A DPP-IV-resistant triple-acting agonist of GIP, GLP-1 and glucagon receptors with potent glucose-lowering and insulinotropic actions in high-fat-fed mice

Diabetologia ◽  
2013 ◽  
Vol 56 (6) ◽  
pp. 1417-1424 ◽  
Author(s):  
V. K. Bhat ◽  
B. D. Kerr ◽  
S. Vasu ◽  
P. R. Flatt ◽  
V. A. Gault
Keyword(s):  
High Fat ◽  
Glucose Lowering ◽  
Dpp Iv ◽  
Glucagon Receptors ◽  
Acting Agonist

scholarly journals Evaluation of the Antidiabetic and Insulin Releasing Effects of A. squamosa, Including Isolation and Characterization of Active Phytochemicals

Plants ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 1348
Author(s):  
Prawej Ansari ◽  
Peter R. Flatt ◽  
Patrick Harriott ◽  
Yasser H.A. Abdel-Wahab
Keyword(s):  
Glucose Tolerance ◽  
Insulin Action ◽  
Plasma Insulin ◽  
Annona Squamosa ◽  
High Fat ◽  
Β Cells ◽  
Dpp Iv ◽  
Glucose Diffusion ◽  
Mouse Islets

Annona squamosa is generally referred to as a ‘custard apple’. Antidiabetic actions of hot water extract of Annona squamosa (HWAS) leaves together with isolation of active insulinotropic compounds were studied. Insulin release, membrane potential and intracellular Ca2+ were determined using BRIN-BD11 cells and isolated mouse islets. 3T3L1 adipocytes and in vitro models were used to determine cellular glucose uptake, insulin action, starch digestion, glucose diffusion, DPP-IV activity and glycation. Glucose intolerant high-fat fed rats were used for in vivo studies. Active compounds were isolated and characterized by HPLC, LCMS and NMR. HWAS stimulated insulin release from clonal β-cells and mouse islets. Using fluorescent indicator dyes and modulators of insulin secretion, effects could be attributed to depolarization of β-cells and influx of Ca2+. Secretion was stimulated by isobutylmethylxanthine (IBMX), tolbutamide or 30 mM KCl, indicating additional non-KATP dependent pathways. Extract stimulated cellular glucose uptake and insulin action and inhibited starch digestion, protein glycation, DPP-IV enzyme activity and glucose diffusion. Oral HWAS improved glucose tolerance and plasma insulin in high-fat fed obese rats. Treatment for 9 days with HWAS (250 mg/5 mL/kg), partially normalised energy intake, body weight, pancreatic insulin content, and both islet size and beta cell mass. This was associated with improved oral glucose tolerance, increased plasma insulin and inhibition of plasma DPP-IV activity. Isolated insulinotropic compounds, including rutin (C27H30O16), recapitulated the positive actions of HWAS on beta cells and in vivo glucose tolerance and plasma insulin responses. Annona squamosa is attractive as a dietary adjunct in treatment of T2DM and as a source of potential antidiabetic agents including rutin.

scholarly journals UCP1-independent glucose-lowering effect of leptin in type 1 diabetes: only in conditions of hypoleptinemia

2020 ◽  
Vol 318 (1) ◽  
pp. E72-E86
Author(s):  
Petr Zouhar ◽  
Günaj Rakipovski ◽  
Muhammad Hamza Bokhari ◽  
Oliver Busby ◽  
Johan F. Paulsson ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Therapeutic Potential ◽  
Uncoupling Protein ◽  
Leptin Resistance ◽  
Diabetic Mice ◽  
High Fat ◽  
Glucose Lowering ◽  
Lowering Effect ◽  
Glucose Lowering Effect

The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity — and thus also leptin levels — in the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.

scholarly journals Novel dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1(7-36)amide have preserved biological activities in vitro conferring improved glucose-lowering action in vivo

2003 ◽  
Vol 31 (3) ◽  
pp. 529-540 ◽  
Author(s):  
BD Green ◽  
VA Gault ◽  
MH Mooney ◽  
N Irwin ◽  
CJ Bailey ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Biological Activities ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Glucose Lowering ◽  
Dpp Iv ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Although the incretin hormone glucagon-like peptide-1 (GLP-1) is a potent stimulator of insulin release, its rapid degradation in vivo by the enzyme dipeptidyl peptidase IV (DPP IV) greatly limits its potential for treatment of type 2 diabetes. Here, we report two novel Ala(8)-substituted analogues of GLP-1, (Abu(8))GLP-1 and (Val(8))GLP-1 which were completely resistant to inactivation by DPP IV or human plasma. (Abu(8))GLP-1 and (Val(8))GLP-1 exhibited moderate affinities (IC(50): 4.76 and 81.1 nM, respectively) for the human GLP-1 receptor compared with native GLP-1 (IC(50): 0.37 nM). (Abu(8))GLP-1 and (Val(8))GLP-1 dose-dependently stimulated cAMP in insulin-secreting BRIN BD11 cells with reduced potency compared with native GLP-1 (1.5- and 3.5-fold, respectively). Consistent with other mechanisms of action, the analogues showed similar, or in the case of (Val(8))GLP-1 slightly impaired insulin releasing activity in BRIN BD11 cells. Using adult obese (ob/ob) mice, (Abu(8))GLP-1 had similar glucose-lowering potency to native GLP-1 whereas the action of (Val(8))GLP-1 was enhanced by 37%. The in vivo insulin-releasing activities were similar. These data indicate that substitution of Ala(8) in GLP-1 with Abu or Val confers resistance to DPP IV inactivation and that (Val(8))GLP-1 is a particularly potent N-terminally modified GLP-1 analogue of possible use in type 2 diabetes.

scholarly journals Predictive blood glucose lowering efficacy by Glucokinase activators in high fat fed female Zucker rats

2006 ◽  
Vol 149 (3) ◽  
pp. 328-335 ◽  
Author(s):  
G J Coope ◽  
A M Atkinson ◽  
C Allott ◽  
D McKerrecher ◽  
C Johnstone ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Zucker Rats ◽  
High Fat ◽  
Glucose Lowering ◽  
Glucokinase Activators

scholarly journals Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

2016 ◽  
Vol 37 (8) ◽  
pp. 1063-1075 ◽  
Author(s):  
Zi-yu Zhou ◽  
Li-wei Ren ◽  
Ping Zhan ◽  
Han-yan Yang ◽  
Dan-dan Chai ◽  
...  
Keyword(s):  
Insulin Signaling ◽  
High Fat ◽  
Glucose Lowering

scholarly journals Mechanisms and Potential Roles of Glucose-Lowering Agents in COVID-19: A Review

2021 ◽  
pp. 106002802199947
Author(s):  
Helen D. Berlie ◽  
Pramodini B. Kale-Pradhan ◽  
Tara Orzechowski ◽  
Linda A. Jaber
Keyword(s):  
Glycemic Control ◽  
English Language ◽  
Current Knowledge ◽  
Data Extraction ◽  
Current Data ◽  
Adverse Outcomes ◽  
Glucose Lowering ◽  
Language Studies ◽  
Dpp Iv ◽  
Analytical Approaches

Objective: To explore mechanistic benefits of glucose-lowering agents that extend beyond glycemic control with the potential to mitigate coronavirus disease 2019 (COVID-19) complications. Data Sources: The following PubMed literature search terms were used from July 2020 to January 2, 2021: diabetes, COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), glucose-lowering agents, and pharmacology. Study Selection and Data Extraction: English-language studies reporting on the association between diabetes, COVID-19 adverse outcomes, and the potential roles of glucose-lowering agents were reviewed. Data Synthesis: Selected glucose-lowering agents have benefits beyond glycemic control, with the potential to reduce the risks of severe complications during SARS-CoV-2 infection. Key benefits include anti-inflammatory, anticoagulant, immune modulating, and enzyme/receptor effects. Relevance to Patient Care and Clinical Practice: This review summarizes the current knowledge of glucose-lowering agents and their potential roles in COVID-19 outcomes. Considering beneficial mechanisms on COVID-19 outcomes that extend beyond glycemic control as well as safety profiles, current data suggest that dipeptidyl peptidase-IV (DPP-IV) inhibitors and metformin may have the most promise and warrant further investigation. Conclusions: Certain glucose-lowering agents may offer additional benefits beyond glucose control—namely, by modulating the mechanisms contributing to adverse outcomes related to COVID-19 in patients with diabetes. DPP-IV inhibitors and metformin appear to have the most promise. However, current published literature on diabetes medications and COVID-19 should be interpreted with caution. Most published studies are retrospective and consist of convenience samples, and some lack adequate analytical approaches with confounding biases. Ongoing trials aim to evaluate the effects of glucose-lowering agents in reducing the severity of COVID-19 outcomes.

scholarly journals Effects of 22 traditional anti-diabetic medicinal plants on DPP-IV enzyme activity and glucose homeostasis in high-fat fed obese diabetic rats

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Prawej Ansari ◽  
Mary P. Hannon-Fletcher ◽  
Peter R. Flatt ◽  
Yasser H.A. Abdel-Wahab
Keyword(s):  
Body Weight ◽  
Enzyme Activity ◽  
Medicinal Plants ◽  
Glucose Homeostasis ◽  
Diabetic Rats ◽  
Hot Water ◽  
High Fat ◽  
Dpp Iv ◽  
Obese Diabetic Rats

Abstract The present study investigated the effects of hot water extracts of 22 medicinal plants used traditionally to treat diabetes on Dipeptidyl peptidase-IV (DPP-IV) activity both in vitro and in vivo in high-fat fed (HFF) obese-diabetic rats. Fluorometric assay was employed to determine the DPP-IV activity. For in vivo studies, HFF obese-diabetic rats were fasted for 6 h and blood was sampled at different times before and after the oral administration of the glucose alone (18 mmol/kg body weight) or with either of the four most active plant extracts (250 mg/5 ml/kg, body weight) or established DPP-IV inhibitors (10 μmol/5 ml/kg). DPP-IV inhibitors: sitagliptin, vildagliptin and diprotin A, decreased enzyme activity by a maximum of 95–99% (P<0.001). Among the 22 natural anti-diabetic plants tested, AnogeissusLatifolia exhibited the most significant (P<0.001) inhibitory activity (96 ± 1%) with IC50 and IC25 values of 754 and 590 μg/ml. Maximum inhibitory effects of other extracts: Aegle marmelos, Mangifera indica, Chloropsis cochinchinensis, Trigonella foenum-graecum and Azadirachta indica were (44 ±7%; 38 ± 4%; 31±1%; 28±2%; 27±2%, respectively). A maximum of 45% inhibition was observed with >25 μM concentrations of selected phytochemicals (rutin). A.latifolia, A. marmelos, T. foenum-graecum and M. indica extracts improved glucose tolerance, insulin release, reduced DPP-IV activity and increased circulating active GLP-1 in HFF obese-diabetic rats (P<0.05–0.001). These results suggest that ingestion of selected natural anti-diabetic plants, in particular A. latifolia, A. marmelos, T. foenum-graecum and M. indica can substantially inhibit DPP-IV and improve glucose homeostasis, thereby providing a useful therapeutic approach for the treatment of T2DM.

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