Monogenic diabetes in adults: A multi-ancestry study reveals strong disparities in diagnosis rates and clinical presentation.

AIM: Identification of monogenic diabetes (MgD) conveys benefits for patients' care. Algorithms for selecting the patients to be genetically tested have been established in EuroCaucasians, but not in non-EuroCaucasian individuals. We assessed the diagnosis rate, the phenotype of MgD, and the relevance of selection criteria, according to ancestry in patients referred for a suspected MgD. METHODS: Seven genes (GCK, HNF1A, HNF4A, HNF1B, ABCC8, KCNJ11, INS) were analyzed in 1975 adult probands (42% non-EuroCaucasians), selected on the absence of diabetes autoantibodies and ≥2 of the following criteria: age ≤40 years and body mass index <30 kg/m2 at diagnosis, and a family history of diabetes in ≥2 generations. RESULTS: Pathogenic/likely pathogenic variants were identified in 6.2% of non-EuroCaucasian and 23.6% of EuroCaucasian patients (OR 0.21, [0.16-0.29]). Diagnosis rate was low in all non-EuroCaucasian subgroups (4.1-11.8%). Common causes of MgD (GCK, HNF1A, HNF4A), but not rare causes, were less frequent in non-EuroCaucasians than in EuroCaucasians (4.1%, vs. 21.1%, OR 0.16 [0.11-0.23]). Using ethnicity-specific body mass index cutoffs increased the diagnosis rate in several non-EuroCaucasian subgroups. CONCLUSION: The diagnosis rate of MgD is low in non-EuroCaucasian patients, but may be improved by tailoring selection criteria according to patients'ancestry.

Anaemia and its risk factors and association with treatments in patients with diabetes: A cross-sectional study.

BACKGROUND: Anaemia is frequently seen in patients with diabetes and the main cause is renal failure. At all stages of renal failure, however, the prevalence of anaemia is higher in diabetes patients than expected for their glomerular filtration rate, suggesting that causes of anaemia other than renal failure are at work. The present cross-sectional study was conducted to investigate the possible iatrogenic causes of anaemia in patients with diabetes. SUBJECTS AND METHODS: This was a hospital-based cross-sectional study of all patients who had biological and clinical data covering a 2-year period. All had been in contact with the diabetes department either as outpatients or as inpatients mostly for educational purposes. Clinical factors, including type of diabetes, known diabetes complications, treatments received and biological data, were reviewed for their possible involvement in anaemia. RESULTS: A total of 4145 consecutive patients were included. Anaemia was observed in 1065 (25.7%) of them. Patients with anaemia were more frequently women and those with longer durations of diabetes. Haemoglobin concentrations were decreased, and prevalence of anaemia was increased at all stages of renal failure, already at stage 2, KDIGO classification. Anaemia patients were more frequently taking insulin, antiplatelet agents and renin-angiotensin system blockers (RASBs). After exclusion of patients with specific causes of anaemia, logistic regression analysis of all parameters correlated with anaemia on univariate analysis revealed that anaemia was associated with gender, antiplatelet agents and RASBs. CONCLUSION: This study has confirmed that anaemia is frequently seen in diabetes patients and strongly associated with renal failure (already at stage 2). Our observations highlight the adjuvant role of drugs, particularly RASBs, in the risk of anaemia in patients with diabetes.

Disagreement between capillary blood glucose and flash glucose monitoring sensor can lead to inadequate treatment adjustments during pregnancy.

OBJECTIVE: Continuous glucose monitoring tends to replace capillary blood glucose (CBG) self-monitoring. Our aim was to determine the agreement between CBG and a flash glucose monitoring system (Flash-GMS) in treatment decision-making during pregnancy. RESEARCH DESIGN AND METHODS: Insulin-treated women with either type 1 (n=25), type 2 (n=4) or gestational diabetes (n=4) were included. A Flash-GMS sensor was applied for 14 days. Women scanned the sensor whenever they monitored their CBG. The primary endpoint was the proportion of discordant therapeutic decisions they would have made based on Flash-GMS rather than CBG results. Glucose averages, mean absolute difference (MAD), mean absolute relative difference (MARD) and Flash-GMS accuracy were also estimated. RESULTS: Data for forty 14-day periods were available. Preprandial Flash-GMS and CBG values were 93±42mg/dL and 105±45mg/dL, respectively (P<10-4), and 2-h postprandial (PP) values were 106±45mg/dL and 119±47mg/dL, respectively (P<10-4). MAD was 14±22mg/dL preprandial and 15±24mg/dL 2-h PP; MARD was 19%; and 99% of glucose value pairs were within the clinically acceptable A and B zones of the Parkes error grid. Concordance rate for therapeutic decision-making was 80-85% according to ADA targets and 65-75% according to a pragmatic threshold. At different time points of the day, 83-92% of discordant results were due to Flash-GMS values being lower than their corresponding CBG values. CONCLUSION: Flash-GMS tends to give lower estimates than CBG. Thus, in cases requiring therapeutic changes to treat or prevent hypo- or hyperglycaemia, 25-35% of choices would have been divergent if based on Flash-GMS rather than CBG.

Determinants of a good perinatal outcome in 588 pregnancies in women with type 1 diabetes.

AIM: This study assessed pregnancy outcomes in women with type 1 diabetes (T1D) over the last 15 years and identified modifiable factors associated with good perinatal outcomes. METHODS: Pregnancy outcomes were prospectively assessed in this cohort study of 588 singleton pregnancies (441 women) managed by standardized care from 2000 to 2014. A good perinatal outcome was defined as the uncomplicated delivery of a normally formed, non-macrosomic, full-term infant with no neonatal morbidity. Factors associated with good perinatal outcomes were identified by logistic regression. RESULTS: The rate of severe congenital malformations was 1.5%, and 0.7% for perinatal mortality. The most frequent perinatal complications were macrosomia (41%), preterm delivery (16%) and neonatal hypoglycaemia (11%). Shoulder dystocia occurred in 2.6% of cases, but without sequelae. Perinatal outcomes were good in 254 (44%) pregnancies, and were associated with lower maternal HbA1c values at delivery [adjusted odds ratio (aOR): 2.78, 95% CI: 2.04-3.70, for each 1% (11mmol/mol) absolute decrease], lower gestational weight gains (aOR: 1.06, 95% CI: 1.02-1.10) and absence of preeclampsia (aOR: 2.63, 95% CI: 1.09-6.25). The relationship between HbA1c at delivery and a good perinatal outcome was continuous, with no discrimination threshold. CONCLUSION: In our study, rates of severe congenital malformations and perinatal mortality were similar to those of the general population. Less severe complications, mainly macrosomia and late preterm delivery, persisted. Also, our study identified modifiable risk factors that could be targeted to further improve the prognosis of pregnancy in T1D.

High-sensitivity C-reactive protein does not improve the differential diagnosis of HNF1A-MODY and familial young-onset type 2 diabetes: A grey zone analysis.

AIM: Low plasma levels of high-sensitivity C-reactive protein (hs-CRP) have been suggested to differentiate hepatocyte nuclear factor 1 alpha-maturity-onset diabetes of the young (HNF1A-MODY) from type 2 diabetes (T2D). Yet, differential diagnosis of HNF1A-MODY and familial young-onset type 2 diabetes (F-YT2D) remains a difficult challenge. Thus, this study assessed the added value of hs-CRP to distinguish between the two conditions. METHODS: This prospective multicentre study included 143 HNF1A-MODY patients, 310 patients with a clinical history suggestive of HNF1A-MODY, but not confirmed genetically (F-YT2D), and 215 patients with T2D. The ability of models, including clinical characteristics and hs-CRP to predict HNF1A-MODY was analyzed, using the area of the receiver operating characteristic (AUROC) curve, and a grey zone approach was used to evaluate these models in clinical practice. RESULTS: Median hs-CRP values were lower in HNF1A-MODY (0.25mg/L) than in F-YT2D (1.14mg/L) and T2D (1.70mg/L) patients. Clinical parameters were sufficient to differentiate HNF1A-MODY from classical T2D (AUROC: 0.99). AUROC analyses to distinguish HNF1A-MODY from F-YT2D were 0.82 for clinical features and 0.87 after including hs-CRP. For the grey zone analysis, the lower boundary was set to miss<1.5% of true positives in non-tested subjects, while the upper boundary was set to perform 50% of genetic tests in individuals with no HNF1A mutation. On comparing HNF1A-MODY with F-YT2D, 65% of patients were classified in between these categories - in the zone of diagnostic uncertainty - even after adding hs-CRP to clinical parameters. CONCLUSION: hs-CRP does not improve the differential diagnosis of HNF1A-MODY and F-YT2D.

Severe acute renal failure in patients treated with glucagon-like peptide-1 receptor agonists.

We report two patients with diabetes in whom acute renal failure requiring hemodialysis occurred while on treatment with glucagon-like peptide-1 receptor agonists. We discuss the mechanisms of this complication and the potential for its prevention.

Factors associated with the presence of glutamic acid decarboxylase and islet antigen-2 autoantibodies in patients with long-standing type 1 diabetes.

AIM: Glutamic acid decarboxylase (GAD) and/or islet antigen-2 (IA-2) autoantibodies (ab) are present in 90% of patients at the onset of type 1 diabetes (T1D). Few studies have shown that they may persist in the long-term. We analysed the frequency of GADab and IA-2ab and the factors associated with their persistency in patients with long-lasting T1D. METHODS: This cross-sectional study included 430 adult patients with T1D of at least 10-year duration, consecutively seen over one year. GADab and IA-2ab were determined by radio-binding assays. Autoantibodies to thyroperoxydase, gastric parietal cells and transglutaminase were assessed in 418 patients, and HLA DRB1 genotyping in 359. Parameters associated with the persistency of antibodies were studied by multivariate analysis. RESULTS: Median age at diagnosis of T1D was 12 years, and median diabetes duration was 19 years. Extrapancreatic autoimmunity was present in 38% of the patients, and associated autoimmune diseases in 21%. GADab and/or IA-2ab were found in 56% of the patients, and in 32% in those with more than 25-year diabetes duration. GADab were more frequent than IA-2ab. Female sex, an older age at diagnosis, and a shorter duration of diabetes were independently associated with the presence of ab. The same factors and the DR3 allele were associated with GADab, while only diabetes duration and the DR4 allele were associated with IA-2ab. CONCLUSION: In a large proportion of the patients with T1D, the long-term persistency of diabetes-associated antibodies allows aetiological diagnosis, even far from the onset of hyperglycaemia.

Allelic variations of the vitamin D receptor (VDR) gene are associated with increased risk of coronary artery disease in type 2 diabetics: the DIABHYCAR prospective study.

AIM: Vitamin D deficiency is associated with coronary artery disease (CAD), and the actions of vitamin D are mediated by binding to a specific nuclear vitamin D receptor (VDR). This study investigated the associations of VDR gene variants with CAD in two cohorts of type 2 diabetes patients. METHODS: A cohort of 3137 subjects from the prospective DIABHYCAR study (CAD incidence: 14.8%; follow-up: 4.4 ± 1.3 years) and an independent, hospital-based population of 713 subjects, 32.3% of whom had CAD, were assessed. Three SNPs in the VDR gene were genotyped: rs1544410 (BsmI); rs7975232 (ApaI); and rs731236 (TaqI). RESULTS: In the DIABHYCAR cohort, an association was observed between the A allele of BsmI and incident cases of CAD (HR: 1.16, 95% CI: 1.05-1.29; P = 0.002). Associations were also observed between BsmI (P = 0.01) and TaqI (P = 0.04) alleles and baseline cases of CAD. The AAC haplotype (BsmI/ApaI/TaqI) was significantly associated with an increased CAD prevalence at the end of the study compared with the GCT haplotype (OR: 1.12, 95% CI: 1.02-1.28; P = 0.04). In a cross-sectional study of the independent hospital-based cohort, associations of ApaI (P = 0.009) and TaqI (P = 0.03) alleles with CAD were observed, with similar haplotype results (OR: 1.33, 95% CI: 1.03-1.73; P = 0.03). CONCLUSION: The haplotype comprising the minor allele of BsmI, major allele of ApaI and minor allele of TaqI of VDR (AAC) was associated with an increased risk of CAD in type 2 diabetes patients. This effect was independent of the effects of other known cardiovascular risk factors.

Zinc transporter (ZnT)8(186-194) is an immunodominant CD8+ T cell epitope in HLA-A2+ type 1 diabetic patients.

AIMS/HYPOTHESIS: Anti-zinc transporter (ZnT)8 autoantibodies are commonly detected in type 1 diabetic patients. We hypothesised that ZnT8 is also recognised by CD8(+) T cells and aimed to identify HLA-A2 (A*02:01)-restricted epitope targets. METHODS: Candidate epitopes were selected by ZnT8 plasmid DNA immunisation of HLA-A2/DQ8 transgenic mice and tested for T cell recognition in peripheral blood mononuclear cells of type 1 diabetic, type 2 diabetic and healthy participants by IFN-γ enzyme-linked immunospot. RESULTS: White HLA-A2(+) adults (83%) and children (60%) with type 1 diabetes displayed ZnT8-reactive CD8(+) T cells that recognised a single ZnT8(186-194) (VAANIVLTV) epitope. This ZnT8(186-194)-reactive fraction accounted for 50% to 53% of total ZnT8-specific CD8(+) T cells. Another sequence, ZnT8(153-161) (VVTGVLVYL), was recognised in 20% and 25% of type 1 diabetic adults and children, respectively. Both epitopes were type 1 diabetes-specific, being marginally recognised by type 2 diabetic and healthy participants (7-12% for ZnT8(186-194), 0% for ZnT8(153-161)). CONCLUSIONS/INTERPRETATION: ZnT8-reactive CD8(+) T cells are predominantly directed against the ZnT8(186-194) epitope and are detected in a majority of type 1 diabetic patients. The exceptional immunodominance of ZnT8(186-194) may point to common environmental triggers precipitating beta cell autoimmunity.

Decreased insulin secretion and increased risk of type 2 diabetes associated with allelic variations of the WFS1 gene: the Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study.

AIMS/HYPOTHESIS: We investigated associations of allelic variations in the WFS1 gene with insulin secretion and risk of type 2 diabetes in a general population prospective study. METHODS: We studied 5,110 unrelated French men and women who participated in the prospective Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Additional cross-sectional analyses were performed on 4,472 French individuals with type 2 diabetes and 3,065 controls. Three single nucleotide polymorphisms (SNPs) were genotyped: rs10010131, rs1801213/rs7672995 and rs734312. RESULTS: We observed statistically significant associations between the major alleles of the three variants and prevalent type 2 diabetes in the DESIR cohort at baseline. Cox analyses showed an association between the G-allele of rs10010131 and incident type 2 diabetes (HR 1.34, 95% CI 1.08-1.70, p = 0.007). Similar results were observed for the G-allele of rs1801213 and the A-allele of rs734312. The GGA haplotype was associated with an increased risk of diabetes as compared with the ACG haplotype (HR 1.26, 95% CI 1.04-1.42, p = 0.02). We also observed statistically significant associations of the three SNPs with plasma glucose, HbA(1c) levels and insulin secretion at baseline and throughout the study in individuals with type 2 diabetes or at risk of developing diabetes. However, no association was observed in those who remained normoglycaemic at the end of the follow-up. Associations between the three variants and type 2 diabetes were replicated in cross-sectional studies of type 2 diabetic patients in comparison with a non-diabetic control group. CONCLUSIONS/INTERPRETATION: The most frequent haplotype at the haplotype block containing the WFS1 gene modulated insulin secretion and was associated with an increased risk of type 2 diabetes.

Poor prognosis of pregnancy in women with autoimmune type 1 diabetes mellitus masquerading as gestational diabetes.

AIM: To describe the clinical presentation and the prognosis of autoimmune type 1 diabetes (T1D) that was first revealed during pregnancy masquerading as gestational diabetes mellitus (GDM). METHODS: We reviewed the files of 21 women in whom diabetes was revealed during a pregnancy ("index pregnancy") and progressed to T1D after delivery, and in whom GAD and/or IA-2 autoantibodies were found. RESULTS: The median age and BMI of the women were 31 years and 19.8 kg/m(2). Eleven women had at least one risk factor for GDM. Eight of the 12 multiparous women had had an abnormal outcome of previous pregnancy, including GDM in five. GDM was diagnosed at week 26 (range: 4-38) of gestation by screening in 18, because of macrosomia in two and during hyperglycaemic crises in three. All were treated with insulin, from the time of diabetes diagnosis in 10 and after 4 weeks (range: 2-15) in 11. Term of delivery was 38 (range: 26-41) weeks. Abnormal outcomes occured in 14 pregnancies, including two fetal deaths, four preterm deliveries and eight macrosomic infants. No congenital malformations were reported. After delivery, insulin therapy was stopped in 18 women for 6 months (range: 2-48). The diagnosis of the autoimmune origin of diabetes was established during the index pregnancy in only eight cases. CONCLUSION: T1D may reveal as GDM in women with or without risk factors for GDM and is associated with a poor prognosis, partly because the correct diagnosis and treatment are delayed. Whether screening for autoimmune markers of T1D should be performed more systematically in women with GDM deserves to be studied.

Diabetes mellitus and glucose-6-phosphate dehydrogenase deficiency: from one crisis to another.

AIM: Epidemiological data suggest that glucose-6-phosphate dehydrogenase (G6PD) deficiency may be a risk factor for diabetes. Also, the occurrence of haemolysis in the context of diabetes crises has been reported in patients with G6PD deficiency. A unifying hypothesis could explain these associations. METHODS: We report two patients in whom haemolytic crises occurred soon after acute diabetes decompensation, and revealed G6PD deficiency. We have reviewed the mechanisms that may link the two diseases. RESULTS: One patient was admitted for decompensated ketosis-prone type-2 diabetes (KPT2D), but no acidosis, and was treated with insulin, then metformin and glibenclamide. The second patient had type-1 diabetes and ketoacidosis treated with insulin. Haemolytic crises were recognized 8 and 4 days after admission, respectively, and G6PD deficiency was confirmed in both patients. These patients and the other published cases share, as a unique characteristic, the occurrence of haemolysis after diabetes decompensation, whatever the treatment or associated conditions. Experimental data show that hyperglycaemia can reduce expression of the G6PD gene and activity of the enzyme. Conversely, G6PD deficiency can promote oxidative stress and impairment of insulin secretion by beta cells. CONCLUSION: In patients at risk of G6PD deficiency, the possibility of haemolysis should be explored in case of diabetes crisis. In African patients with KPT2D diabetes, potentially oxidative hypoglycaemic agents should be avoided in the remission phase of the disease. G6PD deficiency and diabetes can aggravate each other, and diabetes could be aetiologically associated with G6PD deficiency.

Familial young-onset forms of diabetes related to HNF4A and rare HNF1A molecular aetiologies.

OBJECTIVE: We have dissected the rare molecular anomalies that may affect hepatocyte nuclear factor-1a (HNF1A) and hepatocyte nuclear factor-4a (HNF4A) in patients with familial young-onset diabetes for whom HNF1A mutations have been excluded by sequence analysis. METHODS: Eighty-four unrelatedHNF1A-negative patients with diabetes diagnosed before the age of 40 years, a family history of diabetes and the absence of features suggestive of Type 2 diabetes were included. We analysed by sequencing the HNF4A promoter and coding regions, the HNF1A promoter region and specific regions of HNF1A(B) and HNF1A(C) isoforms and searched for large deletions of HNF1A and HNF4A by multiplex ligation-dependent probe amplification (MLPA). RESULTS: We identified five novel HNF4A mutations (5 / 84, 6%), including four missense and one in-frame deletion, and one mutation of the HNF1A promoter (1 / 84). Sequence analysis of isoform-specific coding regions of HNF1A did not reveal any mutation. We next identified two whole gene deletions of HNF1A and HNF4A, respectively (2 / 84, 2.4%). CONCLUSIONS: Altogether, the search for rare molecular events in HNF1A and HNF4A led us to elucidate 8 / 84 (9.5%) of our HNF1A-negative cases.This study shows that genetic aetiologies remain to be elucidated in familial young-onset diabetes. It also highlights the difficulty of the differential diagnosis with Type 2 diabetes because of the wide clinical expression of monogenic young-onset diabetes and the absence of specific biomarkers.

The clinical variability of maternally inherited diabetes and deafness is associated with the degree of heteroplasmy in blood leukocytes.

CONTEXT: Maternally inherited diabetes and deafness (MIDD) is a rare form of diabetes with a matrilineal transmission, sensorineural hearing loss, and macular pattern dystrophy due to an A to G transition at position 3243 of mitochondrial DNA (mtDNA) (m.3243A>G). The phenotypic heterogeneity of MIDD may be the consequence of different levels of mutated mtDNA among mitochondria in a given tissue. OBJECTIVE: The aim of the present study was thus to ascertain the correlation between the severity of the phenotype in patients with MIDD and the level of heteroplasmy in the blood leukocytes. PARTICIPANTS: The GEDIAM prospective multicenter register was initiated in 1995. Eighty-nine Europid patients from this register, with MIDD and the mtDNA 3243A>G mutation, were included. Patients with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) or with mitochondrial diabetes related to other mutations or to deletions of mtDNA were excluded. RESULTS: A significant negative correlation was found between levels of heteroplasmy and age of the patients at the time of sampling for molecular analysis, age at the diagnosis of diabetes, and body mass index. After adjustment for age at sampling for molecular study and gender, the correlation between heteroplasmy levels and age at the diagnosis of diabetes was no more significant. The two other correlations remained significant. A significant positive correlation between levels of heteroplasmy and HbA(1c) was also found and remained significant after adjustment for age at molecular sampling and gender. CONCLUSIONS: These results support the hypothesis that heteroplasmy levels are at least one of the determinants of the severity of the phenotype in MIDD.

Retinal and renal complications in patients with a mutation of mitochondrial DNA at position 3,243 (maternally inherited diabetes and deafness). A case-control study.

AIMS/HYPOTHESIS: We assessed the prevalence and determinants of retinal and renal complications in patients with maternally inherited diabetes and deafness (MIDD). METHODS: This was a multicentre prospective study comparing the prevalence of retinopathy and renal disease in 74 patients with MIDD and 134 control patients matched for sex, age and clinical presentation at onset of diabetes, duration of diabetes and current treatment. Comparisons were adjusted for HbA(1c) and hypertension. RESULTS: In MIDD patients, HbA(1c) (7.6 +/- 1.6 vs 8.5 +/- 2.0%, p < 0.002), systolic blood pressure (126.6 +/- 16.2 vs 133.1 +/- 17.3 mmHg, p < 0.007) and prevalence of hypertension (33.8 vs 64.2%, p < 0.0001) were lower than in control patients. Prevalence of diabetic retinopathy was 3.7-fold lower in MIDD patients (6/74, 8 vs 40/134, 29.6%, p < 0.0001). Differences between groups remained significant after adjustment for hypertension, systolic blood pressure and HbA(1c). In MIDD, urinary albumin excretion (314.8 vs 80.1 mg/24 h, p = 0.035) and creatinine plasma levels (103.5 vs 82.2 micromol/l, p = 0.0178) were higher and GFR was lower. Impaired renal function (GFR <60 ml/min) was four- to sixfold more frequent in MIDD. Differences between MIDD and control diabetic patients further increased when adjusted for HbA(1c) and systolic blood pressure (p < 0.0001). Adjustment for treatment with an ACE inhibitor or angiotensin II receptor antagonist did not modify the results. CONCLUSIONS/INTERPRETATION: This study indicates that diabetic retinopathy is less prevalent in MIDD than in control diabetes. This suggests that retinal alterations due to mitochondrial disease may have a protective role. By contrast, nephropathy is far more frequent in MIDD, suggesting the presence of a specific renal disease independent of diabetic nephropathy.

A standardized protocol to achieve normoglycaemia during labour and delivery in women with type 1 diabetes.

AIM: To evaluate a standardized protocol for maintaining near-normoglycaemia during labour and delivery in women with type 1 diabetes. METHODS: Over a nine-year period (1997-2005), 229 pregnancies in 174 women with type 1 diabetes were delivered at one centre. The same regimen was used for the induction of labour (group 1) and in women admitted in spontaneous labour (group 2): 10% dextrose (80ml/h) intravenous was given along with short-acting insulin, starting at 1IU/h intravenous via an infusion pump. Capillary blood glucose (CBG) was determined hourly, and the insulin infusion rate was modified accordingly. RESULTS: Labour was induced in 85 cases (37%) and spontaneous in 23 cases (10%), and an elective C-section was performed in 121 cases (53%). Maternal glycaemia during labour was 6.1+/-1.6 (range: 3.9-9.2)mmol/l in group 1, and 6.9+/-2.0 (range: 4.7-12.0)mmol/l in group 2. Maternal glycaemia at delivery was 5.8+/-1.5 (range: 3.4-9.4) and 6.3+/-1.9 (range: 4.1-11.4)mmol/l in groups 1 and 2, respectively. Women who underwent an elective C-section were not included in the standardized protocol and had higher glycaemia at delivery 7.1+/-2.0 (range: 2.7-13.5)mmol/l. Neonatal hypoglycaemia occurred in 30 infants (13%), and was only associated with preterm delivery. CONCLUSION: Using a standardized simple protocol during labour, maternal glycaemia was maintained within a near-normal range in 80-85% of cases.

Stress myocardial scintigraphy and dobutamine echocardiography in the detection of coronary disease in asymptomatic patients with type 2 diabetes.

OBJECTIVE: The aims of this prospective study were: (1) to compare stress thallium-201 single photon emission computed tomography (SPECT) and dobutamine echocardiography (DE) in the detection of silent myocardial ischemia (SMI) in asymptomatic high risk diabetic patients; (2) to analyse long-term outcome after intensive care of SMI in these patients. METHODS: SPECT was performed in 100 high risk diabetic patients and DE in the first 75 patients. Coronary angiography was realized in patients with SMI, with revascularization for suitable lesions. Intensive treatment of atherosclerosis risk factors was performed in all patients. Patients were followed 2 +/- 0.5 years for the subsequent occurrence of cardiac death, myocardial infarction and revascularization. RESULTS: SMI was detected by SPECT in 62% and by DE in 10% of the patients (p < 0.0001), whereas significant coronary stenosis at angiography was detected by SPECT in 26% and by DE in 5% of the patients (p < 0.02). Independent predictive factors of significant coronary stenosis were male gender (p < 0.03) and peripheral arterial disease (p < 0.007). Nonfatal acute coronary syndrome occurred during follow-up in 2 patients (2%). Subsequent revascularization procedure was needed in 9 patients. Baseline patients' characteristics, as well as SMI, were not predictive of cardiac event during follow up. CONCLUSION: SPECT seems more accurate than DE to detect significant coronary stenosis in high risk asymptomatic diabetic patients. In this population, aggressive treatment of SMI with systematic revascularization combined with intensive care of risk factors is associated with a favorable long-term prognosis, similar in diabetic patients with and without initial SMI.

The Gly482Ser polymorphism in the peroxisome proliferator-activated receptor-gamma coactivator-1 gene is associated with hypertension in type 2 diabetic men.

AIMS/HYPOTHESIS: Peroxisome proliferator-activated receptor-gamma coactivator-1 (PPARGC1) acts as a cofactor for several nuclear hormone receptors in many tissues and organs implicated in blood pressure regulation. Here, we assessed the association between the Gly482Ser variant of PPARGC1 and the arterial hypertension frequently found in subjects with type 2 diabetes. METHODS: We studied a group of 479 men and 253 women with type 2 diabetes. Arterial hypertension was present in 70% of the men and in 73% of the women. Genotypes were examined by PCR restriction fragment length polymorphism. A logistic regression analysis was performed to assess the covariables associated with arterial hypertension. RESULTS: There was an association between Ser allele homozygosis and arterial hypertension in type 2 diabetic men (odds ratio of 2.52 vs Gly allele homozygosis; 95% CI: 1.32-5.00; p=0.0064), but not in women. The prevalence of arterial hypertension in type 2 diabetic men was 77% vs 73% vs 67% for Ser-Ser, Gly-Ser and Gly-Gly carriers respectively (p=0.021). Age, BMI, the use of insulin, and triglyceride and creatinine levels were also independently associated with arterial hypertension in this cohort. CONCLUSIONS/INTERPRETATION: We have observed a sex-specific association between the PPARGC-1 gene Gly482Ser polymorphism and arterial hypertension in type 2 diabetic men. Further studies are needed to investigate the genetic, biochemical and pathophysiological basis of this allelic association.