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1. Vitamin B12 functionalized layer by layer calcium phosphate nanoparticles: A mucoadhesive and pH responsive carrier for improved oral delivery of insulin.

Author

Verma A, Sharma S, Gupta PK, Singh A, Teja BV, Dwivedi P, Gupta GK, Trivedi R, and Mishra PR

Subjects
Administration, Oral, Alginates chemistry, Animals, Caco-2 Cells, Carbodiimides chemistry, Chitosan chemistry, Diabetes Mellitus, Experimental drug therapy, Electrolytes chemistry, Endocytosis, Flow Cytometry, Fluorescein-5-isothiocyanate chemistry, Glucuronic Acid chemistry, Hexuronic Acids chemistry, Humans, Hydrogen-Ion Concentration, Insulin chemistry, Male, Microscopy, Confocal, Microscopy, Fluorescence, Particle Size, Rats, Rats, Wistar, Calcium Phosphates chemistry, Drug Carriers chemistry, Insulin administration & dosage, Nanoparticles chemistry, Vitamin B 12 chemistry
Abstract

The present study investigates the potential of layer by layer coated calcium phosphate nanoparticles - for oral delivery of insulin where Vitamin B12 grafted chitosan and sodium alginate have been used as cationic and anionic polyelectrolyte respectively. The major emphasis has been given on the role Vitamin B12 conjugated chitosan as cationic polyelectrolyte (VitB12-Chi) in the delivery system. VitB12-Chi conjugate was prepared by carbodiimide reaction. The formulated VirB12-Chi-CPNPs were tested for in vitro and in vivo efficacy studies carried out in Caco-2 monolayers and diabetic rats. VitB12-Chi-CPNPs with particle size <250nm and zeta potential+32.56(±2.34) exhibited pH responsive insulin release at simulated gastric fluid and simulated intestinal fluid. Fluorescence microscopy and flow cytometry studies revealed higher uptake of VitB12-Chi-CPNPs in Caco-2 monolayer in comparison to Chi-CPNPs. Further reduction in TEER supported paracellular transport of insulin because of opening of tight epithelial junctions. In vivo intestinal uptake of FITC tagged Vit-B12-Chi-CPNPs from different intestinal segments supported paracellular and receptor mediated uptake of VitB12-Chi-CPNPs. Plasma insulin and blood glucose levels were measured in diabetic rats and showed about four fold increases in insulin bioavailability and sustained hypoglycemic effects up to 12h of administration with VitB12-Chi-CPNPs in comparison to Chi-CPNPs. Results of the study revealed the potential of layer by layer nanoparticles for oral insulin delivery. The study also specifically highlighted the role of VitB12 as a pH sensitive and targeting ligand which significantly participated in enhancing insulin oral bioavailability., Statement of Significance: Oral delivery of insulin is always the most desirable approach for diabetic patients however it's also the most challenging in respect to formulation development due to harsh gastrointestinal conditions. Several groups have been working from decades for oral delivery of insulin. However the beauty of this prototype formulation is that it exhibits the pH responsive behavior in natural condition of gastrointestinal tract. It resists the release of insulin at gastric condition however stimulate the release at intestinal conditions. Apart from pH responsive behavior it utilizes multiple pathways to improve the overall bioavailability of insulin including paracellular transport and receptor mediated endocytosis., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Published
2016
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2. Diatom-inspired skeletonisation of insulin - Mechanistic insights into crystallisation and extracellular bioactivity.

Author

Véliz DS, Alam C, Nietzel T, Wyborski R, Rivero-Müller A, and Alam P

Subjects
Crystallization, Microscopy, Electron, Scanning, Molecular Dynamics Simulation, Spectroscopy, Fourier Transform Infrared, Diatoms physiology, Insulin physiology
Abstract

In this paper, we encage insulin within calcium carbonate by means of a biomineralisation process. We find that both dogbone and crossbone morphologies develop during the crystallisation process. The crystals break down into small nanocrystals after prolonged immersion in phosphate buffer solution, which adhere extracellularly to mammalian cells without causing any observable damage or early cell-death. The mechanisms behind calcium carbonate encaging of single insulin monomers are detailed. This communication elucidates a novel, diatom-inspired approach to the mineral skeletonisation of insulin., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Published
2015
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3. Genetically modified rice seeds accumulating GLP-1 analogue stimulate insulin secretion from a mouse pancreatic beta-cell line.

Author

Sugita K, Endo-Kasahara S, Tada Y, Lijun Y, Yasuda H, Hayashi Y, Jomori T, Ebinuma H, and Takaiwa F

Subjects
Animals, Base Sequence, Cell Line, Genetic Vectors genetics, Globulins genetics, Globulins metabolism, Glucagon genetics, Glucagon-Like Peptide 1, Insulin Secretion, Islets of Langerhans cytology, Mice, Oryza genetics, Peptide Fragments genetics, Protein Precursors genetics, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Recombinant Fusion Proteins pharmacology, Seeds genetics, Glucagon metabolism, Glucagon pharmacology, Insulin metabolism, Islets of Langerhans drug effects, Islets of Langerhans metabolism, Oryza metabolism, Peptide Fragments metabolism, Peptide Fragments pharmacology, Protein Precursors metabolism, Protein Precursors pharmacology, Seeds metabolism
Abstract

Glucagon-like peptide-1 (7-36) amide (GLP-1) is the most potent physiological insulinotropic hormone in humans. We produced large amounts of a GLP-1 analogue, [Ser8, Gln26, Asp34]-GLP-1, which is resistant to trypsin-digestion, as part of a chimeric rice seed storage protein, a 26 kDa globulin, in genetically modified rice seeds. Junction sites between GLP-1 analogue and globulin were replaced by tryptic cleavage sites. The highest level of GLP-1 analogue accumulation was approximately 20-50 microg per seed. We found that GLP-1 analogue derived from trypsin-digested genetically modified rice seeds stimulated insulin secretion from a mouse pancreatic beta-cell line, MIN6.

Published
2005
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4. Cluster Analysis of Physical Activity Patterns, and Relationship with Sedentary Behavior and Healthy Lifestyles in Prepubertal Children: Genobox Cohort

Author

Gloria Bueno, Francisco Jesus Llorente-Cantarero, Concepción M. Aguilera, Juan Jose Bedoya-Carpente, Augusto Anguita-Ruiz, Mercedes Gil-Campos, Jose Manuel Jurado-Castro, Rosaura Leis, Azahara Iris-Rupérez, Rocío Vázquez-Cobela, Universidade de Santiago de Compostela. Departamento de Ciencias Forenses, Anatomía Patolóxica, Xinecoloxía e Obstetricia, e Pediatría, [Leis,R, Bedoya-Carpente,JJ, Vázquez-Cobela,R] Unidad de Investigación en Nutrición, Crecimiento y Desarrollo Humano de Galicia, Departamento de Pediatría, Hospital Clínico Universitario de Santiago, Universidad de Santiago de Compostela, IDIS, Santiago de Compostela, Spain. [Leis,R, Llorente-Cantarero,FJ, Anguita-Ruiz,A, Vázquez-Cobela,R, Aguilera,CM, Bueno,G, Gil-Campos,M] CIBEROBN, (Physiopathology of Obesity and Nutrition) Institute of Health Carlos III (ISCIII), Madrid, Spain. [Jurado-Castro,JM, Gil-Campos,M] Metabolism and Investigation Unit, Reina Sofia University Hospital, Maimónides Institute of Biomedicine Research of Córdoba (IMIBIC), University of Córdoba, Córdoba, Spain. [Llorente-Cantarero,FJ] Department of Artistic and Corporal Education, Faculty of Education, University of Córdoba, Córdoba, Spain. [Anguita-Ruiz,A, Aguilera,CM] Department of Biochemistry and Molecular Biology II, Institute of Nutrition and Food Technology 'José Mataix', Center of Biomedical Research, University of Granada, Armilla, Granada, Spain. [Anguita-Ruiz,A, Aguilera,CM] Instituto de Investigación Biosanitaria ibs, Granada, Spain. [Iris-Rupérez,A] GENUD Research Group, University of Zaragoza, Instituto Agroalimentario de Aragón (IA2), Instituto de Investigación Sanitaria (IIS) Aragón, Zaragoza, Spain. [Bueno,G] Unidad de Endocrinología Pediátrica, Hospital Clínico Lozano Blesa, Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain., and This work was supported bythe Plan Nacional de Investigación Científica, Desarrollo e InnovaciónTecnológica (I + D + I), Instituto de Salud Carlos III-Health Research Funding (FONDOS FEDER) (PI051968, PI1102042 and PI1600871) and Redes temáticas de investigación cooperativa RETIC (Red SAMID RD12/0026/0015). The authors also acknowledge Instituto de Salud Carlos III for personal funding of A.A.-R: Contratos i-PFIS: doctorados IIS empresa en ciencias y tecnologías de la salud de la convocatoria 2017 de la Acción Estratégica en Salud 2013–2016 (IFI17/00048).This paper will be included in J.M.J.-C. doctorate, under the 'Social and Legal Sciences Program' at theUniversity of Córdoba, Spain.

Subjects
Male, obesity, Mediterranean diet, Health Behavior, Obesidad, Child Behavior, Diet, Mediterranean, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Cohort Studies, 0302 clinical medicine, Surveys and Questionnaires, Cluster Analysis, Insulin, 030212 general & internal medicine, skin and connective tissue diseases, Child, Chemicals and Drugs::Lipids::Glycerides::Triglycerides [Medical Subject Headings], Nutrition and Dietetics, exercise, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Behavior::Health Behavior [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Nutrition Therapy::Diet Therapy::Diet, Mediterranean [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Equipment and Supplies::Electrical Equipment and Supplies [Medical Subject Headings], Conducta sedentaria, Ejercicio físico, Cardiovascular diseases, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Behavior::Child Behavior [Medical Subject Headings], Cohort, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Health Surveys::Nutrition Surveys::Diet Surveys [Medical Subject Headings], Female, Anthropology, Education, Sociology and Social Phenomena::Human Activities::Leisure Activities::Recreation::Sports [Medical Subject Headings], Club, Enfermedades cardiovasculares, lcsh:Nutrition. Foods and food supply, Sports, musculoskeletal diseases, Electrical Equipment and Supplies, Anatomy::Digestive System::Pancreas::Islets of Langerhans::Insulin-Secreting Cells [Medical Subject Headings], Physical activity, Check Tags::Male [Medical Subject Headings], 030209 endocrinology & metabolism, lcsh:TX341-641, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Cluster Analysis [Medical Subject Headings], Disease cluster, Article, Information Science::Information Science::Data Collection::Questionnaires [Medical Subject Headings], 03 medical and health sciences, Screen time, Environmental health, Anthropology, Education, Sociology and Social Phenomena::Human Activities::Exercise [Medical Subject Headings], medicine, Humans, Persons::Persons::Age Groups::Child [Medical Subject Headings], Healthy Lifestyle, Obesity, Exercise, Triglycerides, business.industry, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Psychology, Social::Life Style [Medical Subject Headings], Anthropometry, medicine.disease, Dieta mediterránea, cardiovascular diseases, stomatognathic diseases, Check Tags::Female [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies [Medical Subject Headings], Sedentary Behavior, business, Food Science
Abstract

The authors would like to thank the children and parents who participated in the study and Ana Yara Postigo-Fuentes for the assistance with the English editing., Sedentary habits during childhood are associated with adverse health outcomes. The aim of this work was to cluster lifestyle behaviors and metabolic biomarkers to establish different patterns in children. Their physical and sedentary activities were evaluated by accelerometry, and questionnaires that included lifestyle behaviors, such as adherence to a Mediterranean diet, anthropometry and blood biochemical markers. Cluster analysis was performed to establish different groups based on physical activity levels. A total of 489 children were finally selected. Cluster 1 included children with a mostly sedentary state, whereas Cluster 3 included the most active children and Cluster 2 included children that did not fit into either the sedentary or the highly active groups. In Cluster 3, 56% of children were in a sports club, and a lower percentage used electronic devices in their rooms compared to the other groups. Cluster 1 children exhibited higher insulin, HOMA-IR and triacylglycerides with respect to the other groups. No differences were found regarding adherence to a Mediterranean diet. The choice to practice an extracurricular sport could be an influencing factor to increase exercise and ensure an active lifestyle in children. Reducing or limiting screen time mainly in children’s rooms could contribute to an active lifestyle., Plan Nacional de Investigacion Cientifica, Desarrollo e InnovacionTecnologica (I + D + I), Instituto de Salud Carlos III-Health Research Funding (FONDOS FEDER) PI051968 PI1102042 PI1600871, Redes tematicas de investigacion cooperativa RETIC (Red SAMID) RD12/0026/0015, Instituto de Salud Carlos III IFI17/00048

Published
2020

5. Impact of therapy escalation on ambulatory care costs among patients with type 2 diabetes in France

Author

Florent Guelfucci, Mondher Toumi, Samuel Aballéa, Nicholas Moore, Emilie Clay, Régis Lassalle, Systèmes Intégrés, Environnement et Biodiversité (SIEB), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-HESAM Université (HESAM), Evaluation des systèmes de soins et santé perçue, Université de la Méditerranée - Aix-Marseille 2, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Pharmaco-Epidémiologie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), This study was supported by an unconditional grant from Boehringer Ingelheim. The sponsor had no influence on study design, conduct, analysis or interpretation, or in the writing of this paper., École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), and BMC, Ed.

Subjects
medicine.medical_specialty, medicine.medical_treatment, Endocrinology, Diabetes and Metabolism, Pharmacy, Type 2 diabetes, 03 medical and health sciences, Nursing care, 0302 clinical medicine, Ambulatory care, Internal medicine, Diabetes mellitus, Type 2 diabetes mellitus, medicine, Cost analysis, Insulin, 030212 general & internal medicine, Oral antidiabetics, health care economics and organizations, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, business.industry, 030503 health policy & services, Type 2 Diabetes Mellitus, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Endocrinology, Ambulatory, 0305 other medical science, business, Research Article, Renal function
Abstract

International audience; BACKGROUND: This study compares annual ambulatory care expenditures per patient with type 2 diabetes mellitus (T2DM) in France according to treatment phase and renal function status. METHODS: Records from patients with T2DM were extracted from a health insurance database. Patients were classified in subgroups, by treatment phase: oral/GLP1 monotherapy, double therapy, triple therapy or insulin therapy, and according to renal function status (identified using pharmacy, lab and consultation claims). Annual ambulatory expenditures were estimated from the national insurance perspective by year (from 2005 to 2010) and subgroup. RESULTS: The number of patients ranged from 9,682 to 11,772 between 2005 and 2010. The average annual expenditure per individual in 2010 ranged from [euro sign]3,017 (standard deviation: [euro sign]3,829) for monotherapy to [euro sign]3,609 +/- [euro sign]3,801 for triple therapy, and [euro sign]7,398 +/- [euro sign]5,487 with insulin (adjusted ratio insulin therapy/monotherapy: 2.36, p < 0.001). Similar differences between treatement stages were found in previous years. Additional costs for insulin were mainly related to nursing care (multiplied by 18.42, p < 0.001), medical devices and pharmacy costs. DM-attributable drug costs were mainly related to antidiabetic drugs (28% for monotherapy to 71% for triple therapy), but also to cardiovascular system drugs (21% for monotherapy to 51% with insulin) and nervous system drugs (up to 8% with insulin). Declining renal function was associated with an increase in expenses by 12% to 53% according to treatment stage. CONCLUSIONS: Overall, ambulatory care expenditures increase with treatment escalation and declining renal function amongst patients with T2DM. Insulin therapy is associated with substantially increased costs, related to pharmacy, nursing care and medical device costs.

Published
2013