Blunting of Colon Contractions in Diabetics with Gastroparesis Quantified by Wireless Motility Capsule Methods

<div><p>Generalized gut transit abnormalities are observed in some diabetics with gastroparesis. Relations of gastric emptying abnormalities to colon contractile dysfunction are poorly characterized. We measured colon transit and contractility using wireless motility capsules (WMC) in 41 healthy subjects, 12 diabetics with gastroparesis (defined by gastric retention >5 hours), and 8 diabetics with normal gastric emptying (≤5 hours). Overall numbers of colon contractions >25 mmHg were calculated in all subjects and were correlated with gastric emptying times for diabetics with gastroparesis. Colon transit periods were divided into quartiles by time and contraction numbers were calculated for each quartile to estimate regional colon contractility. Colon transit in diabetics with gastroparesis was prolonged vs. healthy subjects (P<0.0001). Overall numbers of colon contractions in gastroparetics were lower than controls (P = 0.02). Diabetics with normal emptying showed transit and contraction numbers similar to controls. Gastric emptying inversely correlated with overall contraction numbers in gastroparetics (r = -0.49). Numbers of contractions increased from the 1^st to 4^th colon transit quartile in controls and diabetics with normal emptying (P≤0.04), but not gastroparetics. Numbers of contractions in the 3^rd and 4^th quartiles were reduced in gastroparetics vs. healthy controls (P≤0.05) and in the 4^th quartile vs. diabetics with normal emptying (P = 0.02). Numbers of contractions were greatest in the final 15 minutes of transit, but were reduced in gastroparetics vs. healthy controls and diabetics with normal emptying (P≤0.005). On multivariate analyses, differences in numbers of contractions were not explained by demographic or clinical variables. In conclusion, diabetics with gastroparesis exhibit delayed colon transit associated with reductions in contractions that are prominently blunted in latter transit phases and which correlate with delayed gastric emptying, while diabetics with normal emptying show no significant colonic impairments. These findings emphasize diabetic gastroparesis may be part of a generalized dysmotility syndrome.</p></div

Subject Characteristics for Each of the Three Groups.

<p>Subject Characteristics for Each of the Three Groups.</p

Colon Transit Times in Relation to Gastric Emptying.

<p>Colon transit times are compared in individual healthy volunteers, diabetics with normal gastric emptying, and diabetics with gastroparesis. Gastroparesis patients exhibited significant prolongation of colon transit versus healthy subjects (P<0.0001), while diabetics with normal gastric emptying showed colon transit times that were not different from healthy controls (P = NS).</p

Regional Differences in Numbers of Colon Contractions.

<p>Numbers of colon contractions are plotted as a function of colon transit quartile (A) and for the final 15 minutes of colon transit (B). Healthy volunteers (P<0.0001) and diabetics with normal gastric emptying (P = 0.04) showed increased numbers of contractions from the first to fourth quartiles, while contractions did not increase from the first to fourth quartiles in diabetics with gastroparesis (P = NS). Compared to healthy controls, diabetics with gastroparesis exhibited reduced numbers of contractions in the third (P = 0.05) and fourth (P = 0.0006) quartiles. Diabetics with gastroparesis also showed lower numbers of contractions in the fourth quartile than diabetics with normal emptying (P = 0.02). Diabetics with normal emptying exhibited numbers of contractions that were no different from those of the healthy volunteers in any quartile of colon transit (all P = NS). Numbers of contractions in the final 15 minutes were reduced in diabetics with gastroparesis compared to healthy subjects (P = 0.0005) and diabetics with normal gastric emptying (P = 0.005). Numbers of contractions in the final 15 minutes were no different in diabetics without gastroparesis and healthy volunteers (P = NS).</p

Numbers of Colon Contractions.

<p>Overall numbers of colon contractions are plotted for the three groups. Diabetics with gastroparesis showed reductions in overall numbers of contractions compared to healthy subjects (P = 0.02). Overall contractions in diabetics with normal gastric emptying were not different than in diabetic patients with gastroparesis or in healthy controls (P = NS).</p

Correlation of Colon Contraction Numbers with Gastric Emptying.

<p>The correlation of overall numbers of colon contractions with gastric emptying times is plotted for diabetics with gastroparesis. There was a moderately good inverse correlation (r value -0.49) with patients with the most severe emptying delays exhibiting lower numbers of contractions.</p

Representative WMC Recordings.

<p>Representative WMC recordings are shown from a healthy volunteer (A, C) and a diabetic with gastroparesis (B, D). In the complete recording from the healthy subject, there is an abrupt pH decrease (red) at 10 hours and 15 minutes reflecting ileocecal (IC) transit (A). The capsule is expelled at 37 hours and 39 minutes. In the diabetic, IC transit occurs at 33 hours and 15 minutes and the capsule is expelled at 97 hours and 14 minutes (B). Pressure activity (blue) increases prior to WMC expulsion in the healthy subject, but not in the diabetic with gastroparesis. In the final 15 minutes of colon transit, contractions (blue) are frequent and intense in the healthy volunteer (C) but are reduced in the diabetic (D).</p

<i>In Vivo</i> Dissolution and Systemic Absorption of Immediate Release Ibuprofen in Human Gastrointestinal Tract under Fed and Fasted Conditions

<i>In vivo</i> drug dissolution in the gastrointestinal (GI) tract is largely unmeasured. The purpose of this clinical study was to evaluate the <i>in vivo</i> drug dissolution and systemic absorption of the BCS class IIa drug ibuprofen under fed and fasted conditions by direct sampling of stomach and small intestinal luminal content. Expanding current knowledge of drug dissolution <i>in vivo</i> will help to establish physiologically relevant <i>in vitro</i> models predictive of drug dissolution. A multilumen GI catheter was orally inserted into the GI tract of healthy human subjects. Subjects received a single oral dose of ibuprofen (800 mg tablet) with 250 mL of water under fasting and fed conditions. The GI catheter facilitated collection of GI fluid from the stomach, duodenum, and jejunum. Ibuprofen concentration in GI fluid supernatant and plasma was determined by LC–MS/MS. A total of 23 subjects completed the study, with 11 subjects returning for an additional study visit (a total of 34 completed study visits). The subjects were primarily white (61%) and male (65%) with an average age of 30 years. The subjects had a median [min, max] weight of 79 [52, 123] kg and body mass index of 25.7 [19.4, 37.7] kg/m². Ibuprofen plasma levels were higher under fasted conditions and remained detectable for 28 h under both conditions. The AUC_0–24 and <i>C</i>_max were lower in fed subjects vs fasted subjects, and <i>T</i>_max was delayed in fed subjects vs fasted subjects. Ibuprofen was detected immediately after ingestion in the stomach under fasting and fed conditions until 7 h after dosing. Higher levels of ibuprofen were detected in the small intestine soon after dosing in fasted subjects compared to fed. In contrast to plasma drug concentration, overall gastric concentrations remained higher under fed conditions due to increased gastric pH vs fasting condition. The gastric pH increased to near neutrality after feedingbefore decreasing to acidic levels after 7 h. Induction of the fed state reduced systemic levels but increased gastric levels of ibuprofen, which suggest that slow gastric emptying and transit dominate the effect for plasma drug concentration. The finding of high levels of ibuprofen in stomach and small intestine 7 h post dosing was unexpected. Future work is needed to better understand the role of various GI parameters, such as motility and gastric emptying, on systemic ibuprofen levels in order to improve <i>in vitro</i> predictive models

Data on subjects that were studied.

<p>Data on subjects that were studied.</p

Allele distribution in gastroparetic and control subjects.

<p>Allele distribution of long (L), medium (M) and short (S) alleles a) for subjects with gastroparesis is significantly different from the distribution for control subjects (Chi² P value = 0.019) and b) for subjects with idiopathic gastroparesis compared to non-diabetic controls (Chi² P value = 0.049). Short alleles were defined as shorter than 29 polyGT repeats and long alleles were defined as longer than 32 repeats (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0187772#pone.0187772.g001" target="_blank">Fig 1a</a> for definition).</p