Jeannet Lauenborg

High Prevalence of Type 2 Diabetes and Pre-Diabetes in Adult Offspring of Women with Gestational Diabetes Mellitus or Type 1 Diabetes – The Role of Intrauterine Hyperglycemia

OBJECTIVE—The role of intrauterine hyperglycemia and future risk of type 2 diabetes in human offspring is debated. We studied glucose tolerance in adult offspring of women with either gestational diabetes mellitus (GDM) or type 1 diabetes, taking the impact of both intrauterine hyperglycemia and genetic predisposition to type 2 diabetes into account. RESEARCH DESIGN AND METHODS—The glucose tolerance status following a 2-h 75-g oral glucose tolerance test (OGTT) was evaluated in 597 subjects, primarily Caucasians, aged 18–27 years. They were subdivided into four groups according to maternal glucose metabolism during pregnancy and genetic predisposition to type 2 diabetes: 1) offspring of women with diet-treated GDM (O-GDM), 2) offspring of genetically predisposed women with a normal OGTT (O-NoGDM), 3) offspring of women with type 1 diabetes (O-type 1), and 4) offspring of women from the background population (O-BP). RESULTS—The prevalence of type 2 diabetes and pre-diabetes (impaired glucose tolerance or impaired fasting glucose) in the four groups was 21, 12, 11, and 4%, respectively. In multiple logistic regression analysis, the adjusted odds ratios (ORs) for type 2 diabetes/pre-diabetes were 7.76 (95% CI 2.58–23.39) in O-GDM and 4.02 (1.31–12.33) in O-type 1 compared with O-BP. In O-type 1, the risk of type 2 diabetes/pre-diabetes was significantly associated with elevated maternal blood glucose in late pregnancy: OR 1.41 (1.04–1.91) per mmol/l. CONCLUSIONS—A hyperglycemic intrauterine environment appears to be involved in the pathogenesis of type 2 diabetes/pre-diabetes in adult offspring of primarily Caucasian women with either diet-treated GDM or type 1 diabetes during pregnancy.

Overweight and the metabolic syndrome in adult offspring of women with diet-treated gestational diabetes mellitus or type 1 diabetes.

CONTEXT In animal studies, exposure to intrauterine hyperglycemia increases the risk of cardiovascular disease through only partly understood epigenetic mechanisms. Human long-term follow-up studies on the same topic are few. OBJECTIVE The aim was to study the risk of overweight and the metabolic syndrome in adult offspring of women with diet-treated gestational diabetes mellitus (GDM) or type 1 diabetes, and additionally to study associations between estimates of maternal hyperglycemia and outcome in the offspring. DESIGN AND SETTING We conducted a follow-up study of 1066 primarily Caucasian women aged 18-27 yr in the Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen, Denmark. PARTICIPANTS Offspring of women with diet-treated GDM (n = 168) and an unexposed reference group (n = 141) participated, as well as offspring of women with type 1 diabetes (n = 160) and offspring from the background population representing an unexposed reference group (n = 128). The follow-up rate was 56% (597 of 1066). MAIN OUTCOME MEASURES Women with body mass index of at least 25 kg/m(2) were considered overweight. The metabolic syndrome was determined by the International Diabetes Federation 2006 criteria. RESULTS The risk of overweight was doubled in offspring of women with diet-treated GDM or type 1 diabetes compared with offspring from the background population, whereas the risk of the metabolic syndrome was 4- and 2.5-fold increased, respectively. Offspring risk of the metabolic syndrome increased significantly with increasing maternal fasting blood glucose as well as 2-h blood glucose (during oral glucose tolerance test). CONCLUSIONS Adult offspring of women with diet-treated GDM or type 1 diabetes are risk groups for overweight and the metabolic syndrome. Intrauterine hyperglycemia may in addition to genetics and other factors contribute to the pathogenesis of overweight and the metabolic syndrome.

Common type 2 diabetes risk gene variants associate with gestational diabetes.

OBJECTIVE We aimed to examine the association between gestational diabetes mellitus (GDM) and 11 recently identified type 2 diabetes susceptibility loci. RESEARCH DESIGN AND METHODS Type 2 diabetes risk variants in TCF7L2, CDKAL1, SLC30A8, HHEX/IDE, CDKN2A/2B, IGF2BP2, FTO, TCF2, PPARG, KCNJ11, and WFS1 loci were genotyped in a cohort of women with a history of GDM (n = 283) and glucose-tolerant women of the population-based Inter99 cohort (n = 2446). RESULTS All the risk alleles in the 11 examined type 2 diabetes risk variants showed an odds ratio (OR) greater than 1 for the GDM group compared with the control group ranging from 1.13 [95% confidence interval (CI) 0.88-1.46] to 1.44 (95% CI 1.19-1.74) except for the WFS1 rs10010131 variant with OR 0.87 (95% CI 0.73-1.05). Combined analysis of all 11 variants showed a highly significant additive effect of multiple risk alleles on risk of GDM [OR 1.18 (95% CI 1.10-1.27)] per risk allele, P = 3.2 x 10(-6)). Applying receiver-operating characteristic showed an area under the receiver-operating characteristic curve of 0.62 for the genetic test alone and 0.73 when combining information on age, body mass index, and genotypes of the 11 gene variants. CONCLUSIONS The prevalence in a prior GDM group of several previously proven type 2 diabetes risk alleles equals the findings from association studies on type 2 diabetes. This supports the hypothesis that GDM and type 2 diabetes are two of the same entity.

Further evidence that mutations in INS can be a rare cause of Maturity-Onset Diabetes of the Young (MODY)

BackgroundInsulin gene (INS) mutations have recently been described as a common cause of permanent neonatal diabetes (PNDM) and a rare cause of diabetes diagnosed in childhood or adulthood.MethodsINS was sequenced in 116 maturity-onset diabetes of the young (MODYX) patients (n = 48 Danish and n = 68 Czech), 83 patients with gestational diabetes mellitus (GDM), 34 type 1 diabetic patients screened negative for glutamic acid decarboxylase (GAD), and 96 glucose tolerant individuals. The control group was randomly selected from the population-based sampled Inter99 study.ResultsOne novel heterozygous mutation c.17G>A, R6H, was identified in the pre-proinsulin gene (INS) in a Danish MODYX family. The proband was diagnosed at 20 years of age with mild diabetes and treated with diet and oral hypoglycaemic agent. Two other family members who carried the INS R6H were diagnosed with diabetes when 51 years old and with GDM when 27 years old, respectively. A fourth mutation carrier had normal glucose tolerance when 20 years old. Two carriers of INS R6H were also examined twice with an oral glucose tolerance test (OGTT) with 5 years interval. They both had a ~30% reduction in beta-cell function measured as insulinogenic index. In a Czech MODYX family a previously described R46Q mutation was found. The proband was diagnosed at 13 years of age and had been treated with insulin since onset of diabetes. Her mother and grandmother were diagnosed at 14 and 35 years of age, respectively, and were treated with oral hypoglycaemic agents and/or insulin.ConclusionMutations in INS can be a rare cause of MODY and we conclude that screening for mutations in INS should be recommended in MODYX patients.

The FIB-PPH trial: fibrinogen concentrate as initial treatment for postpartum haemorrhage: study protocol for a randomised controlled trial

BackgroundPostpartum haemorrhage (PPH) remains a leading cause of maternal mortality worldwide. In Denmark 2% of parturients receive blood transfusion. During the course of bleeding fibrinogen (coagulation factor I) may be depleted and fall to critically low levels, impairing haemostasis and thus worsening the ongoing bleeding. A plasma level of fibrinogen below 2 g/L in the early phase of postpartum haemorrhage is associated with subsequent development of severe haemorrhage. Use of fibrinogen concentrate allows high-dose substitution without the need for blood type crossmatch. So far no publications of randomised controlled trials involving acutely bleeding patients in the obstetrical setting have been published. This trial aims to investigate if early treatment with fibrinogen concentrate reduces the need for blood transfusion in women suffering severe PPH.Methods/DesignIn this randomised placebo-controlled double-blind multicentre trial, parturients with primary PPH are eligible following vaginal delivery in case of: manual removal of placenta (blood loss ≥ 500 ml) or manual exploration of the uterus after the birth of placenta (blood loss ≥ 1000 ml). Caesarean sections are also eligible in case of perioperative blood loss ≥ 1000 ml. The exclusion criteria are known inherited haemostatic deficiencies, prepartum treatment with antithrombotics, pre-pregnancy weight <45 kg or refusal to receive blood transfusion. Following informed consent, patients are randomly allocated to either early treatment with 2 g fibrinogen concentrate or 100 ml isotonic saline (placebo). Haemostatic monitoring with standard laboratory coagulation tests and thromboelastography (TEG, functional fibrinogen and Rapid TEG) is performed during the initial 24 hours.Primary outcome is the need for blood transfusion. To investigate a 33% reduction in the need for blood transfusion, a total of 245 patients will be included. Four university-affiliated public tertiary care hospitals will include patients during a two-year period. Adverse events including thrombosis are assessed in accordance with International Conference on Harmonisation (ICH) good clinical practice (GCP).DiscussionA widespread belief in the benefits of early fibrinogen substitution in cases of PPH has led to increased off-label use. The FIB-PPH trial is investigator-initiated and aims to provide an evidence-based platform for the recommendations of the early use of fibrinogen concentrate in PPH.Trial registrationClincialTrials.gov NCT01359878.

Studies of the Ala/Val98 polymorphism of the hepatocyte nuclear factor-1alpha gene and the relationship to beta-cell function during an OGTT in glucose-tolerant women with and without previous gestational diabetes mellitus

Aims  In pregnancies complicated by gestational diabetes mellitus (GDM) an increased demand for insulin is not met due to β‐cell dysfunction. An Ala/Val polymorphism at codon 98 of the hepatocyte nuclear factor‐1α (HNF‐1α) gene has been associated with decreased serum insulin and C‐peptide responses during an oral glucose tolerance test (OGTT) in glucose‐tolerant subjects. The aims of the present study were to evaluate the influence of the polymorphism on the serum insulin and C‐peptide responses to an OGTT in glucose‐tolerant women with and without previous GDM and to investigate if this polymorphism is associated with GDM.

High Prevalence of Diabetes-Predisposing Variants in MODY Genes Among Danish Women With Gestational Diabetes Mellitus

Context: Gestational diabetes mellitus (GDM), defined as any degree of glucose intolerance with first recognition during pregnancy, is a heterogeneous form of diabetes characterized by various degrees of β-cell dysfunction. Objectives: We aimed to estimate the prevalence of possibly pathogenic variants in the maturity-onset diabetes of the young genes GCK, HNF1A, HNF4A, HNF1B, and INS among women with GDM. Furthermore, we examined the glucose tolerance status in variant carriers vs noncarriers at follow-up. Design, Setting, and Patients: We sequenced the coding regions and intron/exon boundaries of GCK, HNF1A, HNF4A, HNF1B, and INS using targeted region capture and next-generation sequencing in 354 Danish women with diet-treated GDM. Glucose tolerance was examined at follow-up 10 years after the index pregnancy. Main Outcome Measures: The prevalence of possibly pathogenic variants in GCK, HNF1A, HNF4A, HNF1B, and INS was estimated, and differences in anthropometric traits, high-sensitivity C-Reactive Protein (CRP), and glucose metabolism were measured. Results: At baseline, 17 possibly disease-causing variants were found in 21 women, revealing a combined GCK, HNF1A, HNF4A, HNF1B, and INS variant prevalence of 5.9% (95% confidence interval: 3.5% to 8.4%). At follow-up, 15 out of 135 women with diabetes (11%) were carriers of variants in GCK, HNF1A, HNF4A, HNF1B, or INS. Conclusions: Almost 6% of Danish women with diet-treated GDM have possibly pathogenic variants in GCK, HNF1A, HNF4A, HNF1B, or INS. These women are at high risk of developing diabetes after pregnancy. Thus screening for variants in GCK, HNF1A, HNF4A, HNF1B, and INS should be considered among women with GDM.

Screening for Gestational Diabetes

Gestational diabetes is an asymptomatic condition associated with adverse outcome for mother and child. Overweight and obesity confer a higher risk of gestational diabetes – up to 11-fold. Health care providers of pregnant women should ensure that a strategy for screening gestational diabetes is in place. Either general screening programmes or selective screening programmes may be employed. Women with gestational diabetes should be monitored and treated vigorously. After delivery, glucose metabolism is most often normalised, but women with previous gestational diabetes have an increased risk of developing type-2 diabetes in later years. Therefore, they should be counselled about healthy lifestyles and offered exanimations for diabetes or pre-diabetes with 1–3 year intervals.

The influence of parental history of diabetes and offspring birthweight on offspring glucose metabolism in adulthood

Background. Links are well established between both family history of diabetes and reduced birthweight and increased risk of diabetes in adulthood. Objectives. 1) To investigate the influence of parental history of type 2 diabetes (T2DM) on offspring birthweight and adult offspring glucose tolerance status in non‐diabetic offspring of patients with T2DM and 2) to study the associations of birthweight with measures of pancreatic beta‐cell function and insulin sensitivity. Design. Family cohort study. Population. Offspring of patients with verified T2DM diagnosed after age 40 years with a spouse without known diabetes. Methods. Oral glucose tolerance tests and frequently sampled intravenous glucose tolerance tests (FSIGT) in non‐diabetic offspring. Birthweight and length obtained from birth records. Results. Among 122 offspring with maternal history of T2DM, 14.8% had diabetes compared to 8.0% in 137 offspring with paternal history of diabetes, p=0.09. Offspring with maternal history of T2DM had a mean birthweight 196g higher than offspring with paternal T2DM (3 651±640g (mean±SD) vs. 3 456±472g (p=0.01)). Non‐diabetic offspring with birthweights in the lowest tertile had significantly higher plasma glucose levels after an oral glucose tolerance test (OGTT) [Area under the curveglucOGTT, mean (95%CI), 1 795 (1 725–1 866) vs. 1 683 (1 613–1 753) mmol/L/min, p=0.02], and lower insulin sensitivity index calculated from a frequently sampled intravenous glucose tolerance test – Si 9.60 [10–5(min*pmol/L)–1] (8.23–10.97) vs. 11.79 (10.41–13.18), p=0.02 – in adulthood compared to offspring with birthweights in the upper tertile. Conclusions. Offspring with a family history of maternal T2DM have higher birthweights than those with paternal T2DM. Low birthweight associates with elevated plasma glucose levels after an oral glucose load and decreased insulin sensitivity in adulthood.