Glycemic Reduction Research Articles

A comparative study of the Anti-Diabetic effects of avocado seed extracts and biosynthesized silver nanoparticles in Alloxan-Induced diabetic Albino mice

In this research, a comparative study of the anti-diabetic effects of Avocado (Persea americana) seed extracts and biosynthesized silver nanoparticles (Ag NPs) in alloxan-induced diabetic albino mice was conducted. The animals were assigned into twenty-one groups of five animals each; the diabetes was induced by intraperitoneal injection of 150 mg/kg of the prepared alloxan monohydrate. After 15–25 days of using 7.5 mg/ml aqueous extract of P. americana seeds, it was found that blood sugar levels dropped significantly. In addition, over the 20–25 days treatment period, levels of blood sugar were reduced considerably when doses of 5.0 or 10 mg/ml of the aqueous extract were introduced. However, throughout this treatment period, animals injected with 2.5, 5.0, 7.5, or 10.0 mg/ml of P. americana seed aqueous extract showed a significant rise in weight. In addition, over 20–25 days of treatment, animals treated with 7.5 and 10.0 mg/ml P. americana seed alcoholic extract showed a substantial decrease in blood sugar levels. Over the 25 days of treatment, animals treated with 7.5 mg/ml P. americana seed in alcoholic extract also showed a noticeable rise in weight. On the other hand, the prepared Ag NPs were synthesized and characterized using color changes, UV–visible spectroscopy, SEM, and AFM analysis. A substantial reduction in blood sugar levels was noted with 2.5 mg/ml of biosynthesized Ag NPs, while mice weights significantly increased. The highest substantial reduction in glycaemia occurred by combining 7.5 mg/ml aqueous extract and 2.5 mg/ml biosynthesized Ag NPs, resulting in a high increase in animal weight across all combination concentrations. Regarding the interaction between combination concentrations and treatment periods, animals’ weight increased significantly in all combined concentrations during the 20–25 days compared to the control. Furthermore, an increase in LDL and VLDL concentrations was observed in the negative control group compared to the positive control and other treated groups.

Proteins and Peptides Studied In Silico and In Vivo for the Treatment of Diabetes Mellitus: A Systematic Review.

Bioinformatics has expedited the screening of new efficient therapeutic agents for diseases such as diabetes mellitus (DM). The objective of this systematic review (SR) was to understand naturally occurring proteins and peptides studied in silico and subsequently reevaluated in vivo for treating DM, guided by the question: which peptides or proteins have been studied in silico for the treatment of diabetes mellitus? The RS protocol was registered in the International Prospective Register of Systematic Reviews database. Articles meeting the eligibility criteria were selected from the PubMed, ScienceDirect, Scopus, Web of Science, Virtual Health Library (VHL), and EMBASE databases. Five studies that investigated peptides or proteins analyzed in silico and in vivo were selected. Risk of bias assessment was conducted using the adapted Strengthening the Reporting of Empirical Simulation Studies (STRESS) tool. A diverse range of assessed proteins and/or peptides that had a natural origin were investigated in silico and corresponding in vivo reevaluation demonstrated reductions in glycemia and/or insulin, morphological enhancements in pancreatic β cells, and alterations in the gene expression of markers associated with DM. The in silico studies outlined offer crucial insights into therapeutic strategies for DM, along with promising leads for screening novel therapeutic agents in future trials.

Aerobic Exercise in the Aquatic Environment Suppresses the Plasma Renin Activity in Individuals with Type 2 Diabetes: A Secondary Analysis of a Randomized Clinical Trial.

To compare the acute effects of aquatic walking/running versus dry-land walking/running on blood glucose and plasma renin activity (PRA) in individuals with type 2 diabetes, participants with type 2 diabetes performed deep-water or dry-land walking and/or running sessions in a swimming pool or on an athletics track, respectively. Both sessions comprised seven blocks of 3 min at 85-90% of the heart rate deflection point (HRDP), interspersed with 2 min at <85% HRDP, totaling 35 min, with a 48 h interval between sessions. PRA and blood glucose were assessed before and immediately after the sessions. Generalized estimation equations were used to verify the session effects, with the Bonferroni post hoc test, considering the significance level as 0.05. Twelve individuals (53.2 ± 8.9 years) diagnosed with type 2 diabetes for 6.3 ± 6.34 years participated in the study. A reduction in PRA was found only after the aquatic session (-7.75 ng/mL/h; -69%; p: 0.034), while both aquatic and dry-land sessions similarly reduced the blood glucose levels (aquatic: -38 mg/dL, -21%; dry-land: -26 mg/dL, -14%; time effect, p = 0.007). Despite yielding similar glycemic reductions as dry-land walking/running, aquatic walking/running led to an expressive decrease in PRA among individuals with type 2 diabetes.

#1762 Reduction in intradialytic glycemia and increased oxygen consumption as potential indicators of intradialytic parenchymal stress

Abstract Background and Aims Patients undergoing chronic hemodialysis (HD) face heightened all-cause and cardiovascular mortality due to various risk factors, with intradialytic stress playing a fundamental role. Recently, the assessment of intradialytic oxygen trends has emerged as a potential parameter for evaluating parenchymal stress. Specifically, an intradialytic increase in the oxygen extraction ratio (OER), derived from the ratio of peripherical oxygen saturation to central venous oxygen saturation, identifies patients at a greater risk of intradialytic events and increased clinical risk. In addition to OER, intradialytic consumption of glucose indicates higher tissue metabolic demand, likely indicative of parenchymal stress. We hypothesize that OER and intradialytic glucose consumption may be phenomena related to increased intradialytic parenchymal stress and, therefore, may be correlated. This study aimed to assess the potential correlation between intradialytic glycemia trends and oxygen extraction (OER). Method Patients in chronic HD treatment with a central venous catheter (CVC) for HD were enrolled from January 2019 to January 2020. The exclusion criteria were: ongoing acute pathology, diabetes mellitus, and undergoing hemodialysis for less than six months. OER and glycemia were measured during three consecutive HD sessions at baseline, 15, 30, 60, and 120 minutes into treatment, and post-HD. For statistical analysis, average values for each patient across the three dialysis sessions were considered. Results Twenty patients with a permanent CVC (10 males, 10 females; age 74 ± 13 years; HD vintage 46 ± 34 months) were enrolled. The pre-HD mean OER in the initial three HD sessions was 34 ± 7, increasing to 46 ± 9 post-HD, with a mean percentage delta OER of 39 ± 20%. Evaluating OER trends in the entire population revealed an increase in OER (∆OER) from the first 15 minutes of treatment (∆OER% 15’: 14 ± 7; ∆OER% 30’: 18 ± 22, p &amp;lt; 0.01). Patients' baseline glycemia was 120 ± 31 mg/dl at the start of the HD session and 111 ± 21 at the end, with a delta of −11 ± 21 mg/dl and a glucose delta percentage of 4%. Patients with higher oxygen consumption after 15 and 30 minutes of treatment experienced a greater decrease in glycemia. Specifically, ∆OER at 15’ negatively correlated with glycemia values at 15’ (r: −0.494, p &amp;lt; 0.05), 30’ (r: −0.521, p &amp;lt; 0.05), 60’ (r: −0.644, p &amp;lt; 0.01, Fig. 1), and 120’ (r: −0.714, p &amp;lt; 0.01), and post-HD (r: −0.634, p &amp;lt; 0.05). Patients were then divided based on the magnitude of mean O2 consumption measured post-HD into two groups: ΔOER ≤ mean and ΔOER &amp;gt; mean (threshold 40%). Patients with a higher ∆OER showed a more significant decrease in glycemia from the first 15 minutes of HD, confirmed at the end of HD (ΔOER ≤ 40%: Δglucose post-HD −2 ± 40; ΔOER &amp;gt; 40%: −22 ± 28, p &amp;lt; 0.05, Fig. 2). Conclusion The data confirm that oxygen extraction during hemodialysis progressively increases from the first 30 minutes of treatment. Changes in OER are associated with a reduction in glycemia, particularly patients with higher ΔOER have a more pronounced decrease in glycemia. This association between OER and glycemia supports the hypothesis that these two parameters are linked to the same pathophysiological phenomenon, such as increased intradialytic cellular metabolic activity. Studies with larger populations will help confirm this association and propose glycemia delta as an indicator of intradialytic parenchymal stress.

The IDEAL (Insulin therapy DE-intensificAtion with iglarLixi) Randomised Controlled Trial-Study Design and Protocol.

Multiple daily injection insulin regimen (MDI) represents the most intensive insulin regimen used in the management of people with type 2 diabetes (PwT2D). Its efficacy regarding glycaemic control is counterbalanced by the increased risk of hypoglycaemia, frequently observed tendency to weight gain and necessity for frequent glucose monitoring. Recent introduction of novel antidiabetic medications with pleiotropic effects reaching far beyond the reduction of glycaemia (HbA1c), such as the glucagon-like peptide 1 receptor agonist (GLP-1 RA), has significantly widened the therapeutic options available for management of T2D. Consequently, there is currently asubstantial number of PwT2D for whom the MDI regimen was initiated at a time when no other options were available. Yet, in present times, these individuals could benefit from simplified insulin regimens ideally taking advantage of the beneficial effects of the novel classes of antidiabetic medications. iGlarLixi (Suliqua®) is a once-daily fixed-ratio combination of basal insulin analogue glargine 100U/ml and a GLP-1 RA lixisenatide. Insulin therapy DE-intensificAtion with iglarLixi (IDEAL) is a six-centre, open-label, parallel-group, active comparator, phase IV randomised controlled trial with a 24-week active treatment period examining the efficacy and safety of MDI regimen de-intensification with once-daily administration of iGlarLixi versus MDI regimen continuation in PwT2D on a backgroud therapy with metformin ± sodium-glucose cotransporter 2 inhibitor. The primary objective is to compare the effects of MDI therapy de-intensification with iGlarLixi versus MDI regimen continuation regarding glycaemic control (HbA1c). Secondary objectives include detailed evaluation of the effects of MDI regimen de-intensification with iGlarLixi on glycaemic control using standardised continuous glucose monitoring (CGM) metrics and self-monitoring of plasma glucose. Furthermore, body weight and body composition analysis, quality of life and safety profile are evaluated. ClinicalTrials.gov, identifier NCT04945070.

Effect of active static stretching on glycemia in type 2 diabetes

Background: Type 2 diabetes Mellitus (T2DM) is a chronic disease whose prevalence is increasing worldwide. It is characterized by insulin resistance in insulin-dependent tissues (e.g. skeletal muscle, adipose tissue). Despite new evidence that stretching may aid in glycemic control, this form of physical exercise remains underutilized in the therapy of T2DM. Objective: The objective of this study was to evaluate the effects of active static stretching on the glycemia of individuals with T2DM. Methods: Twenty-nine volunteers participated in the study, divided into 3 randomly assigned groups: 30-second stretching group (GA30) with 10 participants; 45-second stretching group (GA45) with 10 participants; control group (CG) with 9 participants. Results: Analysis of the intervention groups versus the control group showed that the intervention groups GA30 and GA45 had a significant milligrams per deciliter (mg/dl) reduction in glycemia compared to the control group (control Δ-7.9mg/dl, GA30 Δ12.7mg/dl and GA45 Δ18.5mg/dl &gt;0.001) and between intervention groups (GA30 and control Δ 20.5mg/dl, P 0.002), GA45 and control (Δ 26.4mg/dl, P 0.001). There was no difference between the intervention groups. The results suggest that, regardless of the application time, active static stretching reduces glycemia in individuals with T2DM. In an analysis divided into 4 stages (1st and 2nd weeks, 3rd and 4th weeks, 5th and 6th weeks, and 7th and 8th weeks), the results obtained from the glycemic difference before and after each two weeks were as follows: GA30 pre and post (1st ≠ 17.4 mg/dl, 2nd ≠ 5.8 mg/dl, 3rd ≠ 14.5 mg/dl, and 4th ≠ 8.9 mg/dl), GA45 pre and post (1st ≠ 18.1 mg/dl, 2nd ≠ 17.0 mg/dl, 3rd ≠ 19.2 mg/dl, and 4th ≠ 20.0 mg/dl), and CG pre and post (1st ≠ -10.4 mg/dl, 2nd ≠ -3.7 mg/dl, 3rd ≠ -11.4 mg/dl, and 4th ≠ -11.7 mg/dl). Conclusion: This interaction between the two-factor period (Group and Period) did not have a significant effect. Finally, a descriptive analysis of pre- and post-intervention glucose behavior showed the variability of glycemia during the period. Thus, active static stretching significantly reduces acute and chronic glycemia in individuals with T2DM compared to control.

Diabetes in spotlight: current knowledge and perspectives of photobiomodulation utilization.

Diabetes is a global health concern characterized by chronic hyperglycemia resulting from insulinopenia and/or insulin resistance. The rising prevalence of diabetes and its associated complications (ulcers, periodontitis, healing of bone defect, neuropathy, retinopathy, cardiopathy and nephropathy) necessitate innovative therapeutic approaches. Photobiomodulation (PBM), involves exposing tissues and cells to low-energy light radiation, leading to biological effects, largely via mitochondrial activation. This review evaluates preclinical and clinical studies exploring the potential of PBM in diabetes and its complications, as well all clinical trials, both planned and completed, available on ClinicalTrials database. This review highlights the variability in PBM parameters across studies, hindering consensus on optimal protocols. Standardization of treatment parameters and rigorous clinical trials are needed to unlock PBM's full therapeutic potential. 87 clinical trials were identified that investigated PBM in diabetes mellitus (with 5,837 patients planned to be treated with PBM). Clinical trials assessing PBM effects on diabetic neuropathy revealed pain reduction and potential quality of life improvement. Studies focusing on wound healing indicated encouraging results, with PBM enhancing angiogenesis, fibroblast proliferation, and collagen density. PBM's impact on diabetic retinopathy remains inconclusive however, requiring further investigation. In glycemic control, PBM exhibits positive effects on metabolic parameters, including glucose tolerance and insulin resistance. Clinical studies have reported PBM-induced reductions in fasting and postprandial glycemia without an increased hypoglycemic risk. This impact of PBM may be related to its effects on the beta cells and islets in the pancreas. Notwithstanding challenges, PBM emerges as a promising adjunctive therapy for managing diabetic neuropathy, wound healing, and glycemic control. Further investigation into its impact on diabetic retinopathy and muscle recovery is warranted.

Effect of renal replacement therapy on glycaemic variability and indices of carbohydrate metabolism in patients with diabetes mellitus

Background. Patients with diabetes mellitus (DM) on renal replacement therapy (RRT) have high glycaemia variability (GV), the severity of which may depend on the dialysis method.The aim: To study GV in patients with type 1 diabetes and type 2 diabetes (on baseline-bolus insulin therapy) receiving RRT with programmed hemodialysis (PHD) and continuous ambulatory peritoneal dialysis (CAPD).Patients and Methods: Twenty-seven patients with terminal chronic renal failure and DM receiving RRT from July 2022 to March 2023 were studied. Patients underwent flash glucose monitoring (FGM) using FreeStyle Librе portable system with further evaluation of GV parameters and indices, median days of measurement – 14.Results. In the total group, 7 patients (23,3 %) had TIR &gt; 70 %, mean TIR value was 56,3 %±22,0 %, 66,7 % of patients had CV &gt; 36 %, mean CV value was 38,5 %±9,6 %. All indices of GV (MAGE, LBGI, HBGI, M-value, J-index, Conga, LI) exceeded the reference values. When comparing GV indices in patients on PHD and CAPD, it was revealed that LBGI in PHD group was 10,1±5,71 vs CAPD – 5,58±4,22, p=0,025. The critical point of glucose reduction on PHD was the fourth hour from the beginning of the procedure (57.1 % of patients had glycemia &lt; 3.9 mmol/l). Higher median glucose values were found in the first three days of FGM compared to the last three days in both PHD group (p=0.002) and CAPD group (p=0.022).Conclusions. Patients with diabetes on RRT have high GV, low percentage of achieving TIR due to high risk of hypoglycemic conditions in patients on PHD. The critical point of glycaemia reduction is fourth hour after the start of the PHD session. Patients on CAPD have a lower risk of hypoglycemia. FGM improves glycaemic control.

Impact of Glucagon-Like Peptide1 Agonist Deprescription in Type2 Diabetes in a Real-World Setting: A Propensity Score Matched Cohort Study.

Glucagon-like peptide1 receptor agonists (GLP-1) elicit substantial reductions in glycemia and body weight in people with type2 diabetes (T2D) and obesity, but existing data suggest the therapy must be continued indefinitely to maintain clinical improvements. Given the high cost and poor real-world persistence of GLP-1, an effective therapy that enables deprescription with sustained clinical improvements would be beneficial. Thus, the purpose of this real-world study was to assess the effect of GLP-1 deprescription on glycemia and body weight following co-therapy with carbohydrate restricted nutrition therapy (CRNT) supported via telemedicine in a continuous remote care model. A retrospective, propensity score matched cohort study among patients with T2D at a telemedicine clinic was conducted. Patients in whom GLP-1 were deprescribed (DeRx; n = 154) were matched 1:1 with patients in whom GLP-1 were continued (Rx). HbA1c and body weight at enrollment in clinic (pre-CRNT), at date of deprescription or index date (derx/ID), and at 6 and 12months (m) post-derx/ID were utilized in this study. No regression in weight was observed following deprescription with > 70% maintaining ≥ 5% weight loss 12m post-derx/ID. HbA1c rose 6m and 12m post-derx/ID in both DeRx and Rx cohorts, but most patients maintained HbA1c < 6.5%. HbA1c and body weight measured 6m and 12m following derx/ID did not significantly differ between cohorts and were improved at derx/ID and at follow-up intervals compared to pre-CRNT. These results demonstrate the potential for an alternate therapy, such as CRNT supported via telemedicine, to enable maintenance of weight loss and glycemia below therapeutic targets following discontinuation of GLP-1 therapy.

Efficacy and safety of tirzepatide in people with type 2 diabetes by baseline body mass index: An exploratory subgroup analysis of SURPASS-AP-Combo.

To assess the efficacy and safety of tirzepatide versus insulin glargine in people with type 2 diabetes (T2D) by baseline body mass index (BMI). Participants with T2D from the Phase 3 SURPASS-AP-Combo trial (NCT04093752) were categorized into three BMI subgroups (normal weight [<25 kg/m2 ], overweight [≥25 and <30 kg/m2 ], and obese [≥30 kg/m2 ]) according to World Health Organization criteria. Exploratory outcomes including glycaemic control, body weight, cardiometabolic risk, and safety were compared among three tirzepatide doses (5, 10 or 15 mg) and insulin glargine. Of 907 participants, 235 (25.9%) had a BMI <25 kg/m2 , 458 (50.5%) a BMI ≥25 to <30 kg/m2 , and 214 (23.6%) a BMI ≥30 kg/m2 at baseline. At Week 40, all tirzepatide doses led to a greater reduction in mean glycated haemoglobin (HbA1c; -2.0% to -2.8% vs. -0.8% to -1.0%, respectively) and percent change in body weight (-5.5% to -10.8% vs. 1.0% to 2.5%, respectively) versus insulin glargine, across the BMI subgroups. Compared with insulin glargine, a higher proportion of tirzepatide-treated participants achieved treatment goals for HbA1c and body weight reduction. Improvements in other cardiometabolic indicators were also observed with tirzepatide across all the BMI subgroups. The safety profile of tirzepatide was similar across all subgroups by BMI. The most frequent adverse events with tirzepatide were gastrointestinal-related events and decreased appetite, with relatively few events leading to treatment discontinuation. In participants with T2D, regardless of baseline BMI, treatment with tirzepatide resulted in statistically significant and clinically meaningful glycaemic reductions and body weight reductions compared with insulin glargine, with a safety profile consistent with previous reports.

Stimulation of insulin secretion induced by low 4-cresol dose involves the RPS6KA3 signalling pathway.

4-cresol (4-methylphenol, p-cresol) is a xenobiotic substance negatively correlated with type 2 diabetes and associated with health improvement in preclinical models of diabetes. We aimed at refining our understanding of the physiological role of this metabolite and identifying potential signalling mechanisms. Functional studies revealed that 4-cresol does not deteriorate insulin sensitivity in human primary adipocytes and exhibits an additive effect to that of insulin on insulin sensitivity in mouse C2C12 myoblasts. Experiments in mouse isolated islets showed that 4-cresol potentiates glucose induced insulin secretion. We demonstrated the absence of off target effects of 4-cresol on a panel of 44 pharmacological compounds. Screening large panels of 241 G protein-coupled receptors (GPCRs) and 468 kinases identified binding of 4-cresol only to TNK1, EIF2AK4 (GCN2) and RPS6KA3 (RSK2), a kinase strongly expressed in human and rat pancreatic islets. Islet expression of RPS6KA3 is reduced in spontaneously diabetic rats chronically treated with 4-cresol and Rps6ka3 deficient mice exhibit reduction in both body weight and fasting glycemia, modest improvement in glycemic control and enhanced insulin release in vivo. Similar to low doses of 4-cresol, incubation of isolated rat islets with low concentrations of the RPS6KA3 inhibitor BIX 02565 stimulates both glucose induced insulin secretion and β-cell proliferation. These results provide further information on the role of low 4-cresol doses in the regulation of insulin secretion.

Tratamento de diabetes mellitus tipo 2 em um sagui-de-orelha-preta (Callithrix penicillata)

ABSTRACT: Type-2 diabetes mellitus (T2DM) is characterized by defects in insulin secretion and combined peripheral resistance to the hormone. Several non-human primates (NHP) species develop T2DM, mainly captive animals with reduced physical activity and incorrect feeding. This case report describes the T2DM treatment of a black-eared marmoset (Callithrix penicillata) by diet reformulation and metformin oral administration. An adult female was diagnosed with T2DM after hyperglycemia and high serum fructosamine associated with glycosuria and obesity. Metformin hydrochloride (125mg/animal, orally, q24h) associated with feeding intervention was started. After 26 days, a significant reduction in weight, glycemia, and serum fructosamine could be observed, showing satisfactory results for the adopted therapy. Metformin is considered a safe drug for T2DM treatment due to its low hypoglycemia risk. The new diet consisted of sweet potato, squash, and varied fruits offered twice daily. In addition, thawed-mice newborns, egg whites, and small portions of pelleted primate food. In the present report, metformin use, associated with a low glycemic index diet, was effective in treating this particular marmoset and may present a potential for T2DM treatment in other NHPs.

Advantages of glucagon-like peptide agonists in the light of prevention of cardiovascular and renal complications

Glucagon-like peptide-1 receptor agonists (arGPP-1) have proven their advantages in persistent reduction of glycemia and HbA1c and achieving targeted control in patients with type 2 diabetes mellitus (DM2) as monotherapy or in combination with other medications. These drugs are also highly effective in reducing body weight for both patients with and without DM2.The research results indicate the potential of arGPP-1 in reducing cardiovascular events, especially in patients with pre-existing atherosclerotic diseases. Although with a low risk of cardiovascular disease, such effects may be less obvious.The presence of side effects, especially from the gastrointestinal tract (GI tract), the high cost and low availability of drugs may be a limitation for their use. In addition, the advantages in relation to the possible prevention of late complications of DM2 within the group are heterogeneous, if the patient has risk factors, drugs with proven effects on cardiovascular and renal outcomes may have advantages. Thus, in some cases, patients may need to change the drug within this class. At the same time, it is important to make a smooth transition between drugs to optimize the treatment of diabetes mellitus and minimize side effects.

Impact of short-term exercise training on QT dispersion and double product in diabetic patients after surgical aortic valve replacement

Abstract Background QT dispersion (QTd) represents the heterogeneity in the repolarization of the ventricular myocardium and electrical instability of the myocardium, reflecting the increased tendency towards ventricular arrhythmias. Abnormally high QTd has been correlated with risk of cardiac death. Purpose The aim of this study was to establish the influence of short-term exercise training on QT dispersion and double product (DP), in diabetic patients after surgical aortic valve replacement (SAVR). Methods The study involved 147 patients after SAVR, in the sinus rhythm without AV blocks or branch blocks. Average age of patients was 59.3 years. 45 patients were with diabetes mellitus, and 102 were without diabetes. Patients were similar as to age and baseline stress test duration. In all subjects clinical examination, standard ECG and exercise test on treadmill according to Bruce protocol, were performed and after that patients were included in program of physical training for three weeks. Patients were instructed to follow a training program using the bicycle ergometer (10 min, 2 times a day), gymnastic exercises and walking. The patients continued to take the same medicaments in same doses. From standard ECG corrected QT dispersion (QTdc) was calculated. Results Before starting with the program of physical training, patients with diabetes had significantly higher values of QTdc (83.4 ± 15.3 vs 74.6 ± 16.9 ms; p&amp;lt;0.005) in comparison to those without diabetes. After three weeks, significant reduction of QTdc was found (from 83.4 ± 15.3 to 77.3 ± 15.4 ms; p&amp;lt;0.02 in patients with diabetes and from 74.6 ± 16.8 to 68.7 ± 17.1 ms; p&amp;lt;0.005 in patients without diabetes). After three weeks, significant reduction of DP was found (from 11763.8 ± 779.9 to 11314.8 ± 635.8 beat/min x mmHg; p&amp;lt;0.005 in patients with diabetes and from 114376.4 ± 792.3 to 10034.2 ± 521.3 beat/min x mmHg; p&amp;lt;0.001 in patients without diabetes). In diabetic patients, after program of physical training, significant reduction of glycemia was found (from 7.0 ± 2.3 to 5.9 ± 1.5 mmol/L; p&amp;lt;0.005), of total cholesterol from 5.2 ± 1.3 to 4.6 ± 1.1 mmol/L (p&amp;lt;0.025), of LDL cholesterol from 3.2 ± 0.8 to 2.8 ± 0.6 mmol/L (p&amp;lt;0.05). After three weeks, both groups of patients in the exercise test reached a significantly longer time (p&amp;lt;0.001). Conclusions The study showed that patients with diabetes have a higher value QTdc, probably due to diffuse interstitial fibrosis. Short-term exercise training has favourable effects on QT dispersion and double product in patients after SAVR. In patients without diabetes physical training had more favourable effects on the followed parameters. Physical training led to the significant decrease of myocardial oxygen uptake at rest and probably decreased the possibility of arrhythmia events.

Analysis of molecular mechanisms of the development of experimental diabetes in Wistar rats under conditions of intermittent hypoxia

There is strong evidence that hypoxic training, within the context of diabetes, constitutes a specialized form of exercise performed under conditions of intermittent hypoxia. This approach holds promise for effectively managing and enhancing diabetes outcomes, as it has the potential to influence metabolism and physiological processes within the body significantly. The key elements of hypoxic training in diabetes encompass activities geared toward activating metabolic pathways, enhancing mitochondrial function, and regulating blood glucose levels. Such interventions can potentially lead to improvements in insulin resistance, a reduction in glycemia, and an overall enhancement of cardiorespiratory function. Hypoxic training achieves these benefits by heightening insulin sensitivity and reducing blood glucose levels, which can be particularly advantageous for individuals with diabetes. The aim of the work is to determine changes in the expression of genes associated with the course of diabetes under conditions of exposure to intermittent hypoxia in pancreatic tissue samples of Wistar rats. Materials and methods. Analysis of gene expression was used by the polymerase chain reaction method with reverse transcription in real-time using the RT2 Profiler™ PCR Array Rat Diabetes kit (QIAGEN, Germany), where the pancreas of experimental animals was studied. Results. According to the results of the PCR study of animals with experimental diabetes and the influence of hypoxic training on its course, the activity of the studied genes can be divided as follows: genes with low expression compared to the control group of animals, where ∆∆Cт &lt;30 (Ace; Cd28; Ctla4; Dusp4 ; Enpp1; Foxp3; G6pc; Gcgr; Glp1r; Gpd1; Gsk3b; Hmox1; Ide; Ikbkb; Il10; Il6; Ins1; Nfkb1; Nkx2-1; Parp1; Pdx1; Pik3cd; Pik3r1; Ppargc1a; Ptpn1; Rab4a; Retn; Slc14a2 ; Snap25; Sod2; Stx4; Stxbp1; Stxbp2; Tnf; Tnfrsf1a; Tnfrsf1b; Ucp2; Vamp2; Vegfa); genes in which no significant changes were detected in the samples in relation to the control group (Acly; Adra1a; Adrb3; Agt; Akt2; Aqp2; Ccl5; Ccr2; Ceacam1; Cebpa; Dpp4; Fbp1; Foxc2; Foxg1; Gcg; Gck; Hnf1b; Hnf4a ; Icam1; Ifng; Igfbp5; Il12b; Il4r; Inppl1; Irs1; Irs2; Mapk14; Mapk8; Neurod1; Nos3; Nrf1; Nsf; Ppara; Pparg; Pygl; Sell; Serpine1; Slc2a4; Snap23; Srebf1; Stxbp4; Tgfb1; Trib3 ; Vamp3; Vapa); there are no genes with high expression compared to the control group. Conclusions. The Nkx2-1 genes, Pik3r1, and Slc14a2 in rats subjected to experimental diabetes displayed notably reduced protein expression activity. Hypoxic training demonstrated an impact on mitigating the expression of the Nkx2-1 protein, which suggests that it might affect the mitochondrial muscle respiratory chain, modulate insulin signaling, and potentially rectify molecular deficiencies associated with diabetic nephropathy. Expression of Dpp4 genes, Gck, Ifng, Mapk8, Nsf and Sell in rats with experimental diabetes and the effect of hypoxic training on it were reduced to the level of control (intact) rats. As a result of the normalization of Dpp4 gene expression, Gck, Ifng, Mapk8, Nsf and Sell may be the influence of the effects of hypoxic training on molecular mechanisms of regulation of hormones and signals related to metabolism and the endocrine system, effects on the immune system and inflammatory processes, as well as insulin resistance.

Chronic supplementation of noni in diabetic type 1-STZ rats: effects on glycemic levels, kidney toxicity and exercise performance

Noni is a fruit with potential medicinal use preventing elevated blood glucose levels in diabetes mellitus. Its effects have been attributed to an antioxidant property in several other diseases. However, the effects of noni-chronic supplementation on exercise performance in the presence of diabetes conditions are not known. Thirty-two male Wistar rats were used to verify the effects of chronic noni (Morinda citrifolia L) juice administration on glycemia, triglyceride levels, and its relation to physical performance. In addition, it was verified if chronic noni supplementation is safe for clinical use through kidney morphology analysis. In half of the rats, diabetes mellitus (DM) was induced with STZ. All rats were submitted to an incremental workload running test (IWT) until fatigued so that oxygen consumption and performance indexes (exercise time to fatigue and workload) could be analyzed before noni administration. Then, the control and DM groups received a placebo (saline solution) or noni juice (dilution 2:1) at a dose of 2 mL/kg once a day for 60 days. The result was four groups: control + placebo (CP), control + noni (CN), DM + placebo (DMP), and DM + noni (DMN). Our dose was based on in previous study by Nayak et al. (2011) that observed a significant reduction in glycemia with 2 ml/kg of the noni juice without any toxicity effect cited. Groups were then given a third IWT to verify the effect of the noni juice on exercise performance (exercise time to fatigue, workload, maximal oxygen consumption) and glycemia. Twenty-four hours after the third test, all animals were euthanized and blood and kidneys were removed for posterior analysis. The DM induction with STZ impaired the performance by 39%. Noni administration improved the time to fatigue and workload in DM rats beyond reducing hyperglycemia. These results could be associated with an improved energy efficiency promoted by noni ingestion, since the oxygen consumption was not different between the groups, although the exercise was longer in animals with noni ingestion. Our results provided evidence that chronic noni administration causes kidney damage since increased Bowman’s space area in the control rats, suggesting glomerular hyperfiltration at the same magnitude as the non-treated DM group.In conclusion, chronic noni ingestion promoted glycemic control and improved the performance in DM rats but caused kidney toxicity.

Diagnosis and treatment of metabolic-associated fatty liver disease in patients with type 2 diabetes mellitus. Review

Metabolic‑associated fatty liver disease (MAFLD) is a new clinical definition of fatty liver disease that changes the definition of non‑alcoholic fatty liver disease (NAFLD) from a disease of exclusion to a disease of inclusion, in which the main pathogenic processes originate from metabolic dysfunction, primarily in type 2 diabetes mellitus (T2DM) and obesity. In recent years, MAFLD has become an epidemic and is closely associated with T2DM and a significant synergistic increase in the risk of cardiovascular disease. The presence of MAFLD significantly increases the risk of T2DM development, and the risk of new onset of T2DM in patients with MAFLD doubles. When managing patients with MAFLD and T2DM, the presence of fibrous nonalcoholic steatohepatitis (NASH) should be actively detected, for which non‑invasive indicators should first be used, such as FIB‑4 and FNI, which are available at the level of primary care. Despite evidence of utility in improving diagnosis, the effectiveness of many of the above non‑invasive tests for detecting fibrosis, particularly in unselected populations with advanced fibrosis, is low and generally remains uncertain at the primary care level. Modifications of lifestyle and diet have traditionally been considered the best therapeutic option for MAFLD in T2DM, with weight loss of ≥7% significantly improving steatosis, leading to reductions in NASH activity and glycemia. At the same time, only 40% of patients achieve this goal and reduce the activity of steatohepatitis, emphasizing the difficulty in treating MAFLD only by lifestyle changes. Nevertheless, mandatory dietary and lifestyle modification should still be recommended for patients with MAFLD, along with antidiabetic drugs that can reduce liver enzyme activity, inflammation, and fibrosis, such as PPARγ inhibitors, SGLT‑2i, GLP‑1 RA, as well as dual GIP and GLP‑1 RA agonists.&#x0D;

A genetically supported drug repurposing pipeline for diabetes treatment using electronic health records.

The identification of new uses for existing drug therapies has the potential to identify treatments for comorbid conditions that have the added benefit of glycemic control while also providing a rapid, low-cost approach to drug (re)discovery. We developed and tested a genetically-informed drug-repurposing pipeline for diabetes management. This approach mapped genetically-predicted gene expression signals from the largest genome-wide association study for type 2 diabetes mellitus to drug targets using publicly available databases to identify drug-gene pairs. These drug-gene pairs were then validated using a two-step approach: 1) a self-controlled case-series (SCCS) using electronic health records from a discovery and replication population, and 2) Mendelian randomization (MR). After filtering on sample size, 20 candidate drug-gene pairs were validated and various medications demonstrated evidence of glycemic regulation including two anti-hypertensive classes: angiotensin-converting enzyme inhibitors as well as calcium channel blockers (CCBs). The CCBs demonstrated the strongest evidence of glycemic reduction in both validation approaches (SCCS HbA1c and glucose reduction:-0.11%, p=0.01 and-0.85mg/dL, p=0.02, respectively; MR: OR=0.84, 95% CI=0.81, 0.87, p=5.0 x 10-25). Our results support CCBs as a strong candidate medication for blood glucose reduction in addition to cardiovascular disease reduction. Further, these results support the adaptation of this approach for use in future drug-repurposing efforts for other conditions. National Institutes of Health, Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK Medical Research Council, American Heart Association, and Department of Veterans Affairs (VA) Informatics and Computing Infrastructure and VA Cooperative Studies Program.

Antihyperglycemic and antihyperlipidemic effects of Cymbopogon citratus leaves in dexamethasone-induced diabetic rats

Background: In sub-Saharan Africa, especially in Cameroon, different parts of Cymbopogon citrarus (C. citratus) are prescribed as remedies for diabetes mellitus and dyslipidemia. This study was designed to investigate the effects of hydroalcoholic extract of C. citratus (HACC) leaves in dexamethasone-induced-diabetic (Dex-db) rats. Materials and Methods: The HACC was obtained by decoction for 15 min by mixing 250 g of dry powder of the leaves of C. citratus by completing the total volume to 1L with a hydroalcoholic solution (water-ethanol, 30:70). After cooling to room temperature and filtration using Whatman No. 4 filter paper, the extract was concentrated using a rotary evaporator at 45 °C. Moderate diabetes was induced by daily subcutaneous injection of dexamethasone (5 mg/kg) once daily for 7 days. On the 8th day, the animals which have a blood glucose level greater than 120 mg/dL were selected and randomized into 5 groups of 5 animals each who received the different treatments for two weeks as follows: two negative control groups, negative normal control (NNC) and negative dexamethasone control (NDC) received only vehicle (distilled water); one positive control group received glibenclamide (5 mg/kg) and two groups received HACC at doses of 50 and 100 mg/kg respectively. On the other hand, compared to the NDC group, we observed a significant (P&lt;0.001) dose-response after 14 days of treatment a decrease in serum concentrations of TC, LDLc, and AI, and an increase in HDLc. A highly significant decrease (P&lt;0.001) was also observed in serum TG concentration but with a more pronounced action at the lowest dose of HACC (50 mg/kg). Results: After two weeks of administration of the HACC, we observed during the oral glucose tolerance test (OGTT) a highly significant rate of reduction in glycemia (%) at the two doses tested (50 and 100 mg/kg) compared to the NNC group (P&lt;0.001) 2 hours after glucose load, no significant difference was observed (P&gt;0.05). With regard to the serum lipid profile (total cholesterol (TC), HDL cholesterol (HDLc), triglycerides (TG), LDL cholesterol (LDLc) and atherogenicity index (AI)), after 14 days of administration of the various treatments, with the exception of the TC which decreased significantly (P&lt;0.001), no significant difference (P&gt;0.05) was observed on the other parameters in the animals having received the HACC only at the dose of 100 mg/kg compared to the NNC group. Conclusion: This finding suggests that the leaves of C. citratus have a highly significant antihyperglycemic and antihyperlipidemic activity in diabetic rats by preventing the postprandial glycemia peak and by readjusting the lipid profile, in particular by lowering serum LDL-cholesterol, triglycerides and the atherogenicity index.

124-OR: Effects of Dapagliflozin Therapy on Renal Hemodynamics in Type 2 Diabetes Patients

Aim: To investigate the renal hemodynamic effects of SGLT-2i therapy in patients with type 2 diabetes [T2D]. Design &amp; Methods: We recruited 24 drug naïve T2D, not receiving ACEi/ARBs. GFR [&amp;gt;100ml/min/1.73m2] was measured with Iohexol clearance and renal plasma (blood) flow [RP(B)F] with PAH clearance divided by (1-Hct). Mean arterial pressure [MAP] and renal vascular resistance [RVR] were determined before and 4 months after dapagliflozin 10mg/day (DAPA, n=12); results were compared to T2D receiving metformin±glipizide to achieve similar glycemic reduction (CONTROL, n=12). Results: HbA1c decreased equally in DAPA (8.2±0.2 to 7.1±0.2%) and CONTROL (8.4±0.3 to 7.2±0.1%); body weight decreased in DAPA (89.9±4.0 to 86.2±4.2 kg) and rose in CONTROL (86.5±6.2 to 88.9±5.5 kg). GFR [ml/min/1.73m2] declined in DAPA (118±5 to 103±5) but not in CONTROL (113±6 vs. 114±7) (p&amp;lt;0.01). RPF [ml/min] did not change in DAPA (668±65 vs. 676±70) and CONTROL (630±40 vs. 629±39), while filtration fraction [FF] decreased in DAPA (18±1 vs. 15±1%) but not in CONTROL (18±2 vs. 18±2%) (p&amp;lt;0.05). MAP [mmHg] declined in DAPA (95.4±2.6 vs. 89.9±2.5) but not in CONTROL (90.3±4.1 vs. 90.7±2.1) (p&amp;lt;0.05). Thus, calculated RVR [mmHg/L/min] in DAPA decreased (87.0±4.2 to 77.6±2.9), whereas it did not change (86.2±3.8 to 86.4±4.2) in CONTROL after 4 months of therapy (p&amp;lt;0.05). Conclusion: Despite equal glycemic control, treatment with dapagliflozin, but not with metformin+glipizide, reduced glomerular filtration fraction and renal vascular resistance. Thus, unlike studies in T1D, our data suggest that in T2D post-glomerular vasodilatation is the predominant reno-protective mechanism of SGLT-2 inhibitors. Concomitant pre-glomerular vasoconstriction, however, cannot be excluded. Disclosure Y.Qin: None. G.Baskoy: None. C.L.Triplitt: Speaker's Bureau; Novo Nordisk. C.Solis-herrera: None. J.M.Adams: None. R.A.Defronzo: Advisory Panel; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Novo Nordisk, Research Support; AstraZeneca, Boehringer-Ingelheim, Merck &amp; Co., Inc., Speaker's Bureau; AstraZeneca. E.Cersosimo: None. Funding AstraZeneca; Texas Diabetes Institute