Publications (14) View all
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Article: The influence of parental history of diabetes and offspring birthweight on offspring glucose metabolism in adulthood.
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ABSTRACT: Links are well established between both family history of diabetes and reduced birthweight and increased risk of diabetes in adulthood. 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. Family cohort study. Offspring of patients with verified T2DM diagnosed after age 40 years with a spouse without known diabetes. Oral glucose tolerance tests and frequently sampled intravenous glucose tolerance tests (FSIGT) in non-diabetic offspring. Birthweight and length obtained from birth records. 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 196 g higher than offspring with paternal T2DM (3,651 ± 640 g (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 curve(glucOGTT) , 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. 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.Acta Obstetricia Et Gynecologica Scandinavica 09/2011; 90(12):1357-63. · 1.77 Impact Factor -
Article: Further evidence that mutations in INS can be a rare cause of Maturity-Onset Diabetes of the Young (MODY).
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ABSTRACT: Insulin 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. INS 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. One 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 approximately 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. Mutations in INS can be a rare cause of MODY and we conclude that screening for mutations in INS should be recommended in MODYX patients.BMC Medical Genetics 03/2010; 11:42. · 2.33 Impact Factor -
Article: Overweight and the metabolic syndrome in adult offspring of women with diet-treated gestational diabetes mellitus or type 1 diabetes.
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ABSTRACT: 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. 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. 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. 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). 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). 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.The Journal of clinical endocrinology and metabolism 05/2009; 94(7):2464-70. · 6.50 Impact Factor -
Article: Common type 2 diabetes risk gene variants associate with gestational diabetes.
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ABSTRACT: We aimed to examine the association between gestational diabetes mellitus (GDM) and 11 recently identified type 2 diabetes susceptibility loci. 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). 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. 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.Journal of Clinical Endocrinology & Metabolism 12/2008; 94(1):145-50. · 6.50 Impact Factor -
Article: 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.
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ABSTRACT: In pregnancies complicated by gestational diabetes mellitus (GDM) an increased demand for insulin is not met due to beta-cell dysfunction. An Ala/Val polymorphism at codon 98 of the hepatocyte nuclear factor-1alpha (HNF-1alpha) 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. The Ala/Val98 polymorphism was measured in 376 women of Danish origin with previous GDM, and in 724 age-matched and 310 middle-aged glucose tolerant women using polymerase chain reaction-restriction fragment length polymorphism. The allelic frequency of the Ala/Val98 polymorphism was 0.043 [95% confidence interval (CI) 0.028, 0.057] in women with previous GDM vs. 0.037 (95% CI 0.028, 0.047) in age-matched and 0.039 (95% CI 0.024, 0.054) in middle-age women. Among 117 glucose-tolerant women with previous GDM, 10 carriers of the Ala/Val98 polymorphism had a non-significant 27% and 22% reduction in serum C-peptide and insulin levels, respectively, at 30 min during an OGTT. Seventy-eight control subjects carrying the Ala/Val98 polymorphism had a 10% (P = 0.001) and 16% (P = 0.004) reduction in serum C-peptide and insulin levels, respectively, compared with 956 Ala/Ala control subjects. The Ala/Val polymorphism at codon98 of HNF-1alpha is not associated with GDM in Danish women. However, the codon 98 variant is associated with a significant impairment of serum insulin and C-peptide responses during an OGTT in glucose-tolerant women without previous GDM.Diabetic Medicine 01/2005; 21(12):1310-5. · 2.90 Impact Factor
