Reduced Plasma Glucose Levels Research Articles

Effects of tryptophan-selective lipidated GLP-1 peptides on the GLP-1 receptor.

Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RAs) are widely used as antidiabetic and anti-obesity agents. Although conventional GLP-1 RAs such as liraglutide and semaglutide are acylated with fatty acids to delay their degradation by dipeptidylpeptidase-4 (DPP-4), the manufacturing process is challenging. We previously developed selectively lipidated GLP-1 peptides at their only tryptophan residue (peptide A having one 8-amino-3,6-dioxaoctanoic acid (miniPEG) linker and peptide B having three miniPEG linkers). In this study, we evaluated their effects on the GLP-1 receptor in vitro and in vivo. Both novel peptides were shown to increase cyclic adenosine monophosphate (cAMP) production and insulin secretion similarly to that by GLP-1(7-37) and liraglutide in vitro. In addition, these novel peptides lowered blood glucose levels by increasing insulin levels after oral administration of glucose and they suppressed gastrointestinal motility as effectively as liraglutide. The effects of peptide A on activation of satiety-promoting neurons in the arcuate nucleus and the consequent suppression of food intake and body weight were also similar to those of liraglutide, while the effects of peptide B were less than those of liraglutide. Under high-fat diet feeding, both long-term administration of peptide A and peptide B improved glucose tolerance and insulin sensitivity similarly to liraglutide. Thus, tryptophan-selective lipidated GLP-1 peptides are as effective as conventional GLP-1 RAs in reducing plasma glucose levels and body weight and may represent a less demanding method of manufacture of GLP-1 RAs.

Metabolic effects of medium-chain triacylglycerol consumption are preserved in obesity.

Several health-beneficial effects are associated with intake of medium-chain triacylglycerol (MCT); however, the underlying mechanisms are unknown. Furthermore, it remains uncertain whether the acute metabolic effects of MCT differ between lean individuals and individuals with obesity-and whether these effects are sustained following chronic intake. This study aimed to elucidate the postprandial physiological and metabolic effects of MCT before and after 8 days intake compared with intake of energy-matched triacylglycerol consisting of long-chain fatty acids (long-chain triacylglycerols, LCT) using a randomized cross-over design in lean individuals (n = 8) and individuals with obesity (n = 8). The study revealed that consumption of MCT increased ketogenesis and metabolic rate while lowering blood glucose levels over 5 h. The hypoglycemic action of MCT intake was accompanied by a concomitant transient increase in plasma insulin and glucagon levels. Interestingly, the effects on ketogenesis, metabolic rate, and glycemia were preserved in individuals with obesity and sustained after 8 days of daily supplementation. Lipidomic plasma analysis in lean individuals (n = 4) showed that a part of the ingested MCT bypasses the liver and enters the systemic circulation as medium-chain fatty acids (MCFAs). The findings suggest that MCFAs, along with ketone bodies from the liver, may act as signaling molecules and/or substrates in the peripheral tissues, thereby contributing to the effects of MCT intake. In summary, these findings underscore the health benefits of MCT in metabolically compromised individuals after daily supplementation. Moreover, we uncover novel aspects of MCFA biology, providing insights into how these fatty acids orchestrate physiological effects in humans.NEW & NOTEWORTHY We reveal that medium-chain triacylglycerol (MCT) intake increases postprandial ketogenesis and metabolic rate and reduces plasma glucose levels in humans. Notably, these responses persist in individuals with obesity and are maintained following chronic MCT supplementation. Some medium-chain fatty acids entered the circulation, suggesting that these, together with ketone bodies, act as signaling molecules/substrates in peripheral tissues. The findings highlight health beneficial effects of dietary MCT in individuals with obesity and reveal new insights into lipid biology.

Daidzein ameliorates peripheral neuropathy in Sprague Dawley rats.

Neuropathy is the most common disorder comprising peripheral nerve damage in diabetic patients. Prolonged hyperglycaemia and oxidative stress cause metabolic imbalance and are the key reasons for the development of diabetic neuropathy. Daidzein, a soy isoflavone possesses potent anti-hyperglycaemic and antioxidant activity. The present study aims to check the protective effect of Daidzein in diabetic neuropathy in rats. The experimental animal model involved induction of diabetes in rats by intraperitoneal injection of streptozotocin (55mg/kg). Following confirmation of diabetes, the diabetic rats were subjected to oral treatment with varying doses of Daidzein (25, 50, and 100mg/kg) and pregabalin (30mg/kg) for a duration of 4weeks, initiated 6weeks after diabetes induction. Results indicated that Daidzein treatment led to a significant reduction in plasma glucose levels and an improvement in body weight among diabetic animals. Moreover, Daidzein demonstrated a positive impact on sensory functions, as evidenced by the effect on tail withdrawal and response latency. Mechanical hyperalgesia and allodynia, common symptoms of diabetic neuropathy, were also significantly reduced with both Daidzein and pregabalin treatment. Notably, nerve conduction velocities exhibited improvement following the administration of Daidzein and pregabalin. Further investigation into the molecular mechanisms revealed that Daidzein treatment resulted in a notable enhancement of antioxidant enzyme levels and a reduction in the overexpression of NOX-4 in the sciatic nerve. This suggests that Daidzein's therapeutic effect is associated with the inhibition of oxidative stress via NOX-4. In summary, the findings of study suggests that, Daidzein treatment significantly attenuated diabetic neuropathy by inhibiting oxidative stress via NOX-4 inhibition.

Fibroblast growth factor-21 potentiates the stimulatory effects of 1,25-dihydroxyvitamin D3 on transepithelial calcium transport and TRPV6 Ca2+ channel expression

Fibroblast growth factor (FGF)-21 is a salient liver-derived endocrine regulator for metabolism of glucose and triglyceride as well as bone remodeling. Previously, certain peptides in the FGF family have been shown to modulate calcium absorption across the intestinal epithelia. Since FGF21 receptor, i.e., FGF receptor-1, is abundantly expressed in the enterocytes, there was a possibility that FGF21 might exert direct actions on the intestine. Herein, a large-scale production of recombinant FGF21 at the multi-gram level was developed in order to minimize variations among various batches. In the oral glucose tolerance test, recombinant FGF21 was found to reduce plasma glucose levels in mice fed high-fat diet. A series of experiments applying radioactive tracer 45Ca in Ussing chamber showed that FGF21 potentiated the stimulatory effect of low-dose 1,25-dihydroxyvitamin D3 [10 nM 1,25(OH)2D3] on the transepithelial calcium transport across intestinal epithelium-like Caco-2 monolayer. FGF21 + 1,25(OH)2D3 also decreased transepithelial resistance, but had no effect on epithelial potential difference or short-circuit current. Furthermore, 1,25(OH)2D3 alone upregulated the Caco-2 mRNA expression of the major apical calcium channels, i.e., transient receptor potential vanilloid subfamily member 6 (TRPV6), which was further elevated by a combination of FGF21 and 1,25(OH)2D3, consistent with the upregulated TRPV6 protein expression in enterocytes of FGF21-treated mice. However, FGF21 was without effects on the mRNA expression of voltage-gated calcium channel 1.3, calbindin-D9k, plasma membrane Ca2+-ATPase 1b, claudin-12 or claudin-15. In conclusion, FGF21 did exert a direct action on the intestinal epithelial cells by potentiating the 1,25(OH)2D3-enhanced calcium transport, presumably through the upregulation of TRPV6 expression.

Investigating the Impact of Time of Day on Glycaemia in Response to Postprandial Supramaximal Sprints in Adults With Type 1

ObjectivesIn this study, we explore the impact of postprandial exercise timing (morning vs evening) on glycemia in individuals with type 1 diabetes (T1D) during short all-out sprints on a cycle ergometer. MethodsTen healthy, physically sedentary male (n=7) and female (n=3) volunteers with T1D, 22.8±2.8 years of age, and with a diabetes duration of 9.7±5.5 years and glycated hemoglobin level of 8.6±1.2%, underwent comprehensive screening and assessment of their physical health and fitness status before study participation, under the guidance of a physician. Each participant underwent 2 postprandial exercise sessions on separate days: the first in the morning at 8:00 AM and the second in the evening at 8:00 PM, both conducted 60 minutes after a standardized meal. ResultsMorning exercise showed a less pronounced reduction in plasma glucose (PG) levels compared with evening exercise (−2.01±1.24 vs −3.56±1.6 mmol/L, p=0.03). In addition, higher cortisol levels were observed in the morning vs evening (128.59±34 vs 67.79±26 ng/mL, p<0.001). ConclusionsMorning repeated sprint exercise conducted in the postprandial state consistent with the protective effect of higher cortisol levels resulted in a smaller reduction in PG levels compared with evening exercise. This highlights the potential influence of exercise timing on glycemic responses and cortisol secretion in the management of T1D.

Effect of Acute Nutritional Ketosis on Circulating Levels of Growth Differentiation Factor 15: Findings from a Cross-Over Randomised Controlled Trial.

Exogenous supplementation with ketone beverages has been shown to reduce plasma glucose levels during acute nutritional ketosis. It remains to be investigated whether growth differentiation factor 15 (GDF-15)-an anorexigenic hormone-is involved in this process. The aim was to investigate the effect of a ketone ester beverage delivering β-hydroxybutyrate (KEβHB) on plasma levels of GDF-15, as well as assess the influence of eating behaviour on it. The study was a randomised controlled trial (registered at clinicaltrials.gov as NCT03889210). Individuals were given a KEβHB beverage or placebo in a cross-over fashion. Blood samples were collected at baseline, 30, 60, 90, 120, and 150 min after ingestion. Eating behaviour was assessed using the three-factor eating questionnaire. GDF-15 levels were not significantly different (p = 0.503) after the KEβHB beverage compared with the placebo. This finding remained consistent across the cognitive restraint, emotional eating, and uncontrolled eating domains. Changes in the anorexigenic hormone GDF-15, irrespective of eating behaviour, do not appear to play a major role in the glucose-lowering effect of exogenous ketones.

Analytical Method Development and Optimization on High Performance Liquid Chromatography for Related Substances Test of Gliclazide Drug as Active Pharmaceutical Ingredient

Diabetes mellitus, particularly Type 2 Diabetes Mellitus (T2DM), presents a significant global health challenge, necessitating continuous advancements in therapeutic strategies. Gliclazide, an oral selective inhibitor of sodium glucose co-transporter-2 (SGLT2), has emerged as a promising agent for managing T2DM by facilitating urinary glucose excretion and reducing plasma glucose levels. However, ensuring the quality and efficacy of pharmaceutical formulations remains crucial for regulatory approval and clinical effectiveness. In this study, we present the development of an improved stability-indicating Reverse Phase-High Performance Liquid Chromatography (RP-HPLC) method for the precise quantification of Gliclazide. The novel analytical method employs 0.1% Potassium Phosphate in water 0.1% Potassium Phosphate in methanol (MeOH) as the mobile phase, demonstrating enhanced sensitivity, cost-effectiveness, and reduced reliance on organic chemicals. Through rigorous validation following International Conference on Harmonisation (ICH) guidelines, the developed method exhibited superior performance in terms of retention times compared to existing methodologies. The proposed analytical approach holds promise for routine analysis of Gliclazide in both bulk and tablet formulations, offering a valuable tool for pharmaceutical quality control and clinical research in the management of T2DM.

Enhancing insulin sensitivity in type 2 diabetes mellitus using apelin-loaded small extracellular vesicles from Wharton’s jelly-derived mesenchymal stem cells: a novel therapeutic approach

BackgroundType 2 diabetes mellitus (T2DM), characterized by β-cell dysfunction and insulin resistance (IR), presents considerable treatment challenges. Apelin is an adipocyte-derived factor that shows promise in improving IR; however, it is limited by poor targeting and a short half-life. In the present study, engineered small extracellular vesicles (sEVs) derived from Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) loaded with apelin were used to address the limitations of the therapeutic application of apelin.MethodsWJ-MSCs were transduced to obtain engineered sEVs loaded with overexpressed apelin (apelin-MSC-sEVs) and the control sEVs (MSC-sEVs). T2DM mice were injected with apelin-MSC-sEVs and MSC-sEVs, and blood glucose monitoring, glucose and insulin tolerance tests, confocal microscopy, and immunocytochemical analysis were performed. IR models of 3T3-L1 adipocytes were employed to detect GLUT4 expression in each group using western blotting; the affected pathways were determined by measuring the changes in Akt and AMPK signaling and phosphorylation.ResultsUpon successful engineering, WJ-MSCs demonstrated significant overexpression of apelin. The genetic modification did not adversely impact the characteristics of sEVs, ranging from surface protein markers, morphology, to particle size, but generated apelin-overexpressed sEVs. Apelin-MSC-sEVs treatment resulted in notable enhancement of Akt and AMPK pathway activities within 3T3-L1 adipocytes and adipose tissues of T2DM mice. Furthermore, the apelin-loaded sEVs significantly reduced plasma glucose levels, increased pancreatic β-cell proliferation, improved insulin and glucose tolerance, and modulated pro-inflammatory cytokine profiles, compared to mice treated with the control sEVs.ConclusionOur study developed novel genetically engineered apelin-loaded sEVs derived from WJ-MSCs, and demonstrated their potent role in augmenting insulin sensitivity and regulating inflammatory responses, highlighting their therapeutic promise in T2DM management. The findings open new avenues for the development of clinically viable treatments for T2DM in humans using the apelin-loaded sEVs.

Impact of the timing of metformin administration on glycaemic and glucagon-like peptide-1 responses to intraduodenal glucose infusion in type 2 diabetes: a double-blind, randomised, placebo-controlled, crossover study

Aims/hypothesisMetformin 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.MethodsSixteen 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.ResultsThere 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/interpretationIn 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 registrationwww.anzctr.org.au ACTRN12621000878875FundingThe study was not funded by a specific research grant.Graphical

Opisthorchis viverrini excretory-secretory products suppress GLUT8 of cholangiocytes.

Opisthorchis viverrini infection and the subsequent bile duct cancer it induces remains a significant public health problem in Southeast Asia. Opisthorchiasis has been reported to cause reduced plasma glucose levels among infected patients. The underlying mechanism for this phenomenon is unclear. In the present study, evidence is presented to support the hypothesis that O. viverrini exploits host cholangiocyte glucose transporters (GLUTs) in a similar manner to that of rodent intestinal nematodes, to feed on unabsorbed glucose in the bile for survival. GLUT levels in a cholangiocyte H69 cell line co-cultured with excretory-secretory products of O. viverrini were examined using qPCR and immunoblotting. GLUT 8 mRNA and expressed proteins were found to be downregulated in H69 cells in the presence of O. viverrini. This suggests that O. viverrini alters glucose metabolism in cells within its vicinity by limiting transporter expression resulting in increased bile glucose that it can utilize and potentially explains the previously reported anti-insulin effect of opisthorchiasis.

Kadukkai maathirai (Siddha herbal formulation) reverses liver pathology associated with metabolic dysfunction in high fat diet-induced fatty liver disease – a preclinical study

The study explores the hepatoprotective effect of Kadukkai maathirai (KM) in high fat diet (HFD) induced nonalcoholic fatty liver disease (NAFLD) in rats. Total 54 Sprague Dawley rats were used in the study, 9 groups: Group I – IV kept as normal and test drug control and group V - NAFLD disease model- received HFD for 40 weeks. Group VI – IX received HFD for 40 weeks and then test drugs: Group VI – VIII received KM in three different doses for 45 days. Metformin (standard) was administered to Group IX for 45 days. On day 46, the blood and liver tissue were collected for analysis. KM at 36, 144mg/kg and metformin showed a significant decrease in ALP level, all three doses of KM and metformin showed a significant reduction in direct bilirubin levels. A significant improvement in HDL was observed in all doses of KM and metformin-treated groups. Oral glucose tolerance test (OGTT) findings in KM treated test groups showed significantly reduced plasma glucose levels. The KM treated groups and metformin-treated groups showed a reduction in body weight at 47th week, and significantly reduced relative liver weight when compared with the HFD group. Histopathological evaluation of KM treated groups showed normal architecture of central vein and hepatic cords. Portal triads were also generally normal in their location and pattern. No indication of fatty liver. This study confirms the ability of phytoconstituents present in KM in reversing the metabolic dysfunction and liver pathology seen in NAFLD. Further studies are required to evaluate KM as a therapeutic agent.

Apigenin ameliorates diabetic neuropathy in rats by modulating the TLR4/MyD88 signaling pathway

Objective: To determine the neuroprotective effects of apigenin against streptozotocin (STZ)-induced diabetic neuropathy (DN). Methods: To induce DN, Wistar rats (150-200 g) were administered with STZ (55 mg/kg, i.p.). Then they were randomly assigned to various groups, viz., normal, diabetic control, insulin (10 IU/kg, s.c.), apigenin (5, 10, and 20 mg/kg, p.o.), and insulin (10 IU/kg) plus apigenin (20 mg/kg, p.o.). Various behavioral, biochemical, and molecular markers [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, Toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), and nuclear factor erythroid 2-related factor 2 (Nrf2)] were assessed. Results: Apigenin (10 and 20 mg/kg, p.o.) substantially reduced plasma glucose levels, lipid profile, aspartate transaminase, alanine transaminase, glycated hemoglobin, and neural advanced glycation end products in STZ-induced DN rats (P&lt;0.05). After apigenin intervention, STZ-induced changes in food and water intake, body weight, urine output, allodynia, hyperalgesia, and insulin levels were markedly improved (P&lt;0.05). Neural antioxidant enzymes (superoxide dismutase and glutathione) and Na+K+ATPase activity were also considerably elevated (P&lt;0.05) while the level of lipid peroxidation was diminished following apigenin therapy (P&lt;0.05). Furthermore, apigenin markedly upregulated the Nrf2 mRNA level while downregulating the mRNA expressions of TNF-α and ILs and the protein expressions of TLR4 and MyD88 (P&lt;0.05). STZ-induced histological abnormalities in the sciatic nerve were also improved by apigenin treatment. Conclusions: Apigenin exerts its neuroprotective effect by modulating the inflammatory and oxidative stress pathways via regulating the TLR4-MyD88 signaling pathway.

Hidrotherapy to Reduce Plasma Glucose among Patients with Diabetes Mellitus at Rsup Fatmawati (A Case Study)

Background: Diabetes mellitus type 2 occur when there is a problem about insulin production in the body, body resistant to the insulin, or the sensitivity of body to insulin decreased. Management of diabetes mellitus type 2 is needed to prevent further complications. Hydrotherapy is a complementary therapy by using water that can reduce plasma glucose levels among patients with diabetes mellitus. Purpose: the purpose of this case study is to determine the effectiveness of hydrotherapy on reducing plasma glucose level among patients with diabetes mellitus type 2. Methods: the type of this case study is descriptive. Data collection conducted through interviews, observation, and documentation. The subjects in this study were 2 patients with diabetes mellitus type 2 from Fatmawati General Hospital. Result: after finished hydrotherapy for 3 days, the patient's plasma glucose levels decreased significantly with an average decrease in subject I was 41,3 mg/dl and subject II was 23,3 mg/dl. Conclusion: researcher recommends hydrotherapy to be carried out by patient with diabetes mellitus type 2.

Effect of Spring and Summer Seasons on Some Bio-physiological Markers in Buffaloes

Background: The purpose of this study was to ascertain the effects of the hot, dry spring and summer weather on the endocrinological and biochemical properties of buffaloes with the help of physiological as well as biochemical analysis. Methods: Like plasma glucose using GOD-POD kits, total plasma protein using Autospan kits, Blood Urea Nitrogen using MBK Urea kits DAM assay, cortisol hormone by bovine cortisol enzyme linked immunosorbent assay kit etc. Result: During the summer season, there was a significant (P less than 0.01) reduction in plasma glucose level (mg/dl), blood urea nitrogen level (mg/dl) and plasma total protein level (g/dl) in comparison to the spring season, but there was a significant (P less than 0.01) increase in plasma cortisol level in the summer in comparison to the spring season in all three districts. From the current study, it can be inferred that heat stress negatively affects the adaptability and metabolic reactions of buffalo.

LC/MS analysis of mushrooms provided new insights into dietary management of diabetes mellitus in rats.

Mushrooms possess antihyperglycemic effect on diabetic individuals due to their nonfibrous and fibrous bioactive compounds. This study aimed to reveal the effect of different types of mushrooms on plasma glucose level and gut microbiota composition in diabetic individuals. The effects of five different mushroom species (Ganoderma lucidum, GLM; Pleurotus ostreatus, POM; Pleurotus citrinopileatus, PCM; Lentinus edodes, LEM; or Hypsizigus marmoreus, HMM) on alloxan-induced diabetic rats were investigated in this study. The results indicated that LEM and HMM treatments showed lower plasma glucose levels. For the microbiota composition, ACE, Chao1, Shannon, and Simpson were significantly affected by PCM and LEM treatments (p <.05), while ACE, Shannon, and Simpson indexes were affected by HMM treatment (p <.01). Simpson index was affected in positive control (C+) and POM groups. All these four indices were lower in GLM treatment (p <.05). Dietary supplementation of mushrooms reduced plasma glucose level directly through mushrooms' bioactive compounds (agmatine, sphingosine, pyridoxine, linolenic, and alanine) and indirectly through stachyose (oligosaccharide) and gut microbiota modulation. In conclusion, LEM and HMM can be used as food additives to improve plasma glucose level and gut microbiome composition in diabetic individuals.

772-P: Combining Meal-Bolus Reduction and Exercise Announcement Eliminates the Risk of Hypoglycemia during Postprandial Exercise in People Living with Type 1 Diabetes Treated with Automated Insulin Delivery Systems

For people living with type 1 diabetes (PWT1D) post-prandial exercise remains a challenge for the maintenance of glycemic control even with automated insulin delivery systems (AID) . During the postprandial phase, elevated insulin levels, rapid changes in glucose levels with increased CGM lag time make it difficult for AID algorithms to mitigate the risk of hypoglycemia by solely relying on basal rate modulation. The main objective of this study was to assess the safety and efficacy of AID using a combination strategy of pre-meal exercise announcement and meal bolus reduction during exercise bouts performed 1- and 2-hours post-meal. Thirteen adults PWT1D chronically treated with AID (6 females; A1c = 7.9 ± 0.6%; Age= 53,5 ± 15,5 years; T1D duration= 29.0 ± 16.0 years) were included. Participants performed in a randomized crossover fashion 2 60-min exercise sessions (60% of VO2peak) , 1 (60Ex) and 2-h (120Ex) post-meal. A standardized meal was given at 8AM with a 33% insulin bolus reduction and exercise was announced to the AID algorithm (target glucose increased from 6 to 9 mmol/L) up to the end of each exercise session. Plasma glucose was collected regularly. Plasma glucose times in range (3.9-10.0 mmol/L) and above range (&amp;gt;10.0 mmol/L) from exercise onset to 90-min-post-exercise, were similar between Ex60 and Ex120 (63.7 ± 41.4% Ex60 vs. 65.9 ±24.9% Ex120, p=0.3; 36.1 ± 41.6% Ex60 vs. 34.1 ± 24.9% Ex120, p=0.4, respectively) . No hypoglycemic events (&amp;lt;3.9 mmol/L) occurred during the study. The mean reduction in plasma glucose levels were similar during exercise in both conditions (-2.6 ± 1.4 mmol/L Ex60 vs. -3.5 ± 2.2 mmol/L Ex120, p=0.2) Conclusion: combining pre-meal exercise announcement with a meal bolus reduction of 33% was effective and safe at preventing postprandial exercise hypoglycemia in PWT1D treated with AID whether exercise was performed 1 or 2-h after a meal. Disclosure M.Raffray: None. R.Rabasa-lhoret: Consultant; HLS Therapeutics Inc., Pfizer Inc., Other Relationship; Abbott Diabetes, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Janssen Pharmaceuticals, Inc., Medtronic, Merck &amp; Co., Inc., Novo Nordisk Canada Inc., Sanofi, Vertex Pharmaceuticals Incorporated, Research Support; Canadian Institutes of Health Research, Cystic Fibrosis Canada, Diabetes Canada, Fondation Francophone pour la Recherche en Diabète (FFRD) , JDRF, National Institutes of Health, Société Francophone du Diabète (SFD) , Speaker's Bureau; Canadian Medical &amp; Surgical Knowledge Translation Research Group (CMS) , CPD Network, Tandem Diabetes Care, Inc. É.Myette-côté: None. J.Molveau: None. M.Devaux: None. Z.Wu: Other Relationship; Eli Lilly and Company. Funding National Institutes of Health (A12BC345678)

Impact of Cotadutide drug on patients with type 2 diabetes mellitus: a systematic review and meta-analysis

BackgroundThe food and drug administration approved many drugs to treat diabetes mellitus, but those drugs do not have a noticeable effect on weight management. Recently, glucagon-like peptide 1 agonist known as Cotadutide serve as a potent drug in treating type 2 diabetes by reducing blood glucose levels and body weight indices. This study aimed to explore the safety and efficacy of Cotadutide as a treatment for type 2 diabetes individuals.MethodsA comprehensive literature search was done on different databases, including PubMed, Scopus, Web of Science, and Cochrane Library to capture all relevant articles using an established search strategy. The inclusion criteria were randomized controlled trials that assessed the safety and efficacy of Cotadutide versus placebo or any anti-diabetes drugs in patients with type 2 diabetes mellitus and a BMI between 22 kg/m2 and 40 kg/m2. We conducted the analysis using Revman software version 5.4.ResultsWe found 663 relevant articles. From which nine studies were included and subjected to qualitative analysis and eight for quantitative analysis. The pooled effect showed that Cotadutide was better than placebo in reducing body weight (kg) (Mean difference (MD) = 3.31, p < 0.00001), glycated hemoglobin (HbA1c) (MD = 0.68, p > 0.00001), glucose area under the plasma concentration curve (AUC [0-4 h]) (MD = 30.15, p < 0.00001), and fasting plasma glucose over time (mg/dl) (MD = 31.31, p < 0.00001).ConclusionCotadutide is safe and effective in reducing plasma glucose levels, HbA1c and body weight in individuals with type 2 diabetes.Trial registrationThe study protocol was registered on PROSPERO (CRD: CRD42021257670).

High Throughput Study for Molecular Mechanism of Metformin Pre-Diabetic Protection via Microarray Approach

Metformin is a biguanide that exhibits antidiabetic, anticarcinogenic, and anti-inflammatory properties. Despite well-known pancreatic protective effects, metformin's influence on pancreatic islet β-cell is yet considerably unknown. Protecting the functional insulin-producing β-cells in the pancreas is a key therapeutic challenge in patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM). The current study aimed to analyze the protective effects of metformin on streptozocin- induced diabetic rats in T1DM in hepatic tissues. In the present study, male Wistar rats (n=24) were randomly assigned into 2 groups (n=12 for each control and test), and metformin (100 mg/kg/day) was given for 7 weeks. Afterward, diabetes was induced by streptozocin (STZ) at a single dose of 150 mg/kg. Blood glucose was examined daily before and after STZ induction. The animals were euthanized by cervical dislocation 5 days after streptozocin injection, after which liver and pancreas were harvested from each rat. The biochemical analyses revealed that metformin resulted in significantly reduced plasma glucose levels and higher pancreatic insulin levels in the test group. Using a restrictive cut-off of at least 2-FC and an adjusted p-value (q-value) of ≤0.05, a sum of 747 genes for the metformin group were shown to be differentially regulated compared to controls (320 Down and 427 Up), by which they were obtained from the liver. Furthermore, the evidence is attained that metformin may hinder the loss of critical β-cells by reducing inflammatory and apoptosis signaling, promoting fatty acid β-oxidation, and inducing metabolism. Collectively, this study has demonstrated a decrease in blood glucose levels and a rise in insulin-levels and thus consequent prophylactic effects in metformin-given STZ-induced diabetic rats.

Angiotensin Converting Enzyme-2 Therapy Improves Liver Fibrosis and Glycemic Control in Diabetic Mice With Fatty Liver.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is frequently associated with type 2 diabetes. However, there is no specific medical therapy to treat this condition. Angiotensin‐converting enzyme 2 (ACE2) of the protective renin angiotensin system generates the antifibrotic peptide angiotensin‐(1‐7) from profibrotic angiotensin II peptide. In this study, we investigated the therapeutic potential of ACE2 in diabetic NAFLD mice fed a high‐fat (20%), high‐cholesterol (2%) diet for 40 weeks. Mice were given a single intraperitoneal injection of ACE2 using an adeno‐associated viral vector at 30 weeks of high‐fat, high‐cholesterol diet (15 weeks after induction of diabetes) and sacrificed 10 weeks later. ACE2 significantly reduced liver injury and fibrosis in diabetic NAFLD mice compared with the control vector injected mice. This was accompanied by reductions in proinflammatory cytokine expressions, hepatic stellate cell activation, and collagen 1 expression. Moreover, ACE2 therapy significantly increased islet numbers, leading to an increased insulin protein content in β‐cells and plasma insulin levels with subsequent reduction in plasma glucose levels compared with controls. Conclusion: We conclude that ACE2 gene therapy reduces liver fibrosis and hyperglycemia in diabetic NAFLD mice and has potential as a therapy for patients with NAFLD with diabetes.

Anti-diabetic effects of Protaetia brevitarsis in pancreatic islets and a murine diabetic model.

In this study, the antidiabetic efficacy of Protaetia brevitarsis in alloxan-treated pancreatic islets and db/db mice was investigated. P. brevitarsis was tested for alloxan-mediated cytotoxicity and nitric oxide production in mice pancreatic islets. The anti-diabetic effect of P. brevitarsis was also evaluated in db/db mice after 4 weeks of administration. Biochemical analysis, oral glucose tolerance test (OGTT), and pancreatic histological analysis were performed. P. brevitarsis displayed hypoglycemic activity in alloxan-treated mice pancreatic islets. Our results showed that P. brevitarsis protects pancreatic islets from cytotoxicity. Moreover, daily oral supplementation with P. brevitarsis for 4 weeks reduced plasma glucose levels without affecting body weight and food intake, elevated glucose tolerance in OGTT, improved blood lipid parameters, inhibited fat accumulation, and restored islet structure of db/db mice. The present study provided evidence for the anti‑diabetic effect of P. brevitarsis in alloxan-treated pancreatic islets and db/db mice. These results suggest that P. brevitarsis may be used as an adjunctive anti-diabetic agent or as a functional food.