Antidiabetic Research Articles

The effect of antidiabetic drugs on bone metabolism: a concise review.

Diabetes mellitus (DM) is a complex metabolic disorder characterized by chronic hyperglycemia, which derives from either insufficient insulin production [type 1 diabetes mellitus (T1DM)] or both impaired insulin sensitivity along with inadequate insulin production [type 2 diabetes mellitus (T2DM)] and affects millions of people worldwide. In addition to the adverse effects of DM on classical target organs and tissues, skeletal health can also be adversely affected. There is considerable evidence linking DM with osteoporosis. The fracture risk in patients with DM differs upon the type of diabetes, and it appears to be related to the type of anti-diabetic treatment. Antidiabetic drugs may have various effects on bone health. Most of them have neutral or even favorable effects on bone metabolism with the exception of thiazolidinediones (TZDs). Some studies suggest that TZDs may have negative impact on bone health by decreasing bone formation and increasing the fracture risk. There are also limited studies linking the use of canagliflozin, a Sodium-glucose contransporter-2 inhibitor (SGLT2i), with increased fracture risk. On the other hand, therapies that are based on incretin effect, like Dipeptidyl peptidase-4 inhibitors (DPP-4i) and Glucagon-like peptide-1 receptor agonizts (GLP-1RAs) might have positive effects on bone health by promoting bone formation. Herein we review the impact of antidiabetic drugs on bone health, highlighting the potential benefits and risks associated with these medications in an attempt to contribute to the development of personalized treatment strategies for individuals with DM.

Trends in Antidiabetic Drug Use and Safety of Metformin in Diabetic Patients with Varying Degrees of Chronic Kidney Disease from 2010 to 2021 in Korea: Retrospective Cohort Study Using the Common Data Model.

This study aimed to investigate trends in antidiabetic drug use and assess the risk of metformin-associated lactic acidosis (MALA) in patients with chronic kidney disease (CKD). A retrospective observational analysis based on the common data model was conducted using electronic medical records from 2010 to 2021. The patients included were aged ≥18, diagnosed with CKD and type 2 diabetes, and had received antidiabetic medications for ≥30 days. MALA was defined as pH ≤ 7.35 and arterial lactate ≥4 mmol/L. A total of 8318 patients were included, with 6185 in CKD stages 1-2 and 2133 in stages 3a-5. Metformin monotherapy was the most prescribed regimen, except in stage 5 CKD. As CKD progressed, metformin use significantly declined; insulin and meglitinides were most frequently prescribed in end-stage renal disease. Over the study period, the use of SGLT2 inhibitors (13.3%) and DPP-4 inhibitors (24.5%) increased significantly, while sulfonylurea use decreased (p < 0.05). Metformin use remained stable in earlier CKD stages but significantly decreased in stage 3b or worse. The incidence rate (IR) of MALA was 1.22 per 1000 patient-years, with a significantly increased IR in stage 4 or worse CKD (p < 0.001). Metformin was the most prescribed antidiabetic drug in CKD patients in Korea with a low risk of MALA. Antidiabetic drug use patterns varied across CKD stages, with a notable decline in metformin use in advanced CKD and a rise in SGLT2 inhibitor prescriptions, underscoring the need for further optimized therapy.

Method Development and Validation Studies of Anti-diabetic Drug Lobeglitazone from Pharmaceutical Formulation and Human Plasma by HPLC-DAD

Method Development and Validation Studies of Anti-diabetic Drug Lobeglitazone from Pharmaceutical Formulation and Human Plasma by HPLC-DAD

Renoprotective effect of liraglutide on diabetic nephropathy by modulation of Krüppel-like transcription factor 5 expression in rats.

Diabetic nephropathy (DN) is a serious consequence of diabetes that can develop through the lysophosphatidic acid axis. The purpose of this study was to determine whether the antidiabetic drug liraglutide can slow the development of diabetic kidney damage by altering the lysophosphatidic acid axis via KLF5. Wistar albino rats were divided into nondiabetic and diabetic rats (resulting from an intraperitoneal streptozotocin dose of 30mg/kg and a high-fat diet). These rats were further divided into four groups: nondiabetic control, liraglutide-treated nondiabetic, diabetic control, and liraglutide-treated diabetic. The nondiabetic and diabetic control groups received normal saline for 42 days, while the liraglutide-treated nondiabetic and diabetic groups received normal saline for 21 days, followed by a subcutaneous dose of liraglutide (200 μg/kg/day) for 21 days. Subsequently, serum levels of DN biomarkers were evaluated, and kidney tissues were histologically examined. The protein expression of PCNA, autotaxin, and KLF5 was detected. Liraglutide treatment in diabetic rats decreased DN biomarkers, histological abnormalities in kidney tissues, and the protein expression of PCNA, autotaxin, and KLF5. Liraglutide can slow the progression of DN by modulating KLF5-related lysophosphatidic acid axis. Thus, liraglutide may be an effective treatment for preventing or mitigating diabetes-related kidney damage.

Application of Fabric Phase Sorptive Extraction as a Green Method for the Analysis of 10 Anti-Diabetic Drugs in Environmental Water Samples

Due to the increased prevalence of diabetes, the consumption of anti-diabetic drugs for its treatment has likewise increased. Metformin is an anti-diabetic drug that is commonly prescribed for patients with type 2 diabetes and has been frequently detected in surface water and wastewaters, thus representing an emerging contaminant. Metformin can be prescribed in combination with other classes of anti-diabetic drugs; however, these drugs are not sufficiently investigated in environmental samples. Fabric phase sorptive extraction (FPSE) has emerged as a simple and green method for the extraction of analytes in environmental samples. In this study, FPSE coupled with a high-performance liquid chromatography diode array detector (HPLC-DAD) was employed for the simultaneous analysis of different classes of anti-diabetic drugs (metformin, dapagliflozin, liraglutide, pioglitazone, gliclazide, glimepiride, glargine, repaglinide, sitagliptin, and vildagliptin) in environmental water samples. Four different fabric membranes were synthesized but the microfiber glass filter coated with sol-gel polyethylene glycol (PEG 300) was observed to be the best FPSE membrane. The parameters affecting the FPSE process were optimized using a combination of one-factor-at-a-time processes and the design of experiments. The FPSE was evaluated as a green extraction method, based on green sample preparation criteria. The FPSE-HPLC-DAD method achieved acceptable validation results and was applied for the simultaneous analysis of anti-diabetic drugs in surface and wastewater samples. Glimepiride was detected below the quantification limit in both lake and river water samples. Dapagliflozin, liraglutide, and glimepiride were detected at 69.0 ± 1.0 μg·L−1, 71.9 ± 0.4 μg·L−1, and 93.9 ± 1.3 μg·L−1, respectively, in the city wastewater influent. Dapagliflozin and glimepiride were still detected below the quantification limit in city wastewater effluent. For the hospital wastewater influent, metformin and glimepiride were detected at 1158 ± 21 μg·L−1 and 28 ± 0.8 μg·L−1, respectively, while only metformin (392.6 ± 7.7 μg·L−1) was detected in hospital wastewater effluent.

Epidemiology And Biological Mechanisms Of Cardiovascular Disease And Diabetes

The risk of CVDs in T2DM patients in LMICs is higher than in developed nations. It is essential to make an evaluation of the current situation of CVDs among people with T2DM. These CVDs are easily preventable through intervention especially in T2DM patients and this should be done in a comprehensive manner. The following targets and principles should be considered: individual targets of HbA1c for patients, a rigorous control of cardiovascular risk factors such as blood pressure and lipids, and incorporation of newer anti-diabetic, lipid-lowering and anti-hypertensive agents. It is, therefore, crucial to design a stepped-wedge approach that bundles a patient-level intervention, lifestyle, and pharmacological interventions to reduce the risk of CVD in LMIC T2DM populations. When selecting medications for T2DM patients with cardiovascular conditions, several key considerations must be made: When selecting medications for T2DM patients with cardiovascular conditions, several key considerations must be made: It should be noted that the choice of anti-diabetic drugs should take into consideration cardiovascular safety. SGLT2 inhibitors and GLP-1 agonists are newer agents for managing diabetes and have been found to have cardiorenal benefits. The choice of lipid-lowering should be targeted to lower LDL cholesterol and triglycerides as effectively as possible. If the intensity of statin is high; it is considered first-line therapy, and other optional medication includes ezetimibe and PCSK9 inhibitors. To maintain the best pressure level that is suitable for an individual, and as a result control hypertension, the use of antihypertensive drugs is necessary. This makes ACE inhibitors or ARBs the preferred first-line antihypertensive agents because of their cardiovascular benefits. For the purpose of secondary prevention in individuals who have experienced a cardiovascular event, the antiplatelet drug aspirin in a dosage of between 75 to 150 milligrams per day should be administered. This is to minimize the probability of such difficulties re-emerging by influencing platelet activity. In general, adequate blood pressure management and antiplatelet aggregation therapy are key interventions with specific antiplatelet medication needs in this setting.

Identification and in vitro genotoxicity assessment of forced degradation products of glimepiride and glyburide using HEK cell-based COMET assay.

This study focuses on characterizing the forced degradation products of antidiabetic drugs glimepiride (GMD) and glyburide (GBD), with previously unexplored genotoxicity. Drugs underwent stress induced by acid, base, and hydrogen peroxide. For GMD, impurities were profiled and isolated using Hypersil Gold C8 (250 × 10 mm, 5μ) through semi-preparative HPLC with a fraction collector. For GBD, impurity profiling was performed using semi-preparative HPLC (Hypersil GOLD C18, 250 × 10 mm, 5μ), and reverse-phase flash chromatography (FP ECOFLEX C18 4g column) for isolation. Although five GMD and three GBD impurities were detected, only three GMD and two GBD impurities were separated and assessed for purity using analytical RP-HPLC with the purity percentages ranging from 96.6% to 99.9%. LC-Orbitrap MS was used to identify these three GMD impurities (m/z: 408.122, 338.340, 381.160) and two GBD impurities (m/z: 369.065, 325.283). ProTox-II in silico predictions classified all impurities as class 4 and 5, with no positive genotoxicity indications. In vitro comet assays, using HEK cells, indicated that for GMD, impurity 2 and impurity 5 were less genotoxic, whereas impurity 4 exhibited genotoxicity. For GBD, both impurities 1 and 3 were found to be genotoxic, with impurity 3 showing a higher level of genotoxicity than impurity 1.

Click Reaction Inspired Enzyme Inhibitors in Diabetes Care: An Update in the Field of Chronic Metabolic Disorder.

Diabetes is a chronic metabolic disorder that impacts all age groups and affects a large population worldwide. Humans receive glucose from almost every food source, and after absorption from the gut, it reaches the liver, which functions as the distribution center for it. The insulin-responsive glucose transporter type 4 (GLUT-4) is a major carrier of glucose to the various cells (majorly expressed in myocytes, adipocytes, and cardiomyocytes) in a well-fed state. In fasting periods, the glucose supply is maintained by glycogenolysis and gluconeogenesis. In diabetes, the distribution of glucose is hampered due to several reasons. Furthermore, to treat this disorder, several drugs have been synthesized, and click chemistry plays an important role. A more recent concept for producing pharmaceuticals with a click chemistry approach makes any reaction more practical and stereospecific, along with a higher yield of products and a smaller number of by-products. This approach comprises a compiled study of the activity of numerous compelling antidiabetic drugs containing 1, 2, 3-triazole derivatives supported by click chemistry. In this review, we discuss the synthetic antidiabetic drugs made via click chemistry and their commendable role in improving diabetes care.

A new bicyclo [3.3.1]nonadienemethanol-type lignan from the leaves of Taxus wallichiana Zucc.

Following an α-glucosidase inhibitory activity-guided phytochemical study, a rare new bicyclo[3.3.1]nonadienemethanol-type lignan named 9,9′-oxidolanceolatanin B (1) and four known lignans, lanceolatanin B (2), pinoresinol (3), syringaresinol (4), and medioresinol (5), were isolated from a CHCl3-soluble fraction of Taxus wallichiana Zucc. leaves. The absolute configuration of 9,9′-oxidolanceolatanin B was elucidated based on NMR spectroscopic interpretation and ECD data. All isolated compounds 1–5 showed stronger α-glucosidase inhibitory potency than the positive control, acarbose. This data could support the conceit that Taxus wallichiana leaves could be a promising source for plant-based anti-diabetic drug discovery.

Virtual and in Vitro Screening Employing a Repurposing Approach Reveal 13-cis-Retinoic Acid is a PTP1B Inhibitor.

Current treatments for type 2 diabetes (T2D) mainly rely on exercise, dietary control, and anti-diabetic drugs to enhance insulin secretion and improve insulin sensitivity. However, there is a need for more therapeutic options, as approved drugs targeting different pharmacological objectives are still unavailable. One potential target that has attracted attention is the protein tyrosine phosphatase 1B (PTP1B), which negatively regulates the insulin signaling pathway. In this work, a comprehensive computational screening was carried out using cheminformatics and molecular docking on PTP1B, employing a rigorous repurposing approach. The screening involved approved drugs and compounds under research as anti-diabetics that bind to targets such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and α-glucosidase. Several computational hits were then meticulously tested in vitro against PTP1B, with 13-cis-retinoic acid (3a) showing an IC50 of 0.044 mM and competitive inhibition. Molecular dynamics studies further confirmed that 3a can bind to the catalytic binding site of PTP1B. Finally, 3a is the first time it has been reported as an inhibitor of PTP1B, making it a potentially valuable candidate for further studies in D2T treatment.

Computational Drug Design Approaches for the Identification of Novel Antidiabetic Compounds from Natural Resources through Molecular Docking, ADMET, and Toxicological Studies.

Type 2 diabetes mellitus (T2DM) is usually depicted by relative insulin deficiency, raised blood glucose levels, and the predominant risk factor, insulin resistance. Hence, the development of insulin sensitizer drugs targeting PPAR-γ receptors has expanded enormous interest as an attractive choice for T2DM treatment. Thiazolidinediones (TZD) enhance insulin sensitivity either by directly functioning on gene transcription of the PPARγ receptor related to glucose homeostasis or by systemic sensitization of insulin and, therefore, improved hyperglycemia in a wide range of patients. However, severe complications and adverse effects of TZDs necessitate the development of an efficacious and reliable insulin sensitizer from alternative resources. On the contrary, Nature is a rich source of anticipated effective and safer medicine; more than fifty percent of drugs on the market are developed from natural products. Hence, searching for a new PPAR-γ agonist from bioactive secondary compounds of medicinal plants along with greater efficacy and safety is a recognized and consistent tactic for developing novel antidiabetic agents. Pulicaria jaubertii is a fragrant perennial aromatic plant with anti-inflammatory, antidiabetic, antimicrobial, antimalarial, and insecticidal properties. The current study was designed to use a computer-aided drug design to explore the best antidiabetic compounds from P. jaubertii. Herein, the molecular docking study of 80 investigated ligands against the PPAR-γ receptor identifies the highest docking score for five ligands ranging from -8.9 kcal/mol to 8.0 kcal/mol, which is also more significant than the standard drug pioglitazone (-7.7 kcal/mol) determined by the PyRx 8.0 virtual screening software. GLN286, CYS285, SER289, TYR473, MET364, ARG288, ILE341, and LEU333 residues are found to be significant contributors to the non-bonded interaction between ligands and receptors. Molecular electrostatic potential (MEP), DFT, molecular orbital (MO), ADMET, and toxicological analyses were performed on the selected five high-scored ligands of P. jaubertii. Results documented that all investigated ligands, especially L4, show considerably excellent profiles in molecular docking, MEP, DFT, MO, ADMET, and toxicological predictions, suggesting our drug-designing approaches may contribute to the development of a novel antidiabetic drug for the treatment of T2DM from natural resources.

Therapies Using Anti-Diabetics to Prevent and Manage Progression of Parkinson's Disease

&lt;p&gt;Currently, a significant proportion of older individuals have demonstrated connections between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM). Emerging evidence from cohort studies, clinical data, and preclinical meta-analyses reveals that T2DM patients have an increased risk of developing PD, often accompanied by more severe disease progression. These two chronic conditions are believed to share common pathways. The pathways that likely connect the neurodegenerative process of PD include autophagy, mitochondrial dysfunction, dysregulated insulin signaling, inflammation, and insulin resistance. Preclinical PD models highlight the importance of cerebral insulin signaling, which confers numerous neuroprotective benefits. Several ongoing phase II and phase III trials are being conducted in PD-affected populations. These trials reflect the potential of existing anti-diabetic medications to improve PD motor symptoms and halt the progression of neurodegeneration. Brain insulin resistance plays a crucial role in the pathophysiology of PD. The insulin signaling pathway represents a promising novel target for disease modification in both diabetic and non-diabetic PD. Incretin receptors in the brain have emerged as the most promising targets for repurposing existing drugs in PD treatment. Targeting these receptors mitigates inflammation, apoptosis, toxic protein aggregation, long-term potentiation, autophagy, and insulin signaling failure. &lt;/p&gt;&lt;p&gt; Presently, various novel anti-diabetic targets are available that can regulate the insulin signaling pathway in dopaminergic neurons, suggesting improvements in cognitive function and significant neuroprotective effects in PD. Throughout neurodegenerative processes, insulin and incretins exert therapeutic effects in multiple manners. Preclinical studies have demonstrated that glucagon-- like peptide 1 (GLP-1) receptor agonists reduce neuroinflammation, tau phosphorylation, and amyloid deposition while increasing synaptic function and enhancing memory formation. Incretin mimetics may act through the restoration of insulin signaling pathways, inducing further neuroprotective effects. &lt;/p&gt;&lt;p&gt; This review examined the reported shared cellular and molecular pathologies between PD and T2DM, and explored the repurposing of anti-diabetic drugs for the prevention of PD progression through the regulation of insulin signaling pathways.&lt;/p&gt;

In vitro Anti-Diabetic and Antioxidant Potential of the Siddha formulation Mega Sanjeevi Chooranam

Background: The increasing prevalence of type 2 diabetes mellitus (T2DM) presents a significant public health challenge due to its long-term complications and its role as a primary risk factor for cardiovascular diseases, which have both economic and social implications. Plant-derived antidiabetic drugs are being extensively studied due to their safety and efficacy. The main objective of the present study is to evaluate the anti-diabetic and anti-oxidant potential of the formulation Mega Sanjeevi Chooranam (MSC) through in-vitro investigation. Materials and Methods: The in vitro investigation of traditional siddha formulation MSC were performed to ascertain its inhibitory potential against α-amylase and α-glucosidase enzymes along with antioxidant analysis. Results: The MSC displayed the highest activity against α-amylase enzyme, with a percentage inhibition of 73.44 ± 6.87% (IC50, 299.4 ± 27.27 μg/ml), followed by a moderate level of α-glucosidase inhibition at 48.89 ± 13.38% (IC50, 402.2 ± 86 μg/ml). Furthermore, the MSC exhibited the strongest antioxidant activity in quenching ABTS● radicals (IC50, 110.1 ± 18.6 μg/ml), followed by DPPH● (IC50, 144.4 ± 36.8 μg/ml), H2O2● (IC50, 172.7 ± 39.3 μg/ml), and NO● radicals (IC50, 238.4 ± 58.56 μg/ml). Conclusion: In conclusion the formulation MSC demonstrated the significant antioxidant activity and effectively inhibited α-amylase and α-glucosidase enzyme activities. Further study is needed to isolate bioactive phytoconstituents and determine the molecular mechanism behind their antidiabetic effect.

8336 Glycemic Control and Associated Factors During Transition in Youths with Childhood-onset Type 2 Diabetes Mellitus

Abstract Disclosure: J. Yoo: None. H. Woo: None. M. Gu: None. J. Kim: None. Y. Lee: None. C. Shin: None. Y. Lee: None. Background: Childhood-onset type 2 diabetes has increased risk of early diabetes-related complications due to accelerated loss of pancreatic beta cell function. However, no second-choice anti-diabetic drug(such as GLP1 receptor agonists and SGLT2 inhibitors), other than metformin and insulin, is approved to be administered in pediatric patients with type 2 diabetes in South Korea. This study aimed to describe microvascular complications (nephropathy and eye disease) of youths with childhood-onset type 2 diabetes, investigate trends of glycemic control of patients and associated factors across transition period, and analyze change in glycemic control after adding 2nd-choice drug. Method: Among the patients who were treated for type 2 diabetes at Seoul National University Hospital since 2001, 84 patients who were diagnosed under age 18 and reached at age 20 or more on July, 2023 were included. Data of HbA1c, diabetes duration, administered medication, and diabetic complications were collected. Changes in HbA1c from 19 to 22 years of age (transition period) were investigated, and sex, age at diagnosis, and glycemic control at age 19 were analyzed as associated factors. Result: The average age of diagnosis and last follow-up was 14 years and 24.9 years respectively, and the median duration of diabetes was 9.6 years. At the last follow-up, complications developed in 28 patients (33.7%), and the prevalence was 25.3% for nephropathy and 20.6% for eye disease. At the occurrence of complications, the median diabetes duration was 6.2 years for microalbuminuria and 11.3 years for ophthalmic complications. During the transition period, HbA1c showed a significant decline from 8.3% to 7.7% (p=0.007). During this phase HbA1c decreased more significantly in the female (vs. male), in the patients with diagnostic age &amp;lt;15 years (vs. &amp;gt;15 years old), and patients with HbA1c 7% or above at 19-year-old visit(vs. &amp;lt; 7%). During entire follow-up, 59 patients (70%) received diabetes drugs other than metformin and insulin. At diagnosis, the proportion of patients treated with insulin accounted for 55%. At last visit, only few patients were maintained with metformin alone, and most patients required insulin or 2nd-choice antidiabetic drug. Analysis of HbA1c changes in 59 patients with the addition of 2nd-choice drug showed a decrease to 8.5% after 1 year (p=0.006) and to 8.1% at the last visit(p=0.017). Conclusion: Diabetic complications were observed in one-thirds of youths with type 2 diabetes at last follow-up in this study. Glycemic control during transition period to adulthood showed improvement, and factors that influence HbA1c improvement included female, younger age at diagnosis, and better glycemic control at age 19. There is a need to lower the insurance age criteria of South Korea for 2nd-choice antidiabetic drugs, considering that glycemic control significantly improved after adding the 2nd-choice drugs. Presentation: 6/1/2024

Evaluation the efficacy of microneedling with topical metformin solution compared with microneedling with topical vitamin C solution in treatment of melasma.

Several treatment modalities have been used for the treatment of melasma. Topical metformin is an anti-diabetic drug, which has melanopenic action. Vitamin C acts on melanin by inhibiting the tyrosinase enzyme, thus inhibiting melanogenesis. To compare the efficacy and safety of microneedling combined with topical metformin solution versus microneedling combined with topical vitamin C in the treatment of melasma. A spitted-face interventional comparative on 30 female patients suffering from melasma. The right side of the face was treated with microneedling and topical metformin, while the left side was treated with microneedling and topical vitamin C solution. Hemi-MASI score decreased significantly after treatment from before treatment in both groups P-value < 0.001. The percentage of improvement of Hemi-MASI score metformin group was 48.29%, While with vitamin C group was 37.19%. There was a significant improvement in dermoscopic findings in microneedling with topical metformin than with topical vitamin C group. Microneedling with topical metformin or topical vitamin C solution can be an effective and safe therapeutic option for treating melasma with no significant side effects.

12600 Predictors Of Diabetes Remission: The Impact Of Early Intervention Through A Digital Twin Platform

Abstract Disclosure: S.R. Joshi: None. M. Dharmalingam: None. A. Vadavi: None. A. Keshavamurthy: None. S. Bhonsley: None. M. Thajudeen: None. A. Balasubramanian: None. M. Panandikar: None. P. Shamanna: None. Introduction and Objective: Digital twin (DT) platform uses Artificial Intelligence (AI) and Internet of Things, to integrate multi-dimensional data for precision nutrition and health recommendations via the mobile app. We aimed to identify the pre-intervention anthropometric and biochemical parameters that predict diabetes remission (HbA1c &amp;lt; 6.5% without medications for over 3 months). Methods: 209 patients with T2D completed 540 days (18 months) of DT intervention. Results: 129 (61.7%) achieved remission of T2DM (R group). At baseline, patients in R group, compared with patients in the Non-remission Group (group NR) (n=80) had shorter duration of diabetes (yrs) (R: 2.9±2.6, 95% CI 2.5 to 3.4) vs. (NR: 4.7±2.2, 95% CI 4.2 to 5.2), p= &amp;lt;0.0001; lower baseline HbA1c % (R: 8.6±1.9, 95% CI 8.3 to 9) vs. (NR: 9.5±1.7, 95% CI 9.1 to 9.9), p=0.0008; lower estimated HbA1c (eA1C) (R: 7.6±2.2, 95% CI 7.2 to 8) vs. (NR: 8.9±2.3, 95% CI 8.4 to 9.4), p= &amp;lt;0.0001; lower glucose management indicator (GMI) % (R: 7.5±1.6, 95% CI 7.2 to 7.8) vs. (NR: 8.4±1.8, 95% CI 7.9 to 8.8), p=0.0006; ; lower Time Above Range level 1 (TAR1 %; target 180-250 mg/dl &amp;lt; 25% time) (R:21.3±17.6, 95% CI 18.2 to 24.4) vs. (NR: 31.2±17.2, 95% CI 27.3 to 35), p&amp;lt;0.0001; lower Time Above Range level 2 (TAR2 %; target &amp;gt;250 mg/dl &amp;lt; 5% time) (R: 15±24.5, 95% CI 10.8 to 19.3) vs. (NR: 24.2±26.3, 95% CI 18.2 to 29.9), p=0.01; higher Time In Range (TIR; target 70-180 mg/dl &amp;gt;70% time) (R: 59.5±31.5, 95% CI 54 to 65) vs. (NR: 43.3±30.9, 95% CI 36.4 to 50.2), p=0.0003; lower fasting plasma glucose (mg/dl) (R: 161±53.4, 95% CI 151.7 to 170.3) vs. (NR: 186.4±69.3, 95% CI 171 to 201.8), p=0.003; higher HOMA2B (%) (R: 56.6±31.7, 95% CI 51.1 to 62.1) Vs (NR: 43.6±27.5, 95% CI 37.4 to 49.6), p=0.002; and comparable fasting insulin (mIU/L) (R: 13.9±10.1, 95% CI 12.2 to 15.7) vs. (NR: 11.8±7.2, 95% CI 10.2 to 13.4), p=0.09 (ns), HOMA2IR (%) (R:1.9±0.93, 95% CI 1.8 to 2.1) vs (NR:1.8±0.84, 95% CI 1.6 to 2), p=0.33 (ns); weight (kg) (R:78.9±14.4, 95% CI 76.2 to 81.6) vs (NR:78.1±12.8, 95% CI 75.3 to 81), p=0.71 (ns). The mean baseline anti-diabetic drug count was lower in R (1.4) Vs NR (2.1). At 540 days the change was as follows: comparable Time Below Range1 - TBR1 %(&amp;lt; 70-54 mg/dl) &amp;lt; 4% (R: 3.5±14.9, 95% CI 0.92 to 6.1) Vs (NR: 1.9±8.3, 95% CI 0.07 to 3.8), p=0.38 (ns); lower HbA1c (R: 5.9±0.35, 95% CI 5.8 to 6) Vs (NR: 7.2±1.1, 95% CI 7 to 7.5), p&amp;lt;0.0001. Conclusion: Shorter diabetes duration, lower baseline HbA1c, eA1C, GMI, and TAR, higher TIR, lower fasting plasma glucose, and higher beta-cell function are key predictors of diabetes remission. Presentation: 6/3/2024

Male Sprague Dawley Rats with Type 2 Diabetes Mellitus and Obesity on Body Weight, Body Mass Index, and Fat Content as Affected by Alkaloid Fraction of Litsea Glutinosa Leaves (AFLG)

There were 463 million people living with diabetes around the world, and it is expected to increase by 48% in 2045. Dipeptidyl Peptidase 4 (DPP4) inhibitor is asecond-line anti-diabetic drug, that frequently causes weight gain for long term treatment. Alkaloid fraction of L. glutinosa leaves (AFLG) is able to inhibit DPP4 activity in diabetic rats. Therefore, this study aimed to evaluate the effect of AFLG on body weight (BW), BMI, and fat percentage in male rats with model type 2 diabetes mellitus (T2DM) and obesity. Male Sprague Dawley rats, which weighed 200-250 g, were used in this experimental study. Twelve rats were fed with a high-fat diet for 30 days and then were intraperitoneally injected with 230 and 65 mg/kg BW nicotinamide and streptozotocin, respectively. Those rats were randomly divided into 4 groups, control (C) and three treatment (T1-T3) groups, which were orally given 20, 40, and 80 mg/kg BW/day AFLG for 28 days. Collected data were analyzed using a paired t-test, the one-way ANOVA test. Significant differences in BW in T2 and T3 (p = 0.001), Rohrer index in T2 (p = 0.001) and fat content in C (p = 0.013) were observed between before and after treatments. The average of BW, Lee, Rohrer, and TM indexes and fat content in treatment groups did not significantly differ from the C group after 28 days of treatment (p &gt; 0.005). In conclusion, Alkaloid fraction of L. glutinosa leaves does not influence body weight, nutrition status, or fat content of male rats’ models of T2DM and obesity.

Novel sodium tauroursodeoxycholate-based multifunctional liposomal delivery system for encapsulation of oleanolic acid and combination therapy of type 2 diabetes mellitus

Liposomes have demonstrated great potential for drug delivery and diabetes treatment. However, hydrolysis by enzymes and emulsification by endogenous bile salts make liposomes unstable in the gastrointestinal tract. In this study, sodium tauroursodeoxycholate (TUDCNa)-based multifunctional bilosomes were designed to address the deficiencies of conventional liposomes. In the designed bilosomes, cholesterol was replaced by TUDCNa, which served as both a membrane stabilizer and an antidiabetic drug. Oleanolic acid (OA) was encapsulated in both conventional liposomes (OA-Ch-Lip) and bilosomes (OA-Tu-Bil) to compare their properties. Firstly, OA-Tu-Bil exhibited similar encapsulation efficiency and drug loading compared to OA-Ch-Lip, but with a smaller particle size. Secondly, OA-Tu-Bil showed better stability than OA-Ch-Lip. Thirdly, bilosomes exhibited prolonged intestinal retention time and improved permeability and oral bioavailability. Fourthly, in type 2 diabetes mellitus (T2DM) mice model, TUDCNa synergized with OA to exhibit the strongest therapeutic effect. In conclusion, TUDCNa have demonstrated the ability to substitute cholesterol in conventional liposomes, it provided a new approach for oral delivery of hypoglycemic drugs, and offered an innovative strategy for combination therapy.

IGlarLixi effectively reduces residual hyperglycaemia in Chinese people with type 2 diabetes on basal insulin: A post hoc analysis of the LixiLan-L-CN study.

To compare the effects of iGlarLixi versus insulin glargine 100 U/mL (iGlar) on residual hyperglycaemia in Chinese people with uncontrolled type 2 diabetes (T2D) on prior basal insulin (BI) therapy ± oral antidiabetic drugs in the LixiLan-L-CN study (NCT03798080). In this post hoc analysis, residual hyperglycaemia (i.e. HbA1c ≥ 7.0% [≥ 53 mmol/mol] and fasting plasma glucose [FPG] < 7.0 mmol/L) were assessed over 30 weeks. Outcomes were assessed at week 30 in participants with baseline residual hyperglycaemia, including changes from baseline in HbA1c, FPG, 2-hour postprandial glucose (PPG) and daily BI dose, the proportion of participants with HbA1c less than 7.0% (< 53 mmol/mol) and FPG less than 7.0 mmol/L and the incidence of hypoglycaemia. Of 421 participants, 124 (29.5%) had baseline residual hyperglycaemia (iGlarLixi, n = 64 [31.7%]; iGlar, n = 60 [29.1%]). At week 30, the residual hyperglycaemia rate decreased to 7.0% with iGlarLixi and increased to 43.3% with iGlar. Among participants with baseline residual hyperglycaemia, a greater proportion achieved both HbA1c and FPG targets at week 30 with iGlarLixi versus iGlar (43.8% vs. 16.7%), and iGlarLixi provided greater reductions in HbA1c (least squares mean [LSM] difference, -0.9% [-9.4 mmol/mol]) and 2-hour PPG (LSM difference, -4.7 mmol/L; both P < .001). Daily BI dose and incidence of hypoglycaemia were similar in the two groups. The findings of this post hoc analysis suggest that iGlarLixi had greater benefits than iGlar in reducing the rate of residual hyperglycaemia over 30 weeks in Chinese people with suboptimally controlled T2D on prior BI-based therapy.

Genetically Proxied Antidiabetic Drug Target and Primary Open-Angle Glaucoma: A Mendelian Randomization Study.

Observational studies suggest that antidiabetic drugs may lower POAG risk; while the causal relationship remains unclear. Naturally occurring variation in genes encoding antidiabetics drug targets can be used as proxies to investigate long-term therapeutic effect of these drugs on POAG risk. We performed a two-sample Mendelian randomization study to evaluate the potential effect of antidiabetic drug targets on POAG in Europeans and East Asians. To proxy antidiabetic drugs (ABCC8, PPARG, GLP1R, SLC5A2), we leveraged genetic variants located near or within drug target genes that were associated with HbA1c. The validity of our ancestry-specific genetic instrument was checked with multipul positive control outcomes. Genetic summary statistics of POAG from the International Glaucoma Genetics Consortium, Global Biobank Meta-analysis Initiative, and FinnGen consortia were analyzed for Europeans (38,164 cases and 1,576,179 controls) and East Asians (16,650 cases and 288,833 controls) separately. Inverse-variance weighted random-effects models were used as primary method. MR results provided consistent evidence of a protective effect of ABCC8 inhibition on POAG using data sets from IGG, GBMI, and FinnGen. Genetically predicted one-standard deviation reduction in HbA1c from ABCC8 inhibition were significant associated with lower risk of POAG in Europeans (OR = 0.211, 95% CI: 0.133-0.333; p < 0.001) and East Asians (OR = 0.070, 95% CI: 0.011-0.459; p = 0.0056). The association between genetically predicted ABCC8 inhibition and risk of POAG was mainly mediated through intraocular pressure. No association was found for PPARG, SLC5A2, or GLP1R. Sensitivity analyses supported this observation. We found a protective effect of genetically proxied ABCC8 inhibition on POAG risk in both Europeans and East Asians, highlighting ABCC8 as a promising candidate drug target for POAG, and mechanisms underlying the protective effect should also be investigated.