Diabetes and GI Pain

Diabetes and GI Pain Michael Bottros, MD

Disclosure Information  Nothing to Disclose

Learning Objectives  Describe prevalence GI symptoms associated with diabetes  Recognize changes associated with diabetes and neuronal degeneration  Describe the mechanisms underlying diabetic gastrointestinal neuropathy  Discuss potential future research areas and potential therapies to prevent or treat diabetic-associated gastrointestinal pain

Overview  Symptoms and Prevalence  Diabetes and Neuronal Degeneration  Mechanisms of GI Neuropathy  Clinical Presentation  Differential Diagnosis  Diagnostic Tools  Available Therapies  Potential Future Areas for Research

Diabetes and GI Symptoms

Prevalence of upper and lower GI symptoms is increased Considerable turnover in symptoms Transient vs persistent Bytzer P, Talley NJ, Leemon M et al. Prevalence of Gastrointestinal Symptoms Associated With Diabetes Mellitus: A Population-Based Survey of 15,000 Adults. Arch Intern Med 2001; 161: 1989–96.

Diabetes and GI Symptoms (cont’d) Nausea Bloating Abdominal pain Diarrhea Constipation Delayed gastric emptying Bytzer P, Talley NJ, Leemon M et al. Prevalence of Gastrointestinal Symptoms Associated With Diabetes Mellitus: A Population-Based Survey of 15,000 Adults. Arch Intern Med 2001; 161: 1989–96.

Prevalence Rates of Symptoms

Bytzer P, Talley NJ, Leemon M et al. Prevalence of Gastrointestinal Symptoms Associated With Diabetes Mellitus: A Population-Based Survey of 15,000 Adults. Arch Intern Med 2001; 161: 1989–96.

Symptoms and Glycemic Control

Bytzer P, Talley NJ, Leemon M et al. Prevalence of Gastrointestinal Symptoms Associated with Diabetes Mellitus: A Population-Based Survey of 15,000 Adults. Arch Intern Med 2001; 161: 1989–96.

Symptoms and Glycemic Control (cont’d)

Kim JH, Park HS, Ko SY et al. Diabetic Factors Associated With Gastrointestinal Symptoms in Patients With Type 2 Diabetes. World J Gastroenterol. 2010 April 14; 16(14): 1782–1787.

Normal Anatomy and Physiology

Kashyap P, Farrugia G. Diabetic Gastroparesis: What We Have Learned and had to Unlearn in the Past 5 Years. Gut. 2010 Dec;59(12):1716-26.

Pathophysiological Changes

Kashyap P, Farrugia G. Diabetic Gastroparesis: What We Have Learned and had to Unlearn in the Past 5 Years. Gut. 2010 Dec;59(12):1716-26.

Diabetes and Neuronal Degeneration Changes in the number of neurons and their size Alterations in chemical coding Loss of inhibitory neurons Increase in excitatory neurons Reductions in sensory neuropeptides Chandrasekharan B, Srinivasan S. Diabetes and the Enteric Nervous System.

Neurogastroenterol Motil. 2007 Dec;19(12):951-60.

Progression of Neuronal Changes

Chandrasekharan B, Srinivasan S. Diabetes and the Enteric Nervous System.

Neurogastroenterol Motil. 2007 Dec;19(12):951-60.

Alterations in Chemical Coding  Enteric Response – Degeneration – Neurotransmitter content change without degeneration – Some unaffected

 Differential Effect  Ratio imbalance of inhibitory and contractile neurons

Chandrasekharan B, Srinivasan S. Diabetes and the Enteric Nervous System.

Neurogastroenterol Motil. 2007 Dec;19(12):951-60.

Loss of Inhibitory Neurons  In early stages: loss of nNOS neurons – Within the stomach, lesser curvature more affected greater curvature – Mechanism could be secondary to increased apoptosis

 In later stages: regeneration of nNOS neurons  These changes contribute to motility disturbances Chandrasekharan B, Srinivasan S. Diabetes and the Enteric Nervous System.

Neurogastroenterol Motil. 2007 Dec;19(12):951-60.

Increase in Excitatory Neurons  The density of cholinergic innervation increased in: – jejunum – ileum (myenteric plexi) – muscularis propria of duodenum

 Changes in serotonin receptor expression may mediate the sensory component such as: – nausea – early satiety Chandrasekharan B, Srinivasan S. Diabetes and the Enteric Nervous System.

Neurogastroenterol Motil. 2007 Dec;19(12):951-60.

Reduction in Sensory Neuropeptides  In the myenteric and submucosal plexus of rat ileum and colon, CGRP-like immunoreactivity was found to be significantly reduced after 8 weeks of diabetes  A majority of studies support a reduction in Substance P – Exogenous SP may reverse IDDM

Chandrasekharan B, Srinivasan S. Diabetes and the Enteric Nervous System.

Neurogastroenterol Motil. 2007 Dec;19(12):951-60.

Mechanisms of Diabetic GI Neuropathy  Apoptosis – increase in apoptosis of DRG – presence of a calcium channel stimulating auto antibody has been found in DM I and is associated with disrupted intestinal motility – increased caspase-3 and TUNEL positive cells in myenteric plexi

Chandrasekharan B, Srinivasan S. Diabetes and the Enteric Nervous System.

Neurogastroenterol Motil. 2007 Dec;19(12):951-60.

Mechanisms of Diabetic GI Neuropathy (cont’d)

Oxidative stress –Production of ROS and RNS a feature of many neurological diseases –Results in glia-mediated causing secondary neuronal damage –Catalase, superoxide dismutase, malondialdehyde and protein carbonyl content increased, and glutathione peroxidase decreased Chandrasekharan B, Srinivasan S. Diabetes and the Enteric Nervous System.

Neurogastroenterol Motil. 2007 Dec;19(12):951-60.

Mechanisms of Diabetic GI Neuropathy (cont’d)

Oxidative stress –Different populations of sympathetic neurons differ in susceptibility –Indicates that molecular differences between the sympathetic ganglia may be responsible for their differential response –Differences in global gene expression patterns Semra YK, Wang M, Peat NJ et al. Selective Susceptibility of Different Populations of Sympathetic Neurons to Diabetic Neuropathy in Vivo is Reflected by Increased Vulnerability to Oxidative Stress in Vitro. Neurosci Lett 2006; 407: 199– 204.

Mechanisms of Diabetic GI Neuropathy (cont’d)

Advanced glycation end-products (AGE) –Expressed in peripheral neurons –Identified to play a significant role in diabetic neuropathy –High intracellular glucose concentration can trigger protein glycation via increased formation of methyl glyoxal, glyoxal and 3-deoxyglucosones Chandrasekharan B, Srinivasan S. Diabetes and the Enteric Nervous System.

Neurogastroenterol Motil. 2007 Dec;19(12):951-60.

Mechanisms of Diabetic GI Neuropathy (cont’d)  Alteration in intestinal muscle contractility – Increase in intestinal smooth muscle mass and increased muscle contractility – Impairment in smooth muscle contractility via reduction in muscarinic receptors and activation of voltage gated calcium – Altered signaling through the protein kinase C pathway in gastric myocytes may also contribute to diabetic gastroparesis – Recent studies have demonstrated that myopathy may play a role in diabetic gastroparesis • A reduction in insulin/ IGF-I signaling in diabetes causes ICC depletion, subsequent stem cell factor depletion and resultant smooth-muscle atrophy Chandrasekharan B, Srinivasan S. Diabetes and the Enteric Nervous System.

Neurogastroenterol Motil. 2007 Dec;19(12):951-60.

Mechanisms of Diabetic GI Neuropathy (cont’d)  Alterations in brain-gut interactions – Hypothalamus and brain stem along with ENS help in maintaining glucose homeostasis – Vagal nerve dysfunction as evidence by a reduced response to sham feeding-induced serum pancreatic polypeptide and ghrelin is seen in patients with diabetic gastroparesis – Vagally mediated duodenal bicarbonate secretion was impaired at 6 weeks of diabetes in rats – The afferent and efferent innervation of the GI tract is adversely affected in diabetes Chandrasekharan B, Srinivasan S. Diabetes and the Enteric Nervous System.

Neurogastroenterol Motil. 2007 Dec;19(12):951-60.

Mechanisms of Diabetic GI Neuropathy (cont’d)  Alterations in brain-gut interactions – Impaired afferent vagal functions have been demonstrated in patients with diabetic gastroparesis – Both myelinated and unmyelinated fibers in vagus nerve of the diabetic rat have been shown to be decreased in size.

– Changes in sympathetic pre- and postganglionic fibers including a reduction in cytoplasmic area, axonal dwindling have been noted 1 year after the induction of diabetes in rodent models – Sympathetic neuronal dystrophy with accumulation of neurofilaments and mitochondria has been noted in the experimental models of diabetes Chandrasekharan B, Srinivasan S. Diabetes and the Enteric Nervous System.

Neurogastroenterol Motil. 2007 Dec;19(12):951-60.

Clinical Presentation  Clinical presentation can vary and symptoms are quite nonspecific  Often described as burning, vague, or crampy in nature  Minority of patients localize it to the epigastric region  Timing of abdominal pain may vary widely, either manifesting after meals or during nighttime sleep Tang DM, Friedenberg FK. Gastroparesis: Approach, Diagnostic Evaluation, and Management. Dis Mon. 2011 Feb;57(2):74-101.

Clinical Presentation (cont’d)  The mean age of onset is 34 years and 82% of the patients were women  Gastric emptying is overall slower in diabetic females as compared to diabetic males  Some studies have shown that gastric emptying is also slower in normal females  The reasons for the female preponderance of gastroparesis remain largely unknown Keld R, Kinsey L, Athwal V et al. Pathogenesis, Investigation and Dietary and Medical Management of Gastroparesis. J Hum Nutr Diet. 2011 Oct;24(5):421-30.

Differential Diagnosis  Hepatitis  Gallbladder atony and enlargement is often found in diabetic patients – Cholelithiasis – Biliary dyskinesia – Cystic duct blockage leading to cholangitis

 Chronic/acute pancreatitis – Abscesses and pseudocysts

 Splenic abscesses and infarctions Panagoulias G, Tentolouris N, Ladas SS. Abdominal Pain in an Adult with Type 2 Diabetes: A Case Report. Cases J. 2008; 1: 154.

Differential Diagnosis (cont’d) Peptic ulcer disease Inflammatory bowel disease Chronic appendicitis Diverticular disease and diverticulosis Nephrolithiasis Panagoulias G, Tentolouris N, Ladas SS. Abdominal Pain in an Adult with Type 2 Diabetes: A Case Report. Cases J. 2008; 1: 154.

Differential Diagnosis (cont’d)  Abdominal aortic aneurysm or mesenteric ischemia – Patients with type 2 diabetes mellitus are more susceptible

 Infectious diseases causing abdominal pain: – Tuberculosis, yersiniosis and Whipple's disease – Helminthic and other tropical infectious diseases should also be considered in patients with epidemiological history – Diabetic patients with advanced renal stage and those under hemodialysis are more susceptible to such infections

 Partial intestinal obstruction due to incarcerated hernia, intraabdominal adhesions and partial intussusception Panagoulias G, Tentolouris N, Ladas SS. Abdominal Pain in an Adult with Type 2 Diabetes: A Case Report. Cases J. 2008; 1: 154.

Rarer Causes of Abdominal Pain  Painful rib  Wandering spleen syndrome  Eosinophilic gastroenteritis  Fitz-Hugh-Curtis syndrome  Hereditary angioedema  Abdominal malignancies or metastatic disease to abdominal  Psychogenic in origin and somatization – more common in adolescents Panagoulias G, Tentolouris N, Ladas SS. Abdominal Pain in an Adult with Type 2 Diabetes: A Case Report. Cases J. 2008; 1: 154.

Diagnosis  Physical examination and imaging to rule out other causes  Abnormal gastric emptying still remains the only objective marker of an underlying defect in the neuromuscular apparatus of the stomach  Scintigraphy is the most common and widely available modality for measuring gastric emptying

Kashyap P, Farrugia G. Diabetic Gastroparesis: What We Have Learned and had to Unlearn in the Past 5 Years. Gut. 2010 Dec;59(12):1716-26.

Diagnostic Tools Gastric emptying scintigraphy –relatively expensive –associated with some radiation exposure –still not standardized across medical centers –involves scintigraphic determination of emptying of a solid meal –the American Neurogastroenterology and Motility society recommends use of technetium sulphur colloid-labeled egg sandwich as a test meal Kashyap P, Farrugia G. Diabetic Gastroparesis: What We Have Learned and had to Unlearn in the Past 5 Years. Gut. 2010 Dec;59(12):1716-26.

Diagnostic Tools (cont’d) Gastric Emptying Scintigraphy

Tang DM, Friedenberg FK. Gastroparesis: Approach, Diagnostic Evaluation, and Management. Dis Mon. 2011 Feb;57(2):74-101.

Other Diagnostic Tools  Gastric emptying breath test using 13C – Sensitivity 89% and specificity 80%  Gastroduodenal manometry – Invasive, expensive, uncomfortable, and of very limited availability  Transabdominal ultrasonography – Requires considerable technical expertise  MRI – Correlates well with scintigraphy  Non-digestible capsule – Records pH, pressure, and temperature – Sensitivity 87% and specificity 92% Kashyap P, Farrugia G. Diabetic Gastroparesis: What We Have Learned and had to Unlearn in the Past 5 Years. Gut. 2010 Dec;59(12):1716-26.

Treatment

Kashyap P, Farrugia G. Diabetic Gastroparesis: What We Have Learned and had to Unlearn in the Past 5 Years. Gut. 2010 Dec;59(12):1716-26.

Treatment (cont’d) Nonpharmacologic Pharmacologic Interventional

Nutritional Support  often overlooked  lack of randomized controlled trials assessing the effect of nutritional intervention on outcome  advised to eat small frequent meals, chew their food well, avoid fiber and consume a diet low in fat as studies have shown fat can slow gastric emptying in healthy volunteers  encouraged to eat more liquid-based meals, such as soups or stews, since gastric emptying of liquids is often preserved Kashyap P, Farrugia G. Diabetic Gastroparesis: What We Have Learned and had to Unlearn in the Past 5 Years. Gut. 2010 Dec;59(12):1716-26.

Nonpharmacologic Options Biofeedback Relaxation therapy Physical and occupational therapy Cognitive/behavioral strategies –meditation; guided imagery

Acupuncture

Prokinetic Agents

Tang DM, Friedenberg FK. Gastroparesis: Approach, Diagnostic Evaluation, and Management. Dis Mon. 2011 Feb;57(2):74-101.

Antiemetic Agents  Phenothiazine Derivatives – Prochlorperazine  Serotonin 5-HT3 Receptor Antagonists – Ondansetron  Dopamine Receptor Antagonists – Metoclopramide – Domperidone  Histamine H1 Receptor Antagonists – Diphenhydramine – Promethazine – Meclizine  Benzodiazepines – Lorazepam

Tang DM, Friedenberg FK. Gastroparesis: Approach, Diagnostic Evaluation, and Management. Dis Mon. 2011 Feb;57(2):74-101.

Adjuvant Therapies Tricyclic Antidepressants Anticonvulsants Opiates should be used very sparingly No specific studies evaluating their role in gastroparesis

OnabotulinumtoxinA  Pylorospasm has been reported in diabetes  Hypothesized to act as a resistance to emptying of gastric content  This has led to the use of intrapyloric injection of botulinum toxin injection to open the pylorus.  Recent randomized controlled trials have failed to show improvement in symptoms.

Tang DM, Friedenberg FK. Gastroparesis: Approach, Diagnostic Evaluation, and Management. Dis Mon. 2011 Feb;57(2):74-101.

OnabotulinumtoxinA (cont’d)

Tang DM, Friedenberg FK. Gastroparesis: Approach, Diagnostic Evaluation, and Management. Dis Mon. 2011 Feb;57(2):74-101.

OnabotulinumtoxinA (cont’d)

Tang DM, Friedenberg FK. Gastroparesis: Approach, Diagnostic Evaluation, and Management. Dis Mon. 2011 Feb;57(2):74-101.

Gastric Electrical Stimulation  FDA-approved in 2000 for treatment of refractory diabetic or idiopathic gastroparesis  Device sends continuous high-frequency and low-energy waves through electrodes connected to the muscle wall of antrum  These waves stimulate autonomic vagal function allowing for more gastric accommodation  Shown to increase quality of life and decrease GI symptoms Tang DM, Friedenberg FK. Gastroparesis: approach, diagnostic evaluation, and management. Dis Mon. 2011 Feb;57(2):74-101.

Gastric Electrical Stimulation (cont’d)

Tang DM, Friedenberg FK. Gastroparesis: approach, diagnostic evaluation, and management. Dis Mon. 2011 Feb;57(2):74-101.

Summary

Diabetic GI Neuropathy

Chandrasekharan B, Srinivasan S. Diabetes and the enteric nervous system.

Neurogastroenterol Motil. 2007 Dec;19(12):951-60.

Summary Differential diagnosis is long and varied Diagnosis for diabetic GI neuropathy: scintigraphy is the current standard Treatments: modified diet, prokinetic agents, antiemetic agents, anticonvulsants, TCAs, gastric stimulator in refractory cases

Future Research Drugs that target the IGF-1 pathway, reduction in oxidative stress, ICC, dimerization of nNOS, and immune cells New prokinetics Studies on the potential use of stem cell-based therapies Kashyap P, Farrugia G. Diabetic gastroparesis: what we have learned and had to unlearn in the past 5 years. Gut. 2010 Dec;59(12):1716-26.