Alberto de Leiva

Adult-Onset Autoimmune Diabetes in Europe Is Prevalent With a Broad Clinical Phenotype: Action LADA 7

OBJECTIVE Specific autoantibodies characterize type 1 diabetes in childhood but are also found in adult-onset diabetes, even when initially non–insulin requiring, e.g., with latent autoimmune diabetes (LADA). We aimed to characterize adult-onset autoimmune diabetes. RESEARCH DESIGN AND METHODS We consecutively studied 6,156 European diabetic patients attending clinics within 5 years of diagnosis (age range, 30–70 years) examined cross-sectionally clinically and for GAD antibodies (GADA) and antibodies to insulinoma-associated antigen-2 (IA-2A) and zinc-transporter 8 (ZnT8A). RESULTS Of 6,156 patients, 541 (8.8%) had GADA and only 57 (0.9%) IA-2A or ZnT8A alone. More autoantibody-positive than autoantibody-negative patients were younger, leaner, on insulin (49.5 vs. 13.2%), and female (P < 0.0001 for each), though LADA patients (9.7% of total) did not show categorically distinct clinical features from autoantibody-negative type 2 diabetes. Similarly, more GADA patients with high (>200 World Health Organization IU) (n = 403) compared with low (n = 138) titer were female, lean, and insulin treated (54.6 vs. 39.7%) (P < 0.02 for each). Autoantibody-positive patients usually had GADA (541 of 598; 90.5%) and had LADA more often than type 1 autoimmune diabetes (odds ratio 3.3). CONCLUSIONS Adult-onset autoimmune diabetes emerges as a prevalent form of autoimmune diabetes. Our results indicate that adult-onset autoimmune diabetes in Europe encompasses type 1 diabetes and LADA in the same broad clinical and autoantibody-positive spectrum. At diagnosis, patients with adult-onset autoimmune diabetes are usually non–insulin requiring and clinically indistinguishable from patients with type 2 diabetes, though they tend to be younger and leaner. Only with screening for autoantibodies, especially GADA, can they be identified with certainty.

Adult-Onset Autoimmune Diabetes in Europe Is Prevalent With a Broad Clinical Phenotype Action LADA 7

OBJECTIVE Specific autoantibodies characterize type 1 diabetes in childhood but are also found in adult-onset diabetes, even when initially non–insulin requiring, e.g., with latent autoimmune diabetes (LADA). We aimed to characterize adult-onset autoimmune diabetes. RESEARCH DESIGN AND METHODS We consecutively studied 6,156 European diabetic patients attending clinics within 5 years of diagnosis (age range, 30–70 years) examined cross-sectionally clinically and for GAD antibodies (GADA) and antibodies to insulinoma-associated antigen-2 (IA-2A) and zinc-transporter 8 (ZnT8A). RESULTS Of 6,156 patients, 541 (8.8%) had GADA and only 57 (0.9%) IA-2A or ZnT8A alone. More autoantibody-positive than autoantibody-negative patients were younger, leaner, on insulin (49.5 vs. 13.2%), and female (P < 0.0001 for each), though LADA patients (9.7% of total) did not show categorically distinct clinical features from autoantibody-negative type 2 diabetes. Similarly, more GADA patients with high (>200 World Health Organization IU) (n = 403) compared with low (n = 138) titer were female, lean, and insulin treated (54.6 vs. 39.7%) (P < 0.02 for each). Autoantibody-positive patients usually had GADA (541 of 598; 90.5%) and had LADA more often than type 1 autoimmune diabetes (odds ratio 3.3). CONCLUSIONS Adult-onset autoimmune diabetes emerges as a prevalent form of autoimmune diabetes. Our results indicate that adult-onset autoimmune diabetes in Europe encompasses type 1 diabetes and LADA in the same broad clinical and autoantibody-positive spectrum. At diagnosis, patients with adult-onset autoimmune diabetes are usually non–insulin requiring and clinically indistinguishable from patients with type 2 diabetes, though they tend to be younger and leaner. Only with screening for autoantibodies, especially GADA, can they be identified with certainty.

Metabolic Syndrome and Autoimmune Diabetes: Action LADA 3

OBJECTIVE—The purpose of this study was to estimate whether prevalence of metabolic syndrome in adult European diabetic patients is associated with type of diabetes. RESEARCH DESIGN AND METHODS—A consecutive series of patients attending hospital-based diabetes clinics were assessed for the frequency of metabolic syndrome and compared with population-based control subjects as part of the Action LADA study. In total, 2,011 subjects (aged 30–70 years) were studied, including 1,247 patients with recent-onset type 2 diabetes without glutamic acid decarboxylase autoantibodies (GADAs), 117 non–insulin-requiring patients with GADAs who had not received insulin therapy for at least 6 months after diagnosis (designated latent autoimmune diabetes of adults [LADA]), 288 type 1 diabetic patients, and 359 normal subjects. RESULTS—Frequency of metabolic syndrome was significantly different in patients with type 1 diabetes (31.9%) and LADA (41.9%) (P = 0.015) and in both conditions was less frequent than in type 2 diabetic patients (88.8%) (P < 0.0001 for each). Eliminating glucose as a variable, the prevalence of metabolic syndrome was similar in patients with autoimmune diabetes (type 1 diabetes and/or LADA) (17.3%) and control subjects (23.7%) but remained more common in type 2 diabetic patients (47.8%) (P = 0.001 for all groups). In both type 1 diabetic patients and those with LADA, individual components of metabolic syndrome were similar but less common than in type 2 diabetic patients (P < 0.0001 for each). CONCLUSIONS—The prevalence of metabolic syndrome is significantly higher in type 2 diabetic patients than in patients with LADA or adults with type 1 diabetes. Excluding glucose as a variable, metabolic syndrome is not more prevalent in patients with autoimmune diabetes than in control subjects. Metabolic syndrome is not a characteristic of autoimmune diabetes.

Real-Time Continuous Glucose Monitoring Together with Telemedical Assistance Improves Glycemic Control and Glucose Stability in Pump-Treated Patients

BACKGROUND Real-time continuous glucose monitoring (CGM) has recently been incorporated into routine diabetes management because of the potential advantages it offers for glycemic control. The aim of our study was to evaluate the impact of the use of real-time CGM together with a telemedicine system in hemoglobin A1c and glucose variability in patients with type 1 diabetes treated with insulin pumps. METHODS Ten patients (five women, 41.2 [range, 21-62] years old, duration of diabetes 14.9 [range, 3-52] years) were included in this randomized crossover study. Patients used the DIABTel telemedicine system throughout the study, and real-time CGM was used for 3 days every week during the intervention phase. At the end of the control phase, a blind 3-day CGM was performed. Glucose variability was evaluated using the Glucose Risk Index (GRI), a comparative analysis of continuous glucose values over two consecutive hours. RESULTS Hemoglobin A1c decreased significantly (8.1 +/- 1.1% vs. 7.3 +/- 0.8%; P = 0.007) after the intervention phase, while no changes were observed during the control phase. The mean number of daily capillary glucose readings was higher during the intervention phase (4.7 +/- 1.1 vs. 3.8 +/- 1.0; P < 0.01), because of an increase in random analyses (1.22 +/- 0.3 vs. 0.58 +/- 0.1; P < 0.01), and there was also a significant increase in the mean number of bolus doses per day (5.23 +/- 1.1 vs. 4.4 +/- 0.8; P < 0.05). The GRI was higher during the control phase than during the experimental phase (9.6 vs. 6.25; P < 0.05). CONCLUSIONS Real-time CGM in conjunction with the DIABTel system improves glycemic control and glucose stability in pump-treated patients with type 1 diabetes.

Ras Oncogene Mutations in Thyroid Tumors: Polymerase Chain Reaction-Restriction-Fragment-Length Polymorphism Analysis from Paraffin-Embedded Tissues

Ras mutations have been found in thyroid lesions. Different studies have shown different frequencies of mutations among benign and malignant lesions. The presence of point mutations in codons 12 and 13 of the c-K-ras, c-H-ras, and N-ras genes was studied in 58 thyroid lesions (10 nodular goiters, 10 follicular adenomas, and 15 papillary, 10 follicular, and 13 anaplastic carcinomas). DNA was extracted from formalin-fixed paraffin-embedded tissue, and target sequences were amplified in vitro by the polymerase chain reaction. Mutations were detected by the presence of restriction-fragment-length polymorphisms either occurring naturally or introduced artificially by the use of mutant primers. No characterization of the mutations was performed. Results were correlated with clini-copathologic features and patient follow-up. One goiter showed a mutation at codon 13, c-K-ras. All follicular adenomas, including three hyalinizing trabecular adenomas, were negative. Four papillary carcinomas presented mutations (one at codon 13, c-K-ras; three at codon 12, N-ras). Two follicular carcinomas showed mutations at codon 12, N-ras. Five anaplastic carcinomas showed mutations (two at codon 12 and two at codon 13, c-K-ras; one at codon 12, N-ras). In summary, the results confirm that ras oncogenes play a role in thyroid tumorigenesis, probably at an early step. Ras mutations appear not to be related to prognosis.

Effect of physical exercise on lipoprotein(a) and low-density lipoprotein modifications in type 1 and type 2 diabetic patients

To evaluate the effect of physical exercise on blood pressure, the lipid profile, lipoprotein(a) (Lp(a)), and low-density lipoprotein (LDL) modifications in untrained diabetics, 27 diabetic patients (14 type 1 and 13 type 2) under acceptable and stable glycemic control were studied before and after a supervised 3-month physical exercise program. Anthropometric parameters, insulin requirements, blood pressure, the lipid profile, Lp(a), LDL composition, size, and susceptibility to oxidation, and the proportion of electronegative LDL (LDL(-)) were measured. After 3 months of physical exercise, physical fitness improved (maximal O2 consumption [VO2max], 29.6 +/- 6.8 v 33.0 +/- 8.4 mL/kg/min, P < .01). The body mass index (BMI) did not change, but the waist circumference (83.2 +/- 11.8 to 81.4 +/- 11.2 cm, P < .05) decreased significantly. An increase in the subscapular to triceps skinfold ratio (0.91 +/- 0.37 v 1.12 +/- 0.47 cm, P < .01) and midarm muscle circumference ([MMC], 23.1 +/- 3.4 v 24.4 +/- 3.7 cm, P < .001) were observed after exercise. Insulin requirements (0.40 +/- 0.18 v 0.31 +/- 0.19 U/kg/d, P < .05) and diastolic blood pressure (80.2 +/- 10 v 73.8 +/- 5 mm Hg, P < .01) decreased in type 2 diabetic patients. High-density lipoprotein cholesterol (HDL-C) increased in type 1 patients (1.48 +/- 0.45 v1.66 +/- 0.6 mmol/L, P < .05), while LDL cholesterol (LDL-C) decreased in type 2 patients (3.6 +/- 1.0 v3.4 +/- 0.9 mmol/L, P < .01). Although Lp(a) levels did not vary in the whole group, a significant decrease was noted in patients with baseline Lp(a) above 300 mg/L (mean decrease, -13%). A relationship between baseline Lp(a) and the change in Lp(a) (r = -.718, P < .0001) was also observed. After the exercise program, 3 of 4 patients with LDL phenotype B changed to LDL phenotype A, and the proportion of LDL(-) tended to decrease (16.5% +/- 7.4% v 14.0% +/- 5.1%, P = .06). No changes were observed for LDL composition or susceptibility to oxidation. In addition to its known beneficial effects on the classic cardiovascular risk factors, regular physical exercise may reduce the risk of cardiovascular disease in diabetic patients by reducing Lp(a) levels in those with elevated Lp(a) and producing favorable qualitative LDL modifications.

IDDM12 (CTLA4) on 2q33 and IDDM13 on 2q34 in Genetic Susceptibility to Type 1 Diabetes (Insulin-dependent)

Type 1 diabetes (insulin-dependent) is a multifactorial disease with polygenic susceptibility. The major genetic component (IDDM1) resides within the HLA region, but several non-HLA loci have been implicated in the genetic susceptibility. In the present study, we have analysed two such loci, IDDM12 (CTLA4) on 2q33 and IDDM13 on 2q34, in Danish (n = 254) and Spanish (n = 39) type 1 diabetic multiplex families. No significant evidence of linkage of IDDM12 was observed in any of the two studied data sets. However, when the present data were combined with previously published data, they strengthened the evidence of linkage at this locus, p = 0.00002. For the IDDM13 region, we found some positive evidence of linkage of the D2S137-D2S164-D2S1471 markers (p-values 0.007, 0.02, and 0.007, respectively) using transmission disequilibrium testing (TDT) and the Tsp version of the TDT. Importantly, random transmission of all tested alleles was observed in unaffected offspring (p > 0.3). Stratification for HLA (high risk and non-high risk genotypes) in the Danish families did not reveal heterogeneity at IDDM12 or IDDM13. In conclusion, our data on an entirely new family data set did not support the existence of IDDM12 as a type 1 diabetes susceptibility locus in the Danish population. In addition, we found support for evidence of linkage and association of the IDDM13/D2S137-D2S1471 region (approximately 3.5 cM) to type 1 diabetes, however, further studies are needed to substantiate this observation.

In pregnancies with gestational diabetes mellitus and intensive therapy, perinatal outcome is worse in small-for-gestational-age newborns

OBJECTIVE This study analyzed the relationship between birth weight and perinatal outcome among women with gestational diabetes mellitus. STUDY DESIGN The relationship between perinatal outcome and birth weight was analyzed for 821 pregnancies of women with gestational diabetes mellitus attended in a tertiary hospital and receiving intensive metabolic therapy (normocaloric diet, self-monitoring of blood glucose level and individually tailored insulin regimen when needed). The Mantel-Haenszel test was used to adjust for preterm delivery. RESULTS Seven percent of neonates were small for gestational age, 85% were appropriate for gestational age, and 8% were large for gestational age. After adjustment for preterm delivery the rates of adverse fetal outcome, low 1-minute Apgar score, and hypoglycemia were greater among small for gestational age neonates than among appropriate and large for gestational age infants (odds ratios 3.08, 2.51, and 3.17, respectively). CONCLUSION Among women with gestational diabetes mellitus who are receiving intensive therapy, perinatal outcome is worse for small for gestational age neonates than for appropriate and large for gestational age neonates.

Glycemic control and perinatal outcomes of pregnancies complicated by type 1 diabetes: influence of continuous subcutaneous insulin infusion and lispro insulin.

AIMS This study compared glycemic control and maternal and fetal outcomes in pregnant women with type 1 diabetes mellitus (T1DM) treated with multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) using regular (RI) or lispro (LP) insulin. METHODS Three hundred fifteen consecutive singleton pregnancies of T1DM women using the same insulin program since before pregnancy (196 MDI with NPH + RI, 16 MDI with NPH + LP, 44 CSII with RI, 59 CSII with LP) were studied. Variables of glycemic control assessed included glycated hemoglobin, mean blood glucose (MBG), and insulin doses in each trimester, diabetic ketoacidosis, and hypoglycemic comas. Variables of pregnancy outcome included miscarriage, preterm birth, large or small for gestational age (LGA or SGA, respectively) newborns, and perinatal mortality. Multiple linear regression and logistic regression analysis were used. RESULTS Groups differed in baseline and glycemic control but not in maternal or fetal outcomes. In multivariate analysis, LP was associated with higher second trimester MBG and lower rate of hypoglycemic coma, CSII with higher third trimester MBG, and CSII + LP with lower insulin requirements and lower rate of hypoglycemic coma. As to pregnancy outcomes, LP was associated with lower risk of preterm birth and higher risk of SGA, CSII with lower risk of SGA and higher risk of LGA and perinatal mortality, and CSII + LP with higher risk of miscarriage. CONCLUSIONS Pregnant women with T1DM using LP and/or CSII had different characteristics. LP with or without CSII was independently associated with fewer hypoglycemic comas, whereas impact of LP/CSII on the fetus had a favorable or an unfavorable influence depending on the specific outcome.

Period of gestational diabetes mellitus diagnosis and maternal and fetal morbidity

Background.  The aim of the study was to analyze the association between the period of diagnosis of gestational diabetes mellitus (GDM) and maternal and neonatal outcome.