3. Dyspepsia in Diabetic Patients

Dyspeptic symptoms are a frequent finding in patients with diabetes and they are part of the so-called diabetic enteropathy (DE), which includes the GI manifestations of DM ^[13]. Autonomic neuropathy has an important pathogenetic role in DE, together with interstitial cells of Cajal depletion and reduced expression of neuronal nitric oxide syntethase ^[13]. These alterations lead to abnormal GI motility, causing symptoms such as dyspepsia, nausea, vomiting, constipation and fecal incontinence.

Despite the high incidence of dyspepsia in patients with diabetes, the current literature offers limited data about the clinical features and the appropriate management of dyspepsia in this population. In case of a patient with DM presenting with upper GI symptoms, organic disease and medication side effects should be excluded: GLP-1 analogues, for example, can cause nausea and vomiting ^[13]. Moreover, DG should be excluded through GE measurement, as discussed below ^[2][14]. When organic dyspepsia, medication side effects and DG are excluded, the clinical management is analogous to that of non-diabetic patients, except for a more important therapeutic role of prokinetics in patients with DM.

4. H. pylori Infection in Patients with Diabetes

Many studies have analyzed the prevalence of H. pylori infection in symptomatic and asymptomatic patients with DM ^[15][16][17]. Hyperglycemia has been suggested as a predisposing factor for H. pylori colonization ^[15]. A recent case–control serological study demonstrated a significantly higher prevalence of H. pylori infection in patients with DM, who had positive antibody titers in 50.7% of cases, compared to 38.2% of controls ^[16]. Moreover, H. pylori positive patients showed higher incidence of GI symptoms, including bloating, distention, vomiting, abdominal pain, constipation and diarrhea, as well as systemic manifestations such as hypertension, muscular symptoms and chronic bronchitis, which is potentially attributable to H. pylori contribution to inducing systemic inflammation ^[16].

Among patients with DM, H. pylori infection has been shown to be higher in patients with gastroparesis, and bacterial eradication reduced symptoms such as upper abdominal pain and distention, early satiety and anorexia ^[17], thus suggesting a pathogenetic role of H. pylori in DG and reaffirming the therapeutic role of its eradication.

5. Clinical Management of Dyspepsia

The ACG/CAG clinical guidelines ^[5] provide indications on the diagnostic work-up which should be performed in patients with dyspeptic symptoms in addition to pharmacological therapies. According to guidelines, patients under the age of 60 should not undergo endoscopy to exclude malignancy, while, as previously mentioned, upper GI neoplasia should be excluded in elderly and in subjects with neoplastic risk factors ^[5]. The ACG/CAG clinical guidelines do not recommend the routine use of motility studies, which should only be performed in case of FD when gastroparesis is strongly suspected, as in patients with predominant symptoms of nausea and vomiting, who do not respond to empiric therapy. As discussed above, gastroparesis is diagnosed by documentation of delayed GE, investigated through GE scintigraphy or ¹³C-octanoic acid breath test, after exclusion of mechanical obstruction through radiologic or endoscopic examination ^[5].

Patients under the age of 60 should have a non-invasive test for H. pylori infection and they should be subsequently treated if the test is positive, while they should receive an empirical treatment with proton pump inhibitors (PPIs) if they are H. pylori negative or they are still symptomatic after bacterial eradication ^[5]. Even in the absence of gastric acid secretion abnormalities, PPIs showed to be effective in relieving FD symptoms and their efficacy was not related to concomitant GERD or H. pylori positivity ^[18].

Patients with dyspepsia not responding to PPIs and H. pylori eradication, can be offered a prokinetic therapy, despite the limited effectiveness data only available in non-diabetic dyspeptic patients ^[5]. However, only in dyspepsia related to DE, prokinetics have shown efficacy in improving gastric motility and reducing symptoms ^[13]. Prokinetics include serotonin-4 receptor agonists such as cisapride, mosapride and tandospirone citrate, which can be effective in relieving abdominal pain ^[19] and dopamine-2 receptor antagonists, like metoclopramide, which have shown efficacy similar to cisapride in improving GE and a better control of nausea, vomiting and early satiety ^[20]. However, metoclopramide is associated with important side effects, including hyperprolactinemia, closely related to gynecomastia and galactorrhea, and extrapyramidal symptoms, such as drug-induced parkinsonism and tardive dyskinesia ^[2].

Acotiamide is a prokinetic, currently approved for use in Japan and India for FD. It inhibits pre-sinaptic acetil-cholinesterase and antagonized presynaptic M1 and M2 receptors and it seems to relieve PDS symptoms, with a good tolerability ^[21][22].

An alternative to prokinetic drugs is represented by neuromodulators. In fact, triciclic antidepressant therapy (TCAs), such as amitriptyline, showed to relieve abdominal pain and improve the quality of life in patients with dyspepsia ^[23][24]. Data on serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are controversial as some studies showed an efficacy similar to TCAs ^[25], while other studies did not demonstrate any efficacy in symptom relief ^[21]. In the clinical setting the decision between prokinetics and TCAs should be made on a case-by-case basis ^[5].

As previously discussed, microbiota is receiving increasing attention in the context of FD and some authors have studied a potential effect of therapies targeting on gut microbiota, such as rifaximin ^[26] or supplementation with Lactobacillus strains ^[27], which act restoring the physiological microbiota. However, data about the indication to treat dyspeptic patients with probiotics remain scarce.

Finally, patients with FD not responding to drug therapy should be offered psychological therapies. Considering the role of psychological factors in the development of FD, in fact, these treatments may provide a significant symptom relief ^[10]. The quality of evidence about this approach is very low and the available studies are heterogeneous and do not suggest a specific psychological intervention ^[5].

Some authors have also proposed complementary and alternative treatments, such as herbal supplements, acupuncture and hypnosis ^[10], however, the available data are limited and more studies are needed to assess the efficacy of these therapies.

The above discussed therapeutic options for FD are summarized in Figure 1. Together with these pharmacological and non-pharmacological approaches, remains crucial the therapeutic role of lifestyle modifications, such as weight loss in obese patients, cessation of smoking, diet variations, NSAIDs avoidance ^[10]. These interventions represent the first step in FD treatment and should be associated with any other therapy.

Figure 1. Treatment algorithm for functional dyspepsia.