Bharucha, Adil E.

Controlling meal-related glucose excursions continues to be a therapeutic challenge in diabetes mellitus. Mechanistic reasons for this need to be understood better to develop appropriate therapies. To investigate delayed gastric emptying effects on postprandial glucose turnover, insulin sensitivity, and β-cell responsivity and function, as a feasibility study prior to studying patients with type 1 diabetes, we used the triple tracer technique C-peptide and oral minimal model approach in healthy subjects. A single dose of 30 μg of pramlintide administered at the start of a mixed meal was used to delay gastric emptying rates. With delayed gastric emptying rates, peak rate of meal glucose appearance was delayed, and rate of endogenous glucose production (EGP) was lower. C-peptide and oral minimal models enabled the assessments of β-cell function, insulin sensitivity, and β-cell responsivity simultaneously. Delayed gastric emptying induced by pramlintide improved total insulin sensitivity and decreased total β-cell responsivity. However, β-cell function as measured by total disposition index did not change. The improved whole body insulin sensitivity coupled with lower rate of appearance of EGP with delayed gastric emptying provides experimental proof of the importance of evaluating pramlintide in artificial endocrine pancreas approaches to reduce postprandial blood glucose variability in patients with type 1 diabetes.

AbstractBackgroundHeme oxygenase 1 (HO‐1) degrades heme and protects against oxidative stress. In vitro and animal models suggest that HO‐1 is beneficial in several diseases (e.g., postoperative ileus, gastroparesis, acute pancreatitis, and colitis). However, the only drugs (i.e., hemin and heme arginate) which pharmacologically upregulate HO‐1 in humans are expensive and can only be administered intravenously. Our aims were to compare the effects of placebo, aspirin, and simvastatin alone, and with α‐lipoic acid, on HO‐1 protein concentration and activity in humans.MethodsThis randomized, double‐blind, placebo‐controlled study compared the effects of three oral regimens administered for 7 days, i.e., placebo; aspirin (325 mg twice daily) and simvastatin (40 mg twice daily); aspirin, simvastatin, and the sodium salt of R‐ α‐lipoic acid (NaRLA, 600 mg three times daily) on markers of HO‐1 activation (i.e., plasma HO‐1 protein concentration and venous monocyte HO‐1 protein activity) in 18 healthy subjects (14 females). Markers of HO‐1 activation were evaluated at baseline, days 2, and 7.Key ResultsBaseline HO‐1 protein concentrations and activity were similar among the three groups. Compared to placebo, aspirin and simvastatin combined, or together with NaRLA did not affect HO‐1 protein concentration or activity at 2 or 7 days. HO‐1 protein concentrations and activity were correlated on day 7 (r = 0.75, p = 0.0004) but not at baseline and on day 2.Conclusions & InferencesAt therapeutic doses, aspirin, simvastatin, and α‐lipoic acid do not increase plasma HO‐1 protein concentration or venous monocyte HO‐1 activity in healthy humans.

Gastric emptying, accommodation, and motility can be quantified with magnetic resonance imaging (MRI). The first step in image analysis entails segmenting the stomach from surrounding structures, usually by a time-consuming manual process. We have developed a semiautomated process to segment and measure gastric volumes with MRI. Gastric images were acquired with a three-dimensional gradient echo MRI sequence at 5, 10, 20, and 30 min after ingestion of a liquid nutrient (Ensure, 296 ml) labeled with gadolinium in 20 healthy volunteers and 29 patients with dyspeptic symptoms. The agreement between gastric volumes measured by manual segmentation and our new semiautomated algorithm was assessed with Lin's concordance correlation coefficient (CCC) and the Bland Altman test. At 5 min after a meal, food volumes measured by manual (352 ± 4 ml) and semiautomated (346 ± 4 ml) techniques were correlated {CCC[95% confidence interval (CI)] 0.70 (0.52, 0.81)}; air volumes measured by manual (88 ± 6 ml) and semiautomated (84 ± 6 ml) techniques were also correlated [CCC (95% CI) 0.89 (0.82, 0.94)]. Findings were similar at subsequent time points. The Bland Altman test was not significant. The time required for semiautomated segmentation ranged from an average of 204 s for the 5-min images to 233 s for the 20-min images. These times were appreciably smaller than the typical times of many tens of minutes, even hours, required for manual segmentation. To conclude, a semiautomated process can measure gastric food and air volume using MRI with comparable accuracy and far better efficiency than a manual process.

The pathobiology of irritable bowel syndrome (IBS) is multifaceted. We aimed to identify candidate genes predisposing to quantitative traits in IBS. In 30 healthy volunteers, 30 IBS-constipation, and 64 IBS-diarrhea patients, we measured bowel symptoms, bile acid (BA) synthesis (serum 7α-hydroxy-4-cholesten-3-one and FGF19), fecal BA and fat, colonic transit (CT by scintigraphy), and intestinal permeability (IP by 2-sugar excretion). We assessed associations of candidate genes controlling BA metabolism ( KLB rs17618244 and FGFR4 rs351855), BA receptor ( GPBAR1 rs11554825), serotonin (5-HT) reuptake ( SLC6A4 through rs4795541 which encodes for the 44-bp insert in 5HTTLPR), or immune activation ( TNFSF15 rs4263839) with three primary quantitative traits of interest: colonic transit, BA synthesis, and fecal BA excretion. There were significant associations between fecal BA and CT at 48 h ( r = 0.43; P < 0.001) and IP ( r = 0.23; P = 0.015). GPBAR1 genotype was associated with CT48 ( P = 0.003) and total fecal BA [ P = 0.030, false detection rate (FDR) P = 0.033]. Faster CT48 observed with both CC and TT GPBAR1 genotypes was due to significant interaction with G allele of KLB, which increases BA synthesis and excretion. Other univariate associations ( P < 0.05, without FDR correction) observed between GPBAR1 and symptom phenotype and gas sensation ratings support the role of GPBAR1 receptor. Associations between SLC6A4 and stool consistency, ease of passage, postprandial colonic tone, and total fecal BA excretion provide data in support of future hypothesis-testing studies. Genetic control of GPBAR1 receptor predisposing to pathobiological mechanisms in IBS provides evidence from humans in support of the importance of GPBAR1 to colonic motor and secretory functions demonstrated in animal studies.

AbstractBackgroundTreatment options for constipation‐predominant irritable bowel syndrome (IBS‐C) are limited. While linaclotide improved IBS‐C symptoms in randomized controlled trials (RCTs), results vary among studies and the magnitude of benefit is unclear.MethodsTwo investigators independently extracted data on study participants, methods and outcomes (i.e., symptoms, quality of life, and adverse events) from eligible articles i.e., RCTs comparing linaclotide with placebo in adult patients with IBS‐C with a follow‐up of 12 weeks or longer. The grading of recommendations assessment, development and evaluation (GRADE) methodology was used to rate the quality of evidence.Key ResultsOf 182 identified citations, three RCTs enrolling 1773 patients met the inclusion criteria. Compared with placebo, fewer patients on linaclotide failed to achieve responses i.e., FDA endpoint (1604 patients, risk ratio [RR] = 0.80; 95%CI 0.76–0.85), adequate IBS symptom relief (1773 patients, RR = 0.73; 95%CI 0.65–0.82), and clinically meaningful improvement in IBS‐QOL (1659 patients, RR = 0.78; 95%CI 0.72–0.86). The incidence of diarrhea leading to discontinuation of treatment was higher for linaclotide (1773 patients, RR = 14.75; 95%CI 4.04–53.81). The quality of evidence was rated as moderate for FDA endpoint and adequate relief response, high for diarrhea, and low for IBS‐QOL. Generalizability may be limited by the study population (i.e., predominantly white female patients), lack of data regarding prior therapy, and availability of few RCTs. The number of patients is insufficient to identify rare adverse events.Conclusions & InferencesLinaclotide is moderately effective in improving symptoms of IBS‐C with diarrhea being the major side effect. Further studies are needed to evaluate the long‐term efficacy and safety of linaclotide for IBS‐C.

Abstract Background Defecatory disorders can be diagnosed by rectal balloon expulsion ( BE ) and anorectal manometry, which are traditionally evaluated in the seated and left lateral ( LL ) positions, respectively. The aims of this study were to compare BE in the LL and seated positions and to compare anorectal manometric parameters to BE performed in the seated and LL positions. Methods 220 women [healthy (62), chronic constipation (158)] had anorectal high‐resolution manometry and BE , summarized by time required (seated position, normal ≤60 s) or external traction to facilitate expulsion ( LL position, normal ≤100 g). Key Results Balloon expulsion results in both positions were either concordant [normal (141) or abnormal (32)] or discordant [only LL abnormal (30), only seated abnormal (17)]. There was modest agreement [κ = 0.44 (95% CI 0.30–0.57)] between seated and LL BE . Compared with subjects with normal BE in both positions, anal pressure during simulated evacuation ( SE ) was higher, and the rectoanal gradient (rectal‐anal pressure) during SE was more negative in the other 3 categories (i.e., abnormal LL only, abnormal seated only, and both abnormal). High anal pressure during SE ( OR = 1.02, 95% CI 1.00–1.04) and high rectal sensory threshold for desire to defecate ( OR = 1.01, 95% CI 1.00–1.02) were associated with increased risk of abnormal BE in both positions, whereas high rectal pressure during SE ( OR = 0.96, 95% CI 0.93–0.98) was associated with lower risk. Conclusions & Inferences There is modest agreement between rectal BE in LL and seated positions. In addition to abnormal seated BE , which is considered indicative of pelvic floor dysfunction, high resolution manometry findings suggest that even some patients with abnormal BE in the LL position have pelvic floor dysfunction.

We recently demonstrated a diurnal pattern to insulin action (i.e., insulin sensitivity [SI]) in healthy individuals with higher SI at breakfast than at dinner. To determine whether such a pattern exists in type 1 diabetes, we studied 19 subjects with C-peptide–negative diabetes (HbA1c 7.1 ± 0.6%) on insulin pump therapy with normal gastric emptying. Identical mixed meals were ingested during breakfast, lunch, and dinner at 0700, 1300, and 1900 h in randomized Latin square of order on 3 consecutive days when measured daily physical activity was equal. The triple tracer technique enabled measurement of glucose fluxes. Insulin was administered according to the customary insulin:carbohydrate ratio for each participant. Although postprandial glucose excursions did not differ among meals, insulin concentration was higher (P &lt; 0.01) and endogenous glucose production less suppressed (P &lt; 0.049) at breakfast than at lunch. There were no differences in meal glucose appearance or in glucose disappearance between meals. Although there was no statistical difference (P = 0.34) in SI between meals in type 1 diabetic subjects, the diurnal pattern of SI taken across the three meals in its entirety differed (P = 0.016) from that of healthy subjects. Although the pattern in healthy subjects showed decreasing SI between breakfast and lunch, the reverse SI pattern was observed in type 1 diabetic subjects. The results suggest that in contrast to healthy subjects, SI diurnal pattern in type 1 diabetes is specific to the individual and cannot be extrapolated to the type 1 diabetic population as a whole, implying that artificial pancreas algorithms may need to be personalized.