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Tirzepatide is a new drug targeting glucagon-like peptide 1(GLP1) and gastric inhibitory polypeptide (GIP) receptors. This drug has demonstrated great potential in improving the clinical outcomes of patients with type 2 diabetes. It can lead to weight loss, better glycemic control, and reduced cardiometabolic risk factors. GLP1 receptor agonists have been proven effective antidiabetic medications with possible cardiovascular benefits. Even though they have been proven to reduce the risk of major adverse cardiovascular events, their effectiveness in treating heart failure is unknown. Unlike traditional GLP1 receptor agonists, tirzepatide is more selective for the GIP receptor, resulting in a more balanced activation of these receptors. This review article discusses the possible mechanisms tirzepatide may use to improve cardiovascular health. That includes the anti-inflammatory effect, the ability to reduce cell death and promote autophagy, and also its indirect effects through blood pressure, obesity, and glucose/lipid metabolism. Additionally, tirzepatide may benefit atherosclerosis and lower the risk of major adverse cardiac events. Currently, clinical trials are underway to evaluate the safety and efficacy of tirzepatide in patients with heart failure. Overall, tirzepatide's dual agonism of GLP1 and GIP receptors appears to provide encouraging cardiovascular benefits beyond glycemic control, offering a potential new therapeutic option for treating cardiovascular diseases and heart failure., (© 2024. The Author(s).)

Adding mulberry fruit extract (MFE) to carbohydrate-rich meals can reduce postprandial glucose (PPG) and insulin (PPI) responses in healthy individuals. This pilot study assessed the acute postprandial effects of low doses of MFE in individuals with type 2 diabetes. In a randomized cross-over (within-subjects) design, 24 unmedicated adult males and females with type 2 diabetes (mean [SD] age 51.0 [9.3] yr, BMI 27.5 [3.9] kg/m 2 ) consumed meals with 0 (control), 0.37, and 0.75 g of MFE added to ~50 g of available carbohydrates from rice. Primary and secondary outcomes were the PPG 2 hr positive incremental area under the curve and the corresponding PPI. Results were reported as mean differences from the control meal with 95% CI. Relative to control, 0.37 and 0.75 g of MFE reduced the mean 2 hr PPG by 8.2% (-20.8 to 6.6%) and 22.4% (-38.6 to -1.9%), respectively, and reduced PPI by 9.6% (-20.7 to 3.0%) and 17.5% (-27.9 to -5.7%). There were no indications of adverse events or gastrointestinal discomfort. MFE additions also led to dose-related reductions in glucose peak and glucose swing. At these levels, MFE appears to dose-dependently reduce acute PPG and PPI in individuals with type 2 diabetes and may be a feasible dietary approach to help attenuate glycemic exposures.

Diabetes mellitus is a spreading global pandemic. Type 2 diabetes mellitus (T2DM) is the predominant form of diabetes, in which a reduction in blood glucose uptake is caused by impaired glucose transporter 4 (GLUT4) translocation to the plasma membrane in adipose and muscle cells. Antihyperglycemic drugs play a pivotal role in ameliorating diabetes symptoms but often are associated with side effects. Hence, novel antidiabetic compounds and nutraceutical candidates are urgently needed. Phytogenic therapy can support the prevention and amelioration of impaired glucose homeostasis. Using total internal reflection fluorescence microscopy (TIRFM), 772 plant extracts of an open-access plant extract library were screened for their GLUT4 translocation activation potential, resulting in 9% positive hits. Based on commercial interest and TIRFM assay-based GLUT4 translocation activation, some of these extracts were selected, and their blood glucose-reducing effects in ovo were investigated using a modified hen's egg test (Gluc-HET). To identify the active plant part, some of the available candidate plants were prepared in-house from blossoms, leaves, stems, or roots and tested. Acacia catechu (catechu), Pulmonaria officinalis (lungwort), Mentha spicata (spearmint), and Saponaria officinalis (common soapwort) revealed their potentials as antidiabetic nutraceuticals, with common soapwort containing GLUT4 translocation-activating saponarin.

This meta-analysis aimed to summarise clinical evidence regarding the effect of supplementation with cornelian cherry ( Cornus mas L.) on different cardiometabolic outcomes. An extensive literature survey was carried out until 10 April 2024. A total of 415 participants from six eligible studies were included. The overall results from the random-effects model indicated that cornelian cherry supplementation significantly reduced body weight (standardised mean difference [SMD] = -0.27, confidence interval [CI]: -0.52, -0.02, p = 0.03), body mass index (SMD = -0.42, CI: -0.73, -0.12, p = 0.007), fasting blood glucose (SMD = -0.46, CI: -0.74, -0.18, p = 0.001), glycated haemoglobin (SMD = -0.70, CI: -1.19, -0.22, p = 0.005), and HOMA-IR (SMD = -0.89, CI: -1.62, -0.16, p = 0.02), while high-density lipoprotein cholesterol significantly increased (SMD = 0.38, CI: 0.10, 0.65, p = 0.007). A sensitivity analysis showed that cornelian cherry supplementation significantly reduced total plasma triglycerides, total cholesterol, low-density lipoprotein cholesterol, and insulin levels. Cornelian cherry supplementation did not significantly affect waist circumference and liver parameters among the participants. Considering these findings, this meta-analysis indicates that supplementation with cornelian cherry may impact diverse cardiometabolic risk factors among individuals considered to be at a high risk.

Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist used for the treatment of T2D, has been shown to alleviate diabetic cardiomyopathy (DbCM) in experimental T2D, which was associated with increased myocardial glucose oxidation. To determine whether this increase in glucose oxidation is necessary for cardioprotection, we hypothesized that liraglutide's ability to alleviate DbCM would be abolished in mice with cardiomyocyte-specific deletion of pyruvate dehydrogenase (PDH; Pdha1CM-/- mice), the rate-limiting enzyme of glucose oxidation. Male Pdha1CM-/- mice and their α-myosin heavy chain Cre expressing littermates (αMHCCre mice) were subjected to experimental T2D via 10 weeks of high-fat diet supplementation, with a single low-dose injection of streptozotocin (75 mg/kg) provided at week 4. All mice were randomized to treatment with either vehicle control or liraglutide (30 µg/kg) twice daily during the final 2.5 weeks, with cardiac function assessed via ultrasound echocardiography. As expected, liraglutide treatment improved glucose homeostasis in both αMHCCre and Pdha1CM-/- mice with T2D, in the presence of mild weight loss. Parameters of systolic function were unaffected by liraglutide treatment in both αMHCCre and Pdha1CM-/- mice with T2D. However, liraglutide treatment alleviated diastolic dysfunction in αMHCCre mice, as indicated by an increase and decrease in the e'/a' and E/e' ratios, respectively. Conversely, liraglutide failed to rescue these indices of diastolic dysfunction in Pdha1CM-/- mice. Our findings suggest that increases in glucose oxidation are necessary for GLP-1R agonist mediated alleviation of DbCM. As such, strategies aimed at increasing PDH activity may represent a novel approach for the treatment of DbCM.

Introduction: The Bruguiera cylindrica L. is a mangrove plant that is typically found in coastal areas of Asia, including India. It has been known for its medicinal properties, which have been utilized for generations. For example, in Thailand, it has been used to treat wounds and diarrhoea, while in India, it has been effective in addressing diabetes, ulcers, and other health issues. This particular study sought to investigate the potential of B. cylindrica bark extract in reducing the symptoms of diabetes in rats., Methods: In this study, we examined the potential of B. cylindrica bark extract as an inhibitor of α-amylase and α-glucosidase enzymes in vitro. We also evaluated the effects of the extract and Metformin on rats fed high-fat diets and measured their lipid profiles and biochemical parameters. Furthermore, we conducted a network pharmacology analysis to identify proteins and pathways involved in the amelioration of diabetes., Results: Through metabolite profiling, we identified 58 compounds in B. cylindrica hydroalcoholic extract. These compounds include alkaloids, phenolics, flavonoids, and fatty acids. The extract was found to have a dose-dependent inhibition activity against α-amylase and α-glucosidase, with IC50 values similar to acarbose. In rats, oral administration of 200-400 mg/kg of B. cylindrica led to reduced blood glucose levels and normalized serum biochemical parameters., Conclusions: Bruguiera cylindrica bark may reduce blood sugar levels in rats with diabetes. The study found metabolites that interact with protein targets associated with different types of diabetes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Subcutaneous once-weekly (ow) semaglutide is a recent treatment option for type 2 diabetes (T2D) and obesity, but real-world data on weight loss and associated changes in body composition, nutrients intake, and quality of life are still scarce. This observational, prospective clinical study involved all T2D patients starting ow semaglutide according to routine care between December 2021 and February 2022. Clinical information was collected after 6 months (T6) and 12 months (T12) from semaglutide initiation (T0). Bioelectrical Impedance Analysis (BIA) was performed to measure changes in body composition. Diabetes Treatment Satisfaction Questionnaire (DTSQ) and the 36 - items Short Form Health Survey (SF-36) were administered as patient-reported outcomes (PROs). Changes in continuous endpoints (weight, body composition, nutrients intake, other clinical parameters, and PROs) were assessed using mixed models for repeated measurements. Overall, 90 patients (age 63.0 ± 10.0 years; diabetes duration 7.6 ± 5.9 years; 58.9% men; HbA1c 7.7 ± 1.1%; weight 95.4 ± 19.4 Kg, BMI 34.6 ± 6.4 Kg/m 2 ; 36.7% naïve to diabetes treatment, 43.3% on metformin, 10.0% on dual oral therapy, and 10.0% treated with schemes including insulin) were included in the study. After 6 months from semaglutide initiation, body weight significantly decrease by -4.69 Kg (95%CI -6.19;-3.19) (primary endpoint). After 12 months, body weight was further reduced (-5.38 Kg; 95%CI -7.79;-2.97). At BIA, fat mass was significantly reduced by 2.1 Kg after 6 months but only slightly reduced after 12 months vs. baseline; lean mass was also significantly reduced by over 3 Kg both at 6 and 12 months. Intake of all nutrients declined in the first 6 months of therapy, although only lipids reduction reached the statistical significance (-6.73 g; p=0.02). Statistically significant improvements in BMI, waist circumference, glycemic control, blood pressure and lipid profile were documented. Satisfaction with treatment (DTSQ questionnaire) and mental health (MCS score of SF-36 questionnaire) significantly increased during the follow-up. The study documented real-world benefits of semaglutide for treating obesity in T2D subjects, with important changes on clinical and patient-reported outcomes. Loss of lean mass associated with weight loss warrants attention; parallel strategies to preserve skeletal muscle and improve physical function, i.e. nutritional education and structured exercise, are of great importance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pantanetti, Cangelosi, Alberti, Di Marco, Michetti, Cerasoli, Di Giacinti, Coacci, Francucci, Petrelli, Ambrosio and Grinta.)

Background: In patients undergoing total joint arthroplasty (TJA), the administration of dexamethasone may contribute to perioperative blood glucose (BG) disturbances, potentially resulting in complications, even in patients without diabetes. This study aimed to demonstrate the impact of different administration regimens of dexamethasone in postoperative BG levels., Methods: In this randomized, controlled, double-blind trial, 136 patients without diabetes scheduled for TJA were randomly assigned to three groups: two perioperative saline injections (Group A, placebo); a single preoperative injection of 20 mg dexamethasone and a postoperative saline injection (Group B), and two perioperative injections of 10 mg dexamethasone (Group C). Primary outcomes were the postoperative fasting blood glucose (FBG) levels. Secondary outcome parameters were the postoperative postprandial blood glucose (PBG) levels. Postoperative complications within 90 days were also recorded. Risk factors for FBG ≥ 140 mg/dl and PBG ≥ 180 mg/dl were investigated., Results: Compared to Group A, there were transient increases in FBG and PBG on postoperative days (PODs) 0 and 1 in Groups B and C. Statistical differences in FBG and PBG among the three groups were nearly absent from POD 1 onward. Both dexamethasone regimens did not increase the risk for postoperative FBG ≥ 140 mg/dl or PBG ≥ 180 mg/dl. Elevated preoperative HbA1c levels may increase the risk of postoperative FBG ≥ 140 mg/dl or PBG ≥ 180 mg/dl, respectively., Conclusion: Perioperative intravenous high-dose dexamethasone to patients without diabetes has transient effects on increasing BG levels after TJA. However, no differences were found between the split-dose and single high-dose regimens. The elevated preoperative HbA1c, but not the dexamethasone regimens were the risk factor for FBG ≥ 140 mg/dl and PBG ≥ 180 mg/dl., Trial Registration: Chinese Clinical Trail Registry, ChiCTR2300069473. Registered 17 March 2023, https://www.chictr.org.cn/showproj.html?proj=186760 ., (© 2024. The Author(s).)

Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy., (© 2024. The Author(s).)

The percentage of obese people is increasing worldwide, causing versatile health problems. Obesity is connected to diseases such as diabetes and cardiovascular diseases, which are preceded by a state called metabolic syndrome. Diets rich in fruits and vegetables have been reported to decrease the risk of metabolic syndrome and type 2 diabetes. Berries with a high polyphenol content, including lingonberry ( Vaccinium vitis - idaea L.), have also been of interest to possibly prevent obesity-induced metabolic disturbances. In the present study, we prepared an extract from the by-product of a lingonberry juice production process (press cake/pomace) and investigated its metabolic effects in the high-fat diet-induced model of obesity in mice. The lingonberry skin extract partly prevented weight and epididymal fat gain as well as a rise in fasting glucose level in high-fat diet-fed mice. The extract also attenuated high-fat diet-induced glucose intolerance as measured by an intraperitoneal glucose tolerance test (IPGTT). The extract had no effect on the levels of cholesterol, triglyceride or the adipokines adiponectin, leptin, or resistin. The results extend previous data on the beneficial metabolic effects of lingonberry. Further research is needed to explore the mechanisms behind these effects and to develop further health-promoting lingonberry applications.

Background: Pre-diabetes is an important risk factor for the development of type 2 diabetes and is common in Nigeria. Effective intervention can reverse the underlying pathogenesis of insulin resistance in pre-diabetes. This study aimed to determine and compare the impact of moderate exercise and metformin interventions on insulin resistance among participants with pre-diabetes., Materials and Methods: Using a randomised placebo-controlled design, 54 Nigerians with pre-diabetes were selected using simple random sampling. They were offered metformin, moderate exercise or placebo treatment and followed up for 12 weeks. Insulin resistance was assessed before and after the interventions and the outcome was compared., Results: Forty-nine participants with pre-diabetes completed the study. Participants in both the exercise and metformin groups had significantly decreased insulin resistance compared to placebo after 12 weeks of intervention. However, there was a decrease in insulin resistance by 77.3% (homeostasis model assessment-insulin resistance [HOMA-IR]) and an increase in insulin sensitivity by 81.2% (quantitative insulin sensitivity check index [QUICKI]) in the exercise group. In comparison, participants in the metformin group had a decrease in insulin resistance by 66.3% (HOMA-IR) and an increase in insulin sensitivity by 76.2% (QUICKI)., Conclusion: Amongst Nigerians with pre-diabetes, both moderate exercise and metformin have significantly higher efficacy than placebo in improving insulin resistance. However, moderate exercise improved insulin resistance more than the metformin intervention. Participants in this study need to be followed up for a longer period to assess the long-term effects of these interventions., (Copyright © 2024 Copyright: © 2024 Nigerian Postgraduate Medical Journal.)

Aim: To assess the impact of insulin glargine (100 U/mL) and lixisenatide (iGlarLixi) fixed-ratio combination therapy on the overall management of glycaemia in patients with type 2 diabetes (T2D), previously inadequately controlled with oral antidiabetic drugs ± basal insulin or glucagon-like peptide-1 receptor agonists (GLP-1 RAs)., Materials and Methods: This 12-month, international, multicentre, prospective, observational study included patients (age ≥ 18 years) with T2D who had initiated iGlarLixi within 1 month prior to study inclusion. Data were collected at study inclusion, month 3, month 6 and month 12 from patient diaries, self-measured plasma glucose, and questionnaires. The primary endpoint was change in HbA1c from baseline to month 6., Results: Of the 737 eligible participants (mean age: 57.8 [standard deviation: 11.2] years; male: 49%), 685 had baseline and post-baseline HbA1c data available. The least squares mean change in HbA1c from baseline to month 6 was -1.4% (standard error [95% confidence interval (CI)]: 0.05 [-1.5, -1.3]). The absolute change from baseline at month 12 was -1.7% ± 1.9% (95% CI: -1.9, -1.5). There were 72 hypoglycaemia events reported during the study period, with a very low incidence of severe hypoglycaemia (two participants [rate: 0.003 events per patient-year])., Conclusions: This real-world observational study shows that initiation of iGlarLixi in people with T2D inadequately controlled on oral antidiabetic drugs ± basal insulin or GLP-1 RAs improves glycaemic control with a low incidence of hypoglycaemia., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Purpose: To investigate the effect of metformin on gut microbiota imbalance in patients with type 2 diabetes mellitus (T2DM), and the value of probiotic supplementation., Methods: A total of 84 newly diagnosed T2DM patients were randomly divided into probiotics group, metformin group, and control group, with 28 patients in each group. The blood glucose control, islet function, gut microbiota, and inflammatory factors were compared between three groups., Results: After 3 months of treatment, fasting plasma glucose (FPG), 2-h postprandial plasma glucose (2-h PG), and glycosylated hemoglobin A1c (HbA1c) were evidently decreased in both probiotics and metformin groups (P < 0.05) and were lower than that in the control group prior to treatment. Besides, FPG, 2-h PG, and HbA1c were lower in the metformin group than that in the control group. FPG, 2-h PG, and HbA1c were further lower in the probiotic group than in the metformin group (P < 0.05). Fasting insulin (FINS) and islet β cell (HOMA-β) -function were dramatically increased in the same group (P < 0.05), while insulin-resistant islet β cells (HOMA-IR) were significantly lower in the same group (P < 0.05); FINS and HOMA-β were significantly higher, while HOMA-IR was significantly lower (P < 0.05) in both groups than in the control group prior to treatment. HOMA-IR was also lower in the probiotic group than in the metformin group after treatment (P < 0.05); the number of lactobacilli and bifidobacteria increased (P < 0.05) in both probiotic and metformin groups than in the control group prior to treatment, and the number of Enterobacteriaceae and Enterococcus was lower in the control group prior to treatment (P < 0.05). In addition, the number of lactobacilli and bifidobacteria was higher and the number of enterobacteria and enterococci was lower in the probiotic group than that in the metformin group after treatment, and the differences were statistically significant (P < 0.05). Lipopolysaccharide (LPS), interleukin 6 (IL-6), and C-reactive protein (CRP) levels were lower in both probiotic and metformin groups (P < 0.05). The serum LPS, IL-6, and CRP levels were lower in both probiotic and metformin groups, compared to the control group prior to the treatment (P < 0.05)., Conclusion: Metformin while treating T2DM assists in improving the imbalance of gut microbiota., Competing Interests: The authors stated that there was no conflict of interest to disclose.

The aim of the study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of T-glu (GP40321, test drug), and reference insulin glulisine in a hyperinsulinemic-euglycemic clamp procedure. During this study, 34 healthy male volunteers underwent the hyperinsulinemic-euglycemic clamp procedure following subcutaneous 0.3 U/kg injection of T-glu or reference insulin glulisine in a randomized, double-blind, crossover study. Plasma glucose levels were monitored every 5 minutes for 8 hours. Glucose infusion rate adjustment was based on the blood glucose measurements. Evaluation of PD was performed using the glucose infusion rate values, while PK was calculated using insulin concentrations measured via enzyme-linked immunosorbent assay. The study results showed that the 90% CI for the geometric mean ratios of primary PK and PD of T-glu and reference insulin glulisine were within 80%-125% comparability limits, and that the safety profiles were comparable. PK, PD, and safety similarity of T-glu and reference insulin glulisine was demonstrated., (© 2024, The American College of Clinical Pharmacology.)

Aims: Postprandial hyperglycemia can be problematic for people with type 1 diabetes (T1DM) following carbohydrate-restricted diets. Bolus insulin calculated for meal protein plus carbohydrate may help. This study evaluated the effect of additional bolus insulin using an insulin-to-protein ratio (IPR) on glycaemic control., Materials and Methods: Participants with T1DM aged ≥18-years were randomly allocated (1:1) to either carbohydrate and protein-based, or carbohydrate-based insulin dosing alone for 12 weeks while following a carbohydrate-restricted diet (50-100 g/day). Measurement of HbA1c and continuous glucose monitoring occurred at baseline and 12 weeks, with assessment of participant experience at 12 weeks., Results: Thirty-four participants were randomised, 22 female, mean(SD): age 39.2 years (12.6) years; diabetes duration 20.6 years (12.9); HbA1c 7.3 % (0.8), 56.7 mmol/mol (9.2). Seven in each group used insulin pump therapy. HbA1c reduced at 12 weeks with no difference between treatments: mean (SD) control 7.2 % (1.0), 55.7 mmol/mol (10.6); intervention 6.9 % (0.7), 52.3 mmol/mol (7.2) (p = 0.65). Using additional protein-based insulin dosing compared with carbohydrate alone, there was no difference in glycaemic variability, time spent in euglycemic range (TIR), or below range. Participants using IPR reported more control of their diabetes, but varying levels of distress., Conclusions: Additional bolus insulin using an IPR did not improve glycaemic control or TIR in patients with well controlled T1DM following a carbohydrate-restricted diet. Importantly, the use of the IPR does not increase the risk of hypoglycemia and may be preferred., Competing Interests: Declaration of competing interest We, the authors, confirm that there is no financial or personal interest or belief that could affect our objectivity. We do not hold any potential competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Our prior investigations have established that Inonotus obliquus (Chaga) possesses hypoglycemic effects. Persistent hyperglycemia is known to precipitate renal function abnormalities. The functionality of the kidneys is intricately linked to the levels of cyclic guanosine-3',5'-monophosphate (cGMP), which are influenced by the activities of nitric oxide synthase (NOS) and phosphodiesterase (PDE). Enhanced cGMP levels can be achieved either through the upregulation of NOS activity or the downregulation of PDE activity. The objective of the current study is to elucidate the effects of Chaga on disorders of glucolipid metabolism and renal abnormalities in rats with type 2 diabetes mellitus (T2DM), while concurrently examining the NOS-cGMP-PDE5 signaling pathway. A model of T2DM was developed in rats using a high-fat diet (HFD) combined with streptozotocin (STZ) administration, followed by treatment with Chaga extracts at doses of 50 and 100 mg·kg -1 for eight weeks. The findings revealed that Chaga not only mitigated metabolic dysfunctions, evidenced by improvements in fasting blood glucose, total cholesterol, triglycerides, and insulin resistance, but also ameliorated renal function markers, including serum creatinine, urine creatinine (UCr), blood urea nitrogen, 24-h urinary protein, and estimated creatinine clearance. Additionally, enhancements in glomerular volume, GBM thickness, podocyte foot process width (FPW), and the mRNA and protein expressions of podocyte markers, such as nephrin and wilms tumor-1, were observed. Chaga was found to elevate cGMP levels in both serum and kidney tissues by increasing mRNA and protein expressions of renal endothelial NOS and neural NOS, while simultaneously reducing the expressions of renal inducible NOS and PDE5. In summary, Chaga counteracts HFD/STZ-induced glucolipid metabolism and renal function disturbances by modulating the NOS-cGMP-PDE5 signaling pathway. This research supports the potential application of Chaga in the clinical prevention and treatment of T2DM and diabetic nephropathy (DN), with cGMP serving as a potential therapeutic target., (Copyright © 2024 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Aims: To assess adherence and persistence to sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1-RA), and dipeptidyl peptidase-4 inhibitors (DPP4i) in routine care., Methods: Using retrospective healthcare data from the Stockholm region, Sweden, we evaluated new-users of these agents during 2015-2020. We investigated adherence (≥80 % of days covered by an active supply), persistence (no treatment gap ≥ 60 days), and predictors for non-adherence and non-persistence., Results: We identified 24,470 new-users of SGLT2i (10,743), GLP1-RA (10,315), and/or DPP4i (9,488). Over 2.8 years median follow-up, the proportion demonstrating adherence was higher for SGLT2i (57 %) than DPP4i (53 %, comparison p < 0.001), and for GLP1-RA than DPP4i (54 % vs 53 %, p < 0.001). Similarly, persistence was higher for both SGLT2i and GLP-RA than DPP4i (respectively, 50 % vs 44 %, p < 0.001; 49 % vs 44 %, p < 0.001). Overall adherence was better among users who were older, had a history of high blood pressure, used more non-diabetic medications, had lower Hba1c, had better kidney function, and had completed secondary schooling or university. Women had worse adherence to SGLT2i and GLP1-RA than DPP4i., Conclusions: We report adherence and persistence to SGLT2i, GLP1-RA and DPP4i in routine care, and identify prognostic factors that could inform implementation interventions to improve uptake of these important therapies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: . Juan-Jesus Carrero reports a relationship with Amgen, Astellas, AstraZeneca, NovoNordisk, Viforpharma, Boehringer Ingelheim, Nestle, Abbott that includes: funding grants and speaking and lecture fees. Professor Jardine is responsible for research projects that have received unrestricted funding from Amgen, Baxter, CSL, Eli Lilly, Gambro, and MSD; has served on advisory boards and steering committees sponsored by Akebia, Astra Zeneca, Baxter, Bayer, Boehringer Ingelheim, CSL, Janssen, MSD and Vifor; has spoken at scientific meetings sponsored by Amgen, Janssen, Roche and Vifor, with any consultancy, honoraria, or travel support paid to her institution. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Type 2 diabetes (T2D) is a serious health problem, and its prevalence is expected to increase worldwide in the years ahead. Cruciferous vegetables such as Brassica oleracea var. capitata L. (green cabbage) and Raphanus sativus L. (radish) have therapeutic properties that can be used to support the treatment of T2D. This study evaluated the effect of B. oleracea (BAE) and R. sativus (RAE) aqueous extracts on zoometric parameters, glycemic profiles, and pancreas and liver in prediabetic rats induced by a high-sucrose diet (HSD). BAE and RAE were administered to male HSD-induced Wistar rats ( n = 35) at 5 and 10 mg/kg doses for 5 weeks. Zoometric and biochemical changes were measured, and then the pancreas and liver histological preparations were analyzed to observe the protective effect. BAE decreased feed intake and weight gain. Both extracts decreased fasting glucose and insulin levels compared with control (not treated), although not significantly ( P > .05). The extracts significantly ( P < .05) reduced homeostatic model assessment for insulin resistance, homeostasis model assessment of β-cell function, and glucose intolerance, similar to metformin control. In addition, minor damage occurred in the pancreas and liver. The results indicated that BAE and RAE decreased weight gain, improved glucose regulation, and protected the pancreas and liver in HSD rats. Therefore, they have multiple therapeutical properties and may be helpful in the prevention of T2D.

Context/objective: To describe the effect of semaglutide, a glucagon-like peptide-1 (GLP-1) agonist, to reduce body weight and improve glycemic control in overweight or obese individuals with spinal cord injury (SCI)., Design: Open-label, randomized drug intervention case series., Setting: This study was performed at James J. Peters VA Medical Center (JJP VAMC) and Kessler Institute for Rehabilitation (KIR)., Participants: Five individuals with chronic SCI meeting criteria for obesity and abnormal carbohydrate metabolism., Intervention: Administration of semaglutide (subcutaneously once per week) versus no treatment (control) for 26 weeks., Outcome Measures: Change in total body weight (TBW), fat tissue mass (FTM), total body fat percent (TBF%), and visceral adipose tissue volume (VAT vol ) was determined at baseline and after 26 weeks using Dual energy X-ray absorptiometry; fasting plasma glucose (FPG) concentration and serum glycated hemoglobin (HbA1C) values were obtained at the same two time points., Results: In 3 participants, after 26 weeks of semaglutide administration, TBW, FTM, TBF%, and VAT vol decreased, on average, by 6, 4.4 kg, 1.7%, and 674 cm 3 , respectively. In addition, values for FPG and HbA1c decreased by 17 mg/dl and 0.2%, respectively. After 26 weeks of observation in the 2 control participants, TBW, FTM, TBF% and VAT vol increased on average by 3.3 , 4.5 kg, 2.5%, and 991 cm 3 , respectively. The average values for FPG and HbA1c also increased by 11 mg/dl and 0.3%, respectively., Conclusions: Administration of semaglutide for 26 weeks resulted in favorable changes in body composition and glycemic control, suggesting a reduced risk for the development of cardiometabolic disease in obese individuals with SCI. Trial registration: ClinicalTrials.gov identifier: NCT03292315.

Zinc supplementation has therapeutic effects on cardiovascular disease (CVD) risk factors, including dyslipidemia, hyperglycemia, and inflammation as the main contributors to CVD pathogenesis. Since CVD is a major cause of mortality among people with type 2 diabetes mellitus (T2DM), this study aimed to overview the potential effects of zinc supplementation on CVD risk factors in T2DM patients. To determine appropriate randomized clinical trials (RCTs) investigating the effects of zinc supplementation on CVD risk factors, electronic sources including PubMed, Web of Science, and Scopus were systematically searched until January 2023. The heterogeneity of trials was checked using the I 2 statistic. According to the heterogeneity tests, random-effects models were estimated, and pooled data were defined as the weighted mean difference (WMD) with a 95% confidence interval (CI). Of the 4004 initial records, 23 studies that met inclusion criteria were analyzed in this meta-analysis. The pooled findings indicated the significant lowering effects of zinc supplementation on triglycerides (TG), total cholesterol (TC), fasting blood glucose (FBG), hemoglobin A1C (HbA1C), and C-reactive protein (CRP), while high-density cholesterol (HDL) concentrations showed an elevation after zinc supplementation. In addition to statistical significance, the effect of zinc supplementation on most of the variables was clinically significant; however, the quality of evidence in the included studies is regarded as low or very low for most variables. Our study demonstrated that zinc supplementation has beneficial effects on glycemic control markers, lipid profile, and CRP levels as a classic marker of inflammation in T2DM. Due to the high degree of heterogeneity between studies and the low rate of quality in them, further well-designed studies are necessitated to strengthen our findings., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pancreatic diabetes is associated with glycemic variability, poor metabolic control, and reduced quality of life. Though hybrid closed-loop (HCL) insulin delivery systems were not originally developed for these types of diabetes, they could address the therapeutic challenge. We aimed to evaluate long-term metabolic control in ten adult patients (mean ± SD age: 59 ± 12) treated with HCL insulin delivery systems for pancreatitis or pancreatectomy-induced diabetes. After a median of 346 days (range 64 - 631) with HCL insulin delivery, continuous glucose monitoring showed 59±19 % time-in-range [70-180 mg/dl] (versus 49±24 % before HCL insulin delivery, P = 0. 049) and 0.8 ± 1.0 % time-below-range [< 70 mg/dl] (versus 2.2 ± 2.6 %, P = 0.142), with the coefficient of glucose variability at 35.4 ± 7.6 (versus 37.8 ± 7.1, P = 0.047). Hb A1c decreased from 8.5 ± 1.7 % to 7.7 ± 1.3 % [69±18 to 60±14 mmol/mol] (P = 0.076). No patient experienced an acute adverse metabolic event., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alfred Penfornis declares consultant/speaker fees from Medtronic and Dexcom. The other authors do not declare any duality of interest concerning the companies associated with the closed-loop systems used in this study., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Aim: To evaluate whether caffeine combined with a moderate amount of glucose reduces the risk for exercise-related hypoglycaemia compared with glucose alone or control in adult people with type 1 diabetes using ultra-long-acting insulin degludec., Materials and Methods: Sixteen participants conducted three aerobic exercise sessions (maximum 75 min) in a randomized, double-blind, cross-over design. Thirty minutes before exercise, participants ingested a drink containing either 250 mg of caffeine + 10 g of glucose + aspartame (CAF), 10 g of glucose + aspartame (GLU), or aspartame alone (ASP). The primary outcome was time to hypoglycaemia., Results: There was a significant effect of the condition on time to hypoglycaemia (χ 2  = 7.674, p = .0216). Pairwise comparisons revealed an 85.7% risk reduction of hypoglycaemia for CAF compared with ASP (p = .044). No difference was observed between GLU and ASP (p = .104) or between CAF and GLU (p = .77). While CAF increased glucose levels during exercise compared with GLU and ASP (8.3 ± 1.9 mmol/L vs. 7.7 ± 2.2 mmol/L vs. 5.8 ± 1.4 mmol/L; p < .001), peak plasma glucose levels during exercise did not differ between CAF and GLU (9.3 ± 1.4 mmol/L and 9.1 ± 1.6 mmol/L, p = .80), but were higher than in ASP (6.6 ± 1.1 mmol/L; p < .001). The difference in glucose levels between CAF and GLU was largest during the last 15 min of exercise (p = .002). Compared with GLU, CAF lowered perceived exertion (p = .023)., Conclusions: Pre-exercise caffeine ingestion combined with a low dose of glucose reduced exercise-related hypoglycaemia compared with control while avoiding hyperglycaemia., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

The uncontrolled hyperglycemia that characterizes diabetes mellitus (DM) causes several complications in the organism. DM is among the major causes of deaths, and the limited efficacy of current treatments push the search for novel drug candidates, also among natural compounds. We focused our attention on caffeoylmalic acid, a phenolic derivative extracted from Urtica dioica, a plant investigated for its potential against type 2 DM. This compound was tested for its antidiabetic activity in vitro through a glucose uptake assay, in vivo in a mouse DM model and through molecular docking towards α-amylase and α-glucosidase. The effects on glucose blood level, liver enzymes, insulin and creatinine levels as well as on lipid and blood parameters, considered biochemical markers of diabetes, were also evaluated. The results showed an antidiabetic activity in vitro and in vivo, as the compound stimulates glucose absorbtion and reduces blood glucose levels. Moreover, it ameliorates lipid profile, liver and blood parameters, with moderate effect on insulin secretion. Taken together, these findings pave the way for the compounds from this class of caffeoylmalic acid as potential antidiabetic compounds., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The prevalence of testicular dysfunction is increasing as it is a common diabetes mellites (DM) complication. The objective of this study is to explore the potential protective effect of sulbutiamine against testicular hypofunction associated with streptozotocin (STZ)-induced DM in rats. Sulbutiamine was administered orally (60 mg/kg) to male Wistar rats for 8 weeks starting 72 h after a single injection of STZ (45 mg/kg, i.p.). Blood glucose level (BGL), serum testosterone level, sperm number, and motility were determined. Testicular tissue was examined histopathologically, and the Johnson score was evaluated. Levels of malondialdehyde (MDA), protein kinase C (PKC), nuclear factor erythroid-derived 2-like 2 (Nrf2), and proliferating cell nuclear antigen (PCNA) were measured. Apoptosis was evaluated by immunohistochemical determination of B-cell lymphoma protein 2 (Bcl-2), Bcl-2 associated X-protein (Bax), and caspase-3. Sulbutiamine administration managed to reduce BGL and boost testicular function as manifested by increased testicular weight, testosterone level, sperm number, and motility compared to the STZ group. Additionally, histopathological examination revealed an improved histological picture and Johnson score of testicular tissue after sulbutiamine treatment. Sulbutiamine administration reduced testicular PKC, MDA, and PCNA levels and increased Nrf2 compared to the untreated group. Moreover, sulbutiamine treatment suppressed apoptosis triggered by STZ as evidenced by elevated Bcl-2, decreased Bax and reduced caspase-3. The present work revealed for the first time a promising protective role of sulbutiamine against STZ-induced testicular dysfunction which may add to the clinical utility of sulbutiamine. The underlying mechanisms involve reducing BGL and PKC, activating Nrf2 and inhibiting apoptosis., (© 2024 International Union of Biochemistry and Molecular Biology.)

A high risk of glucometabolic disorder severely disturbs compliance and limits the clinical application of olanzapine. MicroRNAs (miRNAs) in extracellular vesicles (EVs) have been reported as emerging biomarkers in glucolipid metabolic disorders. A total of 81 individuals with continuous olanzapine treatment over 3 months were recruited in this study, and plasma EVs from these individuals were isolated and injected into rats via the tail vein to investigate the glucose-regulating function in vivo. Moreover, we performed a miRNA profiling assay by high through-put sequencing to clarify the differentiated miRNA profiles between two groups of patients who were either susceptible or not susceptible to olanzapine-induced insulin resistance (IR). Finally, we administered antagomir and cocultured them with adipocytes to explore the mechanism in vitro. The results showed that individual insulin sensitivity varied in those patients and in olanzapine-administered rats. Furthermore, treatment with circulating EVs from patients with olanzapine-induced IR led to the development of metabolic abnormalities in rats and adipocytes in vitro through the AKT-GLUT4 pathway. Deep sequencing illustrated that the miRNAs of plasma EVs from patients showed a clear difference based on susceptibility to olanzapine-induced IR, and miR-486-5p was identified as a notable gene. The adipocyte data indicated that miR-486-5p silencing partially reversed the impaired cellular insulin sensitivity. Collectively, this study confirmed the function of plasma EVs in the interindividual differences in olanzapine-induced insulin sensitivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: While therapies based on endogenous gut peptides such as glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have been compelling therapeutic agents for obesity and type 2 diabetes (T2D), only a few have achieved long-term weight loss and all have shown significant side-effects, including nausea/malaise and gastrointestinal ailments., Objective: As the pathophysiology of obesity is driven by dysregulation of multiple, inter-related, pathways, we tested a novel peptide targeting multiple receptors of complementary neurocircuits regulating the controls of energy balance., Methods: Response to daily injections of GEP44, a GLP-1R and neuropeptide Y1R and Y2R receptor (Y1R/Y2R) triple agonist was tested vs. the GLP-1R agonist liraglutide (LIRA) in diet-induced obese (DIO) male and female rats. Glucose tolerance tests after intraperitoneal injection of glucose (IPGTT) were performed at baseline and after 14-d of treatment in GEP44 treated rats. Other metabolic parameters were assessed in blood at the end of a 28-d intervention., Results: Upon conclusion at 28-d, body weight reduction compared to vehicle was -15.6%/-11.9% in response to GEP44, vs. -9.7%/-5.1% after LIRA, males, and females, respectively. Significant reductions of cumulative food intake occurred over 28-d in female rats treated with GEP44 (-30%; p < 0.0001), vs. LIRA (-10%), and in male rats GEP44 (-39%; p < 0.0001), vs. LIRA (-20%; p = 0.003). In IPGTTs, a similar stimulation glucose induced insulin secretion was noted in rats treated with GEP44 and LIRA., Conclusion: The strong reductions of body weight in response to long-term applications of the triple agonist GEP44 confirms the therapeutic potential of targeting multiple receptors for achieving more robust and potentially more sustained improvement of energy balance., Competing Interests: Conflict of interest R.P.D. is a Scientific Advisory Board member of Balchem Corporation, New Hampton, NY, which played no role in the design, execution, or analysis of the results of these studies. R.P.D. is a named author of a patent pursuant to the development of GEP44 that is owned by Syracuse University., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Aims/hypothesis: We conducted a systematic review and network meta-analysis to compare the efficacy and safety of s.c. administered tirzepatide vs s.c. administered semaglutide for adults of both sexes with type 2 diabetes mellitus., Methods: We searched PubMed and Cochrane up to 11 November 2023 for RCTs with an intervention duration of at least 12 weeks assessing s.c. tirzepatide at maintenance doses of 5 mg, 10 mg or 15 mg once weekly, or s.c. semaglutide at maintenance doses of 0.5 mg, 1.0 mg or 2.0 mg once weekly, in adults with type 2 diabetes, regardless of background glucose-lowering treatment. Eligible trials compared any of the specified doses of tirzepatide and semaglutide against each other, placebo or other glucose-lowering drugs. Primary outcomes were changes in HbA 1c and body weight from baseline. Secondary outcomes were achievement of HbA 1c target of ≤48 mmol/mol (≤6.5%) or <53 mmol/mol (<7.0%), body weight loss of at least 10%, and safety outcomes including gastrointestinal adverse events and severe hypoglycaemia. We used version 2 of the Cochrane risk-of-bias tool (ROB 2) to assess the risk of bias, conducted frequentist random-effects network meta-analyses and evaluated confidence in effect estimates utilising the Confidence In Network Meta-Analysis (CINeMA) framework., Results: A total of 28 trials with 23,622 participants (44.2% female) were included. Compared with placebo, tirzepatide 15 mg was the most efficacious treatment in reducing HbA 1c (mean difference -21.61 mmol/mol [-1.96%]) followed by tirzepatide 10 mg (-20.19 mmol/mol [-1.84%]), semaglutide 2.0 mg (-17.74 mmol/mol [-1.59%]), tirzepatide 5 mg (-17.60 mmol/mol [-1.60%]), semaglutide 1.0 mg (-15.25 mmol/mol [-1.39%]) and semaglutide 0.5 mg (-12.00 mmol/mol [-1.09%]). In between-drug comparisons, all tirzepatide doses were comparable with semaglutide 2.0 mg and superior to semaglutide 1.0 mg and 0.5 mg. Compared with placebo, tirzepatide was more efficacious than semaglutide for reducing body weight, with reductions ranging from 9.57 kg (tirzepatide 15 mg) to 5.27 kg (tirzepatide 5 mg). Semaglutide had a less pronounced effect, with reductions ranging from 4.97 kg (semaglutide 2.0 mg) to 2.52 kg (semaglutide 0.5 mg). In between-drug comparisons, tirzepatide 15 mg, 10 mg and 5 mg demonstrated greater efficacy than semaglutide 2.0 mg, 1.0 mg and 0.5 mg, respectively. Both drugs increased incidence of gastrointestinal adverse events compared with placebo, while neither tirzepatide nor semaglutide increased the risk of serious adverse events or severe hypoglycaemia., Conclusions/interpretation: Our data show that s.c. tirzepatide had a more pronounced effect on HbA 1c and weight reduction compared with s.c. semaglutide in people with type 2 diabetes. Both drugs, particularly higher doses of tirzepatide, increased gastrointestinal adverse events., Registration: PROSPERO registration no. CRD42022382594., (© 2024. The Author(s).)

Methionine is one of the most frequently supplemented amino acids in raising of poultry. However, an overdose of methionine can cause hyperhomocysteinemia. Folic acid, taking part in the process of homocysteine remethylation, is a factor affecting the reduction of the concentration of this amino acid. The study was carried out in 2 stages. The experiment of step I was to investigate the effect of methionine and/or folic acid administration in ovo in the early stage of embryogenesis (E4), and the experiment of the second stage - in the late stage of embryogenesis (E17) on the following biochemical parameters of chicken blood: glucose concentration in whole blood and concentration of homocysteine and uric acid in plasma of domestic chickens (Gallus gallus domesticus). Our results confirm that methionine supplementation may increase the concentration of uric acid and homocysteine. Moreover, we demonstrated that folic acid administered during embryogenesis decreased homocysteine concentration, also in groups simultaneously supplemented with methionine, especially in the initial stage of postnatal life of the bird., Competing Interests: DISCLOSURES The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Activation of incretin receptors by their cognate agonist augments sustained cAMP generation both from the plasma membrane as well as from the endosome. To address the functional outcome of this spatiotemporal signaling, we developed a nonacylated glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor dual agonist I-M-150847 that reduced receptor internalization following activation of the incretin receptors. The incretin receptor dual agonist I-M-150847 was developed by replacing the tryptophan cage of exendin-4 tyrosine substituted at the amino terminus with the C-terminal undecapeptide sequence of oxyntomodulin that placed lysine 30 of I-M-150847 in frame with the corresponding lysine residue of GIP. The peptide I-M-150847 is a partial agonist of GLP-1R and GIPR; however, the receptors, upon activation by I-M-150847, undergo reduced internalization that promotes agonist-mediated iterative cAMP signaling and augments glucose-stimulated insulin exocytosis in pancreatic β cells. Chronic administration of I-M-150847 improved glycemic control, enhanced insulin sensitivity, and provided profound weight loss in diet-induced obese (DIO) mice. Our results demonstrated that despite being a partial agonist, I-M-150847, by reducing the receptor internalization upon activation, enhanced the incretin effect and reversed obesity. NEW & NOTEWORTHY Replacement of the tryptophan cage (Trp-cage) with the C-terminal oxyntomodulin undecapeptide along with the tyrosine substitution at the amino terminus converts the selective glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 to a novel GLP-1R and GIPR dual agonist I-M-150847. Reduced internalization of incretin receptors upon activation by the GLP-1R and GIPR dual agonist I-M-150847 promotes iterative receptor signaling that enhances the incretin effect and reverses obesity.

Diabetic nephropathy (DN) is a significant global health concern with a high morbidity rate. Accumulating evidence reveals that Galectin-3 (Gal-3), a β-galactoside-binding lectin, is a biomarker in kidney diseases. Our study aimed to assess the advantageous impacts of modified citrus pectin (MCP) as an alternative therapeutic strategy for the initial and ongoing progression of DN in mice with type 2 diabetes mellitus (T2DM). The animal model has been split into four groups: control group, T2DM group (mice received intraperitoneal injections of nicotinamide (NA) and streptozotocin (STZ), T2DM+MCP group (mice received 100 mg/kg/day MCP following T2DM induction), and MCP group (mice received 100 mg/kg/day). After 4 weeks, kidney weight, blood glucose level, serum kidney function tests, histopathological structure alterations, oxidative stress, inflammation, apoptosis, and fibrosis parameters were determined in renal tissues. Our findings demonstrated that MCP treatment reduced blood glucose levels, renal histological damage, and restored kidney weight and kidney function tests. Additionally, MCP reduced malondialdehyde level and restored glutathione level, and catalase activity. MCP demonstrated a notable reduction in inflammatory and apoptosis mediators TNF-α, iNOS, TGF-βRII and caspase-3. Overall, MCP could alleviate renal injury in an experimental model of DN by suppressing renal oxidative stress, inflammation, fibrosis, and apoptosis mediators., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Aims/hypothesis: The aim of this study was to evaluate the impact on metabolic control of periodic use of a 5-day fasting-mimicking diet (FMD) programme as an adjunct to usual care in people with type 2 diabetes under regular primary care surveillance., Methods: In this randomised, controlled, assessor-blinded trial, people with type 2 diabetes using metformin as the only glucose-lowering drug and/or diet for glycaemic control were randomised to receive 5-day cycles of an FMD monthly as an adjunct to regular care by their general practitioner or to receive regular care only. The primary outcomes were changes in glucose-lowering medication (as reflected by the medication effect score) and HbA 1c levels after 12 months. Moreover, changes in use of glucose-lowering medication and/or HbA 1c levels in individual participants were combined to yield a clinically relevant outcome measure ('glycaemic management'), which was categorised as improved, stable or deteriorated after 1 year of follow-up. Several secondary outcome measures were also examined, including changes in body weight., Results: One hundred individuals with type 2 diabetes, age 18-75 years, BMI ≥27 kg/m 2 , were randomised to the FMD group (n=51) or the control group (n=49). Eight FMD participants and ten control participants were lost to follow-up. Intention-to-treat analyses, using linear mixed models, revealed adjusted estimated treatment effects for the medication effect score (-0.3; 95% CI -0.4, -0.2; p<0.001), HbA 1c (-3.2 mmol/mol; 95% CI -6.2, -0.2 and -0.3%; 95% CI -0.6, -0.0; p=0.04) and body weight (-3.6 kg; 95% CI -5.2, -2.1; p<0.001) at 12 months. Glycaemic management improved in 53% of participants using FMD vs 8% of control participants, remained stable in 23% vs 33%, and deteriorated in 23% vs 59% (p<0.001)., Conclusions/interpretation: Integration of a monthly FMD programme in regular primary care for people with type 2 diabetes who use metformin as the only glucose-lowering drug and/or diet for glycaemic control reduces the need for glucose-lowering medication, improves HbA 1c despite the reduction in medication use, and appears to be safe in routine clinical practice., Trial Registration: ClinicalTrials.gov NCT03811587 FUNDING: The project was co-funded by Health~Holland, Top Sector Life Sciences & Health, the Dutch Diabetes Foundation and L-Nutra., (© 2024. The Author(s).)

Aims/hypothesis: Metformin lowers postprandial glycaemic excursions in individuals with type 2 diabetes by modulating gastrointestinal function, including the stimulation of glucagon-like peptide-1 (GLP-1). The impact of varying the timing of metformin administration on postprandial glucose metabolism is poorly defined. We evaluated the effects of metformin, administered at different intervals before an intraduodenal glucose infusion, on the subsequent glycaemic, insulinaemic and GLP-1 responses in metformin-treated type 2 diabetes., Methods: Sixteen participants with type 2 diabetes that was relatively well-controlled by metformin monotherapy were studied on four separate days in a crossover design. On each day, participants were randomised to receive a bolus infusion of metformin (1000 mg in 50 ml 0.9% saline) via a nasoduodenal catheter at t = -60, -30 or 0 min (and saline at the other timepoints) or saline at all timepoints (control), followed by an intraduodenal glucose infusion of 12.56 kJ/min (3 kcal/min) at t = 0-60 min. The treatments were blinded to both participants and investigators involved in the study procedures. Plasma glucose, insulin and total GLP-1 levels were measured every 30 min between t = -60 min and t = 120 min., Results: There was a treatment-by-time interaction for metformin in reducing plasma glucose levels and increasing plasma GLP-1 and insulin levels (p<0.05 for each). The reduction in plasma glucose levels was greater when metformin was administered at t = -60 or -30 min vs t = 0 min (p<0.05 for each), and the increases in plasma GLP-1 levels were evident only when metformin was administered at t = -60 or -30 min (p<0.05 for each). Although metformin did not influence insulin sensitivity, it enhanced glucose-induced insulin secretion (p<0.05), and the increases in plasma insulin levels were comparable on the 3 days when metformin was given., Conclusions/interpretation: In well-controlled metformin-treated type 2 diabetes, glucose-lowering by metformin is greater when it is given before, rather than with, enteral glucose, and this is associated with a greater GLP-1 response. These observations suggest that administration of metformin before meals may optimise its effect in improving postprandial glycaemic control., Trial Registration: www.anzctr.org.au ACTRN12621000878875 FUNDING: The study was not funded by a specific research grant., (© 2024. The Author(s).)

The introduction of glucagon-like peptide 1 (GLP-1)-based therapies has greatly improved the management of type 2 diabetes (T2D), as they ensure good blood glucose control and promote weight loss. Ingestion of standardized herbal remedies that promote the same endogenous metabolic processes affected by the GLP-1-based treatments could provide cheaper alternatives in low- and middle-income countries, where there is currently an increase in the incidence of T2D. The focus in this study was to determine quality control parameters and the prime factors for the Rauvolfia-Citrus tea (RC-tea), as used in Nigerian traditional medicine to treat T2D. We have previously shown that the RC-tea that is made by boiling leaves of Rauvolfia vomitoria Afzel. and fruits of Citrus aurantium L. causes normalization of blood glucose and reduction of ectopic lipid accumulation in genetic diabetic (BKS-db) mice and in humans with T2D. The standardized RC-tea was made by boiling 40 g dried R. vomitoria foliage and 200 g fresh C. aurantium fruits per litre. The resulting golden-brown extract is free of microbial contamination, has pH 5 and contains ca. 230 mg naringin (marker compound for C. aurantium) and 25 mg robinin (marker compound for R. vomitoria) per litre. In addition, the herbal extract has the characteristic HPLC-DAD fingerprint where the marker compounds, naringin and robinin have retention times of approximately 26.3 min and 26.9 min, respectively, when using the outlined column and gradient elution conditions. Comparative evaluations of the antidiabetic effects of the standardized RC-tea and boiling water-extracts made with C. aurantium fruits alone (CA), R. vomitoria foliage alone (RV) and a combination of CA and RV, (CA + RV) in BKS-db mice, indicate that components from R. vomitoria foliage drive the reductions in ectopic lipid accumulation, since CA-treated mice lacked this effect. However, the normalization of blood glucose arises from combination of components from the two source plant materials as administration of either CA or RV resulted in hypoglycaemia. Interestingly, treatment with the CA + RV mixture, generated by mixing individually produced CA and RV plant extracts, resulted in hyperglycaemia, possibly due to drug-drug interactions of the blood glucose-reducing components in either plant extract. Hence, our data show that the best antidiabetic outcome results from the traditional practice of boiling R. vomitoria foliage and C. aurantium fruits together., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Objective: To examine the real-world effects of imeglimin on glycemic control and other metabolic factors in patients with type 2 diabetes (T2DM)., Methods: A retrospective longitudinal study was conducted based on a chart review. We recruited patients with T2DM who took imeglimin continuously for at least 3 months. Data on various metabolic parameters were collected at the first prescription of imeglimin and at 3, 6 and 12 months after the initiation of imeglimin. Statistical comparisons were performed using paired t-tests., Results: 68 patients were eligible for this study. HbA1c decreased by 0.7 % at 3 months, 1.1 % at 6 months and 1.0 % by 12 months after the initiation of imeglimin. The decreases in HbA1c were observed regardless of age, gender, body mass index, duration of diabetes, renal function and concomitant use of hypoglycemic agents. There were also significant decreases in body weight, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and non-HDL-C during imeglimin treatment., Conclusions: This is the first report showing the long-term effects of imeglimin in a real-world setting. We confirmed the glucose-lowering effects of imeglimin. Furthermore, favorable effects of imeglimin on body weight and serum lipids were also suggested., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The prevalence and incidence of type 2 diabetes mellitus (T2DM) have dramatically increased. The intestinal flora and its derived metabolites are demonstrated to play vital roles in the etiology and onset of T2DM. Shouhuitongbian (SHTB) is a traditional Chinese formula to treat constipation. SHTB is composed of seven herbs and components of Colla corii asini (CCA) that are obtained from the hide of Equus asinus L.. Some of herbs in SHTB such as Aloe vera (L.) Burm.f., Cassia obtusifolia L., fruits of Lycium barbarum L., and Citrus aurantium L. have shown to improve insulin resistance (IR) and T2DM in early reports. We hypothesized that SHTB composed of these herbs has antidiabetic effects. The antidiabetic efficacy and mechanism of action of SHTB have not been previously reported., Hypothesis/purpose: To demonstrate the antidiabetic effect and elucidate the underlying mechanisms of SHTB from the perspective of gut microbiota., Study Design: The main compounds were identified and quantified by high-performance liquid chromatography (HPLC)-mass spectrometry analysis. High fat diet (HFD)-fed mice and db/db mice were used to assess the antidiabetic effects and the mechanism of SHTB. The underlying mechanisms were evaluated by enzyme-linked immunosorbent assay (ELISA), western blot analysis, quantitative real time polymerase chain reaction (qPCR) analysis, 16S rRNA high-throughput sequencing, and targeted metabolome analysis., Methods: HFD-fed mice and db/db mice were orally treated with the standard positive drug metformin (100 mg/kg/d) and with SHTB (200 and 100 mg/kg/d), which was chemically characterized according to the European Medicine Agency (EMA) guidelines. The beneficial effects of SHTB were studied by homeostasis model assessment of insulin resistance (HOMA-IR) index, oral glucose tolerance test (OGTT), insulin tolerance test (ITT), total cholesterol (T-CHO), triglyceride (TG), and inflammation. Subsequently, 16S rDNA-based high-throughput pyrosequencing and GC-MS-based targeted metabolomics profiling were performed to analyze the gut microbiota composition and metabolites profile in the gut, respectively. Moreover, the mammalian target of rapamycin complex 1 (mTORC1) / insulin receptor substrate 1 (IRS-1) / phosphoinositide 3-kinase (PI3K) / protein kinase B (AKT) pathway was evaluated via qPCR and western blot., Results: Chemically characterized SHTB, in which six markers were quantified, effectively alleviated glucose intolerance and IR, ameliorated lipid metabolism dysfunction, and reduced inflammation. In addition, 16S rDNA sequencing found that SHTB reshaped the composition of intestinal flora, as indicated by the enrichment of Akkermansia and Parabacteroides in both HFD-fed and db/db mice. Moreover, SHTB enhanced the intestinal production of short-chain fatty acids (SCFAs) and branched short-chain fatty acids (BSCFAs), and reduced the levels of the fecal and circulating branched-chain amino acids (BCAAs). The IRS-1/PI3K/AKT signaling pathway was upregulated after treatment with SHTB., Conclusion: Orally administration of SHTB effectively improved IR and reduced hyperglycemia in mice. Treatment with SHTB regulated the gut BCAAs-mTORC1/IRS-1/PI3K/AKT axis by enhancing the BCAAs catabolism in the gut, which attenuated the deleterious effect of BCAAs on the IRS-1 signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

There have been shortages of glucagon-like peptide-1 receptor agonists (GLP-1 RA) for type 2 diabetes (T2D) care. Analyses of data from 811 T2D adults at an Australian specialist diabetes clinic (1/2019-10/2023) who received ≥ 2 GLP-1 RA prescriptions before and during the shortage showed median HbA1c levels significantly increased by 0.3 %., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [These authors disclose the following: NN has received honoraria/participated a Data Safety Monitoring Board or Advisory Board from Lilly, MH has received Support for attending meetings and/or travel from JDRF Australia and is Associate Editor of Bioscience Reports, AJ is Chair Elect IDF Western Pacific Region, Insulin For Life Global and Australia Board Member NC has received honoraria for lectures from Lectures Novo Nordisk, Lilly, Astra Zeneca, participated a Data Safety Monitoring Board or Advisory Board for Lilly.]., (Copyright © 2024. Published by Elsevier B.V.)

Background: Impaired glycemic control and the subsequent development of Cystic fibrosis Related Diabetes (CFRD) are prevalent complications, affecting up to 50 % of adults with cystic fibrosis (CF). CFTR modulator (CFTRm) therapies improve pulmonary functions, reduce exacerbation rates, increase survival in people with CF (pwCF) and appear to have a positive effect on extrapulmonary manifestations, such as nutritional state, improvements in upper respiratory symptoms, and quality of life. Initial findings indicate that CFTRm may have a positive impact on short-term glycemic control; however, long-term effects remain uncertain at present., Methods: In this retrospective study, data were collected and analyzed on 15 pwCF, ages 13-37 years, started on CFTRm therapy. Oral Glucose Tolerance Test (OGTT) results were compared pre- and post-CFTRm therapy., Results: The 120-min OGTT value decreased from 159.7 mg/dL to 130.4 mg/dL post-CFTRm (p = 0.047). The average time elapsed between the two OGTTs was 49.87 months (ranging 9-157 months, median 38 months). Glycemic status improved in six pwCF (two CFRD to normal (NGT)/indeterminate (INDET) glucose tolerance; two impaired glucose tolerance (IGT) to INDET; two INDET to NGT) and worsened in one (IGT to CFRD). Six pwCF and NGT remained stable with no changes in glycemic status throughout the follow-up period., Conclusions: CFTRm therapy may decelerate the glycemic control deterioration in pwCF over an extended period. These findings indicate the need for periodic OGTTs following the initiation of CFTRm therapy to appropriately adjust insulin requirements and prevent hypoglycemia. Further larger cohorts are required to authenticate and substantiate these findings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: In purpose-bred dogs, insulin glargine 300 U/mL (IGla300) has long duration of action, peakless time-action profile, and low potency, making it suitable for use as a basal insulin., Hypothesis: To evaluate IGla300 in client-owned diabetic dogs monitored using a flash glucose monitoring system (FGMS)., Animals: Ninety-five client-owned diabetic dogs, newly diagnosed or previously treated with other insulin formulations, with or without concurrent diseases., Methods: Prospective multi-institutional study. Clinical signs and standardized assessment of FGMS data, using treatment and monitoring guidelines established a priori, guided dose adjustments and categorization into levels of glycemic control., Results: The initial IGla300 dose was 0.5 U/Kg q24h for newly diagnosed dogs and (median dose [range]) 0.8 U/Kg (0.2-2.5) q24h for all dogs. Glycemic control was classified as good or excellent in 87/95 (92%) dogs. The IGla300 was administered q24h (1.9 U/kg [0.2-5.2]) and q12h (1.9 U/kg/day [0.6-5.0]) in 56/95 (59%) and 39/95 (41%) dogs, respectively. Meal-time bolus injections were added in 5 dogs (0.5 U/kg/injection [0.3-1.0]). Clinical hypoglycemia occurred in 6/95 (6%) dogs. Dogs without concurrent diseases were more likely to receive IGla300 q24h than dogs with concurrent diseases (72% vs 50%, respectively; P = .04)., Conclusions and Clinical Importance: Insulin glargine 300 U/mL can be considered a suitable therapeutic option for once-daily administration in diabetic dogs. Clinicians should be aware of the low potency and wide dose range of IGla300. In some dogs, twice-daily administration with or without meal-time bolus injections may be necessary to achieve glycemic control. Monitoring with FGMS is essential for dose titration of IGla300., (© 2024 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Competing Interests: Declaration of competing interest Dr. Vanneman receives $3,000 annually in patent royalties for novel cancer immunotherapy.

In 2014, the American Diabetes Association instituted a novel funding paradigm to support diabetes research through its Pathway to Stop Diabetes program. This program took a multifaceted approach to providing key funding to diabetes researchers to advance a broad spectrum of research programs on all aspects of understanding, managing, and treating diabetes. Here, the personal perspective of a 2019 Pathway Accelerator awardee is offered, describing a research program seeking to advance a materials-centered approach to engineering glucose-responsive devices and new delivery tools for better therapeutic outcomes in treating diabetes. This is offered alongside a personal reflection on 5 years of support from the ADA Pathway Program., (© 2024 by the American Diabetes Association.)

Despite the risk of atherosclerosis has progressively declined over the past few decades, subjects with type 2 diabetes mellitus (T2DM) continue to experience substantial excess of atherosclerotic cardiovascular disease (ASCVD)-related events. Therefore, there is urgent need to treat ASCVD disease in T2DM earlier, more intensively, and with greater precision. Many factors concur to increase the risk of atherosclerosis, and multifactorial intervention remains the basis for effective prevention or reduction of atherosclerotic events. The role of anti-hyperglycemic medications in reducing the risk of ASCVD in subjects with T2DM has evolved over the past few years. Multiple cardiovascular outcome trials (CVOTs) with new and emerging glucose-lowering agents, namely SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1-RA), have demonstrated significant reductions of major cardiovascular events and additional benefits. This robust evidence has changed the landscape for managing people with T2DM. In addition to glycemic and ancillary extra-glycemic properties, SGLT2i and GLP1-RA might exert favorable effects on subclinical and clinical atherosclerosis. Therefore, the objective of this review is to discuss the available evidence supporting anti-atherosclerotic properties of SGLT2i and GLP1-RA, with a quick nod to sotagliflozin and tirzepatide., Competing Interests: Declaration of competing interest Angela Dardano (AD) reported no duality of interest. Cristina Bianchi (CB) reported consulting fees and grants from Lilly, Novo Nordisk, Merck Sharp & Dohme Corp. Monia Garofolo (MG) reported consulting fees from Novo Nordisk, Eli Lilly, Merck Sharp & Dohme Corp. and Bayer Inc. Stefano Del Prato (SDP) has served as president of EASD/European Foundation for the Study of Diabetes (EFSD) (2020–2022); has received research grants to the institution from AstraZeneca and Boehringer Ingelheim; has served as advisor for Abbott, Amarin Corporation, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., EvaPharma, Jiangsu Hengrui Pharmaceuticals Co., Menarini International, Merck Sharpe & Dohme, Novartis Pharmaceutical Co., Novo Nordisk, Sanofi and Sun Pharmaceuticals; and has received fees for speaking from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Laboratori Guidotti, Menarini International, Merck Sharpe & Dohme, and Novo Nordisk. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Systemic insulin increases muscle sympathetic nerve activity (MSNA) via both central actions within the brainstem and peripheral activation of the arterial baroreflex. Augmented MSNA during hyperinsulinemia likely restrains peripheral vasodilation and contributes to the maintenance of blood pressure (BP). However, in the absence of insulin action within the peripheral vasculature, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans remains unknown. Herein, we hypothesized intranasal insulin administration would increase MSNA and BP in healthy young adults. Participants were assigned to time control [TC, n = 13 (5 females/8 males), 28 ± 1 yr] or 160 IU of intranasal insulin administered over 5 min [ n = 15 (5 females/10 males), 26 ± 2 yr]; five (1 female/4 males) participants completed both conditions. MSNA (fibular microneurography), BP (finger photoplethysmography), and leg blood flow (LBF, femoral Doppler ultrasound) were assessed at baseline, and 15 and 30 min following insulin administration. Leg vascular conductance [LVC = (LBF ÷ mean BP) × 100] was calculated. Venous insulin and glucose concentrations remained unchanged throughout ( P > 0.05). Following intranasal insulin administration, MSNA (burst frequency; baseline = 100%; minute 15 , 121 ± 8%; minute 30 , 118 ± 6%; P = 0.009, n = 7) and mean BP (baseline = 100%; minute 15 , 103 ± 1%; minute 30 , 102 ± 1%; P = 0.003) increased, whereas LVC decreased (baseline = 100%; minute 15 , 93 ± 3%; minute 30 , 99 ± 3%; P = 0.03). In contrast, MSNA, mean BP, and LVC were unchanged in TC participants ( P > 0.05). We provide the first evidence that intranasal insulin administration in healthy young adults acutely increases MSNA and BP and decreases LVC. These results enhance mechanistic understanding of the sympathetic and peripheral hemodynamic response to insulin. NEW & NOTEWORTHY Systemic insulin increases muscle sympathetic nerve activity (MSNA) via central actions within the brainstem and peripheral activation of the arterial baroreflex. In the absence of peripheral insulin action, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans was unknown. We provide the first evidence that intranasal insulin administration increases MSNA and blood pressure and reduces leg vascular conductance. These results enhance mechanistic understanding of the sympathetic and hemodynamic response to insulin.

Procyanidins, which are oligomerized flavan-3-ols with a polyphenolic structure, are bioactive substances that exhibit various biological effects. However, the relationship between the degree of polymerization (DP) of procyanidins and their bioactivities remains largely unknown. In this study, the preventive effects of procyanidins with different DP (EC, PB2 and PC1) on glucose improvement and liver lipid deposition were investigated using a high-fat diet/streptozotocin-induced diabetes mouse model. The results demonstrated that all the procyanidins with different DP effectively reduced fasting blood glucose and glucose/insulin tolerance, decreased the lipid profile (total cholesterol, triglyceride, and low-density lipoprotein cholesterol content) in serum and liver tissue as well as the liver oil red staining, indicating the improvement of glucose metabolism, insulin sensitivity and hepatic lipid deposition in diabetic mice. Furthermore, the procyanidins down-regulated expression of glucose regulated 78-kDa protein (GRP78) and C/EBP homologous protein (CHOP), indicating a regulation role of endoplasmic reticulum (ER) stress. The inhibition of ER stress by tauroursodeoxycholic acid (TUDCA) treatment abolished the effects of procyanidins with different DP in PA-induced HepG2 cells, confirming that procyanidins alleviate liver hyperlipidemia through the modulation of ER stress. Molecular docking results showed that EC and PB2 could better bind GRP78 and CHOP. Collectively, our study reveals that the structure of procyanidins, particularly DP, is not directly correlated with the improvement of blood glucose and lipid deposition, while highlighting the important role of ER stress in the bioactivities of procyanidins., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Metformin, insulin, and insulin secretagogues do not alter HbA1c levels in glucokinase maturity-onset diabetes of the young (GCK-MODY). However, the efficacy of the new hypoglycemic drugs on GCK-MODY remains unclear., Research Design and Methods: We describe a case of GCK-MODY with unchanged blood glucose under different therapies during an 8 years' follow-up. His HbA1c and biochemical indices under different hypoglycemic treatments were recorded., Results: Oral glucose-lowering drugs, including thiazolidinediones, dipeptidyl peptidase 4 inhibitor, α-glucosidase inhibitor, and sodium-glucose cotransporter 2 inhibitor that had not been evaluated previously, did not improve the HbA1c level in this patient. However, the glucokinase activator dorzagliatin effectively and safely lowered his HbA1c level., Conclusions: Dorzagliatin was effective and safe in this patient with GCK-MODY, providing potential application prospects for precise treatment of GCK-MODY with dorzagliatin., (© 2024 by the American Diabetes Association.)

Background: Obesity has become a prevalent issue worldwide, leading to various complications such as hyperlipidemia, diabetes, and cardiovascular problems. Statins, as FDA approved anti-hyperlipidemic drugs, still pose some concerns upon their administration. Recently, researchers have looked for natural products as an alternative to manage hyperlipidemia and obesity., Aim: This work aimed to study the hypolipidemic effect of Lepidium sativum garden cress (GC) from different preparations; orally administered seeds, and hydrogel, in comparison to atorvastatin., Methods: GC hydrogel was prepared from the GC aqueous extract and pharmaceutically evaluated for its pH, spreadability, seeds content, homogeneity, rheology, and in vitro release. The rat's body weight, blood glucose levels, total lipid profile, and liver biomarkers were evaluated on obese rats for one month. In addition, the histopathology study was also performed., Results: GC hydrogel had acceptable pharmaceutical properties and showed a sustained release performance over 24 h. Oral and topical GC significantly reduced the lipid profiles, blood sugar and ALT, AST levels more than the negative control group and comparable to atorvastatin. It was found that oral GC showed a significant effect on the percentage decrease in the rat's body weight than the applied hydrogel. Histopathology study revealed a better outcome in the histological structure of pancreas and liver compared with rats feed on high fat diet post-treatment for one month., Conclusion: GC orally administered, or topically applied hydrogel could be a promising, safe alternative formulation to atorvastatin in managing hyperlipidemia and normalizing body weight of obese rats.

Background: This study aimed to evaluate the effects of rosuvastatin and pravastatin on glucose homeostasis and other biomarkers in individuals at high risk of developing diabetes., Methods: This prospective, randomized, open-labeled, and controlled trial included prediabetic individuals with impaired fasting glucose and impaired glucose tolerance. The participants were randomized into three groups: rosuvastatin (10 mg), pravastatin (40 mg), or control. Biomarkers of diabetes and glucose and insulin responses to oral glucose tolerance tests were assessed at baseline and after 6 months of treatment. The primary outcomes were comparisons of glucose homeostasis and biomarkers of diabetes among groups at baseline and after 6 months of treatment., Results: A total of 141 subjects with impaired fasting glucose (IFG) were screened and 41 participants were recruited. Twenty-two subjects were randomized to either the rosuvastatin or pravastatin group and 19 subjects were assigned to the control group. After 6 months of treatment, all groups had similar cholesterol and triglyceride levels. Likewise, HbA1c levels, glucose, and insulin excursions during oral glucose tolerance test, were similar among the three groups. However, compared to the other groups, the rosuvastatin group had higher homeostasis model assessment for insulin resistance (HOMA-IR) (insulin resistance) and a lower Matsuda index (insulin sensitivity)., Conclusion: Among prediabetic individuals with IFG, rosuvastatin treatment was associated with increased insulin resistance and decreased insulin sensitivity compared to pravastatin and control groups. Further research is needed to elucidate the underlying mechanisms and clinical implications of these findings., Competing Interests: Conflicts of interest: Dr. Harn-Shen Chen, an editorial board member at Journal of the Chinese Medical Association , had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)