Poly(lactic-co-glycolic) acid loaded nano-insulin has greater potentials of combating arsenic induced hyperglycemia in mice: Some novel findings

• Published in: Toxicology and applied pharmacology 2013-02, Vol.267 (1), p.57-73
• Main Authors: Samadder, Asmita, Das, Jayeeta, Das, Sreemanti, De, Arnab, Saha, Santu Kumar, Bhattacharyya, Soumya Sundar, Khuda-Bukhsh, Anisur Rahman
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; ARSENIC; Arsenic - toxicity; Arsenic induced hyperglycemia; ATOMIC FORCE MICROSCOPY; Biological and medical sciences; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; CALCIUM IONS; Carcinogenesis, carcinogens and anticarcinogens; CELL MEMBRANES; Chemical agents; Chemical and industrial products toxicology. Toxic occupational diseases; Circular dichroic spectra; Data processing; Diabetes mellitus; Drug Carriers - administration & dosage; Drug Carriers - chemistry; Drug Carriers - metabolism; Female; Glucokinase; Glucose transporter; GLYCOLIC ACID; GROUND WATER; HYPERGLYCEMIA; Hyperglycemia - chemically induced; Hyperglycemia - metabolism; Hyperglycemia - prevention & control; INSULIN; Insulin - administration & dosage; Insulin - chemistry; Insulin - metabolism; Lactic Acid - administration & dosage; Lactic Acid - chemistry; Lactic Acid - metabolism; Light scattering; Male; Medical sciences; Membrane potential; MESSENGER-RNA; Metals and various inorganic compounds; MICE; MITOCHONDRIA; Mobility; mRNA; Nanoparticles - administration & dosage; Nanoparticles - chemistry; ORAL ADMINISTRATION; Peroxisome proliferator-activated receptors; PLGA; Polyglycolic Acid - administration & dosage; Polyglycolic Acid - chemistry; Polyglycolic Acid - metabolism; polylactide-co-glycolide; Random Allocation; Secondary structure; SIGNALS; Toxicology; Transmission and atomic force microscopy; Tumors; Zeta potential
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2012.12.018

Diabetes is a menacing problem, particularly to inhabitants of groundwater arsenic contaminated areas needing new medical approaches. This study examines if PLGA loaded nano-insulin (NIn), administered either intraperitoneally (i.p.) or through oral route, has a greater cost-effective anti-hyperglycemic potential than that of insulin in chronically arsenite-fed hyperglycemic mice. The particle size, morphology and zeta potential of nano-insulin were determined using dynamic light scattering method, scanning electronic and atomic force microscopies. The ability of the nano-insulin (NIn) to cross the blood–brain barrier (BBB) was also checked. Circular dichroic spectroscopic (CD) data of insulin and nano-insulin in presence or absence of arsenic were compared. Several diabetic markers in different groups of experimental and control mice were assessed. The mitochondrial functioning through indices like cytochrome c, pyruvate-kinase, glucokinase, ATP/ADP ratio, mitochondrial membrane potential, cell membrane potential and calcium-ion level was also evaluated. Expressions of the relevant marker proteins and mRNAs like insulin, GLUT2, GLUT4, IRS1, IRS2, UCP2, PI3, PPARγ, CYP1A1, Bcl2, caspase3 and p38 for tracking-down the signaling cascade were also analyzed. Results revealed that i.p.-injected nano-encapsulated-insulin showed better results; NIn, due to its smaller size, faster mobility, site-specific release, could cross BBB and showed positive modulation in mitochondrial signaling cascades and other downstream signaling molecules in reducing arsenic-induced-hyperglycemia. CD data indicated that nano-insulin had less distorted secondary structure as compared with that of insulin in presence of arsenic. Thus, overall analyses revealed that PLGA nano-insulin showed better efficacy in combating arsenite-induced-hyperglycemia than that of insulin and therefore, has greater potentials for use in nano-encapsulated form. [Display omitted] ► PLGA encapsulated nano-insulin attenuates arsenic-induced diabetes in mice. ► Encapsulated insulin acts effectively at nearly 10 fold lesser dose than insulin. ► Injection route is more effective than oral administration route. ► Nano-insulin can cross blood–brain barrier with added physiological implications. ► Nano-insulin acts mainly through regulation of mitochondrial signaling cascade.