Increased Expression of Pyloric ERβ Is Associated With Diabetic Gastroparesis in Streptozotocin-Induced Male Diabetic Rats

Abstract

BackgroundGastroparesis is a significant co-morbidity affecting up to 50% of patients with diabetes and is disproportionately found in women. Prior studies have suggested that loss of interstitial cells of Cajal, hyperglycemia, and nitric oxide dysfunction are potential causes of gastroparesis. Since diabetic gastroparesis affects more women than men, we performed an exploratory study with a diabetic rat model to determine if sex hormone signaling is altered in those where gastroparesis develops.MethodsWe injected male rats with streptozotocin (STZ) to model type I diabetes, as confirmed by blood glucose levels. Gastroparesis was determined by acetaminophen gavage and serum acetaminophen levels. Rats were grouped based on acetaminophen and blood glucose data: diabetic (DM), diabetic and gastroparetic (DM + GP), and control (CM). Serum levels of testosterone, estrogen, and insulin were determined as well as aromatase expression in pyloric tissue and serum. Androgen receptor and estrogen receptor α (ERα) and β (ERβ) were also measured in the pylorus.ResultsCompared to CM, estrogen increased and testosterone decreased in both DM and DM + GP rats. Sex hormone levels were not different between DM and DM + GP. Serum aromatase was increased in DM and DM + GP rats; however, pyloric tissue levels were not significantly different from controls. ERα was unchanged and androgen receptor decreased in DM and DM + GP. ERβ was increased only in DM + GP animals.ConclusionOur study implicates increased pyloric ERβ in the development of gastroparesis in STZ-induced male diabetic rats. Increased serum aromatase is likely responsible for altered sex hormone levels. Our study supports the implication of sex hormone signaling in diabetic development and demonstrates a potential unique role for pyloric ERβ in male diabetic gastroparesis.

Reactive oxygen species overproduction and MAP kinase phosphatase‐1 degradation are associated with gastroparesis in a streptozotocin‐induced male diabetic rat model

“…This test allowed us to categorize the rats into the following groups: (i) Control: citrate buffer injection (CM); (ii) Diabetic after STZ treatment (DM); (iii) Diabetic and gastroparetic after STZ treatment (DM+GP). Acetaminophen (4 μg/mL) was used as the cutoff for group designation based on previous studies in this laboratory and others . At the end of week 16, serum was collected and, posteuthanasia, pyloric tissues were collected.…”

“…At the end of week 16, serum was collected and, posteuthanasia, pyloric tissues were collected. As reported in our previous study, the serum acetaminophen levels of these rats were as follows: CM (16.16 ± 5.25 μg/mL), DM (9.96 ± 5.58 μg/mL), and DM+GP (2.22 ± 1.05 μg/mL). We tested serum and pyloric tissues from the same rats as were used in our previous study …”

“…Acetaminophen (4 μg/mL) was used as the cutoff for group designation based on previous studies in this laboratory and others. 12,14,15 At the end of week 16, serum was collected and, posteuthanasia, pyloric tissues were collected. As reported in our previous study, 12 the serum acetaminophen levels of these rats were as follows: • This study provides important new insights into the mechanism of gastroparesis by implicating ROS-mediated activation of the JNK/p38MAPK signaling pathways and MAP kinase phosphatase-1 degradation.…”

“…Our previous studies implicated involvement of sex hormone signaling as an associative agent in male gastroparesis . We propose here that male diabetic gastroparesis phenotype may also involve overproduction of ROS, subsequent activation of the JNK/p38MAPK signaling pathways, and loss of MAP kinase‐1.…”

“…We propose here that male diabetic gastroparesis phenotype may also involve overproduction of ROS, subsequent activation of the JNK/p38MAPK signaling pathways, and loss of MAP kinase‐1. Because the pylorus has been reported to be significantly involved in the development of gastroparesis, we measured changes in both serum and pyloric tissue lysates.…”