Reduced Blood Glucose Concentrations Research Articles

Synergistic Effect of Lactobacillus Mixtures and Lagerstroemia speciosa Leaf Extract in Reducing Obesity in High-Fat Diet-Fed Mice.

In this study, we describe the anti-obesity effects of a novel combination of Lactobacillus mixture (Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032) and leaf extract of Lagerstroemia speciosa (L. speciosa) in mice. The administration of the probiotic mixture of HY7601 and KY1032 in combination with the leaf extract of L. speciosa significantly attenuated fat tissue formation and body weight gain in mice fed a high-fat diet. The white adipose fat mass, comprising the inguinal and epididymal fat pads, was most effectively reduced when the probiotic mixture and L. speciosa leaf extract was orally administered to the mice in combination. This combination also reduced the mRNA expression of adipogenic genes (those encoding CCAAT/enhancer-binding protein alpha, peroxisome proliferator-activated receptor gamma, and fatty acid-binding protein 4) in inguinal and epididymal white adipose tissue depots and the liver. Finally, the combination of reduced blood glucose concentrations regulated the insulin resistance of high-fat diet-fed obese mice. These findings provide insight into the mechanisms underlying the effect of this combination and suggest that using Lactobacillus mixture (HY7601 and KY1032) is as safe as microbial monotherapy, but more effective at preventing obesity.

Investigating the antidiabetic properties of Apium graveolens extract and its inhibition of enzymes associated with hyperglycemia.

Apium graveolens Linn., also known as celery, is a member of the Apiaceae family and has shown promising pharmacological properties, including diabetes. Indeed, the current investigation aimed to investigate the potential inhibitory effects of A. graveolens seed aqueous extract on the digestive enzymes involved in carbohydrate metabolism and its efficiency in reducing blood sugar levels in diabetic mice induced by streptozotocin. I administered oral doses of an aqueous extract from A. graveolens seeds to both normal and diabetic animals to evaluate acute toxicity and its potential antidiabetic effects. I observed the glycemia and body weight of the animals for four weeks. In vitro tests were also done to see how the seed extract affected the activities of α-amylase and α-glucosidase. Following administration of the extract, diabetic mice showed a notable reduction in blood glucose concentration. This reduction was similar to the standard metformin treatment after two and four weeks. Moreover, A. graveolens demonstrated significant inhibitory effects on α-amylase and α-glucosidase activity, with IC50 values of 840.15±0.02 and 114.81±0.05, respectively. At 500mg/kg/day, histological analysis indicated degenerative alterations in pancreatic islet cells. These results indicate that the aqueous extract derived from the seeds of A. graveolens possesses promising antihyperglycemic properties in diabetic mice, along with notable inhibition of α-amylase and α-glucosidase activity. Further investigation is needed to characterize the active compounds present in A. graveolens seeds.

Evaluation of the Clinical Safety of the Low-Cost Warburg Therapy for the Treatment of Patients With Advanced Cancers.

Rising cancer care costs are becoming cost prohibitive for lower income people worldwide. We developed the Warburg protocol as a low-cost option for the treatment of cancer that was inspired. It was developed to exploit an Achilles heel which is a hallmark of cancer cells; the metabolic requirement for higher levels of glucose than normal cells. The purpose of this report is to assess the clinical safety and affordability of the Warburg therapy as an option for patients with advanced cancers. Between 2021 and 2023, 251 patients with advanced cancers received a total of 8542 treatments with the Warburg therapy. To restrict the supply of blood glucose to cancerous tumors, regular human insulin was administered (IV) sufficient to reduce blood glucose concentrations to hypoglycemic levels for 40-60 min. Subroutine doses of fluorouracil and cyclophosphamide were administered intravenously during this hypoglycemic period. Food or intravenous glucose was given as needed to return blood glucose to euglycemic levels after treatment. Patient symptoms, status, vitals, blood glucose, and hypoglycemic symptoms were monitored throughout treatment. Various blood parameters were measured before and after patients' course of treatment. There were no irreversible adverse reactions in advanced tumor patients of different ages and different cancer types after treatment. There was no significant fluctuation in blood glucose levels in diabetic and non-diabetic patients after treatment, and the weight, vital index and blood biochemical index of patients before and after multiple treatments exhibited little variation. Warburg therapy for the treatment of advanced tumors is clinically feasible, and safe for multiple treatments. It is inexpensive and widely applicable to different patient groups.

Structural characterization and hypoglycemic effect of polysaccharides of Polygonatum sibiricum.

Polygonatum sibiricum polysaccharide (PSP) was extracted and purified from raw material obtained from P. sibiricum. The structural features of PSP were investigated by Congo red, circular dichroism spectrum, high-performance gel permeation chromatography, scanning electron microscope, atomic force microscope, ultraviolet spectroscopy, and Fourier transform infrared spectroscopy analysis. In vitro simulations were conducted to investigate the kinetics of PSP enzyme inhibition. Moreover, a type II diabetes mouse model (T2DM) with streptozotocin-induced insulin resistance was established, and the indexes of lipid quadruple, insulin resistance index, oral glucose tolerance (OGTT), organ index, and pancreatic morphology of model mice were measured. The results showed that PSP mainly consists of monosaccharides, such as mannose, glucose, galactose, xylose, and arabinose. It also has a β-glycosidic bond of a pyranose ring and an irregular reticulated aggregated structure with a triple helix. In vitro enzyme inhibition assays revealed that PSP acts as a reversible competitive inhibitor of α-glucosidase and α-amylase. Furthermore, PSP was found to reduce insulin resistance index, increase OGTT and serum insulin levels, decrease free fatty acid content to improve lipid metabolism, and lower glycated serum protein content to enhance glucose metabolism in T2DM mice, thereby leading to a reduction in blood glucose concentration. Additionally, PSP exhibited reparative effects on the damaged liver tissue cells and pancreatic tissue in T2DM mice. The experiment results provide a preliminary basis for the therapeutic mechanism of PSP about type II diabetes and a theoretical reference for application in food and pharmaceutical development.

Therapeutic effect of the solvent fraction of hexane leaf extract of Tapinanthus bangwensis (Engl. & K. Krause) (Loranthaceae) in alloxan-induced pathology in diabetic rats

Plant-based products are gradually replacing pharmaceuticals in treating ailments, including diabetes, due to their safety, cost-effectiveness, potency, and availability. Therefore, the current study looked into the therapeutic effect of the solvent fraction of hexane leaf extract of Tapinanthus bangwensis (HEXETACF) (Loranthaceae) in alloxan-induced pathology in diabetic rats. The biochemical parameters were estimated using analytical grade kits via spectrophotometric method. The laboratory rats were distributed into group W (five rats on feed and water), group X (seven rats + 150 mg/kg alloxan solution only), group Y (seven rats + 150 mg/kg alloxan solution + 200 mg/kg BW silymarin for 21 days), and group Z (seven rats + 150 mg/kg alloxan solution + 250 mg/kg BW HEXETACF for 21 days). The results showed that HEXETACF and silymarin (SILY) reduced blood glucose concentration by 33.77% and 34.80%, respectively, after the 21st day of treatment (p < 0.05). Additionally, alkaline phosphatase (ALP) and alanine aminotransferase (ALT) activity in SILY and HEXETACF were significantly decreased compared to the diabetic group (p < 0.05), but no significant decrease in aspartate aminotransferase (AST) activity was observed between the test samples and the diabetic group. Furthermore, the test samples lowered malondialdehyde (MDA) levels, by improving glutathione, superoxide dismutase (SOD), and catalase (CAT) activity. The HEXETACF and SILY significantly decreased triglyceride levels (TG) compared to the diabetic group at p < 0.05. They also reduced low-density lipoprotein (LDL) and cholesterol levels and increased the high-density lipoprotein levels compared to the diabetic group. Additionally, no significant decrease in serum electrolytes (Na+, K+, and Cl-), urea, and creatinine (including albumin and total protein) values was observed in HEXETACF and SILY, while hematological indices increased compared to the diabetic group. Histology results revealed that the test samples had normalized glomeruli, β-islet cells, and hepatocytes. However, a trace of mild congestion was noticed in the STDG. But edemic blood congestion was observed in the diabetic group. In conclusion, the current result demonstrated that HEXETACF may be a promising antidiabetic agent that could replace mSILY.

Enrichment and purification of Torreya grandis peptides by macroporous resin and its hypoglycemic mechanism revealed by transcriptome analysis

The objective of this study was to develop an efficient strategy to prepare high-hypoglycemic efficacy Torreya grandis meal peptides with macroporous resin and investigate the underlying mechanisms through transcriptome analysis. The evaluation of adsorption and desorption abilities of Torreya grandis meal peptides (TGPs) on six different microporous resins were compared. The hypoglycemic activity of prepared TGPs was further measured in a Zebrafish diabetic model, and the underlying mechanisms were investigated through transcriptome analysis. Results showed that DA201-C exhibited the highest adsorption and desorption capacities. After DA201-C resin enrichment, the α-glucosidase inhibition and α-amylase inhibition activities of TGPs in 75% ethanol eluate (TGPs-75) both significantly increased (the IC50 values are 0.41 mg/mL and 1.08 mg/mL, respectively). The in vivo data showed that TGPs-75 remarkably reduced blood glucose concentrations to 7.8, 15.6, and 31.2 μg/mL in an high-sugar-high-fat-treated (HSHF-treated) Zebrafish diabetic model and exerted obvious hypoglycemic activity. According to transcriptome analysis, 382 genes were significantly differentially expressed (229 up-regulated and 153 down-regulated) after TGPs-75 pretreatment. The main functions of these genes are related to gluconeogenesis and insulin resistance. The findings from the present study suggested that TGPs-75 produced positive hypoglycemic efficacy and showed potential to provide a scientific basis for its further utilization as a dietary supplement or an ingredient in functional foods.

A Study of Methods for Predicting and Controlling Blood Glucose in Diabetic Patients

With the development of society and the improvement of people's living standard, diabetes has gradually become one of the world public health problems that endanger human life safety and affect the development of global economy. Type 1 diabetes is a chronic metabolic disorder that prevents the pancreas from producing insulin and requires lifelong treatment with daily insulin injections to prevent high blood sugar. The lack of insulin leads to the continuous high level of blood sugar in patients. The most important thing for patients is to monitor blood sugar changes and control blood sugar within the normal range. In this paper, a systematic literature search is carried out to study these two aspects, and key information such as the learning model adopted in the literature, the main results, the development of relevant technologies, and the limitations are summarized. From the perspective of glucose-insulin prediction model, due to the complex structure of physiological model, many parameters and difficult to identify, most of the modeling methods are data-driven. There is a great room for improvement in the research on how to mine and utilize existing models to effectively establish accurate glucose prediction models for different objects. From the perspective of control theory, after insulin injection, there is a certain delay in the reduction of blood glucose concentration, and the onset time is different depending on the injection site. The rapid development of deep learning and the increase in available data offer the possibility of addressing these challenges in the near future. When designing closed-loop glucose algorithms, consider using a variety of approaches to establish a personalized glucose control algorithm for each diabetic patient.

Comparison of 1-year outcomes between Roux-en-Y gastric bypass and sleeve gastrectomy with Roux-en-Y duodenojejunal bypass in the patients of obesity with type 2 diabetes mellitus

Objective: To compare the 1-year effects of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy with Roux-en-Y duodenal bypass (SG+RYDJB) on weight loss, remission of diabetes, and postoperative complications in patients with obesity and type 2 diabetes. Methods: A single-center retrospective cohort study was conducted at the First Affiliated Hospital of Nanjing Medical University from January 2020 to December 2020. Sixty-four patients with type 2 diabetes and body mass index (BMI) of 27.5-40.0 kg/m2 were included in this study and divided into the RYGB group (n=34) and the SG+RYDJB group (n=30). In both procedures, the biliopancreatic branch was measured 100 cm distal to the Treitz ligament, and the food branch was measured 100 cm distal to the gastric or duodenojejunal anastomosis. Patients were followed up by telephone or WeChat, a free messaging and calling app at 1, 3, 6, and 12 months postoperatively to determine their weight loss and remission of diabetes. The primary outcomes were the weight loss and reduction in blood glucose concentrations at 1 year after surgery and postoperative complications. Other postoperative changes, including body weight, BMI, percentage of total weight loss (%TWL), percentage of excess weight loss (%EWL), glycated hemoglobin A1c (HbA1c), and fasting blood glucose at 1 year after surgery were also assessed. Results: There were no significant differences in baseline data between the two groups (all P>0.05). No conversion to open surgery or death occurred in either group. Operation time was longer in the SG+RYDJB than the RYGB group (137.8±22.1 minutes vs. 80.0±24.9 minutes, t=9.779, P<0.001) and the incidence of perioperative complications was higher in the SG+RYDJB than the RYGB group (20% [6/30] vs. 2.9% [1/34], χ2=4.761, P=0.029). However, the postoperative hospital stay was similar between the two groups [3.0 (3.0, 4.3) days vs. 3.0 (4.0, 6.0) days, U=641.500, P=0.071]. Perioperative complications comprised small gastric pouch anastomotic leakage in one patient in the RYGB group and leakage (three patients) and bleeding (two patients with gastrointestinal bleeding and one with trocar site bleeding) in the SG+RYDJB group. Long-term complications were as follows. The incidence of anemia was significantly higher in the RYGB than the SG+RYDJB group (26.5% [9/34] vs. 3.3% [1/30], χ2=6.472, P=0.011). However, there were no significant differences in incidences of postoperative reflux, dumping syndrome, alopecia, diarrhea, constipation or foul-smelling flatus between the two groups (all P>0.05). Compared with 1 year before surgery, the body weights and fasting plasma glucose concentrations of patients in the SG+RYDJB and RYGB group (72.4±10.6 kg vs. 98.5±14.2 kg, respectively; 68.2±10.0 kg vs. 91.9±14.8 kg, respectively), BMI (25.2±2.9 kg/m2 vs. 34.3±4.2 kg/m2, respectively; 24.3±2.4 kg/m2 vs. 32.7±3.7 kg/m2, respectively) (5.5±1.6 vs. 10.6±3.3, respectively; 5.8±2.1 vs. 9.0±3.4, respectively); HbA1c (5.7±0.8 vs. 9.7±1.2, respectively; 9.1±1.9 vs. 5.9±0.9, respectively) were significantly lower at 1 year after surgery (all P<0.05). However, the % TWL (26.5%±6.0% vs. 25.6%±4.4%, t=0.663, P=0.510) and % EWL (109.1%±38.2% vs. 109.4%±40.3%, t=-0.026, P=0.026), rate of complete remission of diabetes at 1 year (80.0% [24/30] vs. 82.4% [28/34], χ2=0.058, P=0.810] did not differ significantly between the two groups (all P>0.05). Conclusions: Although SG+RYDJB surgery compared with RYGB is more difficult to perform, it can achieve similar weight loss and remission of diabetes and is associated with a lower incidence of anemia because of the preservation of the pylorus.

Modulation of antioxidant activities, markers of hepatic and renal dysfunctions in alloxan-induced diabetic rats by Combretum dolichopetalum

Diabetes mellitus is a metabolic dysfunction of insulin secretion exhibiting hyperglycemia with abnormalities in protein, fat and carbohydrate metabolism. The present study aimed to investigate the effect of Combretum dolichopetalum (CD) on hepatic parameters, renal indices and antioxidant markers of alloxan-induced diabetic rats. Twenty (20) male rats were used, and they were divided into four groups of five rats each. Group 1- Normal control received distilled water (non-diabetic control); Group 2- Diabetic control received distilled water; Group 3 and Group 4 are Diabetic rats treated with 200 mg/kg and 400 mg/kg of CD extract. There were significant decreases in the final body weights of Group 2 compared with Group 1 and an elevation of the body weights of Groups 3 and 4 compared with Group 2. There were significant increases in the blood glucose concentration of Group 2 compared with Group 1 and a reduction in blood glucose concentration of Groups 3 and 4 compared with Group 2. There were increases in the alanine amino transaminase (ALT), alkaline phosphatase (ALP) activities and serum total and conjugated bilirubin levels of Groups 2 and 3 compared with Group 1, but a reduction in the ALP, ALT activities and total bilirubin in Group 4. There was an elevation in the superoxide dismutase (SOD) the activity of Group 4. There were reductions in catalase activities and no change in the renal indices. The study showed ameliorating potentials on hyperglycemia, hepatoprotective activity and antioxidation effects.

Hyperglycemia alters retinoic acid catabolism in embryos exposed to a maternal diabetic milieu.

Pregestational diabetes is highly associated with increased risk of birth defects. We previously reported that the expression of Cyp26a1, the major catabolizing enzyme for controlling retinoic acid (RA) homeostasis, is significantly down-regulated in embryos of diabetic mice, thereby increasing the embryo's susceptibility to malformations caused by RA dysregulation. However, the underlying mechanism for the down-regulation of Cyp26a1 remains unclear. This study aimed to investigate whether elevated maternal blood glucose in the diabetic milieu is a critical factor for the altered Cyp26a1 expression. Streptozotozin-induced diabetic pregnant mice were treated with phlorizin (PHZ) to reduce blood glucose concentrations via induction of renal glucosuria. Embryonic Cyp26a1 expression level, RA catabolic activity and susceptibility to various RA-induced abnormalities were examined. To test the dose-dependent effect of glucose on Cyp26a1 level, early head-fold stage rat embryos of normal pregnancy were cultured in vitro with varying concentrations of D-glucose, followed by quantification of Cyp26a1 transcripts. We found that Cyp26a1 expression, which was down-regulated in diabetic pregnancy, could be normalized under reduced maternal blood glucose level, concomitant with an increase in RA catabolic activity in embryonic tissues. Such normalization could successfully reduce the susceptibility to different RA-induced malformations including caudal regression, cleft palate and renal malformations. The expression level of Cyp26a1 in the embryo was inversely correlated with D-glucose concentrations. Diabetic patients suffer from retinopathy, dermopathy, male infertility and increased cancer risk. Coincidentally, RA dysregulation is also associated with these health problems. Our results provided evidence that elevated glucose can down-regulate Cyp26a1 expression level and disturb RA homeostasis, shedding light on the possibility of affecting the health of diabetic patients via a similar mechanism.

A Pilot Crossover Study of Berberine and its Short-Term Effects on Blood Glucose Levels in Healthy Volunteers

Introduction: Different berberine preparations were evaluated for their effectiveness on lowering blood glucose in a pilot, open-label, crossover study conducted in healthy adults. Methods: Fourteen healthy volunteers of both sexes were recruited, and seven completed all treatments in the study. Study participants ingested one of three berberine preparations containing 500mg of berberine, respectively. A one week wash out period was included between treatments. A control group was included to measure the participants’ baseline response to a 75g glucose solution without any treatment. The following interventions were administered: berberine powder in hard gelatin capsules, berberine in an oil matrix encapsulated in soft-gelatin capsules, and berberine in LipoMicel® matrix encapsulated in soft-gelatin capsules. Blood glucose concentrations in each participant were monitored from pre-dose baseline, before the capsules were ingested, until up to 3 hours after the capsules were ingested. Results: LipoMicel Berberine treatment led to reduced blood glucose concentrations Area Under Curve (AUC, mean difference: 1.57; 95% CI: 0.021 – 3.12; P = 0.046; Cohen’s d = 1.53) and reduced maximum glucose concentration (Gmax, mean difference: 1.07; 95% CI 0.004 – 2.14; P = 0.049; Cohen’s d = 1.52) compared to the control group when no-treatment was given. No adverse events related to berberine treatments were reported by participants throughout the study period. Conclusions: LipoMicel Berberine was effective in lowering blood glucose levels by 12% after two 500mg doses. Berberine in other formulations may require a longer dosing regimen before blood glucose lowering effects can be demonstrated.

Combination treatment of a novel CXCR3 antagonist ACT-777991 with an anti-CD3 antibody synergistically increases persistent remission in experimental models of type 1 diabetes.

Treatment of patients with recent-onset type 1 diabetes with an anti-CD3 antibody leads to the transient stabilization of C-peptide levels in responder patients. Partial efficacy may be explained by the entry of islet-reactive T-cells spared by and/or regenerated after the anti-CD3 therapy. The CXCR3/CXCL10 axis has been proposed as a key player in the infiltration of autoreactive T cells into the pancreatic islets followed by the destruction of β cells. Combining the blockade of this axis using ACT-777991, a novel small-molecule CXCR3 antagonist, with anti-CD3 treatment may prevent further infiltration and β-cell damage and thus, preserve insulin production. The effect of anti-CD3 treatment on circulating T-cell subsets, including CXCR3 expression, in mice was evaluated by flow cytometry. Anti-CD3/ACT-777991 combination treatment was assessed in the virally induced RIP-LCMV-GP and NOD diabetes mouse models. Treatments started at disease onset. The effects on remission rate, blood glucose concentrations, insulitis, and plasma C-peptide were evaluated for the combination treatment and the respective monotherapies. Anti-CD3 treatment induced transient lymphopenia but spared circulating CXCR3+ T cells. Combination therapy in both mouse models synergistically and persistently reduced blood glucose concentrations, resulting in increased disease remission rates compared to each monotherapy. At the study end, mice in disease remission demonstrated reduced insulitis and detectable plasma C-peptide levels. When treatments were initiated in non-severely hyperglycemic NOD mice at diabetes onset, the combination treatment led to persistent disease remission in all mice. These results provide preclinical validation and rationale to investigate the combination of ACT-777991 with anti-CD3 for the treatment of patients with recent-onset diabetes.

Comparative study of the hypoglycemic and cardioprotective effects of glucagon-like peptide-1 receptors agonist exenatide, insulin and their combined use in myocardial ischemia/reperfusion injury in rats with experimental type 2 diabetes

Introduction. Insulin therapy used during acute myocardial infarction (AMI) is associated with a high risk of hypoglycemia and high glycemic variability. Therefore, the search for optimal therapeutic approaches which affect both cardioprotection and glycemic correction is relevant. It is known that agonists of glucagon-like peptide-1 (aGLP1) exhibit a protective effect on the myocardium and are involved in the normalization of carbohydrate metabolism. The combined use of аGLP1 exenatide and insulin can be more effective and safe but not insufficiently studied.The aim of this study was the comparative investigation of the effect of exenatide, insulin, and their combination on the volume of myocardial damage and the level of glycemia in the myocardial ischemia/reperfusion (I/RP) model in rats with experimental diabetes mellitus (DM2).Materials and methods. Neonatal streptozotocin diabetes was modeled in male Wistar rats on the 4th–5th day of life. At the age of 3 months, I/RP was fulfilled in animals with confirmed hyperglycemia. Experimental groups were formed depending on the time of therapy with insulin, exenatide, or their combination; before or after ischemia. Ischemia lasted for 40 min, while reperfusion was 120 min. The size of the myocardium necrosis zone and the changes in glycemia level and its variability were determined.Results. Insulin reduced glycemia, but it increased glycemic variability by 60 % and caused hypoglycemia in 32–37 % of animals. Exenatide reduced blood glucose concentration to the level of fasting glycemia and glycemic variability by 1.5–2 times compared with insulin. Exenatide given before ischemia reduced the area of necrosis by 2.2 times. The combined use of insulin and exenatide was accompanied by the absence of hypoglycemia and a decrease in the necrosis zone by 3.2 times compared to the control.Conclusion. The combined use of aGLP1exenatide and insulin in experimental conditions of I/RP+DM2 is the most effective and safe. This makes promising their joint use in patients with DM2, both at high risk of AMI and those undergoing AMI.

Celebrating a Century of Insulin Discovery: A Critical Appraisal of the Emerging Alternative Insulin Delivery Systems.

Since the discovery of insulin, continuous developments of this peptide have led to better management of diabetes mellitus, thus leading to a decrease in diabetes-related mortality. Despite these developments, we have seen an increase in diabetes cases, which has further necessitated more innovative methods for diabetes management. The subcutaneous administration of insulin remains the mainstay therapy for type 1 diabetes mellitus. However, despite the availability of insulin analogues with improved pharmacokinetics, challenges with conventional administration exist. The challenges associated with insulin injections include hypoglycaemic episodes, needle phobia, and injection-site inflammation, which all have been reported to reduce patient compliance. Ongoing research on diabetes management strives to develop therapies that provide improved glycaemic control with minimal side effects. In part, for these reasons, we have seen an increase in the search and development of alternative insulin delivery systems that are envisaged to circumvent the shortfalls associated with the conventional administration route. Several alternative drug delivery systems, such as oral, pulmonary, buccal, nasal, and transdermal, have been explored in the last century. These efforts have not been without victory, as we have seen the emergence of pulmonary (Exubera and Afrezza) and buccal insulin delivery systems licenced for therapeutic use. Despite the success seen in these two systems, their marketability and popularity have been severely compromised due to reported safety concerns. Although oral insulin delivery has always shown promise in the past decades; however, it was only limited to preclinical trials. The main challenge associated with this delivery route is poor bioavailability, which necessitates high insulin concentration to be administered. Due to recent developments, oral insulin has reached phase 3 clinical trials. It is believed that patients would prefer oral insulin as their preference is often observed for oral antidiabetics over injected ones. In the last decade, transdermal insulin has also gained interest, where delivery of insulin with a concomitant reduction in blood glucose concentration has been demonstrated in vivo. However, at present, there are no clinical studies that have reported the efficacy of transdermal insulin administration. With technological advancement, there is a potential to develop yet another insulin delivery system that would likely enter the markets. As these novel delivery systems have been found to be effective, emerging competing products should be welcome and appreciated.

Fabrication and Evaluation of a pH-Responsive Nanocomposite-Based Colonic Delivery System for Improving the Oral Efficacy of Liraglutide.

Oral administration of liraglutide, a protein drug, suffers from low intestinal absorption and instability in the gastrointestinal tract, resulting in low bioavailability. The present study aimed to develop a pH-responsive nanocomposite based-colonic delivery system to improve the oral efficacy of liraglutide. Nanocomplex (AC-Lira) between aminoclay and liraglutide was prepared by a spontaneous self-assembly. After surface charge reversal using citric acid, AC-Lira was coated with poly(methacrylic acid-co-methyl methacrylate) (1:2). The fabricated nanocomplex underwent various in vitro studies to characterize its physicochemical properties, drug release, and cellular transport. In vivo efficacy studies were also conducted using streptozotocin-induced diabetic rats. Both uncoated (AC-Lira) and coated nanocomplex (EAC-Lira) achieved high entrapment efficiency (> 90%) and showed a narrow size distribution. While exhibiting low drug release at pH 1.2 (approximately 30%), EAC-Lira achieved rapid and extensive drug release (~90%) at pH 7.4, displaying pH-dependent drug release. EAC-Lira showed significant size reduction and surface charge reversal during dissolution at pH 7.4, probably due to the removal of the outer coating layer. Furthermore, EAC-Lira was effective at protecting the entrapped proteins against enzymatic degradation. EAC-Lira also increased the membrane transport of liraglutide by 3.5 folds in Caco-2 cells. Owing to enhanced membrane transport and metabolic stability, EAC-Lira improved in vivo efficacy of orally administered liraglutide, significantly reducing blood glucose concentrations, intake of food and water, and body weight in type 2 diabetes rats. These results suggest EAC-Lira is a promising approach to improving the oral bioavailability and efficacy of liraglutide.

Metabolic markers of short and long-term exogenous DL-beta-hydroxybutyrate supplementation in episodic migraine patients: an exploratory analysis of a randomized-controlled-trial.

Background: Emerging findings propose that the pathophysiology of migraine may be associated with dysfunctional metabolic mechanisms. Recent findings suggest that migraine attacks are a response to the cerebral energy deficit, and ingestion of ketone bodies stabilizes the generation of a migraine attack. Based on these findings, ketone body supplementation is postulated as a prophylactic treatment approach to restore cerebral metabolism deficiency. Metabolic markers are unexplored after exogenous ketone body supplementation in episodic migraineurs. Therefore, the present single-arm uncontrolled explorative analysis evaluated blood ketone body and glucose concentration after short and long-term 6g exogenous DL-Mg-Ca-beta-hydroxybutyrate (DL-βHB) supplementation. Methods: The presented data are part of the MigraKet randomized-control cross-over clinical trial of 41 episodic migraineurs (Number NCT03132233). Patients were given a single dose of 6g DL-βHB. Ketone body and glucose blood concentration were assessed before intake, 20, and 40min after DL-βHB intake. Ketone body, glucose concentration and glycated hemoglobin values were evaluated after 12weeks of 18g DL-βHB ingestion (total dose), taken three times daily (6g/dose; 3x/day). Linear models explored the association between the ketone body and glucose levels. Results: Ketone body concentration increased within-group to a mean of 0.46 (0.30) mmol/L after 40min post- DL-βHB supplementation [estimate = 0.24mmol/L, CI = (0.20.0.27), p < 0.01]. This within-group increase of ketone body concentration did not change after repeated daily intake of DL-βHB supplementation over 12weeks [estimate = 0.00mmol/L, CI = (-0.03.0.04), p = 0.794]. DL-βHB intake significantly reduced blood glucose concentration within-group from a mean baseline of 4.91 (0.42) mmol/L to 4.75 (0.47) mmol/L 40min post-DL-βHB supplementation [estimate = -0.16mmol/L, CI = (-0.15, 0.03), p < 0.01]. Repeated DL-βHB supplementation for 12weeks showed no change within-group in acute ketone bodies concentration [estimate = 0.00mmol/L, CI = (-0.03.0.04), p = 0.794] and in the HbA1c value [estimate = 0.02, CI = (-0.07.0.11), p = 0.69]. Conclusion: A single dose of 6g DL-βHB significantly elevated blood ketone bodies and decreased blood glucose concentration within-group in episodic migraineurs. Long-term DL-βHB supplementation for 12weeks showed no effect within-group on acute ketone body concentration and had not impact on HbA1c. The elevation of the ketone body concentration was moderate, indicating that nutritional ketosis was not reached. Therefore, a dose higher than 6g of DL-βHB is required to reach the nutritional level of ketosis. ClinicalTrials.gov Identifier: NCT03132233.

Comparative effects of curcumin versus nano-curcumin on histological, immunohistochemical expression, histomorphometric, and biochemical changes to pancreatic beta cells and lipid profile of streptozocin induced diabetes in male Sprague–Dawley rats

Diabetes mellitus is a worldwide problem characterized by hyperglycemia as well as the damage of the microscopic structure of the beta cells of Langerhans pancreatic islets. In the present study, the histological, immunohistochemical, morphometric, and biochemical alterations to pancreatic beta cells in streptozocin (STZ)-induced diabetes were assessed in rats treated with curcumin (CU) (100 mg/kg/day) or nano-curcumin (nCU) (100 mg/kg/day) for 1 month. Twenty-four adult male Wistar albino rats were distributed into four groups: the nondiabetic control group, the diabetic untreated group, and two diabetic groups treated with CU or nCUR, respectively. Blood glucose, serum insulin levels, and lipid profile were measured. The pancreatic tissues were collected and processed into paraffin sections for histological and immunohistochemical examination, oxidative stress markers, and real-time PCR expression for pancreatic and duodenal homeobox 1 (PDX1). The insulin expression in beta cells was assessed using immunohistochemistry. Morphometrically, the percentage area of anti-insulin antibody reaction and the percentage area of islet cells were determined. STZ-induced deteriorating alteration in beta cells led to declines in the number of functioning beta cells and insulin immunoreactivity. In STZ-treated rats, CU and nCUR significantly reduced blood glucose concentration while increasing blood insulin level. It also caused a significant increase in the number of immunoreactive beta cells to the insulin expression and significant reduction of the immunoreactive beta cells to the caspase-3 expression. In conclusion, CU and nCUR could have a therapeutic role in the biochemical and microscopic changes in pancreatic beta cells in diabetes-induced rats through STZ administration with more bio-efficacy of nCUR.

Guanidinoacetic acid in human nutrition: Beyond creatine synthesis.

Guanidinoacetic acid (GAA) is a nutrient that has been used in human nutrition since the early 1950s. Recommended for its role in creatine biosynthesis, GAA demonstrated beneficial energy-boosting effects in various clinical conditions. Dietary GAA has also been suggested to trigger several creatine-independent mechanisms. Besides acting as a direct precursor of high-energy phosphagen creatine, dietary GAA is suggested to reduce blood glucose concentration by acting as an insulinotropic food compound, spare amino acid arginine for other metabolic purposes (including protein synthesis), modulate taste, and perhaps alter methylation and fat deposition in various organs including the liver. GAA as a food component can have several important metabolic roles beyond creatine biosynthesis; future studies are highly warranted to address GAA overall role in human nutrition.

Drug Promising Effect for Diabetic Mice of CARICA PAPAYA Leaves

Diabetics Mellitus is a major problem for city people worldwide. The objective of this study is finding the anti-diabetic and anti-hyper lipidaemic activity by using Carica papaya leaves. This leaves are not generally eaten but this leaves were eaten during dengue fever. The leaves extract is used for the treatment of diabetes and cancer. This leaves were collected from different place of Bangladesh and made methanolic extract then this extract was feed four groups of mice. The results showed that there was a significant (p&lt;0.001 to p&lt;0.05) reduction in blood glucose concentration (mmol/L) by the methanolic extract of C. papaya leaves at dose 100 mg/kg, 200 mg/kg and glibenclamide (used as standard) 5mg/kg body weight. C. papaya leaves extract also regulated the serum lipid profile levels significantly (p&lt;0.001) at same dose in experimental model of diabetes mellitus. The level of serum SGPT, SGOT and CRP were also seen change to the normal level notably (p&lt;0.001) by the oral administration of methanolic extract of C. papaya leaves. In conclusion this research finding indicate that the methanolic extract of Carica papaya leaves contains bioactive substances with hypoglycemic potency.

In vitro and in vivo postprandial hypoglycemic effects and comprehensive metabolite profiling of Dangjo chili pepper (Capsicum annuum L. cv. Dangjo)

The Dangjo chili pepper (DJ) has been reported to contain various compounds with α-glucosidase inhibitory activity. However, the hypoglycemic effect of DJ and the active ingredients responsible have not been fully investigated. Herein, the current study aimed to examine DJ as a novel α-glucosidase inhibitor for the prevention of hyperglycemia. The identification of metabolites and the assessment of α-glucosidase inhibitory activity was conducted in three chili pepper species. Glucose uptake inhibition by DJ ethanol extract (DJE) was evaluated in Caco-2 cells. Furthermore, an oral carbohydrate tolerance test was performed in C57BL/6 mice. A total of 18 metabolites were identified in Dangjo, Green, and Cucumber chili peppers. Among these, quercitrin was one the most abundant flavonoid in DJ. The DJ showed the highest inhibition of α-glucosidase activity against both maltose and sucrose compared to other peppers. In addition, isoorientin, quercitrin, and DJE had similar inhibitory activities for both substrates. Glucose uptake was significantly inhibited in the DJE group compared to the control group. The mice were orally administered freeze-dried DJ at 150 and 300 mg/kg body weight (B.W.), and blood glucose levels were measured. Under glucose loading, both groups had significantly reduced blood glucose concentration compared to the control group (p = 0.001). Under maltose loading, the blood glucose concentration was decreased in the 150 mg/kg B.W. group compared to the control group (p = 0.025). These results indicate that Dangjo chili pepper has the potential to function as a postprandial hypoglycemic agent by inhibiting the α-glucosidase activity.