Occupational asthma due to manual metal-arc welding of special stainless steels.

Occupational asthma (OA) can be induced by fumes of manual metal-arc welding on stainless steel. In recent years, the use of special stainless steels (SSS) with high chromium content has increased. This study presents two cases of OA caused by manual metal-arc welding on SSS. In both cases, the diagnosis of OA was based on respiratory symptoms, occupational exposure and positive findings in the specific challenge tests. In the first case, a 46-yr-old welder had experienced severe dyspnoea while welding SSS (SMO steel), but not in other situations. Challenge tests with both mild steel and stainless steel using a common electrode were negative. Welding SSS with a special electrode caused a delayed 37% drop in forced expiratory volume in one second (FEV1). In the second case, a 34-yr-old male had started to experience dyspnoea during the past few years, while welding especially SSS (Duplex steel). The workplace peak expiratory flow monitoring was suggestive of OA. Challenge tests with both mild steel and stainless steel using a common electrode did not cause bronchial obstruction. Welding SSS with a special electrode caused a delayed 31% drop in FEV1. In conclusion, exposure to manual metal-arc welding fumes of special stainless steel should be considered as a new cause of occupational asthma.     

Occurrence of symptomatic knee osteoarthrosis in rural Finland: a prospective follow up study.

All visits to physicians in the Orivesi Region Federation of Municipalities for Public Health Work in Finland paid due to symptomatic osteoarthrosis of the knee joint were prospectively recorded over a period of one year. Two hundred and thirty four visits were made, accounting for 0.63% of all visits. The prevalence of knee osteoarthrosis was 1.11% (men 0.45%, women 1.72%), and the incidence was 0.60%. The disease occurred almost twice as often in the right knee than in the left. The study provides basic information about patients needing medical help because of symptomatic knee osteoarthrosis. The results can be used as an aid to the planning of examination and treatment resources and in assessment of the need for such services.     

Importance of obtaining independent measures of insulin secretion and insulin sensitivity during the same test: results with the Botnia clamp

OBJECTIVE: To validate and apply a method for independent assessment of insulin secretion and insulin sensitivity (S(I)) during the same test; that is, an intravenous glucose tolerance test followed by a euglycemic-hyperinsulinemic clamp, also called the Botnia clamp. This test was then applied to nondiabetic subjects with (FH+) and without (FH-) a first-degree family history of diabetes. RESEARCH DESIGN AND METHODS: The Botnia clamp measures the first-phase insulin response (FPIR) to 0.3g/kg glucose i.v. and insulin sensitivity (M-value) from a 2-h euglycemic clamp begun 60 min after the glucose bolus. The M-value obtained during the Botnia clamp was compared with M-values obtained during a regular euglycemic clamp without prior glucose bolus. Repeated tests were performed in random order in subjects with normal and abnormal glucose tolerance. Finally, the test was applied to subjects with and without a family history of type 2 diabetes. RESULTS: S(I) and insulin secretion from this test showed a high degree of reproducibility, and the M-value obtained with the Botnia clamp correlated strongly with the M-value from a euglycemic clamp without prior glucose bolus (r = 0.953, P < 0.005). FH+ subjects showed decreased S(I) (P = 0.02), but similar FPIR, compared with FH- subjects. However, insulin secretion adjusted for the degree of insulin resistance was significantly impaired (P = 0.04). CONCLUSIONS: In conclusion, the Botnia clamp provides reliable and independent measures of S(I) and beta-cell function during the same test. As illustrated above, knowledge of the degree of S(I) is mandatory when presenting data on insulin secretion.     

The associations of daylight and melatonin receptor 1B gene rs10830963 variant with glycemic traits: the prospective PPP-Botnia study

Background: Seasonal variation in glucose metabolism might be driven by changes in daylight. Melatonin entrains circadian regulation and is directly associated with daylight. The relationship between melatonin receptor 1B gene variants with glycemic traits and type 2 diabetes is well established. We studied if daylight length was associated with glycemic traits and if it modified the relationship between melatonin receptor 1B gene rs10830963 variant and glycemic traits.Materials: A population-based sample of 3422 18–78-year-old individuals without diabetes underwent an oral glucose tolerance test twice, an average 6.8 years (SD = 0.9) apart and were genotyped for rs10830963. Daylight data was obtained from the Finnish Meteorological Institute.Results: Cross-sectionally, more daylight was associated with lower fasting glucose, but worse insulin sensitivity and secretion at follow-up. Longitudinally, individuals studied on lighter days at follow-up than at baseline showed higher glucose values during the oral glucose tolerance test and lower Corrected Insulin Response at follow-up. GG genotype carriers in the rs10830963 became more insulin resistant during follow-up if daylight length was shorter at follow-up than at baseline.Conclusions: Our study shows that individual glycemic profiles may vary according to daylight, MTNR1B genotype and their interaction. Future studies may consider taking daylight length into account.

Key messages

• In Western Finland, the amount daylight follows an extensive annual variation ranging from 4 h 44 min to 20 h 17 min, making it ideal to study the associations between daylight and glycemic traits. Moreover, this allows researchers to explore if the relationship between the melatonin receptor 1B gene rs10830963 variant and glycemic traits is modified by the amount of daylight both cross-sectionally and longitudinally.
• This study shows that individuals, who participated in the study on lighter days at the follow-up than at the baseline, displayed to a greater extent worse glycemic profiles across the follow-up.
• Novel findings from the current study show that in the longitudinal analyses, each addition of the minor G allele of the melatonin receptor 1B gene rs10830963 was associated with worsening of fasting glucose values and insulin secretion across the 6.8-year follow-up.
• Importantly, this study shows that in those with the rs10830963 GG genotype, insulin sensitivity deteriorated the most significantly across the 6.8-year follow-up if the daylight length on the oral glucose tolerance testing date at the follow-up was shorter than at the baseline.
• Taken together, the current findings suggest that the amount of daylight may affect glycemic traits, especially fasting glucose and insulin secretion even though the effect size is small. The association can very according to the rs10830963 risk variant. Further research is needed to elucidate the mechanisms behind these associations.

     

Polymorphisms in the gene encoding the voltage-dependent Ca<Superscript>2+</Superscript> channel Ca<Subscript>V</Subscript>2.3 (<Emphasis Type="Italic">CACNA1E</Emphasis>) are associated with type 2 diabetes and impaired insulin secretion

Aims/hypothesis Glucose-stimulated insulin secretion is dependent on the electrical activity of beta cells; hence, genes encoding beta cell ion channels are potential candidate genes for type 2 diabetes. The gene encoding the voltage-dependent Ca²⁺ channel Ca_V2.3 (CACNA1E), telomeric to a region that has shown suggestive linkage to type 2 diabetes (1q21-q25), has been ascribed a role for second-phase insulin secretion. Methods Based upon the genotyping of 52 haplotype tagging single nucleotide polymorphisms (SNPs) in a type 2 diabetes case–control sample (n = 1,467), we selected five SNPs that were nominally associated with type 2 diabetes and genotyped them in the following groups (1) a new case–control sample of 6,570 individuals from Sweden; (2) 2,293 individuals from the Botnia prospective cohort; and (3) 935 individuals with insulin secretion data from an IVGTT. Results The rs679931 TT genotype was associated with (1) an increased risk of type 2 diabetes in the Botnia case–control sample [odds ratio (OR) 1.4, 95% CI 1.0–2.0, p = 0.06] and in the replication sample (OR 1.2, 95% CI 1.0–1.5, p = 0.01 one-tailed), with a combined OR of 1.3 (95% CI 1.1–1.5, p = 0.004 two-tailed); (2) reduced insulin secretion [insulinogenic index at 30 min p = 0.02, disposition index (D _I) p = 0.03] in control participants during an OGTT; (3) reduced second-phase insulin secretion at 30 min (p = 0.04) and 60 min (p = 0.02) during an IVGTT; and (4) reduced D _I over time in the Botnia prospective cohort (p = 0.05). Conclusions/interpretation We conclude that genetic variation in the CACNA1E gene contributes to an increased risk of the development of type 2 diabetes by reducing insulin secretion. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Association studies of BMI and type 2 diabetes in the neuropeptide Y pathway: a possible role for NPY2R as a candidate gene for type 2 diabetes in men

The neuropeptide Y (NPY) family of peptides and receptors regulate food intake. Inherited variation in this pathway could influence susceptibility to obesity and its complications, including type 2 diabetes. We genotyped a set of 71 single nucleotide polymorphisms (SNPs) that capture the most common variation in NPY, PPY, PYY, NPY1R, NPY2R, and NPY5R in 2,800 individuals of recent European ancestry drawn from the near extremes of BMI distribution. Five SNPs located upstream of NPY2R were nominally associated with BMI in men (P values = 0.001-0.009, odds ratios [ORs] 1.27-1.34). No association with BMI was observed in women, and no consistent associations were observed for other genes in this pathway. We attempted to replicate the association with BMI in 2,500 men and tested these SNPs for association with type 2 diabetes in 8,000 samples. We observed association with BMI in men in only one replication sample and saw no association in the combined replication samples (P = 0.154, OR = 1.09). Finally, a 9% haplotype was associated with type 2 diabetes in men (P = 1.73 x 10(-4), OR = 1.36) and not in women. Variation in this pathway likely does not have a major influence on BMI, although small effects cannot be ruled out; NPY2R should be considered a candidate gene for type 2 diabetes in men.     

Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations

OBJECTIVE—Using the genome-wide association approach, we recently identified the glucokinase regulatory protein gene (GCKR, rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metabolic phenotypes, including measures of glucose homeostasis, to evaluate the GCKR locus in samples of non-European ancestry and to fine- map across the associated genomic interval.RESEARCH DESIGN AND METHODS—We performed association studies in 12 independent cohorts comprising >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the U.S., African Americans from the U.S., Hispanics of Caribbean origin, and Chinese, Malays, and Asian Indians from Singapore). We conducted genetic fine-mapping across the ∼417-kb region of linkage disequilibrium spanning GCKR and 16 other genes on chromosome 2p23 by imputing untyped HapMap single nucleotide polymorphisms (SNPs) and genotyping 104 SNPs across the associated genomic interval.RESULTS—We provide comprehensive evidence that GCKR rs780094 is associated with opposite effects on fasting plasma triglyceride (P_meta = 3 × 10⁻⁵⁶) and glucose (P_meta = 1 × 10⁻¹³) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reactive protein (CRP) level (P = 5 × 10⁻⁵). Both fine-mapping approaches revealed a common missense GCKR variant (rs1260326, Pro446Leu, 34% frequency, r² = 0.93 with rs780094) as the strongest association signal in the region.CONCLUSIONS—These findings point to a molecular mechanism in humans by which higher triglycerides and CRP can be coupled with lower plasma glucose concentrations and position GCKR in central pathways regulating both hepatic triglyceride and glucose metabolism.Recently, in the genome-wide association Diabetes Genetics Initiative (DGI) Study for 19 traits, including plasma lipids, we provided evidence that the glucokinase (GCK) regulatory protein gene (GCKR) region was a novel quantitative trait locus associated with plasma triglyceride concentration (1). Of all single nucleotide polymorphisms (SNPs) tested, an intronic SNP at GCKR (rs780094) explained the greatest proportion of interindividual variability in plasma triglycerides (1).GCKR regulates GCK, which functions as a glucose sensor responsible for glucose phosphorylation in the first step of glycolysis. The discoveries that inactivating mutations in GCK cause maturity onset diabetes of the young type 2 (2) and activating GCK mutations lead to permanent hyperinsulinemic hypoglycemia (3) emphasize that GCK plays a major role in glucose metabolism. GCKR-deficient mice have reduced GCK expression but maintain nearly normal GCK activity and show impaired glucose clearance (4). Furthermore, adenoviral-mediated overexpression of GCKR in mouse liver increased GCK activity and lowered fasting blood glucose (5) and overexpression of GCK in liver led to lowered blood glucose and increased triglyceride concentrations (6,7). Thus, experimental evidence suggests that perturbation of the GCKR pathway has opposing effects of triglyceride and glucose metabolism.In our original report, SNP rs780094 in GCKR was associated with fasting triglyceride levels in two independent samples, each of Northern European ancestry (P = 3.7 × 10⁻⁸ and 8.7 × 10⁻⁸, respectively) (1). After initial identification and replication of a chromosomal region associated with a trait, key next steps include extension of the association finding to related phenotypes, validation of the association finding in different ethnicities, and fine- mapping to identify the putative causal variant. Recently, our initial finding was replicated in a Danish study in which a strong association was found between the rs780094 T allele and elevated fasting triglyceride levels but also lower insulin levels, better insulin sensitivity, and a moderately decreased risk of type 2 diabetes (8). In addition, recent genome-wide association studies identified an association between the same GCKR intronic SNP and C-reactive protein (CRP) levels (9,10).Hereby, we sought to examine the effect of SNP rs780094 on triglycerides and related metabolic traits, including fasting glucose concentrations, in 12 samples representing a range of ancestral groups and including a large prospective study with a mean follow-up time of 23 years. In addition, we performed fine-mapping in one of these samples to identify the strongest association signal in the region.     

Autoantibodies to Glutamic Acid Decarboxylase and Insulin in Islet Cell Antibody Positive Presymptomatic Type 1 Diabetes Mellitus: Frequency and Segregation by Age and Gender

The frequency of antibodies to glutamic acid decarboxylase (GAD) and insulin (IAA) in presymptomatic Type 1 diabetes mellitus with a positive test for antibodies to islet cell antigen (ICA) was examined. Thirty-two persons positive for ICA (> 10 JDF units) were tested 2 to 48 months before their ascertained onset of Type 1 diabetes. ICA was quantitated by immunofluorescence as JDF units, anti-GAD by radioimmunoprecipitation and anti-insulin by radioimmunoassay. There was a positive test for anti-GAD in 25 (78%), and for IAA in 23 (72%), of the 32 prediabetic ICA-positive subjects. Stratification according to age at the onset of diabetes showed differing frequencies of anti-GAD and IAA in the prediabetic stage. Thus the positivity rate for anti-GAD for 18 subjects older than 10 years at onset of diabetes was 83%, and for 14 aged 10 or younger at onset was 71%; conversely, the rate for IAA for 18 subjects older than 10 at onset was 56% and for 14 aged 10 or less at time of onset was 93% (p = 0.01). The frequency of anti-GAD was higher in females (88%) than males (71%) whereas the frequency of IAA was higher in males (82%) than in females (60%). Since autoantibodies to GAD and insulin occur in presymptomatic Type 1 diabetes with differences in frequencies by age and gender, the stimuli to autoimmunity may operate differently at different ages, and may also be gender-related.     

Cardiovascular morbidity and mortality associated with the metabolic syndrome

OBJECTIVE: To estimate the prevalence of and the cardiovascular risk associated with the metabolic syndrome using the new definition proposed by the World Health Organization RESEARCH DESIGN AND METHODS: A total of 4,483 subjects aged 35-70 years participating in a large family study of type 2 diabetes in Finland and Sweden (the Botnia study) were included in the analysis of cardiovascular risk associated with the metabolic syndrome. In subjects who had type 2 diabetes (n = 1,697), impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) (n = 798) or insulin-resistance with normal glucose tolerance (NGT) (n = 1,988), the metabolic syndrome was defined as presence of at least two of the following risk factors: obesity, hypertension, dyslipidemia, or microalbuminuria. Cardiovascular mortality was assessed in 3,606 subjects with a median follow-up of 6.9 years. RESULTS: In women and men, respectively, the metabolic syndrome was seen in 10 and 15% of subjects with NGT, 42 and 64% of those with IFG/IGT, and 78 and 84% of those with type 2 diabetes. The risk for coronary heart disease and stroke was increased threefold in subjects with the syndrome (P < 0.001). Cardiovascular mortality was markedly increased in subjects with the metabolic syndrome (12.0 vs. 2.2%, P < 0.001). Of the individual components of the metabolic syndrome, microalbuminuria conferred the strongest risk of cardiovascular death (RR 2.80; P = 0.002). CONCLUSIONS: The WHO definition of the metabolic syndrome identifies subjects with increased cardiovascular morbidity and mortality and offers a tool for comparison of results from diferent studies.