Cellular changes in diabetic and idiopathic gastroparesis.
TL;DR: It is suggested that on full-thickness biopsy specimens, cellular abnormalities are found in the majority of patients with gastroparesis, and an increase in CD45 and CD68 immunoreactivity is found.
About: This article is published in Gastroenterology.The article was published on 2011-05-01 and is currently open access. It has received 343 citations till now. The article focuses on the topics: Gastroparesis & Smoothelin.
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TL;DR: Current approved treatment options, including metoclopramide and gastric electrical stimulation (GES), do not adequately address clinical need and attention should be given to the development of new effective therapies for symptomatic control.
854 citations
TL;DR: Structural, functional, and molecular features of interstitial cells are described and their contributions in determining the behaviors of smooth muscle tissues are discussed.
Abstract: Smooth muscles are complex tissues containing a variety of cells in addition to muscle cells. Interstitial cells of mesenchymal origin interact with and form electrical connectivity with smooth muscle cells in many organs, and these cells provide important regulatory functions. For example, in the gastrointestinal tract, interstitial cells of Cajal (ICC) and PDGFRα+ cells have been described, in detail, and represent distinct classes of cells with unique ultrastructure, molecular phenotypes, and functions. Smooth muscle cells are electrically coupled to ICC and PDGFRα+ cells, forming an integrated unit called the SIP syncytium. SIP cells express a variety of receptors and ion channels, and conductance changes in any type of SIP cell affect the excitability and responses of the syncytium. SIP cells are known to provide pacemaker activity, propagation pathways for slow waves, transduction of inputs from motor neurons, and mechanosensitivity. Loss of interstitial cells has been associated with motor disorders of the gut. Interstitial cells are also found in a variety of other smooth muscles; however, in most cases, the physiological and pathophysiological roles for these cells have not been clearly defined. This review describes structural, functional, and molecular features of interstitial cells and discusses their contributions in determining the behaviors of smooth muscle tissues.
331 citations
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...Reduced ICC numbers have also been reported in samples of antral muscles from full thickness gastric biopsies from human patients symptomatic of diabetic and nondiabetic gastroparesis (105, 132, 133, 184)....
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TL;DR: The relevance of postprandial glycemia is further increased by the recognition that it may represent an independent risk factor for adverse cardiovascular outcomes in both diabetic and nondiabetic populations.
Abstract: The importance of achieving tight glycemic control, usually assessed by glycated hemoglobin (HbA1c), for both the prevention and delay in the progression of diabetes-related microvascular complications, is established, and the American Diabetes Association/European Association for the Study of Diabetes joint committee has recommended an HbA1c <7% as the goal in patients with type 2 diabetes (1). The relative contributions of pre- and postprandial glycemia to HbA1c have been clarified during the last decade following the seminal report by Monnier et al. (2) indicating that in type 2 diabetes, postprandial glycemic excursions account for about 70% of variability when HbA1c is <7.3%, while the contribution of “fasting” glycemia is greater in less well-controlled patients. Subsequent studies have confirmed the predominance of postprandial glycemia in determining overall glycemic control in “well-controlled” type 2 diabetic patients managed by oral hypoglycemic agents or basal insulin (3). The importance of postprandial glycemia to overall glycemic control is not surprising considering that 1 ) humans in modern societies spend only about 3 or 4 h before breakfast in a truly fasting state because in health, gastric emptying of meals occurs at an overall rate of 1–4 kcal/min (4), and 2 ) postprandial hyperglycemia occurs frequently in diabetes (1). The relevance of postprandial glycemia is further increased by the recognition that it may represent an independent risk factor for adverse cardiovascular outcomes in both diabetic and nondiabetic populations (5).
The determinants of postprandial glycemia include preprandial glycemic levels, meal composition, gastric emptying, insulin secretion, small intestinal glucose absorption, and hepatic and peripheral glucose metabolism. Furthermore, the relative contribution of each of these factors may vary over time during the postprandial state. Nevertheless, both the rate of gastric emptying and the secretion and action of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide …
259 citations
Cites background from "Cellular changes in diabetic and id..."
...like peptide-1(7-36)amide on antro-pyloro-...
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...Loss or dysfunction of the interstitial cells of Cajal and defects in inhibitory transmission, particularly involving neuronal nitric oxide synthase, appear to be of central importance, as well as abnormalities in immune cells (CD45, CD206) and an upregulation of heme oxygenase-1 in macrophages, which impacts on the enteric neurotransmitter carbon monoxide (13,20)....
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TL;DR: High-resolution mapping revealed new categories of abnormal human slow-wave activity that could contribute to the pathogenesis of gastroparesis, including aberrant initiation, aberrant conduction, and low amplitude activity.
254 citations
TL;DR: Gastric emptying accounts for ∼35% of the variance in peak postprandial blood glucose concentrations in healthy individuals and in patients with diabetes mellitus, and the rate of emptying is itself modulated by acute changes in glycaemia, so clinical implementation of incretin-based therapies for the management of T2DM, in part by slowing gastric empties, is widespread.
Abstract: The rate of gastric emptying is a critical determinant of postprandial glycaemia and, accordingly, is fundamental to maintaining blood glucose homeostasis. Disordered gastric emptying occurs frequently in patients with longstanding type 1 diabetes mellitus and type 2 diabetes mellitus (T2DM). A complex bidirectional relationship exists between gastric emptying and glycaemia--gastric emptying accounts for ∼35% of the variance in peak postprandial blood glucose concentrations in healthy individuals and in patients with diabetes mellitus, and the rate of emptying is itself modulated by acute changes in glycaemia. Clinical implementation of incretin-based therapies for the management of T2DM, which diminish postprandial glycaemia, in part by slowing gastric emptying, is widespread. Other therapies for patients with T2DM, which specifically target gastric emptying include pramlintide and dietary-based treatment approaches. A weak association exists between upper gastrointestinal symptoms and the rate of gastric emptying. In patients with severe diabetic gastroparesis, pathological changes are highly variable and are characterized by loss of interstitial cells of Cajal and an immune infiltrate. Management options for patients with symptomatic gastroparesis remain limited in their efficacy, which probably reflects the heterogeneous nature of the underlying pathophysiology.
210 citations
References
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TL;DR: Structural characterization of the cross-links and other products accumulating in collagen in diabetes is needed to gain a better understanding of the relationship between oxidative stress and the development of complications in diabetes.
Abstract: N epsilon-(carboxymethyl)lysine, N epsilon-(carboxymethyl)hydroxylysine, and the fluorescent cross-link pentosidine are formed by sequential glycation and oxidation reactions between reducing sugars and proteins. These compounds, termed glycoxidation products, accumulate in tissue collagen with age and at an accelerated rate in diabetes. Although glycoxidation products are present in only trace concentrations, even in diabetic collagen, studies on glycation and oxidation of model proteins in vitro suggest that these products are biomarkers of more extensive underlying glycative and oxidative damage to the protein. Possible sources of oxidative stress and damage to proteins in diabetes include free radicals generated by autoxidation reactions of sugars and sugar adducts to protein and by autoxidation of unsaturated lipids in plasma and membrane proteins. The oxidative stress may be amplified by a continuing cycle of metabolic stress, tissue damage, and cell death, leading to increased free radical production and compromised free radical inhibitory and scavenger systems, which further exacerbate the oxidative stress. Structural characterization of the cross-links and other products accumulating in collagen in diabetes is needed to gain a better understanding of the relationship between oxidative stress and the development of complications in diabetes. Such studies may lead to therapeutic approaches for limiting the damage from glycation and oxidation reactions and for complementing existing therapy for treatment of the complications of diabetes.
3,933 citations
1,417 citations
TL;DR: Based on observations, eccrine spiradenoma appears to differentiate toward ductal structures of eccrine sweat apparatus.
Abstract: Electron-microscopic studies of two typical lesions of eccrine spiradenoma were performed to correlate ultrastructure and histopathology. The salient ultramorphological features of the parenchyma were an adenoid cystic organization composed of epithelial, myoepithelial, and nonepithelial cell types, and the presence of intracytoplasmic luminae within the epithelial cells. There were no indications that the parenchyma was secretorily active. The stroma ramified through the parenchyma, occupying extensive areas and forming tenuous septa of the loose connective tissue in which blood vessels and nerve fibers were embedded. Profiles of cystoid spaces resulting from invagination of stroma into the parenchyma were frequently encountered. Based on our observations, eccrine spiradenoma appears to differentiate toward ductal structures of eccrine sweat apparatus.
1,079 citations
TL;DR: A literature review and the recommendations herein were prepared for the American Gastroenterological Association Clinical Practice Committee and were approved by the Committee on May 16, 2004, and by the AGA Governing Board on September 23, 2004 as mentioned in this paper.
588 citations