RESUMO
Immune checkpoint inhibitors are now the standard of care in the treatment of several types of cancer. Cutaneous immune-related adverse events (irAEs) are usually of low grade and reversible, while endocrine irAEs are generally irreversible and managed with hormone replacement therapy. We report a 47-year-old patient, treated with the anti-programmed cell death (PD)1 antibody pembrolizumab for a metastatic melanoma, who developed severe lipodystrophy after 10 months of treatment, characterized by the loss of subcutaneous fat tissue, central obesity and insulin resistance with a decreased leptin level. Histological analysis of a cutaneous biopsy revealed subcutaneous fat cell destruction associated with oedema, the presence of lipophages, and a CD3+ lymphocytic infiltrate involving the panniculus. This led to the diagnosis of anti-PD-1-induced acquired generalized lipodystrophy, after ruling out differential diagnoses (i.e. genetic and systemic autoimmune diseases). No corticosteroids were introduced considering the high risk of inducing severe metabolic complications, and pembrolizumab was discontinued as complete response of the melanoma was achieved. However, after 12 months of follow-up, lipodystrophy and its severe metabolic complications are still ongoing. What's already known about this topic? Anti-programmed cell death (PD)1 agents are now a standard of care in the treatment of several cancers, including melanoma. Endocrine and cutaneous immune-related adverse events (irAEs) are among the most frequent irAEs (14-30% and 30-40%, respectively) in patients treated with immune checkpoint inhibitors. What does this study add? Acquired generalized lipodystrophy can occur during anti-PD1 therapy and is associated with severe metabolic complications. With the increase in anti-PD1 prescription in several cancer types, clinicians must be aware of the whole range of irAEs that may occur.
Assuntos
Lipodistrofia Generalizada Congênita , Melanoma , Anticorpos Monoclonais Humanizados , Humanos , Inibidores de Checkpoint Imunológico , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1RESUMO
Recombinant methionyl human leptin (metreleptin) therapy was shown to improve hyperglycaemia, dyslipidaemia and insulin sensitivity in patients with lipodystrophic syndromes, but its effects on insulin secretion remain controversial. We used dynamic intravenous (i.v.) clamp procedures to measure insulin secretion, adjusted to insulin sensitivity, at baseline and after 1 year of metreleptin therapy, in 16 consecutive patients with lipodystrophy, diabetes and leptin deficiency. Patients, with a mean [± standard error of the mean (s.e.m.)] age of 39.2 (±4) years, presented with familial partial lipodystrophy (n = 11, 10 women) or congenital generalized lipodystrophy (n = 5, four women). Their mean (± s.e.m.) BMI (23.9 ± 0.7 kg/m(2) ), glycated haemoglobin levels (8.5 ± 0.4%) and serum triglycerides levels (4.6 ± 0.9 mmol/l) significantly decreased within 1 month of metreleptin therapy, then remained stable. Insulin sensitivity (from hyperglycaemic or euglycaemic-hyperinsulinaemic clamps, n = 4 and n = 12, respectively), insulin secretion during graded glucose infusion (n = 12), and acute insulin response to i.v. glucose adjusted to insulin sensitivity (disposition index, n = 12), significantly increased after 1 year of metreleptin therapy. The increase in disposition index was related to a decrease in percentage of total and trunk body fat. Metreleptin therapy improves not only insulin sensitivity, but also insulin secretion in patients with diabetes attributable to genetic lipodystrophies.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Leptina/análogos & derivados , Lipodistrofia/genética , Adulto , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hiperglicemia/induzido quimicamente , Hipolipemiantes/uso terapêutico , Insulina/administração & dosagem , Resistência à Insulina/fisiologia , Secreção de Insulina , Lamina Tipo A/genética , Leptina/deficiência , Leptina/uso terapêutico , Lipodistrofia/tratamento farmacológico , Masculino , Mutação/genética , Síndrome , Triglicerídeos/metabolismoRESUMO
AIM: Glucagon-like peptide-1 (GLP-1) receptor agonists improve islet function and delay gastric emptying in patients with type 2 diabetes mellitus (T2DM). This meta-analysis aimed to investigate the effects of the once-daily prandial GLP-1 receptor agonist lixisenatide on postprandial plasma glucose (PPG), glucagon and insulin levels. METHODS: Six randomized, placebo-controlled studies of lixisenatide 20 µg once daily were included in this analysis: lixisenatide as monotherapy (GetGoal-Mono), as add-on to oral antidiabetic drugs (OADs; GetGoal-M, GetGoal-S) or in combination with basal insulin (GetGoal-L, GetGoal-Duo-1 and GetGoal-L-Asia). Change in 2-h PPG and glucose excursion were evaluated across six studies. Change in 2-h glucagon and postprandial insulin were evaluated across two studies. A meta-analysis was performed on least square (LS) mean estimates obtained from analysis of covariance (ANCOVA)-based linear regression. RESULTS: Lixisenatide significantly reduced 2-h PPG from baseline (LS mean difference vs. placebo: -4.9 mmol/l, p < 0.001) and glucose excursion (LS mean difference vs. placebo: -4.5 mmol/l, p < 0.001). As measured in two studies, lixisenatide also reduced postprandial glucagon (LS mean difference vs. placebo: -19.0 ng/l, p < 0.001) and insulin (LS mean difference vs. placebo: -64.8 pmol/l, p < 0.001). There was a stronger correlation between 2-h postprandial glucagon and 2-h PPG with lixisenatide than with placebo. CONCLUSIONS: Lixisenatide significantly reduced 2-h PPG and glucose excursion together with a marked reduction in postprandial glucagon and insulin; thus, lixisenatide appears to have biological effects on blood glucose that are independent of increased insulin secretion. These effects may be, in part, attributed to reduced glucagon secretion.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/agonistas , Glucagon/sangue , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Peptídeos/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Esvaziamento Gástrico/efeitos dos fármacos , Glucagon/efeitos dos fármacos , Glucagon/metabolismo , Hemoglobinas Glicadas/metabolismo , Humanos , Insulina/sangue , Secreção de Insulina , Período Pós-Prandial , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The outbreak of COVID-19 led to an unprecedented inflow of hospitalised patients with severe acute respiratory syndrome (SARS), requiring high-flow non-invasive oxygenation, if not invasive mechanical ventilation. While the best option in terms of non-invasive systems of oxygen delivery is still a matter of debate, it also remains unclear as to whether or not the optimal in-bed positioning of patients might also help to improve their oxygen saturation levels. On the basis of three representative cases, it is possible to propose the following hypotheses: (i) how patients are positioned has a strong influence on their oxygen saturation levels; (ii) saturation-optimalised positions are patient-specific; (iii) prone positions require ergonomic devices; and (iv) saturation-optimalised positions should aim to place the most affected part(s) of the lung(s) on top. Considered together, these hypotheses have led us to recommend that COVID-19 patients should undergo a specific assessment at admission to determine their saturation-optimalised in-bed position. However, further studies are still needed to assess the benefits of such a strategy on clinical outcomes.
Assuntos
COVID-19/terapia , Pulmão/diagnóstico por imagem , Idoso , COVID-19/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Equilíbrio Postural , Decúbito Ventral , Respiração Artificial , SARS-CoV-2 , Tomografia Computadorizada por Raios XRESUMO
AIM: To demonstrate non-inferiority of vildagliptin compared with gliclazide, as an add-on therapy, in patients with Type 2 diabetes inadequately controlled with metformin in a 52-week, randomized, double-blind, active-controlled study. METHODS: Patients receiving a stable dose of metformin (> or = 1500 mg) were randomized (1 : 1) to receive vildagliptin (50 mg twice daily; n = 513) or gliclazide (up to 320 mg/day; n = 494). RESULTS: Non-inferiority of vildagliptin was demonstrated (95% confidence interval -0.11%, 0.20%) with a mean change (se) from baseline glycated haemoglobin (HbA(1c)) (approximately 8.5% in both groups) to a 52-week endpoint of -0.81% (0.06) with vildagliptin and -0.85% (0.06) with gliclazide. Although a similar proportion of patients reached HbA(1c) < 7.0%, the total number of hypoglycaemic events was lower in the vildagliptin group (6 vs. 11 events). Vildagliptin was non-inferior (margin 0.6 mmol/l) to gliclazide in reducing fasting plasma glucose (1.31 vs. 1.52 mmol/l, P = 0.257). The overall incidence of any adverse events was similar in both groups (approximately 61%), but the number of serious adverse events was higher in the gliclazide group (8.7 vs. 6.7%). The number of patients who discontinued as a result of an unsatisfactory effect was higher in the vildagliptin group (n = 22 vs. 13, respectively) compared with gliclazide, but vildagliptin did not induce weight gain. CONCLUSION: In patients with Type 2 diabetes inadequately controlled with metformin, addition of vildagliptin provided similar HbA(1c)-lowering efficacy compared with gliclazide after 52 weeks of treatment. Although both treatments were well tolerated, vildagliptin-treated patients had fewer hypoglycaemic events and did not gain weight.
Assuntos
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Gliclazida/uso terapêutico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Nitrilas/uso terapêutico , Pirrolidinas/uso terapêutico , Adamantano/administração & dosagem , Adamantano/efeitos adversos , Adamantano/uso terapêutico , Adolescente , Adulto , Idoso , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Gliclazida/administração & dosagem , Gliclazida/efeitos adversos , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Nitrilas/efeitos adversos , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Vildagliptina , Adulto JovemRESUMO
BACKGROUND: Cardiovascular disease is a leading cause of mortality among patients with type 2 diabetes mellitus (T2DM). Numerous patients with T2DM show resistance to aspirin treatment, which may explain the higher rate of major adverse cardiovascular events observed compared with non-diabetes patients, and it has recently been shown that aspirin resistance is mainly related to accelerated platelet turnover with persistent high platelet reactivity (HPR) 24h after last aspirin intake. The mechanism behind HPR is unknown. The aim of this study was to investigate the precise rate and mechanisms associated with HPR in a population of T2DM patients treated with aspirin. METHODS: Included were 116 consecutive stable T2DM patients who had attended our hospital for their yearly check-up. HPR was assessed 24h after aspirin intake using light transmission aggregometry (LTA) with arachidonic acid (AA) and serum thromboxane B2 (TXB2) measurement. Its relationship with diabetes status, insulin resistance, inflammatory markers and coronary artery disease (CAD) severity, using calcium scores, were investigated. RESULTS: Using LTA, HPR was found in 27 (23%) patients. There was no significant difference in mean age, gender ratio or cardiovascular risk factors in patients with or without HPR. HPR was significantly related to duration of diabetes and higher fasting glucose levels (but not consistently with HbA1c), and strongly related to all markers of insulin resistance, especially waist circumference, HOMA-IR, QUICKI and leptin. There was no association between HPR and thrombopoietin or inflammatory markers (IL-6, IL-10, indoleamine 2,3-dioxygenase activity, TNF-α, C-reactive protein), whereas HPR was associated with more severe CAD. Similar results were found with TXB2. CONCLUSION: Our results reveal that 'aspirin resistance' is frequently found in T2DM, and is strongly related to insulin resistance and severity of CAD, but weakly related to HbA1c and not at all to inflammatory parameters. This may help to identify those T2DM patients who might benefit from alternative antiplatelet treatments such as twice-daily aspirin and thienopyridines.
Assuntos
Aspirina/uso terapêutico , Doença da Artéria Coronariana/diagnóstico por imagem , Diabetes Mellitus Tipo 2/sangue , Resistência a Medicamentos , Ativação Plaquetária , Inibidores da Agregação Plaquetária/uso terapêutico , Calcificação Vascular/diagnóstico por imagem , Idoso , Ácido Araquidônico , Proteína C-Reativa/metabolismo , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/sangue , Inflamação/metabolismo , Resistência à Insulina , Interleucina-10/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária , Testes de Função Plaquetária , Índice de Gravidade de Doença , Trombopoetina/sangue , Tromboxano B2/sangue , Fator de Necrose Tumoral alfa/sangueRESUMO
Mesenchymal stem cells (MSCs) are multipotent non-haematopoietic progenitor cells that are being explored as a promising new treatment for tissue regeneration. Although their immunomodulatory properties are not yet completely understood, their low immunogenic potential together with their effects on immune response make them a promising therapeutic tool for severe refractory autoimmune diseases. Type 1 diabetes is characterized by T cell-mediated autoimmune destruction of pancreatic beta cells. While insulin replacement represents the current therapy for type 1 diabetes, its metabolic control remains difficult, as exogenous insulin cannot exactly mimic the physiology of insulin secretion. Pancreatic or islet transplantation can provide exogenous insulin independence, but is limited by its intrinsic complications and the scarcity of organ donors. In this context, stem cell therapy, based on the generation of insulin-producing cells (IPCs) derived from MSCs, represents an attractive possibility. In this review, we provide a brief characterization of MSC immunomodulatory effects, and present the current experimental evidence for the potential therapeutic efficacy of MSC transplantation in diabetes.
Assuntos
Diabetes Mellitus Tipo 1/terapia , Células Secretoras de Insulina/citologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/fisiologia , Animais , Diferenciação Celular , Modelos Animais de Doenças , Humanos , Terapia de Imunossupressão , Células Secretoras de Insulina/fisiologia , Células-Tronco Mesenquimais/imunologiaRESUMO
AIM: Ketosis prone type 2 diabetes (KPD) is an atypical form of diabetes described mainly in people of sub-Saharan African origin. Its pathogenesis is unknown, although we have previously described a high prevalence of glucose-6-phosphate-dehydrogenase (G6PD) deficiency in patients with KPD. However, 50% of these deficient patients lacked the G6PD gene mutation. The isoforms of the transcription factor sterol regulatory element binding protein 1 (SREBP-1) are known to stimulate G6PD gene expression, and some polymorphisms in the SREBP-1 gene (SREBF-1) have been described only in Africans. We investigated one of these, the Arg585Gln polymorphism, in a candidate gene approach for KPD. METHODS: We examined the presence of the Arg585Gln polymorphism in SREBF-1 in 217 consecutive unrelated Africans [73 patients with KPD, 80 with classical type 2 diabetes (T2D) and 64 nondiabetic subjects]. Patients underwent clinical and biochemical evaluations, and were assessed for G6PD activity and insulin secretion (glucagon test). RESULTS: There were no differences in frequency of the Arg585Gln polymorphism and the 585Gln allele among the three groups (allele frequency: KPD: 0.089, T2D: 0.031, nondiabetic group: 0.070; P=0.1). When the 585Gln allele frequency was compared separately between patients with KPD and those with T2D, it was significantly higher in the former (P=0.032). There was no difference between carriers and noncarriers of the 585Gln allele regarding G6PD activity and insulin secretion. CONCLUSION: The results of this exploratory study show that the polymorphism Arg585Gln in SREBF-1 is not associated with the KPD phenotype. Further studies in larger populations are needed to confirm our findings.
Assuntos
Substituição de Aminoácidos , População Negra/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Polimorfismo Genético , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Adulto , Arginina , Peptídeo C/sangue , Estudos Transversais , Feminino , Glutamina , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
Ketosis-prone diabetes (KPD) is a phenotypically defined form of diabetes characterized by male predominance and severe insulin deficiency. Neurogenin3 (NGN3) is a proendocrine gene, which is essential for the fate of pancreatic beta cells. Mice lacking ngn3 develop early insulin-deficient diabetes. Thus, we hypothesized that gender and variants in NGN3 could predispose to KPD. We have studied clinical and metabolic parameters according to gender in patients with KPD (n = 152) and common type 2 diabetes (T2DM) (n = 167). We have sequenced NGN3 in KPD patients and screened gene variants in T2DM and controls (n = 232). In KPD, male gender was associated with a more pronounced decrease in beta-cell insulin secretory reserve, assessed by fasting C-peptide [mean (ng/ml) +/- s.d., M: 1.1 +/- 0.6, F: 1.5 +/- 0.9; p = 0.02] and glucagon-stimulated C-peptide [mean (ng/ml) +/- s.d., M: 2.2 +/- 1.1, F: 3.1 +/- 1.7; p = 0.03]. The rare affected females were in an anovulatory state. We found two new variants in the promoter [-3812T/C (af: 2%) and -3642T/C (af: 1%)], two new coding variants [S171T (af: 1%) and A185S (af: 1%)] and the variant already described [S199F (af: 69%)]. These variants were not associated with diabetes. Clinical investigation revealed an association between 199F and hyperglycaemia assessed by glycated haemoglobin [HbA1c (%, +/-s.d.) S199: 12.6 +/- 1.6, S199F: 12.4 +/- 1.4 and 199F: 14.1 +/- 2.2; p = 0.01]. In vitro, the P171T, A185S and S199F variants did not reveal major functional alteration in the activation of NGN3 target genes. In conclusion, male gender, anovulatory state in females and NGN3 variations may influence the pathogenesis of KPD in West Africans. This has therapeutic implications for potential tailored pharmacological intervention in this population.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diabetes Mellitus Tipo 2/etiologia , Cetoacidose Diabética/etiologia , Proteínas do Tecido Nervoso/genética , Regiões Promotoras Genéticas , Fatores Sexuais , Adulto , Anovulação , Biomarcadores/sangue , População Negra/genética , Peptídeo C/análise , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etnologia , Cetoacidose Diabética/sangue , Cetoacidose Diabética/etnologia , Feminino , Expressão Gênica , Genótipo , Glucagon , Humanos , Insulina/metabolismo , Secreção de Insulina , Masculino , Pessoa de Meia-IdadeRESUMO
The liver plays a pivotal role in energy metabolism. Under the control of hormones, especially insulin, the liver stores or releases glucose as needed by the body's systems. It is also responsible for an important part of non-esterified fatty-acid and aminoacid metabolism. Assessing hepatic insulin resistance is almost always synonymous with measuring hepatic glucose production (HGP) and calculating indices of hepatic insulin resistance. The most frequently used method to this end is the isotope dilution technique using a tracer. Among tracers, stable isotope-labelled glucose molecules are particularly advantageous over radioactive isotope-labelled glucose and are, therefore, the tracers of choice. The tracer is infused either on its own after an overnight fast to evaluate fasting HGP, or with some among the usual insulin-sensitivity tests to assess HGP suppression by insulin and/or glucose. In a fasting state, HGP is easily calculated whereas, during insulin or glucose infusion, some formula are needed to correct for the non-steady-state condition. The hepatic insulin-resistance index is the product of HGP and the corresponding plasma insulin concentration. Although subject to error, the isotope dilution method nevertheless remains an irreplaceable tool for assessing hepatic insulin resistance in clinical research. From a practical point of view, some easily obtainable indices and clinical or biochemical parameters can serve as surrogates or markers of hepatic insulin resistance in clinical practice. Finally, drugs such as metformin or glitazones can improve hepatic insulin resistance, hence their use in hepatic insulin-resistant states such as type 2 diabetes and non-alcoholic fatty liver disease.
Assuntos
Resistência à Insulina/fisiologia , Insulina/fisiologia , Fígado/fisiopatologia , Adulto , Radioisótopos de Carbono , Criança , Deutério , Metabolismo Energético , Ácidos Graxos não Esterificados/metabolismo , Feminino , Glucose/metabolismo , Humanos , Marcação por Isótopo , Fígado/metabolismo , Fígado/patologia , Modelos Biológicos , Gravidez , Técnica de Diluição de RadioisótoposRESUMO
Incretin hormones are defined as intestinal hormones released in response to nutrient ingestion, which potentiate the glucose-induced insulin response. In humans, the incretin effect is mainly caused by two peptide hormones, glucose-dependent insulin releasing polypeptide (GIP), and glucagon-like peptide-1 (GLP-1). GIP is secreted by K cells from the upper small intestine while GLP-1 is mainly produced in the enteroendocrine L cells located in the distal intestine. Their effect is mediated through their binding with specific receptors, though part of their biological action may also involve neural modulation. GIP and GLP-1 are both rapidly degraded into inactive metabolites by the enzyme dipeptidyl-peptidase-IV (DPP-IV). In addition to its effects on insulin secretion, GLP-1 exerts other significant actions, including stimulation of insulin biosynthesis, inhibition of glucagon secretion, inhibition of gastric emptying and acid secretion, reduction of food intake, and trophic effects on the pancreas. As the insulinotropic action of GLP-1 is preserved in type 2 diabetic patients, this peptide was likely to be developed as a therapeutic agent for this disease.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Polipeptídeo Inibidor Gástrico/fisiologia , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Incretinas/fisiologia , Insulina/metabolismo , Animais , Humanos , Incretinas/biossíntese , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiologia , Células Matadoras Naturais/metabolismo , Proglucagon/fisiologiaRESUMO
AIM: Alteration of functional beta-cell mass in adults can be programmed by adverse events during fetal life. Previously, it was demonstrated that high glucocorticoid (GC) levels during fetal life participate in this programming by inhibition of beta-cell development. More specifically, GC levels stimulate expression of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), a transcriptional co-regulator of the GC receptor (GR), which per se impairs beta-cell mass and function when overexpressed. As PGC-1α is also a potent inducer of mitochondrial biogenesis, our study aimed to determine how PGC-1α modifies mitochondrial function in beta cells and how it might regulate insulin secretion. METHODS: Beta-cell function was studied in mice overexpressing PGC-1α specifically in beta cells and in MIN6 cells overexpressing PGC-1α in vitro. RESULTS: PGC-1α overexpression in beta cells in vivo leads to a reduced beta-cell mass early in fetal life, whereas PGC-1α overexpression in vitro stimulates mitochondrial biogenesis and respiratory activity without improving ATP production, while increasing oxidative stress and impairing insulin secretion in response to glucose. While oxidative stress with PGC-1α overexpression in beta cells activates AMPK, it has also been revealed that blocking such oxidative stress or AMPK activation restores insulin secretion. CONCLUSION: PGC-1α induces oxidative stress, which disrupts insulin secretion by AMPK activation. Thus, control of oxidative or energetic stress in beta cells may help to restore insulin secretion.
Assuntos
Células Secretoras de Insulina/metabolismo , Estresse Oxidativo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Animais , Insulina/metabolismo , Camundongos , Camundongos Transgênicos , Consumo de Oxigênio/genéticaRESUMO
AIMS: To facilitate the transition from urine ketones (acetoacetate) to capillary blood ketones (3-beta-hydroxybutyrate), we studied the correlation between these two tests. METHODS: Retrospective study of all patients with blood glucose greater than or equal to 2.5 g/l on arrival in the Emergency Department. We studied the correlation between urine ketones (Clinitek 50, Bayer) and capillary blood ketones (Optium, Abbott). We then compared the relative risks (RR) of ketoacidosis and hospitalization associated with each of these tests. RESULTS: In 33 months, 529 adult patients with both urine and blood testing for ketones were enrolled (ketoacidosis 8%, admission rate 49%). Urine ketones scored as +, ++ and +++ corresponded to median capillary blood ketone levels of 0.5 mmol/l (IQR: 0.1-0.9), 0.7 mmol/l (IQR: 0.2-1.8) and 3 mmol/l (IQR: 1.4-5.2), respectively. RRs of ketoacidosis or hospitalization associated with blood ketones greater than or equal to 3 mmol/l were higher than those associated with +++ urine ketones: 74 (95% confidence interval [CI]: 48-88) and 2.9 (95% CI: 2.5-3) versus 31 (95% CI: 18-45) and 2 (95% CI: 1.7-2.1), respectively. CONCLUSIONS: In hyperglycaemic patients in the Emergency Department, a good correlation was observed between urine ketones and capillary blood ketones for low values, but a poor correlation was observed for high values. Either test can therefore be used to exclude ketosis, but the capillary blood ketones test is more accurate to confirm ketoacidosis.
Assuntos
Ácido 3-Hidroxibutírico/sangue , Acetoacetatos/urina , Hiperglicemia/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hiperglicemia/urina , Cetonas/sangue , Cetonas/urina , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos RetrospectivosRESUMO
BACKGROUND AND OBJECTIVES: Peripheral tissue resistance to insulin action is a characteristic of type 2 diabetes mellitus (T2DM). It has also been reported that some chronic viral infections can contribute to insulin resistance. Human herpesvirus (HHV)-8 infection has been detected in T2DM patients in previous studies. Our study investigated whether the presence of the virus is associated with insulin resistance in patients with ketosis-prone type 2 diabetes (KPD), as reported with other viruses. RESEARCH DESIGN AND METHODS: A total of 11 insulin-free KPD patients positive (+) and seven patients who were negative (-) for HHV-8 infection were recruited; the latter had KPD that was well controlled (HbA1c=6.2±0.7%). A two-step euglycaemic-hyperinsulinaemic clamp test coupled with deuterated [6,6-2H2]glucose was used to assess insulin sensitivity, non-esterified fatty acid (NEFA) suppression and endogenous glucose production. RESULTS: In KPD patients, whether HHV-8+ or HHV-8-, there were no differences in NEFA release, endogenous glucose production or insulin sensitivity (M value). CONCLUSION: Asymptomatic HHV-8 infection does not appear to be associated with decreased insulin sensitivity in diabetic patients. These results should now be confirmed in a larger sample population.
Assuntos
Diabetes Mellitus Tipo 2 , Cetoacidose Diabética , Infecções por Herpesviridae , Herpesvirus Humano 8 , Resistência à Insulina , Adulto , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/virologia , Cetoacidose Diabética/epidemiologia , Cetoacidose Diabética/virologia , Feminino , Técnica Clamp de Glucose , Infecções por Herpesviridae/complicações , Infecções por Herpesviridae/epidemiologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
PGC-1α is a transcriptional coactivator expressed in brown adipose tissue, liver, pancreas, kidney, skeletal and cardiac muscles, and the brain. This review presents data illustrating how PGC-1α regulates metabolic adaptations and participates in the aetiology of type 2 diabetes (T2D). Studies in mice have shown that increased PGC-1α expression may be beneficial or deleterious, depending on the tissue: in adipose tissue, it promotes thermogenesis and thus protects against energy overload, such as seen in diabetes and obesity; in muscle, PGC-1α induces a change of phenotype towards oxidative metabolism. In contrast, its role is clearly deleterious in the liver and pancreas, where it induces hepatic glucose production and inhibits insulin secretion, changes that promote diabetes. Previous studies by our group have also demonstrated the role of PGC-1α in the fetal origins of T2D. Overexpression of PGC-1α in ß cells during fetal life in mice is sufficient to induce ß-cell dysfunction in adults, leading to glucose intolerance. PGC-1α also is associated with glucocorticoid receptors in repressing expression of Pdx1, a key ß-cell transcription factor. In conclusion, PGC-1α participates in the onset of diabetes through regulation of major metabolic tissues. Yet, it may not represent a useful target for therapeutic strategies against diabetes as it exerts both beneficial and deleterious actions on glucose homoeostasis, and because PGC-1α modulation is involved in neurodegenerative diseases. However, its role in cellular adaptation shows that greater comprehension of PGC-1α actions is needed.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Modelos Biológicos , Fatores de Transcrição/metabolismo , Tecido Adiposo/metabolismo , Animais , Metabolismo Energético , Gluconeogênese , Humanos , Resistência à Insulina , Secreção de Insulina , Fígado/metabolismo , Músculo Esquelético/metabolismo , Especificidade de Órgãos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Termogênese , Fatores de Transcrição/química , Fatores de Transcrição/genéticaRESUMO
AIM: Previously, we described patients with ketosis-prone type 2 diabetes (KPD) and glucose-6-phosphate dehydrogenase (G6PD) deficiency, but no mutation of the G6PD gene. Our present study used two complementary approaches to test whether hyperglycaemia might inhibit G6PD activity: (1) effect of acute hyperglycaemia induced by glucose ramping; and (2) effect of chronic hyperglycaemia using correlation between G6PD activity and HbA1c levels. METHODS: In the first substudy, 16 KPD patients were compared with 11 healthy, non-diabetic control subjects of the same geographical background. Erythrocyte G6PD activity and plasma glucose were assessed at baseline and every 40 min during intravenous glucose ramping that allowed maintaining hyperglycaemia for more than 3h. In the second substudy, erythrocyte G6PD activity and HbA1c levels were evaluated in 108 consecutive African patients with either type 2 diabetes or KPD, and a potential correlation sought between the two variables. RESULTS: The maximum plasma glucose level after 200 min of glucose perfusion was 20.9±3.7 mmol/L for patients and 10.7±2.3mmol/L for controls. There was no difference between baseline and repeated G6PD activity levels during acute hyperglycaemia in either KPD patients (P=0.94) or controls (P=0.57), nor was there any significant correlation between residual erythrocyte G6PD activity and HbA1c levels (r=-0.085, P=0.38). CONCLUSION: Neither acute nor chronic hyperglycaemia affects erythrocyte G6PD activity. Thus, hyperglycaemia alone does not explain cases of G6PD deficiency in the absence of gene mutation as described earlier.
Assuntos
Cetoacidose Diabética/metabolismo , Eritrócitos/metabolismo , Deficiência de Glucosefosfato Desidrogenase/sangue , Glucosefosfato Desidrogenase/metabolismo , Hiperglicemia/complicações , Adulto , Glicemia/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Cetoacidose Diabética/sangue , Cetoacidose Diabética/complicações , Eritrócitos/enzimologia , Feminino , Glucosefosfato Desidrogenase/sangue , Deficiência de Glucosefosfato Desidrogenase/complicações , Humanos , Hiperglicemia/sangue , Hiperglicemia/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: We investigated the effect of an intensive training program on fasting leptin and adiponectin levels. METHODS: Sixteen middle-aged men with type 2 diabetes were randomly assigned to either a training or control group. The training program consisted of 8 weeks of supervised endurance exercise (75% VO(2peak), 45 min) twice a week, with intermittent exercise (five 2 min exercises at 85% VO(2peak) separated by 3 min exercises at 50% VO(2peak)) once a week, on an ergocycle. RESULTS: Training decreased abdominal fat by 44%, increased mid-thigh muscle cross-sectional area by 24%, and improved insulin sensitivity by 58% without significant change in body weight. Compared with controls, no significant variation in leptin or adiponectin levels was observed. However, in the trained group, change in adiponectin correlated with change in body weight (Spearman rank correlation, r(s):-0.76, P=0.03) but not with insulin sensitivity or abdominal adiposity variations. CONCLUSIONS: An 8 week intensive training program inducing a marked reduction in abdominal fat and increase in insulin sensitivity does not affect adiponectin and leptin levels in men with type 2 diabetes.
Assuntos
Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Exercício Físico/fisiologia , Resistência à Insulina , Peptídeos e Proteínas de Sinalização Intercelular , Proteínas/metabolismo , Abdome , Adiponectina , Adulto , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Leptina/metabolismo , Masculino , Pessoa de Meia-Idade , Resistência Física , Redução de PesoRESUMO
We report a case of symptomatic topical corticosteroid-induced adrenal insufficiency and diabetes in a 46-yr old HIV 1 positive woman of African descent. Topical Betamethasone dipropionate 0.05%-containing creams were used for the purpose of bleaching over a 2 month period prior to the acute episode. She recovered from her acute onset diabetes with ketosis and adrenal insufficiency a few months after withdrawal of corticosteroids. Despite possible discussion about pathophysiology of diabetes because acute-onset remitting diabetes is not rare in patients of African descent, and diabetes may occur in patients taking anti-retroviral treatments, no other cause of a hypothalamo-pituitary-adrenal axis disorder was found. This case suggests that chronic use of high dose topical corticosteroid containing creams should be ruled out in patients presenting with Hypothalamo-Pituitary-Adrenal hypofunction.
Assuntos
Insuficiência Adrenal/induzido quimicamente , Anti-Inflamatórios/efeitos adversos , Betametasona/análogos & derivados , Betametasona/efeitos adversos , Diabetes Mellitus/induzido quimicamente , Síndrome da Imunodeficiência Adquirida/complicações , Administração Tópica , África Subsaariana/etnologia , Feminino , França , Glucocorticoides , Humanos , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: We surveyed the residents in their first (R1) and fourth (R4, last) years of residency in anaesthesia and intensive care in France. METHODS: The questionnaires mailed to each resident were designed to obtain personal data, motivation for specializing in anaesthesia and their opinion of their training. RESULTS: The response rates were 48% for the R1 residents and 77% for the R4 residents. There were 40% females in this population and the R1 residents were 25 +/- 1 year old, 29 +/- 2 year-old for the R4 residents. Almost half (46%) of the R1 responders were married as were 74% of the R4 residents. They spent an average of 726 each year on books, computers and other educational items. Most (71%) had opted for anaesthesia after considering other medical specialties, but only 12% had considered surgery. Half (51%) were on a training program that was far away from their home. They thought highly of their training, with the clinical training being rated above the non-clinical component. About half of them had obtained specialized certificates (mainly additional certification in intensive care and antibiotic therapy) during their residency. Two thirds of those in R4 expected to work in a public hospital and about one third expected to work in intensive care. Money was an important factor in their choice of profession. A majority planned to remain in the area where they had graduated in anaesthesia after their residency. Finally, 96% declared that they would choose anaesthesia again if they had to do so. CONCLUSION: French residents in anaesthesia are satisfied of their initial choice for anaesthesia and don't regret it at the end of their residency training.
Assuntos
Anestesiologia/educação , Cuidados Críticos , Internato e Residência/estatística & dados numéricos , Adulto , Fatores Etários , Atitude do Pessoal de Saúde , Coleta de Dados , Feminino , França , Humanos , Masculino , Motivação , Salários e Benefícios , Inquéritos e Questionários , Recursos HumanosRESUMO
Type 2 diabetes (T2D) is a complex, progressive disease with life-threatening complications and one of the most serious public-health problems worldwide. The two main mechanisms of T2D pathogenesis are pancreatic beta cell dysfunction and insulin resistance. It is now recognized that pancreatic beta cell dysfunction is a necessary factor for T2D development. Traditional therapies for controlling blood glucose are suboptimal as they fail to meet target goals for many patients. Glucagon-like peptide-1 receptor agonists (GLP1RA) and dipeptidyl peptidase-4 inhibitors (DPP4I) are an attractive class of therapy because they reduce blood glucose by targeting the incretin hormone system and, in particular, have the potential to positively affect pancreatic beta cell biology. This review outlines our current understanding of pancreatic beta cell incretin system dysfunction in T2D and summarizes recent evidence of the effect of incretin-based therapies on beta cell function and mass. Incretin-based therapies have shown strong evidence for beneficial effects on beta cell function and mass in animal studies. In humans, incretin-based therapies are effective glucose-lowering agents, but further study is still required to evaluate their long-term effects on beta cell function and safety as well as beta cell mass expansion.