Metabolomics reveals that fittest trail runners show a better adaptation of bioenergetic pathways.

OBJECTIVES: To analyze the effect in the blood metabolome of trail running, a demanding sport that takes place in the natural environment, places considerable strain on both muscles and joints. While metabolic responses to aerobic exercise have been analyzed in-depth, few studies have focused on trail running. DESIGN: Observational study to analyze changes in 35 different metabolites - representative of aerobic exercise-induced by a simulated 21-km trail race with an uphill gradient of 1400 m. METHODS: We performed a semiquantitative metabolomics study consisting of capillary blood microsampling and targeted screening with liquid chromatography and mass spectrometry to analyze, in 33 licensed athletes, changes concerning 35 metabolites. RESULTS: We observed significant changes in many metabolites, including increased acetyl-carnitine and taurine concentrations (false discovery rate-corrected paired t-test P value 1.63 × 10-13, and P value 5.021 × 10-12, respectively) and decreased carnitine and proline concentrations (P value 6.33 × 10-10, and P value 1.21 × 10-9, respectively). Metabolic responses to trail running were largely independent of sex but were influenced by the level of training, with runners with a higher level showing resistance to exercise-induced changes in taurine, 1-methyl histidine, acetyl-carnitine, and hypoxanthine concentrations. Performance (measured as race time) was inversely correlated with changes in specific metabolites (including taurine, serotonin, and hypoxanthine) and directly correlated with increases in glutathione. CONCLUSIONS: Our findings demonstrate the usefulness of metabolomics studies for analyzing exercise-induced physiological changes and show individual differences associated with the level of training and performance.

Empathy and COVID-19: Study in Professionals and Students of the Social Health Field in Ecuador.

Empathy plays a fundamental role in health related occupations. In this study, we analysed empathy levels in professionals (117) and students (170) from various healthcare fields in Ecuador during the COVID-19 pandemic. The Interpersonal Reactivity Index was used in an online survey. The results show high levels of empathy in both groups, influenced by age and gender. The students presented higher levels of personal distress, and their age was negatively correlated to empathy. Additionally, professionals working in physical health scored higher levels of personal distress compared to those in the field of emotional health. COVID-19 has placed social health systems in great stress. Despite this, the personal capacities for empathy of both students and health professionals have not been diminished.

First hospital admission due to heart failure: In-hospital mortality and patient profile. / Primera hospitalización por insuficiencia cardiaca: mortalidad hospitalaria y perfil del paciente.

OBJECTIVES: We evaluated the patient profile and outcomes of first heart failure (HF) related hospital admission patients in the 2010-2014 period. DESIGN: Retrospective, single-centre, cohort study. SETTING: We used administrative data from a tertiary care hospital (Hospital Universitari de Bellvitge, Barcelona, Spain). PARTICIPANTS: All patients with primary diagnosis of HF registered at the hospital discharge database from 2010 to 2014 were included, ruling out that HF was present 10 years prior to the current episode. INTERVENTION: Primary care HF diagnosis status was assessed in order to distinguish new onset from no-new onset patients. MAIN MEASURES: Descriptive, bivariate and multivariate analysis were performed using age, previous primary care HF diagnosis and in-hospital death as grouping variables. Significant variables were fitted into a Linear logistic regression model for each outcome. RESULTS: We selected 3,868 first HF-related admissions (56.8% of all HF episodes). In 1,220 patients (31.7%) HF was diagnosed by their primary care physician. Main pattern was a woman (OR=2.4), with higher prevalence of hypertension (OR=1.7), atrial fibrillation (OR=1.3), chronic kidney disease (OR=1.6) and mortality rate (9.8%). In-hospital death rate was 5.8%, age over 85 (OR=5.57), chronic kidney disease (OR=1.44) and length of stay over 7 days (OR=1.90) being the main contributors. CONCLUSIONS: First HF related admissions account for 56.7% of all HF episodes. Roughly one third of patients were already diagnosed by the time of their first hospital admission. Elderly women were the most frequent, but not the only, group of patients. Age, hospital stay and chronic kidney disease were the main contributors for in-hospital death.

T-pattern detection and analysis for the discovery of hidden features of behaviour.

BACKGROUND: The behaviour of all living beings consists of hidden patterns in time; consequently, its nature and its underlying dynamics are intrinsically difficult to be perceived and detected by the unaided observer. METHOD: Such a scientific challenge calls for improved means of detection, data handling and analysis. By using a powerful and versatile technique known as T-pattern detection and analysis (TPA) it is possible to unveil hidden relationships among the behavioural events in time. RESULTS: TPA is demonstrated to be a solid and versatile tool to study the deep structure of behaviour in different experimental contexts, both in human and non human subjects. CONCLUSION: This review deepens and extends contents recently published by adding new concepts and examples concerning the applications of TPA in the study of behaviour both in human and non-human subjects.

[Pituitary apoplexy: a rare complication in the postoperative period]. / Apoplexie hypophysaire: complication postopératoire rare d'une chirurgie réglée.

Postoperative pituitary apoplexy is an exceptional but life-threatening complication. We report the case of a 62-year-old man who underwent a cystoprostatectomy under general anaesthesia. The immediate postoperative course was complicated by asthenia and an altered state of consciousness. A few days later, a homonymous followed by bitemporal hemianopia developed. A CT-scan and magnetic resonance imaging made the diagnosis o pituitary apoplexy. The treatment was a medical one, with rapid improvement in the patient's condition.

Thyroid volume as measured by ultrasonography in patients With type 1 diabetes mellitus without thyroid dysfunction.

The aim of this cross-sectional study was to assess and compare thyroid volume and its derminants in a cohort of type 1 diabetes mellitus (DM1) and compare the results to a healthy control group. We studied 65 DM1 patients treated with an intensive insulin regimen and 65 matched controls. In all participants we evaluated weight, height, BMI, waist-hip ratio, body surface area and body composition variables determined by using a bioelectrical impedance analyser. Thyroid size was estimated by ultrasonography. We determined basal TSH, anti-thyroid antibodies and urinary iodine excretion. Body weight, height, BMI and body surface area were similar in DM1 patients and in controls. Fat-free mass was higher in both male and female DM1 patients than in controls (64.4 +/- 6.9 vs. 60.4 +/- 8.2 kg, p=0.03 and 48.3 +/- 5.7 vs. 45.4 +/- 6, p=0.04, respectively), and fat mass was lower in male DM1 patients than in controls (9.7 +/- 7 vs. 14.2 +/- 8.1 kg, p=0.01). Thyroid volume was greater in both male and female DM1 patients than in controls (11.12 +/- 2.87 vs. 9.63 +/- 2.27 ml, p=0.0001 and 9.5 +/- 2.3 vs. 7.7 +/- 2 ml, p=0.002, respectively). Urinary iodine excretion was similar in the two groups. In both DM1 patients and controls, thyroid volume correlated with weight, height, BMI, waist-hip ratio, body surface area, fat-free mass and the multivariate linear regression analysis with thyroid volume as the dependent variable showed that fat-free mass in either group was the only significant determinant of thyroid volume. We conclude that DM1 patients had larger thyroid volume compared with healthy controls with similar anthropometry; body composition is different in DM1 patients and that the anthropometric and body composition variables, especially fat-free mass and body surface area, predict thyroid volume either in DM1 patients or in healthy controls.

T-cell reactivity to glutamic acid decarboxylase in stiff-man syndrome and cerebellar ataxia associated with polyendocrine autoimmunity.

Antibodies to glutamic acid decarboxilase (GAD-Abs) are present in the serum of 60-80% of newly diagnosed type 1 diabetes (DM1) patients and patients with autoimmune polyendocrine syndrome (APS) associated with DM1. Higher titre of GAD-Abs are also present in the serum of 60% of patients with stiff-man syndrome (SMS) and all reported patients with cerebellar ataxia associated with polyendocrine autoimmunity (CAPA). Several studies suggest that GAD-Abs may play a critical role in the pathogenesis of SMS and CAPA but little is known about T-cell responsiveness to GAD-65 in these neurological diseases. To analyse cell-mediated responses to GAD, we studied the peripheral blood lymphocyte proliferation and cytokine responses to recombinant human GAD-65 in 5 patients with SMS, 6 with CAPA, 9 with DM1, 8 with APS and 15 control subjects. GAD-65-specific cellular proliferation was significantly higher in SMS than in CAPA, DM1, APS or controls. In contrast, only T cells from CAPA patients showed a significantly high production of interferon-gamma after GAD stimulation, compared to all other patients and controls. No differences were found for IL-4 production. These results suggest that, despite similar humoral autoreactivity, cellular responses to GAD are different between SMS and CAPA, with a greater inflammatory response in CAPA, and this difference may be relevant to the pathogenesis of these diseases.

Body composition assessment in type 1 diabetes mellitus patients over 15 years old.

BACKGROUND: The aim of the present study was to assess the anthropometric characteristics and body composition in type 1 diabetic patients and compare the results with a randomly selected control population. MATERIAL AND METHODS: We studied 75 type 1 diabetic patients, 43 male and 32 female, recruited from consecutive diagnosed type 1 diabetic patients attending the Endocrine Unit and treated with a intensive insulin regimen, and 93 control subjects, 44 males and 49 females representative of the census of this city. We performed a dietary recall in patients and determined anthropometric characteristics, both in patients and controls, body weight, height, body-mass index, waist-hip ratio and body composition parameters: total body water, free-fat mass, body free-fat mass, fat mass and body fat by bioelectrical impedance analyser. RESULTS: In diabetic male patients, we observed lower waist-hip ratio than in controls, 0.84 +/- 0.06 vs. 0.88 +/- 0.07, p = 0.021, higher free-fat mass in female diabetic patients, 48.5 +/- 5.6 vs. 45.6 +/- 5.9 kg, p = 0.03, lower fat mass in male diabetic patients, 9.5 +/- 6.9 vs. 14.6 +/- 8.5 kg, p = 0.003. We did not find any correlation among the parameters of body composition and dietary macronutrient intake in patients. CONCLUSIONS: The present study exposes the differences in anthropometric characteristics and body composition in type 1 diabetes mellitus, especially lower waist-hip ratio in male, higher free-fat mass in female and lower fat mass in male.

Leptin in type 2 diabetic or myotonic dystrophic women.

BACKGROUND: Insulin resistance is an important determinant of circulating leptin concentrations in humans, but its independent contribution on plasma leptin levels are controversial. In the present study, we characterized plasma leptin levels and their regulation in women with 2 different insulin resistance states: type 2 diabetes and myotonic dystrophy disease, and in controls. MATERIAL AND METHODS: We studied 3 groups of women: 21 type 2 diabetic patients, 20 myotonic dystrophic patients and a control group of 20 normoglycemic subjects, matched in age and body mass index. Body composition, fasting glucose and insulin, IGF-I, IGF-binding protein-3 and leptin were studied. Body composition was measured using a bioelectrical impedance analyser. Insulin sensitivity (in percentage) was modeled according to a computer-based homeostasis model assessment model. Data are expressed in mean +/- SEM. RESULTS: In both groups of patients, glucose concentrations were higher in type 2 diabetic patients than in myotonic dystrophic patients, and insulin concentrations and insulin sensitivity were similar in the 2 groups of patients (82.4 +/- 18.6% in type 2 diabetic patients vs. 69.7 +/- 9.7% in myotonic dystrophic patients, p = 0.2) and lower than in controls. Serum leptin and leptin/fat mass ratio were higher in myotonic dystrophic patients than in type 2 diabetic patients (30 +/- 4.9 ng/ml vs. 17.7 +/- 2.6 ng/ml, p = 0.03 and 2.32 +/- 0.69 ng/ml/kg vs. 1.07 +/- 0.2 ng/ml/kg, p = 0.02, respectively) or those found in controls. In type 2 diabetic patients, leptin concentrations were correlated with body mass index and body fat, and in myotonic dystrophic patients leptin concentrations were correlated with age, body mass index, fasting insulin and lower insulin sensitivity, whereas leptin concentrations were not correlated with body fat. CONCLUSIONS: These findings suggest that leptin concentrations and regulation in myotonic dystrophic patients are different from type 2 diabetes.

[Analysis of mutations A3243G, C3256T and mitochondrial deletions in 41 diabetic patients]. / Estudio de las mutaciones A3243G, C3256T y deleciones mitocondriales en 41 pacientes diabéticos.

BACKGROUND: Mutations or deletions of mitochondrial DNA (mtDNA) define a new diabetes subtype. PATIENTS AND METHOD: The A3243G and C3256T mutations and mtDNA deletions were studied in 41 diabetic patients with maternally inherited diabetes mellitus or deafness. RESULTS: The A3243G mutation was found in one out of forty-one diabetic patients (2.4%). Neither the C3256T mutation nor mtDNA deletions were detected. CONCLUSIONS: The search of A3243G mutation has to be considered in a diabetic patient with deafness and/or maternal history of diabetes.

Insulin regulation of leptin synthesis and secretion in humans: the model of myotonic dystrophy.

OBJECTIVE: Myotonic dystrophy (MyD) is a systemic disorder in which insulin resistance is well recognized. In the present study we have characterized plasma leptin levels in patients with MyD and in age, sex and body mass index (BMI) matched controls and assessed the influence of leptin on the clinical manifestations of MyD. DESIGN AND PATIENTS: Body composition, plasma leptin, fasting and post-oral glucose tolerance test insulin, IGF-I and IGFBP3 were studied in 34 MyD patients and 33 controls. MEASUREMENTS: Body composition was measured using a bioelectrical impedance analyzer, and circulating levels of insulin, leptin, IGF-I, IGFBP3 were measured by IRMA or RIA. Insulin sensitivity was modelled according to a homeostasis model assessment (HOMA) computer-solved model. RESULTS: Percentage body fat was higher in patients than in controls (25.6 +/- 2.28% vs 18.8 +/- 1.53%, P = 0.013). Insulin levels, both fasting and after oral glucose were higher in patients than in controls, and insulin sensitivity was lower in patients than in controls. Serum leptin was higher in patients than in controls (20.98 +/- 3.11 micrograms/l vs 10.4 +/- 1.31 micrograms/l, P = 0.004), and higher in women than in men, both in patients and in controls. In patients, leptin levels were correlated with age, BMI, fasting insulin, insulin area under curve and lower insulin sensitivity, whereas leptin levels were not correlated with body fat or other parameters of body composition. In controls, leptin levels were correlated with BMI and body fat. The results were evaluated using logistic regression models for each of the 2 populations. In the model of MyD, insulin resistance and age correctly identified higher leptin levels in relation to controls out of 87.88% of patients, and in the model of controls male sex with a negative correlation and BMI correctly identified their leptin levels out of 84.33% cases. CONCLUSIONS: These findings show that MyD provides a different model of leptin regulation in humans, and suggest that in MyD patients there are correlations between leptin and insulin resistance and age, irrespective of body fat. In contrast, leptin levels in controls, correlate with sex and BMI. The data on leptin in this population of patients can not be related aetiologically to the muscle disease itself.

[Insulin resistance and metabolic syndrome in first-degree relatives of patients with NIDDM]. / Resistencia a la insulina y síndrome metabólico en familiares de primer grado de pacientes con diabetes mellitus tipo 2.

BACKGROUND: Relatives of type 2 diabetes mellitus (DM2) patients present or can develop the plurimetabolic syndrome (MS). Insulin sensitivity determination could be useful to detect relatives with higher risk. PATIENTS AND METHODS: Insulin sensitivity (IS) and MS in 106 first degree relatives of DM2 and 52 control subjects, matched for age, sex and body mass index (BMI). Insulin sensitivity was evaluated by the HOMA method. Insulin sensitivity was classified as high, middle or low according to the percentiles 33 and 66 observed in the control group. MS was diagnosed if hyperglycemia, hypertension, hypertriglyceridemia and overweight (two or more) were present. RESULTS: Insulin sensitivity was lower in relatives (36.3 vs 51.8%; p = 0.0001). Relatives with lower insulin sensitivity (n = 56) have higher BMI (29.2 vs 25.6 kg/m2), higher systolic (128 vs 116 mmHg) and diastolic (80 vs 74) blood pressure, hyperglycemia (5.7 vs 5.1 mmol/l), hyperinsulinemia (116 vs 59 pmol/l) and hypertriglyceridemia (1.4 vs 1.0 mmol/l) when compared with the remainder relatives (n = 50). Age, sex, waist/hip ratio and cholesterol level were similar in both groups. 23 relatives have MS (20 of them with low insulin sensitivity, relative risk = 8.7; 95% confidence interval 2.4-31.6). In multiple logistic regression analysis, only age and IS have a significant value to predict the presence of MS. CONCLUSIONS: Relatives of DM2 are insulin-resistant and present a high prevalence of MS. Both insulin sensitivity and MS are highly correlated. Insulin sensitivity evaluation using a simple methodology like HOMA can be useful in the selection of relatives at higher risk of MS.

[Diabetes mellitus associated with the A3243G mutation of mitochondrial DNA. Apropos a case]. / Diabetes mellitus asociada a la mutación A3243G de ADN mitocondrial. A proposito de un caso.

The mitochondrial A3243G mutation of the tRNA(Leu) has been described in pedigrees with maternally inherited diabetes mellitus and deafness. Ten diabetic patients with sensorineural deafness were studied. Polymerase chain reaction and enzyme restriction analysis with Apa I were performed. The mutation was found in heteroplasmy in only one patient (1/10). She was a 43-years-old woman with maternally inherited diabetes and deafness since she was 29. The association of sensorineural deafness and maternal inherited diabetes are the clues to suspect this subtype of diabetes.

Clinical presentation and early course of type 1 diabetes in patients with and without thyroid autoimmunity.

OBJECTIVE: To evaluate the prevalence of thyroid autoimmunity (TAI) in patients with recent-onset type 1 diabetes and to determine the influence of TAI on the clinical presentation and evolution of type 1 diabetes. RESEARCH DESIGN AND METHODS: We studied 111 newly diagnosed type 1 diabetes patients > 13 years old. The diagnosis of TAI was based on medical history and measurement of thyroid peroxidase (microsomal) antibodies (TPOAs). Clinical presentation of diabetes, beta-cell autoimmune markers (GADAs and 1A2As), and evolution of insulin-secretory reserves and metabolic control during the first 2 years of follow-up were analyzed. Differences between groups were evaluated by Student's t test or the chi 2 test. The influence of TAI on follow-up data was evaluated by multiple logistic regression analysis. RESULTS: TAI was present in 31 patients (14 TPOA+ patients with normal thyroid function, 12 TPOA+ patients with thyroid dysfunction, and 5 patients with previously diagnosed TAI). TAI was more prevalent in women than in men (43.7 vs. 15.9%, P = 0.001). beta-Cell autoimmunity was more prevalent in patients with TAI than in those without TAI (93.5 vs. 76.3%, P = 0.03). The evolution of insulin requirements, metabolic control, and insulin-secretory reserves was comparable in the two groups. CONCLUSIONS: TAI is present in many type 1 diabetes patients at the time of diagnosis and is associated with a high prevalence of thyroid dysfunction. The clinical presentation of diabetes and the evolution of metabolic control and insulin-secretory reserves are not influenced by the presence of TAI. Patients with type 1 diabetes should be screened for TAI at diagnosis.

Serum ferritin as a component of the insulin resistance syndrome.

OBJECTIVE: In epidemiological studies, serum ferritin was the second-strongest determinant of blood glucose (after BMI) in regression models and the third-strongest determinant of serum insulin (after BMI and age). Its concentration also correlated positively with plasma triglycerides and apolipoprotein B concentrations, and negatively with HDL2 cholesterol. We hypothesized that serum ferritin could be a marker of insulin resistance. RESEARCH DESIGN AND METHODS: Oral glucose tolerance and insulin sensitivity (SI, minimal model method) were prospectively evaluated in 36 healthy subjects. The relationship between serum ferritin and metabolic control (as measured by HbA1c levels) was also studied in 76 consecutive NIDDM patients. RESULTS: In healthy subjects, log-transformed serum ferritin (LOGFER) correlated with basal serum glucose (r = 0.44, P = 0.007), but not with BMI, age, systolic or diastolic blood pressure, total cholesterol, VLDL cholesterol, HDL cholesterol, total triglycerides, VLDL triglycerides, serum insulin, or HbA1c (all P = NS). Identical results were obtained when the two lowest quartiles of serum ferritin were evaluated separately. However, in the two highest quartiles, LOGFER correlated with BMI (0.50, P = 0.02), diastolic blood pressure (r = 0.8, P < 0.0001), serum LDL cholesterol (r = 0.57, P = 0.01), VLDL cholesterol (r = 0.48, P = 0.03), total cholesterol and HDL2 and HDL3 subtractions of HDL cholesterol (r = -0.68, -0.76, -0.55, P = 0.001. < 0.0001, and 0.01, respectively), total triglycerides (r = 0.60, P = 0.006), HDL2/HDL3 quotient (P = -0.71, P = 0.001), VLDL triglycerides (r = 0.65, P = 0.004), and serum uric acid (r = 0.51, P = 0.03), but not with systolic blood pressure (r = 0.38, P = 0.15). After adjusting for BMI, only the correlations between LOGFER and diastolic blood pressure (r = 0.7, P = 0.002) and HDL2/HDL3 quotient (r = -0.63, P = 0.01) remained significant. Strong correlations between LOGFER and glucose area under the curve during oral glucose tolerance test (Pearson's r = 0.73, P = 0.001) and SI (r = -0.68, P = 0.001), which remained significant after controlling for BMI, were observed. LOGFER (beta = -0.44, P = 0.01) and BMI (beta = -0.52, P = 0.004) constituted independent predictors of insulin sensitivity in a multivariate analysis (R2 = 0.68). In 76 consecutive NIDDM outpatients, serum glucose (P < 0.00001) and LOGFER (P = 0.03) independently predicted the value of HbA1c (R2 = 0.40) in a multiple linear regression analysis. CONCLUSIONS: The correlations among serum ferritin and diastolic blood pressure, HDL quotient, glucose area under the curve, and SI suggest that serum ferritin could be a marker of the insulin resistance syndrome. Serum ferritin may also be an independent determinant of poor metabolic control in the diabetic patient.

[Autoimmune thyroid pathology in recently diagnosed diabetes mellitus type 1]. / Patología tiroidea autoinmunitaria en diabetes mellitus tipo 1 de reciente diagnóstico.

OBJECTIVE: To analyze the prevalence of autoimmune thyroid disease among adult patients with recently diagnosed diabetes mellitus type I and its possible correlation with beta-cell autoimmunity markers (ICA, GAD, and IA 2) and with the presentation characteristics of diabetes mellitus. PATIENTS AND METHODS: A total of 100 patients diagnosed from 1992 to 1996 were included and anti-thyroid antibodies (Ac), anti-thyroglobulin (aTG) and antiperoxidase (aTPO) were measured. A comparison followed of the clinical characteristics, biochemical markers, and beta-cell immunity markers between the group of patients with positive and negative antibody determinations. Differences between groups were compared by the Student "t" test and non-parametric tests were used for cases not fulfilling the application conditions. RESULTS: Among the 100 patients, 25 had Ac+, two with previously known thyroid pathology and eight diagnosed at that moment. The group with Ac+ was characterized by a predominance of females (68% vs 32%; p = 0.001), lower bicarbonate levels (18.6 +/- 6.1 vs 21.3 +/- 6.4; p = 0.026) and higher requirements for insulin at discharge (0.77 +/- 0.22 vs 0.59 +/- 0.25 IU/kg; p = 0.002). Among patients in the Ac+ group, patients with thyroid pathology were characterized by a higher prevalence of females (90% vs 53.3%; p = 0.05) and a higher percentage of individuals with high anti-TPO titres (80% vs 33.3% higher than 400 IU/ml; p = 0.02). ICAs (66.6% vs 26.6% higher than 40 U JDF; p = 0.05) and IA2 (44.4% vs 0% higher than 12 IU/ml, p = 0.01). CONCLUSIONS: There is a high prevalence of thyroid pathology prevalence among our adult population with recently diagnosed DMI. Patients with thyroid autoimmunity have higher antibody titres to beta-cell and a somewhat more severe clinical presentation form. Prospective studies are required to determine the long term relevance of these differences.

Improved metabolic control preserved beta-cell function two years after diagnosis of insulin-dependent diabetes mellitus.

To determine whether improved metabolic control during the first two years of insulin-dependent diabetes (IDDM) modified beta cell function, we studied 108 subjects with recent-onset IDDM diagnosed between March 1986 and April 1992 and followed up prospectively for 2 years. Two insulin regimens were used: 1) conventional insulin treatment (CIT) (1986-90, n = 67) involving a mixture of regular and intermediate insulin before breakfast and dinner; and 2) intensive insulin treatment (IIT) (1990-92, n = 41) providing regular insulin before breakfast and lunch, and a mixture of regular and long-acting insulin before dinner. Glucagon-stimulated C-peptide was determined at diagnosis and at 3, 6, 12 and 24 months. Both groups had similar clinical, metabolic and immunological characteristics at diagnosis. The IIT group had better metabolic control at any given time-point after diagnosis (mean HbA1 during follow-up in CIT: 9.86 +/- 0.28%; IIT: 8.18 +/- 0.04%; p < 0.001) (normal < 9.0%). C-peptide was increased in the IIT group 3 and 6 months after diagnosis (month 0: 0.36 +/- 0.05 nmol/l; month 6: 0.55 +/- 0.06 nmol/l; p < 0.006), but not in the CIT group (month 0: 0.39 +/- 0.04 nmol/l; month 6: 0.45 +/- 0.04 nmol/l; p = NS). Two years after diagnosis, the IIT group maintained initial C-peptide secretion (2 years: 0.37 +/- 0.04 nmol/l) whereas C-peptide was reduced in the CIT group (2 years: 0.23 +/- 0.06 nmol/l) compared to the initial value (p < 0.001) or to that of the IIT group (p = 0.017). Thus, sustained improvement in metabolic control with IIT resulted in better beta-cell function during the first two years after IDDM diagnosis.

The TNF-alpha gene Nco I polymorphism influences the relationship among insulin resistance, percent body fat, and increased serum leptin levels.

Tumor necrosis factor-alpha (TNF-alpha), acting as a modulator of gene expression in adipocytes, is implicated in the development of insulin resistance and obesity. The aim of this study was to investigate whether the Nco I polymorphism of the TNF-alpha gene influences the relationship among insulin resistance, percent body fat, and serum leptin levels. A sample of 38 subjects (19 men, mean age 36.2 +/- 1.9 years, BMI 28.8 +/- 1.2 kg/m2, range 22.2-35.7; and 19 women, age 34.9 +/- 1.4 years, BMI 28.1 +/- 0.8 kg/m2, range 19-37.9) was divided into two groups on the basis of the Nco I genotype. Twenty-three subjects were (+/+) homozygotes for the presence of the Nco I restriction site that is associated with a guanine at position -308 of the TNF-alpha promoter. Of the other subjects, 12 were (+/-) heterozygotes and 3 (-/-) homozygotes for the absence of the restriction site, resulting from a guanine-to-adenine substitution at position -308 of the TNF-alpha promoter. This substitution (termed TNF-2) leads to higher rate of transcription of TNF-alpha than the wild-type allele TNF-1 in vitro. TNF-1 (+/+) and TNF-2 (+/- and -/-) groups of subjects were comparable in sex, age, BMI, waist-to-hip ratio, and several skinfold measurements. Basal serum insulin was greater (14.2 +/- 2 vs. 9.2 +/- 0.9 mU/l, P = 0.041) in the TNF-2 group in the presence of comparable serum glucose concentration. The integrated area under the curve of serum insulin concentrations, measured in response to a 75-g oral glucose challenge, and the percent body fat, measured by bioelectric impedance, were significantly increased in TNF-2 subjects (226.8 +/- 33 vs. 139.4 +/- 17.8 mU/l, P = 0.032; 33.6 +/- 2.8 vs. 24.9 +/- 2%, P = 0.01). TNF-2 subjects also showed a decreased insulin sensitivity index, as determined by the frequently sampled intravenous glucose tolerance test with minimal model analysis (1.9 +/- 0.4 vs. 3.05 +/- 0.3 min(-1) x mU(-1) x l(-1), P = 0.03). These differences were more marked among women. Paralleling the known relationship between insulin and leptin levels, serum leptin concentration was clearly increased in the TNF-2 group (19.6 +/- 3.4 vs. 11.1 +/- 1.5 ng/ml, P = 0.03). Therefore, (+/-) heterozygotes and (-/-) homozygotes may be more susceptible to developing insulin resistance and increased percent body fat. Results of the present study suggest that TNF-alphaNco I polymorphism may exacerbate the alterations in leptin levels normally found among insulin-resistant subjects.

[The influence of clinical presentation and metabolic control of insulin dependent diabetes in the evolution of residual insulin secretion. A prospective study at five years]. / Influencia de la presentación clínica y del control metabólico de la diabetes insulinodependiente en la evolución de la secreción residual de insulina. Estudio prospectivo a cinco años.

BACKGROUND: To study the influence of clinical, metabolic and immunological parameters during the first years of the evolution of insulin-dependent diabetes mellitus (IDDM) on the long-term residual insulin secretion (IS). PATIENTS AND METHODS: 186 IDDM subjects diagnosed from 1986 to 1993 were included; 135 subjects have completed a two year follow-up, and 57 have completed a five year follow-up. The influence of individual characteristics at diagnosis (age, sex, clinical presentation, islet-cell antibodies) and during the first two years of follow-up (IS, metabolic control) on IS at five years was evaluated by multiple linear regression. Differences between groups were evaluated by non-parametric tests. RESULTS: 18 patients had a significant insulin secretion at five years (post-glucagon C-peptide > or = 0.15 nmol/l). They showed minor significant differences in sex (77.7 vs 48.7% of males, p = 0.03), duration of symptoms (12.9 vs 7.2 weeks, p = 0.01), ketoacidosis at diagnosis (23.3 vs 46.1%, p = 0.07) and ICA positivity at diagnosis (41.1 vs 69.4%, p = 0.05). They also had a better metabolic control (8.8 vs 10.8% of HbA1, p < 0.001) with lss insulin (0.48 vs 0.71 Ul/kg, p < 0.001) during the first two years of evolution. Initial IS was similar, but differences became significant at 6 months. In the multivariate analysis, only metabolic control during the second year of evolution (p = 0.008), ketoacidosis at diagnosis (p = 0.026) and sex (p = 0.026) had an independent influence on IS at five years. A more intensified therapeutic approach introduced in 1990 induced a better metabolic control and higher IS during the first years of follow-up. CONCLUSION: The absence of ketoacidosis at diagnosis and a good metabolic control during the first two years can have a positive influence in the long-term preservation of IS in IDDM patients.