Novel germline variants of CDKN1B and CDKN2C identified during screening for familial primary hyperparathyroidism.

PURPOSE: CDKN1B mutations were established as a cause of multiple endocrine neoplasia 4 (MEN4) syndrome in patients with MEN1 phenotype without a mutation in the MEN1 gene. In addition, variants in other cyclin-dependent kinase inhibitors (CDKIs) were found in some MEN1-like cases without the MEN1 mutation. We aimed to describe novel germline mutations of these genes in patients with primary hyperparathyroidism (PHPT). METHODS: During genetic screening for familial hyperparathyroidism, three novel CDKIs germline mutations in three unrelated cases between January 2019 and November 2021 were identified. In this report, we describe clinical features, DNA sequence analysis, and familial segregation studies based on these patients and their relatives. Genome-wide DNA study of loss of heterozygosity (LOH), copy number variation (CNV), and p27/kip immunohistochemistry was performed on tumour samples. RESULTS: DNA screening was performed for atypical parathyroid adenomas in cases 1 and 2 and for cystic parathyroid adenoma and young age at diagnosis of PHPT in case 3. Genetic analysis identified likely pathogenic variants of CDKN1B in cases 1 and 2 and a variant of the uncertain significance of CDKN2C, with uniparental disomy in the tumour sample, in case 3. Neoplasm screening of probands showed other non-endocrine tumours in case 1 (colon adenoma with dysplasia and atypical lipomas) and case 2 (aberrant T-cell population) and a non-functional pituitary adenoma in case 3. CONCLUSION: Germline mutations in CDKIs should be included in gene panels for genetic testing of primary hyperparathyroidism. New germline variants here described can be added to the current knowledge.

Glucagon stimulation test to assess growth hormone status in Prader-Willi syndrome.

PURPOSE: Growth hormone deficiency (GHD) must be confirmed before starting treatment in adults with Prader-Willi syndrome (PWS). Most studies use the growth-hormone-releasing hormone plus arginine (GHRH-arginine) test. No data are available on the glucagon stimulation test (GST) in PWS. We compared the utility of fixed-dose (1 mg) GST versus GHRH-arginine test in diagnosing GHD. METHODS: Adults and late adolescents with PWS underwent both tests on separate days. In the GHRH-arginine test, GHD was defined according to body mass index. In the GST, two cutoffs were analyzed: peak GH concentration < 3 ng/mL and < 1 ng/mL. For analyses, patients were divided into two groups according to body weight (≤ 90 kg and > 90 kg). RESULTS: We analyzed 34 patients: 22 weighing ≤ 90 kg and 12 weighing > 90 kg. In patients weighing ≤ 90 kg, the two tests were concordant in 16 (72.72%) patients (k = 0.476, p = 0.009 with GST cutoff < 3 ng/mL, and k = 0.450, p = 0.035 with GST cutoff < 1 ng/mL). In patients weighing > 90 kg, the two tests were not concordant with GST cutoff < 3 ng/mL, but were concordant in 11 (91.6%) patients (k = 0.833, p = 0.003) with GST cutoff < 1 ng/mL. GH peaks on the two tests correlated (r = 0.725, p = 0.008). CONCLUSION: Fixed-dose (1 mg) GST using a peak GH cutoff of < 3 ng/mL or < 1 ng/mL promises to be useful for screening for GHD in adults and late adolescents with PWS. However, in those weighing > 90 kg, the < 1 ng/mL cutoff seems better. Larger studies are necessary to establish definitive glucagon doses and cutoffs, especially in extremely obese patients.

Low frequency of positive antithyroid antibodies is observed in patients with thyroid dysfunction related to immune check point inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICI), such as programmed death-1 inhibitors (anti-PD1), have become a cornerstone for the treatment of different advanced cancers. These antibodies act as modulators of immune checkpoint proteins. However, ICI can lead to the breaking of immune self-tolerance, inducing autoimmune side effects (irAEs), including endocrinopathies. One of the most frequent endocrine irAE of anti-PD1 is thyroid dysfunction, but the exact mechanism of this disease still remains unknown. MATERIALS AND METHODS: We conducted a descriptive retrospective study, analyzing 11 patients who received at least one dose of anti-PD1 (nivolumab or pembrolizumab) and presented thyroid irAEs. Data were collected between September 2015 and May 2018 in our hospital. The aim was to analyze the clinically relevant features of thyroid irAEs and the frequency of antithyroid antibodies (ATA) positivity observed on them. RESULTS AND DISCUSSION: 8 of the 11 patients were treated with nivolumab and the other three patients received pembrolizumab. Six patients presented silent thyroiditis with a thyrotoxicosis phase; three patients developed directly primary/subclinical hypothyroidism and two patients showed primary hyperthyroidism. Thyroid autoantibodies (anti-Thyroglobulin and anti-Thyroid Peroxidase) were assessed in all the 11 patients, and only in two of them (18%) a positive titer was displayed. Anti-TSH receptor antibodies (TRAbs) were examined in five patients, three with painless thyroiditis at the time of thyrotoxicosis and two with primary hyperthyroidism, and they all had undetectable levels. CONCLUSIONS: In our sample of 11 Caucasian patients with thyroid dysfunction related with anti-PD1, we found low frequency of ATA positive titers, comparable to other recent reports in others ethnicities, which could suggest that silent thyroiditis due to pembrolizumab or nivolumab has a different pathogenesis from the classical autoimmune spontaneous thyroiditis. Further investigations are required to completely understand the immune mechanisms involved.

Lipopolysaccharide-binding protein is increased in patients with psoriasis with metabolic syndrome, and correlates with C-reactive protein.

Lipopolysaccharide-binding protein (LBP) is a reliable indicator of serum lipopolysaccharide (LPS) concentration. Raised levels of circulating LPS can trigger an increase in chronic pro-inflammatory cytokines, which may mediate the development of insulin resistance and obesity. Psoriasis is a chronic inflammatory skin disease that has been associated with metabolic syndrome. We aimed to study the expression of LBP in patients with psoriasis treated with narrowband ultraviolet B phototherapy, and controls matched by age, gender and body mass index (BMI). We did not find any differences in serum LBP concentration between patients and controls, and serum LBP did not correlate with the Psoriasis Area and Severity Index. However, patients with psoriasis and metabolic syndrome had higher serum concentration of LBP than controls. Furthermore, correlation with BMI and apolipoprotein B was present in controls, but not in patients with psoriasis. Serum LBP level did not change significantly after treatment with phototherapy.

Effect of narrowband ultraviolet B therapy on inflammatory markers and body fat composition in moderate to severe psoriasis.

BACKGROUND: Previous studies have shown increased prevalence of metabolic syndrome in patients with psoriasis. OBJECTIVES: To characterize the anthropometric and metabolic profile of Spanish patients with moderate to severe psoriasis compared with controls without psoriasis matched for gender, age and body mass index (BMI), and to evaluate the impact of narrowband ultraviolet B (NB-UVB) therapy on patient profiles. METHODS: Baseline waist circumference, body fat composition, lipid, carbohydrate and calcium metabolism profile, inflammation markers, homocysteine, vitamins D, B(6) and B(12) and folic acid of 50 patients with psoriasis and 50 matched controls were recorded then evaluated after NB-UVB in patients with psoriasis and correlated with clinical outcome. RESULTS: Despite very similar BMIs, 54% of patients met International Diabetes Foundation criteria for metabolic syndrome compared with 42% of controls (P = 0·01); body fat was 29·9% in patients and 28·0% in controls (P = 0·037), correlating with waist circumference; while patient atherogenic profiles were less favourable, with higher apolipoprotein B and low density lipoprotein cholesterol than controls, and both patients and controls showed insufficient vitamin D serum levels (< 20 ng mL(-1)). Mean improvement of Psoriasis Area and Severity Index (PASI) after NB-UVB was 78·2%. Ferritin, B(12) and C-reactive protein decreased significantly after NB-UVB therapy. Vitamin D levels reached adequate levels after phototherapy; however, no relationship with PASI improvement was observed. CONCLUSIONS: We characterized inflammatory and atherogenic profiles of Spanish patients with psoriasis compared with matched controls. After NB-UVB therapy we demonstrated improvement in psoriasis and some systemic inflammation markers, which were not mediated by enhancement of vitamin D synthesis.

Artificial neural network algorithm for online glucose prediction from continuous glucose monitoring.

BACKGROUND AND AIMS: Continuous glucose monitoring (CGM) devices could be useful for real-time management of diabetes therapy. In particular, CGM information could be used in real time to predict future glucose levels in order to prevent hypo-/hyperglycemic events. This article proposes a new online method for predicting future glucose concentration levels from CGM data. METHODS: The predictor is implemented with an artificial neural network model (NNM). The inputs of the NNM are the values provided by the CGM sensor during the preceding 20 min, while the output is the prediction of glucose concentration at the chosen prediction horizon (PH) time. The method performance is assessed using datasets from two different CGM systems (nine subjects using the Medtronic [Northridge, CA] Guardian and six subjects using the Abbott [Abbott Park, IL] Navigator. Three different PHs are used: 15, 30, and 45 min. The NNM accuracy has been estimated by using the root mean square error (RMSE) and prediction delay. RESULTS: The RMSE is around 10, 18, and 27 mg/dL for 15, 30, and 45 min of PH, respectively. The prediction delay is around 4, 9, and 14 min for upward trends and 5, 15, and 26 min for downward trends, respectively. A comparison with a previously published technique, based on an autoregressive model (ARM), has been performed. The comparison shows that the proposed NNM is more accurate than the ARM, with no significant deterioration in the prediction delay. CONCLUSIONS: The proposed NNM is a reliable solution for the online prediction of future glucose concentrations from CGM data.

Consenso sobre el uso de la monitorización continua de glucosa / Position statement on continuous glucose monitoring

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The inflammatory properties of electronegative low-density lipoprotein from type 1 diabetic patients are related to increased platelet-activating factor acetylhydrolase activity.

AIMS/HYPOTHESIS: Chemical and biological characteristics of LDL(-) from type 1 diabetic subjects were analysed. The diabetic patients were studied during poor and optimised glycaemic control. MATERIALS AND METHODS: Total LDL was subfractionated into electropositive LDL(+) and electronegative LDL(-) by anion exchange chromatography and the lipid and protein composition of the two determined. RESULTS: LDL(-) differed from LDL(+) in that it had higher triglyceride, non-esterified fatty acids, apoE, apoC-III and platelet-activating factor acetylhydrolase (PAF-AH), as well as lower apoB relative content. No evidence of increased oxidation was observed in LDL(-). LDL(-) increased two-fold the release of interleukin 8 (IL-8) and monocyte chemotactic protein 1 (MCP-1) in endothelial cells, suggesting an inflammatory role. Optimisation of glycaemic control after insulin therapy decreased the proportion of LDL(-), but did not modify the composition of LDL subfractions, except for a decrease in PAF-AH activity in LDL(-). The possibility that LDL(-) could be generated by non-enzymatic glycosylation was studied. Fructosamine and glycated LDL content in LDL subfractions from type 1 diabetic patients was greater than in LDL subfractions isolated from normoglycaemic subjects, and decreased after glycaemic optimisation in both subfractions. However, no difference was observed between LDL(+) and LDL(-) before and after insulin therapy. CONCLUSIONS/INTERPRETATION: These results provide evidence that LDL(-) is not produced by glycosylation. Nevertheless, LDL(-) from diabetic patients displays inflammatory potential reflected by the induction of chemokine release in endothelial cells. This proatherogenic effect could be related to the high PAF-AH activity in LDL(-).

[Degree of satisfaction of primary health workers regarding a consultancy-based specialty care model]. / Grado de satisfacción de los profesionales de Atención Primaria con un modelo de actividad especializada basado en la consultoría.

OBJECTIVE: To evaluate the degree of satisfaction of primary health care workers with a model of specialty care based on consultancy. METHODS: A questionnaire was delivered to the nurses and physicians of a Primary Care centre, in order to assess their satisfaction with the different activities in the specialty of endocrinology (1-5 points). RESULTS: The consultancy activity itself was given 4.41 +/- 0.89 points by the nurses (n = 39) and 3.60 +/- 0.97 by physicians (n = 32) (p < 0.05), clinical sessions, 4.21 +/- 0.74 and 3.82 +/- 1.02, and diagnostic and therapeutic protocols, 4.12 +/- 0.71 points (physicians) (p < 0.05 vs consultancy). Global scores was 4.33 +/- 0.70 and 3.76 +/- 0.89 points, respectively. 74% and 80% of the nurses and 58% and 69% of the physicians considered the present model appropriate for other specialties and primary care center, respectively. CONCLUSIONS: The health care workers at the primary care center assesse show a high degree of satisfaction with this model of specialised care based on consultancy.

Influence of exogenous insulin on C-peptide levels in subjects with type 2 diabetes.

AIM: The aim of this study was to determine whether the influence of insulin therapy on fasting and stimulated C-peptide levels in type 2 diabetic subjects is due to plasma glucose reduction or a direct effect of exogenous insulin. METHODS: Plasma glucose and serum C-peptide levels were determined before and after IV injection of 1mg glucagon on three separate days in 21 type 2 diabetic subjects. Day 1: without pharmacological treatment and fasting plasma glucose > 11.1 mmol/L; day 2: fasting plasma glucose 4.4-7.8 mmol/L, 1h after withdrawing intravenous regular insulin infusion; day 3: fasting plasma glucose 4.4-7.8 mmol/L with bed-time NPH insulin. RESULTS: Fasting and glucagon stimulated C-peptide levels were higher on day 1 than days 2 and 3. Fasting, but not stimulated C-peptide levels, were lower on day 3 than day 2. These differences were not appeared when the percentage of C-peptide increment or the C-peptide/glucose ratio were compared in the three days. CONCLUSIONS: Blood glucose reduction instead of exogenous insulin is responsible for the C-peptide decrease during insulin therapy in type 2 diabetic subjects.

Grado de satisfacción de los profesionales de Atención Primaria con un modelo de actividad especializada basado en la consultoría / Degree of satisfaction of Primary Health workers regarding a consultancy-based specialty care model

Objetivo. Evaluar el grado de satisfacción de los profesionales de un centro de Atención Primaria con un modelo de asistencia especializada basada en la consultoría. Métodos. Se realizó una encuesta a médicos y enfermería que valoraba cada una de las actividades de Endocrinología en el centro de Atención Primaria y una valoración global (1-5 puntos). Resultados. La consultoría se valoró en 4,41 ± 0,89 por las enfermeras (n = 39) y 3,60 ± 0,97 por los médicos (n = 32) (p < 0,05), las sesiones clínicas en 4,21 ± 0,74 y 3,82 ± 1,02 y los protocolos diagnóstico-terapéuticos en 4,12 ± 0,71 (médicos) (p < 0,05 frente a interconsultas). La puntuación global fue de 4,33 ± 0,70 y 3,76 ± 0,89, respectivamente. El 74% y 80% de las enfermeras y 58% y 69% de los médicos consideran a este modelo apropiado para otras especialidades y centros de Atención Primaria, respectivamente. Conclusiones. Los profesionales del Centro de Atención Primaria Maragall muestran un alto grado de satisfacción con este modelo de atención especializada basado en la consultoría

Objective. To evaluate the degree of satisfaction of Primary Health care workers with a model of specialty care based on consultancy. Methods. A questionnaire was delivered to the nurses and physicians of a Primary Care centre, in order to assess their satisfaction with the different activities in the specialty of Endocrinology (1-5 points). Results. The consultancy activity itself was given 4.41 ± 0.89 points by the nurses (n = 39) and 3.60 ± 0.97 by physicians (n = 32) (p < 0.05), clinical sessions, 4.21 ± 0.74 and 3.82 ± 1.02, and diagnostic and therapeutic protocols, 4.12 ± 0.71 points (physicians) (p < 0.05 vs consultancy). Global scores was 4.33 ± 0.70 and 3.76 ± 0.89 points, respectively. 74% and 80% of the nurses and 58% and 69% of the physicians considered the present model appropriate for other specialties and Primary Care center, respectively. Conclusions. The health care workers at the Primary Care center assesse show a high degree of satisfaction with this model of specialised care based on consultancy

Cetoacidosis diabética grave tratadaexcesivamente con bicarbonato / Excessive bicarbonate treatment in severe diabetic ketoacidosis

La cetoacidosis diabética es una descompensación aguda hiperglucémica definida por la presencia de acidosis (pH < 7,15 y/o bicarbonato sérico < 15 mEq/l) secundaria a un exceso de producción de cuerpos cetónicos. El tratamiento con bicarbonato sódico en la cetoacidosis aguda es objeto de controversia. Muchas guías clínicas recomiendan su administración en aquellas situaciones en las que el pH sea inferior a 7,0. Presentamos el caso de un paciente con diabetes mellitus tipo 1 con descompensación cetoacidótica (pH = 6,65) que recibió más de 200 mEq de bicarbonato sódico durante las primeras 12 h de su asistencia en el servicio de urgencias. El paciente presentó un estado de shock hemodinámico precisando intubación orotraqueal, ventilación mecánica y fármacos vasoactivos. A propósito de este caso, se discuten las ventajas y los inconvenientes del uso de bicarbonato sódico en la cetoacidosis diabética (AU)

LDL-cholesterol/apolipoprotein B ratio is a good predictor of LDL phenotype B in type 2 diabetes.

LDL phenotype B is a component of diabetic dyslipidaemia, but its diagnosis is cumbersome. Our aim was to find easily available markers of phenotype B in a group of type 2 diabetic subjects. We studied 123 type 2 diabetic patients (67.5% male, aged 59.3+/-10.1 years, mean HbA1c 7.4%). Clinical features and fasting total cholesterol, triglyceride, HDL cholesterol, LDL cholesterol (LDLc, using Friedewald's equation and an alternative formula), apolipoprotein B (apoB), lipoprotein (a) and LDL particle size (on gradient polyacrylamide gel electrophoresis) were assessed. Patients with phenotypes A (predominant LDL size > or =25.5 nm) and B (<25.5 nm) were compared, and regression analysis was performed to find the best markers of LDL particle. Cut-off points were obtained and evaluated as predictors of phenotype B (kappa index). Patients with phenotype B (36%) showed higher total cholesterol, triglyceride and apolipoprotein B, and lower HDL cholesterol and LDLc/apoB ratio. Triglyceride was the best predictor of LDL particle size (r=-0.632, p<0.01), but an LDLc/apoB ratio below 1.297 mmol/g detected phenotype B best (sensitivity 65.9%, specificity 92.4%, kappa=0.611). Although triglyceride concentration is the best predictor of LDL size in type 2 diabetes, LDLcholesterol/apolipoproteinB ratio is the best tool to detect phenotype B.

Apo(B)-dependent dyslipidemic phenotypes in type 1 diabetic patients.

BACKGROUND: The prevalence of apo(B)-dependent dyslipidemic phenotypes, which are associated with cardiovascular disease, is increased in normocholesterolemic type 2 diabetic patients. Our aim was to determine the impact of including apo(B) in the evaluation of normocholesterolemic type 1 diabetic patients. METHODS: A total of 123 type 1 diabetic patients (47% male, age 36.6+/-12.5 years) were included. The apo(B) cut-off point (1.14 g/l) was obtained from a group of 53 normolipidemic control subjects of similar age and gender distribution; for low density lipoprotein cholesterol (LDLc), triglycerides, and high density lipoprotein cholesterol (HDLc), we used the cut-off points recommended by the National Cholesterol Education Program. LDLc was determined by ultracentrifugation or Friedewald's equation, depending on triglyceride concentrations, and apo(B) by immunoturbidimetry. RESULTS: A total of 113 (92%) type 1 diabetic patients were normocholesterolemic, and 13% of these were dyslipidemic. The frequency of hyperapo(B) was similar in normocholesterolemic patients and controls (6.2 vs. 9.4%, respectively). Diabetic patients with hyperapo(B) had poorer glycemic control, higher total cholesterol, triglycerides, and LDLc, and a lower HDLc and LDLc/apo(B) ratio. CONCLUSIONS: Unlike type 2 diabetes, type 1 diabetes is not associated with an increased prevalence of hyperapo(B)-dependent dyslipidemic phenotypes. Thus, only in patients with poor glycemic control who display other components of diabetic dyslipidemia, typical for type 2 diabetes, does determining apo(B) concentrations provide additional information in type 1 diabetes.

Effect of glycemic optimization on electronegative low-density lipoprotein in diabetes: relation to nonenzymatic glycosylation and oxidative modification.

The effect of insulin therapy on low-density lipoprotein (LDL) oxidizability, proportion of electronegative LDL [LDL(-)] and LDL composition was studied in 33 type 2 diabetic patients. Before glycemic control improvement, type 2 diabetic subjects presented higher triglyceride and very low-density lipoprotein cholesterol and lower high-density lipoprotein cholesterol than 25 healthy matched subjects. Furthermore, their LDL was more susceptible to oxidation (lag phase 45.9 +/- 5.4 min vs. 49.7 +/- 7.6 min, P < 0.05), contained a higher proportion of LDL(-) (19.0 +/- 8.7% vs. 14.3 +/- 5.5%, P < 0.05), and was enriched in triglyceride and depleted in cholesterol and phopholipids. Lipoprotein profile improved after glycemic optimization but failed to change either LDL oxidizability (45.3 +/- 6.2 min) or LDL(-) (17.9 +/- 8.2%). These data suggest that oxidation rather than nonenzymatic glycosylation could be related to the high LDL(-) found in these patients and disagree with results obtained in a previous study of type 1 diabetic patients. A second study was conducted in 10 type 1 and 10 type 2 diabetic subjects under insulin therapy, and the proportions of glycated LDL (gLDL) and LDL(-) were determined. Basal gLDL (2.8 +/- 0.6%) and LDL(-) (20.7 +/- 6.1%) decreased in type 1 diabetics after glycemic optimization (1.9 +/- 0.6% and 15.4 +/- 3.4%, respectively; P < 0.05). In type 2 patients, even though gLDL decreased (from 2.2 +/- 0.6% to 1.6 +/- 0.6%, P < 0.05) no effect was observed on LDL(-) (from 17.3 +/- 2.9% to 16.0 +/- 4.3%). We conclude that nonenzymatic glycosylation, which appears as a determinant of the high proportion of LDL(-) in type 1 diabetes, does not play a major role in LDL(-) generation in type 2 diabetes.

Physical training decreases plasma thrombomodulin in type I and type II diabetic patients.

AIMS/HYPOTHESIS: Endothelial damage is an early step in the pathogenesis of atherosclerosis and its improvement through physical training can contribute to the known reduction of cardiovascular risk associated with exercise. An increase in some endothelium-dependent haemostatic parameters, considered as markers of endothelial damage, has been observed in diabetic patients. METHODS: The effect of a three-month physical exercise programme on thrombomodulin, tissue factor pathway inhibitor, plasminogen activator inhibitor, tissue-type plasminogen activator and von-Willebrand factor was evaluated in 14 well-controlled patients with Type I (insulin-dependent) diabetes mellitus and 13 patients with Type II (non-insulin-dependent) diabetes mellitus (HbA1c 6.5 +/- 0.8 and 7.4 +/- 0.8%, respectively). A matched control group was also studied. RESULTS: Thrombomodulin at baseline was higher in both Type I and Type II diabetic patients than in their respective matched control subjects (50.0 +/- 16 vs 31.1 +/- 8.7 microg/l, p < 0.05; 51.0 +/- 10 vs 28.5 +/- 11 microg/l, p <0.05, respectively). After the exercise programme, thrombomodulin plasma concentrations had decreased (p < 0.05) in both groups of patients, with final thrombomodulin values being similar to those observed in their control groups (38.2 +/- 11 microg/l for Type I and 34.6 +/- 12 microg/l for Type II patients). The thrombomodulin decrement correlated with baseline thrombomodulin and VO2max increase in Type I diabetic patients. A decrease in tissue factor pathway inhibitor was also observed in Type II diabetic patients. CONCLUSION/INTERPRETATION: We conclude that the normalisation of plasma thrombomodulin concentrations in Type I and Type II diabetic patients after physical training might reflect the improvement in endothelial function associated with physical exercise.

Prevalence and phenotypic distribution of dyslipidemia in type 1 diabetes mellitus: effect of glycemic control.

BACKGROUND: Data on the prevalence of dyslipidemia in type 1 diabetes mellitus are scarce and are based on total triglyceride and total cholesterol concentrations alone. OBJECTIVE: To assess the effect of glycemic optimization on the prevalence of dyslipidemia and low-density lipoprotein cholesterol (LDL-C) concentrations requiring intervention in patients with type 1 diabetes. PATIENTS: A total of 334 adults with type 1 diabetes and 803 nondiabetic control subjects. METHODS: Levels of glycosylated hemoglobin, total cholesterol, total triglyceride, high-density lipoprotein cholesterol (HDL-C), and LDL-C were assessed at baseline and after 3 to 6 months of intensive therapy with multiple insulin doses. RESULTS: Levels of LDL-C greater than 4.13 mmol/L (>160 mg/dL) and total triglyceride greater than 2.25 mmol/L (>200 mg/dL) and low HDL-C levels (<0.9 mmol/L [<35 mg/dL] in men or <1.1 mmol/L [<45 mg/dL] in women) were found in 16%, 5%, and 20% of patients and 13%, 6%, and 9% of controls, respectively (P<.001 for HDL-C). Diabetic women showed more hypercholesterolemia than nondiabetic women (15.6% vs 8.5%; P =.04). After glycemic optimization (mean +/- SD glycosylated hemoglobin decrease, 2.2 +/- 1.96 percentage points), the prevalence of LDL-C levels greater than 4.13 mmol/L (>160 mg/dL) became lower in diabetic men than in nondiabetic men (9.7% vs 17.5%; P =.04), but women showed frequencies of dyslipidemia similar to their nondiabetic counterparts. The proportion of patients with LDL-C concentrations requiring lifestyle (>2.6 mmol/L [>100 mg/dL]) or drug (>3.4 mmol/L [>130 mg/dL]) intervention decreased from 78% and 42% to 66% and 26%, respectively. CONCLUSIONS: Low HDL-C is the most frequent dyslipidemic disorder in patients with poorly controlled insulin-treated type 1 diabetes, and a high proportion show LDL-C levels requiring intervention. Less favorable lipid profiles could explain the absence of sex protection in diabetic women. The improvement caused by glycemic optimization puts forward intensive therapy as the initial treatment of choice for dyslipidemia in poorly controlled type 1 diabetes.

Normalisation of tissue factor pathway inhibitor activity after glycaemic control optimisation in type 1 diabetic patients.

UNLABELLED: Increased plasma concentrations of various markers of endothelial damage have been observed in type I diabetic patients, particularly in those with microangiopathy. OBJECTIVE: To evaluate the effect of near-normalisation of glycaemic control on different markers of endothelial injury involved in haemostasis in poorly-controlled type 1 diabetic patients. MATERIAL AND METHODS: TFPI, thrombomodulin (TM), plasminogen activator inhibitor, tissue-type plasminogen activator and von Willebrand factor were measured in 14 poorly-controlled type 1 diabetic patients free of diabetes-related complications (8 men, 6 women; mean age 29.8 +/- 9.9 years) before (baseline) and after 3 months of intensive therapy and in 14 sex-, age- and BMI-matched control subjects. RESULTS: After a mean follow-up of 107 +/- 49 days (56-210), HbA1c decreased from 11.2 +/- 2.3 to 6.7 +/- 0.7% (p <0.0001). TFPI activity at baseline was higher than in the control group (126.9 +/- 34 vs 92.0 +/- 13%, p <0.005) and decreased after good glycaemic control was achieved (p <0.005), becoming similar to that in the control group (91.0 +/- 16.5%). The TFPI descent correlated with the variations observed in HbA1c (p <0.05; r = 0.54). TM levels at baseline were significantly higher than in the control group (42.3 +/- 9.1 vs 29.00 +/- 10.9; p <0.005) and did not change. The remaining parameters studied were similar between patients and controls and did not change after glycaemic optimisation. CONCLUSIONS: Optimisation of glycaemic control normalises the increased activity of TFPI but not the higher TM levels observed in poorly-controlled type I diabetic patients without chronic complications.