The overall objectives of this proposal (Project 3 of PPG) are to understand the mechanisms of and to develop novel management approaches for gastric emptying (GE) disturbances (i.e., delayed GE or gastroparesis and rapid GE) in idiopathic disorders and diabetes mellitus (DM). Delayed GE is attributed to autonomic dysfunctions, hyperglycemia, and an enteropathy. Exciting preliminary data (Project 1) indicate that failure to upregulate heme oxygenase-1 (HO-1) in response to hyperglycemia-induced oxidative stress causes delayed GE in non-obese diabetic (NOD) mice. HO-1 degrades heme to generate carbon monoxide, which has cytoprotective effects and sustains interstitial cells of Cajal. Hemin increased HO-1 expression in NOD mice. While improved glycemic control reduces the microvascular complications of DM, its effects on GE have not been studied. Although acute hyperglycemia delays GE, our preliminary data suggest that improving glycemic control for 12h or 6 mo does not improve GE in DM with delayed GE. Finally, our preliminary data suggest that nutrient-induced entero-gastric feedback mechanisms mediated by gut peptides (CCK and GLP-1), normally responsible for regulating GE are impaired in patients with rapid GE. Our CENTRAL HYPOTHESIS is that delayed or accelerated GE, due to DM or related disorders, are attributable to vagal neuropathy, hyperglycemia, enteric neuropathy, and/or disordered enterogastric reflexes. Our proposal has three SPECIFIC AIMS. FIRST, we will test the hypothesis that compared to placebo, hemin will increase HO-1 activity and GE in patients with DM and delayed GE. SECOND, we will test the hypothesis that neither acute (12h) nor medium-term (i.e., 6 month) improvements in glycemic control will improve gastric emptying in DM. THIRD, we will test the hypothesis that idiopathic rapid GE results from disordered enterogastric feedback mechanisms (i.e., reduced enteric hormonal release and/or end-organ effects) and increased gastric motility and is associated with impaired glucose tolerance.
Delayed gastric emptying, or gastroparesis, and rapid gastric emptying are poorly understood conditions, which cause indigestion, affect glycemic control in DM, and cannot be not effectively managed by available therapies. This proposal will use state-of-the-art approaches to evaluate gastrointestinal motor activity, entero-gastric reflexes, autonomic functions, and imaging techniques to address the mechanisms and develop novel therapeutic strategies for gastric motor disturbances in idiopathic disorders and DM.
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