Pituitary adenomas (PA) are among the most common human neoplasms. To describe the epidemiology and assess the disease burden of clinically significant PAs, population-based studies are needed. ...Iceland has a small well-defined population. The aim of this study is to describe the epidemiology of PAs in Iceland over an expanded period of time.
This is a retrospective observational study, including all PAs diagnosed in Iceland from 1955 to 2012.
Extensive clinical information was gathered in a database. Prevalence rates for all PA subtypes were calculated along with standardized incidence rates (SIR). Sex ratios and relationships with adenoma size, age, and symptoms were assessed.
We identified 471 individuals: 190 men and 281 women. Total prevalence in 2012 was 115.57/100, 000, prolactinomas were most prevalent (54.37/100, 000) followed by non-functioning adenomas (NFPAs) (42.32/100 ,000). Throughout the period, NFPAs were most common (43.0%) followed by prolactinomas (39.9%) and 11.3% had acromegaly and 5.7% Cushing's disease. Women are diagnosed younger with smaller adenomas. Total SIR has increased significantly and is now 5.8/100 000 per year.
In this nationwide study spanning six decades, we have confirmed PAs rising prevalence and incidence rates noted in recent studies. We demonstrated higher overall prevalence and incidence rates than ever previously recorded with an increasing predominance of NFPAs, which is not explained by incidental findings alone. There is a relationship with the introduction of imaging modalities, but the vast majority of patients are symptomatic at diagnosis. This underlines the importance of increased awareness, education, and appropriate allocation of resources for this growing group of patients.
Lipoprotein(a) Lp(a) is a causal risk factor for cardiovascular diseases that has no established therapy. The attribute of Lp(a) that affects cardiovascular risk is not established. Low levels of ...Lp(a) have been associated with type 2 diabetes (T2D).
This study investigated whether cardiovascular risk is conferred by Lp(a) molar concentration or apolipoprotein(a) apo(a) size, and whether the relationship between Lp(a) and T2D risk is causal.
This was a case-control study of 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8,734 with T2D. This study used measured and genetically imputed Lp(a) molar concentration, kringle IV type 2 (KIV-2) repeats (which determine apo(a) size), and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration to disentangle the relationship between Lp(a) and cardiovascular risk. Loss-of-function homozygotes and other subjects genetically predicted to have low Lp(a) levels were evaluated to assess the relationship between Lp(a) and T2D.
Lp(a) molar concentration was associated dose-dependently with CAD risk, peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size. Homozygous carriers of loss-of-function mutations had little or no Lp(a) and increased the risk of T2D.
Molar concentration is the attribute of Lp(a) that affects risk of cardiovascular diseases. Low Lp(a) concentration (bottom 10%) increases T2D risk. Pharmacologic reduction of Lp(a) concentration in the 20% of individuals with the greatest concentration down to the population median is predicted to decrease CAD risk without increasing T2D risk.
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We recently described an association between risk of type 2diabetes and variants in the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4), with a population attributable risk (PAR) of ...17%-28% in three populations of European ancestry. Here, we refine the definition of the TCF7L2 type 2diabetes risk variant, HapBT2D, to the ancestral T allele of a SNP, rs7903146, through replication in West African and Danish type 2 diabetes case-control studies and an expanded Icelandic study. We also identify another variant of the same gene, HapA, that shows evidence of positive selection in East Asian, European and West African populations. Notably, HapA shows a suggestive association with body mass index and altered concentrations of the hunger-satiety hormones ghrelin and leptin in males, indicating that the selective advantage of HapA may have been mediated through effects on energy metabolism.
Abstract Objective To analyze which factors contribute to improvement in glycemic control in educational interventions in type 2 diabetes reported in randomized controlled trials (RCT) published in ...2001–2005. Methods Papers were extracted from Medline and Scopus using educational intervention and adults with type 2 diabetes as keywords. Inclusion criteria were RCT design. Data were analyzed with a data-mining program. Results Of 464 titles extracted, 21 articles reporting 18 studies met the inclusion criteria. Data mining showed that for initial glycosylated hemoglobin (HbA1c) level ≤7.9% the diabetes education intervention achieved a small change in HbA1c level, or from +0.1 to −0.7%. For initial HbA1c ≥8.0%, a significant drop in HbA1c level of 0.8–2.5% was found. Data mining indicated that duration, educational content and intensity of education did not predict changes in HbA1c levels. Conclusion Initial HbA1c level is the single most important factor affecting improvements in glycemic control in response to patient education. Data mining is an appropriate and sufficiently sensitive method to analyze outcomes of educational interventions. Diversity in conceptualization of interventions and diversity of instruments used for outcome measurements could have hampered actual discovery of effective educational practices. Practice implications Participation in educational interventions generally seems to benefit people with type 2 diabetes. Use of standardized instruments is encouraged as it gives better opportunities to identify conclusive results with consequent development of clinical guidelines.
We report a genomewide linkage study of type 2 diabetes (T2D MIM
125853) in the Icelandic population. A list of type 2 diabetics was cross-matched with a computerized genealogical database clustering ...763 type 2 diabetics into 227 families. The diabetic patients and their relatives were genotyped with 906 microsatellite markers. A nonparametric multipoint linkage analysis yielded linkage to 5q34–q35.2 (LOD = 2.90,
P=1.29×10
−4) in all diabetics. Since obesity, here defined as body mass index (BMI) ⩾30 kg/m
2, is a key risk factor for the development of T2D, we studied the data either independently of BMI or by stratifying the patient group as obese (BMI ⩾30) or nonobese (BMI <30). A nonparametric multipoint linkage analysis yielded linkage to 5q34–q35.2 (LOD = 3.64,
P=2.12×10
−5) in the nonobese diabetics. No linkage was observed in this region for the obese diabetics. Linkage analysis conditioning on maternal transmission to the nonobese diabetics resulted in a LOD score of 3.48 (
P=3.12×10
−5) in the same region, whereas conditioning on paternal transmission led to a substantial drop in the LOD score. Finally, we observed potential interactions between the 5q locus and two T2D susceptibility loci, previously mapped in other populations.
Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or ...genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
Background: The results of epidemiologic studies have linked birth size to adult glucose intolerance. Objective: We investigated this association in a genetically homogeneous population with higher ...birth weights and a lower prevalence of type 2 diabetes than previously studied. Design: The subjects were 2362 men and 2286 women aged 33-65 y. Size at birth was obtained from the National Archives of Iceland. Data for adult anthropometry, fasting blood glucose, and blood glucose after an oral glucose load came from the randomized prospective Reykjavík Study. Results: Postchallenge glucose concentrations were inversely related to birth weight and length in men and inversely related to birth weight and ponderal index in women (P < 0.001). This association was mainly found among those within the highest one-third of adult body mass index values. In men, the prevalence of dysglycemia was lower with increasing weight (P = 0.04) and length (P = 0.003) at birth but there was no relation of dysglycemia to ponderal index. For women, there was no linear trend for dysglycemia in relation to size at birth but the relation with birth length was U shaped. Conclusions: Greater birth weight and length appear to offer a protective effect against glucose intolerance. Adult overweight or obesity enhances the risk associated with low birth weight and length. Because the population studied has higher birth weights and a lower prevalence of type 2 diabetes than are found in neighboring countries, it is possible that decreasing the number of low-birth weight infants might help to stem the increasing prevalence of type 2 diabetes worldwide.
We have previously reported suggestive linkage of type 2 diabetes mellitus to chromosome 10q. We genotyped 228 microsatellite markers in Icelandic individuals with type 2 diabetes and controls ...throughout a 10.5-Mb interval on 10q. A microsatellite, DG10S478, within intron 3 of the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4) was associated with type 2 diabetes (P = 2.1 × 10−9). This was replicated in a Danish cohort (P = 4.8 × 10−3) and in a US cohort (P = 3.3 × 10−9). Compared with non-carriers, heterozygous and homozygous carriers of the at-risk alleles (38% and 7% of the population, respectively) have relative risks of 1.45 and 2.41. This corresponds to a population attributable risk of 21%. The TCF7L2 gene product is a high mobility group box-containing transcription factor previously implicated in blood glucose homeostasis. It is thought to act through regulation of proglucagon gene expression in enteroendocrine cells via the Wnt signaling pathway.
Through whole-genome sequencing of 2,630 Icelanders and imputation into 11,114 Icelandic cases and 267,140 controls followed by testing in Danish and Iranian samples, we discovered 4 previously ...unreported variants affecting risk of type 2 diabetes (T2D). A low-frequency (1.47%) variant in intron 1 of CCND2, rs76895963G, reduces risk of T2D by half (odds ratio (OR) = 0.53, P = 5.0 × 10(-21)) and is correlated with increased CCND2 expression. Notably, this variant is also associated with both greater height and higher body mass index (1.17 cm per allele, P = 5.5 × 10(-12) and 0.56 kg/m(2) per allele, P = 6.5 × 10(-7), respectively). In addition, two missense variants in PAM, encoding p.Asp563Gly (frequency of 4.98%) and p.Ser539Trp (frequency of 0.65%), confer moderately higher risk of T2D (OR = 1.23, P = 3.9 × 10(-10) and OR = 1.47, P = 1.7 × 10(-5), respectively), and a rare (0.20%) frameshift variant in PDX1, encoding p.Gly218Alafs*12, associates with high risk of T2D (OR = 2.27, P = 7.3 × 10(-7)).
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