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BACKGROUND: Exocrine pancreatic insufficiency (EPI) can be associated with all types of diabetes. Pancreatic enzyme replacement therapy (PERT) has short and long-term benefits in subjects with EPI, but its effects on diabetes control are uncertain. We aimed to study the effects of PERT initiation on glycemic control in subjects with diabetes and EPI from any cause. METHODS: In this retrospective study, we compared subjects with EPI and diabetes who were prescribed PERT with subjects with diabetes who had a fecal elastase-1 concentration dosage, but did not receive PERT. The primary outcome was the effect of PERT on hypoglycemia frequency and severity. The secondary outcomes were the effects of PERT on gastro-intestinal disorders, HbA1c and body mass index (BMI). RESULTS: 48 subjects were included in each group. Overall, PERT did not have any significant effect on hypoglycemia frequency or severity, but hypoglycemia frequency tended to decrease in subjects with chronic pancreatitis. While 19% of subjects experienced mild hyperglycemia after PERT initiation, we did not report any keto-acidosis or any other severe adverse event. Gastro-intestinal disorders improved in 80% of subjects treated with PERT, versus in 20% of control subjects (p = 0.02). Gastro-intestinal disorders improved in 87% of subjects with recommended dosage of PERT, versus in 50% of subjects with underdosage (NS). HbA1c and BMI evolution did not differ between the groups. CONCLUSIONS: PERT initiation is safe in subjects with diabetes and EPI. It does not globally decrease hypoglycemia severity of frequency, but is associated with a decrease in gastro-intestinal disorders. Trial registration Retrospectively registered. The database was registered with the Commission Nationale Informatique et Libertés (CNIL), registration number: 2203351v0. The study was approved by the local ethics committee CLEP, registration number: AAA-2023-09047.
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Objective: The use of continuous glucose monitoring (CGM) systems and continuous subcutaneous insulin infusion (CSII) devices adhering to the skin can lead to skin reactions. The objective was to determine the prevalence and consequences of skin reactions at CGM or CSII sites in a large unbiased population. Research Design and Methods: This is a cross-sectional multicenter study. All adult patients with diabetes seen in consultation over a period of 7 months and using or having used a system with skin adhesives (in the last 10 years) were included and filled out a self-assessment questionnaire. Results: Among 851 patients, skin reaction was reported in 28% with CGM and 29% with CSII. Patients reporting reactions were more frequently women using CGM and CSII, and CGM users had type 1 more often than type 2 diabetes (P < 0.001). Manifestations were similar for reactions to CGM and CSII: redness and pruritus in 70%-75% of patients with reactions, pain in 20%-25%, and vesicles and desquamation in 12%-15%. Manifestations occurred within the first 24 h of first use in 22%-24% of patients with reactions to CGM and CSII, but after more than 6 months in 38% and 47% of patients with reactions to CGM and CSII, respectively. Device use was definitively stopped in 12% of patients with reactions to CGM (3.2% of all users) and 7% with reactions to CSII (2.1% of all users). Conclusions: Skin reactions were common, with similar presentations in CGM and CSII users. Manifestations suggested skin irritation rather than allergies. These reactions rarely led to the definitive discontinuation of the use of the device.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Humanos , Adulto , Femenino , Hipoglucemiantes/uso terapéutico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Glucemia , Automonitorización de la Glucosa Sanguínea , Prevalencia , Estudios Transversales , Sistemas de Infusión de Insulina/efectos adversos , Insulina/uso terapéuticoRESUMEN
Hepatocyte nuclear factor-1B (HNF1B) maturity-onset diabetes of the young (MODY), also referred to as "renal cysts and diabetes syndrome" or MODY-5, is a rare form of monogenic diabetes that is caused by a deletion or a point mutation in the HNF1B gene, a developmental gene that plays a key role in regulating urogenital and pancreatic development. HNF1B-MODY has been characterized by its association with renal, hepatic and other extrapancreatic features. We present the case of a 39-year-old female patient who was first diagnosed with type 1 diabetes, but then, owing to the absence of anti-islet autoantibodies and to the disease's progression, was labeled later on as having atypical type 2 diabetes. She was finally recognized as having HNF1B-MODY, a diagnosis that had been suggested by the lack of metabolic syndrome and by the presence of unexplained chronically disturbed liver function tests and hypomagnesemia. There was a 10-year delay between the onset of diabetes and the molecular diagnosis. An atypical form of diabetes, especially in patients with multisystem involvement, should raise suspicion for an alternative etiology. A timely diagnosis of HNF1B-MODY is of utmost importance since it can greatly impact diabetes management and disease progression as well as family history.
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Heterozygous loss-of-function variants of the glucokinase (GCK) gene are responsible for a subtype of maturity-onset diabetes of the young (MODY). GCK-MODY is characterized by a mild hyperglycemia, mainly due to a higher blood glucose threshold for insulin secretion, and an up-regulated glucose counterregulation. GCK-MODY patients are asymptomatic, are not exposed to diabetes long-term complications, and do not require treatment. The diagnosis of GCK-MODY is made on the discovery of hyperglycemia by systematic screening, or by family screening. The situation is peculiar in GCK-MODY women during pregnancy for three reasons: 1. the degree of maternal hyperglycemia is sufficient to induce pregnancy adverse outcomes, as in pregestational or gestational diabetes; 2. the probability that a fetus inherits the maternal mutation is 50% and; 3. fetal insulin secretion is a major stimulus of fetal growth. Consequently, when the fetus has not inherited the maternal mutation, maternal hyperglycemia will trigger increased fetal insulin secretion and growth, with a high risk of macrosomia. By contrast, when the fetus has inherited the maternal mutation, its insulin secretion is set at the same threshold as the mother's, and no fetal growth excess will occur. Thus, treatment of maternal hyperglycemia is necessary only in the former situation, and will lead to a risk of fetal growth restriction in the latter. It has been recommended that the management of diabetes in GCK-MODY pregnant women should be guided by assessment of fetal growth by serial ultrasounds, and institution of insulin therapy when the abdominal circumference is ≥ 75th percentile, considered as a surrogate for the fetal genotype. This strategy has not been validated in women with in GCK-MODY. Recently, the feasibility of non-invasive fetal genotyping has been demonstrated, that will improve the care of these women. Several challenges persist, including the identification of women with GCK-MODY before or early in pregnancy, and the modalities of insulin therapy. Yet, retrospective observational studies have shown that fetal genotype, not maternal treatment with insulin, is the main determinant of fetal growth and of the risk of macrosomia. Thus, further studies are needed to specify the management of GCK-MODY pregnant women during pregnancy.
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Diabetes Mellitus Tipo 2/terapia , Macrosomía Fetal/prevención & control , Feto/metabolismo , Glucoquinasa/genética , Secreción de Insulina/genética , Insulina/uso terapéutico , Embarazo en Diabéticas/terapia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Desarrollo Fetal , Macrosomía Fetal/metabolismo , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/metabolismo , Mutación , Embarazo , Resultado del EmbarazoRESUMEN
The antigenic peptides processed by ß-cells and presented through surface HLA class I molecules are poorly characterized. Each HLA variant (e.g., the most common being HLA-A2 and HLA-A3) carries some peptide-binding specificity. Hence, features that, despite these specificities, remain shared across variants may reveal factors favoring ß-cell immunogenicity. Building on our previous description of the HLA-A2/A3 peptidome of ß-cells, we analyzed the HLA-A3-restricted peptides targeted by circulating CD8+ T cells. Several peptides were recognized by CD8+ T cells within a narrow frequency (1-50/106), which was similar in donors with and without type 1 diabetes and harbored variable effector/memory fractions. These epitopes could be classified as conventional peptides or neoepitopes, generated either via peptide cis-splicing or mRNA splicing (e.g., secretogranin-5 [SCG5]-009). As reported for HLA-A2-restricted peptides, several epitopes originated from ß-cell granule proteins (e.g., SCG3, SCG5, and urocortin-3). Similarly, H-2Kd-restricted CD8+ T cells recognizing the murine orthologs of SCG5, urocortin-3, and proconvertase-2 infiltrated the islets of NOD mice and transferred diabetes into NOD/scid recipients. The finding of granule proteins targeted in both humans and NOD mice supports their disease relevance and identifies the insulin granule as a rich source of epitopes, possibly reflecting its impaired processing in type 1 diabetes.
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Cromograninas/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Adulto , Empalme Alternativo , Animales , Linfocitos T CD8-positivos , Estudios de Casos y Controles , Cromograninas/genética , Simulación por Computador , Minería de Datos , Diabetes Mellitus Tipo 1/genética , Epítopos , Femenino , Regulación de la Expresión Génica , Antígeno HLA-A3 , Humanos , Insulina , Masculino , Ratones , Ratones Endogámicos NOD , Proteína 7B2 Secretora Neuroendocrina/genética , Proteína 7B2 Secretora Neuroendocrina/metabolismo , Unión Proteica , ARN Mensajero/genética , Urocortinas/genética , Urocortinas/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Monogenic diabetes (MgD) accounts for 1-2% of all diabetes cases. In adults, MgD is difficult to distinguish from common diabetes causes. We assessed the diagnosis rate and genetic spectrum of MgD using next-generation sequencing in patients with late adolescence/adult-onset diabetes referred for a clinical suspicion of MgD. METHODS: This cross-sectional study was performed in 1564 probands recruited in 116 Endocrinology departments. Inclusion criteria were the absence of diabetes autoantibodies, and at least two of the three following criteria: an age ≤ 40 years and a body mass index (BMI) < 30 kg/m2 at diagnosis in the proband or in at least two relatives with diabetes, and a family history of diabetes in ≥ 2 generations. Seven genes (GCK, HNF1A, HNF4A, HNF1B, ABCC8, KCNJ11, and INS) were analyzed. Variant pathogenicity was assessed using current guidelines. RESULTS: Pathogenic variants were identified in 254 patients (16.2%) and in 23.2% of EuroCaucasian patients. Using more stringent selection criteria (family history of diabetes in ≥ 3 generations, age at diabetes ≤ 40 years and BMI < 30 kg/m2 in the proband, EuroCaucasian origin) increased the diagnosis rate to 43%, but with 70% of the identified cases being missed. GCK (44%), HNF1A (33%), and HNF4A (10%) accounted for the majority of the cases. HNF1B (6%), ABCC8/KCNJ11 (4.4%), and INS (2.8%) variants accounted for 13% of the cases. As compared to non-monogenic cases, a younger age, a lower BMI and the absence of diabetes symptoms at diagnosis, a EuroCaucasian origin, and a family history of diabetes in ≥ 3 generations were associated with MgD, but with wide phenotype overlaps between the two groups. In the total population, two clusters were identified, that mainly differed by the severity of diabetes at onset. MgDs were more prevalent in the milder phenotypic cluster. The phenotypes of the 59 patients (3.8%) with variants of uncertain significance were different from that of patients with pathogenic variants, but not from that of non-monogenic patients. CONCLUSION: Variants of HNF1B and the K-ATP channel genes were more frequently involved in MgD than previously reported. Phenotype overlapping makes the diagnosis of MgD difficult in adolescents/adults and underlies the benefit of NGS in clinically selected patients.
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Diabetes Mellitus Tipo 2/diagnóstico , Pruebas Genéticas/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Adolescente , Adulto , Estudios Transversales , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
Although CD8+ T-cell-mediated autoimmune ß cell destruction occurs in type 1 diabetes (T1D), the target epitopes processed and presented by ß cells are unknown. To identify them, we combined peptidomics and transcriptomics strategies. Inflammatory cytokines increased peptide presentation in vitro, paralleling upregulation of human leukocyte antigen (HLA) class I expression. Peptide sources featured several insulin granule proteins and all known ß cell antigens, barring islet-specific glucose-6-phosphatase catalytic subunit-related protein. Preproinsulin yielded HLA-A2-restricted epitopes previously described. Secretogranin V and its mRNA splice isoform SCG5-009, proconvertase-2, urocortin-3, the insulin gene enhancer protein ISL-1, and an islet amyloid polypeptide transpeptidation product emerged as antigens processed into HLA-A2-restricted epitopes, which, as those already described, were recognized by circulating naive CD8+ T cells in T1D and healthy donors and by pancreas-infiltrating cells in T1D donors. This peptidome opens new avenues to understand antigen processing by ß cells and for the development of T cell biomarkers and tolerogenic vaccination strategies.
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Presentación de Antígeno , Linfocitos T CD8-positivos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Epítopos de Linfocito T/inmunología , Transcriptoma/inmunología , Animales , Biomarcadores/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Estudios de Casos y Controles , Línea Celular , Hormona Liberadora de Corticotropina/metabolismo , Citocinas/metabolismo , Antígenos HLA/metabolismo , Humanos , Insulina/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Ratones , Proteína 7B2 Secretora Neuroendocrina/metabolismo , Proproteína Convertasa 2/metabolismo , Precursores de Proteínas/metabolismo , Proteómica/métodos , Urocortinas/metabolismoRESUMEN
Post-transplantation diabetes mellitus is defined as diabetes that is diagnosed in grafted patients. It affects 20 to 30 % of kidney transplant recipients, with a high incidence in the first year. The increasing age at transplantation and the rising incidence of obesity may increase its prevalence in the next years. Post-transplantation diabetes mellitus is associated with poor outcomes, such as mortality, cardiovascular events or graft dysfunction. Its occurrence is mainly related to immunosuppressive agents, affecting both insulin secretion and sensibility. Immunosuppressants may be iatrogenic, and as such, induce an early and transient diabetes. They may also precociously determine a permanent diabetes, acting here as a promoting factor in patients proned to the development of type 2 diabetes. Lastly, they may behave, far from transplantation, as an additional risk factor for type 2 diabetes. The screening, management and prognosis of these different subtypes of post-transplantation diabetes mellitus will be different.
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Diabetes Mellitus/inducido químicamente , Inmunosupresores/efectos adversos , Trasplante de Riñón/efectos adversos , Índice de Masa Corporal , Diabetes Mellitus/epidemiología , Diabetes Mellitus Tipo 2/inducido químicamente , Francia/epidemiología , Humanos , Incidencia , Obesidad/complicaciones , PronósticoRESUMEN
OBJECTIVE: Molecular defects of hepatocyte nuclear factor 1B (HNF1B) are associated with a multiorgan disease, including diabetes (maturity-onset diabetes of the young 5) and kidney abnormalities. The HNF1B syndrome is related to HNF1B mutations or to a 17q12 deletion spanning 15 genes, including HNF1B. Here, we described HNF1B-related diabetes and associated phenotypes and assessed genotype/phenotype correlations at diagnosis and in the long-term. RESEARCH DESIGN AND METHODS: This multicenter retrospective cohort study included 201 patients, aged 18 years or older at follow-up, with HNF1B mutations (n = 101) or deletion (n = 100). RESULTS: Diabetes was present in 159 patients. At diagnosis, clinical symptoms of diabetes were present in 67 of 144 patients and HNF1B renal disease in 64 of 102. Although responsiveness to sulfonylureas/repaglinide was observed in 29 of the 51 tested, 111 of 140 patients (79%) were treated with insulin at follow-up. Diabetic retinopathy and/or neuropathy were present in 46 of 114 patients. Renal cysts were present in 122 of 166 patients, chronic kidney disease stages 3-4 (CKD3-4) in 75 of 169 (44%), and end-stage renal disease (ESRD) in 36 of 169 (21%). Compared with the patients with mutations, those with HNF1B deletion less often had CKD3-4/ESRD at diagnosis (11 of 43 vs. 27 of 35, P < 10-4) and in the long term (40 of 78 vs. 71 of 91, P = 0.0003). They were leaner and more frequently treated with insulin. CONCLUSIONS: In patients with HNF1B syndrome, diabetes complications, cardiovascular risk factors, CKD3-4, and ESRD are highly prevalent. At diabetes diagnosis, the presence of morphological and/or functional kidney disease may help etiological diagnosis. Genotype/phenotype correlations may have implications for the care and the prognosis of these patients.
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Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus Tipo 2/diagnóstico , Retinopatía Diabética/epidemiología , Factor Nuclear 1-beta del Hepatocito/genética , Enfermedades Renales/epidemiología , Adolescente , Adulto , Glucemia/metabolismo , Índice de Masa Corporal , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/genética , Niño , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Retinopatía Diabética/complicaciones , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/genética , Femenino , Estudios de Seguimiento , Eliminación de Gen , Estudios de Asociación Genética , Factor Nuclear 1-beta del Hepatocito/metabolismo , Humanos , Insulina/uso terapéutico , Enfermedades Renales/complicaciones , Enfermedades Renales/diagnóstico , Enfermedades Renales/genética , Masculino , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
Hepatocyte nuclear factor 1α (HNF1α) is a transcription factor expressed in the liver, pancreas, and proximal tubule of the kidney. Mutations of HNF1α cause an autosomal dominant form of diabetes mellitus (MODY-HNF1A) and tubular dysfunction. To gain insights into the role of HNF1α in the proximal tubule, we analyzed Hnf1a-deficient mice. Compared with wild-type littermates, Hnf1a knockout mice showed low-molecular-weight proteinuria and a 70% decrease in the uptake of ß2-microglobulin, indicating a major endocytic defect due to decreased expression of megalin/cubilin receptors. We identified several binding sites for HNF1α in promoters of Lrp2 and Cubn genes encoding megalin and cubilin, respectively. The functional interaction of HNF1α with these promoters was shown in C33 epithelial cells lacking endogenous HNF1α. Defective receptor-mediated endocytosis was confirmed in proximal tubule cells from these knockout mice and could be rescued by transfection of wild-type but not mutant HNF1α. Transfection of human proximal tubule HK2 cells with HNF1α was able to upregulate megalin and cubilin expression and to increase endocytosis of albumin. Low-molecular-weight proteinuria was consistently detected in individuals with HNF1A mutations compared with healthy controls and patients with non-MODY-HNF1A diabetes mellitus. Thus, HNF1α plays a key role in the constitutive expression of megalin and cubilin, hence regulating endocytosis in the proximal tubule of the kidney. These findings provide new insight into the renal phenotype of individuals with mutations of HNF1A.
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Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/genética , Endocitosis , Factor Nuclear 1-alfa del Hepatocito/genética , Túbulos Renales Proximales/metabolismo , Mutación , Proteinuria/genética , Adolescente , Adulto , Anciano , Animales , Sitios de Unión , Estudios de Casos y Controles , Células Cultivadas , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/fisiopatología , Femenino , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Factor Nuclear 1-alfa del Hepatocito/deficiencia , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Humanos , Túbulos Renales Proximales/fisiopatología , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Fenotipo , Regiones Promotoras Genéticas , Proteinuria/metabolismo , Proteinuria/fisiopatología , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Transducción de Señal , Transfección , Adulto JovenRESUMEN
Maturity-onset diabetes of the young (MODY) is a group of monogenic diseases that results in primary defects in insulin secretion and dominantly inherited forms of nonautoimmune diabetes. Although many genes may be associated with monogenic diabetes, heterozygous mutations in 6 of them are responsible for the majority of cases of MODY. Glucokinase (GCK)-MODY is due to mutations in the glucokinase gene, 3 MODY subtypes are associated with mutations in the hepatocyte nuclear factor (HNF) transcription factors, and 2 others with mutations in ABCC8 and KCNJ11, which encode the subunits of the ATP-dependent potassium channel in pancreatic beta cells. GCK-MODY and HNF1A-MODY are the most common subtypes. The clinical presentation of MODY subtypes has been reported to differ according to the gene involved, and the diagnosis of MODY may be considered in various clinical circumstances. However, except in patients with GCK-MODY whose phenotype is very homogeneous, in most cases the penetrance and expressivity of a given molecular abnormality vary greatly among patients and, conversely, alterations in various genes may lead to similar phenotypes. Moreover, differential diagnosis among more common forms of diabetes may be difficult, particularly with type 2 diabetes. Thus, careful assessment of the personal and family histories of patients with diabetes is mandatory to select those in whom genetic screening is worthwhile. The diagnosis of monogenic diabetes has many consequences in terms of prognosis, therapeutics and family screening.
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Diabetes Mellitus/diagnóstico , Enfermedades Raras/diagnóstico , Adolescente , Niño , Diabetes Mellitus/genética , Diabetes Mellitus/terapia , Diagnóstico Diferencial , Errores Diagnósticos , Femenino , Regulación de la Expresión Génica , Pruebas Genéticas , Glucoquinasa/genética , Factores Nucleares del Hepatocito/genética , Humanos , Masculino , Canales de Potasio de Rectificación Interna/genética , Guías de Práctica Clínica como Asunto , Enfermedades Raras/genética , Enfermedades Raras/terapia , Receptores de Sulfonilureas/genéticaRESUMEN
We explored in this study the status and potential role of IL-17-producing iNKT cells (iNKT17) in type 1 diabetes (T1D) by analyzing these cells in patients with T1D, and in NOD mice, a mouse model for T1D. Our analysis in mice showed an increase of iNKT17 cells in NOD vs control C57BL/6 mice, partly due to a better survival of these cells in the periphery. We also found a higher frequency of these cells in autoimmune-targeted organs with the occurrence of diabetes, suggesting their implication in the disease development. In humans, though absent in fresh PMBCs, iNKT17 cells are detected in vitro with a higher frequency in T1D patients compared to control subjects in the presence of the proinflammatory cytokine IL-1ß, known to contribute to diabetes occurrence. These IL-1ß-stimulated iNKT cells from T1D patients keep their potential to produce IFN-γ, a cytokine that drives islet ß-cell destruction, but not IL-4, with a reverse picture observed in healthy volunteers. On the whole, our results argue in favour of a potential role of IL-17-producing iNKT cells in T1D and suggest that inflammation in T1D patients could induce a Th1/Th17 cytokine secretion profile in iNKT cells promoting disease development.
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Diabetes Mellitus Tipo 1/inmunología , Interleucina-17/biosíntesis , Células Asesinas Naturales/inmunología , Animales , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NODRESUMEN
BACKGROUND: This study compared the effects of insulin glargine and insulin detemir on blood glucose variability under clinical practice conditions in patients with type 1 diabetes (T1D) using glulisine as the mealtime insulin. METHODS: This was a multicenter, crossover trial in 88 randomized T1D patients: 54 men and 34 women, 46.8±13.7 years old, with a duration of diabetes of 18±9 years and hemoglobin A1c level of 7.1±0.7%. The per-protocol population included 78 patients: 44 received glargine/detemir and 34 detemir/glargine in the first/second 16-week period, respectively. The primary end point was the coefficient of variation (CV) of fasting blood glucose (FBG). Secondary end points included variability of pre-dinner blood glucose, mean amplitude of glycemic excursions, mean of daily differences, and doses and number of daily insulin injections. The non-inferiority criterion was an insulin glargine/insulin detemir FBG CV ratio with a 95% confidence interval (CI) upper limit ≤1.25. RESULTS: The non-inferiority criterion was satisfied with a mean value of 1.016 (95% CI=0.970-1.065). Intention-to-treat analysis confirmed the non-inferiority with a 95% CI upper limit=1.062. No significant differences were found on secondary objectives, but there was a trend to higher doses and number of daily injections with insulin detemir. A total of eight (four glargine and four detemir) patients reported nine serious adverse events (including one severe episode of hypoglycemia). None of them was considered as related to basal insulins. Serious adverse events led to treatment discontinuation in two patients of the detemir group and none in the glargine group. CONCLUSIONS: In T1D patients under clinical practice conditions, insulin glargine was non-inferior to insulin detemir regarding blood glucose variability, as assessed by CV of FBG.
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Glucemia/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Insulina de Acción Prolongada/administración & dosificación , Adulto , Glucemia/análisis , Glucemia/efectos de los fármacos , Estudios Cruzados , Diabetes Mellitus Tipo 1/sangre , Femenino , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Humanos , Insulina Detemir , Insulina Glargina , Masculino , Persona de Mediana EdadRESUMEN
CONTEXT: The diagnosis of maturity-onset diabetes of the young type 3 (MODY3), associated with HNF1A molecular abnormalities, is often missed. OBJECTIVE: The objective of the study was to describe the phenotypes of a large series of MODY3 patients and to reassess parameters that may improve its diagnosis. DESIGN, SETTING, AND PATIENTS: This retrospective multicenter study included 487 unrelated patients referred because of suspicion of MODY3. Genetic analysis identified 196 MODY3 and 283 non-MODY3 cases. Criteria associated with MODY3 were assessed by multivariate analysis. The capacity of the model to predict MODY3 diagnosis was assessed by the area under the receiver-operating characteristic curve and was further validated in an independent sample of 851 patients (165 MODY3 and 686 non-MODY3). RESULTS: In the MODY3 patients, diabetes was revealed by clinical symptoms in 25% of the cases and was diagnosed by screening in the others. Age at diagnosis of diabetes was more than 25 yr in 40% of the MODY3 patients. There was considerable variability and overlap of all assessed parameters in MODY3 and non-MODY3 patients. The best predictive model was based on criteria available at diagnosis of diabetes, including age, body mass index, number of affected generations, presence of diabetes symptoms, and geographical origin. The area under the curve of the receiver-operating characteristic analysis was 0.81. When sensitivity was set to 90%, specificity was 49%. CONCLUSIONS: Differential diagnosis between MODY3 and early-onset type 2 diabetes remains difficult. Whether the proposed model will improve the pick-up rate of MODY3 diagnosis needs to be confirmed in independent populations.
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Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Marcadores Genéticos , Pruebas Genéticas/métodos , Factor Nuclear 1-alfa del Hepatocito/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Niño , Preescolar , Diabetes Mellitus Tipo 2/clasificación , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Estudios Retrospectivos , Adulto JovenRESUMEN
Type 1 diabetes results from the autoimmune destruction of pancreatic islet B cells, leading within various times to absolute insulin deficiency. The pathophysiology of the disease remains partly unclear: only half of the genetic predisposition is known; the nature, and even the reality, of a triggering event in the autoimmune activation are not established; furthermore, the primitive target of the autoimmune process is not fully determined. As immunological markers of the disease have been developped, therapeutic perspectives for type 1 diabetes prevention have emerged. However, little have been sucessful until now, reflecting the disease heterogeneity and complexity and the difficulty to define the best therapeutic window.
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Diabetes Mellitus Tipo 1/fisiopatología , Diabetes Mellitus Tipo 1/etiología , Diabetes Mellitus Tipo 1/inmunología , HumanosRESUMEN
BACKGROUND: A 37-year-old man developed cholestasis-associated pruritus followed by overt hyperglycemia (blood glucose level 23 mmol/l), necessitating insulin treatment, within weeks of undergoing renal transplantation. He had a history of gout, but his fasting blood glucose and glycated hemoglobin concentrations had been normal before transplantation. INVESTIGATIONS: Physical examination; laboratory tests, including assessment of glycated hemoglobin, anti-glutamic-acid-decarboxylase and anti-islet-antigen-2 antibodies, liver enzymes, renal function, tacrolimus blood trough level, exocrine (fecal elastase) and endocrine (C-peptide) pancreatic function; abdominal CT scan; liver biopsy; and screening of the hepatocyte nuclear factor 1 homeobox B (transcription factor 2) gene, HNF1B. DIAGNOSIS: New-onset diabetes after transplantation associated with a newly described deletion in HNF1B. MANAGEMENT: Minimization of tacrolimus exposure and withdrawal of steroids considerably reduced the patient's insulin requirement, and cholestasis-related pruritus was dramatically improved by administration of ursodeoxycholic acid. Renal ultrasonography and screening for the HNF1B molecular abnormality were offered to the patient's relatives.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Factor Nuclear 1-beta del Hepatocito/genética , Trasplante de Riñón , Adulto , Colestasis/inmunología , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/inmunología , Diagnóstico Diferencial , Mutación del Sistema de Lectura , Humanos , Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Masculino , Prurito/inmunologíaRESUMEN
OBJECTIVE: Uncoupling protein 2 (UCP2) is a physiological downregulator of reactive oxygen species generation and plays an antiatherogenic role in the vascular wall. A common variant in the UCP2 promoter (-866G>A) modulates mRNA expression, with increased expression associated with the A allele. We investigated association of this variant with coronary artery disease (CAD) in two cohorts of type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: We studied 3,122 subjects from the 6-year prospective Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria, Cardiovascular Events, and Ramipril (DIABHYCAR) Study (14.9% of CAD incidence at follow-up). An independent, hospital-based cohort of 335 men, 52% of whom had CAD, was also studied. RESULTS: We observed an inverse association of the A allele with incident cases of CAD in a dominant model (hazard risk 0.88 [95% CI 0.80-0.96]; P = 0.006). Similar results were observed for baseline cases of CAD. Stratification by sex confirmed an allelic association with CAD in men, whereas no association was observed in women. All CAD phenotypes considered--myocardial infarction, angina pectoris, coronary artery bypass graft (CABG), and sudden death--contributed significantly to the association. Results were replicated in a cross-sectional study of an independent cohort (odds ratio 0.47 [95% CI 0.25-0.89]; P = 0.02 for a recessive model). CONCLUSIONS: The A allele of the -866G>A variant of UCP2 was associated with reduced risk of CAD in men with type 2 diabetes in a 6-year prospective study. Decreased risk of myocardial infarction, angina pectoris, CABG, and sudden death contributed individually and significantly to the reduction of CAD risk. This association was independent of other common CAD risk factors.