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1.
J Matern Fetal Neonatal Med ; 37(1): 2356031, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38844413

RESUMO

AIMS: To derive accurate estimates of risk of maternal and neonatal complications in women with gestational diabetes mellitus (GDM) and to investigate the association of the effect size of these risks on subgroups of GDM managed with dietary modification, metformin and insulin therapy. METHODS: This was a large retrospective cohort study undertaken at a large maternity unit in the United Kingdom between January 2010 and June 2022. We included singleton pregnancies that booked at our unit at 11-13 weeks' gestation. The rates of maternal and neonatal complications in pregnancies with GDM that were managed by a multidisciplinary team (MDT) in the specialist high-risk clinic were compared to those in non-diabetic pregnancies. We stratified pregnancies with GDM into those that were managed with diet, metformin and insulin to pregnancies without diabetes. Logistic regression analysis was carried out to determine risks of pregnancy complications in pregnancies with GDM and its treatment subgroups. Risks were expressed as absolute risks (AR) and odds ratio (OR) (95% confidence intervals [CI]). Forest plots were used to graphically demonstrate risks. RESULTS: The study population included 51,211 singleton pregnancies including 2089 (4.1%) with GDM and 49,122 (95.9%) controls without diabetes. In pregnancies with GDM, there were 1247 (59.7%) pregnancies managed with diet, 451 (21.6%) with metformin and 391 (18.7%) who required insulin for maintaining euglycaemia. Pregnancies with GDM had higher maternal age, body mass index (BMI), higher rates of Afro-Caribbean and South Asian racial origin and higher rates of chronic hypertension. In pregnancies with GDM compared to non-diabetic controls, there was an increased rate of preterm delivery, delivery of LGA neonate, polyhydramnios, preeclampsia, need for IOL, elective and emergency CS and PPH whereas the rate of delivery of SGA neonates and likelihood of an unassisted vaginal delivery were lower. In pregnancies with GDM, there is significantly increased risk of maternal and neonatal complications in those that require insulin compared to those that are managed on dietary modification alone. CONCLUSIONS: There is a linear association between the risk of adverse outcomes and the severity of GDM with those on insulin treatment demonstrating an increased association with complications compared to those that have milder disease requiring only dietary modification.


Assuntos
Diabetes Gestacional , Hipoglicemiantes , Metformina , Humanos , Feminino , Gravidez , Diabetes Gestacional/epidemiologia , Estudos Retrospectivos , Adulto , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Recém-Nascido , Insulina/uso terapêutico , Resultado da Gravidez/epidemiologia , Reino Unido/epidemiologia , Índice de Gravidade de Doença , Estudos de Casos e Controles
2.
Signal Transduct Target Ther ; 9(1): 154, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844816

RESUMO

Early insulin therapy is capable to achieve glycemic control and restore ß-cell function in newly diagnosed type 2 diabetes (T2D), but its effect on cardiovascular outcomes in these patients remains unclear. In this nationwide real-world study, we analyzed electronic health record data from 19 medical centers across China between 1 January 2000, and 26 May 2022. We included 5424 eligible patients (mean age 56 years, 2176 women/3248 men) who were diagnosed T2D within six months and did not have prior cardiovascular disease. Multivariable Cox regression models were used to estimate the associations of early insulin therapy (defined as the first-line therapy for at least two weeks in newly diagnosed T2D patients) with the incidence of major cardiovascular events including coronary heart disease (CHD), stroke, and hospitalization for heart failure (HF). During 17,158 persons years of observation, we documented 834 incident CHD cases, 719 stroke cases, and 230 hospitalized cases for HF. Newly diagnosed T2D patients who received early insulin therapy, compared with those who did not receive such treatment, had 31% lower risk of incident stroke, and 28% lower risk of hospitalization for HF. No significant difference in the risk of CHD was observed. We found similar results when repeating the aforesaid analysis in a propensity-score matched population of 4578 patients and with inverse probability of treatment weighting models. These findings suggest that early insulin therapy in newly diagnosed T2D may have cardiovascular benefits by reducing the risk of incident stroke and hospitalization for HF.


Assuntos
Diabetes Mellitus Tipo 2 , Insulina , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Insulina/uso terapêutico , Incidência , Idoso , China/epidemiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Adulto , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/tratamento farmacológico
3.
BMC Cancer ; 24(1): 691, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844880

RESUMO

PURPOSE: The potential efficacy of metformin in breast cancer (BC) has been hotly discussed but never conclusive. This genetics-based study aimed to evaluate the relationships between metformin targets and BC risk. METHODS: Metformin targets from DrugBank and genome-wide association study (GWAS) data from IEU OpenGWAS and FinnGen were used to investigate the breast cancer (BC)-metformin causal link with various Mendelian Randomization (MR) methods (e.g., inverse-variance-weighting). The genetic association between type 2 diabetes (T2D) and the drug target of metformin was also analyzed as a positive control. Sensitivity and pleiotropic tests ensured reliability. RESULTS: The primary targets of metformin are PRKAB1, ETFDH and GPD1L. We found a causal association between PRKAB1 and T2D (odds ratio [OR] 0.959, P = 0.002), but no causal relationship was observed between metformin targets and overall BC risk (PRKAB1: OR 0.990, P = 0.530; ETFDH: OR 0.986, P = 0.592; GPD1L: OR 1.002, P = 0.806). A noteworthy causal relationship was observed between ETFDH and estrogen receptor (ER)-positive BC (OR 0.867, P = 0.018), and between GPD1L and human epidermal growth factor receptor 2 (HER2)-negative BC (OR 0.966, P = 0.040). Other group analyses did not yield positive results. CONCLUSION: The star target of metformin, PRKAB1, does not exhibit a substantial causal association with the risk of BC. Conversely, metformin, acting as an inhibitor of ETFDH and GPD1L, may potentially elevate the likelihood of developing ER-positive BC and HER2-negative BC. Consequently, it is not advisable to employ metformin as a standard supplementary therapy for BC patients without T2D.


Assuntos
Neoplasias da Mama , Diabetes Mellitus Tipo 2 , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Metformina , Humanos , Metformina/uso terapêutico , Metformina/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/tratamento farmacológico , Feminino , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicações , Quimioterapia Adjuvante/métodos , Hipoglicemiantes/uso terapêutico , Polimorfismo de Nucleotídeo Único
4.
Medicine (Baltimore) ; 103(23): e38444, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38847728

RESUMO

To investigate changes in skeletal muscle mass and fat fraction in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (T2DM) undergoing treatment with Semaglutide for 6months. This single-arm pilot study included 21 patients with MASLD who received semaglutide for T2DM. Body weight, metabolic parameters, liver enzymes, fibrosis markers, skeletal muscle index (cm2/m2), and fat fraction (%) at the L3 level using the two-point Dixon method on magnetic resonance imaging (MRI), as well as liver steatosis and liver stiffness assessed using MRI-based proton density fat fraction (MRI-PDFF) and MR elastography, respectively, were prospectively examined before and 6 months after semaglutide administration. The mean age of the patients was 53 years and 47.6% were females. The median liver steatosis-fraction (%) and skeletal muscle steatosis-fraction values (%) significantly decreased (22.0 vs 12.0; P = .0014) and (12.8 vs 9.9; P = .0416) at baseline and 6 months, respectively, while maintaining muscle mass during treatment. Semaglutide also dramatically reduced hemoglobin A1c (%) (6.8 vs 5.8, P = .0003), AST (IU/L) (54 vs 26, P < .0001), ALT (IU/L) (80 vs 34, P = .0004), and γ-GTP (IU/L) levels (64 vs 34, P = .0007). Although not statistically significant, Body weight (kg) (79.9 vs 77.4), body mass index (BMI) (kg/m2) (28.9 vs 27.6), and liver stiffness (kPa) (28.9 vs 27.6) showed a decreasing trend. Fibrosis markers such as M2BPGi, type IV collagen, and skeletal muscle area did not differ. Semaglutide demonstrated favorable effects on liver and skeletal muscle steatosis, promoting improved liver function and diabetic status.


Assuntos
Diabetes Mellitus Tipo 2 , Peptídeos Semelhantes ao Glucagon , Fígado , Músculo Esquelético , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Diabetes Mellitus Tipo 2/tratamento farmacológico , Estudos Prospectivos , Músculo Esquelético/efeitos dos fármacos , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Projetos Piloto , Fígado/efeitos dos fármacos , Fígado/diagnóstico por imagem , Fígado/patologia , Hipoglicemiantes/uso terapêutico , Fígado Gorduroso/tratamento farmacológico , Adulto , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Imageamento por Ressonância Magnética , Técnicas de Imagem por Elasticidade , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/análise , Idoso
5.
Afr J Prim Health Care Fam Med ; 16(1): e1-e12, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38832377

RESUMO

BACKGROUND:  The Central Chronic Medicines Dispensing and Distribution (CCMDD) programme facilitates clinically stable patients to collect their chronic medication from community-based pick-up points. AIM:  We determined baseline glycaemic control and rates and predictors of becoming sub-optimally controlled for type 2 diabetes mellitus (T2DM) CCMDD-enrolled patients. SETTING:  The setting of the study was eThekwini, KwaZulu-Natal, South Africa. METHODS:  We performed a cohort study (April 2018- December 2021). We linked T2DM CCMDD-enrolled patients to glycated haemoglobin (HbA1c) data from the National Health Laboratory Service. We selected patients optimally controlled at their baseline HbA1c, with ≥ 1 repeat-test available. We used Kaplan-Meier analysis to assess survival rates and extended Cox regression to determine associations between time to sub-optimal control (HbA1c 7%) and predictors. Adjusted hazard ratios (aHRs), 95% confidence interval (CI), and p-values are reported. RESULTS:  Of the 41145 T2DM patients enrolled in the CCMDD programme, 7960 (19%) had a HbA1c result available. Twenty-seven percent (2147/7960) were optimally controlled at their baseline HbA1c. Of those controlled at baseline, 695 (32%) patients had a repeat test available, with 35% (242/695) changing to sub-optimal status. The HbA1c testing frequency as per national guidelines was associated with a lower hazard of sub-optimal glycaemic control (aHR: 0.46; 95% CI: 0.24-0.91; p-value = 0.024). Patients prescribed dual-therapy had a higher hazard of sub-optimal glycaemic control (aHR: 1.50; 95% CI: 1.16-1.95; p-value = 0.002) versus monotherapy. CONCLUSIONS:  The HbA1c monitoring, in-line with testing frequency guidelines, is needed to alert the CCMDD programme of patients who become ineligible for enrolment. Patients receiving dual-therapy require special consideration.Contribution: Addressing identified shortfalls can assist programme implementation.


Assuntos
Diabetes Mellitus Tipo 2 , Hemoglobinas Glicadas , Controle Glicêmico , Hipoglicemiantes , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , África do Sul , Controle Glicêmico/métodos , Feminino , Masculino , Hemoglobinas Glicadas/análise , Pessoa de Meia-Idade , Estudos de Coortes , Hipoglicemiantes/uso terapêutico , Idoso , Adulto , Glicemia/análise
6.
Front Endocrinol (Lausanne) ; 15: 1382920, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38836230

RESUMO

Background: Tight glycemic control is essential for the normal growth and development of preschool children. The aim of our study was to evaluate the impact of advanced hybrid closed loop (AHCL) systems in a real-life setting in children younger than 6 years. Methods: We conducted a two-center prospective study. We enrolled 19 patients with a median age at disease onset of 2.6 years [interquartile range (IQR) 1.6; 4.4] and a median disease duration of 1.4 years (IQR 0.9; 2.8) who were switched to AHCL from multiple daily injections or open-loop insulin therapy and with a 6-month follow-up. Clinical data, sensor glycemic metrics, and pump settings were collected and analyzed. Results: After 6 months of follow-up, there was a significant reduction in median HbA1c (p = 0.0007) and glucose management indicator (p = 0.03). A reduction in both mild (>180 mg/dL) (p = 0.04) and severe (>250 mg/dL) (p = 0.01) hyperglycemia was observed after 1 month of auto mode, and in mild hyperglycemia, it persisted up to 6 months (p = 0.02). A small increase in time below range (<70 mg/dL) was observed (p = 0.04) without a significant difference in time <54 mg/dL (p = 0.73). Time in range increased significantly, reaching a 10% increment (p = 0.03) compared with baseline. A significant reduction in the average sensor glucose was observed (p = 0.01) while coefficient of glucose variability (CV%) remained stable (p = 0.12). No episodes of ketoacidosis or severe hypoglycemia have been recorded. Conclusion: AHCL systems are effective and safe for children younger than 6 years and should be considered as a valid therapeutic option from diabetes onset.


Assuntos
Glicemia , Diabetes Mellitus Tipo 1 , Hipoglicemiantes , Sistemas de Infusão de Insulina , Insulina , Humanos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/sangue , Masculino , Pré-Escolar , Feminino , Estudos Prospectivos , Glicemia/análise , Insulina/administração & dosagem , Insulina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/administração & dosagem , Lactente , Controle Glicêmico/métodos , Seguimentos , Automonitorização da Glicemia/métodos , Resultado do Tratamento , Hipoglicemia , Hemoglobinas Glicadas/análise , Criança
7.
Cochrane Database Syst Rev ; 6: CD013414, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38837240

RESUMO

BACKGROUND: Metformin has been used in the management of diabetes for decades. It is an effective, low-cost intervention with a well-established safety profile. Emerging evidence suggests that metformin targets a number of pathways that lead to chronic kidney damage, and long-term use may, therefore, slow the rate of kidney function decline and chronic kidney disease (CKD) progression. OBJECTIVES: To evaluate the effect of metformin therapy on kidney function decline in patients with CKD with or without diabetes mellitus and assess the safety and dose tolerability in this population. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 19 July 2023 with assistance from an Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that reported kidney-related outcomes with a minimum duration of 12 months delivery of the metformin intervention and whose eligibility criteria included adult participants with either i) a diagnosis of CKD of any aetiology and/or ii) those with a diagnosis of diabetes mellitus. Comparisons included placebo, no intervention, non-pharmacological interventions, other antidiabetic medications or any other active control. Studies that included patients on any modality of kidney replacement therapy were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently carried out data extraction using a standard data extraction form. The methodological quality of the included studies was assessed using the Cochrane risk of bias tool. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: This review included 11 studies reporting on 8449 randomised participants. Studies were conducted in patient populations with Autosomal Dominant Polycystic Kidney Disease (ADPKD) (four studies) or diabetes mellitus (seven studies). Six studies compared metformin with no active control, four studies compared metformin with active controls (rosiglitazone, glyburide, pioglitazone, or glipizide), and one study included treatment arms that randomised to either metformin, diet and lifestyle modifications, or other antidiabetic therapies. The risk of bias in included studies varied; two studies were abstract-only publications and were judged to have a high risk of bias in most domains. Other included publications were judged to have a low risk of bias in most domains. Across comparisons, GRADE evaluations for most outcomes were judged as low or very low certainty, except for those relating to side effects, tolerance, and withdrawals, which were judged as moderate certainty. The evidence suggests that compared to placebo, metformin may result in i) a slightly smaller decline in kidney function (3 studies, 505 participants: MD 1.92 mL/min, 95% CI 0.33 to 3.51; I2 = 0%; low certainty), ii) very uncertain effects on the incidence of kidney failure (1 study, 753 participants: RR 1.20, 95% CI 0.17 to 8.49), iii) little or no effect on death (3 studies, 865 participants: RR 1.00, 95% CI 0.76 to 1.32; I2 = 0%; moderate certainty), iv) little or no effect on the incidence of serious adverse events (3 studies, 576 participants: RR 1.15, 95% CI 0.76 to 1.72; I2 = 0%; moderate certainty), and v) likely higher incidence of intolerance leading to study withdrawal than placebo (4 studies, 646 participants: RR 2.19, 95% CI 1.46 to 3.27; I2 = 0%; moderate certainty). The certainty of the evidence for proteinuria was very uncertain. Compared to other active controls (rosiglitazone, glyburide, pioglitazone, or glipizide), metformin i) demonstrated very uncertain effects on kidney function decline, ii) may result in little or no difference in death (3 studies, 5608 participants: RR 0.95 95% CI 0.63 to 1.43; I2 = 0%; low certainty), iii) probably results in little or no difference in intolerance leading to study withdrawal (3 studies, 5593 participants: RR 0.92, 95% CI, 0.79 to 1.08; I2 = 0%; moderate certainty), iv) probably results in little or no difference in the incidence of serious adverse events (2 studies, 5545 participants: RR 1.16, 95% CI 0.79 to 1.71; I2 = 0%; moderate certainty), and v) may increase the urinary albumin-creatinine ratio (2 studies, 3836 participants: MD 14.61, 95% CI 8.17 to 21.05; I2 = 0%; low certainty). No studies reported the incidence of kidney failure. AUTHORS' CONCLUSIONS: This review highlights the lack of RCTs reporting on the effects of metformin on kidney function, particularly in patients with CKD. Future research in this field requires adequately powered RCTs comparing metformin to placebo or standard care in those with CKD. Seven ongoing studies were identified in this review, and future updates, including their findings, may further inform the results of this review.


Assuntos
Progressão da Doença , Hipoglicemiantes , Metformina , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica , Metformina/uso terapêutico , Metformina/efeitos adversos , Humanos , Insuficiência Renal Crônica/complicações , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/efeitos adversos , Taxa de Filtração Glomerular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Adulto , Viés
8.
J Diabetes Res ; 2024: 3470654, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38846063

RESUMO

Aims: We compared the glycaemic and cardiorenal effects of combination therapy involving metformin, pioglitazone, sodium-glucose-linked-cotransporter-2 inhibitor (SGLT2i), and glucagon-like peptide-1 receptor agonist (GLP-1RA) versus a more conventional glucocentric treatment approach combining sulphonylureas (SU) and insulin from the point of type 2 diabetes (T2D) diagnosis. Methods: We performed a retrospective cohort study using the Global Collaborative Network in TriNetX. We included individuals prescribed metformin, pioglitazone, an SGLT2i, and a GLP-1 RA for at least 1-year duration, within 3 years of a T2D diagnosis, and compared with individuals prescribed insulin and a SU within the same temporal pattern. Individuals were followed up for 3 years. Results: We propensity score-matched (PSM) for 26 variables. A total of 1762 individuals were included in the final analysis (n = 881 per cohort). At 3-years, compared to the insulin/SU group, the metformin/pioglitazone/SGLT2i/GLP-1 RA group had a lower risk of heart failure (HR 0.34, 95% CI 0.13-0.87, p = 0.018), acute coronary syndrome (HR 0.29, 95% CI 0.12-0.67, p = 0.002), stroke (HR 0.17, 95% CI 0.06-0.49, p < 0.001), chronic kidney disease (HR 0.50, 95% CI 0.25-0.99, p = 0.042), and hospitalisation (HR 0.59, 95% CI 0.46-0.77, p < 0.001). Conclusions: In this real-world study, early, intensive polytherapy, targeting the distinct pathophysiological defects in T2D, is associated with significantly more favourable cardiorenal outcomes, compared to insulin and SU therapy.


Assuntos
Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes , Insulina , Metformina , Inibidores do Transportador 2 de Sódio-Glicose , Compostos de Sulfonilureia , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Masculino , Hipoglicemiantes/uso terapêutico , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Metformina/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Insulina/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Pioglitazona/uso terapêutico , Bases de Dados Factuais , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Resultado do Tratamento
9.
Drug Dev Res ; 85(4): e22216, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38831547

RESUMO

A new series of quinoxaline-sulfonamide derivatives 3-12 were synthesized using fragment-based drug design by reaction of quinoxaline sulfonyl chloride (QSC) with different amines and hydrazines. The quinoxaline-sulfonamide derivatives were evaluated for antidiabetic and anti-Alzheimer's potential against α-glucosidase, α-amylase, and acetylcholinesterase enzymes. These derivatives showed good to moderate potency against α-amylase and α-glucosidase with inhibitory percentages between 24.34 ± 0.01%-63.09 ± 0.02% and 28.95 ± 0.04%-75.36 ± 0.01%, respectively. Surprisingly, bis-sulfonamide quinoxaline derivative 4 revealed the most potent activity with inhibitory percentages of 75.36 ± 0.01% and 63.09 ± 0.02% against α-glucosidase and α-amylase compared to acarbose (IP = 57.79 ± 0.01% and 67.33 ± 0.01%), respectively. Moreover, the quinoxaline derivative 3 exhibited potency as α-glucosidase and α-amylase inhibitory with a minute decline from compound 4 and acarbose with inhibitory percentages of 44.93 ± 0.01% and 38.95 ± 0.01%. Additionally, in vitro acetylcholinesterase inhibitory activity for designed derivatives exhibited weak to moderate activity. Still, sulfonamide-quinoxaline derivative 3 emerged as the most active member with inhibitory percentage of 41.92 ± 0.02% compared with donepezil (IP = 67.27 ± 0.60%). The DFT calculations, docking simulation, target prediction, and ADMET analysis were performed and discussed in detail.


Assuntos
Inibidores da Colinesterase , Inibidores de Glicosídeo Hidrolases , Simulação de Acoplamento Molecular , Quinoxalinas , Sulfonamidas , alfa-Amilases , alfa-Glucosidases , Quinoxalinas/química , Quinoxalinas/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo , alfa-Glucosidases/química , Sulfonamidas/química , Sulfonamidas/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Relação Estrutura-Atividade , Acetilcolinesterase/metabolismo , Modelos Moleculares , Farmacóforo
10.
Pak J Pharm Sci ; 37(2(Special)): 417-421, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38822544

RESUMO

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder with a rising global prevalence. The primary objective of this study was to explore the relationship between the GRK5 variant (rs10886471) and the therapeutic effect of repaglinide in patients of T2DM in Peshawar, Pakistan. A quasi-experimental study was designed. The study group consisted of patients with Type 2 Diabetes Mellitus (T2DM) categorized into responders and non-responders based on their HbA1c level reduction in response to repaglinide treatment. After ethical approval, and consent from the participants, sociodemographic and clinical data was collected from 60 T2DM patients. Blood samples were collected followed by DNA extraction and quantification with UV-Vis Spectroscopy. Genotyping for the GRK5 variant rs10886471 was done using the PCR-based method. Among socio-demographic factors family history and BMI showed significant association (P<0.05) with the therapeutic response to repaglinide. The Statistical analyses, including chi-square tests and logistic regression of GRK5 variant rs10886471 exhibited a significant association with the therapeutic response. Variant allele exhibited significant association (OR: 1.2, p=0.049) with the therapeutic response to repaglinide. The study demonstrated a significant relationship between the GRK5 variant (rs10886471) and the therapeutic response to repaglinide in patients of T2DM of Peshawar, Pakistan.


Assuntos
Carbamatos , Diabetes Mellitus Tipo 2 , Quinase 5 de Receptor Acoplado a Proteína G , Hipoglicemiantes , Piperidinas , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/sangue , Masculino , Feminino , Paquistão , Hipoglicemiantes/uso terapêutico , Pessoa de Meia-Idade , Quinase 5 de Receptor Acoplado a Proteína G/genética , Carbamatos/uso terapêutico , Piperidinas/uso terapêutico , Adulto , Hemoglobinas Glicadas/metabolismo , Resultado do Tratamento , Idoso
11.
Sci Rep ; 14(1): 12638, 2024 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-38825591

RESUMO

In this study, changes in bioactive compound contents and the in vitro biological activity of mixed grains, including oats, sorghum, finger millet, adzuki bean, and proso millet, with eight different blending ratios were investigated. The total phenolic compounds and flavonoid contents ranged from 14.43-16.53 mg gallic acid equivalent/g extract and 1.22-5.37 mg catechin equivalent/g extract, respectively, depending on the blending ratio. The DI-8 blend (30% oats, 30% sorghum, 15% finger millet, 15% adzuki bean, and 10% proso millet) exhibited relatively higher antioxidant and anti-diabetic effects than other blending samples. The levels of twelve amino acids and eight organic acids in the grain mixes were measured. Among the twenty metabolites, malonic acid, asparagine, oxalic acid, tartaric acid, and proline were identified as key metabolites across the blending samples. Moreover, the levels of lactic acid, oxalic acid, and malonic acid, which are positively correlated with α-glucosidase inhibition activity, were considerably higher in the DI-blending samples. The results of this study suggest that the DI-8 blend could be used as a functional ingredient as it has several bioactive compounds and biological activities, including anti-diabetic activity.


Assuntos
Antioxidantes , Grão Comestível , Antioxidantes/farmacologia , Antioxidantes/química , Grão Comestível/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Flavonoides/análise , Flavonoides/química , Flavonoides/farmacologia , Fenóis/análise , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Aminoácidos/metabolismo , Aminoácidos/análise
12.
JAMA Netw Open ; 7(6): e2415392, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38848064

RESUMO

Importance: Evidence regarding the relative effectiveness of bariatric metabolic surgery (BMS) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) in reducing mortality and major adverse cardiovascular events (MACEs) is limited. Objective: To compare all-cause mortality and nonfatal MACEs associated with BMS vs GLP-1RAs for adults with obesity and diabetes and without known cardiovascular disease. Design, Setting, and Participants: This observational, retrospective cohort study was based on data obtained from the electronic medical records of Clalit Health Services (Clalit), the largest health care organization in Israel. The study included 6070 members aged 24 years or older, who had diabetes and obesity and no prior history of ischemic heart disease, ischemic stroke, or congestive heart failure. Patients who underwent BMS and patients who received GLP-1RAs from January 1, 2008, through December 31, 2021, were matched 1:1 by age, sex, and clinical characteristics. Follow-up ended December 31, 2022. Exposures: Initiation of BMS or GLP-1RAs. Main Outcomes and Measures: The primary outcome was all-cause mortality, assessed by multivariate Cox proportional hazards regression models. The secondary outcome was nonfatal MACEs, assessed by multivariate competing risk models. Results: The study included 3035 matched pairs of patients (total, 6070; mean [SD] age, 51.0 [9.5] years; 3938 women [64.9%]), who were followed up for a median of 6.8 years (IQR, 4.1-9.4 years). Among those with a diabetes duration of 10 years or less (2371 pairs), mortality was lower for those who underwent BMS than for those treated with GLP-1RAs (hazard ratio [HR], 0.38; 95% CI, 0.25-0.58). This association became nonsignificant when weight loss during the follow-up period was also included in the model (HR, 0.79; 95% CI, 0.43-1.48). Among patients with a duration of diabetes longer than 10 years (664 pairs), no survival advantage was demonstrated for BMS over GLP-1RA (HR, 0.65; 95% CI, 0.39-1.08). The risk for nonfatal MACEs did not differ between the treatment groups (HR, 0.74; 95% CI, 0.49-1.10 among patients with a diabetes duration of ≤10 years; HR, 1.21; 95% CI, 0.80-1.85 among patients with a diabetes duration of >10 years). Conclusions and Relevance: In this cohort study, BMS was associated with greater reduced mortality compared with first-generation GLP-1RAs among individuals with a diabetes duration of 10 years or less, mediated via greater weight loss. No differences in the risk for mortality were observed between the treatment modalities among individuals with a longer duration of diabetes, nor in the occurrence of nonfatal MACEs among all patients.


Assuntos
Cirurgia Bariátrica , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Cirurgia Bariátrica/mortalidade , Cirurgia Bariátrica/métodos , Adulto , Israel/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/mortalidade , Obesidade , Hipoglicemiantes/uso terapêutico , Doenças Cardiovasculares/mortalidade , Modelos de Riscos Proporcionais , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon
13.
Pak J Pharm Sci ; 37(2(Special)): 459-462, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38822550

RESUMO

The purpose of this study was to examine the potential hypoglycemic effects of administering ginger (Zingiber officinale) and garlic (Allium sativum) to rats with induced type 2 diabetes. A total of forty-five male adult albino rats were randomly assigned to five groups. The groups were named Normal Control, Diabetic Control, Ginger group, Garlic group and a combination group of ginger and garlic. Diabetes was produced in all groups, except the normal control group, using an intraperitoneal injection of streptozotocin at a dosage of 60 mg/body weight. During the course of two months, rats were administered varying amounts of ginger and garlic powders as part of their treatment After the experiment concluded, measurements were taken for glycated hemoglobin, serum glucose, insulin, cholesterol, high density protein, low density protein and liver glycogen levels. These groups exhibited considerably greater serum insulin and high-density lipoprotein concentrations (P<0.05) compared to the diabetic control group. Conversely, body weight, fasting blood glucose, total cholesterol, low density lipoprotein, and glycated hemoglobin levels were significantly lower (P<0.05) in all groups compared to the diabetic control group. A statistically significant increase (P<0.05) increase shown in liver glycogen levels. This study proposes that the utilization of ginger and garlic powders improve the condition of type 2 diabetes and maybe reduce the risk of subsequent diabetic complications.


Assuntos
Glicemia , Diabetes Mellitus Experimental , Alho , Hipoglicemiantes , Insulina , Pós , Zingiber officinale , Animais , Alho/química , Zingiber officinale/química , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/sangue , Masculino , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Ratos , Insulina/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Hemoglobinas Glicadas/metabolismo , Extratos Vegetais/farmacologia , Fitoterapia , Glicogênio Hepático/metabolismo , Estreptozocina
14.
Food Res Int ; 188: 114513, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38823886

RESUMO

This study reports the effect of thermal pretreatment and the use of different commercial proteolytic enzymes (Protamex, Flavourzyme, Protana prime, and Alcalase) on the free amino acid content (FAA), peptide profile, and antioxidant, antidiabetic, antihypertensive, and anti-inflammatory potential (DPPH, FRAP, and ABTS assay, DPP-IV, ACE-I, and NEP inhibitory activities) of dry-cured ham bone hydrolyzates. The effect of in vitro digestion was also determined. Thermal pretreatment significantly increased the degree of hydrolysis, the FAA, and the DPP-IV and ACE-I inhibitory activities. The type of peptidase used was the most significant factor influencing antioxidant activity and neprilysin inhibitory activity. Protana prime hydrolyzates failed to inhibit DPP-IV and neprilysin enzymes and had low values of ACE-I inhibitory activity. After in vitro digestion, bioactivities kept constant in most cases or even increased in ACE-I inhibitory activity. Therefore, hydrolyzates from dry-cured ham bones could serve as a potential source of functional food ingredients for health benefits.


Assuntos
Antioxidantes , Digestão , Animais , Hidrólise , Antioxidantes/metabolismo , Antioxidantes/análise , Osso e Ossos/metabolismo , Suínos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Manipulação de Alimentos/métodos , Temperatura Alta , Aminoácidos/metabolismo , Aminoácidos/análise , Produtos da Carne/análise , Hipoglicemiantes/farmacologia , Anti-Hipertensivos/farmacologia , Anti-Inflamatórios/farmacologia , Peptídeo Hidrolases/metabolismo , Inibidores da Dipeptidil Peptidase IV , Neprilisina/metabolismo , Neprilisina/antagonistas & inibidores , Endopeptidases
15.
Diabetes Metab Res Rev ; 40(5): e3826, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38824455

RESUMO

INTRODUCTION: Early and tight glycaemic control is crucial to prevent long-term complications of Type 1 Diabetes (T1D). The aim of our study was to compare glucose metrics, including Time In Tight Range (TITR), in a real-world setting. METHODS: We performed a single-centre cross-sectional study in 534 children and adolescents with T1D. Participants were divided into four groups (multiple daily injections + real-time Continuous glucose monitoring (CGM), multiple daily injections + intermittently scanned CGM, sensor augmented pump (SAP), and Advanced Hybrid Closed-Loop (AHCL). Demographical and clinical data were collected and analysed. RESULTS: The group with AHCL showed significantly higher Time In Range (TIR) (71.31% ± 10.88) than SAP (57.82% ± 14.98; p < 0.001), MDI + rtCGM (54.56% ± 17.04; p < 0.001) and MDI + isCGM (52.17% ± 19.36; p < 0.001) groups with a lower Time Above Range (p < 0.001). The group with AHCL also showed lower Time Below Range than MDI + isCGM and SAP groups (p < 0.01). The overall TITR was 37% ± 14 with 19% of participants who reached a TITR ≥50% with a mean TIR of 81%. AHCL had significantly higher TITR (45.46% ± 11.77) than SAP (36.25% ± 13.53; p < 0.001), MDI + rtCGM (34.03% ± 13.89; p < 0.001) and MDI + isCGM (33.37% ± 15.84; p < 0.001) groups with a lower Coefficient of Variation (p < 0.001). CONCLUSIONS: Our study indicates that AHCL ensures a better glycaemic control with an improvement in both TIR and TITR, along with a reduction in CV. Implementation of automated insulin delivery systems should be considered in the treatment of children and adolescents with T1D.


Assuntos
Automonitorização da Glicemia , Glicemia , Diabetes Mellitus Tipo 1 , Hipoglicemiantes , Sistemas de Infusão de Insulina , Insulina , Humanos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Estudos Transversais , Criança , Adolescente , Feminino , Masculino , Automonitorização da Glicemia/métodos , Glicemia/análise , Insulina/administração & dosagem , Insulina/uso terapêutico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Controle Glicêmico/métodos , Hemoglobinas Glicadas/análise , Seguimentos , Prognóstico , Biomarcadores/análise , Hipoglicemia/prevenção & controle
16.
BMC Endocr Disord ; 24(1): 77, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38831300

RESUMO

OBJECTIVE: This study aimed to analyze the factors influencing glycemic control in patients with type 2 diabetes mellitus (T2DM). METHODS: Baseline data, encompassing basic information, lifestyle habits, and treatment of 305 T2DM patients from March 2021 to January 2023, were collected and analyzed using SPSS 26.0 software. RESULTS: Univariate and multivariate logistic regression analyses identified insulin therapy (OR = 2.233; 95%Cl = 1.013-4.520; P = 0.026) and regular clinic visits (OR = 0.567; 95%Cl = 0.330-0.973; P = 0.040) as independent factors influencing glycemic control. No observed interactions between the two variables were noted. CONCLUSION: History of insulin therapy and regular clinic visits were significantly and independently associated with glycated hemoglobin control in T2DM patients. Tailored interventions based on individual circumstances are recommended to optimize glycemic control.


Assuntos
Glicemia , Diabetes Mellitus Tipo 2 , Hemoglobinas Glicadas , Controle Glicêmico , Hipoglicemiantes , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Estudos Transversais , Feminino , Masculino , China/epidemiologia , Pessoa de Meia-Idade , Glicemia/análise , Glicemia/metabolismo , Hemoglobinas Glicadas/análise , Hipoglicemiantes/uso terapêutico , Idoso , Insulina/uso terapêutico , Insulina/administração & dosagem , Adulto , Prognóstico
17.
Physiol Rep ; 12(11): e16093, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38845596

RESUMO

Regular exercise and antihyperglycemic drugs are front-line treatments for type-2 diabetes and related metabolic disorders. Leading drugs are metformin, sodium-glucose cotransporter-2 inhibitors, and glucagon-like peptide 1 receptor agonists. Each class has strong individual efficacy to treat hyperglycemia, yet the combination with exercise can yield varied results, some of which include blunting of expected metabolic benefits. Skeletal muscle insulin resistance contributes to the development of type-2 diabetes while improvements in skeletal muscle insulin signaling are among key adaptations to exercise training. The current review identifies recent advances into the mechanisms, with an emphasis on skeletal muscle, of the interaction between exercise and these common antihyperglycemic drugs. The review is written toward researchers and thus highlights specific gaps in knowledge and considerations for future study directions.


Assuntos
Exercício Físico , Hipoglicemiantes , Músculo Esquelético , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Exercício Físico/fisiologia , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina/fisiologia , Metformina/farmacologia , Metformina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
18.
Sci Rep ; 14(1): 13221, 2024 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-38851807

RESUMO

In exploring nature's potential in addressing diabetes-related conditions, this study investigates the therapeutic capabilities of 3-formyl chromone derivatives. Utilizing in silico methodologies, we focus on 6-substituted 3-formyl chromone derivatives (1-16) to assess their therapeutic potential in treating diabetes. The research examined the formyl group at the chromone's C-3 position. ADMET, biological activities, were conducted along with B3LYP calculations using 3 different basis sets. The analogues were analyzed based on their parent structure obtained from PubChem. The HOMO-LUMO gap confirmed the bioactive nature of the derivatives, NBO analysis was performed to understand the charge transfer. PASS prediction revealed that 3-formyl chromone derivatives are potent aldehyde oxidase inhibitors, insulin inhibitors, HIF1A expression inhibitors, and histidine kinase. Molecular docking studies indicated that the compounds had a strong binding affinity with proteins, including CAD, BHK, IDE, HIF-α, p53, COX, and Mpro of SARS-CoV2. 6-isopropyl-3-formyl chromone (4) displayed the highest affinity for IDE, with a binding energy of - 8.5 kcal mol-1. This result outperformed the affinity of the reference standard dapagliflozin (- 7.9 kcal mol-1) as well as two other compounds that target human IDE, namely vitexin (- 8.3 kcal mol-1) and myricetin (- 8.4 kcal mol-1). MD simulations were revealed RMSD value between 0.2 and 0.5 nm, indicating the strength of the protein-ligand complex at the active site.


Assuntos
Cromonas , Hipoglicemiantes , Simulação de Acoplamento Molecular , Cromonas/química , Cromonas/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Simulação por Computador
19.
Front Endocrinol (Lausanne) ; 15: 1384984, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38854687

RESUMO

Introduction: With the increasing prevalence of type 2 diabetes mellitus (T2DM), there is an urgent need to discover effective therapeutic targets for this complex condition. Coding and non-coding RNAs, with traditional biochemical parameters, have shown promise as viable targets for therapy. Machine learning (ML) techniques have emerged as powerful tools for predicting drug responses. Method: In this study, we developed an ML-based model to identify the most influential features for drug response in the treatment of type 2 diabetes using three medicinal plant-based drugs (Rosavin, Caffeic acid, and Isorhamnetin), and a probiotics drug (Z-biotic), at different doses. A hundred rats were randomly assigned to ten groups, including a normal group, a streptozotocin-induced diabetic group, and eight treated groups. Serum samples were collected for biochemical analysis, while liver tissues (L) and adipose tissues (A) underwent histopathological examination and molecular biomarker extraction using quantitative PCR. Utilizing five machine learning algorithms, we integrated 32 molecular features and 12 biochemical features to select the most predictive targets for each model and the combined model. Results and discussion: Our results indicated that high doses of the selected drugs effectively mitigated liver inflammation, reduced insulin resistance, and improved lipid profiles and renal function biomarkers. The machine learning model identified 13 molecular features, 10 biochemical features, and 20 combined features with an accuracy of 80% and AUC (0.894, 0.93, and 0.896), respectively. This study presents an ML model that accurately identifies effective therapeutic targets implicated in the molecular pathways associated with T2DM pathogenesis.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Aprendizado de Máquina , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Ratos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Masculino , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/farmacologia , Ratos Sprague-Dawley , Biomarcadores , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Resistência à Insulina , Quercetina/farmacologia , Quercetina/uso terapêutico , Ácidos Cafeicos
20.
J Agric Food Chem ; 72(23): 13083-13098, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38829529

RESUMO

Type 2 diabetes (T2DM) significantly diminishes people's quality of life and imposes a substantial economic burden. This pathological progression is intimately linked with specific gut microbiota, such as Akkermansia muciniphila. Pasteurized A. muciniphila (P-AKK) has been defined as a novel food by the European Food Safety Authority and exhibited significant hypoglycemic activity. However, current research on the hypoglycemic activity of P-AKK is limited to the metabolic level, neglecting systematic exploration at the pathological level. Consequently, its material basis and mechanism of action for hypoglycemia remain unclear. Drawing upon this foundation, we utilized high-temperature killed A. muciniphila (H-K-AKK) with insignificant hypoglycemic activity as the control research object. Assessments were conducted at pathological levels to evaluate the hypoglycemic functions of both P-AKK and H-K-AKK separately. Our study unveiled for the first time that P-AKK ameliorated symptoms of T2DM by enhancing the generation of glucagon-Like Peptide 1 (GLP-1), with pasteurized A. muciniphila total proteins (PP) being a pivotal component responsible for this activity. Utilizing SDS-PAGE, proteomics, and molecular docking techniques, we deeply analyzed the material foundation of PP. We scientifically screened and identified a protein weighing 77.85 kDa, designated as P5. P5 enhanced GLP-1 synthesis and secretion by activating the G protein-coupled receptor (GPCR) signaling pathway, with free fatty acid receptor 2 (FFAR-2) being identified as the pivotal target protein for P5's physiological activity. These findings further promote the widespread application of P-AKK in the food industry, laying a solid theoretical foundation for its utilization as a beneficial food ingredient or functional component.


Assuntos
Akkermansia , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Pasteurização , Probióticos , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Masculino , Animais , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Camundongos , Glicemia/metabolismo , Hipoglicemiantes/química , Simulação de Acoplamento Molecular
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