RESUMO
Insulin icodec is a once-weekly insulin analogue that has a long half-life of approximately 7 days, making it suitable for once weekly dosing. The Insulin icodec molecule was developed based on the hypothesis that lowering insulin receptor affinity and introducing a strong albumin-binding moiety would result in a long insulin half-life, provided that non-receptor-mediated clearance is diminished. Here, we report an insulin clearance mechanism, resulting in the splitting of insulin molecules into its A-chain and B-chain by a thiol-disulphide exchange reaction. Even though the substitutions in insulin icodec significantly stabilise insulin against such degradation, some free B-chain is observed in plasma samples from minipigs and people with type 2 diabetes. In summary, we identify thiol-disulphide exchange reactions to be an important insulin clearance mechanism and find that stabilising insulin icodec towards this reaction significantly contributes to its long pharmacokinetic/pharmacodynamic profile.
Assuntos
Diabetes Mellitus Tipo 2 , Dissulfetos , Insulina , Animais , Humanos , Masculino , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/sangue , Dissulfetos/química , Meia-Vida , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/química , Insulina/administração & dosagem , Insulina/metabolismo , Insulina/química , Insulina/farmacocinética , Receptor de Insulina/metabolismo , Compostos de Sulfidrila/química , Suínos , Porco MiniaturaRESUMO
Esophageal cancer is common worldwide, including in Japan, and its major histological subtype is squamous cell carcinoma. However, there are some rare esophageal cancers, including neuroendocrine neoplasm, gastrointestinal stromal tumor, carcinosarcoma and malignant melanoma. The biological and clinical features of these cancers differ from those of esophageal squamous cell carcinoma. Therefore, different treatment strategies are needed for these cancers but are based on limited evidence. Neuroendocrine neoplasm is mainly divided into neuroendocrine tumor and neuroendocrine carcinoma by differentiation and the Ki-67 proliferation index or mitotic index. Epidemiologically, the majority of esophageal neuroendocrine neoplasms are neuroendocrine carcinoma. The treatment of neuroendocrine carcinoma is similar to that of small cell lung cancer, which has similar morphological and biological features. Gastrointestinal stromal tumor is known to be associated with alterations in the c-KIT and platelet-derived growth factor receptor genes and, if resectable, is treated in accordance with the modified Fletcher classification. Carcinosarcoma is generally resistant to both chemotherapy and radiotherapy and requires multimodal treatments such as surgery plus chemotherapy to achieve cure. Primary malignant melanoma is resistant to cytotoxic chemotherapy, but immune checkpoint inhibitors have recently demonstrated efficacy for malignant melanoma of the esophagus. This review focuses on the current status and future perspectives for rare cancer of the esophagus.
Assuntos
Carcinoma Neuroendócrino , Carcinossarcoma , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Tumores do Estroma Gastrointestinal , Melanoma , Humanos , Neoplasias Esofágicas/patologia , Carcinossarcoma/patologiaRESUMO
BACKGROUND: We have reported the possible benefits of radical esophagectomy with thoracic duct (TD) resection in elective esophageal cancer surgery. However, the effect of TD resection on the long-term nutrition status remains unclear. METHODS: Patients who underwent esophagectomy at Keio University between January 2006 and December 2018 were included, and those who had no recurrence for more than three years were evaluated. Changes in each body composition (muscle mass and body fat) were comparatively assessed between those who underwent TD resection or not, before and at, one, three and five years after surgery. Computed tomography images were analyzed on postoperative year 1, 3 and 5. RESULTS: This study included 217 patients categorized in the TD-resected (TD-R) (156 patients) and TD-preserved (TD-P) (61 patients) groups. The loss of muscle mass was comparable between the groups. On the other hand, the loss of adipose tissues was significantly greater in the TD-R group than in the TD-P group at one and three years after surgery, while there was no statistical difference five years after surgery. Additionally, among patients with cT1N0M0 disease in whom survival advantage of TD resection has been reported previously, the loss of muscle mass did not differ between each group. CONCLUSIONS: The change of muscle mass between the two groups was comparable. Although body fat mass was reduced by TD resection, it eventually recovered in the long term. In patients with esophageal cancer, TD resection may be acceptable without significant impact on body composition in the long term.
Assuntos
Neoplasias Esofágicas , Ducto Torácico , Humanos , Ducto Torácico/cirurgia , Esofagectomia/métodos , Estudos Retrospectivos , Neoplasias Esofágicas/cirurgia , Composição CorporalRESUMO
PURPOSE: Systematic inflammation has been reported to contribute to cancer progression through various mechanisms; however, the exact mechanism is still the subject of research. In this study, we evaluated the influence of systematic inflammation on lung metastasis, using a murine abdominal sepsis model, and assessed its relationship with pneumonia after curative esophagectomy in patients with esophageal cancer. METHODS: We used a murine abdominal sepsis model given highly metastatic osteosarcoma, to reveal the mechanism of systematic inflammation and its potential for lung metastasis. The therapeutic effect of aspirin (ASA) in preventing distant metastasis was also investigated. Subsequently, we analyzed, retrospectively, the relationship between pneumonia and lung metastasis after esophagectomy in patients who underwent esophagectomy at Keio University between January, 2007 and October, 2020. RESULTS: Abdominal sepsis provoked lung injury in the acute phase. ASA inhibited the recruitment of neutrophils triggered by the lung injury, and it also suppressed lung metastasis. Our retrospective study revealed that lung metastasis was more frequent in patients with postoperative pneumonia. CONCLUSIONS: Postoperative acute lung injury is associated with a higher risk of lung metastasis. ASA may be a potential preoperative treatment for inhibiting lung metastasis by preventing the recruitment of neutrophils.
Assuntos
Lesão Pulmonar Aguda , Neoplasias Pulmonares , Pneumonia , Sepse , Humanos , Animais , Camundongos , Estudos Retrospectivos , Aspirina/farmacologia , Infiltração de Neutrófilos , Pneumonia/etiologia , Pneumonia/prevenção & controle , Inflamação/prevenção & controle , Lesão Pulmonar Aguda/prevenção & controle , Lesão Pulmonar Aguda/complicações , Neutrófilos/patologia , Neoplasias Pulmonares/patologia , Pulmão/patologiaRESUMO
Peptides and proteins are widely used to treat a range of medical conditions; however, they often have to be injected and their effects are short-lived. These shortcomings of the native structure can be addressed by molecular engineering, but this is a complex undertaking. A molecular engineering technology initially applied to insulin - and which has now been successfully applied to several biopharmaceuticals - entails the derivatization of peptides and proteins with fatty acids. Various protraction mechanisms are enabled by the specific characteristics and positions of the attached fatty acid. Furthermore, the technology can ensure a long half-life following oral administration of peptide drugs, can alter the distribution of peptides and may hold potential for tissue targeting. Due to the inherent safety and well-defined chemical nature of the fatty acids, this technology provides a versatile approach to peptide and protein drug discovery.
Assuntos
Descoberta de Drogas , Ácidos Graxos , Proteínas , Humanos , Ácidos Graxos/química , Insulina/química , Peptídeos/química , Proteínas/químicaRESUMO
Changes in muscle mass may be an objective approach toward measuring the quality of life after surgery, but long-term changes due to surgery without the effect of cachexia remain unclear. Patients with esophageal cancer who underwent esophagectomy and did not experience cancer recurrence for 3 years were analyzed. The psoas muscle mass index (PMI) was assessed before surgery and 7 days, 1 year, and 3 years after surgery. Patients with no change or increased PMI within 7 days after surgery were categorized into the Nondecreasing-PMI group, whereas those with decreased PMI were categorized into the Decreasing-PMI group. Eighty-four and 51 patients were categorized into the Nondecreasing- and Decreasing-PMI groups, respectively. The Decreasing-PMI group had a higher incidence rate of anastomotic leakage than the Nondecreasing-PMI group (25% vs. 12%, respectively; P = 0.042). Moreover, the Decreasing-PMI group showed a significantly greater decrease in the PMI 1 year after surgery than the Nondecreasing-PMI group (-9.2% vs. -4.0%, respectively; P = 0.048). However, although the Decreasing-PMI group had a greater decrease in the PMI than the Nondecreasing-PMI group, no significant difference was observed 3 years after surgery (-9.8% vs. -5.3%, respectively; P = 0.115). A decrease in PMI in the acute phase after esophagectomy may contribute to a long-term decrease in the PMI. Intensive interventions may be beneficial for these patients to improve their long-term quality of life.
Assuntos
Neoplasias Esofágicas , Sarcopenia , Humanos , Músculos Psoas/patologia , Esofagectomia/efeitos adversos , Qualidade de Vida , Prognóstico , Recidiva Local de Neoplasia/patologia , Neoplasias Esofágicas/patologia , Sobreviventes , Estudos Retrospectivos , Sarcopenia/etiologiaRESUMO
Esophagectomy is a highly invasive surgical procedure; however, anastomotic leakage is one of the major surgical complications that should be prevented. Institutions have their own inherited or specialized anastomosis methods. The superior anastomosis procedure remains unknown despite the many studies to determine the optimal method. The present study enrolled 341 patients who underwent esophagectomy at Keio University Hospital, Tokyo, Japan, between January 2009 and January 2019. The anastomosis method was changed from circular stapled anastomosis to hand-sewn anastomosis in February 2014 to reduce the risk of anastomotic leakage. We retrospectively compared short-term results (anastomotic leakage and stricture) between hand-sewn and circular stapled anastomoses. Analysis of heterogeneity after propensity score matching between the 107 patients in the hand-sewn anastomosis group and 107 patients in the circular stapled anastomosis group revealed almost equal distributions. The incidence rate of anastomotic leakage was significantly lower in the hand-sewn anastomosis group than in the circular stapled anastomosis group (9 vs. 20%, hazard ratio: 2.521; 95% confidence interval: 1.112-5.716; P = 0.027). No significant difference was found in the incidence of anastomotic stricture (16 vs. 18%, P = 0.844). Furthermore, no significant difference was found in the incidence of anastomotic leakage in any of the tumor locations between the two anastomosis procedures. For esophagogastric anastomosis in the neck after esophagectomy, hand-sewn anastomosis is superior to circular stapled anastomosis with regard to reducing the risk of anastomotic leakage.
Assuntos
Neoplasias Esofágicas , Neoplasias Torácicas , Humanos , Esofagectomia/efeitos adversos , Fístula Anastomótica/etiologia , Constrição Patológica/etiologia , Estudos Retrospectivos , Pontuação de Propensão , Resultado do Tratamento , Neoplasias Esofágicas/cirurgia , Anastomose Cirúrgica/efeitos adversos , Grampeamento Cirúrgico , Neoplasias Torácicas/cirurgia , Complicações Pós-Operatórias/epidemiologiaRESUMO
BACKGROUND: Although proximal gastrectomy (PG) is a function-preserving surgical option, it remains unclear as to which reconstruction method can prevent reflux and maintain body composition. METHODS: Patients who underwent PG at Keio University between April 2011 and November 2018 were analyzed. Changes in the subcutaneous and visceral adipose tissues were comparatively assessed before and after a year of surgery for three common reconstruction methods. We also compared the endoscopic findings of reflux esophagitis and the number of patients prescribed with proton-pump inhibitor after a year of surgery. RESULTS: This study included 76 patients, of which 33 patients underwent esophagogastrostomy with a circular stapler (CS), 35 under double flap (DF) reconstruction, and 8 underwent double tract (DT) reconstruction. Comparing esophagogastrostomy (CS and DF) and DT showed that esophagogastrostomy could significantly preserve both subcutaneous and visceral adipose tissues (P < 0.001 and P = 0.04, respectively). However, the change in the subcutaneous and visceral adipose tissues was comparable between CS and DF. As for reflux esophagitis, DF showed the lowest incidence rate for esophagitis and the least number of patients who were prescribed a proton-pump inhibitor. CONCLUSION: DF is a relatively better reconstruction method for preserving fat mass and preventing reflux among the three common reconstruction methods.
Assuntos
Esofagite Péptica , Refluxo Gastroesofágico , Neoplasias Gástricas , Humanos , Esofagite Péptica/etiologia , Esofagite Péptica/prevenção & controle , Esofagite Péptica/cirurgia , Inibidores da Bomba de Prótons , Neoplasias Gástricas/cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/cirurgia , Gastrectomia/métodos , Refluxo Gastroesofágico/prevenção & controle , Refluxo Gastroesofágico/cirurgia , Refluxo Gastroesofágico/etiologia , Estudos RetrospectivosRESUMO
Here, we describe molecular engineering of monovalent ultra-long acting two-chain insulin-Fc conjugates. Insulin-Fc conjugates were synthesized using trifunctional linkers with one amino reactive group for reaction with a lysine residue of insulin and two thiol reactive groups used for re-bridging of a disulfide bond within the Fc molecule. The ultra-long pharmacokinetic profile of the insulin-Fc conjugates was the result of concertedly slowing insulin receptor-mediated clearance by (1) introduction of amino acid substitutions that lowered the insulin receptor affinity and (2) conjugating insulin to the Fc element. Fc conjugation leads to recycling by the neonatal Fc receptor and increase in the molecular size, both contributing to the ultra-long pharmacokinetic and pharmacodynamic profiles.
Assuntos
Hipoglicemiantes/síntese química , Imunoconjugados/química , Fragmentos Fc das Imunoglobulinas/química , Insulina de Ação Prolongada/síntese química , Sequência de Aminoácidos , Animais , Linhagem Celular , Diabetes Mellitus Experimental/tratamento farmacológico , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Imunoconjugados/farmacocinética , Imunoconjugados/uso terapêutico , Fragmentos Fc das Imunoglobulinas/farmacologia , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Insulina de Ação Prolongada/farmacocinética , Insulina de Ação Prolongada/uso terapêutico , Masculino , Mesocricetus , Engenharia de Proteínas , Ratos Sprague-DawleyRESUMO
INTRODUCTION: Insulin icodec is a novel, long-acting insulin analog designed to cover basal insulin requirements with once-weekly subcutaneous administration. Here we describe the molecular engineering and the biological and pharmacological properties of insulin icodec. RESEARCH DESIGN AND METHODS: A number of in vitro assays measuring receptor binding, intracellular signaling as well as cellular metabolic and mitogenic responses were used to characterize the biological properties of insulin icodec. To evaluate the pharmacological properties of insulin icodec in individuals with type 2 diabetes, a randomized, double-blind, double-dummy, active-controlled, multiple-dose, dose escalation trial was conducted. RESULTS: The long half-life of insulin icodec was achieved by introducing modifications to the insulin molecule aiming to obtain a safe, albumin-bound circulating depot of insulin icodec, providing protracted insulin action and clearance. Addition of a C20 fatty diacid-containing side chain imparts strong, reversible albumin binding, while three amino acid substitutions (A14E, B16H and B25H) provide molecular stability and contribute to attenuating insulin receptor (IR) binding and clearance, further prolonging the half-life. In vitro cell-based studies showed that insulin icodec activates the same dose-dependent IR-mediated signaling and metabolic responses as native human insulin (HI). The affinity of insulin icodec for the insulin-like growth factor-1 receptor was proportionately lower than its binding to the IR, and the in vitro mitogenic effect of insulin icodec in various human cells was low relative to HI. The clinical pharmacology trial in people with type 2 diabetes showed that insulin icodec was well tolerated and has pharmacokinetic/pharmacodynamic properties that are suited for once-weekly dosing, with a mean half-life of 196 hours and close to even distribution of glucose-lowering effect over the entire dosing interval of 1 week. CONCLUSIONS: The molecular modifications introduced into insulin icodec provide a novel basal insulin with biological and pharmacokinetic/pharmacodynamic properties suitable for once-weekly dosing. TRIAL REGISTRATION NUMBER: NCT02964104.
Assuntos
Diabetes Mellitus Tipo 2 , Insulina , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/farmacologia , Insulina de Ação Prolongada , Insulina Regular HumanaRESUMO
The life-saving discovery of insulin in Toronto in 1921 is one of the most impactful achievements in medical history, at the time being hailed as a miracle treatment for diabetes. The insulin molecule itself, however, is poorly amenable as a pharmacological intervention, and the formidable challenge of optimizing insulin therapy has been ongoing for a century. We review early academic insights into insulin structure and its relation to self-association and receptor binding, as well as recombinant biotechnology, which have all been seminal for drug design. Recent developments have focused on combining genetic and chemical engineering with pharmaceutical optimization to generate ultra-rapid and ultra-long-acting, tissue-selective, or orally delivered insulin analogs. We further discuss these developments and propose that future scientific efforts in molecular engineering include realizing the dream of glucose-responsive insulin delivery.
Assuntos
Diabetes Mellitus , Insulina , Diabetes Mellitus/tratamento farmacológico , Humanos , Insulina/metabolismo , Ligação ProteicaRESUMO
Here, we describe the molecular engineering of insulin icodec to achieve a plasma half-life of 196 h in humans, suitable for once-weekly subcutaneously administration. Insulin icodec is based on re-engineering of the ultra-long oral basal insulin OI338 with a plasma half-life of 70 h in humans. This systematic re-engineering was accomplished by (1) further increasing the albumin binding by changing the fatty diacid from a 1,18-octadecanedioic acid (C18) to a 1,20-icosanedioic acid (C20) and (2) further reducing the insulin receptor affinity by the B16Tyr â His substitution. Insulin icodec was selected by screening for long intravenous plasma half-life in dogs while ensuring glucose-lowering potency following subcutaneous administration in rats. The ensuing structure-activity relationship resulted in insulin icodec. In phase-2 clinical trial, once-weekly insulin icodec provided safe and efficacious glycemic control comparable to once-daily insulin glargine in type 2 diabetes patients. The structure-activity relationship study leading to insulin icodec is presented here.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Animais , Cães , Esquema de Medicação , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Injeções Intravenosas , Injeções Subcutâneas , Insulina/administração & dosagem , Insulina/análogos & derivados , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Recently, the first basal oral insulin (OI338) was shown to provide similar treatment outcomes to insulin glargine in a phase 2a clinical trial. Here, we report the engineering of a novel class of basal oral insulin analogues of which OI338, 10, in this publication, was successfully tested in the phase 2a clinical trial. We found that the introduction of two insulin substitutions, A14E and B25H, was needed to provide increased stability toward proteolysis. Ultralong pharmacokinetic profiles were obtained by attaching an albumin-binding side chain derived from octadecanedioic (C18) or icosanedioic acid (C20) to the lysine in position B29. Crucial for obtaining the ultralong PK profile was also a significant reduction of insulin receptor affinity. Oral bioavailability in dogs indicated that C18-based analogues were superior to C20-based analogues. These studies led to the identification of the two clinical candidates OI338 and OI320 (10 and 24, respectively).
Assuntos
Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Acilação , Administração Oral , Sequência de Aminoácidos , Animais , Disponibilidade Biológica , Preparações de Ação Retardada , Cães , Meia-Vida , Humanos , Hipoglicemiantes/farmacocinética , Insulina/química , Insulina/farmacocinética , RatosRESUMO
Recently, the clinical proof of concept for the first ultra-long oral insulin was reported, showing efficacy and safety similar to subcutaneously administered insulin glargine. Here, we report the molecular engineering as well as biological and pharmacological properties of these insulin analogues. Molecules were designed to have ultra-long pharmacokinetic profile to minimize variability in plasma exposure. Elimination plasma half-life of ~20 h in dogs and ~70 h in man is achieved by a strong albumin binding, and by lowering the insulin receptor affinity 500-fold to slow down receptor mediated clearance. These insulin analogues still stimulate efficient glucose disposal in rats, pigs and dogs during constant intravenous infusion and euglycemic clamp conditions. The albumin binding facilitates initial high plasma exposure with a concomitant delay in distribution to peripheral tissues. This slow appearance in the periphery mediates an early transient hepato-centric insulin action and blunts hypoglycaemia in dogs in response to overdosing.
Assuntos
Insulina/administração & dosagem , Engenharia de Proteínas , Administração Oral , Sequência de Aminoácidos , Animais , Glicemia/metabolismo , Simulação por Computador , Cães , Relação Dose-Resposta a Droga , Overdose de Drogas/sangue , Técnica Clamp de Glucose , Meia-Vida , Humanos , Hiperinsulinismo/tratamento farmacológico , Hipoglicemia/diagnóstico , Insulina/análogos & derivados , Insulina/química , Insulina/farmacocinética , Masculino , Estabilidade Proteica , Proteólise , Ratos Sprague-Dawley , Suínos , Resultado do TratamentoRESUMO
BACKGROUND: Oral delivery of insulin was recently demonstrated to have therapeutic relevance in patients with diabetes. Insulin receptors are expressed in the gastrointestinal tract and can be activated by insulin in the bloodstream, but it is not known if the large amount of insulin in the intestinal lumen required for sufficient oral delivery will induce a different effect. The aim of this study was to compare the acute effect in the intestine of insulin administered in the intestinal lumen with that of insulin administered by a parenteral route. METHOD: Intraintestinal (ii) injection in the mid-jejunum of anaesthetized rats with insulin analogue 106 (I106), formulated with the absorption-enhancer sodium caprate, was used as an animal model of oral insulin administration. As control treatment, rats were treated with I106 by iv infusion according to algorithms which precisely mimicked the pharmacokinetic and pharmacodynamic properties of ii administered I106. Several fold more I106 was administered by ii injection than by iv infusion. Phosphorylated Akt (Ser473) was used as indicator of insulin-stimulated acute effects in the intestine. RESULTS: Treatment with I106 resulted in activation of Akt in the intestine, with no significant difference between the effects of ii or iv administration. CONCLUSION: The results from this rat model of orally administered insulin indicate that the unabsorbed insulin in the intestinal lumen after oral administration will not result in an enhanced acute effect in the intestine.
Assuntos
Insulina/análogos & derivados , Insulina/administração & dosagem , Absorção Intestinal/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Receptor de Insulina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Glicemia , Insulina/sangue , Intestino Delgado/metabolismo , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
AIMS: We previously quantified the hypoglycaemia-sparing effect of portal vs peripheral human insulin delivery. The current investigation aimed to determine whether a bioequivalent peripheral vein infusion of a hepatopreferential insulin analog, insulin-406, could similarly protect against hypoglycaemia. MATERIALS AND METHODS: Dogs received human insulin infusions into either the hepatic portal vein (PoHI, n = 7) or a peripheral vein (PeHI, n = 7) for 180 minutes at four-fold the basal secretion rate (6.6 pmol/kg/min) in a previous study. Insulin-406 (Pe406, n = 7) was peripherally infused at 6.0 pmol/kg/min, a rate determined to decrease plasma glucose by the same amount as with PoHI infusion during the first 60 minutes. Glucagon was fixed at basal concentrations, mimicking the diminished α-cell response seen in type 1 diabetes. RESULTS: Glucose dropped quickly with PeHI infusion, reaching 41 ± 3 mg/dL at 60 minutes, but more slowly with PoHI and Pe406 infusion (67 ± 2 and 72 ± 4 mg/dL, respectively; P < 0.01 vs PeHI for both). The hypoglycaemic nadir (c. 40 mg/dL) occurred at 60 minutes with PeHI infusion vs 120 minutes with PoHI and Pe406 infusion. ΔAUCepinephrine during the 180-minute insulin infusion period was two-fold higher with PeHI infusion compared with PoHI and Pe406 infusion. Glucose production (mg/kg/min) was least suppressed with PeHI infusion (Δ = 0.79 ± 0.33) and equally suppressed with PoHI and Pe406 infusion (Δ = 1.16 ± 0.21 and 1.18 ± 0.17, respectively; P = NS). Peak glucose utilization (mg/kg/min) was highest with PeHI infusion (4.94 ± 0.17) and less with PoHI and Pe406 infusion (3.58 ± 0.58 and 3.26 ± 0.08, respectively; P < 0.05 vs Pe for both). CONCLUSIONS: Peripheral infusion of hepatopreferential insulin can achieve a metabolic profile that closely mimics portal insulin delivery, which reduces the risk of hypoglycaemia compared with peripheral insulin infusion.
Assuntos
Hipoglicemiantes , Insulina Regular Humana , Insulina , Veia Porta/metabolismo , Animais , Glicemia/análise , Glicemia/metabolismo , Diabetes Mellitus Tipo 1 , Cães , Gluconeogênese , Humanos , Hipoglicemia/metabolismo , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Infusões Intravenosas , Insulina/administração & dosagem , Insulina/análogos & derivados , Insulina/sangue , Insulina/farmacologia , Insulina Regular Humana/administração & dosagem , Insulina Regular Humana/farmacologia , Fígado/metabolismo , MasculinoRESUMO
Peripheral hyperinsulinemia resulting from subcutaneous insulin injection is associated with metabolic defects which include abnormal glucose metabolism. The first aim of this study was to quantify the impairments in liver and muscle glucose metabolism that occur when insulin is delivered via a peripheral vein compared to when it is given through its endogenous secretory route (the hepatic portal vein) in overnight fasted conscious dogs. The second aim was to determine if peripheral delivery of a hepato-preferential insulin analog could restore the physiologic response to insulin that occurs under meal feeding conditions. This study is the first to show that hepatic glucose uptake correlates with insulin's direct effects on the liver under hyperinsulinemic-hyperglycemic conditions. In addition, glucose uptake was equally divided between the liver and muscle when insulin was infused into the portal vein, but when it was delivered into a peripheral vein the percentage of glucose taken up by muscle was 4-times greater than that going to the liver, with liver glucose uptake being less than half of normal. These defects could not be corrected by adjusting the dose of peripheral insulin. On the other hand, hepatic and non-hepatic glucose metabolism could be fully normalized by a hepato-preferential insulin analog.
Assuntos
Glucose/metabolismo , Hiperglicemia/metabolismo , Hiperinsulinismo/metabolismo , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Fígado/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Veia Porta , Animais , Cães , Técnica Clamp de Glucose , Membro Posterior/irrigação sanguínea , Insulina/análogos & derivados , Fígado/metabolismo , Músculo Esquelético/metabolismo , VeiasRESUMO
Portal vein thrombosis (PVT) is caused by several conditions including infection, malignancies, surgery, medications, and coagulation disorders. However, PVT caused by low-energy injury is very rare. A 51-year-old man visited a clinic with a 2-day history of abdominal pain following blunt abdominal trauma. Contrast-enhanced computed tomography (CT) revealed thrombosis in both the portal vein and splenic vein, and he was transferred to our hospital with a diagnosis of PVT. Anticoagulant therapy was initiated using unfractionated heparin. A repeat CT scan revealed enlargement of the thrombus, which occluded the main trunk and first right branch of the portal vein. Laboratory data before heparin administration suggested low protein C activity. Anticoagulation therapy was continued with intermittent assessment of the size of the thrombus and degree of coagulation. On day 23, enhanced CT showed marked shrinkage of the thrombus compared with that on day 8. On day 30, the patient was discharged with a therapeutic prothrombin time-international normalized ratio. Here we present a case of PVT caused by low-energy trauma of the upper abdomen in a patient with a background of low protein C activity that was successfully treated without invasive surgery.
Assuntos
Traumatismos Abdominais/complicações , Veia Porta , Deficiência de Proteína C/complicações , Trombose Venosa/etiologia , Ferimentos não Penetrantes/complicações , Anticoagulantes/uso terapêutico , Quimioterapia Combinada , Heparina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Trombose Venosa/sangue , Trombose Venosa/tratamento farmacológico , Varfarina/uso terapêuticoRESUMO
The role of the intestinal insulin receptor (IR) is not well understood. We therefore explored the effect of insulin (300 nmol/kg per day for 12 days) on the intestine in sex-matched C57Bl/6J mice. The intestinal and metabolic profiles were also characterized in male and female intestinal-epithelial IR knockout (IE-irKO) mice compared with all genetic controls on a chow diet or Western diet (WD) for 4 to 12 weeks. Insulin treatment did not affect intestinal size, intestinal resistance, or metabolic genes, but it reduced proximal-colon crypt depth and acutely increased colonic serine/threonine-specific protein kinase B (AKT) activation. Feeding with a WD increased body weight and fasting insulin level and decreased oral glucose tolerance in C57Bl/6J and IE-irKO mice. However, although the overall responses of the IE-irKO mice were not different from those of Villin-Cre (Vil-Cre):IRfl/+ and IRfl/fl controls, profound differences were found for female control Vil-Cre mice, which demonstrated reduced food intake, body weight, jejunal glucose transport, oral glucose tolerance, and fasting insulin and cholesterol levels. Vil-Cre mice also had smaller intestines compared with those of IE-irKO and IRfl/fl mice and greater insulin-mediated activation of jejunal IR and AKT. In summary, gain- and loss-of-function studies, with and without caloric overload, indicate that insulin did not exert remarkable effects on intestinal metabolic or morphologic phenotype except for a small effect on the colon. However, the transgenic control Vil-Cre mice displayed a distinct phenotype compared with other control and knockout animals, emphasizing the importance of thoroughly characterizing genetically modified mouse models.