42 Loss/dysfunction of ICC appears to be central to the pathogenesis of diabetic gastroparesis.43 In animal models and humans with diabetic gastroparesis, a reduction in intraneuronal levels of nitric oxide,
an important Palbociclib cell line enteric neurotransmitter, has been observed, reflecting loss of neuronal nitric oxide synthase (nNOS) expression within the myenteric neurons and, potentially, inhibition of nNOS by advanced glycation products.44 Heme-oxygenase-1, the enzyme which gives rise to carbon monoxide (CO), which protects the ICC from oxidative stress, has recently been shown to be reduced in non-obese diabetic (NOD) mice with delayed gastric emptying.45 Administration of hemin, which increases the expression of hem-oxygenase-1,42,45 and administration of CO,46 reversed the loss of ICC with normalization of delayed gastric emptying. Hemin also increases plasma levels of heme-oxygenase-1 when given intravenously to healthy humans47 and may, accordingly, have a therapeutic role. In the initial study, while there was
no significant correlation between plasma glucose levels and the rate of gastric emptying, gastric emptying of liquids and the lag phase for solids were slower when the mean plasma glucose was >15mmol/L. PF-01367338 mouse It was subsequently established, using the glucose “clamp” technique, that acute variations in blood glucose impact significantly on gastric emptying in both healthy and diabetic subjects,48 with marked hyperglycemia (blood glucose ∼15mmol/L) delaying gastric emptying of solids and liquids substantially.49 Gastric emptying is also slower when the blood glucose is at the upper end of the physiological postprandial range (∼8mmol/L), when compared to a blood glucose of ∼4mmol/L, in both healthy subjects and patients with uncomplicated type 1 diabetes.50 The mechanisms by which acute hyperglycemia slows gastric emptying include suppression
Paclitaxel datasheet of antral contractions,48 increased pyloric contractions,48 proximal stomach relaxation48 and induction of gastric electrical dysrhythmias.35 In the initial study, the duration of the lag phase for solids was apparently related to chronic blood glucose control, as assessed by glycated hemoglobin, but the relevance of long-term glycemia to the pathogenesis of gastroparesis remains uncertain. In contrast to the effects of acute hyperglycemia, insulin-induced hypoglycemia accelerates gastric emptying in healthy subjects,51 patients with uncomplicated type 1 diabetes52 and in type 1 diabetics with gastroparesis.53 Such enhanced gastric emptying probably serves as a counter-regulatory mechanism to hasten the delivery of nutrients for absorption.