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1.
Acta Diabetol ; 56(12): 1283-1292, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31407113

RESUMO

AIMS: Subcutaneous administration of insulin in patients suffering from diabetes is associated with the distress of daily injections. Among alternative administration routes, the oral route seems to be the most advantageous for long-term administration, also because the peptide undergoes a hepatic first-pass effect, contributing to the inhibition of the hepatic glucose output. Unfortunately, insulin oral administration has so far been hampered by degradation by gastrointestinal enzymes and poor intestinal absorption. Loading in lipid nanoparticles should allow to overcome these limitations. METHODS: Entrapment of peptides into such nanoparticles is not easy, because of their high molecular weight, hydrophilicity and thermo-sensitivity. In this study, this objective was achieved by employing fatty acid coacervation method: solid lipid nanoparticles and newly engineered nanostructured lipid carriers were formulated. Insulin and insulin analog-glargine insulin-were entrapped in the lipid matrix through hydrophobic ion pairing. RESULTS: Bioactivity of lipid entrapped peptides was demonstrated through a suitable in vivo experiment. Ex vivo and in vivo studies were carried out by employing fluorescently labelled peptides. Gut tied up experiments showed the superiority of glargine insulin-loaded nanostructured lipid carriers, which demonstrated significantly higher permeation (till 30% dose/mL) compared to free peptide. Approximately 6% absolute bioavailability in the bloodstream was estimated for the same formulation through in vivo pharmacokinetic studies in rats. Consequently, a discrete blood glucose responsivity was noted in healthy animals. CONCLUSIONS: Given the optimized ex vivo and in vivo intestinal uptake of glargine insulin from nanostructured lipid carriers, further studies will be carried out on healthy and diabetic rat models in order to establish a glargine insulin dose-glucose response relation.


Assuntos
Portadores de Fármacos , Insulina/administração & dosagem , Lipídeos , Nanopartículas , Administração Oral , Animais , Células Cultivadas , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Humanos , Insulina/análogos & derivados , Insulina/farmacocinética , Insulina Glargina/administração & dosagem , Insulina Glargina/análogos & derivados , Insulina Glargina/farmacocinética , Lipídeos/administração & dosagem , Lipídeos/química , Lipídeos/farmacocinética , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/química , Nanopartículas/metabolismo , Técnicas de Cultura de Órgãos , Tamanho da Partícula , Ratos , Ratos Wistar
2.
Internist (Berl) ; 60(9): 887-894, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31396651

RESUMO

A multitude of short-acting and long-acting insulin analogues are currently available for the treatment of diabetes mellitus, which mimic physiological insulin secretion better than normal insulins. By the use of ultrarapid insulin analogues postprandial glucose increases can be significantly reduced. Newer long-acting insulin analogues have a very stable action profile and reduce the rate of hypoglycemia, especially nocturnal hypoglycemia, even more than first generation long-acting insulin analogues. Future developments focus on a further acceleration of prandial insulin effects with a simultaneous shorter effect time and an even more prolonged action of long-acting insulin analogues.


Assuntos
Medicamentos Biossimilares , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/metabolismo , Insulina/uso terapêutico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglicemia , Hipoglicemiantes/uso terapêutico , Insulina/análogos & derivados , Período Pós-Prandial , Qualidade de Vida
3.
Biophys Chem ; 253: 106226, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31376619

RESUMO

The quaternary structures of insulin glargine and glulisine under formulation conditions and upon dilution using placebo or water were investigated using synchrotron small-angle X-ray scattering. Our results revealed that insulin glulisine in Apidra® is predominantly hexameric in solution with significant fractions of dodecamers and monomers. Upon dilution with placebo, this equilibrium shifts towards monomers. Insulin glargine in Lantus® and Toujeo® is present in a stable hexamer/dimer equilibrium, which is hardly affected by dilution with water down to 1 mg/ml insulin concentration. The results provide exclusive insight into the quaternary structure and thus the association/dissociation properties of the two insulin analogues in marketed formulations.


Assuntos
Hipoglicemiantes/química , Insulina Glargina/química , Insulina/análogos & derivados , Humanos , Insulina/química , Modelos Moleculares , Estrutura Quaternária de Proteína
4.
ACS Chem Biol ; 14(8): 1829-1835, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31343157

RESUMO

Insulin is the principal hormone involved in the regulation of metabolism and has served a seminal role in the treatment of diabetes. Building upon advances in insulin synthetic methodology, we have developed a straightforward route to novel insulins containing a fourth disulfide bond in a [3 + 1] fashion establishing the first disulfide scan of the hormone. All the targeted analogs accommodated the constraint to demonstrate an unexpected conformational flexibility of native insulin. The bioactivity was established for the constrained (4-DS) and unconstrained (3-DS) analogs by in vitro methods, and extended to in vivo study for select peptides. We also identified residue B10 as a preferred anchor to introduce a tether that would regulate insulin bioactivity. We believe that the described [3 + 1] methodology might constitute the preferred approach for performing similar disulfide scanning in peptides that contain multiple disulfides.


Assuntos
Dissulfetos/química , Insulina/análogos & derivados , Sequência de Aminoácidos , Dissulfetos/síntese química , Insulina/síntese química , Conformação Proteica , Engenharia de Proteínas/métodos
6.
Diabetes Metab Syndr ; 13(3): 2126-2141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31235147

RESUMO

Type 2 diabetes mellitus is a progressive disease, which requires insulin treatment when other management is no longer effective. Although, insulin plays a vital role in the treatment of diabetes, conventional basal insulins have certain limitations, which have led to the development of more stable and peak less analogues. OBJECTIVES: To analyze the efficacy and safety of second generation vs. first generation basal insulins, and the efficacy and safety of second generation vs. second generation basal insulins, in patients with type 2 diabetes mellitus, from the evidence provided by head-to-head randomized controlled trials. METHODS: The following electronic databases were searched: PubMed and MEDLINE, Scopus, BIOSIS, Embase, ClinicalTrials.gov, Google Scholar, and Springer Online Archives Collection, from January 1966 to October 2018. Articles resulting from these searches and relevant references cited in those articles were examined. RESULTS: The efficacy among insulins evaluated was similar, however, second generation insulins cause a lower risk of hypoglycemia compared to first generation insulins. A single study showed similar metabolic control with subtle differences in the risk of hypoglycemia among second generation insulins. CONCLUSIONS: The second-generation basal insulins result in metabolic control similar to first generation insulins, with lower risk of hypoglycemia. Second-generation insulins have comparable efficacy, with some differences in the risk of hypoglycemia.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Insulina/análogos & derivados , Humanos , Prognóstico
7.
J Pharm Biomed Anal ; 172: 357-363, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31096094

RESUMO

Direct qualitative methods that allow the rapid screening and identification of insulin products during early stages of the drug development process and those already in the market can be of great utility for manufacturers and regulatory agencies and the recent scientific literature describes several methods. Herein, a qualitative proteomic method is presented for the identification of recombinant human insulin and all marketed biosynthetic analogues -insulin lispro, aspart, glulisine, glargine, detemir and degludec- via tryptic digestion and identification of proteotypic peptides for each insulin. Individual insulins were first denatured under reducing conditions and the cysteine residues blocked by iodoacetamide. The proteins were then digested with trypsin and the peptide products separated by reversed phase liquid chromatography on an Ascentis® Express ES-C18 column and detected by positive polarity ESI-MS/MS. The digestion peptides were characterized using a multiplexed MRM approach that monitors the fragmentation of the doubly charged unlabeled precursor ion of each peptide into a collection of signature y and b ions. The MRM transitions for the individual peptides were optimized to allow maximal ionization on a standard triple quadrupole mass spectrometer. All products of the digestion procedure for all insulins were detected with adequate signal intensity except for the C-terminal B30Thr whenever it was present and cleaved and the tryptic B1-3 tripeptide of insulin glulisine. The unique proteotypic peptides identified for each of the insulin analogues coupled with their signature y and b ions permitted the unambiguous verification of all sequence variations and chemical modifications. The elution of the A polypeptide chain for all insulins and the tryptic peptides of the B chain, with the exception of a very few, occurred around the same time point. This underscores the close similarity in the physicochemical properties between the digestion peptides and is consistent with the subtle variations in amino acid sequence among the various insulins. Therefore, the identification and distinction of the different types of insulin based solely on the chromatographic retention time of their respective proteolytic products can be deceptive without proper mass spectrometric analysis and may result in false positives.


Assuntos
Insulina/química , Peptídeos/química , Sequência de Aminoácidos , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/métodos , Humanos , Insulina/análogos & derivados , Insulina Aspart/química , Insulina Detemir/química , Insulina Glargina/química , Insulina Lispro/química , Insulina de Ação Prolongada/química , Fragmentos de Peptídeos/química , Proteólise , Proteômica/métodos , Espectrometria de Massas em Tandem/métodos
8.
BMJ Case Rep ; 12(3)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30898943

RESUMO

Glycogenic hepatopathy (GH) is a rare complication of poorly controlled type 1 diabetes mellitus (T1DM). We present a 19-year-old woman with T1DM and autoimmune thyroiditis who admitted to our department because of abrupt onset intermittent abdominal pain in the right upper quadrant accompanied by laboratory evidence of acute anicteric hepatitis. Physical examination revealed significant hepatomegaly but the common imagining studies were negative. Following exclusion of common causes of acute hepatitis and because of the presence of smooth muscle antibodies in a young female patient with already established two autoimmune diseases, a liver biopsy was performed in order to exclude the potential presence of autoimmune hepatitis. However, liver histology showed typical findings of GH. Intense treatment targeting strict glycemic control resulted in normalisation of liver biochemistry. This case underlines that GH should be considered as a rare cause of acute hepatitis in T1DM patients with poor glycemic control.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Glicogênio/metabolismo , Hepatomegalia/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Infusões Subcutâneas , Insulina/administração & dosagem , Insulina/análogos & derivados , Testes de Função Hepática , Adulto Jovem
9.
Rev Bras Ginecol Obstet ; 41(2): 104-115, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30786308

RESUMO

Diabetes during pregnancy has been linked to unfavorable maternal-fetal outcomes. Human insulins are the first drug of choice because of the proven safety in their use. However, there are still questions about the use of insulin analogs during pregnancy. The objective of the present study was to determine the effectiveness of insulin analogs compared with human insulin in the treatment of pregnant women with diabetes through a systematic review with meta-analysis. The search comprised the period since the inception of each database until July 2017, and the following databases were used: MEDLINE, CINAHL, EMBASE, ISI Web of Science, LILACS, Scopus, SIGLE and Google Scholar. We have selected 29 original articles: 11 were randomized clinical trials and 18 were observational studies. We have explored data from 6,382 participants. All of the articles were classified as having an intermediate to high risk of bias. The variable that showed favorable results for the use of insulin analogs was gestational age, with a mean difference of - 0.26 (95 % confidence interval [CI]: 0.03-0.49; p = 0.02), but with significant heterogeneity (Higgins test [I2] = 38%; chi-squared test [χ2] = 16.24; degree of freedom [DF] = 10; p = 0.09). This result, in the clinical practice, does not compromise the fetal well-being, since all babies were born at term. There was publication bias in the gestational age and neonatal weight variables. To date, the evidence analyzed has a moderate-to-high risk of bias and does not allow the conclusion that insulin analogs are more effective when compared with human insulin to treat diabetic pregnant women.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Gestacional/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Aborto Espontâneo/etiologia , Peso ao Nascer , Feminino , Macrossomia Fetal/etiologia , Idade Gestacional , Humanos , Hipoglicemia/induzido quimicamente , Insulina/análogos & derivados , Insulina Aspart/uso terapêutico , Insulina Glargina/uso terapêutico , Insulina Lispro/uso terapêutico , Estudos Observacionais como Assunto , Gravidez , Cuidado Pré-Natal/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
10.
J Formos Med Assoc ; 118(4): 843-848, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30704815

RESUMO

Although hypersensitivity reaction to insulin was supposed to be less-frequent with current insulin analogue, case reports with different types of allergic reactions to insulin analogue were still reported. The most common form is type I hypersensitivity reaction with IgE-mediated. Besides, type III (IgG and IgM-mediated) and type IV (T-cell mediated delayed reaction) hypersensitivity reactions were also reported. Here we presented a long-standing type 2 diabetes with insulin requirements with hypersensitivity reactions to insulin actrapid, insulin aspart, insulin glargine, insulin detemir, and biphasic insulin aspart 30. Insulin desensitization was performed as initial management but failed as skin biopsy with immunohistochemical staining proved type IV hypersensitivity reaction. We continued with the next treatment approach using subcutaneous injection with the mixture of biphasic insulin aspart 30 and dexamethasone to alleviate allergy, and the result was successful with steroid-free biphasic insulin aspart 30 injection eight months later. Besides, the treatment effect had lasted after ten years even with switched type of insulin analogue from biphasic insulin aspart 30 to insulin glargine and insulin aspart. The case report demonstrated a good example of how clinicians deal with the rare but important questions of hypersensitivity reactions to insulin analogue.


Assuntos
Dexametasona/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipersensibilidade Tardia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Insulina Aspart/uso terapêutico , Insulina/efeitos adversos , Insulinas Bifásicas , Combinação de Medicamentos , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/análogos & derivados , Insulina Detemir , Insulina Glargina , Insulina Isófana , Insulina de Ação Prolongada , Pessoa de Meia-Idade
11.
ACS Chem Biol ; 14(3): 486-496, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30715843

RESUMO

The aggregation of human islet amyloid polypeptide (hIAPP) is one of the triggering factors of type 2 diabetes mellitus (T2DM). hIAPP is cosynthesized, costored, and cosecreted with insulin in pancreatic ß-cells, and insulin inhibits hIAPP aggregation. In T2DM patients, long-term hyperglycemia causes glycation of near 10% of total insulin. The glycation not only modifies insulin but also cross-links insulin into oligomers. However, the effect of glycated human insulin on hIAPP aggregation is unknown. In this study, four physiologically relevant monosaccharides, methylglyoxal, glucose, fructose, and ribose were used to glycate human insulin and two C-terminus truncated insulin analogues. Glycated insulin monomers or low molecular weight oligomers such as dimers significantly exacerbated the cytotoxicity of hIAPP. Notably, glycation-induced cross-linking of insulin inhibited the aggregation, membrane disruption, and cytotoxicity of hIAPP, which was corroborated by a control study using EGS-induced cross-linking of insulin or lysozyme. Removal of B29Lys on the C terminus of the insulin B chain not only abolished glycation-induced cross-linking but also attenuated the aggravation effect of glycated insulin on hIAPP cytotoxicity. Taken together, this study reveals a vicious cycle in T2DM, that hyperglycemia-driven insulin glycation exacerbates the cytotoxicity of hIAPP, which accelerates ß-cells death and further deteriorates T2DM.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Insulina/análogos & derivados , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Sequência de Aminoácidos , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Insulina/química , Insulina/metabolismo , Peso Molecular , Monossacarídeos/química , Agregados Proteicos/efeitos dos fármacos , Conformação Proteica
12.
J Pharm Biomed Anal ; 166: 71-82, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30616063

RESUMO

The LC methods for related proteins prescribed in the European Pharmacopoeia monographs for insulins and insulin analogues are very similar and present some drawbacks including long run time and low resolution. LC to UHPLC-UV geometrical transfer was attempted to overcome such drawbacks. With the new UHPLC method, additional substances were separated in bovine and porcine insulins. A UHPLC MS-compatible method was developed using a mixed-mode C18 stationary phase with charged surface hybrid technology and a mobile phase containing a low concentration of trifluoroacetic acid and acetonitrile. An unknown peak was detected and identified as being B30-des-Alanine-insulin which was also confirmed by microTOF direct infusion and specific digestion with bovine carboxypeptidase A. Based on the results obtained during geometrical method transfer, a single UHPLC-UV method for human, bovine, porcine insulins and insulin lispro and aspart was developed and validated according to ICH Q2 guidelines. The new method is superior to the current European Pharmacopoeia LC methods with improved selectivity and shorter run time. The method is based on gradient elution and employs a commonly available stationary phase (conventional C18 column) which makes it an appropriate method for pharmacopoeial public quality standards. It may therefore represent a valid alternative to the LC methods currently described in the European Pharmacopoeia for insulins.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Insulina/análogos & derivados , Insulina/análise , Animais , Bovinos , Humanos , Farmacopeias como Assunto , Suínos
13.
Life Sci ; 219: 90-99, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30639280

RESUMO

Insulin remains a predominant life-saving medication for type 1 and type 2 Diabetes Mellites. Natural insulin secretion limits the fluctuation of the narrow and high surge of blood glucose levels. However, imitating the same by external insulin remains a challenge as a variety of insulin analogs (rapid acting, short acting, intermediate acting and long-acting) have different pharmacokinetic (PK) and pharmacodynamic (PD) properties. Inconsistent reduction in overall hyperglycemia level and nocturnal hypoglycemia due to variable absorption time and time action profile predominantly highlights the need of revisiting the PK/PD of insulin analogs as single analog is not yet sufficed to replace internal insulin exogenously. Combination therapy with basal and prandial insulins or intensification of hypoglycemic therapy with premixed insulins are of prime importance in managing diabetes effectively, imitating the natural insulin secretion. Therefore, the knowledge of PK/PD properties might help a practitioner to design, implement and manage insulin replacement therapy effectively and averting adverse events. Present study reports the comparative analysis of PK/PD profile of various insulin analogs based on the concurrent information about clinical aspects. Moreover, study interlinks the major concerns of therapeutic efficacy of insulin analogs with their respective onset of action and duration of effectiveness and reported adverse drug reaction which explore the scope of improvement.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Insulina/análogos & derivados , Previsões , Humanos , Insulina/uso terapêutico , Insulina Aspart/uso terapêutico , Insulina Detemir/uso terapêutico , Insulina Glargina/uso terapêutico , Insulina Lispro/uso terapêutico , Insulina de Ação Prolongada/uso terapêutico
14.
Diabetes Care ; 42(3): 434-442, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30679303

RESUMO

OBJECTIVE: To investigate whether women with type 2 diabetes (T2D) develop a more advanced stage of breast cancer and whether treatment with insulin (analogs) is associated with specific breast cancer characteristics. RESEARCH DESIGN AND METHODS: For this nested case-control study, women with breast cancer diagnosed in 2002-2014 were selected from the linked Netherlands Cancer Registry-PHARMO Database Network (N = 33,377). T2D was defined as receiving two or more dispensings of noninsulin blood glucose-lowering drugs prior to breast cancer diagnosis. Women with T2D were matched to women without diabetes. Among women with T2D, insulin users and nonusers were compared. Multivariable ordinal logistic regression was used to investigate the association between T2D/insulin and breast cancer characteristics, including TNM classification (tumor size, lymph node status, metastasis), morphology, grade, estrogen receptor and progesterone receptor (PR), human epidermal growth factor receptor 2, and molecular subtype. RESULTS: Women with T2D (n = 1,567) were more often diagnosed with a more advanced tumor stage (odds ratio 1.28 [95% CI 13-1.44]) and a higher grade (1.22 [1.08-1.39]) though less often with a PR-negative breast tumor (0.77 [0.67-0.89]) than women without diabetes (n = 6,267). No associations were found for the other breast cancer characteristics. Women with T2D using insulin (n = 388) were not diagnosed with different breast cancer characteristics compared with women with T2D not using insulin (n = 1,179). CONCLUSIONS: Our study suggests that women with T2D are at increased risk to be diagnosed with a more aggressive type of breast cancer than women without diabetes. No evidence was found that the use of insulin (analogs) is associated with developing more advanced breast cancer tumors.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Insulina/uso terapêutico , Adulto , Idoso , Neoplasias da Mama/complicações , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Progressão da Doença , Feminino , Humanos , Insulina/análogos & derivados , Registro Médico Coordenado , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Países Baixos/epidemiologia , Farmácias/estatística & dados numéricos , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos
15.
J Pediatr Endocrinol Metab ; 32(1): 1-9, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30517078

RESUMO

Background Treatment for type 1 diabetes mellitus (T1DM) has greatly changed by the general use of insulin analogs and continuous subcutaneous insulin infusion (CSII). To investigate whether these advances have been translated into continued improvement in glycemic control in Japanese children and adolescents, we analyzed the registration data of the two consecutive recent cohorts of Japanese childhood-onset T1DM patients. Methods The registration data including hemoglobin A1c (HbA1c), hypoglycemia and insulin regimen were compared between the two cohorts (862 patients in the 2008 cohort and 1090 in the 2013 cohort). Results The proportion of subjects with multiple daily insulin injection therapy (MDI) and CSII significantly increased (p<0.0001) from 67.4% and 9.7% to 71.8% and 23.4%, respectively. In the 2013 cohort, almost all patients were treated with basal-bolus treatment using insulin analogs. The use of CSII increased in all age groups, especially in the age group 0-5 years. The rates of overall, moderate and severe hypoglycemia significantly declined from 10.24, 10.18 and 0.056 events/100 persons/period in the 2008 cohort to 0.66, 0.62 and 0.033 in the 2013 cohort (p<0.0001, <0.0001, 0.04), respectively. Contrarily, there were no significant changes in HbA1c values between the two cohorts. Conclusions The popularization of the basal-bolus treatment using insulin analogs hascontributed to a significant decrease in hypoglycemia. In contrast, the intensive insulin treatment may not be enough for the satisfactory improvement of glycemic control in Japanese children and adolescents with T1DM. Considerable points remain, such as diabetic education and support to motivate patients.


Assuntos
Biomarcadores/análise , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Sistemas de Infusão de Insulina , Insulina/uso terapêutico , Adolescente , Adulto , Glicemia/análise , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Hemoglobina A Glicada/análise , Humanos , Lactente , Recém-Nascido , Insulina/análogos & derivados , Masculino , Prognóstico , Adulto Jovem
16.
Diabetes Obes Metab ; 21(1): 160-169, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30095210

RESUMO

AIMS: Current therapy fails to emulate rapid (first-phase) insulin release in relation to a meal, a key defect in types 1 and 2 diabetes. We aimed to quantify the pharmacokinetic (PK) and pharmacodynamic (PD) profile of insulin tregopil, an enterically-absorbed insulin analog that restores the normal distribution of insulin between the hepatic portal and peripheral circulations. MATERIALS AND METHODS: The PK and PD profiles of insulin tregopil were studied in overnight-fasted, catheterized, conscious canines using four approaches: (1) equimolar intraportal infusions of tregopil vs human insulin; (2) escalating doses of oral tregopil; (3) identical, consecutive enteric doses of tregopil; and (4) comparison of oral tregopil to inhaled and subcutaneous human insulin administration. RESULTS: Equimolar intraportal infusions of tregopil and human insulin resulted in very similar PK profiles and PD profiles were nearly identical. Enteric delivery of tregopil brought about rapid absorption with tmax = 20 minutes in most cases. Median tmax was 20 minutes for oral tregopil and inhaled insulin and 88 minutes for subcutaneous human insulin. The time required for arterial plasma insulin levels to return to baseline was approximately 90, 210 and 360 minutes for oral tregopil, inhaled insulin and subcutaneous insulin, respectively. CONCLUSIONS: Enterically delivered tregopil is rapidly absorbed and restores a portal-to-peripheral vascular distribution. These characteristics should improve postprandial hyperglycaemia in types 1 and 2 diabetes.


Assuntos
Glicemia/metabolismo , Insulina Regular Humana/farmacocinética , Insulina/farmacocinética , Animais , Glicemia/análise , Diabetes Mellitus , Cães , Feminino , Glucose/administração & dosagem , Glucose/metabolismo , Humanos , Insulina/administração & dosagem , Insulina/análogos & derivados , Insulina/sangue , Insulina Regular Humana/administração & dosagem , Insulina Regular Humana/sangue , Masculino
17.
Clin Pharmacol Ther ; 105(2): 417-425, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30125349

RESUMO

The goal of this investigation was to examine clinical translation of glucose responsiveness of MK-2640, which is a novel insulin saccharide conjugate that can bind the insulin receptor or mannose receptor C type 1 (MRC1), the latter dependent upon glucose concentration. In a rising dose study in 36 healthy adults under euglycemic clamp conditions, rising exposures revealed saturation of MK-2640 clearance, likely due to saturation of clearance by MRC1. Potency of MK-2640 was ~25-fold reduced relative to regular human insulin. In a randomized, 2-period crossover trial in 16 subjects with type 1 diabetes mellitus to evaluate glucose-responsiveness of i.v. administered MK-2640, we were unable to demonstrate a glucose-dependent change in MK-2640 clearance, although a significant glucose-dependent augmentation of glucose infusion rate was observed. These pharmacokinetic (PK) and pharmacodynamic (PD) data provide crucial insights into next steps for developing an insulin saccharide conjugate as a clinically effective glucose-responsive insulin analog.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/análogos & derivados , Administração Intravenosa , Adolescente , Adulto , Antígenos CD/efeitos dos fármacos , Estudos Cross-Over , Diabetes Mellitus Tipo 1/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Técnica Clamp de Glucose , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Insulina/efeitos adversos , Insulina/farmacocinética , Insulina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Receptor de Insulina/efeitos dos fármacos , Adulto Jovem
18.
Cochrane Database Syst Rev ; 12: CD013228, 2018 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-30556900

RESUMO

BACKGROUND: The use of short-acting insulin analogues (insulin lispro, insulin aspart, insulin glulisine) for adult, non-pregnant people with type 2 diabetes is still controversial, as reflected in many scientific debates. OBJECTIVES: To assess the effects of short-acting insulin analogues compared to regular human insulin in adult, non-pregnant people with type 2 diabetes mellitus. SEARCH METHODS: For this update we searched CENTRAL, MEDLINE, Embase, the WHO ICTRP Search Portal, and ClinicalTrials.gov to 31 October 2018. We placed no restrictions on the language of publication. SELECTION CRITERIA: We included all randomised controlled trials with an intervention duration of at least 24 weeks that compared short-acting insulin analogues to regular human insulin in the treatment of people with type 2 diabetes, who were not pregnant. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias. We assessed dichotomous outcomes by risk ratios (RR), and Peto odds ratios (POR), with 95% confidence intervals (CI). We assessed continuous outcomes by mean differences (MD) with 95% CI. We assessed trials for certainty of the evidence using the GRADE approach. MAIN RESULTS: We identified 10 trials that fulfilled the inclusion criteria, randomising 2751 participants; 1388 participants were randomised to receive insulin analogues and 1363 participants to receive regular human insulin. The duration of the intervention ranged from 24 to 104 weeks, with a mean of about 41 weeks. The trial populations showed diversity in disease duration, and inclusion and exclusion criteria. None of the trials were blinded, so the risk of performance bias and detection bias, especially for subjective outcomes, such as hypoglycaemia, was high in nine of 10 trials from which we extracted data. Several trials showed inconsistencies in the reporting of methods and results.None of the included trials defined all-cause mortality as a primary outcome. Six trials provided Information on the number of participants who died during the trial, with five deaths out of 1272 participants (0.4%) in the insulin analogue groups and three deaths out of 1247 participants (0.2%) in the regular human insulin groups (Peto OR 1.66, 95% CI 0.41 to 6.64; P = 0.48; moderate-certainty evidence). Six trials, with 2509 participants, assessed severe hypoglycaemia differently, therefore, we could not summarise the results with a meta-analysis. Overall, the incidence of severe hypoglycaemic events was low, and none of the trials showed a clear difference between the two intervention arms (low-certainty evidence).The MD in glycosylated haemoglobin A1c (HbA1c) change was -0.03% (95% CI -0.16 to 0.09; P = 0.60; 9 trials, 2608 participants; low-certainty evidence). The 95% prediction ranged between -0.31% and 0.25%. The MD in the overall number of non-severe hypoglycaemic episodes per participant per month was 0.08 events (95% CI 0.00 to 0.16; P = 0.05; 7 trials, 2667 participants; very low-certainty evidence). The 95% prediction interval ranged between -0.03 and 0.19 events per participant per month. The results provided for nocturnal hypoglycaemic episodes were of questionable validity. Overall, there was no clear difference between the two short-acting insulin analogues and regular human insulin. Two trials assessed health-related quality of life and treatment satisfaction, but we considered the results for both outcomes to be unreliable (very low-certainty evidence).No trial was designed to investigate possible long term effects (all-cause mortality, microvascular or macrovascular complications of diabetes), especially in participants with diabetes-related complications. No trial reported on socioeconomic effects. AUTHORS' CONCLUSIONS: Our analysis found no clear benefits of short-acting insulin analogues over regular human insulin in people with type 2 diabetes. Overall, the certainty of the evidence was poor and results on patient-relevant outcomes, like all-cause mortality, microvascular or macrovascular complications and severe hypoglycaemic episodes were sparse. Long-term efficacy and safety data are needed to draw conclusions about the effects of short-acting insulin analogues on patient-relevant outcomes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina Aspart/uso terapêutico , Insulina Lispro/uso terapêutico , Insulina/análogos & derivados , Insulina/uso terapêutico , Adulto , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/mortalidade , Hemoglobina A Glicada/análise , Humanos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
19.
Protein Pept Lett ; 25(12): 1149-1154, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30381053

RESUMO

BACKGROUND: Research has been directed at the optimization of insulin for medicinal purposes. An insulin analog that could be reversibly activated might provide more precise pharmacokinetic control and broaden the inherent therapeutic index of the hormone. The prospect of using intramolecular structural constraint to reversibly inactive insulin might constitute the first step to achieving such an optimized analog. Chemically crosslinked insulin analogs have been reported where two amines are covalently linked by reaction with symmetrical bifunctional active esters. There is little selectivity in this synthetic approach to molecular constraint with multiple derivatives being formed. OBJECTIVE: To systematically evaluate the synthesis of covalently crosslinked insulin analogs by asymmetric methods and the biological consequences. METHOD: We report synthesis of amine crosslinked insulin analogs via a two-step procedure. The stepwise approach was initiated by amide bond formation and followed by second site alkylation to produce site-specific, cross-linked insulin analogs. RESULTS: A set of unique insulin analogs crosslinked at the two of the three native amines were synthesized. They were chemical characterized and assessed by in vitro bioanalysis to result in a significant and reasonably consistent reduction in biological potency. CONCLUSION: We achieved an unambiguous two-step synthesis of several crosslinked insulin analogs differing in location of the chemical tether. Bioanalysis demonstrated the ability of the molecular constraint to reduce bioactivity. The results set the stage for in vivo assessment of whether such a reduction in potency can be used pharmacologically to establish a constrained hormone upon which reversible tethering might be subsequently introduced.


Assuntos
Aminas/química , Insulina/análogos & derivados , Animais , Reagentes para Ligações Cruzadas/química , Humanos , Insulina/síntese química , Insulina/química , Insulina/farmacocinética , Estrutura Molecular
20.
Drug Test Anal ; 10(11-12): 1761-1768, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30298989

RESUMO

While dried blood spot (DBS) analysis concerning low molecular mass molecules has become more and more established in various fields of analytical chemistry, the utility of DBS in determining peptides and proteins from DBS is yet comparably limited. In consideration of the fact that the apparent benefits of DBS sampling are similar for analytes of lower and higher molecular mass, dedicated (non-generic) sample preparation procedures are required that meet the needs for detecting peptidic drugs and hormones in DBS. The analysis of insulin and its synthetic analogs by mass spectrometry has received increased attention in several fields such as doping controls, forensics, and drug metabolism and pharmacokinetics studies. Hence, a strategy facilitating the analysis of insulin and its synthetic or animal analogs (human, Lispro, Aspart, Glulisine, Glargine, Detemir, Tresiba, and porcine and bovine insulin) from DBS was developed. The successful analysis of these substances at physiologically relevant concentrations was realized after ultrasonication-assisted extraction, immunoaffinity purification, and liquid chromatographic separation followed by high resolution mass spectrometric detection (with or without ion mobility). Assay validation demonstrated adequate sensitivity (LOD 0.5 ng/mL for most insulins), as well as precise (< 25%) and reproducible results for all included target insulins. Additionally, proof-of-principle data were obtained by the analysis of DBS samples obtained from healthy volunteers in non-fasting state as well as a sample from a diabetic volunteer treated with the fast acting analog insulin Aspart.


Assuntos
Cromatografia Líquida/métodos , Teste em Amostras de Sangue Seco/métodos , Insulina/análogos & derivados , Insulina/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Bovinos , Humanos , Limite de Detecção , Detecção do Abuso de Substâncias/métodos , Suínos
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