Glucose-lowering Effect Research Articles

Ractopamine residues in meat might reduce the risk of type 2 diabetes.

Background: The overall prevalence of diabetes in the world has risen substantially in the past several decades, so have complications and mortalities associated with it. Aim: Prevention strategies for diabetes thus become an urgent public health need for reducing the burden of diabetes. Methods: Ractopamine, a β1/2-adrenergic receptor agonist, has been approved for use in finishing swine, cattle, and turkey in countries where meat exporting brings tremendous economic benefits. This leanness enhancer is recently found to be a full agonist at trace amine-associated receptor 1 also. A thorough literature review was performed to assess possible effects of ractopamine on glucose metabolism. Results: Activating β-adrenoceptor could lead to glucose-lowering effects independent of insulin while activation on trace amine-associated receptor 1 induces an incretin-like signaling on insulin-secreting pancreatic β-cells. Conclusion: Accordingly, it is hypothesized that long-term consuming meat containing ractopamine might lower the risk of type 2 diabetes.

Real-world experience of angiotensin receptor neprilysin inhibitor on the glucose-lowering effect

We investigated the effect of angiotensin receptor neprilysin inhibitor (ARNI) on glycemic control in Korean patients. This retrospective cohort study was conducted at a single tertiary hospital. We compared the HbA1c level reduction between the ARNI and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) in chronic heart failure patients with diabetes. We also examined whether the target HbA1c level was reached and the time to start insulin between the two groups. Over the study period, ARNI did not significantly lower the HbA1c level after adjusting confounding factors compared to ACEIs or ARBs. However, as a result of a simple comparison using Mann–Whitney U test, ARNI group showed significant decrease in HbA1c at 6, 12, and 24 months compared to ACEIs or ARBs group (p = 0.003, 0.009, and 0.026, respectively). The initiation of insulin was delayed in the ARNI group, but this difference was not significant based on the result of hazard ratio, but cumulative incidence was significantly lower in the ARNI group. In the real world, the blood glucose-control effects of ARNI were not superior to those of ACEIs or ARBs. However, long-term studies are needed as ARNI use increases to obtain more statistically significant results.

Liraglutide treatment attenuates dysfunction-related changes in the cardiac and cerebral microvasculature in streptozotocin-induced diabetic rats

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Background Diabetes mellitus (DM) induces cardiac and cerebral microvascular dysfunction via increased glycation, oxidative stress and endothelial activation. Liraglutide, a glucagon-like peptide-1 receptor analogue, inhibited the reactive oxygen species producing enzyme NOX2 and adhesion molecules in isolated endothelial cells. Here we have studied how Liraglutide affects advanced glycation, NOX expression and inflammatory status of the cardiac and cerebral microvasculature in vivo in diabetic rats. Methods DM was induced in Sprague Dawley rats (n=15) via intraperitoneal streptozotocin (STZ) injection (60 mg/kg body weight). 10 control rats remained non-diabetic. From day 9 post-STZ injection, Liraglutide (200 µg/kg bodyweight; n=7) or vehicle (n=8) was injected subcutaneously daily until termination on day 29. The advanced glycation end-product N-ε-(carboxymethyl)lysine (CML), NOX2, NOX4, ICAM-1 and VCAM-1 were subsequently analysed using immunohistochemistry and quantified to compare Liraglutide treatment to placebo. Results DM increased CML, NOX2, ICAM-1 and VCAM-1 in the intramyocardial vasculature, although not significant for NOX2. NOX4 was not significantly increased in the ventricles and absent in the atria. In the cerebral vasculature, CML, NOX2 and NOX4 were significantly increased, but not ICAM-1 and VCAM-1. Liraglutide significantly reduced the DM-associated CML accumulation and expression of NOX2, ICAM-1 and VCAM-1 in the intramyocardial, and CML, NOX2 and NOX4 in the cerebral vasculature. Liraglutide had these effects without changing blood glucose levels or body weight. Conclusions Our study implies that Liraglutide protects the cardiac and cerebral microvasculature against diabetes-induced dysfunction, independent of a blood glucose lowering effect in a type 1 diabetes rat model.

Faecal microbiota transplantation is better than probiotics for tissue regeneration of type 2 diabetes mellitus injuries in mice

Context Western diet and unhealthy lifestyle have contributed to the continued growth of type 2 diabetes mellitus (T2DM). T2DM is associated with dysbacteriosis, and studies have found that altering the gut microbiota has a positive effect on treatment. Objective In addition to hyperglycaemia, T2DM often causes damage to multiple organs. However, there are few studies on organ damage from faecal microbiota transplantation (FMT). Materials and methods T2DM mice were divided into four groups and were given phosphate buffered saline (PBS) (T2DM group), FMT (FMT group), Lactobacillus (LAB group), and Bifidobacterium (BIO group) by gavage for six weeks, respectively. Mice on a normal diet (control group) were gavaged with PBS for six weeks. Results After gavage treatment, FMT, LAB, and BIO groups were similar in lowering glucose, endotoxemia was slightly reduced, and the colonic mucus layer and liver lobules developed towards normal tissue. Surprisingly, we found that the FMT group had unique effects on islet cell regeneration, increased functional β cells, and insulin sensitivity. Discussion and conclusion Lactobacillus has the best glucose-lowering effect, but FMT has obvious advantages in β-cell regeneration, which provides new treatment ideas for tissue damage caused by T2DM.

Discordance in the reduction rate between glycated albumin and glycated hemoglobin levels in type 2 diabetes patients receiving SGLT2 inhibitors

AimsAlthough the difference in HbA1c reduction between sodium-glucose cotransporter 2 (SGLT2) inhibitors and other oral glucose-lowering agents is relatively small, SGLT2 inhibitors exhibit beneficial cardiorenal protection. This study was based on the hypothesis that changes of HbA1c in patients treated with SGLT2 inhibitors may not accurately reflect an improved glycemic profile. MethodsTwo studies were conducted: 1) a retrospective cohort study of 3039 patients administered with either an SGLT2 or a dipeptidyl peptidase-4 (DPP4) inhibitor for 12 months comparing the changes in glycated albumin (GA) and HbA1c levels and 2) a pilot study of 10 patients whose glycemic dynamics were evaluated using flash glucose monitoring at baseline and 2 months after treatment with an SGLT2 inhibitor. ResultsSGLT2 inhibitors reduced GA more markedly than HbA1c in both studies. DPP4 inhibitors decreased both GA and HbA1c to a comparable degree. The mean glucose levels and glycemic standard deviation were significantly reduced after treatment with an SGLT2 inhibitor, in concordance with GA decline, although the lowering of HbA1c was marginal. ConclusionsChanges in HbA1c levels underestimated the glucose-lowering effect and the diminished glycemic fluctuation induced by SGLT2 inhibitors. Thus, the distinct biomarker roles of GA and HbA1c should be reevaluated.

106-LB: Comparable Total Exposure of Once-Weekly Insulin Icodec between Different Subcutaneous Injection Regions

People with diabetes may inject s.c. insulin in different body regions. To address if choice of injection region affects insulin icodec exposure and glucose-lowering effect, this study compared icodec administration in different s.c. injection regions. In a randomized, open-label, three-period crossover trial, 25 individuals with T2D on basal insulin (22 males; mean±SD age 60±7 yrs, BMI 30.7±4.6 kg/m2) received single s.c. icodec doses (5.6 U/kg) in the thigh, abdomen and upper arm (9-13 weeks washout) . Blood was sampled for pharmacokinetics (PK) until 840 h (35 days) post-dose. Glucose-lowering effect was assessed at 36-60 h post-dose in an automated glucose clamp (target 135 mg/dL) . Total icodec exposure (AUC0-∞,SD) was similar after single-dose s.c. injection in the thigh, abdomen and upper arm (Table) . Maximum concentration (Cmax,SD) was higher for abdomen/upper arm vs. thigh. Extrapolation of PK profiles to steady state using a PK model showed smaller differences in Cmax,SS for abdomen/upper arm vs. thigh than after single dose. Partial glucose-lowering effect 36-60 h after single dose (AUCGIR,36-60h,SD) was comparable across injection regions (geom. mean [CV%] of 1961 [51], 2130 [52] and 2391 [40] mg/kg for thigh, abdomen and upper arm) . In conclusion, insulin icodec can be administered s.c. in the thigh, abdomen or upper arm with essentially similar exposure and glucose-lowering effect. Disclosure L. Plum-moerschel: Other Relationship; Eli Lilly and Company, Gan & Lee Pharmaceuticals, Novo Nordisk A/S. L. R. Andersen: None. S. Hansen: None. U. Hövelmann: None. P. Krawietz: None. N. R. Kristensen: Employee; Novo Nordisk. L. Lang lehrskov: Employee; Novo Nordisk A/S. H. Haahr: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. Funding Novo Nordisk

Effects of Exogenous Ketones on Blood β-OHB and Glucose: A Systematic Review and Meta-Analysis

ObjectivesExogenous ketone (monoester or salt) supplements are increasingly being employed for a variety of research purposes and marketed amongst the general public for their ability to raise blood beta-hydroxybutyrate (β-OHB). Emerging research suggests a blood glucose-lowering effect of exogenous ketones. Here, we systematically review and meta-analyze the available evidence of trials reporting on exogenous ketones and blood glucose. MethodsWe searched 6 electronic databases on December 13, 2021 for trials of any length that reported on the use of exogenous ketones compared to a placebo. We pooled raw mean differences (MD) in (i) blood β-OHB and (ii) blood glucose using random-effects models, and explored differences in the effects of ketone salts compared to ketone monoesters. Publication bias and risk of bias were examined using funnel plots and Cochrane’s risk-of-bias tool, respectively. ResultsTwenty-eight trials including a total of 332 participants met inclusion criteria. There was no evidence for publication bias. Four trials were judged to be at low risk of bias with some concern for risk of bias in the remaining trials. Compared to placebo, consumption of exogenous ketones raised blood β-OHB (MD = 1.98 mM; 95% CI: 1.52 mM, 2.45 mM; P < 0.001) and decreased blood glucose (MD = –0.47 mM; 95% CI: –0.57 mM, –0.36 mM; P < 0.001) across the post-supplementation period of up to 300 minutes. Across both analyses, significantly greater effects were found following ingestion of ketone monoesters compared to ketone salts (P < 0.001). ConclusionsConsumption of exogenous ketone supplements leads to acutely increased blood β-OHB and decreased blood glucose. Ketone monoesters exert a more potent β-OHB-raising and glucose-lowering effect as compared to ketone salts. Funding SourcesMichael Smith Foundation for Health Research (MSFHR) Scholar Award.

1379-P: Combination of FGF21 and ß3-Adrenergic Treatment in Obese Mice

An induction of lipolysis by β3-adrenergic agonist CL316,243 (CL) increases plasma free fatty acid (FFA) level resulting later in ectopic lipid accumulation in liver. The peak of FFA stimulates insulin secretion and causes acute drop of blood glucose (BG) in chow-fed mice. This glucose-lowering effect is attenuated in insulin-resistant dietary obese (DIO) mice. Fibroblast growth factor 21 (FGF21) treatment increases insulin sensitivity while inhibiting lipolysis. Both FGF21 and CL induce uncoupling protein 1 (UCP1) in brown adipose tissue, increasing capacity for combustion of glucose. Thus, the FGF21 treatment has a potential to modulate the glucoregulatory action of CL. Here we aim to characterize the effect of the CL+FGF21 combination and to investigate the role of UCP1 in this effect. DIO C57Bl/6 mice were housed at 30 °C in order to minimize basal adrenergic tone. Animals were treated 2x daily with 65 μg FGF21 or its vehicle for 8 days. This treatment lowered insulin (increased insulin sensitivity) . Subsequently, the mice were injected with 35 μg CL or with saline. CL increased FFA and insulin in control mice, but did not affect BG (probably because of impaired insulin sensitivity) . The day after CL injection, 4-fold rise in ectopic lipid content in liver was observed in comparison to saline-treated group. In FGF21-treated mice, the CL-induced rise of NEFA and insulin was only transient, but sufficient to cause a drop of BG. The hepatic lipid accumulation after CL was completely preveted by FGF21. The same experimental set-up was repeated in DIO UCP1+/+ and -/- mice. Although the BG-lowering effect of the CL+FGF21combination was observed in both genotypes, the effect was significantly stronger in UCP1+/+. Thus, FGF21 sensitizes DIO mice to the BG-lowering effect of adrenergic stimulation while it prevents ectopic lipid accummulation. The drop of BG is observed even in the absence of UCP1, but UCP1 activity is required to reach the maximal BG-lowering effect of the combination. Disclosure P.Zouhar: None. Funding Czech Science Foundation (19-05356Y)

182-OR: Clinical Effects of SGLT2 Inhibitors in HNF1A-Diabetes (MODY3) : A Case Series

Mutations in hepatocyte nuclear factor 1-alpha (HNF1A) cause HNF1A-diabetes (or maturity-onset diabetes of the young type 3 (MODY3)) . Treatment of HNF1A-diabetes is primarily based on sulphonylureas (SU) and secondarily insulins, glucagon-like peptide 1 receptor agonists (GLP1-RA) and dipeptidyl peptidase-4 inhibitors (DPP4i) . Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective glucose-lowering agents, cause body weight loss and protect from chronic kidney disease, heart failure and major adverse cardiovascular events. The utility of SGLT2i in patients with HNF1A-diabetes is unknown. Here, we describe a case series of five patients with HNF1A-diabetes treated with SGLT2i. Patient characteristics (median [range]) : age: 52 [35; 68] years; men/women: n=4/1; diabetes duration: 23 [9; 55] years; age at diabetes onset: 18 [13; 44] years; HbA1c: 6.9 [6.0; 7.4]% (52 [42; 57] mmol/mol) ; body weight: 92.3 [65.5; 95.1] kg; BMI: 25.6 [23.8; 29.4] kg/m2. At baseline, patients were treated with SU (n=5) , insulin (n=3; total daily dose: 15 [6; 25] IE divided into 1-4 injections/day) , DPP-4i (n=3) , GLP1-RA (n=2) , metformin (n=1) . All patients were started on empagliflozin mg QD. Follow-up was 1.5 [0.7; 1.8] years (total 6.2 patient years) . After three to six months of SGLT2i therapy, HbA1c was 6.1 [5.5; 7.5]% (43 [37; 59] mmol/mol) and had decreased in four patients (HbA1c change: -0.5 [-1.3; 0.7]% (-5 [-14; 8] mmol/mol)) , while body weight had decreased in all patients (change: -3.4 [-5.9; -1.5] kg) . During SGLT2i treatment, insulin was fully ceased in two patients and insulin dose was reduced from 15 IE/day to 3 IE/day in one patient. No serious adverse events were reported. Our data suggest that SGLT2i is safe, have glucose-lowering effects and is well-tolerated in HNF1A-diabetes, but randomized controlled trials are needed. Disclosure H.Maagensen: None. S.Haedersdal: None. J.Krogh: None. T.Hansen: None. F.K.Knop: Advisory Panel; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk, Sanofi, ShouTi, Zucara Therapeutics, Consultant; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pharmacosmos A/S, Sanofi, ShouTi, Zealand Pharma A/S, Zucara Therapeutics, Research Support; AstraZeneca, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Stock/Shareholder; Antag Therapeutics. T.Vilsbøll: Consultant; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Merck Sharp &amp; Dohme Corp., Mundipharma, Novo Nordisk, Sun Pharmaceutical Industries Ltd.

722-P: Tirzepatide Improves Multiple Aspects of Beta-Cell Function

We investigated the effect of tirzepatide (TZP) 15 mg (novel GIP-GLP-1 dual receptor agonist) , placebo and semaglutide 1 mg (SEMA) on beta-cell function using euglycaemic and hyperglycemic glucose clamps (EGC, HGC) and Mixed Meal Tolerance Tests (MMTT) in a 28-week double-blind randomized controlled trial of people with type 2 diabetes. During EGC and HGC, TZP improved insulin sensitivity (M-value) , first and second phase insulin secretion (ISR) and beta-cell glucose sensitivity (ratio of ISR and glucose increments) more than SEMA and placebo (Table; EASD symposium 2021) . During MMTT, both fasting and AUC glucose were reduced more with TZP than with SEMA or placebo, while incremental glucose AUC was reduced with TZP and SEMA vs. placebo similarly. Despite similarly reduced incremental glucose AUC, insulin AUC and incremental insulin AUC were reduced by TZP but not by SEMA. Model-derived beta-cell glucose sensitivity was increased with TZP and SEMA from baseline similarly. In contrast, ISR at 7.2 mmol/L glucose increased more with TZP than with placebo and SEMA (Table) . The glucose-lowering effect of TZP is mediated through improvements in multiple aspects of beta-cell function, including beta-cell glucose sensitivity and ISR, and in insulin sensitivity, resulting in pronounced lowering of fasting and postprandial glucose. These effects help explain the superior improvement in glucose control seen with TZP vs. comparators in clinical trials. Disclosure A. Mari: Consultant; Lilly. Research Support; Lilly. J. Li: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. S. Urva: Employee; Eli Lilly and Company. T. Heise: Advisory Panel; Novo Nordisk A/S. Research Support; ADOCIA, AstraZeneca, Biocon, Boehringer Ingelheim International GmbH, Crinetics Pharmaceuticals, Inc., Eli Lilly and Company, Gan &amp; Lee Pharmaceuticals, Genova, Nestlé, Neuraly Inc., Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker's Bureau; Eli Lilly and Company, Gan &amp; Lee Pharmaceuticals, Novo Nordisk A/S. J. De Vries: Advisory Panel; ADOCIA, Novo Nordisk A/S, Zealand Pharma A/S. Speaker's Bureau; Novo Nordisk A/S. E.J. Pratt: Employee; Eli Lilly and Company. R.J. Heine: Employee; Eli Lilly and Company. M.K. Thomas: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Z. Milicevic: Employee; Eli Lilly and Company. K.J. Mather: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company

727-P: Glycemic Effect of Tirzepatide by Duration of Diabetes

Results of SURPASS-1 through -5 trials have shown robust efficacy of novel dual GIP/GLP-1 receptor agonist tirzepatide (TZP) in people with type 2 diabetes. To understand whether glucose-lowering effect of tirzepatide depends on the duration of diabetes we conducted a subgroup analysis within each of the 5 Phase 3 trials. The primary endpoint of the 5 SURPASS clinical trials was mean change from baseline in HbA1c for 5mg, 10mg, and 15mg to 40 or 52 weeks against various comparators in adults with type 2 diabetes. This subgroup analysis of the 5 trials assessed whether mean change of HbA1c from baseline in the overall population were consistent when assessed by baseline duration of diabetes category (≤5 years, 5 to years, &amp;gt;years) in patients while they were on-treatment and without rescue medication (efficacy estimand) . For all 5 studies, analysis of change from baseline in HbA1c at 40 or 52 weeks for all 3 duration of diabetes subgroups were consistent with primary study results, with the treatment differences favoring all 3 doses of TZP compared with placebo or active comparator (Figure) . The most frequent adverse events were mild-to-moderate, gastrointestinal-related and occurred during the dose-escalation period. In conclusion, these results suggest that TZP was effective for mean change from baseline Hba1c for patients regardless of baseline duration of diabetes consistent with the overall patient population across the 5 SURPASS studies. Disclosure C.De block: Advisory Panel; Abbott Diagnostics, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk, Research Support; Indigo Diabetes, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk. C.Mathieu: Advisory Panel; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Imcyse, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca. H.Sapin: Employee; Eli Lilly and Company. J.I.Kiljanski: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.Peleshok: Employee; Eli Lilly and Company, Eli Lilly and Company.

216-OR: Hypoglycemia Frequency and Physiological Response to Double or Triple Doses of Once-Weekly Insulin Icodec vs. Once-Daily Insulin Glargine in T2D

Insulin icodec is a basal insulin in development for once-weekly (OW) dosing. The aim of this study was to compare the hypoglycemia frequency and response after icodec vs. insulin glargine U100 (IGlar) overdosing. In a randomized, open-label, two-period crossover trial, 43 individuals with T2D on basal insulin±metformin (mean±SD age 56±9 yrs, HbA1c 7.2±0.7%) received OW icodec for 6 weeks and once-daily IGlar for 12 days at equimolar total weekly doses based on the individual daily run-in IGlar dose (mean 30±14 U) titrated to a fasting SMPG target of 80-130 mg/dL. Once at steady state, double (DD) and triple (TD) doses of icodec and IGlar were followed by hypoglycemia induction 44 h (icodec) or 7 h (IGlar) post-dose (expected time of maximum glucose-lowering effect) : First, euglycemia was maintained at 100 mg/dL by variable i.v. glucose. Then, PG was allowed to decrease to a nadir of no less than 45 mg/dL maintained for 15 min. Euglycemia was restored by constant i.v. glucose. Hypoglycemic symptom score (HSS) and counterregulatory hormones were assessed at PG 100 mg/dL and at predefined PG levels until nadir PG. For DD, clinically significant hypoglycemia (PG&amp;lt;54 mg/dL) occurred in 40 vs. 36% of subjects for icodec vs. IGlar (odds ratio 1.28; p=0.63) . For TD, clinically significant hypoglycemia occurred in 53 vs. 70% of subjects (odds ratio 0.48; p=0.14) , mean nadir PG was 56 vs. 52 mg/dL (treatment ratio 1.07; p&amp;lt;0.001) , change in HSS at nadir PG was comparable for icodec vs. IGlar (treatment difference 0.46; p=0.77) , responses in adrenaline, noradrenaline and cortisol during hypoglycemia development were greater for icodec vs. IGlar, while glucagon and growth hormone levels increased similarly. In conclusion, a DD or TD of once-weekly insulin icodec does not lead to increased risk of hypoglycemia compared to once-daily IGlar. During hypoglycemia, a comparable symptomatic response and a moderately greater endocrine response were seen for icodec vs. IGlar. Disclosure E.Svehlikova: n/a. K.Niss arfelt: Employee; Novo Nordisk. R.Cailleteau: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. S.Deller: None. K.Thomsen: Employee; Novo Nordisk. M.Hart: None. I.Mursic: None. T.Pieber: Advisory Panel; Arecor, Novo Nordisk A/S, Research Support; AstraZeneca, European Union, JDRF, Novo Nordisk Foundation, Sanofi, Speaker's Bureau; Novo Nordisk A/S, Roche Diagnostics. H.Haahr: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. Funding Novo Nordisk

83-LB: Pharmacokinetic and Pharmacodynamic Studies of Supaglutide in Rats and Monkeys

Supaglutide, a novel GLP-1-IgG Fc fusion protein, exerts hypoglycemic effects in type 2 diabetic db/db mice and spontaneous diabetic monkeys. In this study, we investigated the pharmacokinetics and pharmacodynamics of supaglutide by single or repeated subcutaneous and intravenous injection (s) in rats and rhesus monkeys. We found that the half-life of supaglutide at 0.1 mg/kg in rhesus monkeys was 39.7 hours and 35.8 hours upon subcutaneous or intravenous administration, respectively. The plasma supaglutide peaked at 8-10 hours, while the plasma drug exposure levels increased with the increase of dose, showing approximately a linear pharmacokinetic characteristic. The elimination kinetics was similar between subcutaneous (∼0.025 in rats and ∼0.018 in monkeys) and intravenous administration (0.021 in rats and 0.020 in monkeys) , whereas the bioavailability was found to be 31.1% in rats and 63.9% in monkeys. In monkeys, the marked glucose-lowering effect of a single dose injection of supaglutide peaked at 14-16 hours and lasted for 72 hours. 125I-supaglutide distributed mainly in the serum and organs rich in blood supply. Urine was found to be the primary excretion route of supaglutide, following by feces, but the least by bile. Our results demonstrate that supaglutide has an excellent pharmacokinetic profile with prolonged hypoglycemic effects and is a potential weekly dosing therapeutic agent for the treatment of type 2 diabetes. Disclosure Y. Liao: None. A. Ma: None. Z. Wang: None. Y. Zhou: None. L. Zhang: None. L. Liu: None. N. Zhang: None. G. J. Prud’homme: None. Q. Wang: None.

Qualitative and quantitative phytoconstituent determination, DPPH free radical lowering effect and In-vitro hypoglycemic activity study by alpha amylase enzyme assay along with membrane diffusion technique.

Diabetes mellitus, a physiological disorder is characterized by low secretion of insulin due to the attack in insulin producing beta cell (Type I) or the body cell become insulin resistance (Type II). This study was designed to evaluate the DPPH lowering effect, in-vitro alpha amylase and glucose diffusion inhibition of the selected medicinal plants. Five different plant sample Amomum subulatum, Choerospondias axillaris, Musa sp, Myrica esculenta and Nephrolepis cordifolia were taken for the study. From the result it was revealed that the methanol extracts of Myrica esculenta stem bark and small branches showed potent DPPH free radical scavenging activity with the IC50 value of 4.23 µg/ml and 3.14 µg/ml respectively which is almost comparable to standard Ascorbic acid taken. Meanwhile, alpha-amylase inhibitory study showed that Myrica esculenta stem bark showed potent subsidiary effect on methanol extracts with IC50 value of 0.96 mg/ml which is comparable to standard volgibose taken. Lastly, membrane diffusion study with glucose and plant sample showed that Amomum subulatum seed and Choerospondias axillaris fruit have potent glucose diffusion inhibition with highest GDRI %. From the result, it could be correlated that the free radical scavenging activity and glucose lowering effect of these plant extracts is due to the presence of phytoconstituents like phenolics, flavonoids, alkaloids, terpenoids, glycosides saponins etc. as well as several other uncompetitive modes of inhibition.

Zawał serca u chorych na cukrzycę — nowości terapeutyczne

Diabetes mellitus is a risk factor for coronary heart disease and increase the risk of cardiovascular complications. Moreover, diabetes mellitus adversely affects the prognosis after myocardial infarction increasing the risk of complications in shortand long-term follow-up. Despite early coronary revascularization, diabetes significantly increases the mortality rate in myocardial infarction. Results from clinical trials published in recent years showed, in addition to glucose-lowering effect, sodium-glucose cotransporters inhibitors 2 and glucagon-like peptide-1 receptor agonists proved to reduce the cardiovascular risk and mortality in diabetic patients, which resulted in recommendation in Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology and the European Association for the Study of Diabetes. Moreover, empagliflozin and dapagliflozin reduce the risk of heart failure hospitalization and death in patients with heart failure. This publication aimed to discuss the most important differences in the currently recommended pharmacotherapy, in particular, the above-mentioned new hypoglycaemic drugs and dual antiplatelet therapy, and qualification for invasive and surgical treatment in myocardial infarction and diabetes compared to non-diabetic patients.

The effect of glucagon on local subcutaneous blood flow in non-diabetic volunteers; a proof-of-concept study

IntroductionGlucagon and insulin are the two most important hormones in glucose metabolism and have been incorporated in the dual-hormonal artificial pancreas, a device for automated glucose regulation for people with diabetes type 1. Currently the subcutis is the preferred site of hormone delivery for insulin-only as well as dual-hormonal artificial pancreas systems. The delay in glucose-lowering effect after subcutaneous injection of insulin is substantial, in contrast to the elevation of blood glucose values after subcutaneously injected glucagon which is occurs shortly after injection. We hypothesize that this is caused by properties of glucagon and have investigated the vasodilative effect of glucagon on subcutaneous blood flow in this proof-of-concept study. MethodsTwenty-two volunteers received subcutaneous injections of 0.1 mg and 0.01 mg glucagon, and saline on the abdomen. Blood flow was measured by a laser doppler blood flowmeter for 35 min after injections. ResultsInjection of 0.1 mg glucagon resulted in a significant increase in blood flow compared with baseline blood flow for all time intervals. Significant increase was also observed after the 0.01 mg glucagon injection, except between two- and five-min post injection. The inter-individual variance was large and a third of the subjects did not show an apparent increase in local subcutaneous blood flow after the 0.1 mg glucagon injection. ConclusionThis proof-of-concept study shows that micro-boluses of glucagon increases local subcutaneous blood flow on the abdomen of non-diabetic subjects. However, the vasodilative effect of glucagon is not observed in all subjects. The trial was not registered to protect intellectual property rights.

Palmitoylated prolactin-releasing peptide treatment had neuroprotective but not anti-obesity effect in fa/fa rats with leptin signaling disturbances

Background/ObjectiveAnorexigenic palmitoylated prolactin-releasing peptide (palm11-PrRP) is able to act centrally after peripheral administration in rat and mouse models of obesity, type 2 diabetes mellitus and/or neurodegeneration. Functional leptin and intact leptin signaling pathways are necessary for the body weight reducing and glucose tolerance improving effect of palm11-PrRP. We have previously shown that palm11-PrRP31 had glucose-lowering properties but not anti-obesity effect in Koletsky rats with leptin signaling disturbances, so improvements in glucose metabolism appear to be completely independent of leptin signaling. The purpose of this study was to describe relationship between metabolic and neurodegenerative pathologies and explore if palm11-PrRP31 could ameliorate them in obese fa/fa rat model with leptin signaling disruption.Subject/MethodsThe fa/fa rats and their age-matched lean controls at the age 32 weeks were used for this study. The rats were infused for 2 months with saline or palm11-PrRP31 (n = 7–8 per group) at a dose of 5 mg/kg per day using Alzet osmotic pumps. During the dosing period food intake and body weight were monitored. At the end of experiment the oral glucose tolerance test was performed; plasma and tissue samples were collected and arterial blood pressure was measured. Then, markers of leptin and insulin signaling, Tau phosphorylation, neuroinflammation, and synaptogenesis were measured by western blotting and immunohistochemistry.ResultsFa/fa rats developed obesity, mild glucose intolerance, and peripheral insulin resistance but not hypertension while palm11-PrRP31 treatment neither lowered body weight nor attenuated glucose tolerance but ameliorated leptin and insulin signaling and synaptogenesis in hippocampus.ConclusionWe demonstrated that palm11-PrRP31 had neuroprotective features without anti-obesity and glucose lowering effects in fa/fa rats. This data suggest that this analog has the potential to exert neuroprotective effect despite of leptin signaling disturbances in this rat model.

Anti-Diabetic Drugs GLP-1 Agonists and DPP-4 Inhibitors may Represent Potential Therapeutic Approaches for COVID-19.

The fast spread of coronavirus 2019 (COVID-19) calls for immediate action to counter the associated significant loss of human life and deep economic impact. Certain patient populations like those with obesity and diabetes are at higher risk for acquiring severe COVID-19 disease and have a higher risk of COVID-19 associated mortality. In the absence of an effective and safe vaccine, the only immediate promising approach is to repurpose an existing approved drug. Several drugs have been proposed and tested as adjunctive therapy for COVID-19. Among these drugs are the glucagon-like peptide-1 (GLP-1) 2 agonists and the dipeptidylpeptidase-4 (DPP-4) inhibitors. Beyond their glucose-lowering effects, these drugs have several pleiotropic protective properties, which include cardioprotective effects, anti-inflammatory and immunomodulatory activities, antifibrotic effects, antithrombotic effects, and vascular endothelial protective properties. This narrative review discusses these protective properties and addresses their scientific plausibility for their potential use as adjunctive therapy for COVID-19 disease.

Anti‐hyperglycemic Activities of Korean Red Ginseng (Panax ginseng Meyer) and Arginyl‐fructose‐enriched Red Ginseng Extracts In‐vitro and In‐vivo Animal Models

Maillard reaction that occurs during the manufacturing processes of red ginseng produces a large amount of Amadori rearrangement compounds (ARCs), such as arginyl‐fructose (AF). The antioxidant, anti‐hyperglycemic immune enhancing effects of AF have been reported. Amino acid derivatives such as AF are formed through amadori rearrangement, the early step of maillard reaction from arginine and glucose in heat processed foods. Heat processed red ginseng have high content of AF and saponins. In this study inhibitory activities of red ginseng extract (RG) and AF‐enriched red ginseng extract (ARG) against rat intestinal α‐glucosidases (sucrase, maltase, and glucoamylase) and α‐amylase were evaluated using in‐vitro and Sprague Dawley (SD) rat models. The in‐vitro results showed that ARG have higher α‐glucosidase inhibitory activities than those of RG in a dose‐dependent manner. In SD rat model, postprandial blood glucose levels were measured for 3 hours after oral administration of 0.1 and 0.5 g/kg‐body weight of ARG or RG along with sucrose or starch. The postprandial blood glucose lowering effects of ARG and RG were compared to a known type 2 diabetes medicine (Acarbose®), a strong α‐glucosidase inhibitor in the SD rat model. In rats fed on sucrose, ARG significantly reduced the blood glucose spike after sucrose loading (p &lt; 0.01). The maximum blood glucose concentration (Cmax) in ARG‐treated SD rats (0.1 g‐ARG/kg) was significantly lower than in RG‐treated SD rats (p &lt; 0.01). These results suggest that AF‐enriched red ginseng could have a beneficial effect for blood glucose management relevant to diabetes prevention in normal and pre‐diabetic individuals via inhibition of the carbohydrate hydrolysis enzymes in the colon. AF, ARCs may have high potential as a material for the development of products, nutritious foods with antidiabetic activity. Our findings provide a pharmacological rationale and the basis for further clinical study for AF‐enriched natural products such as ginseng and red ginseng.

Assessment of Antidiabetic Activity of Dried Juice of Andrographis Paniculata Leaves in Alloxan induced Diabetic Rats

Background: Andrographis paniculata (Acanthaceae) is an annual herb and the whole herb is traditionally reported to be used in treatment of diabetes mellitus.&#x0D; Objective: To investigate the anti-diabetic potential of dried juice of Andrographis paniculata leaves in alloxan induced diabetic rats as the decoction of whole plant is used for the treatment of diabetes mellitus traditionally. &#x0D; Method: The fresh leaves of A. paniculata herb were collected and grinded with distilled water into a fine slurry. The resulting juice was filtered and concentrated and used for the study. Three doses (50mg/kg, 100mg/kg and 200mg/kg) of dried juice of leaves were orally administered to the diabetic rats to evaluate blood glucose lowering effect. Metformin hydrochloride drug (120mg/kg) was used as a reference standard. The blood glucose level was measured at 0, 1, 3 and 5 hours after the treatment.&#x0D; Results: After single administration of dried juice of leaves with 50 mg/kg dose there was significant reduction of blood glucose level at 3rd and 5th hour of administration and the % reduction was 24.8 and 37.51 respectively. Similarly 100mg/kg of extract dose showed significant reduction in blood glucose level at1st, 3rd and 5th hour of administration with % reduction of 20.6, 35.2 and 48.28 respectively whereas 200 mg/kg dose caused significant reduction in blood glucose level after 1st, 3rd and 5th hour of intervals and the % reduction was of 21.48, 41.0 and 52.6 respectively. &#x0D; Conclusion: All the three doses of dried juice (50, 100 and 200mg/kg) showed the maximum% reduction in blood glucose level after 5th hour of administration (37.51%, 48.28% and 52.6% respectively) as compared with diabetic control. This in vivo study shows that A. paniculata leaves has significant antidiabetic potential in a dose dependant manner and the results are comparable with the reference standard drug.