Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study
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Background: Diabetic gastroparesis is a disabling condition with no consistently effective treatment. In animals, ghrelin increases gastric emptying and reverses postoperative ileus. We present the results of a double blind, placebo controlled, crossover study of ghrelin in gastric emptying in patients with diabetic gastroparesis. Methods: Ten insulin requiring diabetic patients (five men, six type I) referred with symptoms indicative of gastroparesis received a two hour infusion of either ghrelin (5 pmol/kg/min) or saline on two occasions. Blood glucose was controlled by euglycaemic clamp. Gastric emptying rate (GER) was calculated by real time ultrasound following a test meal. Blood was sampled for ghrelin, growth hormone (GH), and pancreatic polypeptide (PP) levels. Cardiovagal neuropathy was assessed using the Mayo Clinic composite autonomic severity score (range 0 (normal)–3). Results: Baseline ghrelin levels were mean 445 (SEM 36) pmol/l. Ghrelin infusion achieved a peak plasma level of 2786 (188) pmol/l at 90 minutes, corresponding to a peak GH of 70.9 (19.8) pmol/l. Ghrelin increased gastric emptying in seven of 10 patients (30 (6)% to 43 (5)%; p = 0.04). Impaired cardiovagal tone correlated inversely with peak postprandial PP values (p<0.05) but did not correlate with GER. Conclusions: Ghrelin increases gastric emptying in patients with diabetic gastroparesis. This is independent of vagal tone. We propose that analogues of ghrelin may represent a new class of prokinetic agents.Keywords:
Gastroparesis
Crossover study
Motilin
Pancreatic polypeptide
Prokinetics have limited effectiveness for treating symptoms of gastroparesis. Thus, alternative or adjunct therapies, such as gastroparesis diets or neuromodulators, are often prescribed. Their therapeutic benefits alone or in combination remain unclear.
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In structure, ghrelin resembles motilin. The two peptides are considered to be members of the motilin-ghrelin peptide family. Motilin is considered to be an endocrine regulator of the interdigestive migrating contractions, the fasted motor pattern in the gastrointestinal (GI) tract. It has been reported that ghrelin stimulates GI motility. The gastrokinetic capacity of ghrelin has been well documented in the rodent. However, there have been few positive reports of the gastrokinetic capacity of ghrelin in dogs. Some reports with human subjects have shown that an i.v. ghrelin injection accelerated gastric emptying of a meal and improved meal-related symptoms. These results suggest that ghrelin has potential as a prokinetic. However, it seems unlikely that plasma ghrelin would play a physiological role in these digestive physiological events and stimulate gastric emptying, as these outcomes would appear to be in contradiction with the suppression of the endogenous release of ghrelin after eating. The physiological roles of ghrelin need to be clarified.
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Gastroparesis is defined as delayed gastric emptying and is a common medical condition in diabetic patients. Scintigraphy is commonly used as a standard diagnostic procedure for the quantitative assessment of gastroparesis. The aims of this study were to determine an optimum imaging time for the diagnosis of gastroparesis, to assess the prevalence of gastroparesis, to evaluate the correlation between endoscopy and scintigraphy findings as well as the correlation between gastric emptying with patient genders, blood glucose concentration, and functional dyspepsia.Gastric emptying was assessed in 50 diabetic patients with a mean age of 50.16 years. For evaluation of gastric emptying, a test meal containing 2 pieces of toast, 120 cc non-labeled water and fried egg labeled with 1 mCi of 99mTc was given to each patient. The scintigraphy was performed immediately after ingestion and was repeated at 1, 1.5, 2 and 4 hours after ingestion. In some patients, an additional 90-minute dynamic scan was also acquired.The prevalence of gastroparesis in this study population was determined as 64%. Also, the results of this study revealed that a 4-hour scan after ingestion is more relevant than a 90-minute dynamic scan for the evaluation of delayed gastric emptying. There was no statistically significant difference between 1-hour and 2-hour scans, 1-hour and 90-minute scans, 2-hour and 90-minute scans, 2-hour and 4-hour scans. Likewise there was no significant correlation between blood glucose levels, gender and calculated values of gastric emptying time in all groups.According to our findings, it can be suggested that the prevalence of gastroparesis is higher than that mentioned in some previous studies. Also, this study indicates that a gastric emptying scintigraphy at 2 and 4 hours after meal ingestion might provide the anticipated clinical information in diabetic patients with dyspepsia without other evident reasons.Amaç: Gastroparezi gecikmiş mide boşalması olarak tanımlanır ve diyabetik hastalarda sık rastlanan bir tıbbi durumdur. Gastroparezinin kantitatif değerlendirmesi için sintigrafi sıklıkla standart bir diagnostik yöntem olarak kullanılmaktadır. Bu çalışmanın amaçları gastroparezi tanısında optimum görüntüleme zamanını belirlemek, gastroparezi prevalansını belirlemek, endoskopi ve sintigrafi bulguları arasındaki uyumu ve mide boşalması ile cinsiyet, kan glukoz düzeyi ve fonksiyonel dispepsi arasındaki ilişkiyi incelemektir. Yöntem: Ortalama yaşları 50,16 olan 50 diyabetik hastanın mide boşalması değerlendirildi. Mide boşalmasını değerlendirmek için her hastaya 2 dilim tost, 120 cc işaretlenmemiş su ve 1 mCi 99mTc ile işaretlenmiş kızartılmış yumurtadan oluşan bir öğün verildi. Oral alımın hemen sonrasında 1., 1,5., 2. ve 4. saatlerde sintigrafi yapıldı. Bazı hastalarda ek olarak 90. dakika dinamik görüntülemesi de uygulandı. Bulgular: Çalışma grubunda gastroparezi prevalansı %64 olarak bulundu. Aynı zamanda oral alımdan sonra 4. saat görüntülemesinin gecikmiş mide boşalmasının değerlendirilmesinde 90. dakika dinamik görüntülemeden daha uygun olduğu bulundu. Birinci saat ve 2. saat, 1. saat ve 90. dakika, 2. saat ve 90. dakika, 2. saat ve 4. saat görüntülemeleri arasında istatistiksel olarak anlamlı fark yoktu. Benzer şekilde, tüm gruplarda kan glukoz düzeyi, cinsiyet ve hesaplanan mide boşalma zamanı arasında anlamlı bir ilişki saptanmadı. Görüntülemeler arasında cinsiyet, kan şekeri düzeyi ve mide boşalma süreleri açısından da fark tespit edilmedi. Sonuç: Sonuçlarımıza göre gastroparezi prevalansının daha önce bildirilenden daha yüksek olduğu öne sürülebilir. Benzer şekilde, bu çalışma gıda alımından 2 ve 4 saat sonra uygulanan mide boşalma sintigrafisinin dispeptik şikayetleri olan ancak diğer bariz nedenler bulunmayan diyabetik hastalarda gerekli klinik bilgiyi verebileceğini öngörmektedir.
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Ghrelin and Motilin Are Cosecreted from a Prominent Endocrine Cell Population in the Small Intestine
Context: Ghrelin is a novel hormone produced mainly in the gastric body. Hitherto, mapping studies of ghrelin cells covering the entire gastrointestinal (GI) tract in humans have been lacking. Furthermore, the phenotype of extragastric ghrelin cells is not known.
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Current therapy for gastroparesis with prokinetic agents is limited by options and side effects. One macrolide, erythromycin (ERY), is associated with possible sudden cardiac death from QT prolongation due to P450 iso-enzyme inhibition. An alternative, azithromycin (AZI), lacks P450 inhibition. We compared the effect on gastric emptying half-times (t½) between AZI and ERY in patients diagnosed with gastroparesis by gastric emptying scintigraphy.Patients stopped medications known to affect gastric emptying prior to the study, and then ingested 1 scrambled egg meal labeled with 18.5-37 MBq of technetium-99m sulfur colloid followed by continuous imaging for 120 minutes, at 1 minute per frame. A simple linear fit was applied to the rate of gastric emptying, and gastric emptying t½ was calculated (normal = 45-90 minutes). At 75-80 minutes, if the stomach had clearly not emptied, patients were given either ERY (n = 60) or AZI (n = 60) 250 mg IV and a new post-treatment gastric emptying t½ was calculated.Comparison of gastric emptying t½ showed a similar positive effect (mean gastric emptying t½ for AZI = 10.4 ± 7.2 minutes; mean gastric emptying t½ for ERY = 11.9 ± 8.4 minutes; p = 0.30).AZI is equivalent to ERY in accelerating the gastric emptying of adult patients with gastroparesis. Given the longer duration of action, better side effect profile and lack of P450 interaction for AZI as compared with ERY, further research should evaluate the long term effectiveness and safety of AZI as a gastroparesis treatment.
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