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.

Pancreatic enzyme replacement therapy in subjects with exocrine pancreatic insufficiency and diabetes mellitus: a real-life, case-control study.

BACKGROUND: Exocrine pancreatic insufficiency (EPI) can be associated with all types of diabetes. Pancreatic enzyme replacement therapy (PERT) has short and long-term benefits in subjects with EPI, but its effects on diabetes control are uncertain. We aimed to study the effects of PERT initiation on glycemic control in subjects with diabetes and EPI from any cause. METHODS: In this retrospective study, we compared subjects with EPI and diabetes who were prescribed PERT with subjects with diabetes who had a fecal elastase-1 concentration dosage, but did not receive PERT. The primary outcome was the effect of PERT on hypoglycemia frequency and severity. The secondary outcomes were the effects of PERT on gastro-intestinal disorders, HbA1c and body mass index (BMI). RESULTS: 48 subjects were included in each group. Overall, PERT did not have any significant effect on hypoglycemia frequency or severity, but hypoglycemia frequency tended to decrease in subjects with chronic pancreatitis. While 19% of subjects experienced mild hyperglycemia after PERT initiation, we did not report any keto-acidosis or any other severe adverse event. Gastro-intestinal disorders improved in 80% of subjects treated with PERT, versus in 20% of control subjects (p = 0.02). Gastro-intestinal disorders improved in 87% of subjects with recommended dosage of PERT, versus in 50% of subjects with underdosage (NS). HbA1c and BMI evolution did not differ between the groups. CONCLUSIONS: PERT initiation is safe in subjects with diabetes and EPI. It does not globally decrease hypoglycemia severity of frequency, but is associated with a decrease in gastro-intestinal disorders. Trial registration Retrospectively registered. The database was registered with the Commission Nationale Informatique et Libertés (CNIL), registration number: 2203351v0. The study was approved by the local ethics committee CLEP, registration number: AAA-2023-09047.

Prevalence and Description of the Skin Reactions Associated with Adhesives in Diabetes Technology Devices in an Adult Population: Results of the CUTADIAB Study.

Objective: The use of continuous glucose monitoring (CGM) systems and continuous subcutaneous insulin infusion (CSII) devices adhering to the skin can lead to skin reactions. The objective was to determine the prevalence and consequences of skin reactions at CGM or CSII sites in a large unbiased population. Research Design and Methods: This is a cross-sectional multicenter study. All adult patients with diabetes seen in consultation over a period of 7 months and using or having used a system with skin adhesives (in the last 10 years) were included and filled out a self-assessment questionnaire. Results: Among 851 patients, skin reaction was reported in 28% with CGM and 29% with CSII. Patients reporting reactions were more frequently women using CGM and CSII, and CGM users had type 1 more often than type 2 diabetes (P < 0.001). Manifestations were similar for reactions to CGM and CSII: redness and pruritus in 70%-75% of patients with reactions, pain in 20%-25%, and vesicles and desquamation in 12%-15%. Manifestations occurred within the first 24 h of first use in 22%-24% of patients with reactions to CGM and CSII, but after more than 6 months in 38% and 47% of patients with reactions to CGM and CSII, respectively. Device use was definitively stopped in 12% of patients with reactions to CGM (3.2% of all users) and 7% with reactions to CSII (2.1% of all users). Conclusions: Skin reactions were common, with similar presentations in CGM and CSII users. Manifestations suggested skin irritation rather than allergies. These reactions rarely led to the definitive discontinuation of the use of the device.

HNF1B-MODY Masquerading as Type 1 Diabetes: A Pitfall in the Etiological Diagnosis of Diabetes.

Hepatocyte nuclear factor-1B (HNF1B) maturity-onset diabetes of the young (MODY), also referred to as "renal cysts and diabetes syndrome" or MODY-5, is a rare form of monogenic diabetes that is caused by a deletion or a point mutation in the HNF1B gene, a developmental gene that plays a key role in regulating urogenital and pancreatic development. HNF1B-MODY has been characterized by its association with renal, hepatic and other extrapancreatic features. We present the case of a 39-year-old female patient who was first diagnosed with type 1 diabetes, but then, owing to the absence of anti-islet autoantibodies and to the disease's progression, was labeled later on as having atypical type 2 diabetes. She was finally recognized as having HNF1B-MODY, a diagnosis that had been suggested by the lack of metabolic syndrome and by the presence of unexplained chronically disturbed liver function tests and hypomagnesemia. There was a 10-year delay between the onset of diabetes and the molecular diagnosis. An atypical form of diabetes, especially in patients with multisystem involvement, should raise suspicion for an alternative etiology. A timely diagnosis of HNF1B-MODY is of utmost importance since it can greatly impact diabetes management and disease progression as well as family history.

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.

[Physiopathological progress in type 1 diabetes]. / Progrès physiopathologiques dans le diabète de type 1.

Type 1 diabetes results from the autoimmune destruction of pancreatic islet B cells, leading within various times to absolute insulin deficiency. The pathophysiology of the disease remains partly unclear: only half of the genetic predisposition is known; the nature, and even the reality, of a triggering event in the autoimmune activation are not established; furthermore, the primitive target of the autoimmune process is not fully determined. As immunological markers of the disease have been developped, therapeutic perspectives for type 1 diabetes prevention have emerged. However, little have been sucessful until now, reflecting the disease heterogeneity and complexity and the difficulty to define the best therapeutic window.

Peptides Derived From Insulin Granule Proteins Are Targeted by CD8+ T Cells Across MHC Class I Restrictions in Humans and NOD Mice.

The antigenic peptides processed by ß-cells and presented through surface HLA class I molecules are poorly characterized. Each HLA variant (e.g., the most common being HLA-A2 and HLA-A3) carries some peptide-binding specificity. Hence, features that, despite these specificities, remain shared across variants may reveal factors favoring ß-cell immunogenicity. Building on our previous description of the HLA-A2/A3 peptidome of ß-cells, we analyzed the HLA-A3-restricted peptides targeted by circulating CD8+ T cells. Several peptides were recognized by CD8+ T cells within a narrow frequency (1-50/106), which was similar in donors with and without type 1 diabetes and harbored variable effector/memory fractions. These epitopes could be classified as conventional peptides or neoepitopes, generated either via peptide cis-splicing or mRNA splicing (e.g., secretogranin-5 [SCG5]-009). As reported for HLA-A2-restricted peptides, several epitopes originated from ß-cell granule proteins (e.g., SCG3, SCG5, and urocortin-3). Similarly, H-2Kd-restricted CD8+ T cells recognizing the murine orthologs of SCG5, urocortin-3, and proconvertase-2 infiltrated the islets of NOD mice and transferred diabetes into NOD/scid recipients. The finding of granule proteins targeted in both humans and NOD mice supports their disease relevance and identifies the insulin granule as a rich source of epitopes, possibly reflecting its impaired processing in type 1 diabetes.

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.

Conventional and Neo-antigenic Peptides Presented by ß Cells Are Targeted by Circulating Naïve CD8+ T Cells in Type 1 Diabetic and Healthy Donors.

Although CD8+ T-cell-mediated autoimmune ß cell destruction occurs in type 1 diabetes (T1D), the target epitopes processed and presented by ß cells are unknown. To identify them, we combined peptidomics and transcriptomics strategies. Inflammatory cytokines increased peptide presentation in vitro, paralleling upregulation of human leukocyte antigen (HLA) class I expression. Peptide sources featured several insulin granule proteins and all known ß cell antigens, barring islet-specific glucose-6-phosphatase catalytic subunit-related protein. Preproinsulin yielded HLA-A2-restricted epitopes previously described. Secretogranin V and its mRNA splice isoform SCG5-009, proconvertase-2, urocortin-3, the insulin gene enhancer protein ISL-1, and an islet amyloid polypeptide transpeptidation product emerged as antigens processed into HLA-A2-restricted epitopes, which, as those already described, were recognized by circulating naive CD8+ T cells in T1D and healthy donors and by pancreas-infiltrating cells in T1D donors. This peptidome opens new avenues to understand antigen processing by ß cells and for the development of T cell biomarkers and tolerogenic vaccination strategies.

[Post-transplantation diabetes mellitus in kidney recipients]. / Diabètes post-transplantation rénale.

Post-transplantation diabetes mellitus is defined as diabetes that is diagnosed in grafted patients. It affects 20 to 30 % of kidney transplant recipients, with a high incidence in the first year. The increasing age at transplantation and the rising incidence of obesity may increase its prevalence in the next years. Post-transplantation diabetes mellitus is associated with poor outcomes, such as mortality, cardiovascular events or graft dysfunction. Its occurrence is mainly related to immunosuppressive agents, affecting both insulin secretion and sensibility. Immunosuppressants may be iatrogenic, and as such, induce an early and transient diabetes. They may also precociously determine a permanent diabetes, acting here as a promoting factor in patients proned to the development of type 2 diabetes. Lastly, they may behave, far from transplantation, as an additional risk factor for type 2 diabetes. The screening, management and prognosis of these different subtypes of post-transplantation diabetes mellitus will be different.

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.

Potential role of IL-17-producing iNKT cells in type 1 diabetes.

We explored in this study the status and potential role of IL-17-producing iNKT cells (iNKT17) in type 1 diabetes (T1D) by analyzing these cells in patients with T1D, and in NOD mice, a mouse model for T1D. Our analysis in mice showed an increase of iNKT17 cells in NOD vs control C57BL/6 mice, partly due to a better survival of these cells in the periphery. We also found a higher frequency of these cells in autoimmune-targeted organs with the occurrence of diabetes, suggesting their implication in the disease development. In humans, though absent in fresh PMBCs, iNKT17 cells are detected in vitro with a higher frequency in T1D patients compared to control subjects in the presence of the proinflammatory cytokine IL-1ß, known to contribute to diabetes occurrence. These IL-1ß-stimulated iNKT cells from T1D patients keep their potential to produce IFN-γ, a cytokine that drives islet ß-cell destruction, but not IL-4, with a reverse picture observed in healthy volunteers. On the whole, our results argue in favour of a potential role of IL-17-producing iNKT cells in T1D and suggest that inflammation in T1D patients could induce a Th1/Th17 cytokine secretion profile in iNKT cells promoting disease development.