RESUMO
AIMS/HYPOTHESIS: The aim was to evaluate the efficacy and safety of transcutaneous frequency-modulated electromagnetic neural stimulation (frequency rhythmic electrical modulation system, FREMS) as a treatment for symptomatic peripheral neuropathy in patients with diabetes mellitus. METHODS: This was a double-blind, randomised, multicentre, parallel-group study of three series, each of ten treatment sessions of FREMS or placebo administered within 3 weeks, 3 months apart, with an overall follow-up of about 51 weeks. The primary endpoint was the change in nerve conduction velocity (NCV) of deep peroneal, tibial and sural nerves. Secondary endpoints included the effects of treatment on pain, tactile, thermal and vibration sensations. Patients eligible to participate were aged 18-75 years with diabetes for ≥ 1 year, HbA(1c) <11.0% (97 mmol/mol), with symptomatic diabetic polyneuropathy at the lower extremities (i.e. abnormal amplitude, latency or NCV of either tibial, deep peroneal or sural nerve, but with an evocable potential and measurable NCV of the sural nerve), a Michigan Diabetes Neuropathy Score ≥ 7 and on a stable dose of medications for diabetic neuropathy in the month prior to enrolment. Data were collected in an outpatient setting. Participants were allocated to the FREMS or placebo arm (1:1 ratio) according to a sequence generated by a computer random number generator, without block or stratification factors. Investigators digitised patients' date of birth and site number into an interactive voice recording system to obtain the assigned treatment. Participants, investigators conducting the trial, or people assessing the outcomes were blinded to group assignment. RESULTS: Patients (n = 110) with symptomatic neuropathy were randomised to FREMS (n = 54) or placebo (n = 56). In the intention-to-treat population (50 FREMS, 51 placebo), changes in NCV of the three examined nerves were not different between FREMS and placebo (deep peroneal [means ± SE]: 0.74 ± 0.71 vs 0.06 ± 1.38 m/s; tibial: 2.08 ± 0.84 vs 0.61 ± 0.43 m/s; and sural: 0.80 ± 1.08 vs -0.91 ± 1.13 m/s; FREMS vs placebo, respectively). FREMS induced a significant reduction in day and night pain as measured by a visual analogue scale immediately after each treatment session, although this beneficial effect was no longer measurable 3 months after treatment. Compared with the placebo group, in the FREMS group the cold sensation threshold was significantly improved, while non-significant differences were observed in the vibration and warm sensation thresholds. No relevant side effects were recorded during the study. CONCLUSIONS/INTERPRETATION: FREMS proved to be a safe treatment for symptomatic diabetic neuropathy, with immediate, although transient, reduction in pain, and no effect on NCV. TRIAL REGISTRATION: ClinicalTrials.gov NCT01628627. FUNDING: The clinical trial was sponsored by Lorenz Biotech (Medolla, Italy), lately Lorenz Lifetech (Ozzano dell'Emilia, Italy).
Assuntos
Neuropatias Diabéticas/terapia , Campos Eletromagnéticos , Magnetoterapia/métodos , Adolescente , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The IDDM2 type 1 diabetes susceptibility locus was mapped to and identified as allelic variation at the insulin gene (INS) VNTR regulatory polymorphism. In Caucasians, INS VNTR alleles divide into two discrete size classes. Class I alleles (26 to 63 repeats) predispose in a recessive way to type 1 diabetes, while class III alleles (140 to more than 200 repeats) are dominantly protective. The protective effect may be explained by higher levels of class III VNTR-associated INS mRNA in thymus such that elevated levels of preproinsulin protein enhance immune tolerance to preproinsulin, a key autoantigen in type 1 diabetes pathogenesis. The mode of action of IDDM2 is complicated, however, by parent-of-origin effects and possible allelic heterogeneity within the two defined allele classes. We have now analysed transmission of specific VNTR alleles in 1,316 families and demonstrate that a particular class I allele does not predispose to disease when paternally inherited, suggestive of polymorphic imprinting. But this paternal effect is observed only when the father's untransmitted allele is a class III. This allelic interaction is reminiscent of epigenetic phenomena observed in plants (for example, paramutation; ref. 17) and in yeast (for example, trans-inactivation; ref. 18). If untransmitted chromosomes can have functional effects on the biological properties of transmitted chromosomes, the implications for human genetics and disease are potentially considerable.
Assuntos
Diabetes Mellitus Tipo 1/genética , Insulina/genética , Alelos , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Variação Genética , Genética Populacional , Homozigoto , Humanos , MasculinoRESUMO
AIMS/HYPOTHESIS: The purpose of this study was to investigate whether the gut mucosa is a reservoir for enterovirus persistence in patients with type 1 diabetes. METHODS: Small intestine biopsy samples from 25 individuals at different stages of type 1 diabetes, 21 control individuals and 27 individuals with coeliac disease were analysed for the presence of enterovirus RNA by using both radioactive in-situ hybridisation and real-time RT-PCR and for the presence of enterovirus proteins by immunostaining with antibodies against VP1 and VP4-2-3 capsid proteins and virus polymerase. Lymphocytic enteropathy and serum anti-VP1 antibodies were also evaluated at the time of biopsy. Moreover, high-throughput sequencing was performed to identify viral transcripts or genomes. RESULTS: Enterovirus was not detected by in-situ hybridisation or RT-PCR in any of the individuals tested. Immunohistology revealed a few stained cells in the intestinal epithelium in a low number of individuals, with no difference between diabetic and non-diabetic individuals. Levels of serum IgG against VP1 did not differ between control individuals and those with diabetes or coeliac disease and no evidence of diabetes-related lymphocytic enteropathy was detected. High-throughput sequencing did not reveal specific enterovirus sequences in the gut mucosa of individuals with type 1 diabetes. CONCLUSIONS/INTERPRETATION: Prolonged/persistent enterovirus infections in gut mucosa are not common in patients with type 1 diabetes.
Assuntos
Diabetes Mellitus Tipo 1/complicações , Infecções por Enterovirus/patologia , Enterovirus/isolamento & purificação , Mucosa Intestinal/patologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/virologia , Feminino , Humanos , Imuno-Histoquímica , Hibridização In Situ , Mucosa Intestinal/virologia , Masculino , Pessoa de Meia-Idade , RNA Viral , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Replicação Viral , Adulto JovemRESUMO
AIM: This study assessed the efficacy of long-term l-arginine (l-arg) therapy in preventing or delaying type 2 diabetes mellitus. METHODS: A mono-centre, randomized, double-blind, parallel-group, placebo-controlled, phase III trial (l-arg trial) was conducted on 144 individuals affected by impaired glucose tolerance (IGT) and metabolic syndrome (MS). l-Arg/placebo was administered (6.4 g/day) on a background structured lifestyle intervention for 18 months plus a 12-month extended follow-up period after study drug termination. Fasting glucose levels and glucose tolerance after oral glucose tolerance test were evaluated throughout the study. RESULTS: After 18 months, l-arg as compared with placebo did not reduce the cumulative incidence of diabetes [21.4 and 20.8%, respectively, hazard ratio (HR), 1.04; 95% confidence interval (CI), 0.58-1.86] while the cumulative probability to become normal glucose tolerant (NGT) increased (42.4 and 22.1%, respectively, HR, 2.60; 95% CI, 1.51-4.46, p < 0.001). The higher cumulative probability to become of NGT was maintained during the extended period in subjects previously treated with l-arg (HR, 3.21; 95% CI, 1.87-5.51; p < 0.001). At the end of the extended period, the cumulative incidence of diabetes in subjects previously treated with l-arg was reduced as compared with placebo (27.2 and 47.1%, respectively, HR, 0.42; 95% CI, 0.24-0.75, p < 0.05). During both periods, l-arg significantly improved insulin sensitivity and ß-cell function. CONCLUSION: Among persons with IGT and MS, the supplementation of l-arg for 18 months does not significantly reduce the incidence of diabetes but does significantly increase regression to NGT.
Assuntos
Arginina/administração & dosagem , Arginina/farmacologia , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Suplementos Nutricionais , Intolerância à Glucose/tratamento farmacológico , Administração Oral , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Intolerância à Glucose/sangue , Teste de Tolerância a Glucose , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Comportamento de Redução do Risco , Fatores de TempoRESUMO
BACKGROUND AND AIMS: The relationship between atrial natriuretic peptide (ANP), increased free fatty acid (FFA) and insulin resistance in patients with mitral valve disease (MVD), a group characterised by elevated atrial pressure and increased ANP levels, is not defined. The present study was performed to evaluate, in MVD patients, the relationship between increased ANP and FFA levels and insulin resistance and the role of mitral valve replacement/repair in ameliorating these metabolic alterations. Conversely, coronary heart disease (CHD) patients were evaluated before and after coronary artery bypass grafting (CABG), since they are known to be insulin resistant in the presence of chronic FFA increase. METHODS AND RESULTS: Fifty MVD patients and 55 CHD patients were studied before and 2 months after surgery and compared with 166 normal subjects. Before surgery, 56% of MVD patients had impaired glucose tolerance or newly diagnosed type 2 diabetes after a standard oral glucose load and this percentage decreased to 46% after surgery. In CHD, impaired glucose tolerance (IGT) or newly diagnosed type 2 diabetic patients were 67% of patients before and after CABG. In MVD, left atrial (LA) volume, ANP, FFA incremental area and insulin levels were higher and Insulin Sensitivity (IS) index significantly reduced while after surgery, LA volume, ANP and FFA significantly decreased and IS index significantly improved. In CHD, insulin resistance and hyperinsulinaemia were present both before and after surgery with increased tumour necrosis factor (TNF)-α and interleukin (IL)-6 levels. CONCLUSION: In MVD, a higher degree of abnormal glucose tolerance and insulin resistance are associated to increased levels of ANP and FFA, while these metabolic alterations are improved by mitral valve replacement/repair surgery. Clinical Trial.gov registration number NCT 00520962.
Assuntos
Fator Natriurético Atrial/sangue , Diabetes Mellitus Tipo 2/metabolismo , Ácidos Graxos não Esterificados/sangue , Doenças das Valvas Cardíacas/cirurgia , Resistência à Insulina , Idoso , Ponte de Artéria Coronária , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Intolerância à Glucose/metabolismo , Humanos , Interleucina-6/análise , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Valva Mitral/patologia , Análise de Regressão , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/metabolismoRESUMO
AIM: This prospective, observational cohort study aimed to measure HbA1c change over 3-6 months in type 2 diabetes managed with basal-bolus insulin and FreeStyle Libre® Flash Glucose Monitoring System (FSL) use compared to self-monitored blood glucose (SMBG). METHODS: Sixteen Italian hospitals enrolled patients with type 2 diabetes (n = 322, [109 FSL, 213 SMBG users]) using basal-bolus insulin therapy for ≥ 1 year, HbA1c 8.0-12.0% (64-108 mmol/mol), new to FSL use (<3 months) or continuing with SMBG (controls). Eligible FSL and SMBG users were matched (1:2 ratio) for baseline HbA1c (within ± 0.5%, recorded ≤ 3 months previously), study site and baseline data collection date. RESULTS: Overall, baseline HbA1c was 8.9 ± 0.8% (74 ± 9 mmol/mol), age 67.2 ± 10.0 years, BMI 30.5 ± 6.5 kg/m2 and insulin use duration 8.6 ± 6.6 years (mean ± SD), 56.2% were males. After 3-6 months, 234 complete cases (83 FSL, 151 SMBG users) demonstrated significantly reduced HbA1c for FSL use compared to SMBG (0.3% ± 0.12 [3 mmol/mol ± 1.3, (mean ± SE)], p = 0.0112). The difference remained statistically significant after adjusting for confounders. CONCLUSIONS: HbA1c significantly improved in basal-bolus treated type 2 diabetes after flash glucose monitoring use for 3-6 months compared to SMBG.
Assuntos
Diabetes Mellitus Tipo 2 , Insulinas , Idoso , Glicemia , Automonitorização da Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose , Hemoglobinas Glicadas/análise , Controle Glicêmico , Humanos , Hipoglicemiantes , Insulina , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Several new oral antidiabetic agents, known as 'gliptins' or 'enzyme dipeptidyl peptidase-IV (DPP-4) inhibitors', have been developed for the treatment of type 2 diabetes and a key clinical use of the gliptins is in combination with metformin. There are important differences in the kinetics of the interaction of different gliptins with the catalytic site of DPP-4, which may lead to varying pharmacokinetics, pharmacodynamics and dosing regimens. Therefore, individual gliptins need to be characterized and here we discuss the extensively studied DPP-4 inhibitor vildagliptin, which has binding characteristics that ensure inhibition of the enzyme beyond the presence of detectable drug levels in plasma. As vildagliptin has been used most often at doses of 50 mg once or twice daily, in combination with metformin, this review focuses on these dose regimens. All clinical trials employing vildagliptin (50 mg once or twice daily) as an add-on therapy to metformin (identified by MEDLINE search using keywords vildagliptin and metformin or known by authors to be in press) are reviewed, as is current knowledge of the mechanism of action of vildagliptin. Vildagliptin added to a stable dose of metformin elicits a dose-related decrease in both HbA1c and fasting plasma glucose. The additional efficacy seen with 50 mg twice daily [ΔHbA1c â¼- 1.1% (-12.1 mmol/mol)] relative to 50 mg once daily [ΔHbA1c â¼- 0.7% (-7.7 mmol/mol)] is attributable to an overnight effect of the evening dose of vildagliptin, with prolonged DPP-4 inhibition and elevated fasting levels of the intact and insulinotropic form of glucagon-like peptide-1 (GLP-1). Vildagliptin's therapeutic actions are primarily mediated by GLP-1 and metformin enhances vildagliptin's effect to raise plasma levels of intact GLP-1. Vildagliptin is weight-neutral and has a very low hypoglycaemic potential, explained by its remarkable ability to enhance both α-cell and ß-cell sensitivity to glucose. Therefore, vildagliptin offers a clinically important outcome when added to metformin with a twice daily dose regimen, taking advantage of its tight binding and slow dissociation characteristics that lead to a sustained overnight effect.
Assuntos
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Nitrilas/administração & dosagem , Pirrolidinas/administração & dosagem , Adamantano/administração & dosagem , Adamantano/farmacocinética , Esquema de Medicação , Quimioterapia Combinada , Medicina Baseada em Evidências , Humanos , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Nitrilas/farmacocinética , Pirrolidinas/farmacocinética , Resultado do Tratamento , VildagliptinaRESUMO
AIM: To assess the efficacy and safety of adding alogliptin versus uptitrating pioglitazone in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone. METHODS: In this randomized, double-blind, active-controlled, parallel-group study, patients with type 2 diabetes and A1c ≥7.0 and ≤10.0% on metformin (≥1500 mg or maximum tolerated dose; Met) and pioglitazone 30 mg (Pio30) received alogliptin 25 mg (Alo25; n = 404) or pioglitazone 15 mg (n = 399) added to Met+Pio30 for 52 weeks. The primary endpoint was change from baseline (CFB) in A1c at weeks 26 and 52, with sequential testing for non-inferiority of Met+Pio30+Alo25 at weeks 26 and 52 and then for superiority at week 52. RESULTS: Met+Pio30+Alo25 showed superior glycaemic control versus Met+Pio45 at week 52 [least squares (LS) mean CFB in A1c, -0.70 vs. -0.29%; p < 0.001]. At week 52, Met+Pio30+Alo25 resulted in greater CFB in A1c regardless of baseline A1c (p < 0.001); higher proportions of patients achieving A1c ≤7.0 (33.2 vs. 21.3%) and ≤6.5% (8.7 vs. 4.3%; p < 0.001); greater CFB in fasting plasma glucose (FPG; LS mean CFB, -0.8 vs. -0.2 mmol/L; p < 0.001); and greater improvements in measures of ß-cell function (p < 0.001). Hypoglycaemia incidence was low (Met+Pio30+Alo25, 4.5%; Met+Pio45, 1.5%), mostly mild to moderate, but with two severe events in the Met+Pio30+Alo25 group. No meaningful differences in incidences of individual adverse events were observed between treatments. CONCLUSIONS: Adding alogliptin to an existing metformin-pioglitazone regimen provided superior glycaemic control and potentially improved ß-cell function versus uptitrating pioglitazone in patients with type 2 diabetes, with no clinically important differences in safety.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Piperidinas/uso terapêutico , Tiazolidinedionas/uso terapêutico , Uracila/análogos & derivados , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Esquema de Medicação , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Dose Máxima Tolerável , Metformina/administração & dosagem , Pessoa de Meia-Idade , Pioglitazona , Piperidinas/administração & dosagem , Tiazolidinedionas/administração & dosagem , Resultado do Tratamento , Uracila/administração & dosagem , Uracila/uso terapêuticoAssuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas/metabolismo , Hipoglicemiantes/uso terapêutico , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Humanos , Modelos Lineares , Valor Preditivo dos Testes , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Resultado do TratamentoRESUMO
T cells play a major role in the development of insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. Administration of interleukin 12 (IL-12), a key cytokine which guides the development of T helper type 1 (Th1) CD4+ T cells, induces rapid onset of IDDM in NOD, but not in BALB/c mice. Histologically, IL-12 administration induces massive infiltration of lymphoid cells, mostly T cells, in the pancreatic islets of NOD mice. CD4+ pancreas-infiltrating T cells, after activation by insolubilized anti T cell receptor antibody, secrete high levels of interferon gamma and low levels of IL-4. Therefore, IL-12 administration accelerates IDDM development in genetically susceptible NOD mice, and this correlates with increased Th1 cytokine production by islet-infiltrating cells. These results hold implications for the pathogenesis, and possibly for the therapy of IDDM and of other Th1 cell-mediated autoimmune diseases.
Assuntos
Doenças Autoimunes/imunologia , Diabetes Mellitus Tipo 1/imunologia , Interleucina-12/farmacologia , Linfócitos T/imunologia , Animais , Doenças Autoimunes/etiologia , Células CHO , Cricetinae , Diabetes Mellitus Tipo 1/etiologia , Feminino , Interferon gama/biossíntese , Interleucina-12/administração & dosagem , Interleucina-4/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismoRESUMO
AIMS: We previously demonstrated the presence of two different populations among adult-onset autoimmune diabetes (latent autoimmume diabetes of adults; LADA) having high or low titre of antibodies to glutamic acid decarboxylase (GADA). The transcription factor 7-like 2 (TCF7L2) gene has been recognized as the major gene associated with Type 2 diabetes. The aim of the present study was to evaluate whether the phenotypic heterogeneity of LADA based on GADA titre is associated with TCF7L2 polymorphisms. METHODS: Two hundred and fifty patients identified as LADA, divided into two subgroups with low (< or = 32 arbitrary units) or high (> 32 units) GADA titre, 620 subjects with Type 2 diabetes [from the Non-Insulin Requiring Autoimmune Diabetes (NIRAD) study cohort of 5330 subjects] in addition to 551 consecutive cases of Type 1 diabetes and 545 normoglycaemic subjects were analysed for the rs12255372 and rs7903146 polymorphisms of the TCF7L2 gene using Taqman. RESULTS: The genotype and allele distributions of the two polymorphisms revealed similar frequencies in subjects with low GADA titre and Type 2 diabetes. High GADA titre, Type 1 diabetes and controls also showed comparable frequencies. A significant increase of GT/TT genotypes of the rs12255372 single-nucleotide polymorphism (SNP) and CT/TT genotypes of the rs7903146 SNP was observed in low GADA titre and Type 2 diabetes compared with high GADA titre, Type 1 diabetes and controls (P < or = 0.04 for both comparisons). The risk alleles of both variants were increased in low GADA titre and Type 2 diabetes compared with high GADA titre, Type 1 diabetes and control subjects (P < 0.02 for all comparisons). CONCLUSIONS: TCF7L2 common genetic variants of susceptibility are associated only with low GADA antibody titre in LADA patients.
Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Glutamato Descarboxilase/genética , Adulto , Idade de Início , Autoanticorpos/imunologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 2/imunologia , Feminino , Predisposição Genética para Doença , Glutamato Descarboxilase/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Estatística como Assunto , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/imunologiaRESUMO
Metformin is a cornerstone of oral antidiabetic treatment. Recent joint American and European guidelines recommend instituting metformin therapy along with lifestyle modification at the time type 2 diabetes mellitus (T2DM) is diagnosed. Metformin acts to reduce hepatic gluconeogenesis and improve glucose uptake, and it may exert protective effects on pancreatic islet cells. Although metformin therapy produces substantial reductions in HbA1c, it does not produce body weight gain, is not associated with substantial risk for hypoglycaemia and has neutral to positive effects on lipids and blood pressure. The major adverse events associated with metformin are gastrointestinal. T2DM progresses even with initially effective monotherapy, and most patients will therefore receive combination therapy. When selecting agents to coadminister with metformin, a physician must consider efficacy in glycaemic control, safety, tolerability and any effects that may compromise overall efficacy (e.g. effects on body weight, lipids or blood pressure). In this regard, incretin-based therapies have characteristics that make them particularly suitable for add-on therapy with metformin.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Peso Corporal/efeitos dos fármacos , Medicina Baseada em Evidências , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Metformina/efeitos adversos , Metformina/farmacologia , Resultado do TratamentoRESUMO
AIM: To compare the efficacy and safety of vildagliptin and metformin initial combination therapy with individual monotherapies in treatment-naive patients with type 2 diabetes mellitus (T2DM). METHODS: This was a 24-week, randomized, double-blind, active-controlled study. Treatment-naive patients with T2DM who had a glycated haemoglobin (HbA(1c)) of 7.5-11% (N = 1179) were randomized equally to receive vildagliptin plus high-dose metformin combination therapy (50 mg + 1000 mg twice daily), vildagliptin plus low-dose metformin combination therapy (50 mg + 500 mg twice daily), vildagliptin monotherapy (50 mg twice daily) or high-dose metformin monotherapy (1000 mg twice daily). The primary objective was to demonstrate that HbA(1c) reduction from baseline with either combination therapy is superior to both monotherapies at the week 24 endpoint. Patients who failed glycaemic-screening criteria [HbA(1c )>11% or fasting plasma glucose (FPG) >15 mmol/l (270 mg/dl)] could enter a 24-week, single-arm substudy. These patients (N = 94) received open-label vildagliptin plus high-dose metformin combination therapy (100 mg + 1000 mg twice daily). RESULTS: From comparable baseline values (8.6-8.7%), HbA(1c) decreased in all four treatment groups, to the greatest extent with vildagliptin plus high-dose metformin combination therapy. Mean (SE) HbA(1c) change from baseline was -1.8% (0.06%), -1.6% (0.06%), -1.1% (0.06%) and -1.4% (0.06%) with vildagliptin plus high-dose metformin combination therapy, vildagliptin plus low-dose metformin combination therapy, and vildagliptin and metformin monotherapies respectively. The between-group difference was superior with vildagliptin plus high-dose metformin combination therapy (p < 0.001 vs. both monotherapies) and vildagliptin plus low-dose metformin combination therapy (p < 0.001 and p = 0.004, vs. vildagliptin and metformin monotherapies, respectively). Higher baseline HbA(1c) values were linked to greater HbA(1c) reductions, with changes of -3.2% (0.22%), -2.7% (0.22%), -1.5% (0.24%) and -2.6% (0.26%) respectively, occurring in patients with baseline HbA(1c)>or=10%. Reductions in FPG were superior with vildagliptin plus high-dose metformin combination therapy [change from baseline -2.63 (0.13) mmol/l] compared with both monotherapies [-1.26 (0.13) mmol/l and -1.92 (0.13) mmol/l, respectively; p < 0.001]. There was no incidence of hypoglycaemia or severe hypoglycaemia with either combination therapy, and neither was associated with weight gain. All treatments were well tolerated and displayed a comparable incidence of adverse events overall. Despite superior HbA(1c) lowering, the vildagliptin plus low-dose metformin combination therapy group demonstrated a favourable gastrointestinal (GI) tolerability profile compared with metformin monotherapy. CONCLUSIONS: In treatment-naive patients, combinations of vildagliptin and both high-dose and low-dose metformin provide superior efficacy to monotherapy treatments with a comparable overall tolerability profile and low risk of hypoglycaemia. The potential dose-sparing effect of adding vildagliptin to low-dose metformin in preference to the up-titration of metformin may allow patients to achieve equivalent or superior HbA(1c) lowering without the GI tolerability issues associated with higher doses of metformin.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Adamantano/análogos & derivados , Adulto , Idoso , América , Método Duplo-Cego , Quimioterapia Combinada , Europa (Continente) , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Nitrilas , Pirrolidinas , Resultado do Tratamento , Vildagliptina , Adulto JovemRESUMO
AIMS: The study evaluated the efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor, vildagliptin, and metformin in drug-naïve elderly patients with type 2 diabetes. The primary objective was to demonstrate non-inferiority of vildagliptin vs. metformin in glycated haemoglobin (HbA1c) reduction. METHODS: This was a double-blind, randomized, multicentre, active-controlled, parallel-group study of 24-week treatment with vildagliptin (100 mg daily, n=169) or metformin (titrated to 1500 mg daily, n=166) in drug-naïve patients with type 2 diabetes aged>or=65 years (baseline HbA1c 7-9%). RESULTS: Participants had a mean age of 71 years, known duration of diabetes of 3 years and mean baseline HbA1c of 7.7%. At end-point, vildagliptin was as effective as metformin, improving HbA1c by -0.64+/-0.07% and -0.75+/-0.07%, respectively, meeting the predefined statistical criterion for non-inferiority (upper limit of 95% confidence interval for between-treatment differenceAssuntos
Adamantano/análogos & derivados
, Diabetes Mellitus Tipo 2/tratamento farmacológico
, Inibidores da Dipeptidil Peptidase IV/uso terapêutico
, Hipoglicemiantes/uso terapêutico
, Metformina/uso terapêutico
, Nitrilas/uso terapêutico
, Pirrolidinas/uso terapêutico
, Adamantano/efeitos adversos
, Adamantano/uso terapêutico
, Idoso
, Idoso de 80 Anos ou mais
, Glicemia
, Peso Corporal/efeitos dos fármacos
, Inibidores da Dipeptidil Peptidase IV/efeitos adversos
, Método Duplo-Cego
, Quimioterapia Combinada
, Feminino
, Gastroenteropatias/epidemiologia
, Hemoglobinas Glicadas/efeitos dos fármacos
, Humanos
, Hipoglicemia/epidemiologia
, Hipoglicemiantes/efeitos adversos
, Incidência
, Masculino
, Metformina/efeitos adversos
, Nitrilas/efeitos adversos
, Pirrolidinas/efeitos adversos
, Vildagliptina
RESUMO
In this study we analyzed the role of CCL2, a member of the chemokine family, in early graft damage. Using simultaneous kidney-pancreas transplantation (SPK) as a model, we showed that brain death significantly increases circulating CCL2 levels in humans. We found that in such situations, high donor CCL2 levels (measured before organ recovery and at the onset of cold preservation) correlate with increased postreperfusion release of CCL2 by both the graft and recipient throughout the week following transplantation (n = 28). In a retrospective study of 77 SPK recipients, we found a significant negative association between high donor levels of CCL2 and graft survival. Decreased survival in these patients is related to early posttransplant complications, including a higher incidence of pancreas thrombosis and delayed kidney function. Taken together our data indicate that high CCL2 levels in the donor serum predict both an increase in graft/recipient CCL2 production and poor graft survival. This suggests that the severity of the inflammatory response induced by brain death influences the posttransplant inflammatory response, independent of subsequent ischemia and reperfusion.
Assuntos
Morte Encefálica/imunologia , Quimiocina CCL2/sangue , Sobrevivência de Enxerto/imunologia , Transplante de Rim/imunologia , Transplante de Pâncreas/imunologia , Adulto , Quimiocina CCL2/imunologia , Função Retardada do Enxerto , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/cirurgia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/cirurgia , Feminino , Humanos , Falência Renal Crônica/etiologia , Falência Renal Crônica/cirurgia , Masculino , Valor Preditivo dos Testes , Estudos Retrospectivos , Doadores de Tecidos , Tolerância ao TransplanteRESUMO
BACKGROUND: The study was performed to determine whether sucrose-induced insulin resistance could increase the expression of cardiac matrix metalloproteinases (MMPs), indices of matrix remodelling, and whether the addition of 1.25 g day(-1) of L-arginine (ARG) to a sucrose diet could prevent both the sucrose-induced metabolic abnormalities and elevated cardiac expression of matrix metalloproteinases in an insulin resistant stage that precedes frank type 2 diabetes. MATERIALS AND METHODS: Experiments were performed on 38 male Sprague-Dawley rats, 16 rats maintained a standard chow diet (ST), 12 rats were switched to a sucrose enriched diet (SU) and 10 rats to a sucrose plus L-arginine (1.25 g day(-1)) enriched diet (SU + ARG) for a period of 8 weeks. After 8 weeks of different diets, an intravenous glucose tolerance test (IVGTT) was performed and samples were drawn for the measurements of insulin, glucose, triglycerides, free fatty acids (FFA), plasma cyclic guanosine-monophosphate (c-GMP) and retroperitoneal, omental, epididymal fat pad and heart were dissected and weighed. RESULTS: At the end of the study, retroperitoneal fat, heart weight/body weight ratio, fasting plasma glucose, serum insulin, and serum triglyceride levels and integrated insulin area after IVGTT were significantly higher in SU than in SU + ARG and ST. All these parameters were comparable between SU + ARG and ST animals. FFA levels were significantly different among groups, with highest levels in SU and lowest levels in ST. Fasting plasma c-GMP levels and the integrated c-GMP area after IVGTT, an index of nitric oxide activity, were significantly lower in SU than in SU + ARG and ST, the result was similar in SU + ARG and in ST MMP-9 protein expression increased 10.5-fold, MMP-2 protein expression increased 2.4-fold and the expression of tissue inhibitors of metalloproteinase (TIMP-1) increased 1.7-fold in SU rats as compared to ST animals. This was accompanied with a significant increase of cardiac triglyceride concentrations. In contrast, cardiac MMP-9, MMP-2, and TIMP-1 protein expressions were not different between SU + ARG and ST animals. Cardiac triglyceride levels were not significantly different between SU + ARG and ST rats. CONCLUSIONS: SU rats developed insulin resistance and hyperlipidaemia, accompanied with increased fat deposition in the heart and enhanced MMP protein expression. Conversely, ARG supplementation prevents these metabolic abnormalities and restored MMP/TIMP-1 balance.
Assuntos
Arginina/farmacologia , Sacarose Alimentar/farmacologia , Resistência à Insulina/fisiologia , Insulina/farmacologia , Metaloproteinases da Matriz/metabolismo , Síndrome Metabólica/dietoterapia , Tecido Adiposo/patologia , Animais , Arginina/administração & dosagem , Glicemia/metabolismo , Suplementos Nutricionais , Ácidos Graxos não Esterificados/metabolismo , Teste de Tolerância a Glucose , Coração/efeitos dos fármacos , Coração/fisiopatologia , Insulina/administração & dosagem , Insulina/sangue , Masculino , Metaloproteinases da Matriz/efeitos dos fármacos , Síndrome Metabólica/metabolismo , Ratos , Ratos Sprague-Dawley , Triglicerídeos/metabolismoRESUMO
CONTEXT: Hypokalemic periodic paralysis (HypoPP) is a rare disorder consisting of sudden episodes of muscle weakness with areflexia involving all four limbs, which spontaneously resolve within several hours or days. Primary HypoPP is genetically determined, while secondary acquired HypoPP has been described in association with thyreotoxycosis, hyperaldosteronism, kidney diseases, diuretics and liquorice abuse, gastrointestinal potassium loss, or cysplatinum therapy. OBJECTIVE: To report a case of HypoPP associated with GH deficiency. PATIENT: A 33 yr-old man with hypopituitarism and diabetes insipidus secondary to pituitary stalk-localized sarcoidosis, and documented HypoPP episodes. CLINICAL PRESENTATION: Neurologic exam outside HypoPP episodes was normal. Needle electromyography was normal without myotonia or other spontaneous electric activity. Muscle biopsy documented a vacuolar myopathy with tubular aggregates. However, genetic analysis ruled out common mutations of the voltage-gated calcium channel observed in primary HypoPP. Common causes of secondary HypoPP were also ruled out. The patient was diagnosed with severe GH deficiency with modest fasting hyperinsulinemia and insulin resistance and started on GH replacement therapy, an alpha-glucosidase inhibitor (acarbose) and a diet low in simple carbohydrates. CONCLUSIONS: GH replacement therapy, acarbose and a diet low in simple carbohydrates resulted in the complete long-term (>2 yr) remission of HypoPP episodes. This is consistent with the hypothesis that the hyperinsulinemia associated to GH deficiency may trigger HypoPP episodes by increasing Na+/K+ ATPase activity and K+ transport into the intracellular compartment with subsequent hypokalemia.
Assuntos
Nanismo Hipofisário/complicações , Paralisia Periódica Hipopotassêmica/etiologia , Adulto , Nanismo Hipofisário/tratamento farmacológico , Nanismo Hipofisário/patologia , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Paralisia Periódica Hipopotassêmica/tratamento farmacológico , Paralisia Periódica Hipopotassêmica/patologia , Masculino , Músculos/patologiaRESUMO
BACKGROUND: Although hyperglycemia is a strong predictor of postoperative infective complications (PIC), little is known about the effect of basal insulin therapy (BIT) per se on PIC. AIM: To evaluate if there is an association between BIT, independent of glucose levels, and a possible improvement of PIC during the perioperative cardiosurgery period (PCP). METHODS: In 812 patients admitted for cardiac intervention and treated with a continuous intravenous insulin infusion (CIII) for hyperglycemic levels (>130 mg/dl), a retrospective analysis was performed during the PCP (January 2009-December 2011). Upon transfer to the cardiac surgery division, if fasting glucose was ≥130 mg/dl, a basal + premeal insulin therapy was initiated (121 patients, group 1); for <130 mg/dl, a premeal insulin alone was initiated (691 patients, group 2). FINDINGS: Compared with group 2, group 1 showed reductions in PIC (2.48% vs 7.96%, p < 0.049; odds ratio: 0.294; 95% CI: 0.110-0.780), C-Reactive Protein (p < 0.05) and white blood cell (p < 0.05) levels despite glucose levels and CIII that were higher during the first two days after surgery (179.8 ± 25.3 vs 169.5 ± 10.6 mg/dl, p < 0.01; 0.046 ± 0.008 vs 0.037 ± 0.015 U/kg/h, p < 0.05, respectively). Normal glucose levels were achieved in both groups from day 3 before the discharge. The mean length of hospital duration was 18% lower in group 1 than in group 2 (7.21 ± 05.08 vs 8.76 ± 9.08 days, p < 0.007), providing a significant impact on public health costs. CONCLUSIONS: Basal + preprandial insulin therapy was associated with a lower frequency of PIC than preprandial insulin therapy alone, suggesting a beneficial effect of basal insulin therapy on post-surgery outcome.
RESUMO
OBJECTIVE: To characterize the phenotype of a large population of Italian patients with adult onset (> or =40 years) diabetes who were attending outpatient clinics and who were screened for glutamic acid decarboxylase 65 autoantibodies (GADA), protein tyrosine phosphatase IA-2 (IA-2A) and IA-2beta/phogrin (IA-2betaA). DESIGN AND METHODS: This was a cross-sectional study comprising a total of 881 patients, aged < or = 70 years, diagnosed with type 2 diabetes after the age of 40 years, and consecutively recruited in five clinics located in different geographic areas of Italy (Milan, Florence, Rome, Naples and Catania). Their mean disease duration was 8.1 (6.9; s.d.) years. GADA, IA-2A and IA-2betaA were measured with radiobinding assays with in vitro translated S-methionine-labelled glutamic acid decarboxylase 65 (GAD65) or IA-2 or IA-2beta. Anthropometric and clinical data were collected and compared amongst patients with or without autoantibodies. RESULTS: Sixty-three (7.1%) patients had one or more autoantibodies, 58 (6.6%) had GADA, 22 (2.5%) had IA-2A, six (0.7%) had IA-2betaA and 19 (2.15%) had two or more autoantibodies. IA-2A or IA-2betaA, in the absence of GADA, were found in only five patients. Autoantibody-positive patients were more often female (63.5 vs 36.5%; P < 0.009), had higher glycated haemoglobin (Hb A1c) (P < 0.001), lower body mass index (BMI; P < 0.0005) and waist/hip ratio (WHR; P < 0.01); female gender being the main contributor to BMI and WHR. We did not observe any differences in age at diagnosis or duration of disease with respect to the presence or absence of islet autoantibodies. The proportion of patients on insulin therapy was higher in patients with two or more antibodies, compared with those with one antibody only, and no antibodies (P for trend < 0.001), and among patients with GADA, in those with higher antibody titre (73.9% in those with > 10 units vs 42.0% in those with < or = 10 units; P < 0.007). CONCLUSIONS: Patients with adult onset diabetes characterized by autoimmunity to beta-cells showed a clinical phenotype with anthropometric features that differed from those classically observed in patients with type 2 diabetes. The number and titre of autoantibodies, which reflect the severity of autoimmunity and beta-cell impairment, amplified this difference. The usefulness of autoantibody screening in adult-onset diabetes is further emphasized by these findings.