Gastrointestinal Symptoms inDiabetes: Prevalence, Assessment,Pathogenesis, and ManagementDiabetes Care 2018;41:627–637 | https://doi.org/10.2337/dc17-1536

If you haven’t measured something, you really don’t knowmuch about it.—Karl Pearson (attributed)

Gastrointestinal (GI) symptoms represent an important and often unappreciatedcause of morbidity in diabetes, although the significance of this burden across thespectrum of patients and the underlying pathophysiology, including the relationshipof symptoms with glycemic control, remain poorly defined. The relevance of GIsymptoms and the necessity for their accurate assessment have increased withthe greater focus on the gut as a therapeutic target for glucose lowering. This reviewaddresses the prevalence, assessment, pathogenesis, and management of GI symp-toms in diabetes, beginning with broad principles and then focusing on specific seg-ments of the GI tract. We initially performed a literature search of PubMed by usingsynonyms and combinations of the following search terms: “gastrointestinal symp-toms”, “diabetes”, “prevalence”, “pathogenesis”, “diagnosis”, and “management”.We restricted the search results to English only. Review papers and meta-analysesare presented as the highest level of evidence where possible followed by random-ized controlled trials, uncontrolled trials, retrospective and observational data, andexpert opinion.

PREVALENCE AND SIGNIFICANCE OF GASTROINTESTINAL SYMPTOMS INDIABETES

Although gastrointestinal (GI) symptoms generally are accepted as more common inpeople with diabetes than in the general population, the reported prevalence hasvaried substantially, being much higher ($70%) in most but not all outpatient samples(1–5) compared with community studies (6–11) (Table 1). These inconsistencies prob-ably reflect differences in the patient populations and the methodology used to eval-uate symptoms. Whether symptom prevalence differs substantially between type 1and type 2 diabetes is uncertain. In an Australian community study, GI symptomstended to be less common in the former, but the number of patients with type 1diabetes was small (9). In contrast, patients with type 1 diabetes in a U.S. commu-nity study experienced less heartburn but more constipation than those with type 2diabetes (7).A high prevalence of GI symptoms exists in the general population, which may be

influenced by BMI, sex, psychological comorbidities, Helicobacter pylori infection, andage (12). For example, 7–30%of adults in the community have constipation, and 7–10%suffer from bloating (13). GI symptoms, particularly those deemed embarrassing (e.g.,fecal incontinence), often are not reported unless patients are specifically questioned(13). In a community-based study of 777 Australian adults, obesity was independently

1Endocrine and Metabolic Unit, Royal AdelaideHospital, Adelaide, South Australia, Australia2Discipline of Medicine, The University of Ade-laide, Adelaide, South Australia, Australia3National Health and Medical Research CouncilCentre of Research Excellence in Translating Nu-tritional Science to Good Health, The Universityof Adelaide, Adelaide, South Australia, Australia4Department of Gastroenterology and Hepatol-ogy, Royal Adelaide Hospital, Adelaide, SouthAustralia, Australia5Faculty of Health andMedicine, University of New-castle, Newcastle, New South Wales, Australia6Division of Gastroenterology and Hepatology,Mayo Clinic, Rochester, MN7Karolinska Institute, Stockholm, Sweden

Corresponding author: Michael Horowitz, michael.horowitz@adelaide.edu.au.

Received 26 July 2017 and accepted 7 December2017.

© 2018 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered. More infor-mation is available at http://www.diabetesjournals.org/content/license.

Yang T. Du,1,2 Christopher K. Rayner,2,3,4

Karen L. Jones,1,2,3 Nicholas J. Talley,5,6,7

and Michael Horowitz1,2,3

Diabetes Care Volume 41, March 2018 627

REV

IEW

associated with an almost threefold in-creased risk of heartburn (17). A prepon-derance of GI symptoms exists in femalesin control populations (6,9), and the prev-alence of functional GI disorders also ishigher in women (18). Accordingly, theinclusion of an appropriate control groupis essential in studies related to theprevalence of GI symptoms in diabetes.

In both type 1 and type 2 diabetes, GIsymptoms occur more frequently inwomen, who exhibit higher levels of psy-chosocial distress than men (9); psycho-logical comorbidities, including anxietyand depression (9,19), are strongly asso-ciated with GI symptoms. For example,in a community study of.1,000 patientspredominantly with type 2 diabetes,symptoms were about twice as frequentin those with anxiety or depression (19).The fundamental issue of whether psy-chological distress causes symptomsand/or represents the outcome of themremains unclear.

The natural history of GI symptoms indiabetes is poorly defined. In community-based subjects with and without diabe-tes, there is substantial symptom“turnover” (;15–25% over 2 years [11]);the onset of new symptoms appears tobe counterbalanced by the disappear-ance of others so that the overall preva-lence remains relatively constant (11). Incommunity-based patients with type 1and type 2 diabetes, the onset of depres-sion was associated with about a three-fold risk of gaining GI symptoms and itsresolution, with a twofold risk of losingthem (11). Glycemic control and auto-nomic neuropathy have not been con-vincingly associated with symptomturnover (11).

GI symptoms affect quality of life in di-abetes negatively and substantially (20).Scores on all Short Form 36 subscales de-creasemarkedly as the number of distinctGI symptom groups increases (20). In pa-tients with symptomatic diabetic gastro-paresis, annual incomehas been reportedto be reduced by;30% (21). In functionalGI disorders, improvement in health-related quality of life is concordant withGI symptom improvement (13), but thishas not been evaluated in diabetes. GIsymptoms also may affect tolerability ofdiabetesmedications. In newly diagnosedpatients with type 2 diabetes, the occur-rence of GI symptoms with metforminwas associated with an ;40% decreasein adherence to therapy (22).

Tab

le1—

Rep

orted

preva

lence

ofGIsymptomsin

diabetes

Prevalen

ce(%

)

Symptom

Communitystudies

Tertiary

centerstudies

Communitycontrols

Tertiary

centercontrols

Studiesshowinga

sign

ificantdifference

Esop

hageal

Dysph

agia

6.1I5.4IV5.9V

4.0A

12.9B

1.2I1.7IV4.1V

0A7.8B

IVReflux/heartbu

rn;24

I11.6II(type1)

19.8II(type2)

13.5IV19

V8.1A;32

B44

C;5D

58.8E

10–23I23

II11

IV18

V0A

22B21

C4D

I,IV,A,B,C,E

Gastric

Abd

ominalpainor

discom

fort

8.5–12.1I15.1III13.5IV19.3V

16.1

A12.8–15.2C

15.1D

12.2–21.4I12.6III10.8IV14.6V

4.9A2.2–4.5C

10.3D

I,IV,V,A,C

Earlysatiety

26.8I3

2.2III5.2IV

6.7A

55.1B12.5D

6.1I20.2III4.3IV

1.2A49.6B5.4D

I,III,IV,A,D

Postprandialfullness

18.6

I8.6IV

16.8

A8.5I5.2IV

1.2A

I,IV,A

Bloating/abdo

minaldistension

42.3

I21.0III12.3IV29.8V

21.5

A57.8B19.6D

24.4

I15.2III11.4IV26.5V

13.4

A55.0B13.3D

I,III,IV,D

Nausea

22.7

I16.8III11.6II(type1)

6II(type2)

5.2IV11.9V

3.4A45.2B4.3D

9.1I5.5–10.6II12.7III3.5IV5.7V

1.2A32.1B2.6D

I,III,IV,V,B

Vom

iting

12.2

I5.6III1.7IV3V

9.6B

3I4.3III1.1IV2.8V

3.4B

I,IV,B

Smalland

largeintestines

Diarrhea

18.6

I0II15.6IV22

VI18.9V

34.9

A41.0B12.8C17.9D

13.4

I0II10.0IV11.4V9V

I4.9A34.9B2.2C

11.7D

IV,VI,A

,C,D

Con

stipation

14.3

I16.7II(type1)

10.1II(type2)

11.4IV

27.5

A33.7B16.1D

10.3

I11.5–13.5II9.2IV

7.3A32.1B14.6D

IV,A

Fecalincon

tinence

0.7II(type1)

4.6II(type2)

2.6IV9.9V

3.4A8.8C

1.2–1.8II0.8IV4.6V

0A0C

IV,V,C

OnlyEnglish-language

articles

withfulltextavailablefrom

PubM

ed;includ

edmatched

controlsandrepo

rted

crud

eprevalence

ratesareshow

n.I Schvarczet

al.(6):com

mun

itystud

y,qu

estion

naireno

tvalidated,

110patients

withlong-stan

dingtype1diabetes,2

10controls.IIMalekietal.(7):com

mun

itystud

y,used

validated

BDS,138patientswithtype

1diabetes

and170controls,217

patientswithtype

2diabetes

and218controls.IIIRicciet

al.(8):com

mun

itystud

y,face-to-face

interview,483

patientswithdiabetes,422

controls.IVBytzeret

al.(9):com

mun

itystud

y,validated

question

nairethat

was

basedon

theBDQ,

423patientswithtype

1diabetes

(5.2%)andtype

2diabetes

(94.8%

),8,185controls.VIcks

etal.(10):commun

itystud

y,interviewqu

estion

sderivedfrom

Talleyet

al.(1992)qu

estion

naire(14),544

patientswith

type

2diabetes,544

controls.V

I Quanet

al.(11):commun

itystud

y,used

validated

DBSQ

,51patientswithtype

1diabetes,128

patientswithtype

2diabetes,65controls.AKo

etal.(1):tertiaryreferralcenter,interview

question

sderivedfrom

Horow

itzet

al.(1989)qu

estion

naire(15),149

patientswithtype

2diabetes,82controls.BMjornheim

etal.(2):tertiaryreferralcenter,questionn

aire

from

Ruthet

al.(1991)(16),364

patients

withtype

1diabetes,242

controls,highcrud

eprevalence

ratesprob

ablybecausepatientswho

answ

ered

mild,m

oderate,or

severe

toanyqu

estion

wereconsidered

tohave

thesymptom

.CAbidet

al.(3):tertiary

referralcenter,questionn

aire

from

Talleyet

al.(32),250patientswithtype

2diabetes,264

controls.Dde

Kortet

al.(4):tertiaryreferralcenter,G

astrointestinalSym

ptom

RatingScaleandPA

GI-SYM

question

naires

used,280

patientswithtype

1(28.9%

)andtype

2(71.1%

)diabetes,355

controls,prevalenceratesforclinicallyrelevant

GIsym

ptom

s(GastrointestinalSym

ptom

RatingScalescore$3,PA

GI-SYM

score$2).

E Haet

al.(5):tertiaryreferralcenter,G

ERDsymptom

sevaluatedby

usingFrequencyScaleof

theSymptom

sof

GERDqu

estion

naire,258patientswithtype2diabetes,184

controls.

628 GI Symptoms in Diabetes Diabetes Care Volume 41, March 2018

Fromapopulation perspective, GI symp-toms represent a substantial and probablyincreasing contribution to health care costsrelated to diabetes, including outpatient/inpatientservicesanddiagnostic/proceduralinterventions. In the U.S., diabetic gastropa-resis accounted for almost 8,000 inpatientdays, costing.$11million in a single statein 1998 (23).

ASSESSMENT OF GI SYMPTOMS

Methods for determining the presenceand severity of GI symptoms have evolvedsubstantially over recent decades, particu-larly in the area of functional GI disorders(e.g., irritable bowel syndrome [IBS], func-tional dyspepsia),which after theexclusionof structural disease, are defined exclu-sively by symptoms and, unlike diabetes,lack objective biomarkers (18). Althoughvalidated questionnaires are used widelyin diabetes (e.g., to assess neuropathy)(24),most studies, including those relatedto therapeutics, have not used validatedtools to assess GI symptoms, and assess-ment has been based on self-report,which is known to be unreliable (25).For example, in trials of glucagon-likepep-tide 1 receptor agonists (GLP-1 RAs), adrug class associated with both upperand lower GI adverse effects (26), col-lection of GI symptom data has mostlybeen by self-report. Moreover, patientswith significant GI symptoms usuallyhave been excluded from such studiesby poorly defined criteria. The majorityof studies also do not report the informa-tion provided to patients at enrollment,whichmaybe important. In functional gutdisorders, such as IBS, the placebo re-sponse rate is high (;30–40%) (27) andmay be up to 50% in studies related to themanagement of symptomatic diabeticgastroparesis (28). Self-reporting ofsymptoms also may be influenced by anexpectation of adverse GI effects (noceboeffect) or of one drug being less prone toGI effects than another (precebo effect)(27). Furthermore, although validatedquestionnaires are considered the goldstandard for assessment of symptoms,they are limited by recall bias and areless than optimal in monitoring changesin symptoms over time and across con-texts. Ecological momentary assess-ment, which involves repeated samplingof individuals’ symptoms in real timeand in their natural environment, mayminimize the limitations of traditionalquestionnaires (29).

Individuals’ interpretation of terminol-ogy such as diarrhea and constipation,varies widely, encompassing altered stoolform, changes in the frequency of defeca-tion, and/or symptoms such as fecal ur-gency or straining (30). Therefore, precisedefinitions and explicit language must beused. For example, in the Diabetes BowelSymptomQuestionnaire (DBSQ) , diarrheais defined as loose or watery bowel move-ments occurringmore than one-quarter ofthe time (30). Language and culture alsoinfluence the expectation, perception,and reporting of symptoms. Societal atti-tudes toward scientifically based medi-cine may amplify the communicationgap beyond that of just a language barrierper se to result in underreporting, ormisreporting, of symptoms. Regulatorybodies, including the U.S. Food and DrugAdministration (FDA) and EuropeanMed-icines Agency now, appropriately, requirethe use of validated questionnaires whenassessing treatment outcomes in studiesof functional GI disorders (31). An instru-ment to assess GI symptoms in diabetesmust address all relevant symptoms(content validity), relate to other meas-ures of symptom improvement (constructvalidity), yield comparable results whenretested on subjects with stable symp-toms (reliability), detect clinically mean-ingful changes (longitudinal constructvalidity or responsiveness), and relate toclinically meaningful indicators (31). Ide-ally, it should be developed with the in-volvement of patients and include a rangethat allows detection of meaningfulchanges without being compromised byfloor and ceiling effects (i.e., failure todiscriminate among people at the lowerand upper ends of the measurementcontinuum) (31). Some instruments focussolely on the GI dimension, whereasothers are multidimensional, encom-passing socioeconomic and psychologicaldomains, and are linked to quality-of-lifeassessments. Examples of the latter in-clude the Bowel Disease Questionnaire(BDQ) (32) and the Patient Assessmentof Upper Gastrointestinal Symptom Se-verity Index (PAGI-SYM) (33). The DBSQwas developed from the BDQ (30). TheGastroparesis Cardinal Symptom Indexdaily diary (34) can be used to assesssymptoms in gastroparesis, and the Dia-betic Gastroparesis Symptom Severity Di-ary, which consists of seven items and asymptom severity composite score, hasbeen validated specifically for use in trials

of therapies for diabetic gastroparesis(35).

In summary, patientswith diabetesmustbe specifically questioned about GI symp-toms by using validated questionnaires. Fu-ture trials of diabetes therapeutics shouldreport the information provided to enrolledpatients.

PATHOGENESIS OF GI SYMPTOMSIN DIABETES

In the broadest sense, GI symptoms indiabetes can be regarded as the outcomeof a disordered gut-brain axis. Potentialpathogenic factors include autonomic(vagal andmyenteric) and peripheral neu-ropathy, structural and functional centralnervous system (CNS) changes (diabeticencephalopathy), acute and chronic dys-glycemia, psychological dysfunction, andpharmacotherapy. Specific pathogenicfactors relevant to each section of the GItract are discussed subsequently.

The putative association of GI symp-toms with disordered GI motor functionarising from irreversible autonomic (va-gal) neuropathy is long-standing (11).The few tests that specifically evaluateGI autonomic function (e.g., measure-ment of the pancreatic polypeptide re-sponse to sham feeding, postprandialsuperior mesenteric artery blood flow re-sponses) are not widely available (11),and standardized tests of cardiovascularreflexes typically are used as a surrogate(11). Autonomic neuropathy, as assessedby these tests, is closely associated withsymptoms and signs of peripheral neu-ropathy in diabetes (11). However, therelationships between GI symptoms andthe presence of autonomic or peripheralneuropathy are weak (1,2,7).

Structural and functional changes inthe CNS may influence the perceptionand generation of symptoms, with evi-dence of both gastric hypersensitivity (36)and rectosigmoid hyposensitivity (37).Brock et al. (37) investigated neurophysi-ological changes in a predominantlytype 1 diabetes cohort and reported evi-dence of rectosigmoid hyposensitivityandbilateral anterior shifting of the insulaand cingulate sources of brain activity,which correlated positively with post-prandial fullness and nausea.

Acute changes in blood glucose concen-tration affect both GI motor function andthe perception of sensations arising fromthe gut (38). For example, acute hyperglyce-mia increases proximal gastric compliance,

care.diabetesjournals.org Du and Associates 629

slows gastric emptying, and increases per-ceptions of fullness, nausea, and bloating(38). Modest increases in blood glucoseconcentration, within the physiologicalpostprandial range (;8 mmol/L or 140mg/dL), which slow gastric emptying(39), also may affect gut sensations (38).Ketosis and ketoacidosis can cause abdom-inal pain, perhaps reflecting profoundslowing of gastric emptying, or ileus as aresult of metabolic acidosis and associatedelectrolyte abnormalities. Studies areneeded to clarify the magnitude of theseeffects (40). However, a limitation ofmany studies related to GI symptomsand/or motility in diabetes is that bloodglucose concentrations at the time oftesting were not measured let alone con-trolled. Data on the impact of chronic gly-cemic control, as assessed by glycatedhemoglobin, on GI symptoms are limitedand inconsistent (6). Whether the inci-dence of symptoms and disordered mo-tility will diminish with improvement inchronic glycemic control remains to bedetermined.

ESOPHAGUS

Presentation and PrevalenceEsophagealmotility disorders can presentwith symptoms of gastroesophageal re-flux or dysphagia; other specific causesof dysphagia must be excluded. Patientswith diabetes are at an increased risk foresophageal candidiasis, which may pres-ent with odynophagia. There is a highprevalence of esophageal dysmotility indiabetes, but only a minority of patientshave symptoms (41). Gastroesophagealreflux also is frequently asymptomatic,particularly in the presence of establishedautonomic neuropathy (41). Esophagealdysfunction may result in regurgitation,dysphagia, and pill-induced esophagealerosions and strictures (41). Cough andworsening respiratory function may re-flect undetected reflux disease.Whetherthe risk of Barrett esophagus is increasedin diabetes is contentious, but in a largeepidemiological study, type 2 diabeteswas associated with a 49% increasedrisk independent of other known riskfactors (42).

PathophysiologyScintigraphic and manometric studies in-dicate that esophageal motility and tran-sit are abnormal in 40–60% of patientswith long-standing diabetes, but the cor-relation with symptoms is weak (41).

Biomechanical changes in the wall struc-ture, including increased stiffness, re-duced compliance, and diminishedsensitivity to distension of the esophagealbody, have been observed in long-standingdiabetes, which correlated with symp-toms of postprandial fullness/early sati-ety and were associated with peripheralneuropathy (43).

DiagnosisThe investigation of esophageal symp-toms in patients with diabetes follows asimilar approach to patients without di-abetes. Reflux disease can be diagnosedon clinical grounds alone in the setting oftypical symptoms; response to antisecre-tory therapy is an unreliable criterion(44). Endoscopy evaluates mucosal com-plications, whereas esophageal motorfunction can be assessed with manome-try, and contrast video swallow radiologyhighlights both structural and functionaldisorders. pH studiesmay be useful in theassessment of gastroesophageal refluxwith or without impedance monitoring,which allows transit of air and fluid tobe evaluated (45).

ManagementDysphagia and gastroesophageal refluxdisease (GERD) are treated similarly in di-abetes as in the general population. Evi-dence is inconsistent about the efficacy ofprokinetic drugs for treating symptomsattributable to dysmotility or acid reflux.Patients with delayed transit shoulddrink a glass of water immediately aftertaking oral medications to reduce the riskof pill esophagitis.

STOMACH

Presentation and PrevalenceThe broad term gastropathy sometimesis used to describe symptoms (includingpostprandial fullness, early satiety, bloating,nausea, vomiting, and upper abdominalpain [Table 1]) apparently referable tothe stomach, irrespective of whether gas-tric emptying is abnormally slow (46). Incontrast, gastroparesis can be defined asthe objective finding of delayed gastricemptyingwithout gastric outlet or duode-nal obstruction (47); whether symptomsare required for the diagnosis is debatedand has an important bearing on preva-lence. For example, in a U.S. population-based study, the incidenceof symptomaticgastroparesis over a 10-year period was;5% in type 1 diabetes and 0.2% in con-trols (48), whereas follow-up of patients

with long-standing type 1 diabetes fromthe Diabetes Control and ComplicationsTrial (DCCT) showed that 47% had de-layed gastric emptying, which was associ-ated with GI symptoms, albeit weakly(49). Among patients with type 2 diabe-tes, obese women with longstanding,poorly controlled diabetes seem particu-larly predisposed (50). Gastric emptyingand symptoms appear to be relatively sta-ble as assessed by follow-up of small co-horts for up to 25 years (51). Otherstudies compared patients with intracta-ble diabetic and idiopathic gastroparesis(52). Vomiting may be more prominentin the former: ;50% experience weightloss, although weight gain occurs in up to25% (52);.50% with severe diabetic gas-troparesis present with acute symptomonset; and the remainder experience in-sidious symptoms. About one-third havechronic symptoms with periodic exacerba-tions, and one-third experience chronicworsening symptoms (52). The clinicianmay find it helpful to consider clinicallysignificant gastroparesis as delayed gas-tric emptying associated with symptoms,interfering with nutritional status and/orleading to abnormal changes in postpran-dial glycemic patterns (e.g., not matchingthe usual kinetics of rapid-acting insulinpreparations and/or erratic peaks andtroughs in plasma glucose concentrations).

PathophysiologyThe pathophysiology of symptoms in di-abetic gastropathy is complex and in-cludes not only delayed gastric emptyingbut also impaired gastric accommoda-tion, visceral hypersensitivity, and gastricdysrhythmia (the stomach, like the heart,has a pacemaker) (38,46,53), although theassociation with any of these abnormali-ties is weak (46,53,54). Delayed gastricemptying should, therefore, be regardedas a marker of GI dysfunction ratherthan a direct cause of symptoms, and pa-tients with typical symptoms may haverates of emptying in the normal rangeor that are even abnormally rapid (55).

Themotor abnormalities associatedwithdiabetic gastroparesis include impairedpostprandial accommodation, antral hypo-motility, excessive pyloric pressure, and dis-ordered antroduodenal coordination (55).Impaired gastric accommodation mayplay a role in bloating (55), and the per-ception of gastric distension is increasedin patients with type 1 diabetes with(55) and without (38) symptoms. The

630 GI Symptoms in Diabetes Diabetes Care Volume 41, March 2018

availability of full-thickness gastric biopsysamples frompatientswith severe gastro-paresis has demonstrated heterogeneousabnormalities (56), the most consistent ofwhich is a reduction or loss of the intersti-tial cells of Cajal (the pacemaker cells),which correlates with the magnitude ofthe delay in gastric emptying (56); otherabnormalities include immune infiltratescontaining macrophages, decreased in-trinsic nerve fibers, loss of neuronal nitricoxide synthase, and a thickened basallamina around nerves and smoothmusclecells (56) (Fig. 1). Whether these changesrepresent most patients with delayedgastric emptying secondary to diabetesis uncertain.

DiagnosisThe determination of when to evaluatepatients with diabetes and symptoms ofgastropathy may be challenging, particu-larly given the recognition that upper GIsymptoms occur frequently but are notstrongly predictive of disordered gastricemptying. A history of vomiting food con-sumedmany hours earlier is highly sugges-tiveof gastroparesis but rare. Theexclusionof the rumination syndrome, characterizedby effortless regurgitation of food (47), isimportant. Physical examination is usuallyunremarkable, except in severe caseswhere gastric distension and/or a succus-sion splash may be found. Upper GI en-doscopy usually is required to excludegastric outlet or duodenal obstruction aswell as mucosal disorders (47).Measurement of gastric emptying be-

fore initiating therapy is appropriate.Many causes of gastroparesis exist apart

from diabetes, including the use of med-ications (e.g., opioids); however, thewith-drawal of medications that could slowgastric emptying is not always feasible.The gold standard technique for themeasurement of gastric emptying is scin-tigraphy (47), with stable isotope breathtesting being an alternative option (47).Progress has been made toward interna-tional standardization of scintigraphy,with a recommendedmeal of eggs, bread,and jam labeled with 99mTc-sulfur colloidand scintigraphic imaging at 0, 1, 2, and4 h postprandially (47). Measurementof gastric emptying ideally should beperformed during euglycemia and, at aminimum, with regular blood glucosemonitoring (47). A diagnosis of gastro-paresis can be made if meal reten-tion is .90% at 1 h, 60% at 2 h, or 10%at 4 h (47). Stable isotope gastric empty-ing breath tests that use 13C-labeled sub-strates (typically 13C-octanoic acid or13C-Spirulina platensis [blue-green algae])can be performed at the point of care,with subsequent centralized analysis ofstored breath samples, anddonot involveradiation exposure (57). This test relies onthe assumption that gastric emptying isthe rate-limiting step in the excretion of13CO2 after ingestion of a meal incorpo-rating a 13C substrate (57). The modifica-tion of the gastric emptyingbreath test byusing the Wagner-Nelson method hasstrengthened the correlationwith scintig-raphy (58). Magnetic resonance imagingis a reliable, noninvasive method for eval-uating gastric emptying and motilitybut remains a research technique (59).Other techniques for assessing gastric

motility/emptying in diabetes are sum-marized elsewhere (57).

ManagementManagement of symptomatic diabeticgastroparesis should be individualized,influenced by the severity of symptoms(55), and may not necessarily focus onacceleration of gastric emptying (Fig. 2).Anecdotally, treatment is most effectivewith a multidisciplinary team, but out-comes often are suboptimal, perhaps re-flecting the heterogeneous nature of thepathophysiology. Much of the evidencerelated to treatment of diabetic gastropa-resis is alsoof poor quality, particularly fortherapies that have been used for manyyears where formal reevaluation wouldnow be considered unacceptable. Impor-tant goals of treatment in addition tosymptom relief include improving nutri-tional status, addressing weight loss,and optimizing glycemic control.

Symptom improvement may be facili-tated by nonpharmacological interven-tions, including dietary modifications,albeit without a robust evidence base.These include liquid-based or small-particle-size (55) meals (with the ratio-nale that emptying of liquids often isless impaired than that of solids), reduc-ing nondigestible fiber and fat, and havingsmall, frequent meals. A trial of nasojeju-nal tube feeding should be considered inmalnourished patients with refractorysymptoms (55), which also allows theevaluation of response to enteral feedingbefore more permanent solutions, suchas a percutaneous jejunal feeding tube,are considered. Ensuring adequate hydra-tion and maintaining electrolyte balanceis imperative. Although intuitively it is log-ical for glycemic control to be optimized(55), the efficacy of this is not established.Uncontrolled data, however, support theuse of continuous subcutaneous insulinpump therapy in diabetic gastroparesisto improve glycemic control and reducehospitalization (55).

Current pharmacological therapies fordiabetic gastroparesis have limited efficacyand few head-to-head comparisons havebeen done. Some therapies aim to acceler-ate gastric emptying, whereas others strivefor symptom control. Given that these twoobjectives do not usually correlate well,a focus on therapies with evidence ofsymptomatic benefit is appropriate.

Prokinetics most commonly used totreatgastroparesis includemetoclopramide

Figure 1—Hematoxylin and eosin staining of the intermyenteric plexus from patients with gastro-paresis. a: Normal ganglia and nerve fibers (original magnification340). b: Moderate lymphocyticinfiltrate in the intermyenteric plexus (original magnification340) in a patient with severe diabeticgastroparesis. Images reprinted with permission from Harberson et al. (56).

care.diabetesjournals.org Du and Associates 631

(a dopamine D2 antagonist/5-HT4 agonist/5-HT3 antagonist) and erythromycin or azi-thromycin (both motilin agonists). Alongwith cisapride and domperidone, bothhave demonstrated symptomatic benefitin trials, although many of these trialswere small, uncontrolled, and not per-formed exclusively in patients with dia-betic gastroparesis. In general, theseagents appear to reduce symptoms andaccelerate gastric emptying by 25–70%(60). Concerns exist about adverse ef-fects, including tardive dyskinesia withmetoclopramide (which has led to anFDA black box warning highlighting thisrisk, especially in the setting of long-termor high-dose use) and prolongation ofcorrected QT interval with domperidone(not available in the U.S.) and metoclo-pramide; cisapride (a 5-HT4 agonist/

5-HT3 antagonist) was withdrawn fromthe market in 2000 because of a risk offatal arrhythmias. Furthermore, tachy-phylaxis limits the use of agents such asmetoclopramide and the motilin agonists(attributable to downregulation of themoti-lin receptor [61]), including erythromycin,for prolonged periods (62). Metoclopra-mide may be administered subcutane-ously, potentially to abort acute attacksof vomiting (55), and as a nasal spray wasrecently reported to reduce symptomsreferable to diabetic gastroparesis inwomen but not men (63). Anecdotal evi-dence suggests that antiemetics are use-ful in themanagement of nausea and thatcombining a prokinetic and antiemetic iscommon practice.

The motilin agonists are an ongoingfocus of drug development. Parenteral

administration of erythromycin (;3 mg/kgintravenously) may be useful in initialmanagement (64). The outcome of a trialof a small-moleculemotilin agonist, cami-cinal, in diabetic gastroparesis is awaited.Ghrelin, thefirst identified circulating hor-mone that controls hunger, also is involvedin regulating gastricmotility. Relamorelin, asubcutaneously administered pentapep-tide ghrelin agonist, was shown to reducevomiting and accelerate gastric emptyingmodestly compared with placebo (65),with results of another phase 2B trialpending publication. Newer 5-HT4 ago-nists have greater selectivity for the GItract over cardiacmuscle and include pru-calopride, which has shown efficacy inpreliminary studies in gastroparesis (66),and velusetrag, which accelerates gastricemptying in patients with chronic consti-pation (67) and is undergoing trials in gas-troparesis. The tricyclic antidepressantnortriptyline was no better than placebo forsymptomimprovement ingastroparesis (68).

Pyloric interventions have been ap-plied to themanagement of gastroparesison the basis of observations of pyloro-spasm in some cases and the recognitionthat pyloric contractions play a majorphysiological role in regulating gastricemptying (55). Intrapyloric injection ofbotulinum toxin was not superior to pla-cebo in two randomized controlled trials(69). Transpyloric stents, laparoscopic py-loroplasty, and gastric peroral endoscopicmyotomy have been advocated on thebasis of uncontrolled studies but requirerandomized sham-controlled trials to es-tablish their efficacy.

Gastric electrical stimulation (EnterraTherapy; Medtronic, Minneapolis, MN)may improve symptom severity in refrac-tory diabetic gastroparesis (69) and is ap-proved in the U.S. as a compassionatetreatment modality. Although one blindedtrial failed toestablish adifference in symp-toms during randomized periods with thestimulator turned on or off (70), a recentmulticenter French randomized controlledtrial reported symptomatic benefit forvomiting in a cohort of patients with type 1and type 2 diabetes when assigned tothe stimulator being turned on (71). Un-controlled data suggest that pancreatictransplantation may be associated withimprovements in both symptoms and gas-tric emptying (72). Gastrectomy generallyis not recommended (69).

The FDA recently provided clear guide-lines for trials related to gastroparesis

Figure 2—Treatment algorithm for diabetic gastroparesis. PRN, as needed.

632 GI Symptoms in Diabetes Diabetes Care Volume 41, March 2018

(e.g., design, participants, outcomemeas-ures) (73), which has already led to sub-stantial improvements in study quality(66). These guidelines include recommen-dations that patients with diabetic andidiopathic gastroparesis are not includedin the same study and that blood glucoseconcentrations should be stable in dia-betic gastroparesis (73).

SMALL AND LARGE INTESTINES

PathophysiologySmall intestinal transit often is abnormalin patients with diabetes andmay be slowor rapid (74); the former may predisposeto small intestinal bacterial overgrowth(SIBO), itself a cause of malabsorptionand diarrhea. Up to 80% of patients withdiabetic gastroparesis have abnormalsmall intestinal motility (55). Loss of ad-renergic innervation of the small intestinehas been reported in diabetic rodentmodels and may contribute (75). Al-though large intestinal motility has beenless well studied in diabetes, colonic tran-sit often is delayed (74). Colonic tissue hasrevealed myenteric neuronal loss and ev-idence of increased oxidative stress (76).Anorectal dysfunction in diabetes encom-passes impaired external anal sphincterfunction and diminished rectal sensationto distension (74). As with the upper GItract, small intestinal and colonic motorfunction are influenced by acute changesin blood glucose (77).

DiagnosisMedications always should be consideredas the cause of diarrhea (see GI SYMPTOMS

AND GLUCOSE-LOWERING DRUGS). The gold stan-dard for the diagnosis of SIBO is jejunalfluid aspiration and culture, but this re-quires endoscopy and a potential existsfor oropharyngeal contamination andfalse-negative results if patchy over-growth is missed. Noninvasive methodsof diagnosis include hydrogen breathtests, which are reasonably specific(80%) but lack sensitivity (40%) (75) be-cause some bacteria do not produce H2

from glucose. Celiac disease occurs in1% of the general population and is ap-proximately five times more prevalentin type 1 diabetes (78), so serologicalscreening is justified in this population,even in the absence of symptoms. Pan-creatic exocrine insufficiency alsomust beconsidered, particularly because the prev-alence of pancreatitis is increased two tofour times. Although fecal elastase levels

have been reported to be reduced in up toone-third of patients with type 1 and 2 di-abetes (75), evidence that supports theuse of pancreatic enzymatic replacementis lacking particularly because the major-ity of patients do not have clinically sig-nificant exocrine insufficiency (75).Microscopic colitis may be more prevalentin diabetes (75) and is diagnosed with co-lonoscopic biopsy. Otherwise, causes ofdiarrhea that affect the general popula-tion, including common causes such asIBS, also can affect patientswith diabetes.

The diagnostic approach to constipationand fecal incontinence in diabetes is similarto that for thegeneral population. Redflagsformalignancy should dictate careful inves-tigation. Medications that could induceconstipation, such as opiates, anticholiner-gics, and calcium channel blockers,must berecognized as potential causative agents.Investigation with anorectal manometryto identify a defecatory disorder and/or aradiopaque marker test to identify slowtransit constipationmaybewarranted (79).

ManagementAs with the upper GI tract, the generalprinciples of management involve cor-rection of fluid and electrolyte deficits,improvement of nutritional status, opti-mization of glycemic control, treatmentof specific causes if found, and symptomrelief. Antibiotics, such as rifaximin (themost studied antibiotic in the context ofbacterial overgrowth), eradicate bacterialovergrowth in up to 84% of patients after10–14 days of therapy (80) and improvesymptoms in 30–90%. Other antibiotics,including amoxicillin-clavulanate, doxycy-cline, quinolones, and metronidazole, arewidely used, largely on an empirical basis.SIBO may recur if attention is not alsogiven to the underlying motility disorder.Pancreatic enzyme supplementationshould be tried in patients with clear ev-idence of exocrine insufficiency; besidesthe potential for improving steatorrhea/diarrhea, beneficial effects may occurfrom postprandial glycemic control as aresult of restoration of the hormonalfeedback (including incretin release)from the small intestine, although Knopet al. (81) found no difference in post-prandial glucose despite increases inGLP-1, glucose-dependent insulinotropicpolypeptide, and insulin after pancreaticenzyme supplementation.

Symptomatic relief of diarrhea may re-quireopioidmedication, although judicious

use for limited periods is advisable. Loper-amide, which acts on m-opioid receptors,reduces diarrhea and slightly increases in-ternal sphincter tone and may be helpfulin preventing fecal incontinence, espe-cially when outside the home (82). Elux-adoline, which acts on diverse opioidreceptors, has recently been approvedby the FDA for the management of diar-rhea associated with IBS (83). Tricyclicantidepressants may be beneficial be-cause of their anticholinergic properties.Case reports have supported the efficacyof somatostatin analogs in otherwiserefractory, apparently secretory, diarrheain patients with autonomic neuropathy(84). Clonidine, an a-2-adrenergic RA iseffective in the treatment of refractorydiarrhea (85), but patients must be mon-itored for hypotension, especially whendehydrated.

Constipation may respond to a high-fiber diet or traditional laxatives such aslactulose. Few pharmacological agentshave been specifically evaluated. Lubipro-stone, a prostaglandin derivative thatactivates chloride channels, has beenshown to increase spontaneous bowelmovements and decrease colonic transittime in patients with diabetes and consti-pation over an 8-week period (86). Lina-clotide, which acts through guanylatecyclase C, is FDA approved for the man-agement of constipation but has not beenevaluated specifically in diabetes.

GI SYMPTOMS ANDGLUCOSE-LOWERING DRUGS

Several diabetes-specific medications, in-cluding metformin, a-glucosidase in-hibitors, and, more recently, the amylinanalog pramlintide and GLP-1 RAs arestrongly associated with GI adverse ef-fects (Fig. 3). As discussed, these studieshave almost exclusively assessed symp-toms by self-report, compromising datainterpretation. Whether preexisting GIsymptoms increase the propensity for ad-verse GI effects from these drugs remainsto be determined.

The capacity of metformin to cause GIsymptoms is well-recognized. Diarrheaappears to be most common, followedby nausea, flatulence, indigestion, vomit-ing, and abdominal discomfort (87). Ratesof diarrhea resulting from immediate-release metformin were 8–24% in trialsinvolving treatment-naive patients, and20–60% in real-world observational stud-ies (87). Diarrhea is usually not nocturnal

care.diabetesjournals.org Du and Associates 633

or strongly dose related, ceases whentherapy is withheld, and occurs typicallyat initiation of treatment (87). Increasingevidence shows that metformin’s mainsite of action is the gut rather than theliver (87). Putative mechanisms for GIsymptoms include effects on the micro-biome, intestinal glucose turnover, bilesalt malabsorption, and stimulationof GLP-1 (87). Comorbidities, includingasymptomatic chronic gastritis andH. pylori infection, and other diabetesmedications may increase the potentialfor GI symptoms with metformin (87).Moderate-quality evidence shows thatswitching to extended release metforminmay alleviate GI intolerance to the imme-diate release formulation (87). More re-cently, the once-daily delayed-releasemetformin, by achieving similar efficacyas metformin extended release but atmuch lower dose and plasma exposure,

holds promise in causing fewer GI symp-toms, but this has yet to be convincinglyborne out in trials (87).

The a-glucosidase inhibitors (e.g.,acarbose, miglitol) frequently induce GIsymptoms, including flatulence, loosestools, abdominal distension, and diar-rhea (88), reflecting the presence of un-digested complex carbohydrates in thelarge intestine, which undergoes bacterialfermentation with production of short-chain fatty acids and hydrogen (88). Inclinical trials, the prevalence of GI symp-toms with acarbose has varied widely;symptoms tend to subside with contin-ued treatment and adherence to dietaryrestrictions (88). Lipase inhibitors suchas orlistat and sugar alcohols such assorbitol and mannitol also may causediarrhea (75).

Pramlintide, a synthetic analog of amy-lin (cosecreted with insulin from b-cells)

was FDA approved in 2005 for use in bothtype 1 and 2 diabetes and slows gastricemptyingmarkedly (89). Nausea occurs in10–60% of cases, particularly with higherdoses, but is usually transient (90).

GI symptoms are the most commonlyreported adverse effect of GLP-1 RAs,although they are usually transient. GIadverse effects only infrequently (1–6%) necessitate cessation of treatment(26), but this figure may be higher (upto 15%) (89). Nausea is apparently themost common adverse effect, whichwas reported in up to 50% of subjects inclinical trials (26). Vomiting and diarrheaoccur in ;5–20% (26). A recent system-atic analysis (91) indicated that nauseaand vomiting are dose dependent, occurmore frequently with short- rather thanlong-acting GLP-1 RAs, and occur whenmetformin is used concurrently. In con-trast, diarrhea is apparently not dose de-pendent and occurs more often withlonger-acting compounds (91). Higherrates of nausea and vomiting with short-than with long-acting GLP-1 RAs are un-likely related todifferences in their effectson gastric emptying (i.e., more markedand sustained slowing with short-actingdrugs [26]), particularly given the weakassociation between upper GI symptomsanddelayed gastric emptying (53); rather,nausea probably is primarily centrallyme-diated (26). Accordingly, differencesamong compoundsmay reflect the greaterpropensity for smallermolecules (e.g., ex-enatide, liraglutide, lixisenatide) to crossthe blood-brain barrier compared withlarger molecules (e.g., albiglutide) (26).GLP-1 RAs also may activate the CNS indi-rectly through peripheral receptors on thevagus nerve (92). How GLP-1 RAs inducediarrhea is not well understood, althougheffects on small intestinal motilitymay berelevant (26).

CONCLUSIONS

GI symptoms occur frequently and havea substantial impact on quality of life inpeople with diabetes. Symptoms maynot be volunteered and should be specif-ically elicited and quantified by usingvalidated measures. The underlying path-ophysiology of symptoms is heteroge-neous and poorly understood, whichhas major implications for effective diag-nosis and management. Dietary andpharmacological strategies to achieveglucose lowering in type 2 diabetes areincreasingly used. For a number of drugs,

Figure 3—PrevalentGI symptoms in type1 and 2diabetes, andmedications for diabeteswithwhich theymay be associated.

634 GI Symptoms in Diabetes Diabetes Care Volume 41, March 2018

an association with GI symptoms has beenestablished and may, in some cases, leadto cessation of therapy. However, inter-pretation of the outcomes of the majorityof studies is compromised by the subopti-mal assessment of symptoms that use self-reported rather than validated measures.

Acknowledgments.Theauthors thankDr.HenryParkman (Temple University) for providing theimage used in Fig. 1.Funding.No specific funding for this reviewwasreceived. K.L.J. has been supportedby aNationalHealth and Medical Research Council SeniorCareer Development Award (627011) and iscurrently supported by a University of AdelaideBeacon Research Fellowship.Duality of Interest. C.K.R has received researchfunding from AstraZeneca, Merck Sharp &Dohme, Eli Lilly, Novartis, and Sanofi and hasserved on advisory boards for Allergan. K.L.J.has received research funding from Sanofi andAstraZeneca. N.J.T. has received grant supportand honoraria from the Rome Foundation; grantsupport and consulting fees from GI Therapies inwhich he has a potential financial interest; grantsupport from Prometheus, Abbott, and JanssenPharmaceuticals; grant support to theMayo Clinicfrom Pfizer and Salix Pharmaceuticals; consultingfees and honoraria from Yuhan; consulting feesfrom CJ HealthCare, Ardelyx, Takeda Pharmaceut-icals, Forest Laboratories, Furiex Pharmaceuticals,Synergy Pharmaceuticals, GiCare, Outpost Medi-cine, and Samsung Bioepis; fees for serving on anadvisory board from Allergan and Napo Pharma-ceuticals; and grant support and fees for servingon an advisory board from Commonwealth Labo-ratories. He has served on an advisory board forDanone, has received development fees fromAdelphi Values, has received licensing fees fromthe Mayo Clinic for questionnaires on bowel dis-ease and dysphagia, and holds a patent on IBSbiomarkers (U.S. 12735358.9-1405/2710383)and a pending patent application for “Nanotech-nology drug delivery EoE” (Nestec EuropeanPatent 12735358.9). M.H. has participated in ad-visory boards and/or symposia for Novo Nordisk,Sanofi, Novartis, Eli Lilly, Merck Sharp & Dohme,Boehringer Ingelheim, and AstraZeneca and hasreceived honoraria for these activities. No otherpotential conflicts of interest relevant to this arti-cle were reported.Author Contributions. Y.T.D., C.K.R., K.L.J.,N.J.T., and M.H. critically reviewed the manu-script. Y.T.D., C.K.R., and M.H. were involved indrafting the manuscript. Y.T.D. and M.H. wereinvolved in the conception and design of thereview.

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