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Volčanšek Š, Koceva A, Jensterle M, Janež A, Muzurović E. Amylin: From Mode of Action to Future Clinical Potential in Diabetes and Obesity. Diabetes Ther 2025; 16:1207-1227. [PMID: 40332747 DOI: 10.1007/s13300-025-01733-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 03/19/2025] [Indexed: 05/08/2025] Open
Abstract
Precision diabetology is increasingly becoming diabetes phenotype-driven, whereby the specific hormonal imbalances involved are taken into consideration. Concomitantly, body weight-favorable therapeutic approaches are being dictated by the obesity pandemic, which extends to all diabetes subpopulations. Amylin, an anorexic neuroendocrine hormone co-secreted with insulin, is deficient in individuals with diabetes and plays an important role in postprandial glucose homeostasis, with additional potential cardiovascular and neuroprotective functions. Its actions include suppressing glucagon secretion, delaying gastric emptying, increasing energy expenditure and promoting satiety. While amylin holds promise as a therapeutic agent, its translation into clinical practice is hampered by complex receptor biology, the limitations of animal models, its amyloidogenic properties and pharmacokinetic challenges. In individuals with advanced β-cell dysfunction, supplementing insulin therapy with pramlintide, the first and currently only approved injectable short-acting selective analog of amylin, has demonstrated efficacy in enhancing both postprandial and overall glycemic control in both type 2 diabetes (T2D) and type 1 diabetes (T1D) without increasing the risk of hypoglycemia or weight gain. Current research focuses on several key strategies, from enhancing amylin stability by attaching polyethylene glycol or carbohydrate molecules to amylin, to developing oral amylin formulations to improve patients' convenience, as well as developing various combination therapies to enhance weight loss and glucose regulation by targeting multiple receptors in metabolic pathways. The novel synergistically acting glucagon-like peptide-1 (GLP-1) receptor agonist combined with the amylin agonist, CagriSema, shows promising results in both glucose regulation and weight management. As such, amylin agonists (combined with other members of the incretin class) could represent the elusive drug candidate to address the multi-hormonal dysregulations of diabetes subtypes and qualify as a precision medicine approach that surpasses the long overdue division into T1DM and T2DM. Further development of amylin-based therapies or delivery systems is crucial to fully unlock the therapeutic potential of this intriguing hormone.Graphical abstract available for this article.
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Affiliation(s)
- Špela Volčanšek
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia
- Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Andrijana Koceva
- Department of Endocrinology and Diabetology, University Medical Centre Maribor, Maribor, Slovenia
- Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Mojca Jensterle
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia
- Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Andrej Janež
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia
- Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Emir Muzurović
- Endocrinology Section, Department of Internal Medicine, Clinical Centre of Montenegro, Podgorica, Montenegro.
- Faculty of Medicine, University of Montenegro, Podgorica, Montenegro.
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Walker CS, Aitken JF, Vazhoor Amarsingh G, Zhang S, Cooper GJS. Amylin: emergent therapeutic opportunities in overweight, obesity and diabetes mellitus. Nat Rev Endocrinol 2025:10.1038/s41574-025-01125-9. [PMID: 40360789 DOI: 10.1038/s41574-025-01125-9] [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] [Accepted: 04/25/2025] [Indexed: 05/15/2025]
Abstract
The identification of amylin as a glucoregulatory peptide hormone with roles in meal-ending satiation sparked a surge of experimental development, which culminated in the amylin mimetic drug pramlintide. Pramlintide was approved by the FDA in 2005 for the treatment of type 1 diabetes mellitus and insulin-requiring type 2 diabetes, and was also explored as a novel anti-obesity treatment. Despite this exciting potential, efforts to develop an amylin-based anti-obesity therapeutic stalled owing to challenges around dosage frequency, safety and formulation. Generally, anti-obesity therapies have displayed modest efficacy and mixed safety profiles, leaving a clear unmet clinical need that requires addressing. Advances in peptide chemistry have reinvigorated the amylin field by enabling the manufacture of effective new amylin-based molecules, resulting in therapeutics that are now on the cusp of approval. At present, there are growing concerns around GLP1 receptor agonist-based therapeutics, in particular their association with loss of lean body mass. Additionally, treatment of patients with overweight or obesity without associated comorbidities is increasingly common. The widespread pharmacotherapy of otherwise healthy populations with overweight or obesity with the goal of improving future health requires further regulatory and ethical consideration. This Review describes how amylin controls energy homeostasis and provides a current overview of amylin-based therapeutic development.
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Affiliation(s)
| | - Jacqueline F Aitken
- School of Biological Sciences, University of Auckland, Auckland, New Zealand
| | | | - Shaoping Zhang
- School of Biological Sciences, University of Auckland, Auckland, New Zealand
| | - Garth J S Cooper
- School of Biological Sciences, University of Auckland, Auckland, New Zealand.
- Department of Pharmacology, Medical Sciences Division, University of Oxford, Oxford, UK.
- School of Medical Sciences, Division of Cardiovascular Sciences, University of Manchester, Manchester, UK.
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Kern KA, DiBrog AM, Kaur K, Przybysz JT, Mietlicki-Baase EG. Chronic pramlintide decreases feeding via a reduction in meal size in male rats. Peptides 2024; 176:171197. [PMID: 38493922 PMCID: PMC11323829 DOI: 10.1016/j.peptides.2024.171197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 02/29/2024] [Accepted: 03/14/2024] [Indexed: 03/19/2024]
Abstract
Amylin, a pancreatic hormone, is well-established to suppress feeding by enhancing satiation. Pramlintide, an amylin analog that is FDA-approved for the treatment of diabetes, has also been shown to produce hypophagia. However, the behavioral mechanisms underlying the ability of pramlintide to suppress feeding are unresolved. We hypothesized that systemic pramlintide administration in rats would reduce energy intake, specifically by reducing meal size. Male rats were given b.i.d. administration of intraperitoneal pramlintide or vehicle for 1 week, and chow intake, meal patterns, and body weight were monitored throughout the test period. Consistent with our hypothesis, pramlintide decreased chow intake mainly via suppression of meal size, with corresponding reductions in meal duration on several days. Fewer effects on meal number or feeding rate were detected. Pramlintide also reduced weight gain over the 1-week study. These results highlight that the behavioral mechanisms by which pramlintide produces hypophagia are similar to those driven by amylin itself, and provide important insight into the ability of this pharmacotherapy to promote negative energy balance over a period of chronic administration.
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Affiliation(s)
- Katherine A Kern
- Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, State University of New York, Buffalo, NY 14214, USA
| | - Adrianne M DiBrog
- Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, State University of New York, Buffalo, NY 14214, USA
| | - Kiran Kaur
- Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, State University of New York, Buffalo, NY 14214, USA
| | - Johnathan T Przybysz
- Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, State University of New York, Buffalo, NY 14214, USA
| | - Elizabeth G Mietlicki-Baase
- Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, State University of New York, Buffalo, NY 14214, USA; Center for Ingestive Behavior Research, University at Buffalo, State University of New York, Buffalo, NY 14260, USA.
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4
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Bennici G, Almahasheer H, Alghrably M, Valensin D, Kola A, Kokotidou C, Lachowicz J, Jaremko M. Mitigating diabetes associated with reactive oxygen species (ROS) and protein aggregation through pharmacological interventions. RSC Adv 2024; 14:17448-17460. [PMID: 38813124 PMCID: PMC11135279 DOI: 10.1039/d4ra02349h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 05/22/2024] [Indexed: 05/31/2024] Open
Abstract
Diabetes mellitus, a complex metabolic disorder, presents a growing global health challenge. In 2021, there were 529 million diabetics worldwide. At the super-regional level, Oceania, the Middle East, and North Africa had the highest age-standardized rates. The majority of cases of diabetes in 2021 (>90.0%) were type 2 diabetes, which is largely indicative of the prevalence of diabetes in general, particularly in older adults (K. L. Ong, et al., Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021, Lancet, 2023, 402(10397), 203-234). Nowadays, slowing the progression of diabetic complications is the only effective way to manage diabetes with the available therapeutic options. However, novel biomarkers and treatments are urgently needed to control cytokine secretion, advanced glycation end products (AGEs) production, vascular inflammatory effects, and cellular death. Emerging research has highlighted the intricate interplay between reactive oxygen species (ROS) and protein aggregation in the pathogenesis of diabetes. In this scenario, the main aim of this paper is to provide a comprehensive review of the current understanding of the molecular mechanisms underlying ROS-induced cellular damage and protein aggregation, specifically focusing on their contribution to diabetes development. The role of ROS as key mediators of oxidative stress in diabetes is discussed, emphasizing their impact on cellular components and signaling. Additionally, the involvement of protein aggregation in impairing cellular function and insulin signaling is explored. The synergistic effects of ROS and protein aggregation in promoting β-cell dysfunction and insulin resistance are examined, shedding light on potential targets for therapeutic intervention.
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Affiliation(s)
- Giulia Bennici
- Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900 Saudi Arabia
| | - Hanan Almahasheer
- Department of Biology, College of Science, Imam Abdulrahman Bin Faisal University (IAU) Dammam 31441-1982 Saudi Arabia
| | - Mawadda Alghrably
- Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900 Saudi Arabia
| | - Daniela Valensin
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena Via Aldo Moro 2 53100 Siena Italy
| | - Arian Kola
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena Via Aldo Moro 2 53100 Siena Italy
| | - Chrysoula Kokotidou
- Department of Materials Science and Technology, University of Crete 70013 Heraklion Crete Greece
- Institute of Electronic Structure and Laser (IESL) FORTH 70013 Heraklion Crete Greece
| | - Joanna Lachowicz
- Department of Population Health, Division of Environmental Health and Occupational Medicine, Wroclaw Medical University Mikulicza-Radeckiego 7 Wroclaw PL 50-368 Poland
| | - Mariusz Jaremko
- Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900 Saudi Arabia
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Gray ALH, Norman V, Oluwatoba DS, Prosser RA, Do TD. Potential Protective Function of Aβ 42 Monomer on Tauopathies. JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY 2023; 34:472-483. [PMID: 36693165 DOI: 10.1021/jasms.2c00343] [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] [Indexed: 06/17/2023]
Abstract
While soluble forms of amyloid-β (Aβ) and Tau work together to drive healthy neurons into a disease state, how their interaction may control the prion-like propagation and neurotoxicity of Tau is not fully understood. The cross-linking via disulfide bond formation is crucial for Tau oligomers to obtain stable conformers and spread between cells. This work thus focuses on how Aβ42 regulates this critical process. By studying the interactions between Aβ42 and TauPHF43, a construct that mimics the Tau R3 isoform, has a similar length to Aβ42, and contains one cysteine (Cys-322), we discovered that fresh Aβ42 could protect Tau against the formation of disulfide cross-linked dimers. We showed that the monomeric and small Aβ oligomers (the "nonamyloidogenic Aβ") efficiently disassembled tau dimers and heparin-induced Tau oligomers to recover Tau monomers. Interestingly, Aβ serves the role of an antioxidant to prevent disulfide bond formation, as supported by the experiments of Aβ with cystine. Furthermore, using cyclosporine A (CycA), a macrocyclic β-sheet disruptor, we demonstrated that targeting amyloidogenic Aβ with CycA does not affect the TauPHF43 disassembly driven by Aβ42. Separately, we assessed the initial toxicity of Aβ42 and TauPHF43 in acute brain slices and found that Aβ42 is more toxic than TauPHF43 or the two peptides combined. Our work highlights a potential protective role of Aβ42 monomers in AD that was previously overlooked while focusing on the mechanism behind Aβ42 aggregation leading to tau dysfunction.
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Affiliation(s)
- Amber L H Gray
- Department of Chemistry, University of Tennessee, Knoxville, Tennessee 37996, United States
| | - Victoria Norman
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996, United States
| | - Damilola S Oluwatoba
- Department of Chemistry, University of Tennessee, Knoxville, Tennessee 37996, United States
| | - Rebecca A Prosser
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996, United States
| | - Thanh D Do
- Department of Chemistry, University of Tennessee, Knoxville, Tennessee 37996, United States
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6
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Evidence of the different effect of mercury and cadmium on the hIAPP aggregation process. Biophys Chem 2022; 290:106880. [DOI: 10.1016/j.bpc.2022.106880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 08/26/2022] [Accepted: 08/26/2022] [Indexed: 11/22/2022]
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Mathiesen DS, Lund A, Holst JJ, Knop FK, Lutz TA, Bagger JI. THERAPY OF ENDOCRINE DISEASE: Amylin and calcitonin - physiology and pharmacology. Eur J Endocrinol 2022; 186:R93-R111. [PMID: 35353712 DOI: 10.1530/eje-21-1261] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 03/30/2022] [Indexed: 11/08/2022]
Abstract
Type 2 diabetes is a common manifestation of metabolic dysfunction due to obesity and constitutes a major burden for modern health care systems, in concert with the alarming rise in obesity worldwide. In recent years, several successful pharmacotherapies improving glucose metabolism have emerged and some of these also promote weight loss, thus, ameliorating insulin resistance. However, the progressive nature of type 2 diabetes is not halted by these new anti-diabetic pharmacotherapies. Therefore, novel therapies promoting weight loss further and delaying diabetes progression are needed. Amylin, a beta cell hormone, has satiating properties and also delays gastric emptying and inhibits postprandial glucagon secretion with the net result of reducing postprandial glucose excursions. Amylin acts through the six amylin receptors, which share the core component with the calcitonin receptor. Calcitonin, derived from thyroid C cells, is best known for its role in humane calcium metabolism, where it inhibits osteoclasts and reduces circulating calcium. However, calcitonin, particularly of salmon origin, has also been shown to affect insulin sensitivity, reduce the gastric emptying rate and promote satiation. Preclinical trials with agents targeting the calcitonin receptor and the amylin receptors, show improvements in several parameters of glucose metabolism including insulin sensitivity and some of these agents are currently undergoing clinical trials. Here, we review the physiological and pharmacological effects of amylin and calcitonin and discuss the future potential of amylin and calcitonin-based treatments for patients with type 2 diabetes and obesity.
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Affiliation(s)
- David S Mathiesen
- Center for Clinical Metabolic Research, Gentofte Hospital, Hellerup, Denmark
| | - Asger Lund
- Center for Clinical Metabolic Research, Gentofte Hospital, Hellerup, Denmark
- Department of Medicine, Gentofte and Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, Hellerup, Denmark
- Department of Medicine, Gentofte and Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Thomas A Lutz
- Institute of Veterinary Physiology, Vetsuisse-Faculty, University of Zurich, Zurich, Switzerland
| | - Jonatan I Bagger
- Center for Clinical Metabolic Research, Gentofte Hospital, Hellerup, Denmark
- Department of Medicine, Gentofte and Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
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Mediators of Amylin Action in Metabolic Control. J Clin Med 2022; 11:jcm11082207. [PMID: 35456307 PMCID: PMC9025724 DOI: 10.3390/jcm11082207] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 04/08/2022] [Accepted: 04/13/2022] [Indexed: 02/06/2023] Open
Abstract
Amylin (also called islet amyloid polypeptide (IAPP)) is a pancreatic beta-cell hormone that is co-secreted with insulin in response to nutrient stimuli. The last 35 years of intensive research have shown that amylin exerts important physiological effects on metabolic control. Most importantly, amylin is a physiological control of meal-ending satiation, and it limits the rate of gastric emptying and reduces the secretion of pancreatic glucagon, in particular in postprandial states. The physiological effects of amylin and its analogs are mediated by direct brain activation, with the caudal hindbrain playing the most prominent role. The clarification of the structure of amylin receptors, consisting of the calcitonin core receptor plus receptor-activity modifying proteins, aided in the development of amylin analogs with a broad pharmacological profile. The general interest in amylin physiology and pharmacology was boosted by the finding that amylin is a sensitizer to the catabolic actions of leptin. Today, amylin derived analogs are considered to be among the most promising approaches for the pharmacotherapy against obesity. At least in conjunction with insulin, amylin analogs are also considered important treatment options in diabetic patients, so that new drugs may soon be added to the only currently approved compound pramlintide (Symlin®). This review provides a brief summary of the physiology of amylin’s mode of actions and its role in the control of the metabolism, in particular energy intake and glucose metabolism.
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9
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Lutz TA. Creating the amylin story. Appetite 2022; 172:105965. [DOI: 10.1016/j.appet.2022.105965] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/28/2022] [Accepted: 02/04/2022] [Indexed: 02/07/2023]
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10
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Memaj P, Jornayvaz FR. Non-alcoholic fatty liver disease in type 1 diabetes: Prevalence and pathophysiology. Front Endocrinol (Lausanne) 2022; 13:1031633. [PMID: 36531463 PMCID: PMC9752856 DOI: 10.3389/fendo.2022.1031633] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/11/2022] [Indexed: 12/03/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in the general population with a global prevalence of 25%. It is often associated with metabolic syndrome and type 2 diabetes, as insulin resistance and hyperinsulinemia are known to be favoring factors. Recent studies have described growing incidence of NAFLD in type 1 diabetes (T1D) as well. Although increasing prevalence of metabolic syndrome in these patients seems to explain part of this increase in NAFLD, other underlying mechanisms may participate in the emergence of NAFLD. Notably, some genetic factors are more associated with fatty liver disease, but their prevalence in T1D has not been evaluated. Moreover, oxidative stress, poor glucose control and long-lasting hyperglycemia, as well as exogenous insulin administration play an important role in intrahepatic fat homeostasis. The main differential diagnosis of NAFLD in T1D is glycogenic hepatopathy, which needs to be considered mostly in T1D patients with poor glycemic control. This article aims to review the prevalence and pathophysiology of NAFLD in T1D and open perspectives for clinicians taking care of T1D patients with potential hepatopathy.
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Affiliation(s)
- Plator Memaj
- Division of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Department of Medicine, Geneva University Hospitals, Geneva, Switzerland
| | - François R. Jornayvaz
- Division of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Department of Medicine, Geneva University Hospitals, Geneva, Switzerland
- Diabetes Center, Faculty of Medicine, Geneva University, Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, Geneva University, Geneva, Switzerland
- *Correspondence: François R. Jornayvaz,
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Mertens J, De Block C, Spinhoven M, Driessen A, Francque SM, Kwanten WJ. Hepatopathy Associated With Type 1 Diabetes: Distinguishing Non-alcoholic Fatty Liver Disease From Glycogenic Hepatopathy. Front Pharmacol 2021; 12:768576. [PMID: 34759828 PMCID: PMC8573337 DOI: 10.3389/fphar.2021.768576] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/06/2021] [Indexed: 12/14/2022] Open
Abstract
Autoimmune destruction of pancreatic β-cells results in the permanent loss of insulin production in type 1 diabetes (T1D). The daily necessity to inject exogenous insulin to treat hyperglycemia leads to a relative portal vein insulin deficiency and potentiates hypoglycemia which can induce weight gain, while daily fluctuations of blood sugar levels affect the hepatic glycogen storage and overall metabolic control. These, among others, fundamental characteristics of T1D are associated with the development of two distinct, but in part clinically similar hepatopathies, namely non-alcoholic fatty liver disease (NAFLD) and glycogen hepatopathy (GlyH). Recent studies suggest that NAFLD may be increasingly common in T1D because more people with T1D present with overweight and/or obesity, linked to the metabolic syndrome. GlyH is a rare but underdiagnosed complication hallmarked by extremely brittle metabolic control in, often young, individuals with T1D. Both hepatopathies share clinical similarities, troubling both diagnosis and differentiation. Since NAFLD is increasingly associated with cardiovascular and chronic kidney disease, whereas GlyH is considered self-limiting, awareness and differentiation between both condition is important in clinical care. The exact pathogenesis of both hepatopathies remains obscure, hence licensed pharmaceutical therapy is lacking and general awareness amongst physicians is low. This article aims to review the factors potentially contributing to fatty liver disease or glycogen storage disruption in T1D. It ends with a proposal for clinicians to approach patients with T1D and potential hepatopathy.
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Affiliation(s)
- Jonathan Mertens
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium.,Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Wilrijk, Belgium
| | - Christophe De Block
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Wilrijk, Belgium
| | - Maarten Spinhoven
- Department of Radiology, Antwerp University Hospital, Edegem, Belgium
| | - Ann Driessen
- Department of Pathology, Antwerp University Hospital, Antwerp, Belgium.,CORE, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Sven M Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Wilrijk, Belgium
| | - Wilhelmus J Kwanten
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Wilrijk, Belgium
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12
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Kern KA, DiBrog AM, Przybysz JT, Mietlicki-Baase EG. Effects of pramlintide on energy intake and food preference in rats given a choice diet. Physiol Behav 2021; 240:113541. [PMID: 34332974 DOI: 10.1016/j.physbeh.2021.113541] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 07/22/2021] [Accepted: 07/23/2021] [Indexed: 10/20/2022]
Abstract
Amylin is a peptide hormone involved in the control of energy balance, making the amylin system a potential target for pharmacotherapies to treat obesity. Pramlintide, an amylin analogue, is an FDA-approved medication for the treatment of diabetes that also has food intake- and body weight-suppressive effects. However, it is unknown whether pramlintide may preferentially reduce intake of highly palatable, energy dense food, the overconsumption of which is thought to play a role in the etiology of obesity. Here, we investigate the effects of pramlintide on food intake and body weight in rats given a choice of chow and high fat diet (HFD). Systemic pramlintide injection in rats reduced HFD intake at 3h post-injection, with no effects at other times and no significant effects on chow intake, body weight, or percent preference for HFD. In a separate experiment, the effects of central injection of pramlintide on food intake and body weight were similarly evaluated. Intracerebroventricular pramlintide significantly reduced HFD intake throughout the 24h post-injection, with some suppressive effects on chow intake, and also decreased 24h body weight change. Again, no significant changes were observed in the proportion of calories obtained from HFD. The same intracerebroventricular doses of pramlintide did not induce pica, suggesting that pramlintide-mediated reductions in feeding are not due to nausea/malaise. Our results suggest that pramlintide reduces food intake in rats largely via reductions in intake of HFD versus chow, supporting the idea that the potent effects of pramlintide on palatable food intake may have utility in the treatment of obesity.
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Affiliation(s)
- Katherine A Kern
- Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, State University of New York, Buffalo, NY 14214, USA
| | - Adrianne M DiBrog
- Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, State University of New York, Buffalo, NY 14214, USA
| | - Johnathan T Przybysz
- Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, State University of New York, Buffalo, NY 14214, USA
| | - Elizabeth G Mietlicki-Baase
- Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, State University of New York, Buffalo, NY 14214, USA; Center for Ingestive Behavior Research, University at Buffalo, State University of New York, Buffalo, NY 14214, USA.
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13
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Zhu X, Lin C, Li L, Hu S, Cai X, Ji L. SGLT2i increased the plasma fasting glucagon level in patients with diabetes: A meta-analysis. Eur J Pharmacol 2021; 903:174145. [PMID: 33957085 DOI: 10.1016/j.ejphar.2021.174145] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 04/11/2021] [Accepted: 04/28/2021] [Indexed: 02/06/2023]
Abstract
Increased glucagon level was hypothesized to participate in the ketoacidosis associated with sodium-glucose co-transporter 2 inhibitors (SGLT2i) treatment. However, the effect of SGLT2i on glucagon remains controversial. Hence, we conducted this meta-analysis to assess the overall effect of SGLT2i treatment on plasma fasting glucagon level in patients with diabetes. PubMed/MEDLINE, Embase, and Cochrane databases were searched for studies published before August 2020. Clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus with reports of glucagon changes before and after SGLT2i intervention were included. Eligible trials were analyzed by fixed-effect model, random effect model, and meta-regression analysis accordingly. In total, ten trials were included in this meta-analysis. Compared with the non-SGLT2i treatment group, SGLT2i treatment resulted in increased plasma fasting glucagon levels with significance (WMD, 8.35 pg/ml; 95% CI, 2.17-14.54 pg/ml, P＜0.01) in patients with diabetes mellitus. Besides, when compared with non-SGLT2i control group, the insulin level decreased (WMD, -2.78 μU/ml; 95% CI, -5.11 to -0.46 μU/ml, P = 0.02) and ketone body level increased (WMD, 0.17 mmol/l; 95% CI, 0.09-0.25 mmol/l, P＜0.01) in patients with type 2 diabetes. In conclusion, our result indicated SGLT2i intervention would increase the plasma fasting glucagon level in patients with diabetes mellitus. The increase in plasma fasting glucagon level may be associated with reduced insulin level. The increased glucagon-insulin ratio after the use of SGLT2i may make diabetic patients susceptible to ketosis.
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Affiliation(s)
- Xingyun Zhu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
| | - Chu Lin
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
| | - Li Li
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
| | - Suiyuan Hu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
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14
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Sonne N, Karsdal MA, Henriksen K. Mono and dual agonists of the amylin, calcitonin, and CGRP receptors and their potential in metabolic diseases. Mol Metab 2021; 46:101109. [PMID: 33166741 PMCID: PMC8085567 DOI: 10.1016/j.molmet.2020.101109] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/28/2020] [Accepted: 10/29/2020] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Therapies for metabolic diseases are numerous, yet improving insulin sensitivity beyond that induced by weight loss remains challenging. Therefore, search continues for novel treatment candidates that can stimulate insulin sensitivity and increase weight loss efficacy in combination with current treatment options. Calcitonin gene-related peptide (CGRP) and amylin belong to the same peptide family and have been explored as treatments for metabolic diseases. However, their full potential remains controversial. SCOPE OF REVIEW In this article, we introduce this rather complex peptide family and its corresponding receptors. We discuss the physiology of the peptides with a focus on metabolism and insulin sensitivity. We also thoroughly review the pharmacological potential of amylin, calcitonin, CGRP, and peptide derivatives as treatments for metabolic diseases, emphasizing their ability to increase insulin sensitivity based on preclinical and clinical studies. MAJOR CONCLUSIONS Amylin receptor agonists and dual amylin and calcitonin receptor agonists are relevant treatment candidates, especially because they increase insulin sensitivity while also assisting weight loss, and their unique mode of action complements incretin-based therapies. However, CGRP and its derivatives seem to have only modest if any metabolic effects and are no longer of interest as therapies for metabolic diseases.
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Affiliation(s)
- Nina Sonne
- Nordic Bioscience Biomarkers and Research, Herlev, Denmark
| | - Morten A Karsdal
- Nordic Bioscience Biomarkers and Research, Herlev, Denmark; KeyBioscience AG, Stans, Switzerland
| | - Kim Henriksen
- Nordic Bioscience Biomarkers and Research, Herlev, Denmark; KeyBioscience AG, Stans, Switzerland.
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15
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Rahman I, Athar MT, Islam M. Type 2 Diabetes, Obesity, and Cancer Share Some Common and Critical Pathways. Front Oncol 2021; 10:600824. [PMID: 33552973 PMCID: PMC7855858 DOI: 10.3389/fonc.2020.600824] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 11/24/2020] [Indexed: 12/13/2022] Open
Abstract
Diabetes and cancer are among the most frequent and complex diseases. Epidemiological evidence showed that the patients suffering from diabetes are significantly at higher risk for a number of cancer types. There are a number of evidence that support the hypothesis that these diseases are interlinked, and obesity may aggravate the risk(s) of type 2 diabetes and cancer. Multi-level unwanted alterations such as (epi-)genetic alterations, changes at the transcriptional level, and altered signaling pathways (receptor, cytoplasmic, and nuclear level) are the major source which promotes a number of complex diseases and such heterogeneous level of complexities are considered as the major barrier in the development of therapeutic agents. With so many known challenges, it is critical to understand the relationships and the commonly shared causes between type 2 diabetes and cancer, which is difficult to unravel and understand. Furthermore, the real complexity arises from contended corroborations that specific drug(s) (individually or in combination) during the treatment of type 2 diabetes may increase or decrease the cancer risk or affect cancer prognosis. In this review article, we have presented the recent and most updated evidence from the studies where the origin, biological background, the correlation between them have been presented or proved. Furthermore, we have summarized the methodological challenges and tasks that are frequently encountered. We have also outlined the physiological links between type 2 diabetes and cancers. Finally, we have presented and summarized the outline of the hallmarks for both these diseases, diabetes and cancer.
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Affiliation(s)
- Ishrat Rahman
- Department of Basic Dental Sciences, College of Dentistry, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Md Tanwir Athar
- Scientific Research Center, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Mozaffarul Islam
- Scientific Research Center, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
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16
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Abstract
In spite of developments with novel insulin preparations, novel modes of insulin delivery with insulin infusion pumps, and the facility of continuous glucose monitoring, only 20% of patients with type 1 diabetes are under adequate control. The need for innovation is clear, and, therefore, the use of adjunct therapies with other pharmacological agents currently in use for type 2 diabetes, has been tried. Currently, pramlintide is the only agent licensed for use in this condition in addition to insulin. Global trials have been conducted with liraglutide, a glucagon-like peptide 1 receptor agonist (GLP-1RA), dapagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, and sotagliflozin, an inhibitor of both SGLT1 and SGLT2 transporters. While dapagliflozin and sotagliflozin have now been licensed for clinical use in this condition in Europe and Japan, they have hitherto not been licensed in the United States due to a small increase in the risk of diabetic ketoacidosis. However, these agents reduce glycosylated hemoglobin (HbA1c) by 0.4%, reduce glycemic oscillations, and do not increase the risk of hypoglycemia. Liraglutide, on the other hand, induced a smaller reduction in HbA1c and thus was not considered for a license. However, further trials are currently being conducted with a combination of semaglutide, the most potent GLP-1RA, and dapagliflozin to determine whether this approach would yield better outcomes.
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Affiliation(s)
- Itivrita Goyal
- Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, Williamsville, New York
| | - Alamgir Sattar
- Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, Williamsville, New York
| | - Megan Johnson
- Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, Williamsville, New York
| | - Paresh Dandona
- Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, Williamsville, New York
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17
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Muzurović E, Dragnić S, Medenica S, Smolović B, Bulajić P, Mikhailidis DP. Weight-centric pharmacological management of type 2 diabetes mellitus - An essential component of cardiovascular disease prevention. J Diabetes Complications 2020; 34:107619. [PMID: 32499116 DOI: 10.1016/j.jdiacomp.2020.107619] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 04/26/2020] [Accepted: 05/06/2020] [Indexed: 12/19/2022]
Abstract
Obesity and overweight are contributing factors for diseases such as type 2 diabetes mellitus (T2DM), hypertension, hyperlipidemia, and ultimately, cardiovascular (CV) disease. Obesity is imposing an increasing health burden in rich and poor nations, with almost 30% of people globally now either obese or overweight - a staggering 2.1 billion. The link between obesity and T2DM is widely held to involve two adverse effects: obesity-induced insulin resistance and β-cell failure. This "unified field theory" raises questions about whether defects favoring progressive weight gain and metabolic impairment also contribute to β-cell decompensation. The concept of weight-centric management of T2DM is considered justified because of the strong negative impact of obesity on the effects of treatment of diabetes. Two pharmacotherapy options are considered: drugs developed primarily for blood glucose control that also exert a favorable effect on body weight and drugs developed primarily to induce weight loss that also have a favorable effect on glycemia. Treating hunger counter-regulatory mechanisms will have an additional effect on glucose control in T2DM. This narrative review addresses advances in pharmacotherapy for the management of obesity and obesity-related co-morbidities, with a focus on T2DM. It is also important to identify the correct balance between weight-centric and glucose-centric management of T2DM.
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Affiliation(s)
- Emir Muzurović
- Department of Internal Medicine, Endocrinology Section, Clinical Center of Montenegro, Ljubljanska bb, 81000 Podgorica, Montenegro; Faculty of Medicine, University of Montenegro, Kruševac bb, 81000, Podgorica, Montenegro.
| | - Siniša Dragnić
- Faculty of Medicine, University of Montenegro, Kruševac bb, 81000, Podgorica, Montenegro
| | - Sanja Medenica
- Department of Internal Medicine, Endocrinology Section, Clinical Center of Montenegro, Ljubljanska bb, 81000 Podgorica, Montenegro; Faculty of Medicine, University of Montenegro, Kruševac bb, 81000, Podgorica, Montenegro
| | - Brigita Smolović
- Faculty of Medicine, University of Montenegro, Kruševac bb, 81000, Podgorica, Montenegro
| | - Predrag Bulajić
- Department of Internal Medicine, Endocrinology Section, Clinical Center of Montenegro, Ljubljanska bb, 81000 Podgorica, Montenegro
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), Pond Street, London NW3 2QG, UK
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18
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Sonne N, Larsen AT, Andreassen KV, Karsdal MA, Henriksen K. The Dual Amylin and Calcitonin Receptor Agonist, KBP-066, Induces an Equally Potent Weight Loss Across a Broad Dose Range While Higher Doses May Further Improve Insulin Action. J Pharmacol Exp Ther 2020; 373:92-102. [PMID: 31992608 DOI: 10.1124/jpet.119.263723] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 01/21/2020] [Indexed: 12/27/2022] Open
Abstract
Pharmacological treatment with dual amylin and calcitonin receptor agonists (DACRAs) cause significant weight loss and improvement of glucose homeostasis. In this study, the maximally efficacious dose of the novel DACRA, KeyBiosciencePeptide (KBP)-066, was investigated. Two different rat models were used: high-fat diet (HFD)-fed male Sprague-Dawley rats and male Zucker diabetic fatty (ZDF, fa/fa) rats to determine the maximum weight loss and glucose homeostatic effect, respectively. One acute study and one chronic study was performed in HFD rats. Two chronic studies were performed in ZDF rats: a preventive and an interventive. All studies covered a dose range of 5, 50, and 500 µg/kg KBP-066 delivered by subcutaneous injection. Treatment with KBP-066 resulted in a significant weight reduction of 13%-16% and improved glucose tolerance in HFD rats, which was independent of dose concentration. Dosing with 50 and 500 µg/kg led to a transient but significant increase in blood glucose, both in the acute and the chronic study in HFD rats. All doses of KBP-066 significantly improved glucose homeostasis in ZDF rats, both in the preventive and interventive study. Moreover, dosing with 50 and 500 µg/kg preserved insulin secretion to a greater extent than 5 µg/kg when compared with ZDF vehicle rats. Taken together, these results show that maximum weight loss is achieved with 5 µg/kg, which is within the range of previously reported DACRA dosing, whereas increasing dosing concentration to 50 and 500 µg/kg may further improve preservation of insulin secretion compared with 5 µg/kg in diabetic ZDF rats. SIGNIFICANCE STATEMENT: Here we show that KeyBiosciencePeptide (KBP)-066 induces an equally potent body weight loss across a broad dose range in obese rats. However, higher dosing of KBP-066 may improve insulin action in diabetic rats both as preventive and interventive treatment.
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Affiliation(s)
- Nina Sonne
- Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark
| | - Anna Thorsø Larsen
- Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark
| | - Kim Vietz Andreassen
- Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark
| | - Morten Asser Karsdal
- Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark
| | - Kim Henriksen
- Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark
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19
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Davis EM, Sandoval DA. Glucagon‐Like Peptide‐1: Actions and Influence on Pancreatic Hormone Function. Compr Physiol 2020; 10:577-595. [DOI: 10.1002/cphy.c190025] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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20
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Poulson BG, Szczepski K, Lachowicz JI, Jaremko L, Emwas AH, Jaremko M. Aggregation of biologically important peptides and proteins: inhibition or acceleration depending on protein and metal ion concentrations. RSC Adv 2019; 10:215-227. [PMID: 35492549 PMCID: PMC9047971 DOI: 10.1039/c9ra09350h] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Accepted: 12/14/2019] [Indexed: 01/03/2023] Open
Abstract
The process of aggregation of proteins and peptides is dependent on the concentration of proteins, and the rate of aggregation can be altered by the presence of metal ions, but this dependence is not always a straightforward relationship. In general, aggregation does not occur under normal physiological conditions, yet it can be induced in the presence of certain metal ions. However, the extent of the influence of metal ion interactions on protein aggregation has not yet been fully comprehended. A consensus has thus been difficult to reach because the acceleration/inhibition of the aggregation of proteins in the presence of metal ions depends on several factors such as pH and the concentration of the aggregated proteins involved as well as metal concentration level of metal ions. Metal ions, like Cu2+, Zn2+, Pb2+ etc. may either accelerate or inhibit aggregation simply because the experimental conditions affect the behavior of biomolecules. It is clear that understanding the relationship between metal ion concentration and protein aggregation will prove useful for future scientific applications. This review focuses on the dependence of the aggregation of selected important biomolecules (peptides and proteins) on metal ion concentrations. We review proteins that are prone to aggregation, the result of which can cause serious neurodegenerative disorders. Furthering our understanding of the relationship between metal ion concentration and protein aggregation will prove useful for future scientific applications, such as finding therapies for neurodegenerative diseases.
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Affiliation(s)
- Benjamin Gabriel Poulson
- Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900 Saudi Arabia
| | - Kacper Szczepski
- Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900 Saudi Arabia
| | - Joanna Izabela Lachowicz
- Department of Medical Sciences and Public Health, University of Cagliari, Cittadella Universitaria 09042 Monserrato Italy
| | - Lukasz Jaremko
- Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900 Saudi Arabia
| | - Abdul-Hamid Emwas
- Core Labs, King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900 Saudi Arabia
| | - Mariusz Jaremko
- Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900 Saudi Arabia
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21
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Ling W, Huang YM, Qiao YC, Zhang XX, Zhao HL. Human Amylin: From Pathology to Physiology and Pharmacology. Curr Protein Pept Sci 2019; 20:944-957. [DOI: 10.2174/1389203720666190328111833] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 03/12/2019] [Accepted: 03/15/2019] [Indexed: 12/18/2022]
Abstract
The histopathological hallmark of type 2 diabetes is islet amyloid implicated in the developing treatment options. The major component of human islet amyloid is 37 amino acid peptide known as amylin or islet amyloid polypeptide (IAPP). Amylin is an important hormone that is co-localized, copackaged, and co-secreted with insulin from islet β cells. Physiologically, amylin regulates glucose homeostasis by inhibiting insulin and glucagon secretion. Furthermore, amylin modulates satiety and inhibits gastric emptying via the central nervous system. Normally, human IAPP is soluble and natively unfolded in its monomeric state. Pathologically, human IAPP has a propensity to form oligomers and aggregate. The oligomers show misfolded α-helix conformation and can further convert themselves to β-sheet-rich fibrils as amyloid deposits. The pathological findings and physiological functions of amylin have led to the introduction of pramlintide, an amylin analog, for the treatment of diabetes. The history of amylin’s discovery is a representative example of how a pathological finding can translate into physiological exploration and lead to pharmacological intervention. Understanding the importance of transitioning from pathology to physiology and pharmacology can provide novel insight into diabetes mellitus and Alzheimer's disease.
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Affiliation(s)
- Wei Ling
- Center for Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin 541004, China
| | - Yan-Mei Huang
- Center for Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin 541004, China
| | - Yong-Chao Qiao
- Department of Laboratory, the Affiliated Hospital of Guilin Medical University, Guilin 541004, China
| | - Xiao-Xi Zhang
- Center for Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin 541004, China
| | - Hai-Lu Zhao
- Center for Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin 541004, China
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22
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Sah SK, Samuel VP, Dahiya S, Singh Y, Gilhotra RM, Gupta G, Mishra A, Sharma RK, Kumar GS, SreeHarsha N, Chellappan DK, Dua K. A contemporary biological pathway of islet amyloid polypeptide for the management of diabetic dementia. Chem Biol Interact 2019; 306:117-122. [PMID: 31004596 DOI: 10.1016/j.cbi.2019.04.022] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 04/11/2019] [Accepted: 04/17/2019] [Indexed: 01/07/2023]
Abstract
Major challenges of dealing elder patients with diabetes mellitus (DM) are the individualization of consideration in persons with various comorbid types of conditions. In spite of the fact that microvascular and macrovascular problems associated with DM are well documented, there is only a few numbers of reports viewing different conditions, for example, cognitive dysfunction. Cognitive dysfunction is of specific significance due to its effect on self-care and quality of life. All in all, the etiology of cognitive dysfunction in the maturing populace is probably going to be the grouping of ischemic and degenerative pathology. It is likewise trusted that Hyperglycemia is engaged with the system of DM-related cognitive dysfunction. At present, it isn't certain in the case of enhancing glycemic control or utilizing therapeutic agents can enhance the risk of cognitive decay. Amylin was later characterized as an amyloidogenic peptide, confined from a beta cell tumor and called islet amyloid polypeptide (IAPP), and after that, amylin. Conversely, we investigate the beneficial role and hypothesizing the mechanism of amylin related expanding the level and activation of CGRP receptor to enhance the cognition declination amid diabetic dementia.
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Affiliation(s)
| | - Vijaya Paul Samuel
- Department of Anatomy, RAK College of Medicine, RAK Medical and Health Sciences, University, Ras Al Khaimah, United Arab Emirates
| | - Sunita Dahiya
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico, USA
| | - Yogendar Singh
- Department of Pharmaceutical Sciences, Mahatma Gandhi College of Pharmaceutical Sciences, Sitapura, Jaipur, India
| | - Ritu M Gilhotra
- School of Pharmacy, Suresh Gyan Vihar University, Mahal Road, Jagatpura, Jaipur, India
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Mahal Road, Jagatpura, Jaipur, India.
| | - Anurag Mishra
- School of Pharmacy, Suresh Gyan Vihar University, Mahal Road, Jagatpura, Jaipur, India
| | - Rakesh Kumar Sharma
- School of Pharmacy, Suresh Gyan Vihar University, Mahal Road, Jagatpura, Jaipur, India
| | | | - Nagaraja SreeHarsha
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur, 57000, Malaysia
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney (UTS), Ultimo, NSW 2007, Australia; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute (HMRI) & School of Biomedical Sciences and Pharmacy, The University of Newcastle (UoN), Callaghan, NSW 2308, Australia.
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23
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Krane EJ, Rhodes ET, Claure RE, Rowe E, Wolfsdorf JI. Essentials of Endocrinology. A PRACTICE OF ANESTHESIA FOR INFANTS AND CHILDREN 2019:629-654.e6. [DOI: 10.1016/b978-0-323-42974-0.00027-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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24
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Frandsen CS, Dejgaard TF, Madsbad S, Holst JJ. Non-insulin pharmacological therapies for treating type 1 diabetes. Expert Opin Pharmacother 2018; 19:947-960. [PMID: 29991320 DOI: 10.1080/14656566.2018.1483339] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Despite intensified insulin treatment, many persons with type 1 diabetes (T1D) do not achieve glycemic and metabolic targets. Consequently, non-insulin chemical therapies that improve glycemic control and metabolic parameters without increasing the risk of adverse events (including hypoglycemia) are of interest as adjunct therapies to insulin. AREAS COVERED In this review, the authors discuss the efficacy and safety of non-insulin therapies, including pramlintide, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 inhibitors (DPP-4), sodium-glucose cotransporter (SGLT1 and SGLT2) inhibitors, metformin, sulfonylureas, and thiazolidinediones as add-on therapies to insulin in T1D. EXPERT OPINION The current evidence shows that the efficacy of non-insulin therapies as add-on therapies to insulin is minimal or modest with an average HbA1c reduction of 0.2-0.5% (2-6 mmol/mol). Indeed, the current focus is on the development of SGLT inhibitors as adjuncts to insulin in type 1 diabetes. Studies of subgroups with obesity, residual beta-cell function (including newly diagnosed patients) and patients prone to hypoglycemia could be areas of future research.
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Affiliation(s)
| | - Thomas Fremming Dejgaard
- a Department of Endocrinology , Hvidovre Hospital, University of Copenhagen , Hvidovre , Denmark.,b Steno Diabetes Center Copenhagen , Gentofte , Denmark
| | - Sten Madsbad
- a Department of Endocrinology , Hvidovre Hospital, University of Copenhagen , Hvidovre , Denmark
| | - Jens Juul Holst
- c Department of Biomedical Sciences and NNF Center for Basic Metabolic Research , University of Copenhagen , Copenhagen , Denmark
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25
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Hædersdal S, Lund A, Knop FK, Vilsbøll T. The Role of Glucagon in the Pathophysiology and Treatment of Type 2 Diabetes. Mayo Clin Proc 2018; 93:217-239. [PMID: 29307553 DOI: 10.1016/j.mayocp.2017.12.003] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 12/04/2017] [Accepted: 12/07/2017] [Indexed: 12/19/2022]
Abstract
Type 2 diabetes is a disease involving both inadequate insulin levels and increased glucagon levels. While glucagon and insulin work together to achieve optimal plasma glucose concentrations in healthy individuals, the usual regulatory balance between these 2 critical pancreatic hormones is awry in patients with diabetes. Although clinical discussion often focuses on the role of insulin, glucagon is equally important in understanding type 2 diabetes. Furthermore, an awareness of the role of glucagon is essential to appreciate differences in the mechanisms of action of various classes of glucose-lowering therapies. Newer drug classes such as dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists improve glycemic control, in part, by affecting glucagon levels. This review provides an overview of the effect of glucose-lowering therapies on glucagon on the basis of an extensive PubMed literature search to identify clinical studies of glucose-lowering therapies in type 2 diabetes that included assessment of glucagon. Clinical practice currently benefits from available therapies that impact the glucagon regulatory pathway. As clinicians look to the future, improved treatment strategies are likely to emerge that will either use currently available therapies whose mechanisms of action complement each other or take advantage of new therapies based on an improved understanding of glucagon pathophysiology.
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Affiliation(s)
- Sofie Hædersdal
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Asger Lund
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Filip K Knop
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark; Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
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26
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Denroche HC, Verchere CB. IAPP and type 1 diabetes: implications for immunity, metabolism and islet transplants. J Mol Endocrinol 2018; 60:R57-R75. [PMID: 29378867 DOI: 10.1530/jme-17-0138] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 12/06/2017] [Indexed: 01/12/2023]
Abstract
Islet amyloid polypeptide (IAPP), the main component of islet amyloid in type 2 diabetes and islet transplants, is now recognized as a contributor to beta cell dysfunction. Increasingly, evidence warrants its investigation in type 1 diabetes owing to both its immunomodulatory and metabolic actions. Autoreactive T cells to IAPP-derived epitopes have been described in humans, suggesting that IAPP is an islet autoantigen in type 1 diabetes. In addition, although aggregates of IAPP have not been implicated in type 1 diabetes, they are potent pro-inflammatory stimuli to innate immune cells, and thus, could influence autoimmunity. IAPP aggregates also occur rapidly in transplanted islets and likely contribute to islet transplant failure in type 1 diabetes through sterile inflammation. In addition, since type 1 diabetes is a disease of both insulin and IAPP deficiency, clinical trials have examined the potential benefits of IAPP replacement in type 1 diabetes with the injectable IAPP analogue, pramlintide. Pramlintide limits postprandial hyperglycemia by delaying gastric emptying and suppressing hyperglucagonemia, underlining the possible role of IAPP in postprandial glucose metabolism. Here, we review IAPP in the context of type 1 diabetes: from its potential involvement in type 1 diabetes pathogenesis, through its role in glucose metabolism and use of IAPP analogues as therapeutics, to its potential role in clinical islet transplant failure and considerations in this regard for future beta cell replacement strategies.
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Affiliation(s)
- Heather C Denroche
- Department of Surgery, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - C Bruce Verchere
- Department of Surgery, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Pathology and Laboratory Medicine, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
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27
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Grøndahl MF, Keating DJ, Vilsbøll T, Knop FK. Current Therapies That Modify Glucagon Secretion: What Is the Therapeutic Effect of Such Modifications? Curr Diab Rep 2017; 17:128. [PMID: 29080075 DOI: 10.1007/s11892-017-0967-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW Hyperglucagonemia contributes significantly to hyperglycemia in type 2 diabetes and suppressed glucagon levels may increase the risk of hypoglycemia. Here, we give a brief overview of glucagon physiology and the role of glucagon in the pathophysiology of type 2 diabetes and provide insights into how antidiabetic drugs influence glucagon secretion as well as a perspective on the future of glucagon-targeting drugs. RECENT FINDINGS Several older as well as recent investigations have evaluated the effect of antidiabetic agents on glucagon secretion to understand how glucagon may be involved in the drugs' efficacy and safety profiles. Based on these findings, modulation of glucagon secretion seems to play a hitherto underestimated role in the efficacy and safety of several glucose-lowering drugs. Numerous drugs currently available to diabetologists are capable of altering glucagon secretion: metformin, sulfonylurea compounds, insulin, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter 2 inhibitors and amylin mimetics. Their diverse effects on glucagon secretion are of importance for their individual efficacy and safety profiles. Understanding how these drugs interact with glucagon secretion may help to optimize treatment.
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Affiliation(s)
- Magnus F Grøndahl
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Damien J Keating
- Discipline of Human Physiology and Centre for Neuroscience, Flinders University of South Australia, Adelaide, Australia
- Nutrition and Metabolism, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia
| | - Tina Vilsbøll
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark
| | - Filip K Knop
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.
- Department of Clinical Medicine, Faculty of Health and Medical sciences, University of Copenhagen, Copenhagen, Denmark.
- Novo Nordisk Foundation Center for Metabolic Research, Faculty of Health and Medical sciences, University of Copenhagen, Copenhagen, Denmark.
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Huang WQ, Guo JH, Zhang XH, Yu MK, Chung YW, Ruan YC, Chan HC. Glucose-Sensitive CFTR Suppresses Glucagon Secretion by Potentiating KATP Channels in Pancreatic Islet α Cells. Endocrinology 2017; 158:3188-3199. [PMID: 28977595 DOI: 10.1210/en.2017-00282] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 07/18/2017] [Indexed: 12/14/2022]
Abstract
The secretion of glucagon by islet α cells is normally suppressed by high blood glucose, but this suppressibility is impaired in patients with diabetes or cystic fibrosis (CF), a disease caused by mutations in the gene encoding CF transmembrane conductance regulator (CFTR), a cyclic adenosine monophosphate-activated Cl- channel. However, precisely how glucose regulates glucagon release remains controversial. Here we report that elevated glucagon secretion, together with increased glucose-induced membrane depolarization and Ca2+ response, is found in CFTR mutant (DF508) mice/islets compared with the wild-type. Overexpression of CFTR in AlphaTC1-9 cells results in membrane hyperpolarization and reduced glucagon release, which can be reversed by CFTR inhibition. CFTR is found to potentiate the adenosine triphosphate-sensitive K+ (KATP) channel because membrane depolarization and whole-cell currents sensitive to KATP blockers are significantly greater in wild-type/CFTR-overexpressed α cells compared with that in DF508/non-overexpressed cells. KATP knockdown also reverses the suppressive effect of CFTR overexpression on glucagon secretion. The results reveal that by potentiating KATP channels, CFTR acts as a glucose-sensing negative regulator of glucagon secretion in α cells, a defect of which may contribute to glucose intolerance in CF and other types of diabetes.
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Affiliation(s)
- Wen Qing Huang
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Jing Hui Guo
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou 510632, People's Republic of China
| | - Xiao Hu Zhang
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
- Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, People's Republic of China
| | - Mei Kuen Yu
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Yiu Wa Chung
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Ye Chun Ruan
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
- Interdisciplinary Division of Biomedical Engineering, the Hong Kong Polytechnic University, Hong Kong, Hong Kong
| | - Hsiao Chang Chan
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
- Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, People's Republic of China
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Aronoff SL. Rationale for treatment options for mealtime glucose control in patients with type 2 diabetes. Postgrad Med 2017; 129:231-241. [PMID: 28118069 DOI: 10.1080/00325481.2017.1285191] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
While glycemic control is routinely assessed using HbA1c and fasting glucose measures, postprandial glucose (PPG) is also an important contributor of overall glycemia. Furthermore, PPG excursions have been linked to complications of diabetes. This review examines the effects of glucose-lowering therapies (including treatments administered at mealtime) on postprandial hyperglycemia in patients with type 2 diabetes. A PubMed search was conducted to identify clinical studies of treatments for mealtime glucose control in type 2 diabetes. Different treatments may have comparable effects on HbA1c but varying effects on PPG control and glucose fluctuations. Older classes of oral glucose-lowering treatments administered at mealtime to lower PPG include meglitinides and α-glucosidase inhibitors. Injectable therapies, including prandial insulin analogs, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and the amylin analog pramlintide, all effectively target postprandial hyperglycemia. Compared with longer-acting GLP-1RAs, short-acting GLP-1RAs, such as exenatide twice daily and lixisenatide once daily, have a greater effect on PPG control, which is primarily mediated by a more pronounced effect on delayed gastric emptying. Dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors also reduce postprandial hyperglycemia. To achieve more physiologically normal glycemic control, choice of therapy should ideally aim to address daily glucose fluctuations, including hyperglycemic peaks and hypoglycemic troughs, and long-term glycemic control.
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Affiliation(s)
- Stephen L Aronoff
- a Endocrine Associates of Dallas, Research Institute of Dallas , Dallas , TX , USA
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Odegard PS, Setter SM, Iltz JL. Update in the Pharmacologic Treatment of Diabetes Mellitus. DIABETES EDUCATOR 2016; 32:693-712. [PMID: 16971704 DOI: 10.1177/0145721706294003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
There are now more than 20 million people in America with diabetes mellitus (DM), and the prevalence of this illness continues to increase especially in those with type 2 DM. Over the past decade, research in the area of DM treatment has focused on pharmacologic approaches to modifying glucose metabolism as well as on lifestyle interventions to prevent and manage DM. Pharmacologic research has been guided by an improved understanding of the human physiology of glucose metabolism, allowing for development of new hormonal drug therapies and improved insulin formulations. As a result, there are several new pharmacologic treatments now available or on the horizon for DM. In this article, the authors review the first of the new hormonal therapies for DM, with a focus on information that will be useful for diabetes educators including the medication actions, side effects, patient counseling points, monitoring, and place in therapy in comparison to existing DM treatments. This series on new therapies has been divided into 3 parts, with this first part devoted to an update on the new incretin mimetic and amylin analog agents recently approved for use in DM. Subsequent parts in this series will focus on the new insulin products and oral therapies available or soon to be available. Cases will be used to assist with understanding the type of patient who will benefit from each of these new therapies.
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Affiliation(s)
- Peggy Soule Odegard
- The School of Pharmacy, University of Washington, Seattle, and Evergreen Senior Health Specialists, Kirkland, Washington (Dr Odegard)
| | - Stephen M Setter
- The College of Pharmacy, Washington State University, Spokane (Dr Setter, Dr Iltz)
| | - Jason L Iltz
- The College of Pharmacy, Washington State University, Spokane (Dr Setter, Dr Iltz)
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Kruger DF, Aronoff SL, Edelman SV. Through the Looking Glass. DIABETES EDUCATOR 2016; 33 Suppl 2:32S-46S; quiz 47S-48S. [PMID: 17483531 DOI: 10.1177/0145721707299766] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Davida F Kruger
- The Division of Endocrinology and Metabolism, Henry Ford Health System, Detroit, Michigan (Ms Kruger)
| | - Stephen L Aronoff
- The Research Institute of Dallas, University of Texas Southwestern Medical School at Dallas, and Endocrine Associates of Dallas, Texas (Dr Aronoff)
| | - Steven V Edelman
- Taking Control of Your Diabetes, Del Mar, California, and the Division of Endocrinology, Diabetes and Metabolism, University of California, San Diego, School of Medicine (Dr Edelman)
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32
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Bacha F, Klinepeter Bartz S. Insulin resistance, role of metformin and other non-insulin therapies in pediatric type 1 diabetes. Pediatr Diabetes 2016; 17:545-558. [PMID: 26592507 DOI: 10.1111/pedi.12337] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 09/17/2015] [Accepted: 10/12/2015] [Indexed: 12/28/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) in youth is a challenging chronic medical condition. Its management should address not only the glycemic control but also insulin resistance and cardiovascular disease risk factors which are increasingly recognized to be present in youth with TID. Current knowledge on the mechanisms of insulin resistance in T1DM is reviewed. The use of adjunctive therapies that are beneficial to achieve adequate glycemic control while mitigating the effects of insulin resistance are discussed with a focus on metformin therapy and an overview of other new pharmacologic agents.
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Affiliation(s)
- Fida Bacha
- Children's Nutrition Research Center, Texas Children's Hospital, Baylor College of Medicine Houston, Houston, TX, USA. .,Division of Pediatric Endocrinology and Diabetes, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
| | - Sara Klinepeter Bartz
- Children's Nutrition Research Center, Texas Children's Hospital, Baylor College of Medicine Houston, Houston, TX, USA.,Division of Pediatric Endocrinology and Diabetes, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
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Gupta P, Bala M, Gupta S, Dua A, Dabur R, Injeti E, Mittal A. Efficacy and risk profile of anti-diabetic therapies: Conventional vs traditional drugs—A mechanistic revisit to understand their mode of action. Pharmacol Res 2016; 113:636-674. [DOI: 10.1016/j.phrs.2016.09.029] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2016] [Revised: 09/23/2016] [Accepted: 09/23/2016] [Indexed: 12/17/2022]
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Frandsen CS, Dejgaard TF, Madsbad S. Non-insulin drugs to treat hyperglycaemia in type 1 diabetes mellitus. Lancet Diabetes Endocrinol 2016; 4:766-780. [PMID: 26969516 DOI: 10.1016/s2213-8587(16)00039-5] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Revised: 12/10/2015] [Accepted: 01/26/2016] [Indexed: 02/06/2023]
Abstract
Insulin treatment of individuals with type 1 diabetes has shortcomings and many patients do not achieve glycaemic and metabolic targets. Consequently, the focus is on novel non-insulin therapeutic approaches that reduce hyperglycaemia and improve metabolic variables without increasing the risk of hypoglycaemia or other adverse events. Several therapies given in conjunction with insulin have been investigated in clinical trials, including pramlintide, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter inhibitors, metformin, sulfonylureas, and thiazolidinediones. These drugs have pleiotropic effects on glucose metabolism and different actions complementary to those of insulin-this Review reports the effects of these drugs on glycaemic control, glucose variability, hypoglycaemia, insulin requirements, and bodyweight. Existing studies are of short duration with few participants; evidence for the efficacy of concomitant treatments is scarce and largely clinically insignificant. A subgroup of patients with type 1 diabetes for whom non-insulin antidiabetic drugs could significantly benefit glycaemic control cannot yet be defined, but we suggest that obese patients prone to hypoglycaemia and patients with residual β-cell function are populations of interest for future trials.
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Affiliation(s)
| | - Thomas Fremming Dejgaard
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; Steno Diabetes Center, Gentofte, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
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35
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Tomita T. Apoptosis in pancreatic β-islet cells in Type 2 diabetes. Bosn J Basic Med Sci 2016; 16:162-79. [PMID: 27209071 DOI: 10.17305/bjbms.2016.919] [Citation(s) in RCA: 132] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 01/16/2016] [Accepted: 01/20/2016] [Indexed: 12/25/2022] Open
Abstract
Apoptosis plays important roles in the pathophysiology of Type 2 diabetes mellitus (T2DM). The etiology of T2DM is multifactorial, including obesity-associated insulin resistance, defective insulin secretion, and loss of β-cell mass through β-cell apoptosis. β-cell apoptosis is mediated through a milliard of caspase family cascade machinery in T2DM. The glucose-induced insulin secretion is the principle pathophysiology of diabetes and insufficient insulin secretion results in chronic hyperglycemia, diabetes. Recently, hyperglycemia-induced β-cell apoptosis has been extensively studied on the balance of pro-apoptotic Bcl-2 proteins (Bad, Bid, Bik, and Bax) and anti-apoptotic Bcl family (Bcl-2 and Bcl-xL) toward apoptosis in vitro isolated islets and insulinoma cell culture. Apoptosis can only occur when the concentration of pro-apoptotic Bcl-2 exceeds that of anti-apoptotic proteins at the mitochondrial membrane of the intrinsic pathway. A bulk of recent research on hyperglycemia-induced apoptosis on β-cells unveiled complex details on glucose toxicity on β-cells in molecular levels coupled with cell membrane potential by adenosine triphosphate generation through K+ channel closure, opening Ca2+ channel and plasma membrane depolarization. Furthermore, animal models using knockout mice will shed light on the basic understanding of the pathophysiology of diabetes as a glucose metabolic disease complex, on the balance of anti-apoptotic Bcl family and pro-apoptotic genes. The cumulative knowledge will provide a better understanding of glucose metabolism at a molecular level and will lead to eventual prevention and therapeutic application for T2DM with improving medications.
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36
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Zhang XX, Pan YH, Huang YM, Zhao HL. Neuroendocrine hormone amylin in diabetes. World J Diabetes 2016; 7:189-97. [PMID: 27162583 PMCID: PMC4856891 DOI: 10.4239/wjd.v7.i9.189] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 03/16/2016] [Accepted: 04/05/2016] [Indexed: 02/05/2023] Open
Abstract
The neuroendocrine hormone amylin, also known as islet amyloid polypeptide, is co-localized, co-packaged and co-secreted with insulin from adult pancreatic islet β cells to maintain glucose homeostasis. Specifically, amylin reduces secretion of nutrient-stimulated glucagon, regulates blood pressure with an effect on renin-angiotensin system, and delays gastric emptying. The physiological actions of human amylin attribute to the conformational α-helix monomers whereas the misfolding instable oligomers may be detrimental to the islet β cells and further transform to β-sheet fibrils as amyloid deposits. No direct evidence proves that the amylin fibrils in amyloid deposits cause diabetes. Here we also have performed a systematic review of human amylin gene changes and reported the S20G mutation is minor in the development of diabetes. In addition to the metabolic effects, human amylin may modulate autoimmunity and innate inflammation through regulatory T cells to impact on both human type 1 and type 2 diabetes.
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Circulating Differentially Methylated Amylin DNA as a Biomarker of β-Cell Loss in Type 1 Diabetes. PLoS One 2016; 11:e0152662. [PMID: 27111653 PMCID: PMC4844136 DOI: 10.1371/journal.pone.0152662] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Accepted: 03/17/2016] [Indexed: 01/07/2023] Open
Abstract
In type 1 diabetes (T1D), β-cell loss is silent during disease progression. Methylation-sensitive quantitative real-time PCR (qPCR) of β-cell-derived DNA in the blood can serve as a biomarker of β-cell death in T1D. Amylin is highly expressed by β-cells in the islet. Here we examined whether demethylated circulating free amylin DNA (cfDNA) may serve as a biomarker of β-cell death in T1D. β cells showed unique methylation patterns within the amylin coding region that were not observed with other tissues. The design and use of methylation-specific primers yielded a strong signal for demethylated amylin in purified DNA from murine islets when compared with other tissues. Similarly, methylation-specific primers detected high levels of demethylated amylin DNA in human islets and enriched human β-cells. In vivo testing of the primers revealed an increase in demethylated amylin cfDNA in sera of non-obese diabetic (NOD) mice during T1D progression and following the development of hyperglycemia. This increase in amylin cfDNA did not mirror the increase in insulin cfDNA, suggesting that amylin cfDNA may detect β-cell loss in serum samples where insulin cfDNA is undetected. Finally, purified cfDNA from recent onset T1D patients yielded a high signal for demethylated amylin cfDNA when compared with matched healthy controls. These findings support the use of demethylated amylin cfDNA for detection of β-cell-derived DNA. When utilized in conjunction with insulin, this latest assay provides a comprehensive multi-gene approach for the detection of β-cell loss.
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Amylin-mediated control of glycemia, energy balance, and cognition. Physiol Behav 2016; 162:130-40. [PMID: 26922873 DOI: 10.1016/j.physbeh.2016.02.034] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 02/20/2016] [Accepted: 02/22/2016] [Indexed: 12/26/2022]
Abstract
Amylin, a peptide hormone produced in the pancreas and in the brain, has well-established physiological roles in glycemic regulation and energy balance control. It improves postprandial blood glucose levels by suppressing gastric emptying and glucagon secretion; these beneficial effects have led to the FDA-approved use of the amylin analog pramlintide in the treatment of diabetes mellitus. Amylin also acts centrally as a satiation signal, reducing food intake and body weight. The ability of amylin to promote negative energy balance, along with its unique capacity to cooperatively facilitate or enhance the intake- and body weight-suppressive effects of other neuroendocrine signals like leptin, have made amylin a leading target for the development of novel pharmacotherapies for the treatment of obesity. In addition to these more widely studied effects, a growing body of literature suggests that amylin may play a role in processes related to cognition, including the neurodegeneration and cognitive deficits associated with Alzheimer's disease (AD). Although the function of amylin in AD is still unclear, intriguing recent reports indicate that amylin may improve cognitive ability and reduce hallmarks of neurodegeneration in the brain. The frequent comorbidity of diabetes mellitus and obesity, as well as the increased risk for and occurrence of AD associated with these metabolic diseases, suggests that amylin-based pharmaceutical strategies may provide multiple therapeutic benefits. This review will discuss the known effects of amylin on glycemic regulation, energy balance control, and cognitive/motivational processes. Particular focus will be devoted to the current and/or potential future clinical use of amylin pharmacotherapies for the treatment of diseases in each of these realms.
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Abstract
OBJECTIVE There is general recognition that insulin and glucagon are the main hormones involved in the pathophysiology of diabetes, but the role of glucagon in diabetes is complex and in some circumstances controversial. The increasing appreciation of the role of glucagon in currently used hypoglycemic agents and the ongoing development of glucagon-targeted therapies underscores glucagon's important contribution in optimizing diabetes management. The current review provides a background on glucagon physiology and pathophysiology and an update for investigators, endocrinologists, and other healthcare providers on glucagon-modulating therapies. METHODS A literature review was conducted utilizing published literature in PubMed and AccessMedicine including the years 1922-2015 using the following key words: glucagon, bihormonal, diabetes mellitus, glucagon antagonists, glucagon-targeted therapies. RESULTS Glucagon is a counterregulatory hormone that promotes hepatic glucose production, thus preventing hypoglycemia in normal physiology. In patients with diabetes mellitus, glucagon secretion may be unregulated, which contributes to problems with glucose homeostasis. Several of the most effective therapies for diabetes have been found to suppress glucagon secretion or action, which may contribute to their success. Additionally, glucagon-specific targeted therapies, such as glucagon receptor antagonists, are being studied at a basic and clinical level. CONCLUSION Glucagon plays an important role in contributing to hyperglycemia in patients with diabetes. Utilizing hypoglycemic agents that decrease glucagon secretion or inhibit glucagon action can help improve glycemic control, making these agents a valuable resource in diabetes therapy.
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Barbonta DH, Loughlan CW, Dickerson JEC, Baicus C. Pramlintide for diabetes mellitus. Hippokratia 2015. [DOI: 10.1002/14651858.cd008383.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Diana Hortensia Barbonta
- Emergency Hospital Alba; Endocrinology, Diabetes and Metabolic Disorders Department; 23, 1989 Revolutiei Blvd. Alba-Iulia Transylvania Romania 510053
| | | | - JE Claire Dickerson
- University of Hertfordshire; School of Education; de Havilland Campus Hatfield Hertfordshire UK AL10 9AB
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The Constitutive Activation of Egr-1/C/EBPa Mediates the Development of Type 2 Diabetes Mellitus by Enhancing Hepatic Gluconeogenesis. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:513-23. [DOI: 10.1016/j.ajpath.2014.10.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Revised: 09/28/2014] [Accepted: 10/02/2014] [Indexed: 12/13/2022]
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Wang H, Abedini A, Ruzsicska B, Raleigh DP. Rationally designed, nontoxic, nonamyloidogenic analogues of human islet amyloid polypeptide with improved solubility. Biochemistry 2014; 53:5876-84. [PMID: 25140605 PMCID: PMC4172205 DOI: 10.1021/bi500592p] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
![]()
Human
islet amyloid polypeptide (hIAPP or amylin) is a polypeptide
hormone produced in the pancreatic β-cells that plays a role
in glycemic control. hIAPP is deficient in type 1 and type 2 diabetes
and is a promising adjunct to insulin therapy. However, hIAPP rapidly
forms amyloid, and its strong tendency to aggregate limits its usefulness.
The process of hIAPP amyloid formation is toxic to cultured β-cells
and islets, and islet amyloid formation in vivo has
been linked to β-cell death and islet graft failure. An analogue
of hIAPP with a weakened tendency to aggregate, denoted pramlintide
(PM), has been approved for clinical applications, but suffers from
poor solubility, particularly at physiological pH, and its unfavorable
solubility profile prevents coformulation with insulin. We describe
a strategy for rationally designing analogues
of hIAPP with improved properties; key proline mutations are combined
with substitutions that increase the net charge of the molecule. An
H18R/G24P/I26P triple mutant and an H18R/A25P/S28P/S29P quadruple
mutant are significantly more soluble at neutral pH than hIAPP or
PM. They are nonamyloidogenic and are not toxic to rat INS β-cells.
The approach is not limited
to these examples; additional analogues can be designed using this
strategy. To illustrate this point, we show that an S20R/G24P/I26P
triple mutant and an H18R/I26P double mutant are nonamyloidogenic
and significantly more soluble than human IAPP or PM. These analogues
and second-generation derivatives are potential candidates for the
coformulation
of IAPP with insulin and other polypeptides.
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Affiliation(s)
- Hui Wang
- Department of Chemistry, State University of New York at Stony Brook , Stony Brook, New York 11794-3400, United States
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Oral salmon calcitonin protects against impaired fasting glycemia, glucose intolerance, and obesity induced by high-fat diet and ovariectomy in rats. Menopause 2014; 20:785-94. [PMID: 23793169 DOI: 10.1097/gme.0b013e31827c58ab] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Oral salmon calcitonin (sCT) has demonstrated clinical efficacy in treating osteoporosis in postmenopausal women. The postmenopausal state is also associated with obesity-related insulin resistance (IR) and type 2 diabetes. The aim of this study was to investigate the preventive effects of oral sCT on energy and glucose homeostasis in high-fat diet (HFD)- and ovariectomy (OVX)-induced obese rats. Furthermore, the weight-regulatory and gluco-regulatory effects of short-term oral sCT intervention on HFD-induced obese rats were explored. METHODS For prevention, female rats exposed to HFD with or without OVX were treated with oral sCT for 5 weeks. As intervention, HFD-induced obese male rats were treated with oral sCT for 4 days. Body weight, food intake, and plasma glucose, insulin, and leptin levels were measured, and the clinical homeostasis model assessment for insulin resistance (HOMA-IR) index was calculated. In addition, oral glucose tolerance was evaluated in the systemic and portal circulations. RESULTS For prevention, oral sCT reduced body weight by ∼16% to 19% (P < 0.001), reduced plasma insulin and leptin by ∼50%, and improved impaired fasting glycemia (P < 0.05) concomitantly with amelioration of IR (HOMA-IR; P < 0.01) in HFD- and OVX-induced obesity. Furthermore, oral sCT significantly reduced the incremental area under the curve for plasma glucose and insulin by ∼40% and ∼70%, respectively, during glucose tolerance testing. As intervention in HFD-induced obese rats, oral sCT reduced body weight, fasting glycemia, and insulinemia in conjunction with HOMA-IR (P < 0.001). Finally, oral sCT alleviated glucose intolerance predominantly in the portal circulation. CONCLUSIONS Oral sCT treatment displays weight-regulatory and glucoregulatory efficacy in HFD- and OVX-induced obese rats, indicating the clinical usefulness of oral sCT in postmenopausal obesity-related IR and type 2 diabetes.
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Abstract
Current strategies for the treatment of type 2 diabetes mellitus promote individualized plans to achieve target glucose levels on a patient-by-patient basis while minimizing treatment related risks. Maintaining glycemic control over time is a significant challenge because of the progressive nature of diabetes as a result of declining β-cell function. This article identifies complications of non-insulin treatments for diabetes. The major classes of medications are reviewed with special focus on target population, mechanism of action, effect on weight, cardiovascular outcomes and additional class-specific side effects including effects on bone. Effects on β-cell function are also highlighted.
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Affiliation(s)
- Sarah D Corathers
- Division of Endocrinology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7012, Cincinnati, OH 45229, USA; Division of Endocrinology, University of Cincinnati Medical Center, 260 Stetson, Suite 4200, Cincinnati, OH 45229, USA.
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Abstract
PURPOSE OF REVIEW The purpose of this review is to examine recently published literature in the areas of incretins and amylin in the management of pediatric diabetes. RECENT FINDINGS Recent studies have begun to explore the use of longer-acting GLP-1 analogues that can be given once daily, such as liraglutide, and the use of DPP-IV inhibitors in the management of type 2 diabetes. In addition, recent studies have been published on the use of exenatide in the management of pediatric obesity and newly diagnosed type 1 diabetes. SUMMARY Very few medications are approved for management of type 2 diabetes in youth. In addition, monotherapy of type 1 diabetes in youth with insulin does not achieve HbA1c targets in the majority of youth despite the use of rapid-acting insulin analogues, insulin pump therapy, and continuous glucose monitoring. Novel therapies that target physiologic modalities other than enhancing or replacing insulin secretion or improving insulin sensitivity have shown efficacy in adults. Studies with these drugs are being done in the pediatric population and should provide additional treatment options for these patients.
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Qi T, Dong M, Watkins HA, Wootten D, Miller LJ, Hay DL. Receptor activity-modifying protein-dependent impairment of calcitonin receptor splice variant Δ(1-47)hCT((a)) function. Br J Pharmacol 2013; 168:644-57. [PMID: 22946511 DOI: 10.1111/j.1476-5381.2012.02197.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Revised: 08/07/2012] [Accepted: 08/10/2012] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND AND PURPOSE Alternative splicing expands proteome diversity to GPCRs. Distinct receptor variants have been identified for a secretin family GPCR, the calcitonin receptor (CTR). The possible functional contributions of these receptor variants are further altered by their potential interactions with receptor activity-modifying proteins (RAMPs). One variant of the human CTR lacks the first 47 residues at its N terminus [Δ(1-47)hCT((a)) ]. However, very little is known about the pharmacology of this variant or its ability to interact with RAMPs to form amylin receptors. EXPERIMENTAL APPROACH Δ(1-47)hCT((a)) was characterized both with and without RAMPs in Cos7 and/or HEK293S cells. The receptor expression (ELISA assays) and function (cAMP and pERK1/2 assays) for up to six agonists and two antagonists were determined. KEY RESULTS Despite lacking 47 residues at the N terminus, Δ(1-47)hCT((a)) was still able to express at the cell surface, but displayed a generalized reduction in peptide potency. Δ(1-47)hCT((a)) retained its ability to interact with RAMP1 and formed a functional amylin receptor; this also appeared to be the case with RAMP3. On the other hand, its interaction with RAMP2 and resultant amylin receptor was reduced to a greater extent. CONCLUSIONS AND IMPLICATIONS Δ(1-47)hCT((a)) acts as a functional receptor at the cell surface. It exhibits altered receptor function, depending on whether it associates with a RAMP and which RAMP it interacts with. Therefore, the presence of this variant in tissues will potentially contribute to altered peptide binding and signalling, depending on the RAMP distribution in tissues.
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Affiliation(s)
- T Qi
- School of Biological Sciences, University of Auckland, Auckland, New Zealand
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Grunberger G. Novel therapies for the management of type 2 diabetes mellitus: part 1. pramlintide and bromocriptine-QR. J Diabetes 2013; 5:110-7. [PMID: 23452312 DOI: 10.1111/1753-0407.12034] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Revised: 02/02/2013] [Accepted: 02/12/2013] [Indexed: 11/28/2022] Open
Abstract
Several classes of antidiabetic agents have been introduced into the market place over the past dozen years. As our understanding of the underlying pathophysiology of type 2 diabetes has advanced, attempts have been made to address these defects specifically. This brief review focuses on our experience with two such pharmacological approaches: (i) a synthetic amylin analog addressing amylin deficiency; and (ii) a dopaminergic agonist, focused on enhancing the lowered dopaminergic tone in patients with type 2 diabetes. Importantly, the use of these agents is not associated with hypoglycemia or weight gain.
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Feigh M, Andreassen KV, Neutzsky-Wulff AV, Petersen ST, Hansen C, Bay-Jensen AC, Henriksen JE, Beck-Nielsen H, Christiansen C, Henriksen K, Karsdal MA. Oral salmon calcitonin attenuates hyperglycaemia and preserves pancreatic beta-cell area and function in Zucker diabetic fatty rats. Br J Pharmacol 2013; 167:151-63. [PMID: 22506938 DOI: 10.1111/j.1476-5381.2012.01979.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND AND PURPOSE Oral salmon calcitonin (sCT), a dual-action amylin and calcitonin receptor agonist, improved glucose homeostasis in diet-induced obese rats. Here, we have evaluated the anti-diabetic efficacy of oral sCT using parameters of glycaemic control and beta-cell morphology in male Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. EXPERIMENTAL APPROACH Male ZDF rats were treated with oral sCT (0.5, 1.0 or 2 mg·kg(-1) ) or oral vehicle twice daily from age 8 to 18 weeks. Zucker lean rats served as control group. Fasting and non-fasted blood glucose, glycosylated haemoglobin (HbA1c) and levels of pancreas and incretin hormones were determined. Oral glucose tolerance test and i.p. glucose tolerance test were compared, and beta-cell area and function were evaluated. KEY RESULTS Oral sCT treatment dose-dependently attenuated fasting and non-fasted hyperglycaemia during the intervention period. At the end of the study period, oral sCT treatment by dose decreased diabetic hyperglycaemia by ∼9 mM and reduced HbA1c levels by 1.7%. Furthermore, a pronounced reduction in glucose excursions was dose-dependently observed for oral sCT treatment during oral glucose tolerance test. In addition, oral sCT treatment sustained hyperinsulinaemia and attenuated hyperglucagonaemia and hypersecretion of total glucagon-like peptide-1 predominantly in the basal state. Lastly, oral sCT treatment dose-dependently improved pancreatic beta-cell function and beta-cell area at study end. CONCLUSIONS AND IMPLICATIONS Oral sCT attenuated diabetic hyperglycaemia in male ZDF rats by improving postprandial glycaemic control, exerting an insulinotropic and glucagonostatic action in the basal state and by preserving pancreatic beta-cell function and beta-cell area.
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Affiliation(s)
- M Feigh
- Nordic Bioscience, Herlev, Denmark Diabetes Research Centre, Department of Endocrinology M, Odense University Hospital, Odense, Denmark.
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Abstract
Amylin is a naturally occurring hormone that regulates food intake and postprandial glucose excursions. Amylin is synthesized in the β cell and cosecreted with insulin. Type 1 diabetes and insulin-requiring Type 2 diabetes are amylin-deficient as well as insulin-deficient states. Pramlintide is a synthetic amylin analog that is used for replacement therapy. Pramlintide therapy slows diabetes-mediated accelerated gastric emptying and restores meal-mediated suppression of glucagon secretion in patients with diabetes. Amylin receptors are primarily located in the CNS, which mediates all of its effects including decreases in food intake. In patients with diabetes, pramlintide treatment reduces hemoglobin A1C (HbA1c) 0.3-0.7% and decreases bodyweight. Side effects include nausea and hypoglycemia. Both can be minimized by an appropriate titration program. Recent pramlintide studies address improvements in delivery systems, use in pediatric and Type 2 diabetic populations, patient treatment satisfaction and new insights into its mechanisms of action.
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Affiliation(s)
- Harold E Lebovitz
- a Department of Medicine, Division of Endocrinology, State University of New York Health Science Center at Brooklyn, NY, USA.
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