A 50-year-old woman presented with early satiety, nausea, and vomiting. Her father had diabetes and kidney complications from diabetes. Testing showed she had diabetes. A 52-year-old woman also presented with similar symptoms for 2 years and was known to have type 2 diabetes for 15 years with heart and nerve complications. Testing of both women found delayed emptying of food from the stomach due to effects of long-term diabetes on the nerves and muscles of the digestive system.

1. Case history: 50 years old woman, married with 5 children. Presented with early satiety, nausea & vomiting. Her father was diabetic & died from diabetic nephropathy with retinopathy. Upper GI endoscopy revealed gastric stasis inspite of prolonged fasting with antral changes due to food stasis. RBS, FBS & GTT; proved to be diabetic.

2. Case history: 52 years old woman, gravida 5 para 5. Presented with early satiety, nausea & vomiting for the last 2 years. Known case of T2DM for the last 15 years, complicated by IHD, but no evidence of autonomic/peripheral neuropathy or nephropathy/retinopathy. Upper GI endoscopyu revealed gastric stasis in spite of prolonged fasting with antral changes due to food stasis + prepyloric polyp for which biopsies were done & sent for histopatholohy. Scheduled for snare polyp removal after knowing the biopsy results. FBS 300, BU/S.Cr normal, s.cholestero 254, s.triglyceride normal.

4. GIT complications of DM : Pathophysiology / management: Prepared by: Dr. Mohammad Shaikhani. Assistant professor Sulaimani University College of Medicine. From nature clinical GEH 2008.

5. Introduction: Diabetics have GIT complications more frequently than non-diabetics. UGI symptoms: nausea, vomiting, heartburn, are the most frequent. Diabetic diarrhea is as an important problem, but constipation is more frequently found. Diabetic women are more at risk of developing GIT symptoms than men.

6. DM/GIT Pathophysiology: glycemic control DM can potentially affect any part of GIT. No single RFs identified& mostly multifactorial, involving reversible/irreversible processes. Both hypoglycemia/hyperglycemia, can have a reversible effect on the metabolic&signaling pathways of enteric neurons & alter intestinal function. Hyperglycemia,inhibits vagal nerve activity. GIT symptoms / complications do not always correlate with the DM duration or glycemic control.

7. Many GI symptoms, can precede or not correlate with the presence of autonomic neuropathy, often assumed to be the major cause of many GIT symptoms. Other pathophysiologic processes; enteric myopathy&neuropathy from autoimmune damage& metabolic insults altering critical cellular pathways & essential trophic factor signaling, resulting in smooth muscle atrophy& neural apoptosis, or trans differentiation , loss of ICC& an imbalance in the number of excitatory / inhibitory enteric nerves ICC serve as pacemaker cells responsible for initiating & organizing phasic contractions& propagation of electrical activity in smooth muscles, analogous to cardiac Purkinje fibers. DM/GIT Pathophysiology: Autonomic neuropathy

8. Hypoxia from microvascular disease, mitochondrial dysfunction, formation of irreversible advanced glycation end products, peroxynitrite-mediated endothelial/ enteric neuron damage. H yperglycemia can induce apoptosis of enteric neurons &impair activity of the phosphatidylinositol 3-kinase (PI3K) pathway; apoptosis can be prevented by glial-cell-derived neurotrophic factor DM/GIT Pathophysiology: Others

9. Imbalances in the number of excitatory / inhibitory enteric neurons alter complex motor functions as peristalsis, reflexive relaxation, sphincter tone, vascular flow / intestinal segmentation. Defective trophic signaling / enteric innervation cause abns in epithelial function &development, resulting in enhanced nutrient transport potentially complicate glycemic control & abnormalities in salt / water transport,contribute to diabetic diarrhea. Compromised intestinal vascular flow can also cause abdominal pain, bleeding, mucosal dysfunction. These motor function alterations causes dysphagia /reflux esophagitis in the esophagus, gastroparesis / dyspepsia in the stomach, pseudo-obstruction in SI, constipation, diarrhea/ incontinence in the colon. DM/GIT Pathophysiology: Others

10. Clinical effects: Eso: dysphagia /reflux esophagitis Stomach: Gastroparesis / dyspepsia SI: Pseudo-obstruction Colon: Constipation, diarrhea/ incontinence.

11. ESOPHAGEAL COMPLICATIONS: Up to 50% have eso abns: motility disturbance /or GERD Eso dysfunction correlates best with the presence of diabetic motor neuropathy & not with autonomic neuropathy In patients with diabetic motor neuropathy, abnormalities as increased acid reflux, reduced amplitude of peristaltic waves, reduced rate of smooth muscle contraction, decreased peristaltic efficacy, impaired lower esophageal sphincter tone / function particularly prevalent. Esophageal symptoms are slightly more common& proportionately less common than motility manometric changes. 25% had reflux symptoms vs 9.5% of control.

12. ESOPHAGEAL COMPLICATIONS: Candida esophagitis is also prevalent, particularly with poor glycemic control. Factors that predispose to oral/esophageal candidiasis include defective esophageal clearance secondary to dysmotility, high glucose content of secretions& decreased candicidal activity of polymorphonuclear cells. In many cases the eso complications successfully treated. GERD, can be managed effectively with conventional anti GERD trts. Antireflux operations, should be reserved only for those patients with disease that is refractory to medical treatment.

13. ESOPHAGEAL COMPLICATIONS:trt Oral/eso candidiasis are best treated by improving glycemic control & the use of oral antifungal agents as fluconazole. Symptomatic dysphagia is more difficult to manage, particularly if it exists in the presence of advanced diabetic motor neuropathy. Early diagnosis of dysphagia is important so that better glycemic control can be initiated when this condition is still reversible.

14. GASTRIC COMPLICATIONS: Diabetic gastroparesis Common, sometimes &very troubling. Symptoms: epigastric fullness, bloating, nausea,vomiting suggest paresis, but relatively nonspecific, usually, not always, caused by delayed gastric emptying. Although pain can occur, it is not an integral component&if present,suggests alternative diagnosis or additional complicating factors. Symptoms clearly wax / wane, suggests some temporal variability. Usually occurs in the setting of chronic diabetes in which there is evidence of generalized end-organ damage, as retinopathy, neuropathy & nephropathy. In PC, occur in 5–12% &in referral centers,much higher, 50%.

15. GASTRIC COMPLICATIONS: Diabetic gastroparesis It can has a major effect on the management of diabetes as it: Complicates glycemic control & effectiveness of OHD. Recurrent symptoms can prompt multiple hospitalizations Have a deleterious impact on nutrition. Can cause recurrent episodes of hypoglycemia. It does not seem to increase mortality It is not certain whether therapeutic interventions alter its long-term course.

16. Diabetic gastroparesis:pathogenesis Not clear. Chronic hyperglycemia leads to neuropathic changes/ dysfunctional innervation of the stomach& delayed gastric emptying. Modest increases in blood sugar can delay gastric emptying, alter antroduodenal motility, induce a sense of fullness&limit efficacy of some prokinetics. Hormonal changes:diabetic& idiopathic gastroparesis, occurs primarily in females. Concomitant psychiatric disorders. Medications:synthetic analogs of amylin (e.g.pramlinitide)& functional analogs of GLP1(e.g. exanatide). Psychiatric factors may correlate better with symptoms than the results of emptying studies.

17. Diabetic gastroparesis:diagnosis Suggested by history. PE does not usually useful, but rarely a succussion splash can provide an evidence. Concomitant GI pathology must be ruled out, usually by OGD. The gold standard is nuclear scintigraphy: Delayed emptying of a labeled solid meal in the absence of any anatomic abnormalities. Involves scans every 15 minutes, usually, 4–6 scans for 4 hours; gastric retention of >10% of the meal at 4 hours is diagnostic. Other measures:breath tests, radioopaque markers,EGG, capsule endoscopy& measurement of antroduodenal motility. Documented gastric emptying abns are common in T1 or T2 DM, the relationship with specific symptoms is not particularly tight. Gastric emptying can be accelerated in some patients with T2DM. Nonspecific UGI symptoms are common in the general population&in individuals with functional dyspepsia. Some favor the ‘diabetic gastropathy’

18. Diabetic gastroparesis:Trt Depend on the severity of symptoms, the ability of the patient to maintain adequate nutrition& their responsiveness to therapy. The primary aim is to optimize glycemic control, as hyperglycemia induces environmental changes in the enteric nervous circuitry. Beyond glycemic control, the treatment parallels that of gastroparesis in general&include: Diet modification. Pharmacotherapy. More invasive approaches for ‘gastric failure’.

19. Diabetic gastroparesis Trt: Diet Dietary modifications have some success. A ‘grazing diet’ of frequent small meals can minimize postprandial fullness. Avoidance of nutrients that delay gastric emptying (fat, fiber) might also be helpful. As the rate of emptying of liquids is generally preserved in diabetic gastroparesis, the consumption of foods that have been blended&liquid nutritional supplements might be reasonable approach.

20. Diabetic gastroparesis Trt: drugs More severe symptoms require pharmacologic intervention. Prokinetic /or anti-emetics (metochlopromide/doperidone): enhance coordinated pressure waves moving through the antrum, pylorus&duodenum. Cholinergic agonists (e.g. bethanechol) increase the frequency &/ or amplitude of gastric contractions, but not necessarily in a peristaltic sequence. Metoclopramide / domperidone are dopamine receptor antagonists. Metoclopramide crosses BBB, but domperidone does not ,so limited CNS effects.

21. Diabetic gastroparesis:Trt Endogenous dopamine inhibits gastric emptying, dopamine-receptor- mediated pathways in the brain stem affect nausea. By blocking these sites, metoclopramide/domperidone exert their therapeutic effect. Metoclopramide can also act as a 5-HT receptor 4 agonist to stimulate cholinergic neural pathways in the stomach. A patients who do not respond to one prokinetic might respond to another.

22. Diabetic gastroparesis Trt: Metochlopromide Metaclopramide is the most commonly used prokinetic, effective in the short term, improving both symptoms /gastric emptying rates, but its long-term efficacy has not been proven& limited data on benefits of periodic or cyclical use. Adverse effects from minor to severe; tardive dyskinesia is an uncommon but serious adverse effect can persist despite withdrawal, dictating a thorough discussion with patients. Milder adverse effects including drowsiness,fatigue, restlessness , irritability, are relatively common. Acute dystonic reactions can occur in up to 1%. Prolonged treatment can produce Parkinsonian-like symptoms. In women, increases in prolactin result in lactation, breast engorgement/ irregular periods.

23. Diabetic gastroparesisTrt: domperidone Domperidone’s mechanism of action / effect on gastric emptying are similar to those of metoclopramide,with development of tachyphylaxis/loss of efficacy over time. Can result in symptomatic relief without a corresponding improvement in gastric emptying, which suggests that the anti-emetic effect may be important. Does not cross BBB, it is unlikely that it will induce extra-pyramidal side effects.

24. Diabetic gastroparesis Trt: Erythromycin A molecular mimic of motilin, an endogenous peptide that initiates the migrating motor complex in the upper gut. Itbinds to the motilin receptor/initiates similar biologic effects,explains the frequent GIT intolerance experienced. IV erythromycin a more potent prokinetic than the oral preps. Liquid suspension may have rapid absorption/ convenient dosage modification. Long-term efficacy is limited. The potential benefit of developing a motilin analog still not successful.

25. Diabetic gastroparesis Trt: cisapride Cisapride /tegasorod are 5-HT receptor 4 agonists induce the release of acetylcholine from myenteric cholinergic neurons. Cisapride was originally targeted for GERD& tegasorod for constipation-predominant IBS. Both stimulate gastric emptying, with cisapride a more potent prokinetic than tegasorod. Both have been withdrawn because of cardiac complications.

26. Diabetic gastroparesis Trt: others GIT hormon ghrelin, sildenafil,clonidine, opioid receptor agonists, antidepressants, yet to be proven clinically effective.

27. Diabetic gastroparesis Trt: new Considered for individuals who do not respond to dietary/pharmacologic therapy. Two innovative approaches, but their place remains to be determined. Intrapyloric inj of botulinum toxin may decrease pylorospasm& improve symptoms with 50% improvement in gastric emptying or symptoms.

28. Diabetic gastroparesis trts:OTHERS Gastric electrical stimulation (‘pacing’) (Enterra, Medtronic Inc.) A significant symptom relief (decreased nausea/ vomiting) Diabetics particularly benefited compared with those who had idiopathic gastroparesis. Involves surgical intervention, sometimes has to be removed because of complications.

29. Venting gastrostomies or jejunal feeding tubes Venting gastrostomy will relieve distention, nausea/vomiting. In individuals who are undernourished, enteral feeding can be an option. As the dysfunctional stomach needs to be bypassed, access to the small bowel is necessary either via PEG or PEJ, or a surgical jejunostomy. Diabetic gastroparesis trts: OTHERS

30. Surgery: drainage procedures (e.g. pyloroplasty) or subtotal (or near-total) gastrectomy with Rouxen-Y anastamosis Although reports of symptom relief after surgical intervention, there are considerable postoperative complications,so extremely limited. Diabetic gastroparesis trts:Surgery

31. Diabetic gastroparesis:Trt

32. UGIB: Patients who have hyperglycemia/or DKA frequently present with hematemesis The Mallory–Weiss tear is often considered bz of nausea/ vomiting accompanying DKA The most common finding in patients with hematemesis is esophagitis, secondary to vomiting. Negative endoscopy findings are not uncommon. Hematemesis resolves quickly when the underlying metabolic abnormalities are treated.

33. SI:Diarrhea Diabetic duarrhea. Concomitant celiac disease Medications Fecal incontinence.

34. SI:Diarrhea Constipation is a more common but diarrhea is more clinically relevant / troubling. At least 2 mechanisms plus others: 1. Impaired adrenergic regulation of fluid / electrolyte transport secondary to decreased α2-adrenergic input. 2. Slow intestinal transit/subsequent bacterial overgrowth.

35. SI,Diarrhea: diagnosis A combination of hydrogen breath testing&nuclear scintigraphy provide a more accurate assessment of the relationships among small bowel transit, nutrient absorption& small bowel bacterial overgrowth. Individuals with diarrhea&associated autonomic neuropathy, primarily diabetes, can have an extremely rapid orocecal transit time (<20 minutes) associated with a positive glucose or lactulose hydrogen breath test. Differentiation of rapid-transit from slow-transit diarrhea in patients with diabetes is important. Obviously, antibiotic treatment is appropriate for slow-transit diarrhea with bacterial overgrowth, whereas rapid-transit diarrhea might be more effectively treated with more conventional antimotility drugs as loperamide.

36. SI:Diarrhea Celiac disease occurs in 5% of patients with type 1 diabetes. Serologic testing followed by small bowel biopsy is appropriate for the majority. Metformin is the medication most commonly associated with diarrhea in this population, but newer medications as acarbose/ miglitol,artificial sweeteners

37. SI:Diarrhea Fecal incontinence particularly affects elderly patients, can be described as diarrhea. ?Pancreatic insufficiency / islet cell tumors

38. Diarrhea: trt Specifically tailored to the underlying pathophysiology (e.g. diet modification for patients with celiac disease or rotating antibiotics for those with small bowel bacterial overgrowth). If no specific cause of the diarrhea is identified, empiric therapy with simple antidiarrheal agents (e.g. loperamide) is a reasonable. A trial of clonidine is an option for patients in whom it is well tolerated. Octreotide effective in diabetic diarrhea,but not often required.

39. Colonic comps:constipation Constipation requiring laxative is the most common GIT symptom higher in women than men, more in those who take medications that promote constipation (e.g. CCBs). Most likely results from slow transit caused by loss of ICC function & smooth muscle myopathy, although autonomic neuropathy/neuroendocrine imbalances might also contribute. There are no specific trts for diabetes-associated constipation, although better glycemic control may be of some benefit. In most cases, treated the same as idiopathic chronic constipation Anorectal dysfunction, from anorectal sensory or motor abns, can benefit from biofeedback training. In the absence of defecatory dysfunction, bulking agents, osmotic laxatives (e.g. polyethylene glycol), stimulant laxatives tried.

40. Colonic comps:constipation The new Cl–-channel agonist, lubiprostone, might also be effective in chronic constipation. The prevalence of fecal incontinence secondary to anorectal dysfunction increased in DM. Fecal incontinence in DM not well understood& involve many factors, including: Aberrant autonomic/enteric regulation of the internal anal sphincter, rectal contraction,acute hyperglycemia, as it inhibits external anal sphincter function /decreases rectal compliance& tighter glycemic control can improve symptoms.

41. Summary:

42. Summary: Patients with DM often have GIT symptoms, but the extent/ severity & the specificity of the symptoms are not nearly as well defined as frequently assumed. Any part of GIT affected& the presenting symptoms depend on the composite of dysfunctional elements. GERD, Candida esophagitis,gastroparesis, diarrhea and constipation are among the many common GIT complications of DM. No specific RF has been identified & their etiology is most likely to be multifactorial, involving both reversible /irreversible processes.

43. Summary: Trt directed at tighter glycemic /symptom control in most. For others, effective management is problematic because no therapies are available to prevent or correct the underlying disease mechanisms. Reduced key trophic factors cause trans differentiation of pacemaker interstitial cells of Cajal into a smooth-muscle-like phenotype. Therapies directed at restoring the normal milieu of trophic signals could correct the dysfunction of the interstitial cells of Cajal& resolve many GI complications. Advances in stem cell technology hold promise.