Improved HbA1c and body weight in GADA-positive individuals treated with tirzepatide: A post hoc analysis of SURPASS.

CONTEXT: People with clinically diagnosed type 2 diabetes (T2D) but positive anti-glutamic acid decarboxylase autoantibodies (GADA), referred to here as latent autoimmune diabetes in adults (LADA), may experience more rapid glycemic deterioration than those with T2D and may benefit from effective diabetes treatment with additional metabolic benefits. OBJECTIVE: Assess glycated hemoglobin (HbA1c) and body weight (BW) changes associated with tirzepatide in GADA-positive versus GADA-negative participants with clinical T2D diagnosis. DESIGN: Post hoc analyses based on pooled data from SURPASS 2-5, using mixed-model repeated measures from the efficacy analysis set, adjusting for study and baseline covariates including age, sex, baseline values, body mass index (BMI), and GADA status. SETTING: N/A. PATIENTS: N = 3791. INTERVENTION: Tirzepatide (5, 10, 15 mg). MAIN OUTCOME MEASURE(S): Change from baseline in HbA1c at Weeks 40 (SURPASS-2, -3, -5) and 42 (SURPASS-4)by GADA status. RESULTS: In participants with confirmed GADA status, 3671 (96.8%) were GADA-negative and 120 (3.2%) were GADA-positive (76 [63.3%] with low and 44 [36.7%] with high GADA levels). Baseline characteristics were similar between groups, except for slightly lower BMI in GADA-positive versus GADA-negative participants (mean [SD] BMI 32.2 [6.1] versus 33.6 [6.3] kg/m2). At Week 40/42, both groups achieved robust reductions in HbA1c (-2.11% versus -2.32%) and BW (9.2 kg versus -9.6 kg) (p < 0.001, both groups). HbA1c reductions were greater in GADA-negative participants (estimated difference [95% CI]: 0.21% [0.03, 0.39]; p = 0.024) and BW reductions did not differ between groups (0.38 kg [-0.99, 1.75]; p = 0.588). CONCLUSIONS: In this post hoc analysis, tirzepatide was associated with substantial reductions in HbA1c and BW irrespective of GADA status in adults diagnosed with T2D, suggesting that tirzepatide may improve glycemic control in individuals with LADA.

Carrier proteins boost expression of PR-39-derived peptide in Pichia pastoris.

AIMS: Multidrug resistance presents difficulties in preventing and treating bacterial infections. Proline-rich antimicrobial peptides (PrAMPs) inhibit bacterial growth by affecting the intracellular targets rather than by permeabilizing the membrane. The aim of this study was to develop a yeast-based fusion carrier system using calmodulin (CaM) and xylanase (XynCDBFV) as two carriers to express the model PrAMP PR-39-derived peptide (PR-39-DP) in Pichia pastoris. METHODS AND RESULTS: Fusion protein secreted into the culture supernatant was purified in a one-step on-column digestion using human rhinovirus 3C protease, obtaining the target peptide PR-39-DP. The growth curves of Escherichia coli were monitored by recording the OD600 values of the bacteria. The antibacterial activity of PR-39-DP was evaluated in killing assays performed on E. coli. The yield of PR-39-DP was 1.0-1.2 mg l-1 in the CaM fusion carrier system, approximately three times that of the XynCDBFV fusion carrier system. The minimal inhibitory concentration of PR-39-DP was ∼10.5 µg ml-1. CONCLUSIONS: CaM and XynCDBFV provide increased stability and promote the expression and secretion of active PR-39-DP.

Berberine combined with stachyose improves glycometabolism and gut microbiota through regulating colonic microRNA and gene expression in diabetic rats.

AIMS: Berberine is effective for type 2 diabetes mellitus (T2DM), but has limited use in clinic. This study aims to evaluate the effect of berberine combined with stachyose on glycolipid metabolism and gut microbiota and to explore the underlying mechanisms in diabetic rats. MAIN METHODS: Zucker diabetic fatty (ZDF) rats were orally administered berberine, stachyose and berberine combined with stachyose once daily for 69 days. The oral glucose tolerance and levels of blood glucose, insulin, triglyceride and total cholesterol were determined. The gut microbial profile, colonic miRNA and gene expression were assayed using Illumina sequencing. The quantitative polymerase chain reaction was used to verify the expression of differentially expressed miRNAs and genes. KEY FINDINGS: Repeated treatments with berberine alone and combined with stachyose significantly reduced the blood glucose, improved the impaired glucose tolerance, and increased the abundance of beneficial Akkermansiaceae, decreased that of pathogenic Enterobacteriaceae in ZDF rats. Furthermore, combined treatment remarkably decreased the abundances of Desulfovibrionaceae and Proteobacteria in comparison to berberine. Combined treatment evidently decreased the expression of intestinal early growth response protein 1 (Egr1) and heparin-binding EGF-like growth factor (Hbegf), and significantly increased the expression of miR-10a-5p, but berberine alone not. SIGNIFICANCE: Berberine combined with stachyose significantly improved glucose metabolism and reshaped gut microbiota in ZDF rats, especially decreased the abundance of pathogenic Desulfovibrionaceae and Proteobacteria compared to berberine alone, providing a novel strategy for treating T2DM. The underlying mechanisms may be associated with regulating the expression of intestinal Egr1, Hbegf and miR-10a-5p, but remains further elucidation.

[Structure, function and application of serine carboxypeptidase-like acyltransferases from plants].

Plant serine carboxypeptidase-like acyltransferases (SCPL-AT) have similar structural characteristics and high homology compared to the serine carboxypeptidase. They can transfer the acyl from acyl glucose esters to many natural products, participate in the acylation modification of plant secondary metabolites, enrich the structural diversity of natural products, and improve the physicochemical properties such as water solubility and stability of compounds. This review summarizes the structural characteristics, catalytic mechanism, functional characterization, and biocatalytic applications of SCPL-AT from plants. This will help to promote the functional characterization of these acyltransferase genes and the biosynthesis of useful plant secondary metabolites by synthetic biotechnology.

Efficacy of once-daily glucagon-like peptide-1 receptor agonist lixisenatide as an add-on treatment to basal insulin in Asian and white adults with type 2 diabetes mellitus: An individual-level pooled analysis of phase III studies.

AIMS/INTRODUCTION: The prevalence and pathophysiological background of type 2 diabetes mellitus vary across ethnicities, and can affect treatment responses. Adding lixisenatide to basal insulin (BI) in type 2 diabetes mellitus patients has shown improvements in glycated hemoglobin (HbA1c) and postprandial glycemic (PPG) excursions, without increasing hypoglycemic events. We aim to compare the efficacy of lixisenatide in Asian and white patients inadequately controlled with basal insulin. MATERIALS AND METHODS: An individual-level pooled analysis of two multi-national phase III studies, GetGoal-L and GetGoal-L-C, was carried out to assess the efficacy of lixisenatide versus placebo as an add-on treatment to BI ± metformin in Asian and white patients with type 2 diabetes mellitus. Change in HbA1c, 2-h PPG and PPG excursion were analyzed, along with possible predictors of glycemic control. RESULTS: Pooled data showed that baseline characteristics were similar between Asian and white patients with the exception of bodyweight, body mass index and BI dose being higher in white patients. After 24 weeks, lixisenatide reduced HbA1c in both ethnic groups, with no statistically significant difference between the two groups (Asian patients least squares mean difference -0.49, 95% confidence interval -0.68 to - 0.30 and white patients least squares mean difference -0.45, 95% confidence interval -0.63 to - 0.26; P = 0.6287). Similarly, no significant difference was found in 2-h PPG reduction between both groups (least squares mean difference for Asian vs white patients: -3.37 vs -3.93; P = 0.3203). Treatment with lixisenatide contributed to HbA1c reduction of -0.56% after adjustment of baseline HbA1c level in Asian patients, and -0.41% in white patients. CONCLUSIONS: Adding lixisenatide to BI significantly reduced HbA1c and 2-h PPG levels in both Asian and white participants with type 2 diabetes mellitus. No differences in treatment effect were observed between the two populations.

Effects of a ready-to-eat cereal formula powder on glucose metabolism, inflammation, and gut microbiota in diabetic db/db mice.

The cereal formula powder, Zhengda Jingshan (ZDJS), comprises dietary fiber, multivitamins, fine protein, and various cereal ingredients. The present study evaluated the effects of ZDJS on glucose metabolism and explored the corresponding mechanisms in terms of modulating gut microbiota and the fecal metabolome. Type 2 diabetic db/db mice were given ZDJS (1 g/kg) orally twice daily for 55 days, after which glucose metabolism, inflammation, gut microbiota, and fecal metabolomics were assayed. Repeated administration of ZDJS was associated with a trend toward decreasing fasting blood glucose and a 0.12% decrease in hemoglobin A1c (HbA1c), as well as statistically significant increases in the insulin sensitivity index and decreases in serum levels of tumor necrosis factor (TNF-α) and ileum expression of mucin-2. ZDJS also ameliorated the compensatory enlargement of islets and decreased the ratio of the α-cell area to total islet area; however, this amelioration of impaired oral glucose tolerance became less pronounced as treatment continued. In addition, ZDJS remarkably decreased the abundance of phylum Proteobacteria and the phylum ratio of Firmicutes to Bacteroidetes, as well as altered the fecal metabolic profile. Taken together, our findings demonstrate that ZDJS improved glucose metabolism and reduced inflammation in type 2 diabetic db/db mice, which may be associated with a reshaping of the gut microbiome and fecal metabolome in db/db mice. Thus, our study suggests that ZDJS may represent a complementary therapy for patients with type 2 diabetes.

iGlarLixi effectively reduces residual hyperglycaemia in patients with type 2 diabetes on basal insulin: A post hoc analysis from the LixiLan-L study.

Globally, nearly half of patients with type 2 diabetes (T2D) do not successfully achieve target HbA1c with basal insulin, despite meeting fasting plasma glucose (FPG) targets. In this post hoc analysis of the LixiLan-L study, we determined whether iGlarLixi, a fixed-ratio combination of insulin glargine Gla-100 (iGlar) and the glucagon-like peptide-1 receptor agonist lixisenatide (Lixi), addresses the challenge of reducing residual hyperglycaemia in patients with T2D. In LixiLan-L, a randomized, open-label study, 1018 patients with T2D on basal insulin for ≥6 months ± oral antidiabetes drugs entered a 6-week run-in period, during which they were switched to and/or optimized for a daily dose of iGlar while continuing only metformin. Following the run-in period, 736 patients were then randomized to receive iGlarLixi or were continued on iGlar for 30 weeks ± metformin. Residual hyperglycaemia was defined as HbA1c ≥ 7.0% despite FPG of <140 mg/dL. The proportion of patients with residual hyperglycaemia was similar in both treatment arms at screening (~~42%), and increased after the run-in period (~~62%). After 30 weeks, the proportion of patients with residual hyperglycaemia declined to 23.8% in the iGlarLixi versus 47.1% in the iGlar arm (P < .0001). The proportion of patients achieving both HbA1c (<7.0%) and FPG (<140 mg/dL) targets was higher in the iGlarLixi compared with the iGlar arm (50.3% vs. 27.4%, respectively; P < .0001). iGlarLixi effectively reduces residual hyperglycaemia in patients with T2D on basal insulin therapy.

Impact of disease duration and ß-cell reserve on the efficacy of switching to iGlarLixi in adults with type 2 diabetes on glucagon-like peptide-1 receptor agonist therapy: Exploratory analyses from the LixiLan-G trial.

AIM: To evaluate the efficacy of iGlarLixi by C-peptide levels and duration of diabetes in an exploratory analysis of the LixiLan-G study. METHODS: LixiLan-G was a 26-week, randomized, open-label study in adults with type diabetes (T2D) inadequately controlled while on a glucagon-like peptide-1 receptor agonist (GLP-1 RA), with metformin, with or without pioglitazone and/or a sodium-glucose co-transporter-2 inhibitor. This analysis investigated the efficacy of switching to iGlarLixi by fasting baseline quartile C-peptide levels and baseline quartile of duration of T2D compared with continued GLP-1 RA use. RESULTS: Change in glycated hemoglobin (HbA1c) from baseline to week 26 was significantly greater with iGlarLixi compared with continued GLP-1 RAs across all fasting C-peptide quartiles (-1.00% to -1.06% vs. -0.23% to -0.54% range, respectively) and irrespective of all T2D duration quartiles (-0.94% to -1.07% vs. -0.25% to -0.50% range). A significantly greater proportion of participants in the iGlarLixi arm achieved an HbA1c of <7% across all C-peptide quartiles (51%-73% range) than in the GLP-1 RA arm (19%-32% range). The greatest reductions in HbA1c in participants receiving iGlarLixi were observed in those with the shortest duration of disease, although consistently greater than reductions observed with continued GLP-1 RAs. Reductions in HbA1c were comparable across C-peptide quartiles within the iGlarLixi arm. CONCLUSIONS: The results of this study suggest that iGlarLixi is an effective treatment option, irrespective of C-peptide levels or duration of diabetes, in adults with insufficiently controlled T2D receiving GLP-1 RAs.

cDNA isolation and functional characterization of UDP-glucose 4-epimerase from Davallia divaricate.

UDP-glucose 4-epimerase (UGE) is a universal enzyme responsible for interconversion of UDP-glucose and UDP-galactose. However, the gene encoding UGE from Davallia divaricate is elusive. In this study, two UGE genes, ddUGE1 and ddUGE2, were isolated and cloned from D. divaricate using a transcriptome-guided search strategy. Two unigenes sharing high sequence identity with UGE homologous genes were selected from transcriptome assembly. The enzymes, further functionally expressed in Escherichia coli, exhibit narrow substrate specificity. The biochemical characterization assays of DdUGE1 and DdUGE2 showed good thermal and pH stability, and metal ion independence, which provides a meaningful feature for biotechnological applications.[Formula: see text].

Efficacy and Safety of iGlarLixi, Fixed-Ratio Combination of Insulin Glargine and Lixisenatide, Compared with Basal-Bolus Regimen in Patients with Type 2 Diabetes: Propensity Score Matched Analysis.

INTRODUCTION: Basal-bolus (BB) regimens are generally used to intensify basal insulin therapy in patients with type 2 diabetes (T2D) not meeting glycemic targets. However, drawbacks include multiple injection burden and risk of weight gain and hypoglycemia. A once-daily titratable fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide (iGlarLixi) may provide a simple, well-tolerated, and efficacious alternative. We compared these treatments in a post hoc propensity score matched analysis using randomized trial data. METHODS: From the LixiLan-L study, 195 patients who had been randomized to iGlarLixi were matched for age, sex, race, T2D duration, baseline body mass index, glycated hemoglobin (HbA1c), fasting plasma glucose, insulin dose, and metformin use to 195 patients who had been randomized to a BB regimen in the GetGoal Duo-2 trial. RESULTS: At study end, estimated treatment differences for reduction in HbA1c and weight change, and ratio of hypoglycemia events per patient-year (BB vs iGlarLixi) were - 0.28% (standard error 0.08, P = 0.0002), - 1.32 kg (standard error 0.30, P < 0.0001), and 2.85 (P < 0.0001), respectively, all favoring iGlarLixi over BB. Also, proportions of patients reaching individual and composite goals (HbA1c < 7% [< 53 mmol/mol], no weight gain, and no hypoglycemia) were higher in the iGlarLixi compared with the BB treatment group. Gastrointestinal side effects were more common with iGlarLixi. CONCLUSIONS: In patients with T2D inadequately controlled on basal insulin, iGlarLixi offers an effective alternative to BB regimen for reducing HbA1c, without increased risk of hypoglycemia and weight gain. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02058160 (LixiLan-L trial); NCT01768559 (GetGoal Duo-2 trial). Plain language summary available for this article.

Berberine combined with stachyose induces better glycometabolism than berberine alone through modulating gut microbiota and fecal metabolomics in diabetic mice.

Berberine (BBR), a small alkaloid, is used as a hypoglycemic agent in China. Stachyose (Sta), a Rehmannia glutinosa oligosaccharide, acts as a prebiotic. This study aimed to evaluate whether BBR combined with Sta produced better glycometabolism than BBR alone, and explored the effects on gut microbiota and metabolomics. Type-2 diabetic db/db mice were administered BBR (100 mg/kg), Sta (200 mg/kg), or both by gavage once daily. Glucose metabolism, the balance of α- and ß-cells, and mucin-2 expression were ameliorated by combined treatment of BBR and Sta, with stronger effects than upon treatment with BBR alone. The microbial diversity and richness were altered after combined treatment and after treatment with BBR alone. The abundance of Akkermansia muciniphila was increased by combined treatment compared to treatment with BBR alone, while the levels of the metabolite all-trans-heptaprenyl diphosphate were decreased and the levels of fumaric acid were increased, which both showed a strong correlation with A. muciniphila. In summary, BBR combined with Sta produced better glycometabolism than BBR alone through modulating gut microbiota and fecal metabolomics, and may aid in the development of a novel pharmaceutical strategy for treating Type 2 diabetes mellitus.

The Impact of Sotagliflozin on Renal Function, Albuminuria, Blood Pressure, and Hematocrit in Adults With Type 1 Diabetes.

OBJECTIVE: In people with type 2 diabetes, sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce cardiovascular risk and progression of diabetic kidney disease. Our aim was to determine whether sotagliflozin (SOTA), a dual SGLT1i and SGLT2i, had favorable effects on clinical biomarkers suggestive of kidney protection in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: In this 52-week pooled analysis, 1,575 adults enrolled in the inTandem1 and inTandem2 trials were randomized to SOTA 200 mg, 400 mg, or placebo in addition to optimized insulin therapy. Changes in cardiorenal biomarkers were assessed. RESULTS: At 52 weeks, in response to SOTA 200 and 400 mg, the placebo-corrected least squares mean change from baseline in estimated glomerular filtration rate was -2.0 mL/min/1.73 m2 (P = 0.010) and -0.5 mL/min/1.73 m2 (P = 0.52), respectively. Systolic blood pressure difference was -2.9 and -3.6 mmHg (P < 0.0001 for both); diastolic blood pressure changed by -1.4 (P = 0.0033) and -1.6 mmHg (P = 0.0008). In participants with baseline urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g, UACR decreased by 23.7% (P = 0.054) and 18.3% (P = 0.18) for SOTA 200 and SOTA 400 mg, respectively, versus placebo. Increases in serum albumin and hematocrit and reductions in uric acid were observed throughout 52 weeks with both SOTA doses. CONCLUSIONS: SOTA was associated with short- and long-term renal hemodynamic changes, which were similar to those seen with SGLT2i in type 2 diabetes. Further investigation around cardiorenal effects of SOTA in people with type 1 diabetes is justified.

Achievement of glycaemic control is associated with improvements in lipid profile with iGlarLixi versus iGlar: A post hoc analysis of the LixiLan-L trial.

Diabetic dyslipidaemia is a major risk factor for accelerated atherosclerosis. Glycaemic treatments that improve dyslipidaemia may help reduce the burden of atherosclerosis. This analysis investigated the effect of iGlarLixi [insulin glargine U100 (iGlar) and lixisenatide] versus iGlar on lipid profiles in patients with type 2 diabetes uncontrolled on basal insulin. Data from LixiLan-L were used to estimate changes in fasting lipid levels from baseline to week 30, overall and in patients stratified by achievement of glycaemic targets {2-hour postprandial glucose [≤10, >10 mmoL/L], fasting plasma glucose [≤6.1, >6.1 mmoL/L], HbA1c [≤7, >7% (≤53, >53 mmol/mol)]}. At week 30, median percentage change in triglycerides remained nearly unchanged (0.3% increase) with iGlarLixi versus a 6.5% increase with iGlar (P = 0.035; overall); similarly, trends towards better total and LDL cholesterol levels were observed with iGlarLixi versus iGlar. In patient subgroups achieving glycaemic targets, all lipid variables except for HDL cholesterol improved with iGlarLixi but not with iGlar. In summary, patients with type 2 diabetes uncontrolled on basal insulin showed improved fasting lipid profiles with iGlarLixi compared with iGlar, particularly when achieving glycaemic targets.

Efficacy and safety of lixisenatide as add-on therapy to basal insulin in older adults with type 2 diabetes in the GetGoal-O Study.

BACKGROUND: This study compared the efficacy and safety of lixisenatide with placebo as add-on therapy to basal insulin (BI) in adults aged ≥70 years with type 2 diabetes (T2D), with or without moderate renal insufficiency. METHODS: This post hoc analysis evaluated data from non-frail patients with T2D inadequately controlled on BI with or without oral antidiabetic drugs (n = 108), randomized to once-daily lixisenatide 20 µg or placebo for 24 weeks (GetGoal-O Study). The primary endpoint was the change in HbA1c from baseline to Week 24. Secondary endpoints included changes from baseline in fasting plasma glucose, 2-hour postprandial plasma glucose (PPG), average seven-point self-monitored plasma glucose (SMPG), area under the curve for SMPG, daily BI dose, body weight, proportion of patients achieving HbA1c > 0.5%, and composite endpoints. Safety outcomes included the incidence of documented symptomatic hypoglycemia (plasma glucose <60 mg/dL) and gastrointestinal treatment-emergent adverse events (TEAEs). Outcomes were also analyzed by the occurrence of moderate renal insufficiency. RESULTS: Compared with placebo, lixisenatide-treated patients had significantly greater reductions in HbA1c, 2-hour PPG, average seven-point SMPG, and body weight. Documented symptomatic hypoglycemia was approximately two-fold higher in patients treated with placebo than lixisenatide (12.7% vs 5.7%). GI TEAEs occurred more frequently in the lixisenatide- than placebo-treated group (34% vs 9.1%). Moderate renal insufficiency (estimated glomerular filtration rate between ≥30 and <60 mL/min/1.73 m2 ) did not negatively affect lixisenatide efficacy or safety. A greater proportion of patients treated with lixisenatide than placebo achieved composite endpoints. CONCLUSIONS: Add-on therapy with lixisenatide in non-frail patients aged ≥70 years with T2D uncontrolled with BI is effective, safe, and well tolerated and should be considered in this population.

Identification and Characterization of Two New 1- O-Acyl-glucose-ester Forming Glucosyltransferases from Erigeron breviscapus.

Two versatile UDP-glucosyltransferases, UGT75L25 and UGT75X1, were isolated from Erigeron breviscapus. The enzymes display high sequence identity to flavonoid 7- O-glucosyltransferase from Malus species and cluster to the phylogenetic group L of plant glucosyltransferases, also involved in the formation of hydroxycinnamoyl glucose esters, which are used as bifunctional donors in the glucosylation or acylation of anthocyanins. The enzymes, functionally expressed in Escherichia coli, exhibit broad substrate specificity toward 21 structurally diverse types of phenolic acids, including (hydroxy)cinnamates, vanillic acid, 3-hydroxycoumarin, and 7-hydroxyflavonoids. The catalytic characteristics of UGT75L25 and UGT75X1 were exploited to generate the corresponding acyl-glucose-esters or glucosides with high efficiency. These findings demonstrate the significant potential of acyl-glucose-esters in the further enzymatic synthesis of bioactive anthocyanins.

Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial.

BACKGROUND: The results of the ELIXA trial demonstrated the cardiovascular safety of lixisenatide, a short-acting glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes and acute coronary syndrome. In this exploratory analysis of ELIXA, we investigate the effect of lixisenatide on renal outcomes. METHODS: ELIXA was a randomised, double-blind, placebo-controlled trial, done at 828 sites in 49 countries. Patients with type 2 diabetes and a recent coronary artery event were randomly assigned (1:1) to a daily subcutaneous injection of lixisenatide (10-20 µg) or volume-matched placebo, in addition to usual care, until at least 844 patients had an adjudicated major adverse cardiovascular event included in the primary outcome. Patients, study staff, and individuals involved in analysis of trial data were masked to treatment assignment. The primary and secondary endpoints of this trial have been reported previously. Here, in an exploratory analysis of ELIXA, we investigated percentage change in urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) according to prespecified albuminuria status at baseline (normoalbuminuria [UACR <30 mg/g]; microalbuminuria [≥30 to ≤300 mg/g]; and macroalbuminuria [>300 mg/g]) using a mixed-effect model with repeated measures. Time to new-onset macroalbuminuria and doubling of serum creatinine were also assessed with Cox proportional hazards models. The ELIXA trial is registered with ClinicalTrials.gov, number NCT01147250, and is completed. FINDINGS: Of 6068 patients randomly allocated between July 9, 2010, and Aug 2, 2013, baseline UACR data were available for 5978 (99%). Median follow-up time was 108 weeks. 4441 (74%; 2191 assigned to placebo and 2250 assigned to lixisenatide) had normoalbuminuria, 1148 (19%; 596 assigned to placebo and 552 assigned to lixisenatide) had microalbuminuria, and 389 (7%; 207 assigned to placebo and 182 assigned to lixisenatide) had macroalbuminuria. After 108 weeks, the placebo-adjusted least-squares mean percentage change in UACR from baseline with lixisenatide was -1·69% (95% CI -11·69 to 8·30; p=0·7398) in patients with normoalbuminuria, -21·10% (-42·25 to 0·04; p=0·0502) in patients with microalbuminuria, and -39·18% (-68·53 to -9·84; p=0·0070) in patients with macroalbuminuria. Lixisenatide was associated with a reduced risk of new-onset macroalbuminuria compared with placebo when adjusted for baseline HbA1c (hazard ratio [HR] 0·808 [95% CI 0·660 to 0·991; p=0·0404]) or baseline and on-trial HbA1c (HR 0·815 [0·665 to 0·999; p=0·0491]); point estimates were similar when adjusted for other traditional renal risk factors. At week 108, the largest eGFR decline from baseline was observed in the macroalbuminuric group, but no significant differences were observed between the two treatment groups. No significant differences in eGFR decline were identified between treatment groups in any UACR subgroup. In the trial safety population, doubling of serum creatinine occurred in 35 (1%) of 3032 patients in the placebo group and 41 (1%) of 3031 patients in the lixisenatide group (HR 1·163, 95% CI 0·741-1·825; p=0·5127). As previously reported in the ELIXA trial, the proportion of patients with renal adverse events was low (48 [1·6%] of 3032 patients in the placebo group vs 48 [1·6%] of 3031 patients in the lixisenatide group) and did not significantly differ between treatment groups. INTERPRETATION: Lixisenatide reduces progression of UACR in macroalbuminuric patients, and is associated with a lower risk of new-onset macroalbuminuria after adjustment for baseline and on-trial HbA1c and other traditional renal risk factors. FUNDING: Sanofi.

Propensity-score-matched comparative analyses of simultaneously administered fixed-ratio insulin glargine 100 U and lixisenatide (iGlarLixi) vs sequential administration of insulin glargine and lixisenatide in uncontrolled type 2 diabetes.

AIM: To conduct two exploratory analyses to compare indirectly the efficacy and safety of simultaneous administration of insulin glargine 100 U (iGlar) and the glucagon-like peptide-1 receptor agonist (GLP-1RA) lixisenatide (Lixi) as a single-pen, titratable, fixed-ratio combination (iGlarLixi [LixiLan trials]) vs sequential administration of iGlar + Lixi (GetGoal Duo trials) in people with type 2 diabetes (T2D). MATERIALS AND METHODS: Propensity-score matching based on baseline covariates was used to compare simultaneous iGlarLixi vs sequential combination of iGlar + Lixi with the addition of Lixi in patients who did not reach the glycated haemoglobin (HbA1c) goal of <53 mmol/mol (<7%) after short-term use of iGlar alone (LixiLan-O vs GetGoal Duo-1 comparison) and vs sequential addition of Lixi in uncontrolled patients after long-term use of iGlar alone (LixiLan-L vs GetGoal Duo-2 comparison). RESULTS: In both analyses, compared with sequential iGlar + Lixi, iGlarLixi led to significantly greater HbA1c reductions with associated weight loss and significantly more patients reaching target HbA1c <53 mmol/mol despite lower insulin doses. Symptomatic hypoglycaemia rates were similar, despite greater HbA1c reductions with iGlarLixi. Lower rates of gastrointestinal adverse events were observed with iGlarLixi, probably as a result of the more gradual titration of Lixi with iGlarLixi. CONCLUSIONS: Indirect propensity-score-matched exploratory comparisons suggest that early treatment with a simultaneous, titratable, fixed-ratio combination of basal insulin and a GLP-1RA (iGlarLixi) may be more effective and possess better gastrointestinal tolerability than a sequential approach of adding a GLP-1RA in patients with uncontrolled T2D initiating or intensifying basal insulin therapy.

More patients reach glycaemic control with a fixed-ratio combination of insulin glargine and lixisenatide (iGlarLixi) than with basal insulin at 12 weeks of treatment: A post hoc time-to-control analysis of LixiLan-O and LixiLan-L.

The present post hoc analysis of two 30-week clinical trials compared efficacy and hypoglycaemia outcomes at early study visits with iGlarLixi (insulin glargine U100 [iGlar] and lixisenatide) vs iGlar alone in patients with type 2 diabetes (T2D) uncontrolled on oral antidiabetic drugs (OADs; LixiLan-O trial) or basal insulin (LixiLan-L trial). Time to control, defined as days to achieve glycated haemoglobin (HbA1c) <53 mmol/mol (<7%) or fasting plasma glucose (FPG) ≤7.2 mmol/L, was estimated using the Kaplan-Meier method. In the LixiLan-O and LixiLan-L trials, 60% and 46% of patients, respectively, reached HbA1c <53 mmol/mol (<7%) with iGlarLixi at 12 weeks, vs 45% and 24%, respectively, with iGlar. In the LixiLan-O trial, the median time to target HbA1c was approximately half with iGlarLixi vs iGlar (85.0 vs 166.0 days; P < .0001). In the LixiLan-L trial, the median time to target HbA1c was 153.0 days with iGlarLixi, while target HbA1c was never reached by 50% of patients with iGlar (P < .0001). Time-to-target FPG and hypoglycaemia outcomes were similar between treatments. In T2D uncontrolled on OADs or basal insulin, iGlarLixi resulted in glycaemic control in more patients than did iGlar at early treatment time points.

Acrolein-stressed threshold adaptation alters the molecular and metabolic bases of an engineered Saccharomyces cerevisiae to improve glutathione production.

Acrolein (Acr) was used as a selection agent to improve the glutathione (GSH) overproduction of the prototrophic strain W303-1b/FGPPT. After two rounds of adaptive laboratory evolution (ALE), an unexpected result was obtained wherein identical GSH production was observed in the selected isolates. Then, a threshold selection mechanism of Acr-stressed adaption was clarified based on the formation of an Acr-GSH adduct, and a diffusion coefficient (0.36 ± 0.02 µmol·min-1·OD600-1) was calculated. Metabolomic analysis was carried out to reveal the molecular bases that triggered GSH overproduction. The results indicated that all three precursors (glutamic acid (Glu), glycine (Gly) and cysteine (Cys)) needed for GSH synthesis were at a relativity higher concentration in the evolved strain and that the accumulation of homocysteine (Hcy) and cystathionine might promote Cys synthesis and then improve GSH production. In addition to GSH and Cys, it was observed that other non-protein thiols and molecules related to ATP generation were at obviously different levels. To divert the accumulated thiols to GSH biosynthesis, combinatorial strategies, including deletion of cystathionine ß-lyase (STR3), overexpression of cystathionine γ-lyase (CYS3) and cystathionine ß-synthase (CYS4), and reduction of the unfolded protein response (UPR) through up-regulation of protein disulphide isomerase (PDI), were also investigated.