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Yaseen Z, Nandave M, Sharma L. Anti-diabetic Biologicals: Exploring the Role of Different Analytical Techniques. Crit Rev Anal Chem 2025:1-22. [PMID: 40088445 DOI: 10.1080/10408347.2025.2472793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2025]
Abstract
Antidiabetic biologicals (ADBs) have revolutionized the treatment of diabetes mellitus, once considered incurable through conventional medicine. These biological products, derived from natural sources via extraction, semi-synthesis, or recombinant DNA technology, include insulin and its analogs, GLP-1 receptor agonists, amylin analogs, and the recently approved monoclonal antibody teplizumab. Regulatory authorities worldwide have established QC parameters outlined in pharmacopoeias, alongside analytical techniques to ensure their safety and efficacy. This review focuses on the analytical techniques used to assess QC parameters of ADBs, including chromatographic methods, spectroscopic techniques, capillary electrophoresis, immunoassays, and endotoxin testing. Key parameters such as identification, potency, purity, and impurity profiling are thoroughly examined. The paper provides a comprehensive and up-to-date compilation of QC requirements and methodologies, along with a detailed comparison of analytical techniques. In doing so, it highlights their advantages and limitations, offering valuable insights for researchers and regulatory professionals involved in selecting suitable methods for QC assessment and understanding the complexities of ADBs evaluation. Furthermore, the article discusses the paramount importance of QC and future perspectives, emphasizing the transition to advanced versions of current techniques driven by the need for efficiency and reliability in quality testing.
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Affiliation(s)
- Zahid Yaseen
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology and Management Sciences, Solan, Himachal Pradesh, India
- Department of Pharmaceutical Biotechnology, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, India
| | - Mukesh Nandave
- Department of Pharmacology, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, India
| | - Lalit Sharma
- Department of Pharmacology, School of Pharmaceutical Sciences, Shoolini University of Biotechnology and Management Sciences, Solan, Himachal Pradesh, India
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2
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Khalifa AK, Abdelrahim DS, Mekawy DM, Hamed RMR, Mohamed WR, Ramadan NM, Wael M, Ellackany R, Albadawi EA, Osman WA. New horizon of the combined BCG vaccine with probiotic and liraglutide in augmenting beta cell survival via suppression of TXNIP/NLRP3 pyroptosis signaling in Streptozocin-Induced diabetes mellitestype-1 in rats. Heliyon 2024; 10:e38932. [PMID: 39640632 PMCID: PMC11620097 DOI: 10.1016/j.heliyon.2024.e38932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 10/01/2024] [Accepted: 10/02/2024] [Indexed: 12/07/2024] Open
Abstract
Background An ideal anti-diabetic type-1 pharmacotherapy should combine abrogation of beta cell pyroptosis with enhancement of beta cell mass. Objectives The study investigated the potential synergism from combining the Bacillus Calmette-Guerin (BCG) vaccine with liraglutide (LIR) and probiotics in mitigating Streptozocin (STZ)-induced Type1diabetes mellitus in albino rats via suppression of TXNIP/NLRP3 signaling. Methods: Induction of diabetes was performed by two I.V. injections of 50 mg/kg of STZ in male Wistar rats. Forty-eight rats were randomly allocated into six groups: Normal control group; STZ -diabetic group; BCG group; BCG + LIR group; BCG + probiotic group; BCG + LIR + probiotic group. The rats were sacrificed after 8 weeks of treatment. Results The STZ-diabetic group exhibited significant elevation of fasting blood sugar and HbA1c with remarkably decreased serum insulin along with a considerable increase in pancreatic proinflammatory cytokines (TNF-α, NLRP3, IL-1β, and NFκB) and apoptotic markers (ASK-1, IAPP, TXNIP, and Caspase-3) with prominently compromised oxidative scavenging capacity in addition to structural alteration in the pancreatic histoarchitecture with decreased insulin immunostaining. Conversely, diabetic-treated groups, especially the BCG + LIR + probiotic group, were superior in amelioration of STZ-induced pyroptosis of pancreatic islets evidenced by a significant decline in inflammatory cytokines and apoptotic markers with a remarkable upgrade in redox balance, Furthermore, the mitigation in the altered histopathological picture of the pancreas with enhanced insulin immunostaining has been was mirrored on the significant improvement of glucose homeostasis parameters. Conclusions Noteworthy, BCG combination with liraglutide and probiotic might be a promising repurposed therapeutic modality in the management of type-1 diabetes mellites via targeting pancreatic TXNIP/NLRP3 signaling pathway.
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Affiliation(s)
- Amira Karam Khalifa
- Department of Medical Pharmacology, Faculty of Medicine, Cairo University, El- Manial, Cairo 11562, Egypt
- Department of Medical Pharmacology, Faculty of Medicine, Nahda University, 62521, Beni Suef, Egypt
| | - Dina Sayed Abdelrahim
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Egypt
- Department of Pharmacology, Faculty of Medicine, Modern University for Technology and Information, Cairo, Egypt
| | - Dina Mohamed Mekawy
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Badr University in Cairo, Badr City, Egypt
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Wafaa Rabee Mohamed
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Egypt
- Department of Histology and Cell Biology, Faculty of Medicine, Modern University for Technology and Information, Egypt
| | - Nagwa Mahmoud Ramadan
- Department of Physiology, Faculty of Medicine, Cairo University, El Manial, Cairo 11562, Egypt
| | - Mostafa Wael
- Faculty of Medicine, Modern University for Technology and Information, Cairo, Egypt
| | - Rawan Ellackany
- Faculty of Medicine, Modern University for Technology and Information, Cairo, Egypt
| | - Emad Ali Albadawi
- Department of Basic Medical Science, College of Medicine, Taibah University, KSA, Saudi Arabia
| | - Walla'a A. Osman
- Department of Medical Pharmacology, Faculty of Medicine, Cairo University, El- Manial, Cairo 11562, Egypt
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Attri B, Nagendra L, Dutta D, Shetty S, Shaikh S, Kalra S, Bhattacharya S. Prandial Insulins: A Person-Centered Choice. Curr Diab Rep 2024; 24:131-145. [PMID: 38568467 DOI: 10.1007/s11892-024-01540-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/21/2024] [Indexed: 05/12/2024]
Abstract
PURPOSE OF REVIEW Postprandial hyperglycemia, or elevated blood glucose after meals, is associated with the development and progression of various diabetes-related complications. Prandial insulins are designed to replicate the natural insulin release after meals and are highly effective in managing post-meal glucose spikes. Currently, different types of prandial insulins are available such as human regular insulin, rapid-acting analogs, ultra-rapid-acting analogs, and inhaled insulins. Knowledge about diverse landscape of prandial insulin will optimize glycemic management. RECENT FINDINGS Human regular insulin, identical to insulin produced by the human pancreas, has a slower onset and extended duration, potentially leading to post-meal hyperglycemia and later hypoglycemia. In contrast, rapid-acting analogs, such as lispro, aspart, and glulisine, are new insulin types with amino acid modifications that enhance their subcutaneous absorption, resulting in a faster onset and shorter action duration. Ultra-rapid analogs, like faster aspart and ultra-rapid lispro, offer even shorter onset of action, providing better meal-time flexibility. The Technosphere insulin offers an inhaled route for prandial insulin delivery. The prandial insulins can be incorporated into basal-bolus, basal plus, or prandial-only regimens or delivered through insulin pumps. Human regular insulin, aspart, lispro, and faster aspart are recommended for management of hyperglycemia during pregnancy. Ongoing research is focused on refining prandial insulin replacement and exploring newer delivery methods. The article provides a comprehensive overview of various prandial insulin options and their clinical applications in the management of diabetes.
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Affiliation(s)
- Bhawna Attri
- Department of Endocrinology, Sarvodaya Hospital, Faridabad, Haryana, India
| | - Lakshmi Nagendra
- Department of Endocrinology, JSS Medical College and Hospital, JSS Academy of Higher Education and Research, Mysore, Karnataka, India
| | - Deep Dutta
- Department of Endocrinology, Center for Endocrinology Diabetes Arthritis and Rheumatism (CEDAR) Super-Speciality Healthcare, Dwarka, Delhi, India
| | - Sahana Shetty
- Department of Endocrinology, Kasturba Medical College, Manipal, Karnataka, India
| | - Shehla Shaikh
- Department of Endocrinology, Saifee Hospital, Mumbai, Maharashtra, India
| | - Sanjay Kalra
- Department of Endocrinology, Bharti Hospital, Karnal, Haryana, India
| | - Saptarshi Bhattacharya
- Department of Endocrinology, Indraprastha Apollo Hospitals, Sarita Vihar, Mathura Road, Delhi, 110076, India.
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Hadid S, Zhang E, Frishman WH, Brutsaert E. Insulin's Legacy: A Century of Breakthroughs and Innovation. Cardiol Rev 2024:00045415-990000000-00229. [PMID: 38477588 DOI: 10.1097/crd.0000000000000680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/14/2024]
Abstract
The clinical use of insulin to treat diabetes started just over 100 years ago. The past century has witnessed remarkable innovations in insulin therapy, evolving from animal organ extracts to bioengineered human insulins with ultra-rapid onset or prolonged action. Insulin delivery systems have also progressed to current automated insulin delivery systems. In this review, we discuss the history of insulin and the pharmacology and therapeutic indications for a variety of available insulins, especially newer analog insulins. We highlight recent advances in insulin pump therapy and review evidence on the therapeutic benefits of automated insulin delivery. As with any form of progress, there have been setbacks, and insulin has recently faced an affordability crisis. We address the challenges of insulin accessibility, along with recent progress to improve insulin affordability. Finally, we mention research on glucose-responsive insulins and hepato-preferential insulins that are likely to shape the future of insulin therapy.
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Affiliation(s)
- Somar Hadid
- From the School of Medicine, New York Medical College, Valhalla NY
| | - Emily Zhang
- From the School of Medicine, New York Medical College, Valhalla NY
| | - William H Frishman
- From the School of Medicine, New York Medical College, Valhalla NY
- Department of Cardiology, Westchester Medical Center, Valhalla NY
| | - Erika Brutsaert
- From the School of Medicine, New York Medical College, Valhalla NY
- Department of Endocrinology, Westchester Medical Center, Hawthorne NY
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Shankar K, Ramborger J, Bonnet-Zahedi S, Carrette LLG, George O. Acute nicotine intake increases feeding behavior through decreasing glucagon signaling in dependent male and female rats. Horm Behav 2024; 159:105447. [PMID: 37926623 PMCID: PMC11384237 DOI: 10.1016/j.yhbeh.2023.105447] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 09/26/2023] [Accepted: 10/20/2023] [Indexed: 11/07/2023]
Abstract
Chronic use of nicotine is known to dysregulate metabolic signaling through altering circulating levels of feeding-related hormones, contributing to the onset of disorders like type 2 diabetes. However, little is known about the acute effects of nicotine on hormonal signaling. We previously identified an acute increase in food intake following acute nicotine, and we sought to determine whether this behavior was due to a change in hormone levels. We first identified that acute nicotine injection produces an increase in feeding behavior in dependent rats, but not nondependent rats. We confirmed that chronic nicotine use increases circulating levels of insulin, leptin, and ghrelin, and these correlate with rats' body weight and food intake. Acute nicotine injection in dependent animals decreased circulating GLP-1 and glucagon levels, and administration of glucagon prior to acute nicotine injection prevented the acute increase in feeding behavior. Thus, acute nicotine injection increases feeding behavior in dependent rats by decreasing glucagon signaling.
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Affiliation(s)
- Kokila Shankar
- Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA; The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Jarryd Ramborger
- Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
| | - Sélène Bonnet-Zahedi
- Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA; Institut de Neurosciences de la Timone, Aix-Marseille Université, Marseille 13005, France
| | - Lieselot L G Carrette
- Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
| | - Olivier George
- Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA.
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Joshi S, Jayanth V, Loganathan S, Sambandamurthy VK, Athalye SN. Insulin Tregopil: An Ultra-Fast Oral Recombinant Human Insulin Analog: Preclinical and Clinical Development in Diabetes Mellitus. Drugs 2023; 83:1161-1178. [PMID: 37578592 DOI: 10.1007/s40265-023-01925-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2023] [Indexed: 08/15/2023]
Abstract
Insulin therapy is indispensable for achieving glycemic control in all patients with type 1 diabetes mellitus and many patients with type 2 diabetes mellitus. Insulin injections are associated with negative connotations in patients owing to administration discomfort and adverse effects such as hypoglycemia and weight gain. Insulin administered orally can overcome these limitations by providing a convenient and effective mode of delivery with a potentially lower risk of hypoglycemia. Oral insulin mimics the physiologic process of insulin secretion, absorption into the portal circulation, and subsequent peripheral delivery, unlike the subcutaneous route that results in peripheral hyperinsulinemia. Insulin tregopil (IN-105), a new generation human recombinant insulin, methoxy (polyethylene glycol) hexanoyl human recombinant insulin, is developed by Biocon as an ultra-fast onset short-acting oral insulin analog. This recombinant oral insulin is a single short-chain amphiphilic oligomer modified with the covalent attachment of methoxy-triethylene-glycol-propionyl moiety at Lys-β29-amino group of the B-chain via an amide linkage. Sodium caprate, an excipient in the insulin tregopil formulation, is a permeation enhancer that increases its absorption through the gastrointestinal tract. Also, meal composition has been shown to non-significantly affect its absorption. Several global randomized, controlled clinical trials have been conducted in type 1 and type 2 diabetes patients towards the clinical development of insulin tregopil. The formulation shows post-prandial glucose control that is more effective than placebo throughout the meal period; however, compared with an active comparator insulin aspart, the post-prandial control is more effective mainly in the early post-meal period. It shows a good safety profile with a lower incidence of clinically significant hypoglycemia. This review covers the overall clinical development of insulin tregopil establishing it as an ultra-fast onset, short-acting oral insulin analog for optimizing post-prandial glucose.
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Affiliation(s)
- Shashank Joshi
- Joshi Clinic and Lilavati Hospital, Mumbai, Maharashtra, India
| | - Vathsala Jayanth
- Biocon Biologics Ltd, Biocon House, Semicon Park, Electronic City Phase 2, Bengaluru, Karnataka, 560100, India
| | - Subramanian Loganathan
- Biocon Biologics Ltd, Biocon House, Semicon Park, Electronic City Phase 2, Bengaluru, Karnataka, 560100, India.
| | | | - Sandeep N Athalye
- Biocon Biologics Ltd, Biocon House, Semicon Park, Electronic City Phase 2, Bengaluru, Karnataka, 560100, India
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Elsayed S, Soliman AT, De Sanctis V, Fawzy D, Ahmed S, Alaaraj N. Insulin-induced lipodystrophy and predisposing factors in children and adolescents with type 1 diabetes mellitus (T1DM) in a tertiary care Egyptian center. ACTA BIO-MEDICA : ATENEI PARMENSIS 2023; 94:e2023078. [PMID: 37326270 PMCID: PMC10308467 DOI: 10.23750/abm.v94i3.14117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Accepted: 01/04/2023] [Indexed: 06/17/2023]
Abstract
BACKGROUND Lipodystrophy (LH) is one of the most common complications of subcutaneous insulin injection. Many factors are incriminated in the evolution of LH in children with diabetes type 1 (T1DM). LH may affect insulin absorption in the skin areas involved, resulting in a negative impact on blood glucose levels and glycemic variability. PATIENTS AND METHODS We calculated and evaluated the prevalence of LH in relation to possible clinical factors associated with the development of LH in a cohort of children (n =115) with T1DM using insulin pens or syringes and we studied possible predisposing factors including their age, duration of T1DM, injection technique, insulin dose/kg, degree of pain perception, and HbA1c level. RESULTS In our cross-sectional study, 84% of patients were using pens for insulin injection and 52.2 % of them were rotating the site of injection on daily basis. 27 % did not experience pain during an injection while 6 % had the worst hurt. 49.5 % had clinically detectable LH. Those with LH had higher HbA1c levels and more unexplained hypoglycemic events compared to those without LH (P: 0.058). The hypertrophied site was related to the preferred site of injection which was the arms in 71.9 % of the cases. Children who had LH were older with a longer duration of T1DM, rotating sites of injection less frequently, and were more frequently reusing needles compared to children without LH (P: < 0.05). CONCLUSION Improper insulin injection technique, older age, and longer duration of T1DM were associated with LH. Proper education of patients and their parents must include correct injection techniques, rotating injection sites, and minimal reuse of needles.
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Affiliation(s)
- Shaymaa Elsayed
- Pediatric Endocrinology and Diabetology Unit, Faculty of Medicine, Alexandria University, Egypt.
| | | | - Vincenzo De Sanctis
- Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara, Italy.
| | - Dina Fawzy
- Pediatric Endocrinology and Diabetology Unit, Faculty of Medicine, Alexandria University, Egypt.
| | - Shaymaa Ahmed
- Department of Pediatrics, Hamad General Hospital, Doha, Qatar.
| | - Nada Alaaraj
- Department of Pediatrics, Hamad General Hospital, Doha, Qatar.
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Curreri AM, Kim J, Dunne M, Angsantikul P, Goetz M, Gao Y, Mitragotri S. Deep Eutectic Solvents for Subcutaneous Delivery of Protein Therapeutics. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2205389. [PMID: 36642846 PMCID: PMC9982585 DOI: 10.1002/advs.202205389] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 11/17/2022] [Indexed: 05/14/2023]
Abstract
Proteins are among the most common therapeutics for the treatment of diabetes, autoimmune diseases, cancer, and metabolic diseases, among others. Despite their common use, current protein therapies, most of which are injectables, have several limitations. Large proteins such as monoclonal antibodies (mAbs) suffer from poor absorption after subcutaneous injections, thus forcing their administration by intravenous injections. Even small proteins such as insulin suffer from slow pharmacokinetics which poses limitations in effective management of diabetes. Here, a deep eutectic-based delivery strategy is used to offer a generalized approach for improving protein absorption after subcutaneous injections. The lead formulation enhances absorption of mAbs after subcutaneous injections by ≈200%. The same composition also improves systemic absorption of subcutaneously injected insulin faster than Humalog, the current gold-standard of rapid acting insulin. Mechanistic studies reveal that the beneficial effect of deep eutectics on subcutaneous absorption is mediated by their ability to reduce the interactions of proteins with the subcutaneous matrix, especially collagen. Studies also confirm that these deep eutectics are safe for subcutaneous injections. Deep eutectic-based formulations described here open new possibilities for subcutaneous injections of therapeutic proteins.
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Affiliation(s)
- Alexander M. Curreri
- John A. Paulson School of Engineering and Applied SciencesHarvard University150 Western AveAllstonMA02134USA
- Wyss Institute for Biologically Inspired Engineering at Harvard University3 Blackfan StBostonMA02115USA
| | - Jayoung Kim
- John A. Paulson School of Engineering and Applied SciencesHarvard University150 Western AveAllstonMA02134USA
- Wyss Institute for Biologically Inspired Engineering at Harvard University3 Blackfan StBostonMA02115USA
| | - Michael Dunne
- John A. Paulson School of Engineering and Applied SciencesHarvard University150 Western AveAllstonMA02134USA
- Wyss Institute for Biologically Inspired Engineering at Harvard University3 Blackfan StBostonMA02115USA
| | - Pavimol Angsantikul
- John A. Paulson School of Engineering and Applied SciencesHarvard University150 Western AveAllstonMA02134USA
- Wyss Institute for Biologically Inspired Engineering at Harvard University3 Blackfan StBostonMA02115USA
- Present address:
The Population CouncilOne Dag Hammarskjold PlazaNew YorkNY10017USA
| | - Morgan Goetz
- John A. Paulson School of Engineering and Applied SciencesHarvard University150 Western AveAllstonMA02134USA
- Wyss Institute for Biologically Inspired Engineering at Harvard University3 Blackfan StBostonMA02115USA
| | - Yongsheng Gao
- John A. Paulson School of Engineering and Applied SciencesHarvard University150 Western AveAllstonMA02134USA
- Wyss Institute for Biologically Inspired Engineering at Harvard University3 Blackfan StBostonMA02115USA
| | - Samir Mitragotri
- John A. Paulson School of Engineering and Applied SciencesHarvard University150 Western AveAllstonMA02134USA
- Wyss Institute for Biologically Inspired Engineering at Harvard University3 Blackfan StBostonMA02115USA
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Eksi YE, Bisgin A, Sanlioglu AD, Azizoglu RO, Balci MK, Griffith TS, Sanlioglu S. Generation of a Beta-Cell Transplant Animal Model of Diabetes Using CRISPR Technology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1409:145-159. [PMID: 36289162 DOI: 10.1007/5584_2022_746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Since insulin deficiency results from pancreatic beta-cell destruction, all type 1 and most type 2 diabetes patients eventually require life-long insulin injections. Insulin gene synthesis could also be impaired due to insulin gene mutations as observed in diabetic patients with MODY 10. At this point, insulin gene therapy could be very effective to recompense insulin deficiency under these circumstances. For this reason, an HIV-based lentiviral vector carrying the insulin gene under the control of insulin promoter (LentiINS) was generated, and its therapeutic efficacy was tested in a beta-cell transplant model lacking insulin produced by CRISPR/Cas9-mediated genetically engineered pancreatic beta cells. To generate an insulin knockout beta-cell transplant animal model of diabetes, a dual gene knockout plasmid system involving CRISPR/Cas9 was transfected into a mouse pancreatic beta cell line (Min6). Fluorescence microscopy and antibiotic selection were utilized to select the insulin gene knockout clones. Transplantation of the genetically engineered pancreatic beta cells under the kidney capsule of STZ-induced diabetic rats revealed LentiINS- but not LentiLacZ-infected Ins2KO cells transiently reduced hyperglycemia similar to that of MIN6 in diabetic animals. These results suggest LentiINS has the potential to functionally restore insulin production in an insulin knockout beta-cell transplant animal model of diabetes.
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Affiliation(s)
- Yunus Emre Eksi
- Department of Gene and Cell Therapy, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Atil Bisgin
- Department of Medical Genetics, Cukurova University, Faculty of Medicine, Adana, Turkey
| | - Ahter D Sanlioglu
- Department of Gene and Cell Therapy, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Reha Onur Azizoglu
- Department of Gene and Cell Therapy, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Mustafa Kemal Balci
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Thomas S Griffith
- Department of Urology, University of Minnesota, School of Medicine, Minneapolis, MN, USA
| | - Salih Sanlioglu
- Department of Gene and Cell Therapy, Akdeniz University Faculty of Medicine, Antalya, Turkey.
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Lebovitz HE, Fleming A, Cherrington AD, Joshi S, Athalye SN, Loganathan S, Vishweswaramurthy A, Panda J, Marwah A. Efficacy and safety of Tregopil, a novel, ultra-rapid acting oral prandial insulin analog, as part of a basal-bolus regimen in type 2 diabetes: a randomized, active-controlled phase 2/3 study. Expert Opin Pharmacother 2022; 23:1855-1863. [DOI: 10.1080/14656566.2022.2141569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Harold E Lebovitz
- Department of Medicine, State University of New York Health Science Center at Brooklyn, Brooklyn, NY, USA
| | | | - Alan D Cherrington
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine-Basic Sciences, Nashville, TENN, USA
| | - Shashank Joshi
- Consultant Endocrinologist, Joshi Clinic and Lilavati Hospital, Mumbai, India
| | - Sandeep N Athalye
- Clinical Development and Medical Affairs, Biocon Biologics Limited, Bengaluru, Karnataka, India
| | - Subramanian Loganathan
- Clinical Development and Medical Affairs, Biocon Biologics Limited, Bengaluru, Karnataka, India
| | | | - Jayanti Panda
- Clinical Development and Medical Affairs, Biocon Biologics Limited, Bengaluru, Karnataka, India
| | - Ashwani Marwah
- Clinical Development and Medical Affairs, Biocon Biologics Limited, Bengaluru, Karnataka, India
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11
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Šakić Z, Rudež KD, Radoš Kajić A, Klobučar Majanović S, Rahelić D. CELEBRATING 100 YEARS OF INSULIN USE. Acta Clin Croat 2022; 61:482-487. [PMID: 37492355 PMCID: PMC10364106 DOI: 10.20471/acc.2022.61.03.13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 02/08/2022] [Indexed: 07/27/2023] Open
Abstract
The year 2022 marked the one-hundredth anniversary of the first application of insulin. November 14th, the birth date of one of its main discoverers, Frederick Banting, was designated as World Diabetes Day. This paper comprises a narrative review of the history of the discovery of diabetes and insulin, progress in insulin development, important breakthroughs in insulin production and delivery, and a short commentary regarding potential future developments in insulin treatment. Diabetes, as one of the earliest recorded illnesses in medical writings, has been a focus of research for almost the entire written human history. Groundbreaking discoveries during the early 20th century have resulted in type 1 diabetes mellitus becoming a treatable, chronic condition. The relationship between good glycemic control and reduced occurrence of diabetes complications was established, which has enticed further development and refinements in insulin treatment, ranging from the purification and increased quality of insulin itself, as well as various inventions in its administration. Despite great achievements in insulin therapy so far, future research aims to avoid the need for subcutaneous administration and to create non-invasive means of insulin application.
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Affiliation(s)
- Zrinka Šakić
- Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Merkur University Hospital, Zagreb, Croatia
| | - Kristian Dominik Rudež
- Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Merkur University Hospital, Zagreb, Croatia
| | - Anica Radoš Kajić
- Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Merkur University Hospital, Zagreb, Croatia
| | - Sanja Klobučar Majanović
- Department of Endocrinology, Diabetes and Metabolic Diseases, Clinical Hospital Center Rijeka, Rijeka, Croatia
- Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Dario Rahelić
- Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Merkur University Hospital, Zagreb, Croatia
- Catholic University of Croatia School of Medicine, Zagreb, Croatia
- Josip Juraj Strossmayer University School of Medicine, Osijek, Croatia
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12
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Al Hayek AA, Alwin Robert A, Al Saeed AH, Al Dawish MA. Evaluation of Patient Reported Satisfaction and Clinical Efficacy of Insulin Glargine 300 U/mL Versus 100 U/mL in Patients With Type 1 Diabetes Using Flash Glucose Monitoring System. Clin Med Insights Endocrinol Diabetes 2022; 15:11795514221098415. [PMID: 35601879 PMCID: PMC9121452 DOI: 10.1177/11795514221098415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 04/08/2022] [Indexed: 11/16/2022] Open
Abstract
Background and Aims: To analyze patient-reported satisfaction and clinical effectiveness of
concentrated insulin glargine 300 U/mL (Gla-300) among patients with type 1
diabetes (T1D) using a flash glucose monitoring (FGM) system. Methods: This comparative study was conducted among 86 patients with T1D (aged
14-40 years), who were treated with Glargine 100 U/mL (Gla-100) and switched
to Gla-300 at day 1 (baseline). The following data were collected from each
patient: demographic information, clinical parameters, and glycemic control
markers. All patients completed the Diabetes Treatment Satisfaction
Questionnaire (Arabic version), first at baseline and then after 12 weeks. A
comparison was done for all the data recorded at baseline (on Gla-100) and
after 12 weeks (on Gla-300) and subjected to analysis. Results: Compared to patients treated with Gla-100, significant improvements were
observed in the Gla-300 group, in terms of the ambulatory glucose profile
(AGP) markers, such as percentage of time spent within the target range of
the glucose levels (70-180 mg/dL) (P = .037), percentage
which fell below the target (<70 mg/dL) (P = .027), and
percentage of time spent (<54 mg/dL) (P = .043).
Compared to Gla-100, patients treated with Gla-300 experienced significant
improvements in the current treatment satisfactions
(P = .047), convenient finding treatment recently
(P = .034), and flexible finding treatment recently
(P = .041), recommend the current treatment
(P = .042) and satisfied to continue the current
treatment (P = .035). Conclusion: Compared to the patients on Gla-100, patients treated with Gla-300 exhibited
significant improvements in the AGP markers and degree of treatment
satisfaction.
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Affiliation(s)
- Ayman Abdullah Al Hayek
- Department of Endocrinology and Diabetes, Diabetes Treatment Center, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Asirvatham Alwin Robert
- Department of Endocrinology and Diabetes, Diabetes Treatment Center, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Abdulghani H Al Saeed
- Department of Endocrinology and Diabetes, Diabetes Treatment Center, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Mohamed Abdulaziz Al Dawish
- Department of Endocrinology and Diabetes, Diabetes Treatment Center, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
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13
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Hanif N, Wu H, Xu P, Li Y, Bibi A, Zulfiqar A, Iqbal MZ, Tahir M, Zhang X, Ali A. Proteomic Changes to the Updated Discovery of Engineered Insulin and Its Analogs: Pros and Cons. Curr Issues Mol Biol 2022; 44:867-888. [PMID: 35723344 PMCID: PMC8929101 DOI: 10.3390/cimb44020059] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 02/04/2022] [Accepted: 02/07/2022] [Indexed: 11/17/2022] Open
Abstract
The destruction of β-cells of the pancreas leads to either insulin shortage or the complete absence of insulin, which in turn causes diabetes Mellitus. For treating diabetes, many trials have been conducted since the 19th century until now. In ancient times, insulin from an animal's extract was taken to treat human beings. However, this resulted in some serious allergic reactions. Therefore, scientists and researchers have tried their best to find alternative ways for managing diabetes with progressive advancements in biotechnology. However, a lot of research trials have been conducted, and they discovered more progressed strategies and approaches to treat type I and II diabetes with satisfaction. Still, investigators are finding more appropriate ways to treat diabetes accurately. They formulated insulin analogs that mimic the naturally produced human insulin through recombinant DNA technology and devised many methods for appropriate delivery of insulin. This review will address the following questions: What is insulin preparation? How were these devised and what are the impacts (both positive and negative) of such insulin analogs against TIDM (type-I diabetes mellitus) and TIIDM (type-II diabetes mellitus)? This review article will also demonstrate approaches for the delivery of insulin analogs into the human body and some future directions for further improvement of insulin treatment.
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Affiliation(s)
- Naeema Hanif
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Rice Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (N.H.); (P.X.)
- Department of Biomedical Sciences, National University of Science and Technology, Islamabad 44000, Pakistan
| | - Hezhou Wu
- Hunan Taohuayuan Agricultural Technologies Co., Ltd., Yueyang 415000, China;
| | - Peizhou Xu
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Rice Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (N.H.); (P.X.)
| | - Yun Li
- Chengdu Academy of Agricultural and Forestry Sciences, Chengdu 611130, China;
| | - Amir Bibi
- Department of Plant Breeding and Genetics, University of Agriculture, Faisalabad 38000, Pakistan;
| | - Asma Zulfiqar
- Department of Botany, Quaid-e-Azam Campus, University of Punjab, Lahore 05422, Pakistan;
| | - Muhammad Zafar Iqbal
- College of Grassland Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; (M.Z.I.); (M.T.)
| | - Muhammad Tahir
- College of Grassland Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; (M.Z.I.); (M.T.)
| | - Xiangyang Zhang
- Branch of China National Hybrid Rice Research and Development Centre, Sichuan Tiland Huizhi Biology Science and Technology Co., Ltd., Chengdu 611130, China
| | - Asif Ali
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Rice Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (N.H.); (P.X.)
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14
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Arya S, Gourley AJ, Penedo JC, Blindauer CA, Stewart AJ. Fatty acids may influence insulin dynamics through modulation of albumin-Zn 2+ interactions. Bioessays 2021; 43:e2100172. [PMID: 34725844 DOI: 10.1002/bies.202100172] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 10/12/2021] [Accepted: 10/13/2021] [Indexed: 01/02/2023]
Abstract
Insulin is stored within the pancreas in an inactive Zn2+ -bound hexameric form prior to release. Similarly, clinical insulins contain Zn2+ and form multimeric complexes. Upon release from the pancreas or upon injection, insulin only becomes active once Zn2+ disengages from the complex. In plasma and other extracellular fluids, the majority of Zn2+ is bound to human serum albumin (HSA), which plays a vital role in controlling insulin pharmacodynamics by enabling removal of Zn2+ . The Zn2+ -binding properties of HSA are attenuated by non-esterified fatty acids (NEFAs) also transported by HSA. Elevated NEFA concentrations are associated with obesity and type 2 diabetes. Here we present the hypothesis that higher NEFA levels in obese and/or diabetic individuals may contribute to insulin resistance and affect therapeutic insulin dose-response profiles, through modulation of HSA/Zn2+ dynamics. We envisage this novel concept to have important implications for personalized treatments and management of diabetes-related conditions in the future.
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Affiliation(s)
- Swati Arya
- School of Medicine, University of St. Andrews, St. Andrews, Fife, UK
| | - Adam J Gourley
- School of Medicine, University of St. Andrews, St. Andrews, Fife, UK
| | - J Carlos Penedo
- Biomedical Sciences Research Complex, University of St. Andrews, St. Andrews, Fife, UK
| | | | - Alan J Stewart
- School of Medicine, University of St. Andrews, St. Andrews, Fife, UK
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15
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De la Paz E, Barfidokht A, Rios S, Brown C, Chao E, Wang J. Extended Noninvasive Glucose Monitoring in the Interstitial Fluid Using an Epidermal Biosensing Patch. Anal Chem 2021; 93:12767-12775. [PMID: 34477377 DOI: 10.1021/acs.analchem.1c02887] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
An effective, noninvasive glucose monitoring technology could be a pivotal factor for addressing the major unmet needs for managing diabetes mellitus (DM). Here, we describe a skin-worn, disposable, wireless electrochemical biosensor for extended noninvasive monitoring of glucose in the interstitial fluid (ISF). The wearable platform integrates three components: a screen-printed iontophoretic electrode system for ISF extraction by reverse iontophoresis (RI), a printed three-electrode amperometric glucose biosensor, and an electronic interface for control and wireless communication. Prolonged on-body glucose monitoring of up to 8 h, including clinical trials conducted in individuals with and without DM, demonstrated good correlation between glucose blood and ISF concentrations and the ability to monitor dynamically changing glucose levels upon food consumption, with no evidence of skin irritation or discomfort. Such successful extended operation addresses the challenges reported for the GlucoWatch platform by using a lower RI current density at shorter extraction times, along with a lower measurement frequency. Such a noninvasive skin-worn platform could address long-standing challenges with existing glucose monitoring platforms.
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Affiliation(s)
- Ernesto De la Paz
- Department of Nanoengineering, University of California, San Diego, La Jolla, San Diego, California 92093, United States
| | - Abbas Barfidokht
- Department of Nanoengineering, University of California, San Diego, La Jolla, San Diego, California 92093, United States
| | - Samantha Rios
- Department of Nanoengineering, University of California, San Diego, La Jolla, San Diego, California 92093, United States
| | - Christopher Brown
- Department of Nanoengineering, University of California, San Diego, La Jolla, San Diego, California 92093, United States
| | - Edward Chao
- School of Medicine, University of California, San Diego, La Jolla, San Diego, California 92093, United States
| | - Joseph Wang
- Department of Nanoengineering, University of California, San Diego, La Jolla, San Diego, California 92093, United States
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16
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Eksi YE, Sanlioglu AD, Akkaya B, Ozturk BE, Sanlioglu S. Genome engineering and disease modeling via programmable nucleases for insulin gene therapy; promises of CRISPR/Cas9 technology. World J Stem Cells 2021; 13:485-502. [PMID: 34249224 PMCID: PMC8246254 DOI: 10.4252/wjsc.v13.i6.485] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/02/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
Targeted genome editing is a continually evolving technology employing programmable nucleases to specifically change, insert, or remove a genomic sequence of interest. These advanced molecular tools include meganucleases, zinc finger nucleases, transcription activator-like effector nucleases and RNA-guided engineered nucleases (RGENs), which create double-strand breaks at specific target sites in the genome, and repair DNA either by homologous recombination in the presence of donor DNA or via the error-prone non-homologous end-joining mechanism. A recently discovered group of RGENs known as CRISPR/Cas9 gene-editing systems allowed precise genome manipulation revealing a causal association between disease genotype and phenotype, without the need for the reengineering of the specific enzyme when targeting different sequences. CRISPR/Cas9 has been successfully employed as an ex vivo gene-editing tool in embryonic stem cells and patient-derived stem cells to understand pancreatic beta-cell development and function. RNA-guided nucleases also open the way for the generation of novel animal models for diabetes and allow testing the efficiency of various therapeutic approaches in diabetes, as summarized and exemplified in this manuscript.
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Affiliation(s)
- Yunus E Eksi
- Department of Gene and Cell Therapy, Akdeniz University Faculty of Medicine, Antalya 07058, Turkey
| | - Ahter D Sanlioglu
- Department of Gene and Cell Therapy, Akdeniz University Faculty of Medicine, Antalya 07058, Turkey
| | - Bahar Akkaya
- Department of Gene and Cell Therapy, Akdeniz University Faculty of Medicine, Antalya 07058, Turkey
| | - Bilge Esin Ozturk
- Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA 15213, United States
| | - Salih Sanlioglu
- Department of Gene and Cell Therapy, Akdeniz University Faculty of Medicine, Antalya 07058, Turkey.
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17
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Manu P, Rogozea LM, Cernea S. Pharmacological Management of Diabetes Mellitus: A Century of Expert Opinions in Cecil Textbook of Medicine. Am J Ther 2021; 28:e397-e410. [PMID: 34228650 DOI: 10.1097/mjt.0000000000001401] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Drug therapy for diabetes mellitus (DM) has had a significant impact on quality of life and work potential of affected persons and has contributed to a remarkable decrease in the frequency and severity of complications, hospitalizations, and mortality. The current approach is the result of incremental progress in using technological advances to increase the safety and effectiveness of insulin therapy and the introduction of new molecules as oral and injectable antidiabetic drugs. STUDY QUESTION What are the milestones of the changes in the expert approach to the pharmacological management of DM in the past century? STUDY DESIGN To determine the changes in the experts' approach to the management of DM, as presented in a widely used textbook in the United States. DATA SOURCES The chapters on describing the management of DM in the 26 editions of Cecil Textbook of Medicine published from 1927 to 2020. RESULTS In 1927, DM was treated with insulin extracted from the pancreas of large animals (cattle, hogs, and sheep) and purified with alcohol to prevent the tissues' proteolytic action on the hormone. The therapeutic milestones in DM marked 2 avenues for innovation. The first created advances in insulin therapy, starting with processes that led to the production of crystalline insulin and protamine zinc insulin (1937), synthetic human insulin (1996), and prandial (2000) and basal (2004) insulin analogues. The second was an effort to develop and introduce in clinical practice in the United States oral antidiabetic drugs, starting with tolbutamide, a sulfonylurea (1955), followed by metformin, a biguanide (1996), thiazolidinediones, alpha-glucosidase inhibitors, and benzoic acid derivatives (2000), dipeptidyl peptidase-4 inhibitors and glucagon-like peptide 1 receptor agonists (2008), and sodium glucose cotransporter 2 inhibitors (2020). A latent period of 40 years between significant advances was likely because of searches for new technologies (eg, recombinant DNA for the production of synthetic insulin and analogues) and, at least in part, to the impact of the controversial University Group Diabetes Project on the development and acceptance of oral antidiabetic drugs. CONCLUSIONS The pharmacological management of DM has progressed unevenly, with a long latency period in the second half of the last century followed by highly encouraging advances in the first 2 decades of the 21st century. In chronological order, the major advances were synthetic insulins obtained through DNA recombinant technology, adoption of metformin as first line therapy, and introduction of antidiabetic medication classes that also promote weight reduction and cardiovascular health.
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Affiliation(s)
- Peter Manu
- Department of Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY
| | - Liliana M Rogozea
- Basic, Preventive and Clinical Sciences Department, Transilvania University, Brasov, Romania
| | - Simona Cernea
- Department M3 Internal Medicine I "George Emil Palade" University of Medicine, Pharmacy, Science and Technology of Târgu Mure, Romania; and
- Diabetes, Nutrition and Metabolic Diseases Outpatient Unit, Emergency County Clinical Hospital, Târgu Mureş, Romania
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18
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Erendor F, Sahin EO, Sanlioglu AD, Balci MK, Griffith TS, Sanlioglu S. Lentiviral gene therapy vectors encoding VIP suppressed diabetes-related inflammation and augmented pancreatic beta-cell proliferation. Gene Ther 2021; 28:130-141. [PMID: 32733091 DOI: 10.1038/s41434-020-0183-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 07/16/2020] [Accepted: 07/22/2020] [Indexed: 02/06/2023]
Abstract
Type 1 diabetes (T1DM) is an autoimmune condition in which the immune system attacks and destroys insulin-producing beta cells in the pancreas leading to hyperglycemia. Vasoactive intestinal peptide (VIP) manifests insulinotropic and anti-inflammatory properties, which are useful for the treatment of diabetes. Because of its limited half-life due to DPP-4-mediated degradation, constant infusions or multiple injections are needed to observe any therapeutic benefit. Since gene therapy has the potential to treat genetic diseases, an HIV-based lentiviral vector carrying VIP gene (LentiVIP) was generated to provide a stable VIP gene expression in vivo. The therapeutic efficacy of LentiVIP was tested in a multiple low-dose STZ-induced animal model of T1DM. LentiVIP delivery into diabetic animals reduced hyperglycemia, improved glucose tolerance, and prevented weight loss. Also, a decrease in serum CRP levels, and serum oxidant capacity, but an increase in antioxidant capacity were observed in LentiVIP-treated animals. Restoration of islet cell mass was correlated with an increase in pancreatic beta-cell proliferation. These beneficial results suggest the therapeutic effect of LentiVIP is due to the repression of diabetes-induced inflammation, its insulinotropic properties, and VIP-induced beta-cell proliferation.
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Affiliation(s)
- Fulya Erendor
- Department of Gene and Cell Therapy, Akdeniz University, Faculty of Medicine, 07058, Antalya, Turkey
| | - Elif Ozgecan Sahin
- Department of Gene and Cell Therapy, Akdeniz University, Faculty of Medicine, 07058, Antalya, Turkey
| | - Ahter D Sanlioglu
- Department of Gene and Cell Therapy, Akdeniz University, Faculty of Medicine, 07058, Antalya, Turkey
| | - Mustafa Kemal Balci
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Akdeniz University Faculty of Medicine, 07058, Antalya, Turkey
| | - Thomas S Griffith
- Department of Urology, University of Minnesota, School of Medicine, Minneapolis, MN, 55455, USA
| | - Salih Sanlioglu
- Department of Gene and Cell Therapy, Akdeniz University, Faculty of Medicine, 07058, Antalya, Turkey.
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19
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Di Iorio AB, Orozco Beltrán D, Quesada Rico JA, Carratalá Munuera MC. The Adaptation of the Carbohydrate Counting Method Affects HbA1c and Improves Anthropometric Indicators in Patients With Diabetes Mellitus 2. Front Nutr 2021; 7:577797. [PMID: 33575268 PMCID: PMC7870683 DOI: 10.3389/fnut.2020.577797] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 11/05/2020] [Indexed: 12/21/2022] Open
Affiliation(s)
- Adriana Beatriz Di Iorio
- Food Agroindustry, Zamorano University, Yaguare Valley, Tegucigalpa, Honduras
- Clinical Medicine, Miguel Hernández University, Alicante-Valencia, Spain
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20
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Erendor F, Eksi YE, Sahin EO, Balci MK, Griffith TS, Sanlioglu S. Lentivirus Mediated Pancreatic Beta-Cell-Specific Insulin Gene Therapy for STZ-Induced Diabetes. Mol Ther 2021; 29:149-161. [PMID: 33130311 PMCID: PMC7791084 DOI: 10.1016/j.ymthe.2020.10.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 08/31/2020] [Accepted: 10/23/2020] [Indexed: 02/07/2023] Open
Abstract
Autoimmune destruction of pancreatic beta cells is the characteristic feature of type 1 diabetes mellitus. Consequently, both short- and intermediate-acting insulin analogs are under development to compensate for the lack of endogenous insulin gene expression. Basal insulin is continuously released at low levels in response to hepatic glucose output, while post-prandial insulin is secreted in response to hyperglycemia following a meal. As an alternative to multiple daily injections of insulin, glucose-regulated insulin gene expression by gene therapy is under development to better endure postprandial glucose excursions. Controlled transcription and translation of proinsulin, presence of glucose-sensing machinery, prohormone convertase expression, and a regulated secretory pathway are the key features unique to pancreatic beta cells. To take advantage of these hallmarks, we generated a new lentiviral vector (LentiINS) with an insulin promoter driving expression of the proinsulin encoding cDNA to sustain pancreatic beta-cell-specific insulin gene expression. Intraperitoneal delivery of HIV-based LentiINS resulted in the lowering of fasting plasma glucose, improved glucose tolerance and prevented weight loss in streptozoticin (STZ)-induced diabetic Wistar rats. However, the combinatorial use of LentiINS and anti-inflammatory lentiviral vector (LentiVIP) gene therapy was required to increase serum insulin to a level sufficient to suppress non-fasting plasma glucose and diabetes-related inflammation.
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Affiliation(s)
- Fulya Erendor
- Department of Gene and Cell Therapy, Faculty of Medicine, Akdeniz University, Antalya 07058, Turkey
| | - Yunus Emre Eksi
- Department of Gene and Cell Therapy, Faculty of Medicine, Akdeniz University, Antalya 07058, Turkey
| | - Elif Ozgecan Sahin
- Department of Gene and Cell Therapy, Faculty of Medicine, Akdeniz University, Antalya 07058, Turkey
| | - Mustafa Kemal Balci
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Akdeniz University, Antalya 07058, Turkey
| | - Thomas S Griffith
- Department of Urology, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
| | - Salih Sanlioglu
- Department of Gene and Cell Therapy, Faculty of Medicine, Akdeniz University, Antalya 07058, Turkey.
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21
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Reyes Barron C, Augustine M, Zhang YV. Recurrent Hypoglycemic Episodes with Hypoinsulinemia in a Patient with Diabetes. Clin Chem 2020; 67:345-348. [PMID: 33523220 DOI: 10.1093/clinchem/hvaa301] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Accepted: 09/09/2020] [Indexed: 01/10/2023]
Affiliation(s)
- Cynthia Reyes Barron
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - Marilyn Augustine
- Department of Medicine, Division of Endocrinology and Metabolism, University of Rochester Medical Center, Rochester, NY
| | - Y Victoria Zhang
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
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22
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Li H, Wang D, Guo X, Xia L, Wu Q, Cheng X. Comparison of four matrixes for diluting insulin in routine clinical measurements. J Clin Lab Anal 2020; 34:e23396. [PMID: 32506749 PMCID: PMC7521276 DOI: 10.1002/jcla.23396] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 04/02/2020] [Accepted: 04/13/2020] [Indexed: 11/15/2022] Open
Abstract
Objective In our laboratory, 2.36% (6626/280765) samples obtained for insulin evaluation have serum insulin concentrations higher than 300 mU/L, resulting in curves outside the linear range in the insulin release test (IRT). Accordingly, using appropriate dilution protocols to determine insulin concentration accurately is important. Here, we compared the effectiveness and economy of four different solutions for diluting high‐insulin serum in routine clinical measurements. Method Residual serum samples with high‐insulin concentrations ranging from 200 to 300 mU/L were collected in Peking Union Medical College Hospital from August to November 2017. Four different matrixes including a Siemens original diluent, pure water, 0.9% NaCl, and low‐insulin serum (labeled as A to D, respectively) were used to dilute the serum in the ratios of 1:2, 1:5, and 1:10. Results We found that the linear correlation coefficients of A to D were higher than 0.9. The recovery rates of A to D were 86.4%–104.0%, 73.2%–99.3%, 76.4%–101.3%, and 84.2%–99.7%, respectively. We conclude that the use of 0.9% NaCl, pure water, or low‐insulin serum to dilute high‐serum insulin (>300 mU/L) is feasible and cost‐effective. Conclusion We recommend a dilution factor of 1:5 on a Siemens ADVIA Centaur XP® instrument. The clinically reported range was 0.5‐1500 mU/L. For specific samples (>1500 mU/L), we recommended using low‐insulin serum samples for dilution.
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Affiliation(s)
- Honglei Li
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Danchen Wang
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiuzhi Guo
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Liangyu Xia
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Qiong Wu
- Department of Laboratory Medicine, Affiliated Hospital of Chifeng University, Inner Mongolia, China
| | - Xinqi Cheng
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
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23
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Fagbohun OF, Awoniran PO, Babalola OO, Agboola FK, Msagati TAM. Changes in the biochemical, hematological and histopathological parameters in STZ-Induced diabetic rats and the ameliorative effect of Kigelia africana fruit extract. Heliyon 2020; 6:e03989. [PMID: 32462092 PMCID: PMC7243140 DOI: 10.1016/j.heliyon.2020.e03989] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 04/01/2020] [Accepted: 04/12/2020] [Indexed: 02/07/2023] Open
Abstract
Background Biochemical, hematological and histological changes are major observable clinical and pathological factors associated with Diabetes mellitus. Derangement in the levels of these parameters increases the risk of the development of complications. In another hand, gastrointestinal intolerance due to the development of lactic acidosis on the gastrointestinal tract and the intestinal microbiome is the toxic side effect of various synthetic antidiabetic agents. The use of Kigelia africana fruit extract for the treatment of diabetes has been scientifically validated. This study therefore aimed at investigating changes in the biochemical, hematological and histological parameters as well as the determination of the functional groups present in the hexane fraction of the fruit. Methods The fruits were extracted with ethanol and partitioned with n-hexane to obtain the hexane fraction. Diabetic rats induced with streptozotocin (STZ) were divided into 5 groups of 5 animals each and treated with 100, 200 and 400 mg/kg body weight (BW) hexane fraction alongside reference standard; glibenclamide. Fasting blood glucose levels and their body weights were monitored weekly. Animals were sacrificed at the end of 28-day treatment. Blood, liver, and kidney were collected for biochemical, hematological and histopathological analyses. Fourier transform infrared resonance (FTIR) spectroscopic analysis was carried out on the hexane fraction for functional group determination. Results The hexane fraction of K. africana fruit extract decreased fasting blood glucose (FBG) levels significantly with ameliorative effects on the hematological parameters such as packed cell volume (PCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red blood cells (RBC) etc. There were significant regenerative differences in the biochemical activities as well as the renal cortex and midzone sections of the rat's kidney and liver when compared with untreated diabetic rats. The presence of polyphenolic functional groups via FTIR analysis suggested high antioxidant activities of the fruit extract. Conclusion The use of Kigelia africana fruit extracts protects against biochemical, hematological and histological changes that are injurious to diabetic patients. Therefore, Kigelia africana fruit is a good hepatic- and nephroprotective agent and has a hemato-protective ability.
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Affiliation(s)
- Oladapo F Fagbohun
- Department of Biomedical Engineering, First Technical University, Ibadan, Oyo State, Nigeria
| | - Paul O Awoniran
- Department of Anatomy and Cell Biology, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
| | - Olubunmi O Babalola
- Department of Biochemistry and Molecular Biology, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
| | - Femi K Agboola
- Department of Biochemistry and Molecular Biology, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
| | - Titus A M Msagati
- Nanotechnology and Water Sustainability Research Unit, College of Science Engineering and Technology, University of South Africa (UNISA), Florida Park, Johannesburg, South Africa
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Fumagalli G, Monfrini M, Donzelli E, Rodriguez-Menendez V, Bonandrini B, Figliuzzi M, Remuzzi A, D’Amico G, Cavaletti G, Scuteri A. Protective Effect of Human Mesenchymal Stem Cells on the Survival of Pancreatic Islets. Int J Stem Cells 2020; 13:116-126. [PMID: 31887847 PMCID: PMC7119207 DOI: 10.15283/ijsc19094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 10/09/2019] [Accepted: 10/17/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Transplantation of pancreatic islets is an intriguing new therapeutic option to face the worldwide spread problem of Type-I diabetes. Currently, its clinical use is limited by several problems, mainly based on the high number of islets required to restore normoglycaemia and by the low survival of the transplanted tissue. A promising attempt to overcome the limits to such an approach was represented by the use of Mesenchymal Stem Cells (MSC). Despite the encouraging results obtained with murine-derived MSC, little is still known about their protective mechanisms. The aim of the present study was to verify the effectiveness, (besides murine MSC), of clinically relevant human-derived MSC (hMSC) on protecting pancreatic islets, thus also shedding light on the putative differences between MSC of different origin. METHODS AND RESULTS Threefold kinds of co-cultures were therefore in vitro set up (direct, indirect and mixed), to analyze the hMSC effect on pancreatic islet survival and function and to study the putative mechanisms involved. Although in a different way with respect to murine MSC, also human derived cells demonstrated to be effective on protecting pancreatic islet survival. This effect could be due to the release of some trophic factors, such as VEGF and Il-6, and by the reduction of inflammatory cytokine TNF-α. CONCLUSIONS Therefore, hMSC confirmed their great clinical potential to improve the feasibility of pancreatic islet transplantation therapy against diabetes.
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Affiliation(s)
- Giulia Fumagalli
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB), Italy
- PhD Program in Neuroscience, University of Milano-Bicocca, Monza (MB), Italy
| | - Marianna Monfrini
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB), Italy
| | - Elisabetta Donzelli
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB), Italy
- NeuroMi, Milan Center for Neurosciences, Milano, Italy
| | - Virginia Rodriguez-Menendez
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB), Italy
- NeuroMi, Milan Center for Neurosciences, Milano, Italy
| | - Barbara Bonandrini
- Department of Biomedical Engineering, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Marina Figliuzzi
- Department of Biomedical Engineering, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Andrea Remuzzi
- Department of Management, Information and Production Engineering, University of Bergamo, Dalmine (BG), Italy
| | - Giovanna D’Amico
- Centro Ricerca Tettamanti, Clinica Pediatrica, Università Milano-Bicocca, Monza (MB), Italy
| | - Guido Cavaletti
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB), Italy
- NeuroMi, Milan Center for Neurosciences, Milano, Italy
| | - Arianna Scuteri
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB), Italy
- NeuroMi, Milan Center for Neurosciences, Milano, Italy
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Liu H, Bolleddula J, Nichols A, Tang L, Zhao Z, Prakash C. Metabolism of bioconjugate therapeutics: why, when, and how? Drug Metab Rev 2020; 52:66-124. [PMID: 32045530 DOI: 10.1080/03602532.2020.1716784] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Bioconjugation of therapeutic agents has been used as a selective drug delivery platform for many therapeutic areas. Bioconjugates are prepared by the covalent linkage of active compounds (small or large molecule) to a carrier molecule (lipids, proteins, peptides, carbohydrates, and polymers) through a chemical linker. The linkage of the active component to a carrier molecule enhances the therapeutic window through a targeted delivery and by reducing toxicity. Bioconjugates also possess improved pharmacokinetic properties such as a long half-life, increased stability, and cleavage by intracellular enzymes/environment. However, premature cleavage of the bioconjugates and the resulting metabolites/catabolites may produce undesirable toxic effects and, hence, it is critical to understand cleavage mechanisms, metabolism of bioconjugates, and translatability to human in the discovery stages. This article provides a comprehensive overview of linker cleavage pathways and catabolism/metabolism of antibody-drug conjugates, glycoconjugates, polymer-drug conjugates, lipid-drug conjugates, folate-targeted small molecule-drug conjugates, and drug-drug conjugates.
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Affiliation(s)
- Hanlan Liu
- KSQ Therapeutics Inc., Cambridge, MA, USA
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26
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Role of ultrafast-acting insulin analogues in the management of diabetes. J Am Assoc Nurse Pract 2019; 31:537-548. [DOI: 10.1097/jxx.0000000000000261] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Abstract
Insulin is an important polypeptide hormone that regulates carbohydrate metabolism.
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Affiliation(s)
- Yixiao Shen
- Department of Food Science
- Shenyang Agricultural University
- Shenyang
- China
| | - Witoon Prinyawiwatkul
- School of Nutrition and Food Sciences
- Louisiana State University
- Agricultural Center
- Baton Rouge
- USA
| | - Zhimin Xu
- School of Nutrition and Food Sciences
- Louisiana State University
- Agricultural Center
- Baton Rouge
- USA
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28
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Tasyurek HM, Altunbas HA, Balci MK, Griffith TS, Sanlioglu S. Therapeutic Potential of Lentivirus-Mediated Glucagon-Like Peptide-1 Gene Therapy for Diabetes. Hum Gene Ther 2018; 29:802-815. [PMID: 29409356 DOI: 10.1089/hum.2017.180] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Postprandial glucose-induced insulin secretion from the islets of Langerhans is facilitated by glucagon-like peptide-1 (GLP-1)-a metabolic hormone with insulinotropic properties. Among the variety of effects it mediates, GLP-1 induces delta cell secretion of somatostatin, inhibits alpha cell release of glucagon, reduces gastric emptying, and slows food intake. These events collectively contribute to weight loss over time. During type 2 diabetes (T2DM), however, the incretin response to glucose is reduced and accompanied by a moderate reduction in GLP-1 secretion. To compensate for the reduced incretin effect, a human immunodeficiency virus-based lentiviral vector was generated to deliver DNA encoding human GLP-1 (LentiGLP-1), and the anti-diabetic efficacy of LentiGLP-1 was tested in a high-fat diet/streptozotocin-induced model of T2DM. Therapeutic administration of LentiGLP-1 reduced blood glucose levels in obese diabetic Sprague Dawley rats, along with improving insulin sensitivity and glucose tolerance. Normoglycemia was correlated with increased blood GLP-1 and pancreatic beta cell regeneration in LentiGLP-1-treated rats. Plasma triglyceride levels were also normalized after LentiGLP-1 injection. Collectively, these data suggest the clinical potential of GLP-1 gene transfer therapy for the treatment of T2DM.
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Affiliation(s)
- Hale M Tasyurek
- 1 Human Gene and Cell Therapy Center of Akdeniz University Hospitals , Antalya, Turkey
| | - Hasan Ali Altunbas
- 2 Department of Internal Medicine, Division of Endocrinology and Metabolism, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Mustafa Kemal Balci
- 2 Department of Internal Medicine, Division of Endocrinology and Metabolism, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Thomas S Griffith
- 3 Department of Urology, University of Minnesota , School of Medicine, Minneapolis, Minnesota
| | - Salih Sanlioglu
- 1 Human Gene and Cell Therapy Center of Akdeniz University Hospitals , Antalya, Turkey
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29
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Tasyurek HM, Eksi YE, Sanlioglu AD, Altunbas HA, Balci MK, Griffith TS, Sanlioglu S. HIV-based lentivirus-mediated vasoactive intestinal peptide gene delivery protects against DIO animal model of Type 2 diabetes. Gene Ther 2018; 25:269-283. [PMID: 29523882 DOI: 10.1038/s41434-018-0011-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 12/25/2017] [Accepted: 02/13/2018] [Indexed: 12/30/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is characterised by insulin resistance, glucose intolerance and beta cell loss leading to hyperglycemia. Vasoactive intestinal peptide (VIP) has been regarded as a novel therapeutic agent for the treatment of T2DM because of its insulinotropic and anti-inflammatory properties. Despite these beneficial properties, VIP is extremely sensitive to peptidases (DPP-4) requiring constant infusion or multiple injections to observe any therapeutic benefit. Thus, we constructed an HIV-based lentiviral vector encoding human VIP (LentiVIP) to test the therapeutic efficacy of VIP peptide in a diet-induced obesity (DIO) animal model of T2DM. VIP gene expression was shown by immunocytochemistry (ICC) and VIP peptide secretion was confirmed by ELISA both in HepG2 liver and MIN6 pancreatic beta cell lines. Functional properties of VIP were demonstrated by cAMP production assay and glucose-stimulated insulin secretion test (GSIS). Intraperitoneal (IP) delivery of LentiVIP vectors into mice significantly increased serum VIP concentrations compared to control mice. Most importantly, LentiVIP delivery in DIO animal model of T2DM resulted in improved insulin sensitivity, glucose tolerance and protection against STZ-induced diabetes in addition to reduction in serum triglyceride/cholesterol levels. Collectively, these data suggest LentiVIP delivery should be evaluated as an experimental therapeutic approach for the treatment of T2DM.
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Affiliation(s)
- Hale M Tasyurek
- Human Gene and Cell Therapy Center of Akdeniz University Hospitals, 07058, Antalya, Turkey
| | - Yunus E Eksi
- Human Gene and Cell Therapy Center of Akdeniz University Hospitals, 07058, Antalya, Turkey
| | - Ahter D Sanlioglu
- Human Gene and Cell Therapy Center of Akdeniz University Hospitals, 07058, Antalya, Turkey
| | - Hasan A Altunbas
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Akdeniz University Faculty of Medicine, 07058, Antalya, Turkey
| | - Mustafa K Balci
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Akdeniz University Faculty of Medicine, 07058, Antalya, Turkey
| | - Thomas S Griffith
- Department of Urology, University of Minnesota, School of Medicine, Minneapolis, MN, 55455, USA
| | - Salih Sanlioglu
- Human Gene and Cell Therapy Center of Akdeniz University Hospitals, 07058, Antalya, Turkey.
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30
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Chao PC, Li Y, Chang CH, Shieh JP, Cheng JT, Cheng KC. Investigation of insulin resistance in the popularly used four rat models of type-2 diabetes. Biomed Pharmacother 2018; 101:155-161. [PMID: 29486333 DOI: 10.1016/j.biopha.2018.02.084] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Revised: 02/07/2018] [Accepted: 02/19/2018] [Indexed: 12/12/2022] Open
Abstract
Animal models are widely used to develop drugs for treating diabetes mellitus (DM). Insulin resistance (IR) is one of the main problems in type-2 DM (T2DM). Streptozotocin (STZ) is used to damage pancreatic cells for induction of DM. Many rat models were applied in research as T2DM. However, the degree of IR in each model is unknown. In the present study, IR and insulin signaling were compared in four models of type 2 diabetes: rats fed a fructose-rich chow for 8 weeks, rats feed high-fat chow for 4 weeks followed by injection with streptozotocin (35 mg/kg, i.p.), rats injected with a single low dose streptozotocin (45 mg/kg, i.p.), and rats injected with a single dose of nicotinamide followed by a single high dose of streptozotocin (60 mg/kg, i.p.). Values from these determinations in diabetic rats showing the order that insulin resistance is most marked in rats received fructose-rich chow followed by high-fat diet before STZ injection induced model (HFD/STZ rats), and rats injected with low dose of STZ but it is less marked in rats induced by nicotinamide and STZ. Additionally, insulin secretion was reduced in three rat models except the rats receiving fructose-rich chow. Western blots also showed the same changes in phosphorylation of IRS-1 or Akt using soleus muscle from each model. The obtained data suggest a lack of pronounced IR in the rats with acute diabetes induced by nicotinamide and STZ while IR is markedly identified in rats fed fructose-rich chow. However, the increase of plasma glucose levels in fructose-rich chow-fed rats was not so significant as other groups. Therefore, HFD/STZ rats is an appropriate and stable animal model which is analogous to the human T2DM through a combination of high-fat diet with multiple low-dose STZ injections.
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Affiliation(s)
- Pin-Chun Chao
- Bachelor Program of Senior Services, College of Humanities and Social Sciences, Southern Taiwan University of Science and Technology, Yong Kang, Tainan City, 71005, Taiwan
| | - Yingxiao Li
- Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, 890-8520, Japan; Department of Medical Research, Chi-Mei Medical Center, Yong Kang, Tainan City, 71003, Taiwan
| | - Chin-Hong Chang
- Department of Neurosurgery, Chi-Mei Medical Center, Yong Kang, Tainan City, 71003, Taiwan
| | - Ja Ping Shieh
- Department of Anesthesiology, Chi-Mei Medical Center, Yong Kang, Tainan City, 71003, Taiwan
| | - Juei-Tang Cheng
- Department of Medical Research, Chi-Mei Medical Center, Yong Kang, Tainan City, 71003, Taiwan; Institute of Medical Sciences, Chang Jung Christian University, Gueiren, Tainan City, 71101, Taiwan.
| | - Kai-Chun Cheng
- Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, 890-8520, Japan.
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31
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Gazzina S, Alberici A, Padovani A, Borroni B. Myoclonic dystonia (DYT11) responsive to insulin therapy: A case report. Neurology 2017; 89:517-518. [DOI: 10.1212/wnl.0000000000004182] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Accepted: 04/24/2017] [Indexed: 12/24/2022] Open
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Rosenfield DA, Nichi M, Pizzutto CS. C-Peptides for diagnostics and therapy: a veterinary medicine point of view. PESQUISA VETERINÁRIA BRASILEIRA 2017. [DOI: 10.1590/s0100-736x2017000100006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
ABSTRACT: Empirical studies proved that C-peptides are performing numerous intrinsic biological roles, and serve as a marker for pancreatic performance analysis. Since the last decade, C-peptide assays for differential diagnosis in veterinary diabetic patients are becoming more available, but still only for a very limited number of species. Studies on C-peptide as a diagnostic tool, therapy for associated complications, or as replacement therapies for C-peptide deficiency still showed not to be a common practice in veterinary medicine. This review was conducted to determine the potential importance of C-peptide in Veterinary Medicine, relevant in the diagnosis of diabetes and for other metabolic processes, as well as its proposed therapeutic benefits. Numerous articles were identified that reported positive results in their experimental studies, whether C-peptide as a biomarker for pancreatic performance in dogs, cats, and horses, as a non-invasive method to monitor nutritional status in primates, or to investigate its potential therapeutic benefits for diabetes-related illnesses.
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Olczyk P, Komosinska-Vassev K, Ramos P, Mencner Ł, Olczyk K, Pilawa B. Interactions of short-acting, intermediate-acting and pre-mixed human insulins with free radicals--Comparative EPR examination. Int J Pharm 2015; 490:9-15. [PMID: 25975232 DOI: 10.1016/j.ijpharm.2015.05.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 05/06/2015] [Accepted: 05/07/2015] [Indexed: 10/23/2022]
Abstract
Electron paramagnetic resonance (EPR) spectroscopy was used to examine insulins interactions with free radicals. Human recombinant DNA insulins of three groups were studied: short-acting insulin (Insuman Rapid); intermediate-acting insulins (Humulin N, Insuman Basal), and pre-mixed insulins (Humulin M3, Gensulin M50, Gensulin M40, Gensulin M30). The aim of an X-band (9.3GHz) study was comparative analysis of antioxidative properties of the three groups of human insulins. DPPH was used as a stable free radical model. Amplitudes of EPR lines of DPPH as the paramagnetic free radical reference, and DPPH interacting with the individual tested insulins were compared. For all the examined insulins kinetics of their interactions with free radicals up to 60 min were obtained. The strongest interactions with free radicals were observed for the short-acting insulin - Insuman Rapid. The lowest interactions with free radicals were characteristic for intermediate-acting insulin - Insuman Basal. The pre-mixed insulins i.e. Humulin M3 and Gensulin M50 revealed the fastest interactions with free radicals. The short acting, intermediate acting and premixed insulins have been found to be effective agents in reducing free radical formation in vitro and should be further considered as potential useful tools in attenuation of oxidative stress in diabetic patients.
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Affiliation(s)
- Paweł Olczyk
- Department of Community Pharmacy, School of Pharmacy and Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Kasztanowa 3, 41-200 Sosnowiec, Poland.
| | - Katarzyna Komosinska-Vassev
- Department of Clinical Chemistry and Laboratory Diagnostics, School of Pharmacy and Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Jedności 8, 41-200 Sosnowiec, Poland.
| | - Paweł Ramos
- Department of Biophysics, School of Pharmacy and Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Jedności 8, 41-200 Sosnowiec, Poland.
| | - Łukasz Mencner
- Department of Clinical Chemistry and Laboratory Diagnostics, School of Pharmacy and Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Jedności 8, 41-200 Sosnowiec, Poland.
| | - Krystyna Olczyk
- Department of Clinical Chemistry and Laboratory Diagnostics, School of Pharmacy and Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Jedności 8, 41-200 Sosnowiec, Poland.
| | - Barbara Pilawa
- Department of Biophysics, School of Pharmacy and Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Jedności 8, 41-200 Sosnowiec, Poland.
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Nair S, Chik Z, Noordin MI. In vitrocharacteristics of an insulin suppository developed using palm oil base (HAMIN®) and its hypoglycaemic effect on rabbits. FRONTIERS IN LIFE SCIENCE 2015. [DOI: 10.1080/21553769.2015.1063549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Tasyurek HM, Altunbas HA, Balci MK, Sanlioglu S. Incretins: their physiology and application in the treatment of diabetes mellitus. Diabetes Metab Res Rev 2014; 30:354-71. [PMID: 24989141 DOI: 10.1002/dmrr.2501] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Revised: 11/06/2013] [Accepted: 11/12/2013] [Indexed: 12/18/2022]
Abstract
Therapies targeting the action of incretin hormones have been under close scrutiny in recent years. The incretin effect has been defined as postprandial enhancement of insulin secretion by gut-derived factors. Likewise, incretin mimetics and incretin effect amplifiers are the two different incretin-based treatment strategies developed for the treatment of diabetes. Although, incretin mimetics produce effects very similar to those of natural incretin hormones, incretin effect amplifiers act by inhibiting dipeptidyl peptidase-4 (DPP-4) enzyme to increase plasma concentration of incretins and their biologic effects. Because glucagon-like peptide-1 (GLP-1) is an incretin hormone with various anti-diabetic actions including stimulation of glucose-induced insulin secretion, inhibition of glucagon secretion, hepatic glucose production and gastric emptying, it has been evaluated as a novel therapeutic agent for the treatment of type 2 diabetes mellitus (T2DM). GLP-1 also manifests trophic effects on pancreas such as pancreatic beta cell growth and differentiation. Because DPP-4 is the enzyme responsible for the inactivation of GLP-1, DPP-4 inhibition represents another potential strategy to increase plasma concentration of GLP-1 to enhance the incretin effect. Thus, anti-diabetic properties of these two classes of drugs have stimulated substantial clinical interest in the potential of incretin-based therapeutic agents as a means to control glucose homeostasis in T2DM patients. Despite this fact, clinical use of GLP-1 mimetics and DPP-4 inhibitors have raised substantial concerns owing to possible side effects of the treatments involving increased risk for pancreatitis, and C-cell adenoma/carcinoma. Thus, controversial issues in incretin-based therapies under development are reviewed and discussed in this manuscript.
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Abstract
Glucagon-like peptide (GLP)-1 is an incretin hormone with several antidiabetic functions including stimulation of glucose-dependent insulin secretion, increase in insulin gene expression and beta-cell survival. Despite the initial technical difficulties and profound inefficiency of direct gene transfer into the pancreas that seriously restricted in vivo gene transfer experiments with GLP-1, recent exploitation of various routes of gene delivery and alternative means of gene transfer has permitted the detailed assessment of the therapeutic efficacy of GLP-1 in animal models of type 2 diabetes (T2DM). As a result, many clinical benefits of GLP-1 peptide/analogues observed in clinical trials involving induction of glucose tolerance, reduction of hyperglycaemia, suppression of appetite and food intake linked to weight loss have been replicated in animal models using gene therapy. Furthermore, GLP-1-centered gene therapy not only improved insulin sensitivity, but also reduced abdominal and/or hepatic fat associated with obesity-induced T2DM with drastic alterations in adipokine profiles in treated subjects. Thus, a comprehensive assessment of recent GLP-1-mediated gene therapy approaches with detailed analysis of current hurdles and resolutions, is discussed.
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