scholarly journals Multiphasic effect of vinyl pyrrolidone polymers on amyloidogenesis, from macromolecular crowding to inhibition

2018 ◽  
Vol 475 (21) ◽  
pp. 3417-3436 ◽  
Author(s):  
Richard Berwick ◽  
David J. Vaux ◽  
Létitia Jean
Keyword(s):  
Molecular Mass ◽  
Surface Activity ◽  
Type Ii Diabetes ◽  
Volume Fraction ◽  
Macromolecular Crowding ◽  
Monomer Concentration ◽  
Vinyl Pyrrolidone ◽  
Bulk Solution ◽  
Type Ii

Deposition of misfolded amyloid polypeptides, associated with cell death, is the hallmark of many degenerative diseases (e.g. type II diabetes mellitus and Alzheimer's disease). In vivo, cellular and extracellular spaces are occupied by a high volume fraction of macromolecules. The resulting macromolecular crowding energetically affects reactions. Amyloidogenesis can either be promoted by macromolecular crowding through the excluded volume effect or inhibited due to a viscosity increase reducing kinetics. Macromolecular crowding can be mimicked in vitro by the addition of non-specific polymers, e.g. Ficoll, dextran and polyvinyl pyrrolidone (PVP), the latter being rarely used to study amyloid systems. We investigated the effect of PVP on amyloidogenesis of full-length human islet amyloid polypeptide (involved in type II diabetes) using fibrillisation and surface activity assays, ELISA, immunoblot and microscale thermophoresis. We demonstrate that high molecular mass PVP360 promotes amyloidogenesis due to volume exclusion and increase in effective amyloidogenic monomer concentration, like other crowders, but without the confounding effects of viscosity and surface activity. Interestingly, we also show that low molecular mass PVP10 has unique inhibitory properties as inhibition of fibril elongation occurs mainly in the bulk solution and is due to PVP10 directly and strongly interacting with amyloid species rather than the increase in viscosity typically associated with macromolecular crowding. In vivo, amyloidogenesis might be affected by the properties and proximity of endogenous macromolecular crowders, which could contribute to changes in associated pathogenesis. More generally, the PVP10 molecular backbone could be used to design small compounds as potential inhibitors of toxic species formation.

scholarly journals The kinetics of islet amyloid polypeptide phase separated system and hydrogel formation are critically influenced by macromolecular crowding

2021 ◽  
Author(s):  
Lior Pytowski ◽  
David Vaux ◽  
Létitia Jean
Keyword(s):  
Type Ii Diabetes ◽  
Volume Fraction ◽  
Biological Fluids ◽  
Islet Amyloid Polypeptide ◽  
Macromolecular Crowding ◽  
Type Ii ◽  
Amyloid Aggregation ◽  
Islet Amyloid ◽  
Kinetics Of

Many protein misfolding diseases (e.g. type II diabetes and Alzheimer’s disease) are characterised by amyloid deposition. Human islet amyloid polypeptide (hIAPP, involved in type II diabetes) spontaneously undergoes liquid-liquid phase separation (LLPS) and a kinetically complex hydrogelation, both catalysed by hydrophobic-hydrophilic interfaces (e.g. air-water interface and/or phospholipids-water interfaces). Gelation of hIAPP phase separated liquid droplets initiates amyloid aggregation and formation of clusters of interconnected aggregates, which grow and fuse to eventually percolate the whole system. Droplet maturation into irreversible hydrogels via amyloid aggregation is thought to be behind the pathology of several diseases. Biological fluids contain a high volume fraction of macromolecules, leading to macromolecular crowding. Despite crowding agent addition in in vitro studies playing a significant role in changing protein phase diagrams, the mechanism underlying enhanced LLPS, and the effect(s) on stages beyond LLPS remain poorly or not characterised.  We investigated the effect of macromolecular crowding and increased viscosity on the kinetics of hIAPP hydrogelation using rheology and the evolution of the system beyond LLPS by microscopy. We demonstrate that increased viscosity exacerbated the kinetic variability of hydrogelation and of the phase separated-aggregated system, whereas macromolecular crowding abolished heterogeneity. Increased viscosity also strengthened the gel meshwork and accelerated aggregate cluster fusion. In contrast, crowding either delayed cluster fusion onset (dextran) or promoted it (Ficoll). Our study highlights that an in vivo crowded environment would critically influence amyloid stages beyond LLPS and pathogenesis.

In vitro and in vivo sustained release of exenatide from vesicular phospholipid gels for type II diabetes

2015 ◽  
Vol 42 (7) ◽  
pp. 1042-1049 ◽  
Author(s):  
Yu Zhang ◽  
Ying Zhong ◽  
Mei Hu ◽  
Nanxi Xiang ◽  
Yao Fu ◽  
...  
Keyword(s):  
Sustained Release ◽  
Type Ii Diabetes ◽  
Type Ii

scholarly journals Potent Natural Inhibitors of Alpha-Glucosidase and Alpha-Amylase against Hyperglycemia in Vitro and in Vivo

2017 ◽  
Author(s):  
Jirawat Riyaphan ◽  
Chien-Hung Jhong ◽  
May-Jwan Tsai ◽  
Der-Nan Lee ◽  
Max K. Leong ◽  
...  
Keyword(s):  
Type Ii Diabetes ◽  
Herbal Medicines ◽  
Alpha Amylase ◽  
Type Ii ◽  
Reference Drug ◽  
Significant Difference ◽  
Natural Inhibitors ◽  
Alpha Glucosidase

The inhibition of alpha-glucosidase and alpha-amylase is one of clinic strategies for remedy the type II diabetes. Herbal medicines are reported to alleviate hyperglycemia. However, the constituents from those sources whether are targeted to the alpha-glucosidase and alpha-amylase still unexplored. This study attempted to select the compounds for efficacy of hypoglycemia via cellular and mouse levels. The results illustrated that the cytotoxicity in all tested compounds at various concentrations except the concentration of 16-hydroxy-cleroda-3,13-dine-16,15-olide (HCD) at 30 µM were not significant difference (p > 0.05) when compared with the untreated control. Acarbose (reference drug), Antroquinonol, Catechin, Quercetin, Actinodaphnine, Curcumin, HCD, Docosanol, Tetracosanol, Berberine, and Rutin could effectively inhibit the alpha-glucosidase activity of Caco-2 cells when compared with the control (maltose). The compounds (Curcumin, HCD, Tetracosanol, Antroquinonol, Berberine, Catechin, Actinodaphnine, and Rutin) could reduce blood sugar level at 30 min in tested mice. The effects of tested compounds on area under curve (AUC) were significant (p < 0.05) among Acarbose, Tetracosanol, Antroquinonol, Catechin, Actinodaphnine, and Rutin along with Berberine and Quercetin. In in vitro (alpha-glucosidase) with in vivo (alpha-amylase) experiments suggest that bioactive compounds can be a potential inhibitor candidate of alpha-glucosidase and alpha-amylase for the alleviation of type II diabetes.

Insulin resistance in obesity, type II diabetes and stress

1983 ◽  
Vol 104 (4_Suppl) ◽  
pp. S67-S69
Author(s):  
Ulf Smith
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Key Words ◽  
Glucose Transport ◽  
Type Ii Diabetes ◽  
Insulin Receptors ◽  
In Vitro Studies ◽  
Type Ii

ABSTRACT. Insulin resistance plays a major role for the reduced glucose tolerance in obesity, type II diabetes and stress. Both in vivo and in vitro studies strongly support the major importance of post-receptor perturbations as the cause of the insulin resistance in these conditions. One likely level for the post-receptor alterations is the reported reduction in glucose transport. Key words: Insulin resistance, diabetes, obesity, insulin receptors, glucose transport.

Paraoxonase-1 (PON-1) genotype and activity and in vivo oxidized plasma low-density lipoprotein in Type II diabetes

2005 ◽  
Vol 109 (2) ◽  
pp. 189-197 ◽  
Author(s):  
Mike J. Sampson ◽  
Simon Braschi ◽  
Gavin Willis ◽  
Sian B. Astley
Keyword(s):  
Type Ii Diabetes ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Paraoxonase 1 ◽  
Ldl Oxidation ◽  
Phenyl Acetate ◽  
Low Density ◽  
Type Ii

The HDL (high-density lipoprotein)-associated enzyme PON (paraoxonase)-1 protects LDL (low-density lipoprotein) from oxidative modification in vitro, although it is unknown if this anti-atherogenic action occurs in vivo. In a cross-sectional study of 58 Type II diabetic subjects and 50 controls, we examined the fasting plasma LDL basal conjugated diene concentration [a direct measurement of circulating oxLDL (oxidatively modified LDL)], lipoprotein particle size by NMR spectroscopy, PON-1 polymorphisms (coding region polymorphisms Q192R and L55M, and gene promoter polymorphisms −108C/T and −162G/A), PON activity (with paraoxon or phenyl acetate as the substrates) and dietary antioxidant intake. Plasma oxLDL concentrations were higher in Type II diabetic patients (males, P=0.048; females, P=0.009) and unrelated to NMR lipoprotein size, PON-1 polymorphisms or PON activity (with paraoxon as the substrate) in any group. In men with Type II diabetes, however, there was a direct relationship between oxLDL concentrations and PON activity (with phenyl acetate as the substrate; r=0.611, P=0.0001) and an atherogenic NMR lipid profile in those who were PON-1 55LL homozygotes. Circulating oxLDL concentrations in vivo were unrelated to PON-1 genotypes or activity, except in male Type II diabetics where there was a direct association between PON activity (with phenyl acetate as the substrate) and oxLDL levels. These in vivo data contrast with in vitro data, and may be due to confounding by dietary fat intake. Male Type II diabetic subjects with PON-1 55LL homozygosity have an atherogenic NMR lipid profile independent of LDL oxidation. These data do not support an in vivo action of PON on LDL oxidation.

PDH kinase inhibitors: a novel therapy for Type II diabetes?

2005 ◽  
Vol 33 (2) ◽  
pp. 367-370 ◽  
Author(s):  
R.M. Mayers ◽  
B. Leighton ◽  
E. Kilgour
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Type Ii Diabetes ◽  
Kinase Inhibitors ◽  
Pyruvate Dehydrogenase Kinase ◽  
Zucker Rats ◽  
Oxidative Decarboxylation ◽  
Type Ii ◽  
Novel Therapy ◽  
Specific Expression

The pyruvate dehydrogenase multienzyme complex catalyses the oxidative decarboxylation of pyruvate, which is an important regulatory step in oxidative metabolism. Phosphorylation of the E1 (pyruvate decarboxylase) subunit on one of three specific serine residues results in loss of enzyme activity. Four dedicated PDHK (pyruvate dehydrogenase kinase) isoenzymes have been identified, each of which display a distinct tissue-specific expression profile, and have differential regulatory properties. Thus PDHK play a key role in controlling the balance between glucose and lipid oxidation according to substrate supply. Increasing glucose oxidation by inhibiting PDHK may be an effective mechanism to increase glucose utilization; additionally, increasing pyruvate oxidation may further contribute to lowering of glucose level by decreasing the supply of gluconeogenic substrates. A number of PDHK inhibitors are now available to enable this mechanism to be evaluated as a therapy for diabetes. The isoenzyme selectivity profile of AZD7545 and related compounds will be described and evidence for their non-ATP-competitive mode of action presented. These compounds increase PDH activity in vivo, and when dosed chronically, improve glycaemic control in Zucker rats. Furthermore, glucose lowering has been demonstrated in the hyperglycaemic Zucker diabetic fatty rat. This result supports the hypothesis that inhibition of PDHK may be an effective therapy for Type II diabetes.

scholarly journals A SYNERGISTIC INSULINOTROPIC EFFECT OF GREEN TEA EXTRACT AND POMEGRANATE EXTRACT WITH ROSIGLITAZONE: BOTH IN VIVO AND IN VITRO EXPERIMENT

2020 ◽  
pp. 96-99
Author(s):  
REKHA S ◽  
CHANDRASHEKHARA S
Keyword(s):  
Green Tea ◽  
Type Ii Diabetes ◽  
Body Weight Gain ◽  
Serum Insulin ◽  
In Vivo Studies ◽  
Albino Rats ◽  
Type Ii ◽  
Insulinotropic Effect

Objective: Scientists have growing interest in traditional medicinal plants as they contain active ingredients for the treatment of various diseases. Tea is one of the most popular beverages worldwide. The variety of tea and tea extracts in the market has different polyphenol profiles, which are the bioactive chemical entities. We performed a direct comparison between Thea sinensis, green tea extracts (GTEs), and Punica granatum peel powder (PGPP), which have been chemically well characterized in a type II diabetic mouse model. Methods: We conducted both in vivo and in vitro experiments in the present paper. In vivo studies were carried out on male Swiss albino rats having type II diabetes, induced by single intravenous injection of streptozotocin (0.7 mg/Kg i.m.) and IDDM rats received either PGPP (200 mg/kg) or GTE (100 mg/kg) as a single oral dose. After the above result, the extracts were further subjected to know the effect of insulin secretion by RIN-5F cells providing confirmation of insulinotropic effect. Results: The results revealed that both PGPP and GTE substantially lowered blood glucose levels and ameliorated glucose intolerance, both were effective in antihyperglycemic activity and in lowering body weight gain. Serum insulin levels significantly increased in GTE group as well as in PGPP group, suggesting that they were exerting hypoglycemic effects through different pathways. Conclusion: Synergistic action of PGPP and GTE is an effective alternative for the treatment of type II diabetes through the regeneration of β cells of pancreas.

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