mTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases.

Mitochondrial diseases represent a significant clinical challenge. Substantial efforts have been devoted to identifying therapeutic strategies for mitochondrial disorders, but effective interventions have remained elusive. Recently, we reported attenuation of disease in a mouse model of the human mitochondrial disease Leigh syndrome through pharmacological inhibition of the mechanistic target of rapamycin (mTOR). The human mitochondrial disorder MELAS/MIDD (Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes/Maternally Inherited Diabetes and Deafness) shares many phenotypic characteristics with Leigh syndrome. MELAS/MIDD often leads to organ failure and transplantation and there are currently no effective treatments. To examine the therapeutic potential of mTOR inhibition in human mitochondrial disease, four kidney transplant recipients with MELAS/MIDD were switched from calcineurin inhibitors to mTOR inhibitors for immunosuppression. Primary fibroblast lines were generated from patient dermal biopsies and the impact of rapamycin was studied using cell-based end points. Metabolomic profiles of the four patients were obtained before and after the switch. pS6, a measure of mTOR signaling, was significantly increased in MELAS/MIDD cells compared to controls in the absence of treatment, demonstrating mTOR overactivation. Rapamycin rescued multiple deficits in cultured cells including mitochondrial morphology, mitochondrial membrane potential, and replicative capacity. Clinical measures of health and mitochondrial disease progression were improved in all four patients following the switch to an mTOR inhibitor. Metabolomic analysis was consistent with mitochondrial function improvement in all patients.

Next-generation sequencing identifies monogenic diabetes in 16% of patients with late adolescence/adult-onset diabetes selected on a clinical basis: a cross-sectional analysis.

BACKGROUND: Monogenic diabetes (MgD) accounts for 1-2% of all diabetes cases. In adults, MgD is difficult to distinguish from common diabetes causes. We assessed the diagnosis rate and genetic spectrum of MgD using next-generation sequencing in patients with late adolescence/adult-onset diabetes referred for a clinical suspicion of MgD. METHODS: This cross-sectional study was performed in 1564 probands recruited in 116 Endocrinology departments. Inclusion criteria were the absence of diabetes autoantibodies, and at least two of the three following criteria: an age ≤ 40 years and a body mass index (BMI) < 30 kg/m2 at diagnosis in the proband or in at least two relatives with diabetes, and a family history of diabetes in ≥ 2 generations. Seven genes (GCK, HNF1A, HNF4A, HNF1B, ABCC8, KCNJ11, and INS) were analyzed. Variant pathogenicity was assessed using current guidelines. RESULTS: Pathogenic variants were identified in 254 patients (16.2%) and in 23.2% of EuroCaucasian patients. Using more stringent selection criteria (family history of diabetes in ≥ 3 generations, age at diabetes ≤ 40 years and BMI < 30 kg/m2 in the proband, EuroCaucasian origin) increased the diagnosis rate to 43%, but with 70% of the identified cases being missed. GCK (44%), HNF1A (33%), and HNF4A (10%) accounted for the majority of the cases. HNF1B (6%), ABCC8/KCNJ11 (4.4%), and INS (2.8%) variants accounted for 13% of the cases. As compared to non-monogenic cases, a younger age, a lower BMI and the absence of diabetes symptoms at diagnosis, a EuroCaucasian origin, and a family history of diabetes in ≥ 3 generations were associated with MgD, but with wide phenotype overlaps between the two groups. In the total population, two clusters were identified, that mainly differed by the severity of diabetes at onset. MgDs were more prevalent in the milder phenotypic cluster. The phenotypes of the 59 patients (3.8%) with variants of uncertain significance were different from that of patients with pathogenic variants, but not from that of non-monogenic patients. CONCLUSION: Variants of HNF1B and the K-ATP channel genes were more frequently involved in MgD than previously reported. Phenotype overlapping makes the diagnosis of MgD difficult in adolescents/adults and underlies the benefit of NGS in clinically selected patients.

Tubular proteinuria in patients with HNF1α mutations: HNF1α drives endocytosis in the proximal tubule.

Hepatocyte nuclear factor 1α (HNF1α) is a transcription factor expressed in the liver, pancreas, and proximal tubule of the kidney. Mutations of HNF1α cause an autosomal dominant form of diabetes mellitus (MODY-HNF1A) and tubular dysfunction. To gain insights into the role of HNF1α in the proximal tubule, we analyzed Hnf1a-deficient mice. Compared with wild-type littermates, Hnf1a knockout mice showed low-molecular-weight proteinuria and a 70% decrease in the uptake of ß2-microglobulin, indicating a major endocytic defect due to decreased expression of megalin/cubilin receptors. We identified several binding sites for HNF1α in promoters of Lrp2 and Cubn genes encoding megalin and cubilin, respectively. The functional interaction of HNF1α with these promoters was shown in C33 epithelial cells lacking endogenous HNF1α. Defective receptor-mediated endocytosis was confirmed in proximal tubule cells from these knockout mice and could be rescued by transfection of wild-type but not mutant HNF1α. Transfection of human proximal tubule HK2 cells with HNF1α was able to upregulate megalin and cubilin expression and to increase endocytosis of albumin. Low-molecular-weight proteinuria was consistently detected in individuals with HNF1A mutations compared with healthy controls and patients with non-MODY-HNF1A diabetes mellitus. Thus, HNF1α plays a key role in the constitutive expression of megalin and cubilin, hence regulating endocytosis in the proximal tubule of the kidney. These findings provide new insight into the renal phenotype of individuals with mutations of HNF1A.

Pregnancy in Women With Monogenic Diabetes due to Pathogenic Variants of the Glucokinase Gene: Lessons and Challenges.

Heterozygous loss-of-function variants of the glucokinase (GCK) gene are responsible for a subtype of maturity-onset diabetes of the young (MODY). GCK-MODY is characterized by a mild hyperglycemia, mainly due to a higher blood glucose threshold for insulin secretion, and an up-regulated glucose counterregulation. GCK-MODY patients are asymptomatic, are not exposed to diabetes long-term complications, and do not require treatment. The diagnosis of GCK-MODY is made on the discovery of hyperglycemia by systematic screening, or by family screening. The situation is peculiar in GCK-MODY women during pregnancy for three reasons: 1. the degree of maternal hyperglycemia is sufficient to induce pregnancy adverse outcomes, as in pregestational or gestational diabetes; 2. the probability that a fetus inherits the maternal mutation is 50% and; 3. fetal insulin secretion is a major stimulus of fetal growth. Consequently, when the fetus has not inherited the maternal mutation, maternal hyperglycemia will trigger increased fetal insulin secretion and growth, with a high risk of macrosomia. By contrast, when the fetus has inherited the maternal mutation, its insulin secretion is set at the same threshold as the mother's, and no fetal growth excess will occur. Thus, treatment of maternal hyperglycemia is necessary only in the former situation, and will lead to a risk of fetal growth restriction in the latter. It has been recommended that the management of diabetes in GCK-MODY pregnant women should be guided by assessment of fetal growth by serial ultrasounds, and institution of insulin therapy when the abdominal circumference is ≥ 75th percentile, considered as a surrogate for the fetal genotype. This strategy has not been validated in women with in GCK-MODY. Recently, the feasibility of non-invasive fetal genotyping has been demonstrated, that will improve the care of these women. Several challenges persist, including the identification of women with GCK-MODY before or early in pregnancy, and the modalities of insulin therapy. Yet, retrospective observational studies have shown that fetal genotype, not maternal treatment with insulin, is the main determinant of fetal growth and of the risk of macrosomia. Thus, further studies are needed to specify the management of GCK-MODY pregnant women during pregnancy.

Determinants of the persistency of macrosomia and shoulder dystocia despite treatment of gestational diabetes mellitus.

AIMS: to identify potentially modifiable risk factors associated with the persistency of macrosomia and/or shoulder dystocia in infants born to women treated for gestational diabetes mellitus (GDM). METHODS: this case-control retrospective study included 113 cases complicated by macrosomia (ponderal index ≥97th percentile) and/or shoulder dystocia, and 226 controls without these complications. Factors associated with macrosomia and/or shoulder dystocia and with failure of diabetes management were assessed by multivariable analyses. RESULTS: Macrosomia and/or shoulder dystocia were associated with previous delivery of a large for gestational age (LGA) infant (adjusted odds ratio, 2.34, 95% confidence interval [1.01-5.45]), three abnormal glucose values during oral glucose tolerance test (2.83 [1.19-6.72]), a higher gestational weight gain before treatment (1.08 [1.01-1.15]), and failure of diabetes management (2.68 [1.32-5.45]). A non-Euro Caucasian origin (3.08 [1.37-6.93]), previous delivery of a LGA infant (3.21 [1.31-7.87]), institution of treatment after 32 weeks of gestation (3.92 [1.86-8.25]), and insulin therapy (2.91 [1.20-7.03]) were associated with failure of diabetes management. CONCLUSIONS: supportive care in at risk women, limitation of weight gain in early pregnancy, shortened delay between diagnosis and treatment of GDM, and intensive insulin dosage adjustments might be means to improve the neonatal prognosis of GDM.

Liver adenomatosis in patients with hepatocyte nuclear factor-1 alpha maturity onset diabetes of the young (HNF1A-MODY): Clinical, radiological and pathological characteristics in a French series.

BACKGROUND: Liver adenomatosis (LA) is a rare disease resulting from biallelic inactivation of the hepatocyte nuclear factor-1 alpha (HNF1A) gene, which induces the proliferation of adenoma cells in liver parenchyma. Liver adenomatosis has only been documented in case reports from patients carrying a HNF1A germline mutation. We have evaluated the frequency of LA among a large cohort of patients with HNF1A-maturity onset diabetes of the young (MODY), previously termed "MODY3," and herein describe its clinical, radiological, and pathological characteristics. METHODS: In all, 137 HNF1A-MODY subjects from 74 families were screened by liver ultrasonography in 13 centers, and 15 additional cases of LA were later included in the series. Liver adenomatosis was confirmed by liver computed tomography, magnetic resonance imaging (MRI), and/or histopathology. RESULTS: Among 137 carriers of an HNF1A mutation, 9 patients (6.5%) from seven families were diagnosed with LA. Diabetes mellitus was present in 87.5% of patients with LA. In 25% of patients, LA was diagnosed due to intra-abdominal or intratumoral bleeding. Liver biochemistry was near normal in all patients. Liver imaging showed adenomas of various sizes and numbers. On MRI, most nodules had the radiological characteristics of steatotic adenomas. Histopathological confirmation of LA was available in 13 cases, and these adenomas were mostly steatotic. Surgery was initially performed in 37.5% of patients, and liver disease progression was observed in 30%. No disease progression was observed in 14 pregnancies. CONCLUSIONS: The frequency of LA in a cohort of screened HNF1A-MODY patients and the high incidence of LA progression and/or hemorrhage warrants systematic screening for liver adenomatosis in HNF1A-MODY families.

PTPN22 R620W functional variant in type 1 diabetes and autoimmunity related traits.

The PTPN22 gene, encoding the lymphoid-specific protein tyrosine phosphatase, a negative regulator in the T-cell activation and development, has been associated with the susceptibility to several autoimmune diseases, including type 1 diabetes. Based on combined case-control and family-based association studies, we replicated the finding of an association of the PTPN22 C1858T (R620W) functional variant with type 1 diabetes, which was independent from the susceptibility status at the insulin gene and at HLA-DR (DR3/4 compared with others). The risk contributed by the 1858T allele was increased in patients with a family history of other autoimmune diseases, further supporting a general role for this variant on autoimmunity. In addition, we found evidence for an association of 1858T allele with the presence of GAD autoantibodies (GADA), which was restricted to patients with long disease duration (>10 years, P < 0.001). This may help define a subgroup of patients with long-term persistence of GADA. The risk conferred by 1858T allele on GAD positivity was additive, and our meta-analysis also supported an additive rather than dominant effect of this variant on type 1 diabetes, similar to previous reports on rheumatoid arthritis and systemic lupus erythematosus.

FCRL3 -169CT functional polymorphism in type 1 diabetes and autoimmunity traits.

A functional variant located in the promoter region of the Fc receptor like 3 gene (FCRL3, -169CT variant) has been recently shown to be associated with several autoimmune diseases in the Japanese population. Following the concept of shared genetic determinants between autoimmune diseases, we tested this variant for association to Type 1 diabetes (T1D) and T1D-related phenotypes in two independent settings: a family-based association study (French and US families) and a case-control study (French population). We found suggestive evidence for association of the FCRL3 -169CC genotype, corresponding to the susceptibility genotype for rheumatoid arthritis, with an increased risk of additional autoimmunity markers (OR=1.97, P=0.01) and of other autoimmune diseases (OR=1.75, P=0.05). However, there was no evidence of association of this variant with T1D in these cohorts, separately and combined, nor in subgroups of patients defined based on their major T1D risk factors at HLA-DRB1, insulin and PTPN22. Hence, this variant may help define subgroups of T1D patients with contrasted risk of other autoimmune diseases.

Exonic duplication of the hepatocyte nuclear factor-1beta gene (transcription factor 2, hepatic) as a cause of maturity onset diabetes of the young type 5.

CONTEXT: Maturity onset diabetes of the young (MODY) type 5 has been described as the association of early-onset diabetes and renal disease. Actually, MODY5 encompasses multiple phenotypes, including nondiabetic progressive renal failure, kidney and genital tract malformations, atypical familial hyperuricemic nephropathy, pancreas atrophy, and liver test abnormalities. The occurrence of MODY5 has been associated with various molecular abnormalities of TCF2, including missense, nonsense, small insertion/deletions, and splice site mutations, as well as large genomic deletions or single exonic deletion of TCF2. DESIGN: Using quantitative multiplex PCR amplification of short fluorescent fragments, we have analyzed the TCF2 gene in a French family of which three relatives presented a MODY5 phenotype. The proband had an extended clinical phenotype, including hyperuricemic nephropathy and early gout, chronic renal failure, renal morphological abnormalities, abnormal liver tests, and diabetes. His son had almost no clinical expression of the disease, whereas his grandson had a restricted but severe renal phenotype present from birth. RESULTS: We show that a duplication of the exon 5 of TCF2 is responsible for the MODY5 phenotypes in this family. CONCLUSIONS: Thus, we describe a novel molecular mechanism that may be responsible for MODY5, and we emphasize the wide intrafamilial variability of MODY5 expressivity. These observations suggest that the diagnosis of MODY5 may be raised even in subjects with partial phenotypes. They also confirm that quantitative multiplex PCR amplification of short fluorescent fragments analysis should be the first step of genetic screening in patients with a MODY5 phenotype.

Silent myocardial ischemia screening in patients with diabetes mellitus.

The prevalence of diabetes mellitus is fairly increasing, especially in the developing countries. Diabetes is a major cardiovascular risk factor; it often leads to severe cardiovascular complications, and coronary artery disease (CAD) is the main cause of death in diabetic patients. Silent myocardial ischemia (SMI) is more frequent in diabetic patients. The progress made in detection and treatment of CAD allows reconsidering the screening of SMI, in the hope that early CAD diagnosis leads to a more effective therapy and the decrease of cardiovascular complications and mortality. However, the benefit of systematic SMI screening remains discussed. Current guidelines recommend screening SMI in asymptomatic diabetic patients selected for high cardiovascular risk (i.e. with two or more other cardiovascular risk factors, or peripheral or carotid arterial disease, or proteinuria). ECG stress test can be recommended in first intention if maximal heart rate can be achieved. For patient with inconclusive ECG stress test, myocardial scintigraphy seems more accurate than stress echocardiography. Coronary angiogram should be performed in case of positive stress test. Further evaluations of systematic screening have to be conducted on broad randomized trial.

Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B (HNF1B) Molecular Defects.

OBJECTIVE: Molecular defects of hepatocyte nuclear factor 1B (HNF1B) are associated with a multiorgan disease, including diabetes (maturity-onset diabetes of the young 5) and kidney abnormalities. The HNF1B syndrome is related to HNF1B mutations or to a 17q12 deletion spanning 15 genes, including HNF1B. Here, we described HNF1B-related diabetes and associated phenotypes and assessed genotype/phenotype correlations at diagnosis and in the long-term. RESEARCH DESIGN AND METHODS: This multicenter retrospective cohort study included 201 patients, aged 18 years or older at follow-up, with HNF1B mutations (n = 101) or deletion (n = 100). RESULTS: Diabetes was present in 159 patients. At diagnosis, clinical symptoms of diabetes were present in 67 of 144 patients and HNF1B renal disease in 64 of 102. Although responsiveness to sulfonylureas/repaglinide was observed in 29 of the 51 tested, 111 of 140 patients (79%) were treated with insulin at follow-up. Diabetic retinopathy and/or neuropathy were present in 46 of 114 patients. Renal cysts were present in 122 of 166 patients, chronic kidney disease stages 3-4 (CKD3-4) in 75 of 169 (44%), and end-stage renal disease (ESRD) in 36 of 169 (21%). Compared with the patients with mutations, those with HNF1B deletion less often had CKD3-4/ESRD at diagnosis (11 of 43 vs. 27 of 35, P < 10-4) and in the long term (40 of 78 vs. 71 of 91, P = 0.0003). They were leaner and more frequently treated with insulin. CONCLUSIONS: In patients with HNF1B syndrome, diabetes complications, cardiovascular risk factors, CKD3-4, and ESRD are highly prevalent. At diabetes diagnosis, the presence of morphological and/or functional kidney disease may help etiological diagnosis. Genotype/phenotype correlations may have implications for the care and the prognosis of these patients.

Large genomic rearrangements in the hepatocyte nuclear factor-1beta (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5.

Maturity-onset diabetes of the young (MODY) 5 is caused by mutations in the TCF2 gene encoding the transcription factor hepatocyte nuclear factor-1beta. However, in 60% of the patients with a phenotype suggesting MODY5, no point mutation is detected in TCF2. We have hypothesized that large genomic rearrangements of TCF2 that are missed by conventional screening methods may account for this observation. In 40 unrelated patients presenting with MODY5 phenotype, TCF2 was screened for mutations by sequencing. Patients without mutations were then screened for TCF2 rearrangements by the quantitative multiplex PCR of short fluorescent fragments (QMPSF). Among the 40 patients, the overall detection rate was 70%: 18 had point mutations, 9 had whole-gene deletions, and 1 had a deletion of a single exon. Similar phenotypes were observed in patients with mutations and in subjects with large deletions. These results suggest that MODY5 is more prevalent than previously reported, with one-third of the cases resulting from large deletions of TCF2. Because QMPSF is more rapid and cost effective than sequencing, we propose that patients whose phenotype is consistent with MODY5 should be screened first with the QMPSF assay. In addition, other MODY genes should be screened for large genomic rearrangements.

Searching for Maturity-Onset Diabetes of the Young (MODY): When and What for?

Maturity-onset diabetes of the young (MODY) is a group of monogenic diseases that results in primary defects in insulin secretion and dominantly inherited forms of nonautoimmune diabetes. Although many genes may be associated with monogenic diabetes, heterozygous mutations in 6 of them are responsible for the majority of cases of MODY. Glucokinase (GCK)-MODY is due to mutations in the glucokinase gene, 3 MODY subtypes are associated with mutations in the hepatocyte nuclear factor (HNF) transcription factors, and 2 others with mutations in ABCC8 and KCNJ11, which encode the subunits of the ATP-dependent potassium channel in pancreatic beta cells. GCK-MODY and HNF1A-MODY are the most common subtypes. The clinical presentation of MODY subtypes has been reported to differ according to the gene involved, and the diagnosis of MODY may be considered in various clinical circumstances. However, except in patients with GCK-MODY whose phenotype is very homogeneous, in most cases the penetrance and expressivity of a given molecular abnormality vary greatly among patients and, conversely, alterations in various genes may lead to similar phenotypes. Moreover, differential diagnosis among more common forms of diabetes may be difficult, particularly with type 2 diabetes. Thus, careful assessment of the personal and family histories of patients with diabetes is mandatory to select those in whom genetic screening is worthwhile. The diagnosis of monogenic diabetes has many consequences in terms of prognosis, therapeutics and family screening.

Diagnosis and management of maturity-onset diabetes of the young.

Maturity-onset diabetes of the young (MODY) is a dominantly inherited form of non-ketotic diabetes mellitus. It results from a primary defect of insulin secretion, and usually develops at childhood, adolescence, or young adulthood. MODY is a heterogeneous disease with regard to genetic, metabolic, and clinical features. All MODY genes have not been identified, but heterozygous mutations in six genes cause the majority of the MODY cases. By far MODY2 (due to mutations of the glucokinase gene) and MODY3 (due to mutations in hepatocyte nuclear factor-1alpha) are the most frequent. As with MODY3, all the other MODY subtypes are associated with mutations in transcription factors. The clinical presentations of the different MODY subtypes differ, particularly in the severity and the course of the insulin secretion defect, the risk of microvascular complications of diabetes, and the defects associated with diabetes. Patients with MODY2 have mild, asymptomatic, and stable hyperglycemia that is present from birth. They rarely develop microvascular disease, and seldom require pharmacologic treatment of hyperglycemia. In patients with MODY3, severe hyperglycemia usually occurs after puberty, and may lead to the diagnosis of type 1 diabetes. Despite the progression of insulin defects, sensitivity to sulfonylureas may be retained in MODY3 patients. Diabetic retinopathy and nephropathy frequently occur in patients with MODY3, making frequent follow-up mandatory. By contrast, other risk factors are not present in patients with MODY and the frequency of cardiovascular disease is not increased. The clinical spectrum of MODY is wider than initially described, and might include multi-organ involvement in addition to diabetes. In patients with MODY5, due to mutations in hepatocyte nuclear factor-1beta, diabetes is associated with pancreatic atrophy, renal morphologic and functional abnormalities, and genital tract and liver test abnormalities. Although MODY is dominantly inherited, penetrance or expression of the disease may vary and a family history of diabetes is not always present. Thus, the diagnosis of MODY should be raised in various clinical circumstances. Molecular diagnosis has important consequences in terms of prognosis, family screening, and therapy.

Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations.

BACKGROUND: Maturity-onset diabetes of the young type 5 (MODY5), a type of dominantly inherited diabetes mellitus and nephropathy, has been associated with mutations of the hepatocyte nuclear factor-1beta (HNF-1beta) gene, mostly generating truncated protein. Various phenotypes, including urogenital malformations, are related to HNF-1beta mutations. OBJECTIVE: To describe clinical and genetic findings in 13 patients with 8 novel HNF-1beta mutations. DESIGN: Multicenter, descriptive study. SETTING: 2 departments of diabetes, 1 department of internal medicine, and 1 department of nephrology. PARTICIPANTS: 8 probands with diabetes diagnosed before 40 years of age and nondiabetic kidney disease who were selected independent of their family history of diabetes, and 5 offspring. MEASUREMENTS: Characteristics of diabetes, renal function and structure, genital tract abnormalities, pancreas structure, insulin secretion, exocrine pancreas function, and liver test results. RESULTS: All mutations, including 5 missense changes, were found in the DNA-binding domain. Cosegregation of the mutation and MODY5 phenotype was observed in 4 families. Occurrence of a de novo mutation was demonstrated in 2 families. Diabetes was present in 10 of 13 mutation carriers. It was clinically overt in 5 participants and found by screening at age 19 to 38 years in 5 participants. Pancreas atrophy was observed in 5 of 6 probands, and pancreas exocrine insufficiency was observed in 6 of 7 probands. Renal involvement, consisting of structural changes and slowly progressive renal failure, was recognized in 9 patients at 18 to 41 years of age. Dysplastic kidneys were found by ultrasonography in 3 fetuses who subsequently showed transient neonatal renal failure. Genital tract abnormalities were present in 5 probands and liver enzyme levels were abnormal in 11 of 13 patients. LIMITATIONS: Since the study was small and not population-based, it could not estimate the prevalence of MODY5. Other phenotypes might be associated with HNF-1beta mutations. CONCLUSIONS: Maturity-onset diabetes of the young type 5 encompasses a wide clinical spectrum. Analysis for mutations of HNF-1beta is warranted, even without a family history of diabetes, in nonobese patients with diabetes and slowly progressive nondiabetic nephropathy, particularly when pancreatic atrophy or genital abnormalities are present.

Factors associated with preterm delivery in women with type 1 diabetes: a cohort study.

OBJECTIVE: The reported rate of preterm delivery in women with type 1 diabetes ranges from 22 to 45%, but the reasons are unclear. The purpose of this study was to identify factors associated with preterm delivery in these women. RESEARCH DESIGN AND METHODS: We studied the influence of maternal and diabetes-related factors on the occurrence of preterm delivery in 168 single pregnancies occurring in 127 women with type 1 diabetes. Women with spontaneous or indicated preterm delivery were compared with those who delivered after 37 weeks of gestation using polytomous logistic regression. RESULTS: The overall rate of preterm delivery was 24%, fivefold higher than the French prematurity rate in single pregnancy. Preterm delivery was spontaneous in 9% and indicated in 15%. HbA1c > or =7% at delivery was associated with spontaneous preterm delivery (odds ratio [OR] 5.3 [95% CI 1.1-26.8]). Nulliparity (12.0 [2.3-64.1]), progression of nephropathy (7.7 [1.3-46.9]), preeclampsia (12.0 [3.1-47.1]), and HbA1c > or =7% (7.5 [1.5-37.9]) at delivery were all associated with indicated preterm delivery. Preterm delivery was associated with significant neonatal morbidity as the risks for neonatal hypoglycemia and respiratory distress syndrome were increased by three- to sixfold compared with the reference group. CONCLUSIONS: The rate of preterm delivery remains high in women with type 1 diabetes. Different factors were associated with spontaneous and indicated preterm delivery, respectively. Because poor glycemic control was a risk factor for both outcomes, part of preterm delivery might be preventable.

French multicentric survey of outcome of pregnancy in women with pregestational diabetes.

OBJECTIVE: To evaluate perinatal outcome in pregnancies in women with type 1 and type 2 diabetes and the influence of preconception care 10 years after the St. Vincent's declaration. RESEARCH DESIGN AND METHODS: A cross-sectional study was conducted in 12 perinatal centers in France in 2000-2001. The main investigated outcomes were perinatal mortality, major congenital malformations, and preterm delivery. RESULTS: Among 435 single pregnancies, 289 (66.4%) were from women with type 1 and 146 (33.6%) from women with type 2 diabetes. Perinatal mortality rate was 4.4% (0.7% national rate), severe congenital malformations rate was 4.1% (2.2% national rate), and preterm delivery rate was 38.2% (4.7% national rate). Preconception care was provided in 48.5% women with type 1 diabetes and in 24.0% women with type 2 diabetes. Women whose first trimester HbA(1c) was >8% had higher rates of perinatal mortality (9.2 vs. 2.5%; odds ratio 3.9; 95% CI 1.5-9.7; P < 0.005), major congenital malformations (8.3 vs. 2.5%; 3.5; 1.3-8.9; P < 0.01), and preterm delivery (57.6 vs. 24.8%; 1.4; 1.1-1.7; P < 0.005) than those with first trimester HbA(1c) <8%. These results are similar to those reported in France in 1986-1988. CONCLUSIONS: Pregnancies in women with diabetes are still poorly planned and complicated by higher rates of perinatal mortality and major congenital malformations. Despite knowledge of the importance of intensified glycemic control before pregnancy, reaching the St. Vincent's target needs further implementation in France.

[MODY, a model of genotype/phenotype interactions in type 2 diabetes]. / Le MODY: modèle d'étude d'interactions génotype/phénotype dans le diabète de type 2.

Maturity onset diabetes of the young (MODY) is a subtype of familial diabetes mellitus characterised by early onset, autosomal dominant inheritance and primary defects of insulin secretion. Mutations in six known genes (the enzyme glucokinase and five transcription factors expressed in pancreatic beta-cells) cause most of the MODY cases. This genetic heterogeneity is associated with metabolic and clinical heterogeneity making MODY an interesting model of genotype/phenotype interaction in diabetes.