedevices are available in the United States, further controlled trials are needed todefine their role in the management of refractory diabetic gastroparesis. Select patients with refractory diabetic gastroparesis have been referred to sur- gery for total gastrectomy and formation of an esophago-jejunostomy. This extensiveprocedure should be reserved for those medical centers in which there is experiencein the complex preoperative and postoperative evaluation and management of thesepatients.
IX. FUTURE STUDIES
Diabetes mellitus is a common medical problem that can result in gastrointestinaldysmotility secondary to acute hyperglycemic changes or chronic changes resultingin neuropathic or myopathic disorders. The most common presenting symptoms ofpatients with diabetic gastroparesis are nausea, vomiting, bloating, early satiety,postprandial fullness, and upper-abdominal discomfort and pain. Available clinicaltreatments are often unsatisfactory for refractory patients. Future research goalscould include studies of micronutrient supplementation or studies of improved gly-cemic control by pancreas or islet-cell transplantation. It will be important to assesstheir effects on clinical symptoms, gastric emptying, and myopathic and neuropathicchanges in the gut. REFERENCES
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REGLAMENTO PARA LA EMISION E INSCRIPCION DE VALORES REPRESENTADOS POR MEDIO DE ANOTACIONES EN CUENTA DISPOSICIONES GENERALES Artículo 1. OBJETO. El presente reglamento tiene por objeto normar los aspectos relacionados con la actuación de Central de Valores Nacional, S.A. (CVN) como registro consignatario de valores representados por anotaciones en cuenta (en adelante denom

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Servizio di Informazione sul Farmaco Servizio di Informazione sul Farmaco: importanza nella generazione di segnali d’allarme R. Ardau*, M.E. Stochino*, R. De Lisa*, G. Severino*, C. Chillotti*, M.S. Ledda**, T. Sau**, M. Del Zompo* * Sezione di Farmacologia Clinica, Dipartimento di Neuroscience “B.B. Brodie”, Università degli Studi di Cagliari – ASL 8 Cagliari

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