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.

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.

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.

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.

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.

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.

Factors associated with urgent cesarean delivery in women with type 1 diabetes mellitus.

OBJECTIVE: Type 1 diabetes mellitus (DM) is associated with a threefold to fivefold increased risk for stillbirth during pregnancy. The objective of the present study was to identify factors associated with prelabor urgent cesarean delivery for fetal compromise in women with type 1 DM. METHODS: We performed a nested case-control study within a prospective cohort of single pregnancies in women with type 1 DM managed with standardized protocols regarding treatment of diabetes and prenatal care. Twice-weekly home antenatal surveillance including nonstress test was initiated at 32 weeks of gestation and continued until planned delivery at 38-39 weeks of gestation. We identified factors associated with urgent cesarean delivery for an abnormal nonstress test. The calculated total sample size was 416 pregnancies. Independent factors and adjusted odds ratio (OR) were identified by logistic regression. RESULTS: Among 479 pregnancies, the rate of urgent cesarean delivery for an abnormal nonstress test was 4%. A hemoglobin A1C (Hb A1C) level at delivery of 6.4% or higher occurred in 34% of the pregnancies and was independently associated with urgent cesarean delivery (2% compared with 8%, P=.003, OR 4.16, 95% confidence interval 1.40-12.32). In the multivariable analysis, lack of preconception care and occurrence of gestational hypertension or preeclampsia were not associated with urgent cesarean delivery. The rate of stillbirth was 2 per 1,000. CONCLUSION: In women with type 1 DM, an Hb A1C level at delivery of 6.4% or higher was associated with prelabor urgent cesarean delivery. This suggests that tight glycemic control throughout pregnancy might reduce the risk of late fetal compromise. LEVEL OF EVIDENCE: III.

Clinical characteristics and diagnostic criteria of maturity-onset diabetes of the young (MODY) due to molecular anomalies of the HNF1A gene.

CONTEXT: The diagnosis of maturity-onset diabetes of the young type 3 (MODY3), associated with HNF1A molecular abnormalities, is often missed. OBJECTIVE: The objective of the study was to describe the phenotypes of a large series of MODY3 patients and to reassess parameters that may improve its diagnosis. DESIGN, SETTING, AND PATIENTS: This retrospective multicenter study included 487 unrelated patients referred because of suspicion of MODY3. Genetic analysis identified 196 MODY3 and 283 non-MODY3 cases. Criteria associated with MODY3 were assessed by multivariate analysis. The capacity of the model to predict MODY3 diagnosis was assessed by the area under the receiver-operating characteristic curve and was further validated in an independent sample of 851 patients (165 MODY3 and 686 non-MODY3). RESULTS: In the MODY3 patients, diabetes was revealed by clinical symptoms in 25% of the cases and was diagnosed by screening in the others. Age at diagnosis of diabetes was more than 25 yr in 40% of the MODY3 patients. There was considerable variability and overlap of all assessed parameters in MODY3 and non-MODY3 patients. The best predictive model was based on criteria available at diagnosis of diabetes, including age, body mass index, number of affected generations, presence of diabetes symptoms, and geographical origin. The area under the curve of the receiver-operating characteristic analysis was 0.81. When sensitivity was set to 90%, specificity was 49%. CONCLUSIONS: Differential diagnosis between MODY3 and early-onset type 2 diabetes remains difficult. Whether the proposed model will improve the pick-up rate of MODY3 diagnosis needs to be confirmed in independent populations.

Onset of autoimmune type 1 diabetes during pregnancy: Prevalence and outcomes.

Although this has been recently challenged, gestational diabetes mellitus (gestational diabetes) is still defined as an "impairment of glucose tolerance with onset or first recognition during pregnancy". According to this definition, all pathophysiological conditions leading to beta cell deficiency may reveal as gestational diabetes, due to the physiological insulin resistance associated with pregnancy. In rare patients, gestational diabetes is associated with the presence of islet autoantibodies and with a high risk of progression to overt type 1 diabetes after delivery. This condition has often been compared to the Latent Autoimmune Diabetes in Adults. The frequency of islet autoantibodies in gestational diabetes has been assessed in many studies, but data about the clinical presentation of this subtype and about its prognosis are few. We review these studies and discuss the links of autoimmune gestational diabetes with type 1 diabetes mellitus.

Factors associated with cesarean delivery in nulliparous women with type 1 diabetes.

OBJECTIVE: To identify factors associated with cesarean delivery in nulliparous women with type 1 diabetes mellitus. METHODS: We performed a nested case-control study within a cohort of nulliparous women with type 1 diabetes mellitus. Independent factors and odds ratios were identified by logistic regression. RESULTS: Among 209 women, a cesarean delivery was performed without labor in 94 women (45%). Gestational weight gain higher than 15 kg (39% compared with 23%; odds ratio [OR], 2.2; 95% confidence interval [CI], 1.1-4.5) and suspected macrosomia (79% compared with 21%; OR, 13.1; 95% CI, 5.3-32.2) were independently associated with cesarean delivery without labor. Among 115 women who underwent a trial of labor, 54 (47%) had a cesarean delivery. Prepregnancy body mass index more than 25 kg/m2 (84% compared with 39%; OR, 7.5; 95% CI, 1.9-29.4) and Bishop score 3 or lower (66% compared with 25%; OR, 5.9; 95% CI, 2.2-16.1) were independently associated with cesarean delivery in labor. Preconception care, presence of a nephropathy, hemoglobin A1C levels during pregnancy, preeclampsia, and preterm delivery were not associated with cesarean delivery. The rates of wound infection and endometritis were 0.7% and 3%, respectively. CONCLUSION: The rate of cesarean delivery in nulliparous women with type 1 diabetes mellitus is very high. Prepregnancy body weight, gestational weight gain, and accuracy of the prediction of fetal macrosomia are potentially modifiable risk factors for cesarean delivery.

HNF1B-related diabetes triggered by renal transplantation.

BACKGROUND: A 37-year-old man developed cholestasis-associated pruritus followed by overt hyperglycemia (blood glucose level 23 mmol/l), necessitating insulin treatment, within weeks of undergoing renal transplantation. He had a history of gout, but his fasting blood glucose and glycated hemoglobin concentrations had been normal before transplantation. INVESTIGATIONS: Physical examination; laboratory tests, including assessment of glycated hemoglobin, anti-glutamic-acid-decarboxylase and anti-islet-antigen-2 antibodies, liver enzymes, renal function, tacrolimus blood trough level, exocrine (fecal elastase) and endocrine (C-peptide) pancreatic function; abdominal CT scan; liver biopsy; and screening of the hepatocyte nuclear factor 1 homeobox B (transcription factor 2) gene, HNF1B. DIAGNOSIS: New-onset diabetes after transplantation associated with a newly described deletion in HNF1B. MANAGEMENT: Minimization of tacrolimus exposure and withdrawal of steroids considerably reduced the patient's insulin requirement, and cholestasis-related pruritus was dramatically improved by administration of ursodeoxycholic acid. Renal ultrasonography and screening for the HNF1B molecular abnormality were offered to the patient's relatives.