Thomas V. Nowak

Highly variable gastric emptying in patients with insulin dependent diabetes mellitus.

Some diabetic patients--particularly those with nausea and vomiting--frequently have evidence of delayed gastric emptying while other diabetic patients may in fact exhibit accelerated gastric emptying. Whether the presence or absence of symptoms of upper gastrointestinal dysfunction correlated with objective measures of gastric emptying in insulin dependent diabetic subjects was investigated. Twenty one insulin dependent diabetic patients underwent a solid phase gastric emptying scintiscan using in vivo labelled chicken liver. Thirteen patients had symptoms suggestive of gastrointestinal dysfunction (nausea, vomiting, early satiety, or constipation), while eight patients had no gastrointestinal symptoms. Eleven patients had orthostatic hypotension. All patients had been diabetic since childhood or adolescence. As a group, the diabetic patients showed a half time (T50) of gastric emptying (mean (SD) 150.0 min (163.7) that was not significantly different from that of 12 healthy control subjects (148.1 min (62.4)). Those diabetic patients without gastrointestinal symptoms and without orthostatic hypotension, however, showed a gastric emptying half time (70.1 min (41.6)) that was significantly faster than that of the control subjects. Conversely, those diabetic patients with nausea, vomiting, and early satiety (or early satiety alone) showed T50 values that were significantly greater than those of the diabetic patients without these symptoms. No correlation was found between the T50 value and the duration of diabetes, the fasting blood glucose at the time of study, or the respiratory variation in heart rate (E:I ratio). These observations indicate that highly variable rates of gastric emptying occur in insulin dependent diabetic patients, and that accelerated gastric emptying may occur in diabetic patients who have no symptoms of gastrointestinal dysfunction.

Gastric Electrical Stimulation With Enterra Therapy Improves Symptoms From Diabetic Gastroparesis in a Prospective Study

BACKGROUND & AIMS Gastric electrical stimulation (GES) treats refractory gastroparesis by delivering electric current, via electrodes, to gastric smooth muscle. Enterra therapy (Medtronic, Inc, Minneapolis, MN) uses an implantable neurostimulator with a high-frequency, low-energy output. We performed a controlled, multicenter, prospective study to evaluate the safety and efficacy of Enterra therapy in patients with chronic intractable nausea and vomiting from diabetic gastroparesis (DGP). METHODS Patients with refractory DGP (n = 55; mean age, 38 y; 66% female, 5.9 years of DGP) were given implants of the Enterra gastric stimulation system. After surgery, all patients had the stimulator turned on for 6 weeks and then they randomly were assigned to groups that had consecutive 3-month, cross-over periods with the device on or off. After this period, the device was turned on in all patients and they were followed up, unblinded, for 4.5 months. RESULTS The median reduction in weekly vomiting frequency (WVF) at 6 weeks, compared with baseline, was 57% (P < .001). There was no difference in WVF between patients who had the device turned on or off during the cross-over period (median reduction, 0%; P = .215). At 1 year, the WVF of all patients was significantly lower than baseline values (median reduction, 67.8%; P < .001). Patients also had significant improvements in total symptom score, gastric emptying, quality of life, and median days in the hospital. CONCLUSIONS In patients with intractable DGP, 6 weeks of GES therapy with Enterra significantly reduced vomiting and gastroparetic symptoms. Patients had improvements in subjective and objective parameters with chronic stimulation after 12 months of GES, compared with baseline.

A familial visceral myopathy with external ophthalmoplegia and autosomal recessive transmission

A new visceral myopathy family was identified. The disease in this family is transmitted by an autosomal recessive gene. Only 3 patients were identified from approximately 1500 family members. All 3 patients are the products of intermarriage. The patients had gastric atony, dilatation of the entire small bowel, and multiple diverticula throughout. Pathology of the jejunum showed fibrosis and degeneration, mainly of the longitudinal muscle layer, indistinguishable from that of previously reported families. Two of the patients also had ptosis and external ophthalmoplegia. Jejunal manometric studies were performed on the probands asymptomatic mother and five siblings. All had normal esophageal manometric studies and upper gastrointestinal x-rays. The mother and three siblings had abnormal jejunal manometric studies characterized by the absence of phase 1 in some of the migrating motor complexes and increased motility indices in phase 2. We conclude that familial visceral myopathy can be transmitted by an autosomal recessive gene, and that jejunal manometry is a sensitive technique to identify asymptomatic heterozygotes.

Diabetic gastroparesis. What to do when gastric emptying is delayed.

Preview As many as 30% of patients with long-standing diabetes mellitus may have symptoms of gastroparesis, and others are found to have the condition despite being asymptomatic. When should diabetic gastroparesis be suspected, and which are the best tests for detecting it? What factors can exacerbate it? Drs Clark and Nowak address these questions and discuss the therapeutic value of dietary modification, pro- kinetic agents, and surgical intervention.

Evolution of acute cytomegalovirus gastritis to chronic gastrointestinal dysmotility in a nonimmunocompromised adult

A 30-year-old nonimmunocompromised woman developed chronic gastrointestinal dysmotility as a consequence of acute cytomegalovirus infection. The acute nature of the infection was documented by high immunoglobulin M antibody titer to cytomegalovirus (CMV); the chronicity of the infection was shown by persistence of CMV in biopsy specimens of her gastrointestinal tract over a 21/2-year period. Gastrointestinal dysmotility was confirmed by delayed emptying on gastric nuclear scintigraphy, by retrograde propagation of migrating myoelectric complexes on small intestinal manometry, and by presence of tachygastria on cutaneous electrogastrography. The patients nausea, vomiting, abdominal pain, and early satiety resolved after a short course of treatment with leuprolide acetate but returned after medication was discontinued. Her symptoms persisted despite clearance of CMV from the gastrointestinal tract after a course of treatment with ganciclovir. These observations show that acute CMV infection can cause gastrointestinal dysmotility in nonimmunocompromised individuals and that the disturbance in gastrointestinal motor function may persist for years after viral infection of the gastrointestinal tract has been eradicated.

Untreated diabetes mellitus promotes intestinal microbial overgrowth

Gastrointestinal dysfunction is a common secondary complication of insulin-dependent diabetes mellitus, yet its etiology is unclear. Enteric microbial overgrowth may play a role. To quantitate the changes in mucosal-adherent enteric microbial populations in untreated diabetes mellitus and to assess the impact of two forms of insulin replacement therapy upon enteric microbial populations, age-matched male Lewis rats were rendered diabetic by the administration of intravenous streptozotocin (55 mg/kg). After diabetes was confirmed (blood glucose level greater than 250 mg/dL), rats were divided into three groups: no treatment (no insulin), treatment with daily insulin to maintain normoglycemia (3 to 7 units of protamine zinc insulin subcutaneously), or transplantation with a vascularized heterotopic duct-ligated pancreatic isograft. After 1 month, rats were killed, and segments of the proximal, middle, and distal small bowel were obtained. Mucosal samples were rinsed in phosphate-buffered saline to remove nonadherent bacteria prior to aerobic and anaerobic culturing. Microbial recovery was expressed as the log10 colony-forming unit/mg tissue wet weight. Untreated diabetes resulted in an overgrowth of mucosal-associated small bowel aerobic and anaerobic microbial populations compared with populations in normal nondiabetic age-matched control rats. Insulin treatment and pancreatic transplantation prevented microbial overgrowth in the diabetic small intestine. Pancreatic transplantation resulted in strict normoglycemia equivalent to that in nondiabetic control rats, whereas insulin treatment resulted in slightly higher blood glucose levels at sacrifice and wide fluctuations in blood glucose levels compared with nondiabetic control rats. These data suggest that sustained normalization of glucose levels is not required to prevent microbial overgrowth in diabetic rats.

Effect of Cholinergic Agonists on Muscle From Rodent Proximal and Distal Small Intestine

Proximal and distal rat small intestine was cut into strips measuring 6.0 X 10.0 mm. Strips cut along the oral-caudal axis were called longitudinal strips, whereas those cut 90 degrees to that axis were called circular strips. Stress in circular and longitudinal muscle strips was measured continuously as they were superfused with acetylcholine, carbamylcholine, methacholine, bethanechol, or physostigmine. Resting stress during stretch, acetylcholine-stimulated active stress, and total stress were determined. Proximal circular muscle was five times as sensitive to acetylcholine as distal circular muscle (p less than 0.05); proximal longitudinal muscle was 2.8 times as sensitive to bethanechol as distal muscle (p less than 0.05). Resting, active, and total stress were similar in proximal and distal muscle, but circular muscle showed nearly twice the resting stress of longitudinal muscle at either proximal or distal sites (p less than 0.05). Physostigmine (10(-6) M) increased acetylcholine-stimulated active stress in proximal and distal circular muscle by 29% and 70%, respectively (p less than 0.05), but not in longitudinal muscle (p greater than 0.05). This difference between proximal and distal circular muscle (41%) was also significant (p less than 0.05). Thus, the proximal and distal muscle of the rat small intestine differs in its sensitivity to various cholinergic agonists, but not in its length-stress properties.

Adaptation of Cholinergic Enteric Neuromuscular Transmission in Diabetic Rat Small Intestine

Representative longitudinal muscle strips (6 × 10 mm) from distal small intestine were obtained from rats after 1, 2, and 3 mo of streptozocin-induced diabetes. The strips were stretched to their optimum lengths and subjected to electrical field stimulation (1-ms pulse duration, 30–270 mA, 10 Hz) in the presence of Krebs solution and Krebs solution plus 10−6 M atropine. Field stimulation produced atropine-sensitive and atropine-resistant contractions in all strips. After 1 mo, significant differences in the amplitudes of the atropine-sensitive contractions were found between the diabetic rats and nondiabetic controls. Insulintreated diabetic rats showed contraction responses that were intermediate in amplitude. After 2 mo, the difference between the control and diabetic groups was less evident but still significant. After 3 mo, the previously noted difference in the atropine-sensitive contractions between the diabetic and control groups had resolved. No significant differences among the three groups were noted in the amplitudes of the atropine-resistant contractions. Field stimulation delivered at pulse durations of 50 ms in the presence of neural blockade with tetrodotoxin (5 × 10−6 M) produced similar contraction amplitudes among the three groups at any respective time phase of the study. Dose-response studies of intestinal muscle after 3 mo of untreated diabetes showed normal tension development to both bethanechol chloride and physostigmine. These results indicate that streptozocin-induced diabetes is acutely associated with defective cholinergic neuromuscular transmission in the myenteric plexus of the distal small intestine The abnormality is less evident after 2 mo of untreated diabetes and resolves spontaneously after 3 mo. Insulin treatment appears to accelerate this resolution.

Effect of streptozotocin-induced diabetes mellitus on release of vasoactive intestinal polypeptide from rodent small intestine.

Representative longitudinal muscle strips (6 × 10 mm) from proximal and distal small intestine were excised from control and streptozotocin-treated rats after one month of untreated and insulin-treated diabetes. Untreated diabetes significantly reduced tissue concentrations of vasoactive intestinal polypeptide (VIP) at both intestinal loci. Insulin treatment of the diabetic animals restored tissue VIP concentrations to control group levels, although the beneficial effect of insulin treatment was only significant in the duodenum. Spontaneous release of VIP was significantly attenuated by untreated diabetes at both intestinal sites. In the duodenum, insulin treatment of the diabetic animals restored VIP release to levels indistinguishable from control group values. In the ileum, insulin treatment produced levels of VIP release that were not significantly different from those of the control and untreated diabetic groups. Tetrodotoxin (5 × 10−6 M) significantly—but incompletely—inhibited VIP release from control group animals at both intestinal sites. These observations indicate that diabetes mellitus significantly diminishes VIP tissue concentrations and release from intestinal myenteric nerves. These abnormalities improve with insulin treatment. However, the mechanisms of VIP release from proximal and distal intestine appear to differ not only in their response to the diabetic state, but also in their response to insulin treatment.

Familial occurrence of intrathoracic gastric volvulus.

SummaryThis report describes the first documented familial occurrence of gastric volvulus in two consecutive generations. Consideration is given to familial transmission of other foregut disorders. The report reviews the different types of gastric volvulus and considers their pathogenesis, clinical presentation, and treatment.