title: Combination therapy via oral co-administration of insulin- and exendin-4-loaded nanoparticles to treat type 2 diabetic rats undergoing OGTT.
abstract: Current insulin therapy via subcutaneous administration can lead to occasional hypoglycemia and peripheral hyperinsulinemia, due to its nonphysiological route. This study evaluates the feasibility of using bovine insulin and exendin-4 in a form of combination therapy, as orally delivered by nanoparticles composed of chitosan and poly(γ-glutamic acid) (CS/γPGA NPs), to control blood glucose levels in rats with type 2 diabetes mellitus (T2DM) undergoing the oral glucose tolerance test. Experimental results indicate that CS/γPGA NPs could enhance the intestinal paracellular permeation; consequently, the exogenous bovine insulin and exendin-4 could be delivered into the liver and pancreas, where they could elicit their glucoregulatory activities. In response to the stimulus of exogenously delivered bovine insulin and the endogenously secreted rat insulin stimulated by the ingested exendin-4, significant glucose utilizations were found in the cardiac and skeletal muscles, resulting in the glucose-lowering effect. Owing to its synergic stimulation effects, the hypoglycemic effect of oral ingestion of NPs containing bovine insulin and exendin-4 was significantly greater than that of the group solely treated with insulin NPs. Above results demonstrate that oral combination therapy with bovine insulin and exendin-4 improves the modulation of blood glucose levels in T2DM rats, making it highly promising for treating those T2DM patients not adequately controlled by the current insulin therapy.
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC.
authors.forename: Er-Yuan
authors.initials: EY
authors.lastname: Chuang
authors.forename: Giang Thi Ha
authors.initials: GT
authors.lastname: Nguyen
authors.forename: Fang-Yi
authors.initials: FY
authors.lastname: Su
authors.forename: Kun-Ju
authors.initials: KJ
authors.lastname: Lin
authors.forename: Chiung-Tong
authors.initials: CT
authors.lastname: Chen
authors.forename: Fwu-Long
authors.initials: FL
authors.lastname: Mi
authors.forename: Tzu-Chen
authors.initials: TC
authors.lastname: Yen
authors.forename: Jyuhn-Huarng
authors.initials: JH
authors.lastname: Juang
authors.forename: Hsing-Wen
authors.initials: HW
authors.lastname: Sung
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002417:Cattle; D048271:Chitosan / Q000737:chemistry; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004338:Drug Combinations; D016503:Drug Delivery Systems; D000077270:Exenatide; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007328:Insulin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D010455:Peptides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011099:Polyglutamic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D014688:Venoms / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D004338:Drug Combinations; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms; C511775:poly(gamma-glutamic acid); D011099:Polyglutamic Acid; D048271:Chitosan; D000077270:Exenatide
keywords: Glucoregulatory activity; Glucose utilization; Hyperinsulinemia; Postprandial hyperglycemia; Translational medicine