Abstract
Context
Novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control ...and weight loss (WL) compared with selective GLP-1RA dulaglutide.
Objective
Explore mechanisms of glucose control by tirzepatide.
Design
Post hoc analyses of fasting biomarkers and multiple linear regression analysis.
Setting
Forty-seven sites in 4 countries.
Patients or other Participants
Three hundred and sixteen subjects with type 2 diabetes.
Interventions
Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo.
Main Outcome Measures
Analyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks.
Results
Homeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (P ≤ .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P ≤ .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (P ≤ .033) and tirzepatide 10 mg significantly decreased HOMA2-IR (P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of tirzepatide (P < .05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and glycated hemoglobin A1c was conducted. WL significantly (P ≤ .028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively.
Conclusions
Tirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.
Crohn's disease (CD) and ulcerative colitis (UC) actually had different pathological mechanisms, as the former was mainly induced by Th1 and Th17 response and the latter by Th2 response. Our previous ...study found that oxazolone-induced Th2-mediated colitis could not be attenuated by vitamin D supplementation. This study investigated the influence of intestinal vitamin D receptor (VDR) knockout on oxazolone-induced colitis and explored the possible immunological mechanism. Intestinal VDR knockout mice had milder oxazolone-induced colitis than wildtype controls, as demonstrated by less body weight decrease and faster recovery, more intact local structure, reduced cell apoptosis, and better preserved barrier function. Th2-mediated inflammation was significantly inhibited by VDR deficiency. Meanwhile, the percentage of invariant natural killer T (iNKT) cells did not increase as much in intestinal VDR knockout mice as in wild-type controls, nor did the iNKT cells develop normally as in the controls. Intestinal VDR knockout protected against oxazolone-induced colitis in mice by blocking Th2 cell response and reducing the function of intestinal iNKT cells. Vitamin D status had no influence on the severity of colitis. This study may explain the diverse outcomes after vitamin D supplementation in literature and add some clue to the targeted therapy of IBD.
A novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists ...in type 2 diabetes mellitus (T2DM).
LY3298176 is a fatty acid modified peptide with dual GIP and GLP-1 receptor agonist activity designed for once-weekly subcutaneous administration. LY3298176 was characterised in vitro, using signaling and functional assays in cell lines expressing recombinant or endogenous incretin receptors, and in vivo using body weight, food intake, insulin secretion and glycemic profiles in mice.
A Phase 1, randomised, placebo-controlled, double-blind study was comprised of three parts: a single-ascending dose (SAD; doses 0.25–8 mg) and 4-week multiple-ascending dose (MAD; doses 0.5–10 mg) studies in healthy subjects (HS), followed by a 4-week multiple-dose Phase 1 b proof-of-concept (POC; doses 0.5–15 mg) in patients with T2DM (ClinicalTrials.gov no. NCT02759107). Doses higher than 5 mg were attained by titration, dulaglutide (DU) was used as a positive control. The primary objective was to investigate safety and tolerability of LY3298176.
LY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist.
A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25–15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean LSM difference 95% CI: −49.12 mg/dL −78.14, −20.12 and −43.15 mg/dL −73.06, −13.21, respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference 95% CI: −1.75 kg −3.38, −0.12, −5.09 kg −6.72, −3.46 and −4.61 kg −6.21, −3.01, respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference 95% CI: −2.62 kg −3.79, −1.45 and −2.07 kg −3.25, −0.88, respectively.
The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity.
Based on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity.
•LY3298176 activates both GIP and GLP-1 receptor signaling in vitro.•LY3298176 lowers blood glucose in mice through actions on both incretin receptors.•LY3298176 reduced fasting glucose in humans with type 2 diabetes.•Weight loss was greater with LY3298176 than the selective GLP-1 receptor agonist, dulaglutide in healthy humans.•Tolerability of LY3298176 was comparable to GLP-1 receptor agonists.
Background
This study investigated whether 8-hydroxy-2’-deoxyguanosine (8-OHdG) and N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations in the urine could predict bronchopulmonary ...dysplasia (BPD) in preterm infants.
Methods
This prospective cohort study enrolled 165 preterm infants, of whom 70 developed BPD. We measured urinary 8-OHdG and NT-proBNP concentrations from day of life (DOL) 7 to 28. Then, we evaluated the prediction efficiency by receiver operating characteristic curves and assessed correlations between the two biomarkers. Finally, we identified the predictive risk factors for BPD by multivariable logistic regression.
Results
8-OHdG and NT-proBNP levels were significantly higher from DOL 7 to 28 in the BPD group than in the control group (
P
< 0.05). Additionally, the 8-OHdG level was positively correlated with the NT-proBNP level (r: 0.655–0.789,
P
< 0.001), and the 8-OHdG and NT-proBNP levels were positively correlated with mechanical ventilation duration and oxygen exposure time (r: 0.175–0.505,
P
< 0.05) from DOL 7 to 28. Furthermore, the 8-OHdG (DOL 14–28) and NT-proBNP (DOL 7–28) levels were significantly associated with BPD development (
P
< 0.05).
Conclusion
The urine 8-OHdG concentrations from DOL 14 to 28 and NT-proBNP concentrations from DOL 7 to 28 may be practical non-invasive predictors of BPD development in preterm infants.
Despite remarkable breakthroughs in diagnosis and treatment, the prevalence of bronchopulmonary dysplasia (BPD) in preterm infants and the consequent mortality have remained high over the last ...half-century. The pathophysiology of BPD is complicated, with several causes. In addition, infants with severe BPD are predisposed to a variety of complications that need multidisciplinary collaboration during hospitalisation and post-discharge home treatment. Consequently, early prediction, precise prevention and individualised management have become the cornerstones of therapeutic care of preterm infants with BPD, thereby improving patient survival and prognosis. BPD has an operational clinical description; however, it has various clinical phenotypes and endotypes, making accurate prediction challenging. Currently, most approaches for predicting BPD in preterm infants include invasive collection of biofluids, which is inappropriate in fragile neonates. Consequently, researchers and clinicians are becoming more interested in noninvasive monitoring for BPD prediction. Comprehensive assessments of pertinent research, however, remain scarce. In this review, we compared many noninvasive monitoring techniques that contribute to early prediction of BPD development in premature infants.
Dramatic intestinal epithelial cell death leading to barrier dysfunction is one of the mechanism of neonatal necrotizing enterocolitis (NEC), in which Toll-like receptor 4 (TLR4) plays a pivotal ...role. This study explored the role of necroptosis, a drastic way of cell death in NEC.
The expression of necroptotic proteins was tested in NEC intestinal tissue and compared with controls. NEC was induced in neonatal wild-type mice and a necroptosis inhibitor was given to investigate whether NEC could be relieved. The general condition, macroscopic scoring, and histological evaluations were performed. The expression of tight junction proteins, inflammatory cytokines, and necroptosis-related proteins was measured, and barrier function was examined. Then, NEC was induced in TLR4-knockout pups to confirm the role of TLR4 in necroptosis.
Necroptotic proteins were significantly upregulated in both NEC patient and animal models, together with the expression of TLR4. NEC could be relieved and inflammatory infiltration was decreased by necrostatin-1s. TLR4-knockout mice showed milder tissue degradation and less necroptosis after NEC induction.
Necroptosis is an essential pathological process of NEC. TLR4 may be one stimulator of necroptosis in NEC. Inhibiting the intestinal cell necroptosis might be a useful strategy in the treatment of NEC.
Necroptosis is a key pathological process in NEC, which appears to involve TLR4. Anti-necroptosis treatment is a promising strategy that could significantly relieve the symptoms of NEC.
The effect of dual glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) receptor agonist (RA) tirzepatide on gastric emptying (GE) was compared to that of GLP‐1RAs ...in non‐clinical and clinical studies. GE was assessed following acute and chronic treatment with tirzepatide in diet‐induced obese mice versus semaglutide or long‐acting GIP analogue alone. Participants with and without type 2 diabetes (T2DM) from a phase 1, 4‐week multiple dose study received tirzepatide, dulaglutide or placebo. GE was assessed by acetaminophen absorption. In mice, tirzepatide delayed GE to a similar degree to that achieved with semaglutide; however, these acute inhibitory effects were abolished after 2 weeks of treatment. GIP analogue alone had no effect on GE or on GLP‐1's effect on GE. In participants with and without T2DM, once‐weekly tirzepatide (≥5 and ≥4.5 mg, respectively) delayed GE after a single dose. This effect diminished after multiple doses of tirzepatide or dulaglutide in healthy participants. In participants with T2DM treated with an escalation schedule of tirzepatide 5/5/10/10 or 5/5/10/15 mg, a residual GE delay was still observed after multiple doses. These data suggest that tirzepatide's activity on GE is comparable to that of selective GLP‐1RAs.
Tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide/ glucagon-like peptide-1 receptor agonist, is approved in the United States, Europe and Japan for the treatment of type 2 ...diabetes. Across the SURPASS-1 to -5 clinical studies, tirzepatide 5, 10 and 15 mg demonstrated significant improvements in glycated haemoglobin A1c (HbA1c) (- 1.9 to - 2.6%), body weight (- 6.6 to - 13.9%) and systolic blood pressure (SBP) (- 2.8 to - 12.6 mmHg) at the end of study treatment.
Post-hoc mediation analyses were conducted to evaluate weight-loss dependent and weight-loss independent effects of tirzepatide on SBP reductions across the 5 SURPASS studies. The safety population (all randomized patients who took at least 1 dose of study drug) of each study was analyzed. Additional analyses were conducted at individual study level or pooled across 5 SURPASS trials.
The difference in mean SBP change from baseline at 40 weeks (total effect) between the tirzepatide and comparator groups was - 1.3 to - 5.1 mmHg (tirzepatide 5 mg), - 1.7 to - 6.5 mmHg (tirzepatide 10 mg) and - 3.1 to - 11.5 mmHg (tirzepatide 15 mg). These SBP reductions were primarily mediated through weight loss, with different degrees of contributions from weight-loss independent effects across the different trials. In the SURPASS-4 study, which enrolled patients with established cardiovascular disease, weight-loss independent effects explained 33% to 57% of difference in SBP change between tirzepatide and insulin glargine groups. In a pooled analysis of the SURPASS-1 to -5 studies, there was a significant (p < 0.001) but weak correlation (r = 0.18 to 0.22) between change in body weight and SBP. Reductions in SBP with tirzepatide were not dependent on concomitant antihypertensive medications at baseline as similar reductions were observed whether participants were receiving them or not (interaction p = 0.77). The largest SBP reductions were observed in the highest baseline category (> 140 mmHg), while those in the first quartile of baseline SBP category (< 122 mmHg) observed no further decrease in SBP.
Tirzepatide-induced SBP reduction was primarily mediated through weight loss, with different degrees of contributions from weight-loss independent effects across the different trials. SBP reduction was not dependent on antihypertensive medication use but dependent on baseline SBP value, alleviating theoretical concerns of hypotension.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Preterm infants have immature gastrointestinal tracts and poor immunity. In this study, the effects of Lactobacillus reuteri DSM 17938 first on early feeding tolerance, growth, and second on ...infection prevention in preterm infants were evaluated.
One hundred fourteen formula-fed preterm infants with a gestational age between 30 weeks and 37 weeks, and a birth weight between 1500 and 2000 g were enrolled; 57 in the intervention and 57 in the control group:the intervention group was given a dose of 1 × 10
colony-forming units (5 drops) of L. reuteri DSM 17938 once daily, beginning with the first feeding until discharge. The control group did not receive probiotics. Early feeding tolerance (as time to full enterla feeding and number of reflux), growth, incidences of sepsis, localized infection, NEC, and adverse effects were recorded for both groups.
The number of Daily reflux episodes (times/d) was lower (2.18 ± 0.83 vs. 3.77 ± 0.66, P < 0.01) and time to full enteral feedings (120 mL/kg/d) (9.95 ± 2.46 d vs. 13.80 ± 3.47 d, P < 0.05) was shorter in the intervention group. Average daily weight gain (14.55 ± 3.07 g/d vs. 10.12 ± 2.80 g/d), head circumference increas e(0.0760 ± 0.0157 cm/d vs. 0.0681 ± 0.0108 cm/d), and body length increase (0.1878 ± 0.0151 cm/d vs. 0.1756 ± 0.0166 cm/d) of the intervention group were higher (P < 0.01). There were no significant differences in the incidences of sepsis (4.44% vs. 8.33%), localized infection (6.67% vs. 8.33%), or NEC (2.22% vs. 10.42%) between the 2 groups (P > 0.05). The number of daily defecations (times/d) in the intervention group was higher (3.08 ± 0.33 vs. 2.29 ± 0.20, P < 0.01) and the length of hospital stay was shorter than that in the control group (20.60 ± 5.36 d vs. 23.75 ± 8.57 d, P < 0.05). No adverse effects were noted among the infants receiving L. reuteri.
L. reuteri may be an useful tool in improving early feeding tolerance in preterm infants, promoting growth, increasing the frequency of defecation, and shortening the length of hospital stay.
ChiCTR, ChiCTR1900025590. Registered 1 February 2019- Retrospectively registered, http://www.chictr.org.cn/listbycreater.aspx.
The original version of this Article contained an error in the author affiliations. The affiliation of Tianjing Liu with Department of Pediatrics, Shengjing Hospital of China Medical University, ...Shenyang, China was inadvertently omitted. This has now been corrected in both the PDF and HTML versions.
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