Transcriptional programs of Pitx2 and Tfap2a/Tfap2b controlling lineage specification of mandibular epithelium during tooth initiation.

How the dorsal-ventral axis of the vertebrate jaw, particularly the position of tooth initiation site, is established remains a critical and unresolved question. Tooth development starts with the formation of the dental lamina, a localized thickened strip within the maxillary and mandibular epithelium. To identify transcriptional regulatory networks (TRN) controlling the specification of dental lamina from the naïve mandibular epithelium, we utilized Laser Microdissection coupled low-input RNA-seq (LMD-RNA-seq) to profile gene expression of different domains of the mandibular epithelium along the dorsal-ventral axis. We comprehensively identified transcription factors (TFs) and signaling pathways that are differentially expressed along mandibular epithelial domains (including the dental lamina). Specifically, we found that the TFs Sox2 and Tfap2 (Tfap2a/Tfap2b) formed complimentary expression domains along the dorsal-ventral axis of the mandibular epithelium. Interestingly, both classic and novel dental lamina specific TFs-such as Pitx2, Ascl5 and Zfp536-were found to localize near the Sox2:Tfap2a/Tfap2b interface. To explore the functional significance of these domain specific TFs, we next examined loss-of-function mouse models of these domain specific TFs, including the dental lamina specific TF, Pitx2, and the ventral surface ectoderm specific TFs Tfap2a and Tfap2b. We found that disruption of domain specific TFs leads to an upregulation and expansion of the alternative domain's TRN. The importance of this cross-repression is evident by the ectopic expansion of Pitx2 and Sox2 positive dental lamina structure in Tfap2a/Tfap2b ectodermal double knockouts and the emergence of an ectopic tooth in the ventral surface ectoderm. Finally, we uncovered an unappreciated interface of mesenchymal SHH and WNT signaling pathways, at the site of tooth initiation, that were established by the epithelial domain specific TFs including Pitx2 and Tfap2a/Tfap2b. These results uncover a previously unknown molecular mechanism involving cross-repression of domain specific TFs including Pitx2 and Tfap2a/Tfap2b in patterning the dorsal-ventral axis of the mouse mandible, specifically the regulation of tooth initiation site.

Design, synthesis, and biological evaluation of novel 2,3-Di-O-Aryl/Alkyl sulfonate derivatives of l-ascorbic acid: Efficient access to novel anticancer agents via in vitro screening, tubulin polymerization inhibition, molecular docking study and ADME predictions.

A series of novel l-ascorbic acid derivatives bearing aryl and alkyl sulfonate substituents were synthesized and characterized. In vitro anticancer evaluation against MCF-7 (breast) and A-549 (lung) cancer cell lines revealed potent activity for most of the compounds, with 2b being equipotent to the standard drug colchicine against MCF-7 (IC50 = 0.04 µM). Notably, compound 2b displayed 89-fold selectivity for MCF-7 breast cancer over MCF-10A normal breast cells. Derivatives with two sulfonate groups (2a-g, 3a-g) exhibited superior potency over those with one sulfonate (4a-c,5g, 6b). Compounds 2b and 2c potently inhibited tubulin polymerization in A-549 cancer cells (73.12 % and 62.09 % inhibition, respectively), substantiating their anticancer potential through microtubule disruption. Molecular docking studies showed higher binding scores and affinities for these compounds at the colchicine-binding site of α, ß-tubulin compared to colchicine itself. In-silico ADMET predictions indicated favourable drug-like properties, with 2b exhibiting the highest binding affinity. These sulfonate derivatives of l-ascorbic acid represents promising lead scaffolds for anticancer drug development.

The inclusion of adults with intellectual disabilities in health research - challenges, barriers and opportunities: a mixed-method study among stakeholders in England.

BACKGROUND: The study aims to understand system barriers to research participation for people with intellectual disabilities. METHODS: A mixed-methods approach examined the inclusivity of people with intellectual disabilities (IDs) in a random sample of National Institute for Health and Care Research (NIHR) studies conducted in 2019-2020. An online questionnaire (stage 1) was sent to the selected studies lead investigators. An expert by experience panel of 25 people with intellectual disabilities (IDs, stage 2), discussed the stage 1 feedback. Descriptive statistics for quantitative data and thematic analysis for qualitative data was conducted. RESULTS: Of 180 studies reviewed, 131 studies (78%) excluded people with IDs. Of these, 45 (34.3%) study researchers provided feedback. Seven (20%) of the 34 studies which included people with IDs gave feedback. Of all respondents over half felt their study had some relevance to people with IDs. A minority (7.6%) stated their study had no relevance. For a quarter of respondents (23.5%), resource issues were a challenge. Qualitative analysis of both stages produced four overarching themes of Research design and delivery, Informed consent, Resource allocation, and Knowledge and skills. CONCLUSION: Health research continues to exclude people with IDs. Researchers and experts by experience identified non-accessible research design, lack of confidence with capacity and consent processes, limited resources such as time and a need for training as barriers. Ethics committees appear reluctant to include people with cognitive deficits to 'protect' them. People with IDs want to be included in research, not only as participants but also through coproduction.

Clinical characteristics of people with intellectual disability admitted to hospital with constipation: identifying possible specific high-risk factors.

BACKGROUND: People with intellectual disabilities (ID) die on an average 20 years earlier to the general population. They have higher rates of multimorbidity and polypharmacy. Around 25% of people with ID report chronic constipation. The England Learning Disabilities Mortality Review found that nearly 25% of deaths identified constipation as a long-term health problem. However, the likely risk factors for constipation related harm are poorly enumerated. We sought to identify possible specific high-risk factors by examining the clinical characteristics of people with ID admitted to hospital with constipation. METHODS: Data of people with ID admitted with constipation in two general hospitals covering a population of 1.3 million from 2017 to 2022 were reported using the STROBE guideline for cohort studies. Collected data included age, gender, intellectual disability severity, recorded medication, presenting complaint and co-morbidities. The medication anticholinergic burden was calculated using the anticholinergic burden scale. Continuous variables were summarised by mean and standard deviation if normally distributed, with categorical variables summarised by the number and percentage in each category. RESULTS: Of 46 admissions (males 52%), 57% had moderate to profound ID, 37% had epilepsy, 41% prescribed antiseizure medication (ASM) and 45% were on laxatives. Average age was 46 years. The anticholinergic burden score mean was 2.3 and median, one. CONCLUSIONS: We can hypothesise that people with more severe ID, suffering from epilepsy and on ASM may be more at risk of developing severe constipation. Some admissions may be avoided with earlier use of laxatives in the community.

HMGN2 represses gene transcription via interaction with transcription factors Lef-1 and Pitx2 during amelogenesis.

The chromatin-associated high mobility group protein N2 (HMGN2) cofactor regulates transcription factor activity through both chromatin and protein interactions. Hmgn2 expression is known to be developmentally regulated, but the post-transcriptional mechanisms that regulate Hmgn2 expression and its precise roles in tooth development remain unclear. Here, we demonstrate that HMGN2 inhibits the activity of multiple transcription factors as a general mechanism to regulate early development. Bimolecular fluorescence complementation, pull-down, and coimmunoprecipitation assays show that HMGN2 interacts with the transcription factor Lef-1 through its HMG-box domain as well as with other early development transcription factors, Dlx2, FoxJ1, and Pitx2. Furthermore, EMSAs demonstrate that HMGN2 binding to Lef-1 inhibits its DNA-binding activity. We found that Pitx2 and Hmgn2 associate with H4K5ac and H3K4me2 chromatin marks in the proximal Dlx2 promoter, demonstrating Hmgn2 association with open chromatin. In addition, we demonstrate that microRNAs (miRs) mir-23a and miR-23b directly target Hmgn2, promoting transcriptional activation at several gene promoters, including the amelogenin promoter. In vivo, we found that decreased Hmgn2 expression correlates with increased miR-23 expression in craniofacial tissues as the murine embryo develops. Finally, we show that ablation of Hmgn2 in mice results in increased amelogenin expression because of increased Pitx2, Dlx2, Lef-1, and FoxJ1 transcriptional activity. Taken together, our results demonstrate both post-transcriptional regulation of Hmgn2 by miR-23a/b and post-translational regulation of gene expression by Hmgn2-transcription factor interactions. We conclude that HMGN2 regulates tooth development through its interaction with multiple transcription factors.

A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: This study assessed the effects of the glucagon-like peptide-1 (GLP-1)/glucagon receptor co-agonist efinopegdutide relative to the selective GLP-1 receptor agonist semaglutide on liver fat content (LFC) in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: This was a phase IIa, randomized, active-comparator-controlled, parallel-group, open-label study. A magnetic resonance imaging-estimated proton density fat fraction assessment was performed to determine LFC at screening and Week 24. Participants with an LFC of ≥10% at screening were randomized 1:1 to efinopegdutide 10 mg or semaglutide 1 mg, both administered subcutaneously once weekly for 24 weeks. Participants were stratified according to the concurrent diagnosis of type 2 diabetes mellitus (T2DM). Both drugs were titrated to the target dose over an 8-week time period. The primary efficacy endpoint was relative reduction from baseline in LFC (%) after 24 weeks of treatment. RESULTS: Among 145 randomized participants (efinopegdutide n = 72, semaglutide n = 73), 33.1% had T2DM. At baseline, mean BMI was 34.3 kg/m2 and mean LFC was 20.3%. The least squares (LS) mean relative reduction from baseline in LFC at Week 24 was significantly (p <0.001) greater with efinopegdutide (72.7% [90% CI 66.8-78.7]) than with semaglutide (42.3% [90% CI 36.5-48.1]). Both treatment groups had an LS mean percent reduction from baseline in body weight at Week 24 (efinopegdutide 8.5% vs. semaglutide 7.1%; p = 0.085). Slightly higher incidences of adverse events and drug-related adverse events were observed in the efinopegdutide group compared with the semaglutide group, primarily related to an imbalance in gastrointestinal adverse events. CONCLUSIONS: In patients with NAFLD, treatment with efinopegdutide 10 mg weekly led to a significantly greater reduction in LFC than semaglutide 1 mg weekly. CLINICAL TRIAL NUMBER: EudraCT: 2020-005136-30; NCT: 04944992. IMPACT AND IMPLICATIONS: Currently, there are no approved therapies for non-alcoholic steatohepatitis (NASH). The weight loss associated with glucagon-like peptide-1 (GLP-1) receptor agonists has been shown to decrease hepatic inflammation in patients with NASH. In addition to reducing liver fat content (LFC) indirectly through weight loss, glucagon receptor agonism may also reduce LFC by acting on the liver directly to stimulate fatty acid oxidation and reduce lipogenesis. This study demonstrated that treatment of patients with non-alcoholic fatty liver disease with the GLP-1/glucagon receptor co-agonist efinopegdutide (10 mg weekly) led to a significantly greater reduction in LFC compared to treatment with the GLP-1 receptor agonist semaglutide (1 mg weekly), suggesting that efinopegdutide may be an effective treatment for NASH.

Awareness of social care needs in people with epilepsy and intellectual disability.

BACKGROUND: Nearly a quarter of people with intellectual disability (ID) have epilepsy with large numbers experiencing drug-resistant epilepsy, and premature mortality. To mitigate epilepsy risks the environment and social care needs, particularly in professional care settings, need to be met. PURPOSE: To compare professional care groups as regards their subjective confidence and perceived responsibility when managing the need of people with ID and epilepsy. METHOD: A multi-agency expert panel developed a questionnaire with embedded case vignettes with quantitative and qualitative elements to understand training and confidence in the health and social determinants of people with ID and epilepsy. The cross-sectional survey was disseminated amongst health and social care professionals working with people with ID in the UK using an exponential non-discriminative snow-balling methodology. Group comparisons were undertaken using suitable statistical tests including Fisher's exact, Kruskal-Wallis, and Mann-Whitney. Bonferroni correction was applied to significant (p < 0.05) results. Content analysis was conducted and relevant categories and themes were identified. RESULTS: Social and health professionals (n = 54) rated their confidence to manage the needs of people with ID and epilepsy equally. Health professionals showed better awareness (p < 0.001) of the findings/recommendations of the latest evidence on premature deaths and identifying and managing epilepsy-related risks, including the relevance of nocturnal monitoring. The content analysis highlighted the need for clearer roles, improved care pathways, better epilepsy-specific knowledge, increased resources, and better multi-disciplinary work. CONCLUSIONS: A gap exists between health and social care professionals in awareness of epilepsy needs for people with ID, requiring essential training and national pathways.

A randomized clinical trial of the efficacy and safety of sitagliptin as initial oral therapy in youth with type 2 diabetes.

OBJECTIVE: To assess the efficacy and safety of DPP-4 inhibition with sitagliptin in youth with type 2 diabetes (T2D). STUDY DESIGN: This was a 54-week, double-blind, randomized, controlled clinical trial evaluating the safety and efficacy of DPP-4 inhibition with sitagliptin 100 mg once daily as initial oral therapy in youth with T2D. The 190 participants, aged 10-17 years, had HbA1c 6.5%-10% (7.0%-10% if on insulin). All were negative for pancreatic autoantibodies and overweight/obese at screening or diagnosis. The trial was placebo controlled for the first 20 weeks, after which metformin replaced placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean ± SD HbA1c = 7.5% ± 1.0, BMI percentile = 97.1% ± 6.8, age = 14.0 years ± 2.0 [57.4% <15], 60.5% female). At Week 20, least squares mean changes from baseline in HbA1c were -0.01% (sitagliptin) and 0.18% (placebo); between-group difference (95% CI) = -0.19% (-0.68, 0.30), p = 0.448. At Week 54, the changes in HbA1c were 0.45% (sitagliptin) and -0.11 (placebo/metformin). There were no notable between-group differences in the adverse event profiles through Week 54. CONCLUSIONS: DPP-4 inhibition with sitagliptin did not provide significant improvement in glycemic control. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01485614; EudraCT: 2011-002528-42).

Efficacy and safety of the addition of sitagliptin to treatment of youth with type 2 diabetes and inadequate glycemic control on metformin without or with insulin.

OBJECTIVE: To assess the efficacy and safety of sitagliptin in youth with type 2 diabetes (T2D) inadequately controlled with metformin ± insulin. STUDY DESIGN: Data were pooled from two 54-week, double-blind, randomized, placebo-controlled studies of sitagliptin 100 mg daily or placebo added onto treatment of 10- to 17-year-old youth with T2D and inadequate glycemic control on metformin ± insulin. Participants (N = 220 randomized and treated) had HbA1c 6.5%-10% (7.0%-10% if on insulin), were overweight/obese at screening or diagnosis and negative for pancreatic autoantibodies. The primary endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean HbA1c = 8.0%, BMI = 30.9 kg/m2 , age = 14.4 years [44.5% <15], 65.9% female). The dose of background metformin was >1500 mg/day for 71.8% of participants; 15.0% of participants were on insulin therapy. At Week 20, LS mean changes from baseline (95% CI) in HbA1c for sitagliptin/metformin and placebo/metformin were -0.58% (-0.94, -0.22) and -0.09% (-0.43, 0.26), respectively; difference = -0.49% (-0.90, -0.09), p = 0.018; at Week 54 the LS mean (95% CI) changes were 0.35% (-0.48, 1.19) and 0.73% (-0.08, 1.54), respectively. No meaningful differences between the adverse event profiles of the treatment groups emerged through Week 54. CONCLUSIONS: These results do not suggest that addition of sitagliptin to metformin provides durable improvement in glycemic control in youth with T2D. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01472367, NCT01760447; EudraCT: 2011-002529-23/2014-003583-20, 2012-004035-23).

Black carbon over a high altitude Central Himalayan Glacier: Variability, transport, and radiative impacts.

Ambient equivalent black carbon (BC) measurements spanning from June to October have been carried out over an adjoining location of Satopanth and Bhagirath-Kharak Glaciers (3858m, amsl) of Central Himalaya during the year 2019. Hourly BC varied from 12 ng m-3 to 439 ng m-3 during the entire period of observation. Monthly averaged BC values showed the highest concentration during June (230.96 ± 85.46 ng m-3) and the lowest in August (118.02 ± 71.63 ng m-3). The decrease in BC during monsoon months is attributed to limited long-range transport and rapid wet scavenging processes. Transport model studies indicate a higher retention time of tracer in Uttarakhand, Punjab, Haryana, and adjacent polluted valley regions with increased biomass burning (BB) incidences. The high rate of BC influx during June, September, and October was attributed to transport from the polluted Indo-Gangetic Plain (IGP) region, wildfires, and vehicular emissions in the valley region. Higher equivalent brown carbon (BrC) influx is linked to BB, especially wood-burning, during intense forest fires at slopes of mountains. Data obtained from limited BC observations during the 2011-19 period showed no significant BC influx change during post-monsoon. The strong correlation between BC mass and BB affirms the dominant role of BB in contributing BC to the Glacier region. Increased TOA forcing induced by surface darkening and BC atmospheric radiative heating indicate an additional warming and possible changes of the natural snow cycle over the glacier depending on the characteristics and extent of debris cover.

Design and synthesis of novel conformationally constrained 7,12-dihydrodibenzo[b,h][1,6] naphthyridine and 7H-Chromeno[3,2-c] quinoline derivatives as topoisomerase I inhibitors: In vitro screening, molecular docking and ADME predictions.

Novel non-camptothecin (non-CPT) class of conformationally constrained, hitherto unknown 7,12-dihydrodibenzo[b,h][1,6] naphthyridine and 7H-Chromeno[3,2-c] quinoline derivatives have been designed, synthesized and evaluated for anti-cancer activity. In vitro anti-proliferation evaluation against human cancer cell lines (A549 and MCF-7) exhibited significant cytotoxicity. Among the derivatives (8-24), 8 (IC50 0.44 µM and IC50 0.62 µM) and 12 (IC50 0.69 µM and IC50 0.54 µM) were identified as the most promising candidate against A-549 and MCF-7 cancer cell lines respectively. Topo I inhibitory activity of 8 and 12 suggested that, they may be developed as potential anti-cancer molecules in future and rationalized by docking analysis with effective binding modes. Further, in silico ADME prediction studies of all derivatives were found promising, signifying the drug like properties. In precise, the present investigation displays a new strategy to synthesize and emphasis on anticancer activities of conformationally constrained dibenzo[b,h][1,6] naphthyridine derivatives and Chromeno[3,2-c] quinoline derivatives in the context of cancer drug development and refinement.

N-Benzylation of 6-aminoflavone by reductive amination and efficient access to some novel anticancer agents via topoisomerase II inhibition.

Series of novel N-benzyl derivatives of 6-aminoflavone (9a-n) were synthesized and evaluated for anticancer and topoisomerase II enzyme inhibition activity. All the synthesized compounds were screened for in vitro anticancer activity against human breast cancer cell line (MCF-7) and human lung cancer cell line (A-549). Among the synthesized compounds, 9f and 9g were found to be the most potent anticancer agents against human breast cancer cell line (MCF-7) with IC50 values of 9.35 µM and 9.58 µM, respectively. Compounds 9b, 9c and 9n exhibited promising anticancer activity against human lung cancer cell line (A-549) with 43.71%, 46.48% and 44.26% inhibition at the highest concentration of 10 µM, respectively. Compounds 9c, 9f and 9g have ability to inhibit the topoisomerase II enzyme. Compound 9f showed most potent topoisomerase II enzyme inhibition activity with IC50 value of 12.11 µM. Further, these compounds have a high potential to be developed as a promising topoisomerase II inhibitors.

Synthesis and evaluation of novel sulfonamide analogues of 6/7-aminoflavones as anticancer agents via topoisomerase II inhibition.

A series of new sulfonamide analogues of 6/7-aminoflavones were synthesized by using molecular hybridization approach. These new sulfonamide analogues were screened for antiproliferative activity against human hepatocellular carcinoma (HepG-2), human lung cancer cell line (A-549), human colorectal adenocarcinoma (Caco-2) cancer cell lines. Compounds 5p, 5q, 5t, 5v, 5w and 5x exhibited good anticancer activity against selected cancer cell lines. These compounds were further evaluated to predict their ability to inhibit topoisomerase-II enzyme. Compound 5x has shown potent antiproliferative activity (IC50 value 0.98 µM) as compared to standard drug Adriamycin (IC50 = 0.94 µM) indicating that these compounds exhibits anticancer activity via inhibition of topoisomerase-II enzyme. Docking results also have supported above observations by indicating that compounds are held in the active pocket by combination of various hydrogen and hydrophobic interactions with Top II-DNA-etoposide enzyme.

Protective Effect of Tamarind Seed Coat Ethanol Extract on Eryptosis Induced by Oxidative Stress.

Suicidal erythrocyte death, or eryptosis, is the key event in eliciting anemia in numerous pathological conditions, including diabetes, chronic kidney disease, cancer, sepsis, etc. Oxidative stress is an important trigger in the acceleration of erythrocyte loss via eryptosis and an underlying mechanism of anemia emergence in the above pathologies. Therefore, there is an increasing demand for identification of antioxidants and anti-eryptotic agents for the management of stress-related ailments. Here, we demonstrated the antioxidant and anti-eryptotic properties of the tamarind seed coat ethanol extract (TSCEE) against 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH)-induced oxidative stress and eryptosis. The presence of probable secondary metabolites in the TSCEE extract was investigated by RP-HPLC. Active groups present in the TSCEE were studied by the Fourier-transform infrared spectroscopy. Cyclic voltammetric studies confirmed the antioxidant potential of TSCEE. The protective effect of TSCEE on red blood cells was confirmed by assessing various eryptotic markers, such as reactive oxygen species generation, intracellular calcium levels, and phosphatidylserine exposure. TSCEE reduced lipid peroxidation and protein carbonyl content and restored the levels of glutathione, antioxidant enzymes, and enzymes involved in glutathione replenishment. In conclusion, TSCEE was found to exhibit multiple therapeutic properties, which makes it a promising agent for treating oxidative stress-induced eryptosis and subsequent anemia in various pathologies.

Efficacy and safety of sitagliptin added to treatment of patients with type 2 diabetes inadequately controlled with premixed insulin.

To improve understanding of the safety and efficacy of adding sitagliptin to treatment of patients with type 2 diabetes taking premixed insulin, data from patients using premixed insulin ± metformin (screening HbA1c ≥7.5% and ≤11%) in either of two clinical trials in which sitagliptin 100 mg once-daily or placebo was added to various formulations of insulin treatment, were analysed. In both trials, insulin doses were to remain stable throughout the 24-week trial period. At week 24, the between-group difference (sitagliptin - placebo) in the least squares mean (95% confidence intervals) change from baseline in HbA1c in patients using premixed insulin was -0.43% (-0.58, -0.28), P <0.001. Adverse events were generally similar between the treatment groups. The incidence of symptomatic hypoglycaemia was slightly higher with sitagliptin, and the incidence of hypoglycaemia requiring medical attention was slightly higher with placebo; in both cases the difference was not statistically significant. The data from this pooled analysis confirm the utility of sitagliptin used in combination with premixed insulin in patients with type 2 diabetes.

Double-blind, randomized clinical trial comparing the efficacy and safety of continuing or discontinuing the dipeptidyl peptidase-4 inhibitor sitagliptin when initiating insulin glargine therapy in patients with type 2 diabetes: The CompoSIT-I Study.

AIMS: To compare the effects of continuing versus discontinuing sitagliptin when initiating and intensively titrating insulin glargine. MATERIALS AND METHODS: Eligible patients had inadequately controlled type 2 diabetes on metformin (≥1500 mg/d) in combination with a dipeptidyl peptidase-4 (DPP-4) inhibitor and/or a sulphonylurea. Those on metformin + sitagliptin were directly randomized; all others were switched to metformin + sitagliptin (discontinuing other DPP-4 inhibitors and sulphonylureas) and stabilized during a run-in period. At randomization, patients were allocated to continuing sitagliptin or discontinuing sitagliptin, with both groups initiating insulin glargine and titrating to a target fasting glucose of 4.0 to 5.6 mmol/L. RESULTS: A total of 743 participants (mean glycated haemoglobin [HbA1c] 72.6 mmol/mol [8.8%], disease duration 10.8 years), were treated. After 30 weeks, the mean HbA1c and least squares (LS) mean change from baseline in HbA1c were 51.4 mmol/mol (6.85%) and -20.5 mmol/mol (-1.88%) in the sitagliptin group and 56.4 mmol/mol (7.31%) and -15.5 mmol/mol (-1.42%) in the placebo group; the difference in LS mean changes from baseline HbA1c was -5.0 mmol/mol (-0.46%; P < 0.001). The percentage of participants with HbA1c <53 mmol/mol (<7.0%) was higher (54% vs. 35%) and the mean daily insulin dose was lower (53 vs. 61 units) in the sitagliptin group. Despite lower HbA1c, event rates and incidences of hypoglycaemia were not higher in the sitagliptin group. Adverse events overall and changes from baseline in body weight were similar between the two treatment groups. CONCLUSION: When initiating insulin glargine therapy, continuation of sitagliptin, compared with discontinuation, resulted in a clinically meaningful greater reduction in HbA1c without an increase in hypoglycaemia. ClinicalTrials.gov Identifier: NCT02738879.

Prevalence of type 1 and type 2 diabetes among US pediatric population in the MarketScan Multi-State Database, 2002 to 2016.

OBJECTIVES: To estimate the prevalence of type 1 (T1DM) and type 2 diabetes mellitus (T2DM) among U.S. Medicaid pediatric population aged <18 years 2002 to 2016 by age, sex, and race/ethnicity. METHODS: Participants aged <18 years old from 2002 to 2016 were identified from the MarketScan Multi-State Medicaid Database. Diabetes was defined as having (a) ≥1 claims for an outpatient or inpatient diabetes diagnosis and ≥2 prescriptions for any anti-diabetes medications or (b) records of ≥2 claims for an outpatient or inpatient diabetes diagnosis that were at least 30 days apart. Annual prevalence of diabetes and 95% confidence intervals (CIs) were calculated. Age-, sex-, and race-stratified prevalence were also assessed. RESULTS: The annual prevalence of T1DM increased from 1.29 to 2.34/1000 pediatric persons from 2002 to 2016. The prevalence of T2DM rose from 0.70 in 2002 to 2.76/1000 in 2011, but then dropped to 2.12/1000 pediatric persons in 2016 in the Medicaid population. Prevalence of both T1DM and T2DM increased with age. While the prevalence of T1DM was similar in both sexes, and was most prevalent in Whites, prevalence of T2DM was higher in girls and was most prevalent in Blacks. CONCLUSIONS: While the annual prevalence of T1DM in pediatric persons enrolled in Medicaid increased continuously from 2002 to 2016, the annual prevalence of T2DM increased from 2002 to 2011, with a subsequent decrease in 2016, possibly because of the increase of relatively healthier participants with the expanded eligibility through the ACA between 2011 and 2016.

Insulin secretory effect of sitagliptin: assessment with a hyperglycemic clamp combined with a meal challenge.

Sitagliptin, a dipeptidyl peptidase-IV inhibitor (DPP-4), sustains activity of the incretin hormones GLP-1 and GIP and improves hyperglycemia in Type 2 diabetes mellitus (T2DM). It has however proven challenging to quantify the effect of sitagliptin on rates of insulin secretion (ISR) during a prandial challenge. The tight feedback governance of ISR by plasma glucose means that in the face of treatment-related lowering of postprandial glycemia, corresponding stimulation of ISR is lessened. We postulated that sustaining a stable level of moderate hyperglycemia before and during a meal challenge (MC) would be a platform that enables greater clarity to assess the effect of sitagliptin on ISR and an approach that could be valuable to evaluate novel targets that increase insulin secretion directly and by augmenting incretins. A hyperglycemic clamp (HGC) at 160 mg/dl was conducted in 12 healthy volunteers (without diabetes) for 6 h; 3 h into the HGC, MC was administered while maintaining stable hyperglycemia of the HGC for an additional 3 h. Modeling of C-peptide response was used to calculate ISR. In crossover design of three periods (sitagliptin twice and placebo once), the effect of sitagliptin vs. placebo on ISR and the reproducibility of the response to sitagliptin were assessed. Sitagliptin increased ISR compared with placebo by 50% and 20% during the HGC alone and the HGC-MC phases, respectively ( P < 0.001 for both). There was an associated significant treatment-based increase in circulating insulin, as well as active levels of GLP-1. Robust reproducibility of the sitagliptin-mediated ISR response was observed; the intraclass correlation value was 0.94. The findings delineate the effect of sitagliptin to stimulate insulin secretion, and these benchmark data also demonstrate that an HGC-MC can be a useful platform for interrogating therapeutic targets that could potentially modulate ISR via direct action on beta-cells as well as by augmenting release or action of incretins.