The escalating prevalence of Type-2 diabetes mellitus (T2DM) poses a significant global health challenge. Utilizing integrative proteomic analysis, this study aimed to identify a panel of potential protein markers for T2DM, enhancing diagnostic accuracy and paving the way for personalized treatment strategies.

Proteome profiles from two independent cohorts were integrated: cohort 1 composed of 10 T2DM patients and 10 healthy controls (HC), and cohort 2 comprising 87 T2DM patients and 60 healthy controls. Differential expression analysis, functional enrichment analysis, receiver operating characteristic (ROC) analysis, and classification error matrix analysis were employed.

Comparative proteomic analysis identified the differential expressed proteins (DEPs) and changes in biological pathways associated with T2DM. Further combined analysis refined a group of protein panel (including CA1, S100A6, and DDT), which were significantly increased in T2DM in both two cohorts. ROC analysis revealed the area under curve (AUC) values of 0.94 for CA1, 0.87 for S100A6, and 0.97 for DDT; the combined model achieved an AUC reaching 1. Classification error matrix analysis demonstrated the combined model could reach an accuracy of 1 and 0.875 in the 60% training set and 40% testing set.

This study incorporates different cohorts of T2DM, and refines the potential markers for T2DM with high accuracy, offering more reliable markers for clinical translation.

The online version contains supplementary material available at 10.1007/s40200-025-01562-3.

Type 2 diabetes mellitus (T2DM) represents a chronic metabolic disorder characterized by disrupted carbohydrate and lipid balance, resulting in hyperglycemia. This study evaluated the impact of polysaccharides derived from Cynanchum auriculatum Royle ex Wight (CRP) on mitigating hyperglycemia and modulating intestinal microbiota in T2DM mice. Findings indicated that CRP is mainly linked by →6)α-D-Glcp-(1→ and CRP-H demonstrated greater efficacy than CRP-L in regulating hypoglycemic-related indicators such as serum high-density lipoprotein cholesterol (HDL-c) level. Additionally, CRP at varying doses enhanced the mRNA expression of insulin receptor substrate 1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT-1), and glucose transporter 2 (GLUT-2). Following a 4-week CRP-H treatment, a significant reduction in the Firmicutes/Bacteroidetes ratio at the phylum level was observed, alongside a marked increase in the relative abundance of beneficial genera such as Limosillactobacillus and Prevotella. Overall, CRP-H displayed enhanced hypoglycemic properties by activating the IRS-1/PI3K/AKT-1/GLUT-2 pathway and enriching beneficial gut bacteria, including Prevotella and Limosillactobacillus. This study establishes a foundational framework for further development and application of Cynanchum auriculatum Royle ex Wight resources, emphasizing the hypoglycemic potential of CRP.

Circulating Gremlin 2 (Grem2) has recently been linked to human obesity, but its role in type 2 diabetes (T2D) remains unclear. This study aims to explore the association of circulating Grem2 with β-cell function.

A post hoc analysis was conducted using data from three clinical trials, in which all participants underwent the oral glucose tolerance test (OGTT). Circulating Grem2 levels were measured at 0, 1, and 2 h during the OGTT. In Trial 1, Grem2 levels were compared between participants with T2D (n = 59) and without T2D (n = 119). We further examined changes in Grem2 levels in response to oral antidiabetic drugs in participants with T2D in Trial 2 (n = 67) and calorie restriction in participants with prediabetes in Trial 3 (n = 231). The relationship between Grem2 levels and β-cell function was analyzed across all trials.

Fasting and 1-h Grem2 levels were lower in participants with T2D compared with those without T2D (728 ± 25 vs. 649 ± 31 pg/mL, p = 0.020; 631 ± 26 vs. 537 ± 31 pg/mL, p = 0.007). Fasting Grem2 levels were restored after antidiabetic treatment (550 ± 12 vs. 575 ± 12 pg/mL, p = 0.019), and 1-h Grem2 levels increased following calorie restriction (1118 ± 89 vs. 1144 ± 90 vs. 1253 ± 89 pg/mL, p for trend = 0.002). The 1-h Grem2 levels were positively associated with β-cell function assessed by the oral disposition index and HOMA-β.

Reduced circulating Grem2 levels are associated with impaired β-cell function in T2D, and could be restored through antidiabetic interventions.

ClinicalTrials.gov: NCT01959984, NCT01758471, NCT03856762.

The aim of this study was to elucidate the potential mechanism of the antihyperglycemic action of the donut-shaped Preyssler-Pope-Jeannin polyanion salt (NH4)14[NaP5W30O110] 31H2O (NaP5W30) and its effect on metabolic disorders associated with diabetes. For this purpose, relevant parameters of blood glucose regulation, lipid profile, and electrolyte status were monitored in streptozotocin (STZ)-induced diabetic rats that were orally treated with 20 mg/kg/day NaP5W30 for three weeks. The serum insulin concentration was increased in diabetic animals treated with NaP5W30 (20 mg/kg/day, per os, three weeks), which could be one of the possible mechanisms of the confirmed antihyperglycemic effect. In addition, the administration of NaP5W30 significantly reduced hyperglycemia and glycated haemoglobin A1c (HbA1c) in STZ-induced diabetic rats, although normoglycemic values were not achieved. Furthermore, a statistically significant 1.3-fold reduction in serum total cholesterol and a 1.7-fold reduction in high-density lipoprotein (HDL) cholesterol were observed in the NaP5W30 treatment group compared to the diabetic control group. In contrast, NaP5W30 had no effect on homeostasis model assessment of insulin resistance (HOMA-IR) index values, electrolyte concentrations, or serum concentrations of low-density lipoprotein (LDL) cholesterol, apolipoprotein A1 (Apo A1), apolipoprotein B (Apo B), or total triglycerides. In summary, NaP5W30 effectively improved glycoregulation in diabetic rats via the considerable stimulation of insulin as a putative mechanism. Moreover, NaP5W30 did not affect rat weight or disrupt lipid and electrolyte status, common diabetes-followed side effects and risk factors for various life-threatening complications. Thus, NaP5W30 could be considered a promising antidiabetic drug-candidate that deserves further investigation.

Type 2 diabetes mellitus (T2DM) is a global health burden, with hyperglycemia as the main hallmark. This review commences with a concise overview of the intricate mechanisms underlying glucose uptake and utilization in organisms. Notably, we emphasize that T2DM management strategies pivot on delaying carbohydrate digestion, augmenting insulin secretion, and enhancing insulin sensitivity in target tissues. Unfortunately, the drugs currently available in the market for the treatment of T2DM have unpleasant side effects, spurring an urgent quest for safer and more efficacious alternatives. Flavonoids, emerging as a promising class of bioactive compounds derived from plants, offer a multi-faceted approach to diabetes treatment. Specifically, they potently inhibit enzymes such as α-amylase, α-glucosidase, dipeptidyl peptidase-4 (DPP-4), glycogen phosphorylase (GP) and protein-tyrosine phosphatase-1B (PTP1B). Through an in-depth analysis, this review not only summarizes these inhibitory actions but also establishes the structure-activity relationship (SAR), providing a blueprint for rational drug design. However, the clinical translation of flavonoids has been hampered by their suboptimal water solubility and bioavailability, attributable to the characteristic carbonyl and hydroxyl groups. Ingeniously, this chemical quirk has been harnessed to engineer metal chelates, which exhibit enhanced pharmacokinetic profiles. Herein, we offer an exhaustive overview of the latest advancements in flavonoid metal complexes research, spotlighting their potential as next-generation diabetes therapeutics. Available data are poised to galvanize the development of novel flavonoid derivatives, be it as potent drugs or functional foods, for combating T2DM.

Epigallocatechin gallate (EGCG), the predominant catechin in green tea, comprises approximately 50% of its total polyphenol content and has garnered widespread recognition for its significant therapeutic potential. As the principal bioactive component of Camellia sinensis, EGCG is celebrated for its potent antioxidant, anti-inflammatory, cardioprotective, and antitumor properties. The bioavailability and metabolism of EGCG within the gut microbiota underscore its systemic effects, as it is absorbed in the intestine, metabolized into bioactive compounds, and transported to target organs. This compound has been shown to influence key physiological pathways, particularly those related to lipid metabolism and inflammation, offering protective effects against a variety of diseases. EGCG's ability to modulate cell signaling pathways associated with oxidative stress, apoptosis, and immune regulation highlights its multifaceted role in health promotion. Emerging evidence underscores EGCG's therapeutic potential in preventing and managing a range of chronic conditions, including cancer, cardiovascular diseases, neurodegenerative disorders, and metabolic syndromes. Given the growing prevalence of lifestyle-related diseases and the increasing interest in natural compounds, EGCG presents a promising avenue for novel therapeutic strategies. This review aims to summarize current knowledge on EGCG, emphasizing its critical role as a versatile natural bioactive agent with diverse clinical applications. Further exploration in both experimental and clinical settings is essential to fully unlock its therapeutic potential.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-Like peptide-1 receptor agonists (GLP-1 RA) are recommended in people with type 2 diabetes (T2D) for glycaemic control and for people with high cardiovascular risk. However, current guidelines do not specifically address the role of initial early combination therapy with SGLT2i and GLP-1 RA or dual gastric inhibitory polypeptide (GIP)/GLP-1 RA, but rather sequential initiation with either in T2D. This review synthesizes the available evidence on the use of SGLT2i and GLP-1-based therapies for T2D and provides a rationale for their combination. The combination of SGLT2i with GLP-1-based therapies addresses complementary pathophysiological mechanisms and enhances efficacy in achieving target haemoglobin A1C (HbA1c) levels. SGLT2i and GLP-1 RA also have been shown to prevent complications of T2D. While both classes reduce adverse cardiorenal events, SGLT2i has a predominant effect on prevention of kidney dysfunction and heart failure, whereas GLP-1 RA has a more marked effect on the risk of atherosclerotic cardiovascular disease. Both drug classes have favourable safety profiles. Finally, weight loss with combination therapy may have disease-modifying effects that may reverse T2D progression. We propose that the combination of SGLT2i with GLP-1 RA or dual GIP/GLP-1 RA should be considered for most patients with T2D who do not have contraindications.

Insulin resistance and pancreatic β-cell dysfunction are the main pathogenesis of type 2 diabetes mellitus (T2DM). However, insulin therapy and diabetes medications do not effectively solve the two problems simultaneously. In this study, a biomimetic oral hydrogen nanogenerator that leverages the benefits of edible plant-derived exosomes and hydrogen therapy was constructed to overcome this dilemma by modulating gut microbiota and ameliorating oxidative stress and inflammatory responses. Hollow mesoporous silica (HMS) nanoparticles encapsulating ammonia borane (A) were used to overcome the inefficiency of H2 delivery in traditional hydrogen therapy, and exosomes originating from ginger (GE) were employed to enhance biocompatibility and regulate intestinal flora. Our study showed that HMS/A@GE not only considerably ameliorated insulin resistance and liver steatosis, but inhibited the dedifferentiation of islet β-cell and enhanced pancreatic β-cell proportion in T2DM model mice. In addition to its antioxidant and anti-inflammatory effects, HMS/A@GE augmented the abundance of Lactobacilli spp. and tryptophan metabolites, such as indole and indole acetic acid, which further activated the AhR/IL-22 pathway to improve intestinal-barrier function and metabolic impairments. This study offers a potentially viable strategy for addressing the current limitations of diabetes treatment by integrating gut-microbiota remodelling with antioxidant therapies.

Functional foods that are illegally adulterated with chemical hypoglycemic drugs or their derivatives pose serious risks to human health. However, the detection of these compounds is a challenge due to the unknown nature of their structures, particularly as many of these compounds are newly synthesized and lack standardized references. In this study, we developed a non-targeted screening strategy for detecting illegally added hypoglycemic drugs and their derivatives in oral solution and hard capsule functional foods. This strategy utilizes a self-established characteristic fragment ions mass spectrum database based on ultrahigh-performance liquid chromatography-quadrupole/orbitrap high-resolution mass spectrometry. Nine characteristic fragment ions were identified by analyzing the mass spectrometric fragmentation patterns of hypoglycemic drugs. Meanwhile, the precursor and fragment ions of 38 known hypoglycemic drugs were collected and incorporated into the mass database. The detection limits of hypoglycemic drugs in oral solution and hard capsule samples were 0.01-10 μg/L and 0.01-50 μg/kg, respectively. Applying the non-targeted method to 20 batches of suspicious samples, we found that 3 batches of samples contained illegal added drugs. Furthermore, we identified a previously unrecorded hypoglycemic drug not present in the mass database. These results indicate that the developed strategy is a powerful tool for the rapid and highly sensitive identification of both known and unknown hypoglycemic drugs, as well as their derivatives in functional foods.

Currently, available therapies for diabetes cannot achieve normal sugar values in a high percentage of treated patients. This work synthesized a series of carbazole-triazole-thione derivatives, and their potential antidiabetic activity was investigated against the key diabetic enzymes α-amylase and glycosidase. Normal human hepatic stellate cells (LX-2) were employed to assess their cytotoxicity and safety, followed by in vivo testing to investigate the hypoglycemic effect of the most promising agent. As a result, a set of 18 carbazole-1,2,4-triazole-thione derivatives were synthesized. Seven structures demonstrated potential inhibitory activity against α-amylase enzyme, with IC50 lower than 6.4 μM. Among them, compounds C5f, C5o, and C5r exhibited the highest potency, with IC50 values of 0.56, 0.53, and 0.97 μM, respectively, compared to the well-known α-amylase inhibitor acarbose, which has an IC50 value of 5.31 μM. Exploring the inhibition potency of these series against α-glucosidase enzyme revealed that C5f and C5r compounds act as moderate inhibitors, with IC50 values of 11.03 and 13.76 μM, respectively. Moreover, at 100 μM concentration, most of the evaluated compounds showed negligible cytotoxic effect against LX-2 cell lines, particularly compounds C5o and C5s, that demonstrated lower cytotoxic activity by 3-fold compared to the positive control 5-Flururicle (cell viability 13.45%). Thus, the C5f compound was selected for in vivo evaluation, and after administering five doses of this compound (10 mg/kg) to group III of mice, a significant reduction in glucose concentration was observed, bringing it down from 290.54 to 216.15 mg/dL, in comparison with the control group which did not show a reduction in blood glucose level. These observed in vitro and in vivo results were upheld by performing a set of chemoinformatic studies that elucidated the binding interactions of the most active derivatives within the enzyme's active site and highlighted the critical roles of both the 1,2,4-triazole-3-thione and carbazole scaffolds in these interactions. Finally, the drug-likeness profiles of our carbazole-triazole-thione derivatives suggest their potential as candidates for further in vivo studies and clinical trials.

Glucagon-like peptide-1 receptor (GLP-1R) agonists, such as exenatide (Byetta, Bydureon), liraglutide (Victoza, Saxenda), albiglutide (Tanzeum), dulaglutide (Trulicity), lixisenatide (Lyxumia, Adlyxin), semaglutide (Ozempic, Rybelsus, Wegovy), and tirzepatide (Mounjaro, Zepbound), are widely used for the treatment of type 2 diabetes mellitus (T2DM) and obesity. While these agents are well known for their metabolic benefits, there is growing interest in their potential effects on cancer biology. However, the role of GLP-1R agonists in cancer remains complex and not fully understood, particularly across different tumor types. This study aimed to evaluate the prognostic significance of GLP1R expression on overall survival across various cancer types. Using a comprehensive analysis of gene expression data and survival outcomes a large cohorts of different tumor types, we employed Cox proportional hazards survival analyses, coupled with false discovery rate determinations, to explore correlations between GLP1R expression and survival. The integrated database included thousands of cancer specimens with available overall survival time and event data from numerous independent cohorts, providing a robust platform for survival analysis. Our findings reveal that increased GLP1R expression is associated with improved overall survival in cancers such as bladder cancer, breast cancer, esophageal adenocarcinoma, renal clear cell carcinoma, and thyroid carcinoma. Conversely, higher GLP1R expression is linked to poorer survival outcomes in cervical squamous cell carcinoma, lung squamous cell carcinoma, stomach adenocarcinoma, and uterine corpus endometrial carcinoma. Additionally, GLP1R expression showed no significant impact on overall survival in cancers such as esophageal squamous cell carcinoma, colon cancer, head-neck squamous cell carcinoma, renal papillary cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, ovarian cancer, and pancreatic cancer. In conclusion, GLP1R expression levels serve as an important biomarker with potential prognostic significance across multiple cancers, demonstrating both protective and adverse associations depending on the tumor type. These findings highlight the complex role of GLP-1R agonists in cancer risk and survival, suggesting that the therapeutic use of these agents should be carefully tailored to the individual patient's cancer risk profile.

Bile acids (BAs), a category of amphiphilic metabolites synthesized by liver cells and released into the intestine via the bile duct, serve a vital role in the emulsification of ingested fats during the digestive process. Beyond their conventional emulsifying function, BAs, with their diverse structures, also act as significant hormones within the body. They are pivotal in facilitating nutrient absorption by interacting with the farnesoid X receptor (FXR), and they serve as key regulators of lipid and glucose metabolism, as well as immune system balance. Consequently, BAs contribute to the metabolism of glucose and lipids, enhance the digestion and absorption of lipids, and maintain the equilibrium of the bile pool. Their actions are instrumental in addressing obesity, managing cholestasis, and treating diabetes, and are involved in the onset and progression of cancer. This paper presents an updated systematic review of the pharmacological mechanisms by which BAs target the FXR, incorporating recent findings and discussing their signaling pathways in the context of novel research, including their distinct roles in various disease states and populations. The aim is to provide a theoretical foundation for the continued research and clinical application of BAs.

Blueberries are rich in polyphenols, which exhibit significant anti-diabetic activity. In this study, polyphenolic compounds with potential hypoglycemic activity were identified from blueberry polyphenol extract (BPE). This research focused on assessing the hypoglycemic effects of BPE and its polyphenolic compounds (dihydroquercetin and gallic acid) on diabetic mice induced by streptozotocin (STZ) and high-fat diet (HFD), as well as the related fundamental mechanisms. The findings revealed that BPE treatment effectively reduced levels of fasting blood glucose (FBG) by decreasing hepatic oxidative stress, regulating lipid metabolism disorders and improving insulin resistance. Investigations into the insulin signaling pathway revealed that BPE can modulate the expression of Egfr, Insr, Irs-1, Pi3k and Akt, thereby influencing glucose metabolism. This study provides a research foundation for considering blueberry polyphenols as a nutritional dietary supplement for the prevention and intervention of diabetes.

To evaluate the efficacy and safety of combination therapy with sodium-glucose cotransporter2(SGLT-2) inhibitors and glucagon-like peptide-1(GLP-1) receptor agonists in the treatment of type 2 diabetes mellitus (T2DM).

To construct an exhaustive database of randomized controlled trials (RCTs) concerning SGLT-2 inhibitors and GLP-1 agonists, a methodical search was undertaken across a range of databases, such as Embase, PubMed, and the Cochrane Central Register of Controlled Trials, from their inception to January 2023. Following this, a meta-analysis was executed to amalgamate the collected data, which allowed for the calculation of standardized mean differences (SMDs), odds ratios (ORs), and 95 % confidence intervals (CIs) for a spectrum of outcomes. This analytical approach was designed to yield a quantitative evaluation of the therapeutic efficacy and safety profile of SGLT-2 inhibitors and GLP-1 agonists for the treatment of diabetes mellitus.

When compared to GLP-1 agonist therapy alone, the combination therapy did not significantly reduce fasting plasma glucose (FPG) levels (95 % confidence interval [CI]: -0.27, 0.10; p = 0.35), body weight (95 % CI: -0.18, 0.18; p = 1.00), Glycosylated Hemoglobin, Type A1C (HbA1c) (95 % CI: -0.29, 0.07; p = 0.22), or systolic blood pressure (SBP) values (95 % CI: -0.29, 0.06; p = 0.21). In contrast, when compared to SGLT-2 inhibitor therapy alone, combination therapy significantly decreased FPG by 0.24 mmol/L (95 % CI: -0.43, -0.05; p = 0.01), HbA1c by 0.45 % (95 % CI: -0.72, -0.18; p = 0.001), and SBP by 0.12 mmHg (95 % CI: -0.24, 0.00; p = 0.05). However, the combination therapy failed to demonstrate a significant reduction in body weight when compared with either SGLT-2 inhibitor therapy (95 % CI: -0.20, 0.05; p = 0.24) or GLP-1 agonist therapy (95 % CI: -0.18, 0.18; p = 1.00). Additionally, the combination therapy did not increase the incidence of hypoglycemia. It should be noted that data regarding mortality and cardiovascular outcomes were limited.

The combination treatment of SGLT-2 inhibitors and GLP-1 receptor agonists effectively reduces HbA1c, FPG, and SBP without elevating the risk of hypoglycemia when compared to monotherapy with SGLT-2 inhibitors. However, these beneficial effects were not observed when the combination therapy was compared with GLP-1 receptor agonist treatment alone.

Whether the cardiovascular treatment benefits of sodium-glucose co-transporter 2 inhibitors (SGLT-2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) differ by baseline use of statins/lipid lowering therapy is unclear. This systematic review and meta-analysis investigated whether baseline statin use (users vs non-users) influences the cardiovascular and kidney benefits of SGLT-2is and GLP-1RAs in patients with type 2 diabetes (T2D).

We identified relevant cardiovascular outcome trials (CVOTs) and observational cohort studies from MEDLINE, Embase, the Cochrane Library, and bibliographic searches up to March 2024. The analysis pooled study-specific hazard ratios (HRs) with 95 % confidence intervals (CIs) for outcomes, categorized by baseline statin use status. We also assessed the interactions between these medications and baseline statin use by calculating and pooling the ratio of HRs (RHRs) within each trial.

Twenty-five articles (13 articles comprising 6 unique CVOTs and 12 articles comprising 9 unique cohort studies) were eligible. In CVOTs of SGLT-2is, the HRs (95 % CIs) of MACE; composite of CVD death or hospitalisation for heart failure; stroke; and kidney events in statin users were 0.90 (0.82-1.00), 0.78 (0.60-1.02), 1.00 (0.77-1.31), and 0.60 (0.53-0.69), respectively. The corresponding estimates were similar in non-statin users. In CVOTs of GLP-1RAs, the HRs (95 % CIs) for MACE in statin and non-statin users were 0.81 (0.73-0.90) and 0.92 (0.77-1.11), respectively. In observational cohort studies, SGLT-2is similarly reduced the risk of several cardiovascular and kidney outcomes in both statin and non-statin users. The estimated RHRs and p-values for interaction indicated that baseline statin use status did not significantly modify the cardio-kidney benefits of SGLT-2is and GLP-1RAs.

Aggregate analyses of intervention and real-world evidence show that SGLT-2is and GLP-1RAs provide comparable cardio-kidney benefits in patients with T2D, regardless of baseline statin use status. PROSPERO Registration: CRD42024498939.

Type 2 Diabetes Mellitus (T2D) is a significant health concern worldwide, necessitating novel therapeutic approaches beyond conventional treatments.

To assess isorhamnetin's potential in improving insulin sensitivity and mitigating T2D characteristics through oxidative and glycative stress modulation.

T2D was induced in mice with a high-fat diet and streptozotocin injections. Isorhamnetin was administered at 10 mg/kg for 12 weeks. HepG2 cells were used to examine in vitro effects on stress markers and insulin sensitivity. Molecular effects on the PGK1 and AKT signalling pathway were also analyzed.

The administration of isorhamnetin significantly impacted both in vivo and in vitro models. In HepG2 cells, oxidative and glycative stresses were markedly reduced, indicating a direct effect of isorhamnetin on cellular stress pathways, which are implicated in the deterioration of insulin sensitivity. Specifically, treated cells showed a notable decrease in markers of oxidative stress, such as malondialdehyde, and advanced glycation end products, highlighting isorhamnetin's antioxidant and antiglycative properties. In vivo, isorhamnetin-treated mice exhibited substantially lower fasting glucose levels compared to untreated T2D mice, suggesting a strong hypoglycemic effect. Moreover, these mice showed improved insulin responsiveness, evidenced by enhanced glucose tolerance and insulin tolerance tests. The molecular investigation revealed that isorhamnetin activated PGK1, leading to the activation of the AKT signalling pathway, crucial for promoting glucose uptake and reducing insulin resistance. This molecular action underscores the potential mechanism through which isorhamnetin exerts its beneficial effects in T2D management.

The study underscores isorhamnetin's multifaceted role in T2D management, emphasizing its impact on oxidative and glycative stress reduction and molecular pathways critical for insulin sensitivity.

Isorhamnetin presents a promising avenue for T2D treatment, offering a novel approach to enhancing insulin sensitivity and managing glucose levels through the modulation of key molecular pathways. Further research is needed to translate these findings into clinical practice.

Glucose metabolism is essential for the maintenance and function of the central nervous system. Although the brain constitutes only 2% of the body weight, it consumes approximately 20% of the body's total energy, predominantly derived from glucose. This high energy demand of the brain underscores its reliance on glucose to fuel various functions, including neuronal activity, synaptic transmission, and the maintenance of ion gradients necessary for nerve impulse transmission. Increasing evidence shows that many neurodegenerative diseases, including Parkinson's disease (PD), are associated with abnormalities in glucose metabolism. PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, accompanied by the accumulation of α-synuclein protein aggregates. These pathological features are exacerbated by mitochondrial dysfunction, oxidative stress, and neuroinflammation, all of which are influenced by glucose metabolism disruptions. Emerging evidence suggests that targeting glucose metabolism could offer therapeutic benefits for PD. Several antidiabetic drugs have shown promise in animal models and clinical trials for mitigating the symptoms and progression of PD. This review explores the current understanding of the association between PD and glucose metabolism, emphasizing the potential of antidiabetic medications as a novel therapeutic approach. By improving glucose uptake and utilization, enhancing mitochondrial function, and reducing neuroinflammation, these drugs could address key pathophysiological mechanisms in PD, offering hope for more effective management of this debilitating disease.

Polygoni Cuspidati Rhizoma et Radix (Huzhang in Chinese), refers to the root and rhizome of Polygonum cuspidatum Sieb. et Zucc. Huzhang is commonly used in clinical practice for the prevention and treatment of diabetes and its complications, but its active components and regulatory mechanisms have not yet been thoroughly analyzed.

The network pharmacology combined with multi-omics analysis will be employed to dissect the substance basis and action mechanism of Huzhang in exerting its anti-diabetic activity.

This study employed phenotypic indicators for baseline assessment, followed by integrated analysis using network pharmacology, metabolomics, transcriptomics, and qPCR technology to elucidate the active components and pharmacological mechanisms of Huzhang.

The analysis of network pharmacology revealed that polydatin is a potential active component responsible for the anti-T2DM pharmacological effects of Huzhang. In vivo experimental results demonstrated that polydatin significantly regulates blood glucose, lipid levels, liver function, and liver pathological damage in diabetic rats. Analysis results from transcriptomics, metabolomics, and qPCR validation showed that polydatin comprehensively regulates glucose and lipid metabolism in T2DM by modulating bile acid metabolism, fatty acid oxidation, and lipogenesis.

Polydatin is a key component of Huzhang in treating T2DM, and its regulatory mechanisms are diverse, indicating significant development potential.

Type 2 diabetes mellitus is a prevalent metabolic disease, posing a considerable threat to public health. Oligonucleotide drugs have proven to be a promising field of therapy for the diseases. In this study, we reported that a herbal small RNA (sRNA), JGL-sRNA-h7 (B34735529, F1439.L002444.A11), could exhibit potent hypoglycemic effects by targeting glucose-6-phosphatase. Oral administration of sphingosine (d18:1)-JGL-sRNA-h7 bencaosomes ameliorated hyperglycemia and diabetic kidney injury better than metformin in db/db mice. Furthermore, glucose tolerance was also improved in sphingosine (d18:1)-JGL-sRNA-h7 bencaosomes-treated beagle dogs. Our study indicates that JGL-sRNA-h7 could be a promising hypoglycemic oligonucleotide drug.

Jiedu Tongluo Tiaogan Formula (JTTF), a traditional Chinese herbal decoction, exhibits the potential to treat type 2 diabetes mellitus (T2DM) by inhibiting endoplasmic reticulum stress (ERS) and excessive autophagy, which are the risk factors for the abnormal development and progression of β cells.

We aimed to assess the effect of JTTF on pancreatic glucotoxicity by inhibiting ERS and excessive autophagy, for which db/db mice and INS-1 insulinoma cells were used.

The chemical composition of the JTTF was analyzed by UPLC-Q/TOF-MS. Diabetic (db/db) mice were treated with distilled water or JTTF (2.4 and 7.2 g/kg/day) for 8 weeks. Furthermore, INS-1 cells induced by high glucose (HG) levels were treated with or without JTTF (50, 100, and 200 μg/mL) for 48 h to elucidate the protective mechanism of JTTF on glucose toxicity. The experimental methods included an oral glucose tolerance test, hematoxylin-eosin staining, immunohistochemistry, western blotting, RT-qPCR, and acridine orange staining.

28 chemical components of JTTF were identified. Additionally, treatment with JTTF significantly decreased the severity of glycemic symptoms in the db/db mice. Moreover, the treatment partially restored glucose homeostasis in the db/db mice and protected the pancreatic β-cell function. JTTF protected INS-1 cells from HG injury by upregulating GSIS and PDX1, MafA mRNA expression. Further, treatment with JTTF downregulated GRP78 and ATF6 expression, whereas it inhibited Beclin-1 and LC3 activation. The treatment protected the cells from HG-induced ERS and excessive autophagy by downregulating the CaMKKβ/AMPK pathway.

The present study findings show that JTTF may protects β-cells by inhibiting the CaMKKβ/AMPK pathway, which deepens our understanding of the effectiveness of JTTF as a treatment strategy against T2DM.

Diabetes mellitus (DM) has emerged as an international health epidemic due to its rapid rise in prevalence. Consequently, scientists and or researchers will continue to find novel, safe, effective, and affordable anti-diabetic medications. The goal of this review is to provide a thorough overview of the role that lifestyle changes play in managing diabetes, as well as the standard medications that are currently being used to treat the condition and the most recent advancements in the development of novel medical treatments that may be used as future interventions for the disease. A literature search was conducted using research databases such as PubMed, Web of Science, Scopus, ScienceDirect, Wiley Online Library, Google Scholar, etc. Data were then abstracted from these publications using words or Phrases like "pathophysiology of diabetes", "Signe and symptoms of diabetes", "types of diabetes", "major risk factors and complication of diabetes", "diagnosis of diabetes", "lifestyle modification for diabetes", "current antidiabetic agents", and "novel drugs and targets for diabetes management" that were published in English and had a strong scientific foundation. Special emphasis was given to the importance of lifestyle modification, as well as current, novel, and emerging/promising drugs and targets helpful for the management of both T1DM and T2DM.

The optimal design for pharmacoepidemiologic drug-drug interactions (DDIs) studies is unclear. Using the association between concomitant use of sulfonylureas and warfarin and the risk of severe hypoglycemia as a case study, a DDI with little or no clinical impact, we tested whether the prevalent new-user design can be applied in the area.

Among all patients initiating sulfonylureas in the UK's Clinical Practice Research Datalink (1998-2020), we identified those adding-on warfarin while on a sulfonylurea. For each co-exposed patient, we defined a prescription-based exposure set including other sulfonylurea users not adding-on warfarin (comparators). Within each exposure set, we matched each co-exposed patient to five comparators on time-conditional propensity scores (TCPS) and followed them using an as-treated approach. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) of severe hypoglycemia associated with concomitant use of sulfonylureas and warfarin compared to use of sulfonylureas alone. Sensitivity analyses addressed the impact of different potential sources of bias.

The study cohort included 17 890 patients co-exposed to sulfonylureas and warfarin and 88 749 matched comparators. After TCPS matching, patient characteristics were well-balanced between groups. Compared to use of sulfonylureas alone, concomitant use of sulfonylureas and warfarin was not associated with the risk of severe hypoglycemia (HR, 1.04; 95% CI, 0.92-1.17). Sensitivity analyses were consistent with the primary analysis (HRs ranging from 1.01 to 1.15, all not statistically significant).

Our study suggests that the prevalent new-user design could be used for the assessment of clinical effects of DDIs.

Compound 1 was previously identified by our team as a glycogen phosphorylase (GP) inhibitor with glucose-lowering activity and demonstrated to have protective effects against myocardial and cerebral ischemia. However, its impact on muscle function has not been clarified. This study is the first to evaluate the long-term effects of GP inhibitors on muscle function and metabolism. After a 28-day administration of Compound 1, we performed assays to assess muscle function and biochemical parameters in rats. We observed reductions in peak holding force, duration, tetanic contraction force, single-contraction force, and electromyographic signals under 20 s and 10 min contraction stimuli. The metabolic analysis showed no significant effects on muscle glycogen, ATP, lactic acid, and uric acid levels at low doses. In contrast, medium to high doses resulted in increased glycogen, decreased ATP, and reduced lactic acid (only at high doses), without affecting uric acid. These findings suggest that Compound 1 may adversely affect muscle function in rats, potentially due to the glycogen inhibition effects of GP inhibitors. This study provides crucial safety data and insights into the long-term effects of GP inhibitors on rat muscles, which will guide future developments and applications.

Owing to their potent glucose-lowering efficacy and substantial weight loss effects, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are now considered part of the frontline therapeutic options to treat both type 2 diabetes mellitus and nondiabetic overweight/obesity. Stemming from successful demonstration of their cardiometabolic modulation and reduction of major adverse cardiovascular events in clinical outcome trials, GLP-1 RAs have since been validated as agents with compelling cardiovascular protective properties. Studies spanning from the bench to preclinical and large-scale randomised controlled trials have consistently corroborated the cardiovascular benefits of this pharmacological class. Most notably, there is converging evidence that they exert favourable effects on atherosclerotic ischaemic endpoints, with preclinical data indicating that they may do so by directly modifying the burden and composition of atherosclerotic plaques. This narrative review examines the underlying pharmacology and clinical evidence behind the cardiovascular benefits of GLP-1 RAs, with particular focus on atherosclerotic cardiovascular disease. It also delves into the mechanisms that underpin their putative plaque-modifying actions, addresses existing knowledge gaps and therapeutic challenges and looks to future developments in the field, including the use of combination incretin agents for diabetes and weight loss management.

Western guidelines often recommend biguanides as the first-line treatment for diabetes. However, dipeptidyl peptidase-4 (DPP-4) inhibitors, alongside biguanides, are increasingly used as the first-line therapy for type 2 diabetes (T2DM) in Japan. However, there have been few studies comparing the effectiveness of biguanides and DPP-4 inhibitors with respect to diabetes-related complications and cardio-cerebrovascular events over the long term, as well as the costs associated.

We aimed to compare the outcomes of patients with T2DM who initiate treatment with a biguanide versus a DPP-4 inhibitor and the long-term costs associated.

We performed a cohort study between 2012 and 2021 using a new-user design and the Shizuoka Kokuho database. Patients were included if they were diagnosed with T2DM. The primary outcome was the incidence of cardio-cerebrovascular events or mortality from the initial month of treatment; and the secondary outcomes were the incidences of related complications (nephropathy, renal failure, retinopathy, and peripheral neuropathy) and the daily cost of the drugs used. Individuals who had experienced prior events during the preceding year were excluded, and events within 6 months of the start of the study period were censored. Propensity score matching was performed to compare between two groups.

The matched 1:5 cohort comprised 529 and 2,116 patients who were initially treated with a biguanide or a DPP-4 inhibitor, respectively. Although there were no significant differences in the incidence of cardio-cerebrovascular events or mortality and T2DM-related complications between the two groups (p = 0.139 and p = 0.595), daily biguanide administration was significantly cheaper (mean daily cost for biguanides, 61.1 JPY; for DPP-4 inhibitors, 122.7 JPY; p<0.001).

In patients with T2DM who initiate pharmacotherapy, there were no differences in the long-term incidences of cardio-cerebrovascular events or complications associated with biguanide or DPP-4 use, but the former was less costly.

The cardiorenal protective effects of sodium-glucose co-transporter 2 inhibitors (SGLT2-Is) and glucagon-like peptide 1 receptor agonists (GLP1-RAs) across racial and ethnic groups are not well defined. By conducting a systematic review and meta-analysis of all randomised, placebo-controlled, cardiovascular disease (CVD) outcomes trials (CVOTs), we aimed to compare racial/ethnic as well as regional patterns in the effects of SGLT2-Is and GLP1-RAs on cardiovascular and renal outcomes in patients with type 2 diabetes (T2D).

Trials were identified from MEDLINE, Embase, the Cochrane Library, and search of bibliographies to 7 July 2023. Setting North America, South/Central America, Europe (Eastern and Western), Asia, Australia-New Zealand (Pacific), Asia/Pacific, and Africa.

North America, South/Central America, Europe (Eastern and Western), Asia, Australia-New Zealand (Pacific), Asia/Pacific, and Africa.

people with type 2 diabetes enrolled in cardiovascular outcome trials of SGLT2-Is and GLP1-RAs.

Outcomes were (i) major adverse cardiovascular events (MACE), (ii) composite CVD death/heart failure (HF) hospitalization; (iii) composite renal outcome; and (iv) their components. Study-specific hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled.

In total, 14 unique CVOTs (7 comparing SGLT2-Is vs placebo and 7 comparing GLP1-RAs vs placebo) were eligible. The proportion of participants enrolled in the trials ranged from 66.6-93.2% for White populations, 1.2-21.6% for Asian populations, 2.4-8.3% for Black populations and 0.9-23.1% for Other populations. The HR (95% CI) for MACE comparing SGLT2-Is vs placebo was 0.92 (0.86-0.98), 0.69 (0.53-0.92) and 0.70 (0.54-0.91) for White, Asian and Hispanic/Latino populations, respectively. Comparing GLP1-RAs vs placebo, the corresponding HR (95% CI) was 0.88 (0.80-0.97), 0.76 (0.63-0.93) and 0.82 (0.70-0.95), respectively. SGLT2-Is reduced the risk of all other cardiorenal outcomes in White and Asian populations, except for HF hospitalizations in Asians. No effects were observed in Black populations except for a reduced risk of HF hospitalizations by SGLT2-I. SGLT1-Is reduced the risk of composite CVD death/HF hospitalization in North America and Europe, whereas GLP1-RAs reduced the risk of MACE in Europe. GRADE certainty of evidence ranged from moderate to high.

There appears to be substantial racial/ethnic differences in the cardiorenal effects of SGLT2-Is and GLP1-RAs in patients with T2D, with consistent benefits observed among White and Asian populations and consistent lack of benefits in Black populations. Whether the differences are due to issues with under-representation of Black populations and low statistical power or racial/ethnic variations in the pharmacokinetics, pharmacodynamics and safety of SGLT2-Is and GLP1-RAs need further investigation.PROSPERO Registration: CRD42023401734.

Currently, several studies have demonstrated the benefits of medicinal plants in managing type 2 diabetes. In this work, we evaluated the beneficial effects of the polyphenolic extract (PESB) from Salvia blancoana subsp. mesatlantica in the management of hypercaloric-feeding and small-dose alloxan-brought type 2 diabetes in rats. We analyzed the chemical constituents of the extract, including flavones and flavonols content, to understand its biological action. The antioxidant activities were evaluated by total antioxidant action, scavenging effect of the free radical DPPH, and reducing power. The obtained results showed that the value of TFC was estimated at 31.90 ± 0.34 mgEQ/g in the PESB extract. The total antioxidant capacity was estimated at 593.51 ± 4.09 mg (EAA)/g, the value of DPPH IC50 was 7.3 ± 0.00 μg/mL, and the value of EC50 of reducing power was estimated at 6.43 ± 0.01 μg/mL. In total, 14 phenolic compounds were identified and the naringin was the most dominant (63.19%) while the vanillin was the less recorded (0.10%). Serum glucose decreased significantly (p < 0.05) in rats given PESB (100 mg/kg) after four weeks. Glibenclamide (GLB) and PESB reduced HbA1c and increased plasma insulin in diabetic rats, restoring HOMA-β and HOMA-IR levels to near-normal. Additionally, diabetic rats treated with GLB or PESB showed statistically equivalent results to those of non-diabetic rats regarding hepatic enzymes, renal and lipid markers, as well as cardiovascular indices. The weight loss was significantly lower in diabetic rats receiving a dose of PESB (100 mg/kg), and GLB compared to corresponding untreated diabetic rats (p < 0.01). PESB and GLB showed a prominent protective function in the pancreas, liver, and kidney tissues. This investigation demonstrates the capacity of extracts from leaves of S. blancoana subsp. mesatlantica to manage diabetes mellitus due to their richness in a wide range of bioactive compounds. Therefore, more investigations are required to estimate the safety of the plant use.

Glucagon like peptide-1 (GLP-1) is an effective hypoglycemic drug that can repair the pancreas β cells and promote insulin secretion. However, GLP-1 has poor stability and lacks of target ability, which makes it difficult to reach the site of action to exert its efficacy. Here, GLP-1-expressing plasmids are introduced into the Escherichia coli Nissle 1917 (EcN) and a lipid membrane is formed through simple self-assembly on its surface, resulting in an oral delivery system (LEG) capable of resisting the harsh environment of the gastrointestinal tract. The system utilizes the chemotactic properties of probiotics to achieve efficient enrichment at the pancreatic site, and protects islet β cells from destruction by regulating the balance of immune cells. More interestingly, LEG not only continuously produces GLP-1 to restore pancreatic islet β cell function and secrete insulin to control blood sugar levels, but also regulates the intestinal flora and increases the richness and diversity of probiotics. In mice diabetes models, oral administration of LEG only once every other day has good biosafety and compliance, and achieves long-term control of blood glucose. Therefore, this strategy not only provides an oral delivery platform for pancreatic targeting, but also opens up new avenues for reversing diabetes.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that arises when the body cannot respond fully to insulin, leading to impaired glucose tolerance. Currently, the treatment embraces non-pharmacological actions (e.g., diet and exercise) co-associated with the administration of antidiabetic drugs. Metformin is the first-line treatment for T2DM; nevertheless, alternative therapeutic strategies involving glucagon-like peptide-1 (GLP-1) analogs have been explored for managing the disease. GLP-1 analogs trigger insulin secretion and suppress glucagon release in a glucose-dependent manner thereby, reducing the risk of hyperglycemia. Additionally, GLP-1 analogs have an extended plasma half-life compared to the endogenous peptide due to their high resistance to degradation by dipeptidyl peptidase-4. However, GLP-1 analogs are mainly administered via subcutaneous route, which can be inconvenient for the patients. Even considering an oral delivery approach, GLP-1 analogs are exposed to the harsh conditions of the gastrointestinal tract (GIT) and the intestinal barriers (mucus and epithelium). Hereupon, there is an unmet need to develop non-invasive oral transmucosal drug delivery strategies, such as the incorporation of GLP-1 analogs into nanoplatforms, to overcome the GIT barriers. Nanotechnology has the potential to shield antidiabetic peptides against the acidic pH and enzymatic activity of the stomach. In addition, the nanoparticles can be coated and/or surface-conjugated with mucodiffusive polymers and target intestinal ligands to improve their transport through the intestinal mucus and epithelium. This review focuses on the main hurdles associated with the oral administration of GLP-1 and GLP-1 analogs, and the nanosystems developed to improve the oral bioavailability of the antidiabetic peptides. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Type 2 diabetes mellitus (T2DM) is a major worldwide chronic disease and can lead to serious diabetic complications. Despite the availability of many anti-diabetic agents in the market, they are unable to meet the long-term treatment goals. Also, they cause many side effects which justify the need for novel class of anti-diabetic drugs with newer mechanism of action. Wnt signaling is one of such novel target pathways which can be explored for metabolic disorders. Many key components of the Wnt signaling are involved in the regulation of glucose homeostasis. Polymorphism in the Transcription factor 7-like 2 (TCF7L2) gene, and mutations in the LRP5 (LDL Receptor Related Protein 5) gene lead to disturbed glucose metabolism and obesity. Despite of several years of research in this field, there is no concrete proof of concept available on whether Wnt activation or Wnt inhibition is the beneficial approach for the treatment of T2DM. Here, we have summarized the conclusions of relevant published research studies to give structured insights into possibilities to explore Wnt modulation as a novel target pathway for the treatment of T2DM. The review also highlights the present challenges and future opportunities towards the development of anti-diabetic small molecules targeting the Wnt signaling pathway.

Sarcopenia is an age-related condition characterized by the loss of skeletal muscle mass, muscular strength, and muscle function. In older adults, type 2 diabetes mellitus (T2DM) constitutes a significant health burden. Skeletal muscle damage and deterioration have emerged as novel chronic complications in patients with diabetes, often linked to their increased longevity. Diabetic sarcopenia has been associated with increased rates of hospitalization, cardiovascular events, and mortality. Nevertheless, effectively managing metabolic disorders in patients with T2DM through appropriate therapeutic interventions could potentially mitigate the risk of sarcopenia. Utilizing imaging technologies holds substantial clinical significance in the early detection of skeletal muscle mass alterations associated with sarcopenia. Such detection is pivotal for arresting disease progression and preserving patients' quality of life. These imaging modalities offer reproducible and consistent patterns over time, as they all provide varying degrees of quantitative data. This review primarily delves into the application of dual-energy X-ray absorptiometry, computed tomography, magnetic resonance imaging, and ultrasound for both qualitative and quantitative assessments of muscle mass in patients with T2DM. It also juxtaposes the merits and limitations of these four techniques. By understanding the nuances of each method, clinicians can discern how best to apply them in diverse clinical scenarios.

Metabolic disorders are characterized by an imbalance in muscle fiber composition, and a potential therapeutic approach involves increasing the proportion of oxidative muscle fibers. Prokineticin receptor 1 (PROKR1) is a G protein-coupled receptor that plays a role in various metabolic functions, but its specific involvement in oxidative fiber specification is not fully understood. Here, we investigated the functions of PROKR1 in muscle development to address metabolic disorders and muscular diseases. A meta-analysis revealed that the activation of PROKR1 upregulated exercise-responsive genes, particularly nuclear receptor subfamily 4 group A member 2 (NR4A2). Further investigations using ChIP-PCR, luciferase assays, and pharmacological interventions demonstrated that PROKR1 signaling enhanced NR4A2 expression by Gs-mediated phosphorylation of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) in both mouse and human myotubes. Genetic and pharmacological interventions showed that the PROKR1-NR4A2 axis promotes the specification of oxidative muscle fibers in both myocytes by promoting mitochondrial biogenesis and metabolic function. Prokr1-deficient mice displayed unfavorable metabolic phenotypes, such as lower lean mass, enlarged muscle fibers, impaired glucose, and insulin tolerance. These mice also exhibited reduced energy expenditure and exercise performance. The deletion of Prokr1 resulted in decreased oxidative muscle fiber composition and reduced activity in the Prokr1-CREB-Nr4a2 pathway, which were restored by AAV-mediated Prokr1 rescue. In summary, our findings highlight the activation of the PROKR1-CREB-NR4A2 axis as a mechanism for increasing the oxidative muscle fiber composition, which positively impacts overall metabolic function. This study lays an important scientific foundation for the development of effective muscular-metabolic therapeutics with unique mechanisms of action.

Cutaneous wound healing consists of four stages: hemostasis, inflammation, proliferation/repair, and remodeling. While healthy wounds normally heal in four to six weeks, a variety of underlying medical conditions can impair the progression through the stages of wound healing, resulting in the development of chronic, non-healing wounds. Great progress has been made in developing wound dressings and improving surgical techniques, yet challenges remain in finding effective therapeutics that directly promote healing. This review examines the current understanding of the pro-healing effects of targeted pharmaceuticals, re-purposed drugs, natural products, and cell-based therapies on the various cell types present in normal and chronic wounds. Overall, despite several promising studies, there remains only one therapeutic approved by the United States Food and Drug Administration (FDA), Becaplermin, shown to significantly improve wound closure in the clinic. This highlights the need for new approaches aimed at understanding and targeting the underlying mechanisms impeding wound closure and moving the field from the management of chronic wounds towards resolving wounds.

In the long-term management of chronic diseases, adherence and persistence to prescribed medications are continuous challenges in order to obtain all the potential benefits of drug therapies. Suboptimal drug adherence and discontinuations of therapies remain the most frequent reasons why several diseases are poorly controlled in the population. One the main issue is that physicians are relatively limited in time and tools to detect patients with a poor adherence. The present review discusses present and future strategies that are now available or are being developed to detect and to support adherence in patients with chronic diseases and provides some simple clues to identify patients at high risk of discontinuation in the clinic.

The prevalence rate of type 2 diabetes mellitus (T2DM) has been increasing and a large proportion of patients still do not achieve adequate or sustainable glycemic control on the basis of previous hypoglycemic treatment. In this present study, we explored whether dorzagliatin, a novel glucokinase activator (GKA), could improve glycemic control and lessen glucose fluctuation in drug-naïve patients with T2DM.

A self-comparative observational study of 25 drug-naïve patients with T2DM (aged 18-75 years and HbA1c of 7.5%-11.0%) treated with dorzagliatin 75 mg twice daily for 52 weeks. Before and after dorzagliatin intervention, the serum levels of hemoglobin A1c (HbA1c), insulin, and C-peptide were measured repeatedly during fasting and after a mixed meal. The continuous glucose monitoring (CGM) device was also used to obtain 24-hour glucose profiles and assess the changes in glycemic variability parameters.

After 52 weeks of treatment with dorzagliatin, a numerally greater reduction in HbA1c of 1.03% from the baseline was observed in patients with T2DM, accompanied by significant improvement in insulin resistance and insulin secretion. Moreover, the standard deviation of blood glucose (SDBG) and the mean amplitude of glycemic excursion (MAGE) derived from CGM data were significantly decreased after dorzagliatin therapy. The 24-h glucose variation profile showed that study patients had obviously lower mean glucose levels during the postprandial period from the baseline to week 52, an effect also demonstrated by the significant decrease in the incremental area under glucose concentration versus time curve for 2 h (iAUC0-2 h) after meals.

This study suggests that dorzagliatin therapy could effectively improve glycemic control and glucose fluctuation in drug-naïve patients with T2DM.

Early detection and effective treatment of thyroid cancer are vital due to the aggressiveness and high mortality rate of the cancer. Nevertheless, the exploration of dipeptidyl peptidase-IV (DPP-IV) as a biomarker for thyroid diseases has not been widely conducted. In this study, we developed a novel non-π-conjugated near-infrared fluorescent probe, MB-DPP4, specifically designed to visualize and detect endogenous DPP-IV. Traditional DPP-IV-specific fluorescent probes rely primarily on the intramolecular charge transfer mechanism. For this reason, these probes are often hampered by high background levels that can inhibit their ability to achieve a fluorescence turn-on effect. MB-DPP4 successfully surmounts several drawbacks of traditional DPP-IV probes, boasting unique features such as exceptional selectivity, ultrahigh sensitivity (0.29 ng/mL), innovative structure, low background, and long-wavelength fluorescence. MB-DPP4 is an "off-on" chemosensor that exhibits strong fluorescence at 715 nm and releases a methylene blue (MB) fluorophore upon interacting with DPP-IV, resulting in a visible color change from colorless to blue. Given these remarkable attributes, MB-DPP4 shows great promise as a versatile tool for advancing research on biological processes and for evaluating the physiological roles of DPP-IV in living systems. Finally, we conducted a comprehensive investigation of DPP-IV expression in human serum, urine, thyroid cells, and mouse thyroid tumor models. Our findings could potentially establish a foundation for the early diagnosis and treatment of thyroid diseases.

Cushing's syndrome, acromegaly and neuroendocrine disorders are characterized by an excess of counterregulatory hormones, able to induce insulin resistance and glucose metabolism disorders at variable degrees and requiring immediate treatment, until patients are ready to undergo surgery. This review focuses on the management of diabetes mellitus in endocrine disorders related to an excess of counterregulatory hormones. Currently, the landscape of approved agents for treatment of diabetes is dynamic and is mainly patient-centred and not glycaemia-centred. In addition, personalized medicine is more and more required to provide a precise approach to the patient's disease. For this reason, we aimed to define a practical therapeutic algorithm for management of diabetes mellitus in patients with glucagonoma, pheochromocytoma, Cushing's syndrome and acromegaly, based on our practical experience and on the physiopathology of the specific endocrine disease taken into account. This document is addressed to all specialists who approach patients with diabetes mellitus secondary to endocrine disorders characterized by an excess of counterregulatory hormones, in order to take better care of these patients. Care and control of diabetes mellitus should be one of the primary goals in patients with an excess of counterregulatory hormones requiring immediate and aggressive treatment.

The aim of this study was to evaluate the in situ insulinotropic effects of pea protein hydrolysates (PPHs) mediated by active glucagon-like peptide-17-36 (active GLP-1) using a 2D and dual-layered coculture cell model. Following this model, a mixed Caco-2 and NCI-H716 cell monolayer was differentiated on the apical side to study the effects of PPHs on active GLP-1 levels; meanwhile, the beta-TC-6 cells were seeded on the basolateral side to investigate the insulin responses induced by active GLP-1. The in situ DPP-4 half-maximal inhibitory concentration (IC50) of PPHs, PPHs-120G, and PPHs-120I was 2.94, 3.43, and 2.26 mg/mL, respectively. They directly stimulated active GLP-1 secretion in NCI-H716 cells by 3.03 ± 0.21, 1.99 ± 0.03, and 2.24 ± 0.02 times, respectively. Insulin release in beta-TC-6 cells was directly stimulated by PPHs but not by PPHs-120G and PPHs-120I. Interestingly, PPHs-120G and PPHs-120I indirectly stimulated insulin release in this coculture cell model by enhancing active GLP-1 concentrations. More importantly, PPHs, PPHs-120G, and PPHs-120I increase active GLP-1 levels by their dual function of stimulating active GLP-1 secretion and DPP-4 inhibition. This study suggests that the 2D and dual-layered coculture cell model supports a more comprehensive assessment of in situ insulinotropic effects of protein hydrolysates mediated by active GLP-1.

Actinidia arguta leaves (AAL) are an excellent source of bioactive components for the food industry and possess many functional properties. However, the hypoglycemic effect and mechanism of AAL remain unclear. The aim of this work was to investigate the potential hypoglycemic effect of AAL and explore its possible mechanism using 16S rRNA sequencing and serum metabolomics in diabetic mice induced by high-fat feeding in combination with streptozotocin injection. A total of 25 flavonoids from AAL were isolated and characterized, and the contents of the extract from the AAL ranged from 0.14 mg/g DW to 8.97 mg/g DW. The compound quercetin (2) had the highest content of 8.97 ± 0.09 mg/g DW, and the compound kaempferol-3-O-(2'-O-D-glucopyl)-β-D-rutinoside (12) had the lowest content of 0.14 ± 0.01 mg/g DW. In vivo experimental studies showed that AAL reduced blood glucose and cholesterol levels, improved insulin sensitivity, and ameliorated oxidative stress and liver and kidney pathological damage. In addition, gut microbiota analysis found that AAL significantly reduced the F/B ratio, enriched the beneficial bacteria Bacteroides and Bifidobacterium, and inhibited the harmful bacteria Lactobacillus and Desulfovibrio, thereby playing an active role in intestinal imbalance. In addition, metabolomics analysis showed that AAL could improve amino acid metabolism and arachidonic acid metabolism, thereby exerting a hypoglycemic effect. This study confirmed that AAL can alleviate type 2 diabetes mellitus (T2DM) by regulating intestinal flora and interfering with related metabolic pathways, providing a scientific basis for its use as a dietary supplement and for further exploration of the mechanism of AAL against T2DM.