A. de Leiva

Plasma homocysteine is related to albumin excretion rate in patients with diabetes mellitus: a new link between diabetic nephropathy and cardiovascular disease?

Summary The high risk of cardiovascular disease in patients with diabetes mellitus, particularly in those with nephropathy, is not completely explained by classical risk factors. A high plasma homocysteine concentration is an independent risk factor for cardiovascular disease but information on its association with diabetes is limited. Fasting homocysteine concentrations were measured in the plasma of 165 diabetic patients (75 with insulin-dependent [IDDM]; 90 with non-insulin-dependent diabetes [NIDDM]) and 56 non-diabetic control subjects. Other measurements included the prevalence of diabetic complications, glycaemic control, lipid and lipoprotein levels, vitamin status and renal function tests. Patients with NIDDM had higher homocysteine levels than control subjects, whereas IDDM patients did not (9.2 ± 4.5 vs 7.7 ± 2 μmol/l, p < 0.01; and 7.0 ± 3 vs 7.4 ± 2 μmol/l, NS). Univariate correlations and multiple regression analysis showed albumin excretion rate to be the parameter with the strongest independent association with homocysteine. Patients with both types of diabetes and nephropathy had higher plasma homocysteine concentrations than those without nephropathy. Increases of homocysteine in plasma were related to increases in the severity of the nephropathy. Fasting hyperhomocysteinaemia was considered as the mean of the plasma homocysteine for all control subjects (7.5 ± 2.1 μmol/l) + 2 SD (cut-off =11.7 μmol/l). Nephropathy was present in 80 % of diabetic patients with fasting hyperhomocysteinaemia. In conclusion, increases in fasting homocysteine in diabetic patients are associated with increased albumin excretion rate, especially in those with NIDDM, thus providing a potential new link between microalbuminuria, diabetic nephropathy and cardiovascular disease. [Diabetologia (1998) 41: 684–693]

Assessment of insulin sensitivity and beta-cell function from measurements in the fasting state and during an oral glucose tolerance test.

Aims/hypothesis. We aimed to find if the relation between insulin sensitivity and beta-cell function assessed from fasting and OGTT measurements has a physiological shape (hyperbolic with the reference methods). Methods. Healthy women without diabetic first-degree relatives underwent a 75 g OGTT with plasma glucose and insulin (n = 35) concentrations being measured at 0, 30, 60 and 120 min. Beta-cell function and insulin sensitivity were estimated using previously described indices from fasting (1 for beta-cell function, 6 for insulin sensitivity) and OGTT measurements (3 for beta-cell function and 5 for insulin sensitivity). A hyperbolic relation was tested for the 21 beta-cell function-insulin sensitivity pairs using a non-lineal regression method. Results. The assessment of beta-cell function from OGTT was impossible in seven women and one had outlier indices. For the remaining 27 women, only 8 combinations adjusted to a hyperbolic relation. The best adjustment was achieved using the fasting glucose to insulin ratio as the estimation of insulin sensitivity and the homeostasis model assessment (HOMA) index (single fasting sample) as the estimation of beta-cell function (r2 0.802, k 869.71, p < 0.001). Conclusion/interpretation. In this group of healthy women, the estimation of insulin sensitivity and beta-cell function by most methods using OGTT-derived glucose and insulin measurements did not adjust to a hyperbolic relation but all fasting indices combinations did. Beta-cell function estimated with the HOMA index and insulin sensitivity with fasting glucose to insulin ratio had the best adjustment. [Diabetologia (2000) 43: 1507–1511]

Diabetes classification: grey zones, sound and smoke: Action LADA 1

Diseases gain identity from clinical phenotype as well as genetic and environmental aetiology. The definition of type 1 diabetes is clinically exclusive, comprising patients who are considered insulin dependent at diagnosis, whilst the definition of type 2 diabetes is inclusive, only excluding those who are initially insulin dependent. Ketosis‐prone diabetes (KPD) and latent autoimmune diabetes in adults (LADA) are each exclusive forms of diabetes which are, at least initially, clinically distinct from type 2 diabetes and type 1 diabetes, and each have a different natural history from these major types of diabetes.

Optimization of Glycemic Control by Insulin Therapy Decreases the Proportion of Small Dense LDL Particles in Diabetic Patients

Small dense LDL particles (B phenotype) are considered to be more atherogenic than large buoyant LDL particles. The influence of glycemic control on LDL particle size and density is still under debate. The aim of this study was to determine LDL subfraction phenotype in both IDDM and NIDDM patients in poor glycemic control compared with that of respective matched control groups. In addition, we evaluated the effect of a 3-month period of optimized glycemic control on this parameter. Thirty-seven IDDM patients and 33 NIDDM patients, together with two respective age-, sex-, and BMI-matched control groups were studied. Non-A phenotype prevalence in IDDM patients before (19%) and after blood glucose optimization (11%) was similar to that of their control group (12%). However, NIDDM patients displayed a higher proportion of the non-A phenotype (51%) than did the control group (28%), but it became closer (30%, P < 0.05) after glycemic control improved. All subjects with non-A phenotype that changed to A phenotype showed triglyceride levels below 1.63 mmol/1 and a greater decrease in HbA1c than did subjects whose phenotype did not change (4.9 ± 1.5 vs. 3.1 ± 1.4%, P < 0.05). A higher proportion of small dense LDL was observed in NIDDM women than in nondiabetic women (LDL5 10.0 ± 4.8 vs. 6.3 ± 1.5%, LDL6 6.1 ± 2.2 vs. 4.2 ± 0.8%, P < 0.05) during both stages of glycemic control, but no differences were observed between NIDDM and nondiabetic men. In conclusion, these findings provide new evidence for the relevance of near-normal glycemic control in the prevention of macrovascular disease and could contribute to an explanation of the loss of protection for cardiovascular disease in diabetic women.

Molecular profiling related to poor prognosis in thyroid carcinoma. Combining gene expression data and biological information.

Undifferentiated and poorly differentiated thyroid tumors are responsible for more than half of thyroid cancer patient deaths in spite of their low incidence. Conventional treatments do not obtain substantial benefits, and the lack of alternative approaches limits patient survival. Additionally, the absence of prognostic markers for well-differentiated tumors complicates patient-specific treatments and favors the progression of recurrent forms. In order to recognize the molecular basis involved in tumor dedifferentiation and identify potential markers for thyroid cancer prognosis prediction, we analysed the expression profile of 44 thyroid primary tumors with different degrees of dedifferentiation and aggressiveness using cDNA microarrays. Transcriptome comparison of dedifferentiated and well-differentiated thyroid tumors identified 1031 genes with >2-fold difference in absolute values and false discovery rate of <0.15. According to known molecular interaction and reaction networks, the products of these genes were mainly clustered in the MAPkinase signaling pathway, the TGF-β signaling pathway, focal adhesion and cell motility, activation of actin polymerization and cell cycle. An exhaustive search in several databases allowed us to identify various members of the matrix metalloproteinase, melanoma antigen A and collagen gene families within the upregulated gene set. We also identified a prognosis classifier comprising just 30 transcripts with an overall accuracy of 95%. These findings may clarify the molecular mechanisms involved in thyroid tumor dedifferentiation and provide a potential prognosis predictor as well as targets for new therapies.

Incidence of Type 1 (insulin-dependent) diabetes mellitus in Catalonia, Spain

SummaryThe incidence of Type 1 (insulin-dependent) diabetes mellitus was prospectively evaluated in Catalonia, Spain in patients up to 30 years of age during the period 1987–1990. The population at risk (0–29 years) consisted of 2,690,394 inhabitants (total population of Catalonia 5,978,638). All the cases were independently identified from four sources: endocrinologists, sales of blood glucose monitors and insulin pen injectors, diabetes societies and diabetic summer camps. The degree of ascertainment was 90.1 %. The overall observed incidence rate was 10.7 per 100,000 per year, being 11.5 per 100,000 per year in the 0–14 age group. The incidence in males (12.0 per 100,000 per year) was higher than in females (9.3 per 100,000 per year), with a male/female ratio of 1.36/l. The sex differences were only present in cases over 14 years of age. Age specific incidence rates per 100,000 per year were 4.4 (confidence interval 95%: 3.2–5.7) in the age group 0–4, 9.9 (8.5–11.4) in 5–9, 17.5 (15.7–19.4) in 10–14, 11.4 (9.9–13.0) in 15–19, 11.3 (9.7–13.0) in 20–24 and 8.5 (7.2–9.9) in 25–29. There was a seasonal onset pattern, with the highest incidence in winter (December–February). We conclude that the incidence of Type 1 diabetes observed in Catalonia during the period 1987–1990 is higher than that recently reported in other Mediterranean countries. This study offers the first standardized data on Type 1 diabetes incidence in Catalonia, including cases up to 30 years, and contributes to the knowledge of the epidemiology of diabetes in South Europe.

In human gestational diabetes mellitus congenital malformations are related to pre-pregnancy body mass index and to severity of diabetes

AbstractAims/hypothesisThis study analysed the relationship between congenital malformations (CM) and severity of gestational diabetes mellitus.MethodsA cohort of 2060 infants of mothers with gestational diabetes was studied. Universal screening and 3rd Workshop-Conference criteria were used to diagnose gestational diabetes. The severity of diabetes was assessed on the basis of previous hyperglycaemia, blood glucose values in diagnostic OGTT, area under the glucose curve, gestational age and HbA1c at diagnosis, insulin requirements during pregnancy, and OGTT after delivery. Potentially confounding variables (age, pre-pregnancy BMI, smoking) were considered. The relationship of potential predictors with CM was analysed with several multivariate logistic regression analyses.ResultsThe rate of CM was 6% for minor and 3.8% for major malformations (1.4% heart, 0.8% renal/urinary, 0.7% skeletal, 0.3% hypospadias, 0.2% central nervous system, 0.2% cleft lip/palate, 0.1% digestive tract, 0.3% other). In the final models, forward logistic regression analysis identified pre-pregnancy BMI as the predictor of CM (area under receiver operating characteristic curve 0.616); in the backward analysis additional predictors were 1-h blood glucose in diagnostic OGTT and gestational age at diagnosis (area under receiver operating characteristic curve 0.646). Both BMI and severity of gestational diabetes were predictors of heart and minor CM, whereas BMI predicted renal/urinary CM and severity of diabetes predicted skeletal CM.Conclusions/interpretationIn these infants of mothers with gestational diabetes, severity of diabetes and pre-pregnancy BMI were predictors of CM, in accordance with the well-documented pathogenic role of BMI (in the general population) and hyperglycaemia (in diabetic pregnancy). BMI was the main predictor of more prevalent CM.

Electronegative low density lipoprotein subform is increased in patients with short-duration IDDM and is closely related to glycaemic control

Summary We evaluated the effect of improving glycaemic control with intensive insulin therapy on LDL susceptibility to oxidation, electronegative LDL proportion, and LDL subfraction phenotype in a group of 25 patients with short-duration insulin-dependent diabetes mellitus (IDDM); 25 matched healthy control subjects were also studied. LDL susceptibility to oxidation was measured by continuous monitoring of conjugated diene formation. Electronegative LDL was isolated by anion exchange chromatography, and quantified as percentage of total LDL. Six LDL subfractions were isolated by density gradient ultracentrifugation and phenotype A or B classified as the quotient (LDL1-LDL3)/(LDL4-LDL6). Compared to the control group, IDDM subjects with poor glycaemic control showed higher electronegative LDL (19.03 ± 10.09 vs 9.59 ± 2.98 %, p < 0.001), similar LDL subfraction phenotype and lower susceptibility to oxidation (lag phase 45.6 ± 8.8 vs 41.2 ± 4.7 min, p < 0.05). After three months of intensive insulin therapy, HbA1 c decreased from 10.88 ± 2.43 to 5.69 ± 1.54 % (p < 0.001), and electronegative LDL to 13.84 ± 5.15 % (p < 0.05). No changes in LDL susceptibility to oxidation or LDL subfraction phenotype were observed. Electronegative LDL appeared significantly correlated to HbA1 c and fructosamine (p < 0.01 and p < 0.001) only in poorly controlled IDDM patients. These findings suggest that high electronegative LDL in IDDM subjects is related to the degree of glycaemic control, and could therefore be due to LDL glycation rather than to LDL oxidation or changes in LDL subfraction phenotype. [Diabetologia (1996) 39: 1469–1476]

Insulin Antibody Response to a Short Course of Human Insulin Therapy in Women With Gestational Diabetes

OBJECTIVE To assess the insulin antibody (IA) response to human insulin (HI) therapy in women with gestational diabetes. RESEARCH DESIGN AND METHODS IAs were measured by a competitive radiobinding assay in 50 women with gestational diabetes before and during treatment with HI and after delivery. At delivery, 15 maternal-cord blood sample pairs were analyzed for IA. As a reference, we searched for IA in 25 new-onset type I diabetic patients, before and at 3, 6, and 12 months after insulin therapy. RESULTS Insulin autoantibodies (IAAs) were detected in 1 of 50 women with gestational diabetes and 4 of 16 type I diabetic patients (P < 0.05). At the end of pregnancy after 9.3 ± 6.8 weeks on insulin therapy, 22 of 50 (44%) women with gestational diabetes became IA+ and 4 additional women were found to be positive 2 months postpartum. After 3 months on insulin, type I diabetic patients showed a higher rate of IA positivity (92%, P < 0.001). IA titers at the end of pregnancy were associated with the cumulative insulin dose (r = 0.29, P < 0.05). Postpartum, IA disappeared slowly in most IA+ women, but two women still showed IA 2 years after delivery Titers in cord blood were strongly related to those in maternal blood (r = 0.74, P < 0.01). The rate of adverse fetal outcome did not differ in IA− and IA+ mothers (27 vs. 40%, NS). CONCLUSIONS HI is immunogenic, and a short course of HI therapy induces IA in ∼ 50% of women with gestational diabetes and 92% of type I diabetic patients. In women with gestational diabetes, insulin dose is slightly associated with IA titers. These IAs apparently cross the placenta. Fetal outcome does not differ according to the maternal IA status, and IAs disappear gradually after delivery but may remain positive for 2 years after delivery.

p53 in a thyroid follicular carcinoma with foci of poorly differentiated and anaplastic carcinoma.

The clinical and pathologic features of a rare case of follicular carcinoma with small foci of poorly differentiated and anaplastic carcinoma are presented. Eight years after the removal of the primary neoplasm, the patient developed pulmonary and brain metastases that were predominantly composed of the poorly differentiated and anaplastic components. A comparative immunohistochemical and molecular analysis of p53 status in the follicular, poorly differentiated and anaplastic components of the tumor was performed. p53 immunostaining was restricted to the poorly differentiated and anaplastic areas. Single strand conformation polymorphism analysis (SSCP-PCR) from DNA obtained by microdissection demonstrated the presence of a mutation (TAT-->TGT; Tyr-->Cys) in codon 220, exon six of the p53 gene in the anaplastic component, that was absent in the well-differentiated follicular areas. The results of that study in this rare tumor support that p53 has a tumor progression role in thyroid tumorigenesis.