Heterogeneity of Patients With Latent Autoimmune Diabetes in Adults: Linkage to Autoimmunity Is Apparent Only in Those With Perceived Need for Insulin Treatment: Results from the Nord-Tr?ndelag Health (HUNT) study

OBJECTIVE—Subjects with the diagnosis of latent autoimmune diabetes in adults (LADA) are more prone to need insulin treatment than those with type 2 diabetes. However, not all patients with LADA develop the need for insulin treatment, indicating the heterogeneity of LADA. We investigated this heterogeneity by comparing phenotypes of LADA with and without perceived need for insulin treatment (data obtained at times when diagnosis of LADA was not investigated) and also compared LADA and type 2 diabetes phenotypes.RESEARCH DESIGN AND METHODS—We used data from the all population–based Nord-Trøndelag Health study (n = 64,931), performed in 1995–1997. Data were assembled for individuals with LADA (n = 106) and type 2 diabetes (n = 943).RESULTS—In the comparison of individuals with LADA both with and without the need for insulin, insulin-treated subjects had higher titers of GAD antibodies (P < 0.001) and lower fasting C-peptide levels (P < 0.001). GAD antibodies and C-peptide correlated negatively (r = −0.40; P = 0.009). In the comparison of individuals with LADA and type 2 diabetes, all without the need for insulin, markers of metabolic syndrome were equally prevalent and pronounced. Age, C-peptide, and glucose levels were also similar. In the comparison of insulin-treated individuals with LADA and type 2 diabetes, more patients with LADA received insulin (40 vs. 22%, P < 0.001) and C-peptide levels were lower (P < 0.001). Patients with LADA were leaner but were still overweight (mean BMI 28.7 vs. 30.9 kg/m² in type 2 diabetes, P < 0.001). In the comparison of type 2 diabetic patients with and without insulin, insulin-treated subjects were more obese and had higher A1C and lower C-peptide levels (P < 0.001).CONCLUSIONS—Our conclusions are that 1) the need for insulin treatment in LADA is linked to the degree of autoimmunity and β-cell failure, 2) subjects with LADA and type 2 diabetes without the need for insulin treatment are phenotypically similar, and 3) insulin treatment in type 2 diabetic patients is associated with both insulin resistance and β-cell insufficiency.Autoimmunity is the major cause of type 1 diabetes. Autoimmunity is also assumed to be the major cause of latent autoimmune diabetes in adults (LADA) because this category of diabetes shares biochemical markers of β-cell–directed autoimmunity with “classic” type 1 diabetes. In clinical practice, autoimmunity in classic type 1 diabetes as well as in LADA is usually documented by antibodies against GAD.LADA is considered a “mild” form of type 1 diabetes. Mild indicates the fact that patients with LADA do not by clinical judgment need insulin from the time of diagnosis. However, within the first few years after the diagnosis of diabetes a need for insulin treatment develops in many patients with LADA. This distinguishes patients with LADA from those with nonautoimmune type 2 diabetes in whom a need for insulin treatment develops later than in those with LADA (1). An early need for insulin treatment in patients with LADA points to ongoing autoimmune-mediated destruction of β-cells in these patients.Risk factors for type 2 diabetes, such as age, obesity, and lack of physical activity, are associated with the development of LADA (2). In fact, odds ratios in terms of risk for diabetes for these factors of insulin resistance were the same for LADA and type 2 diabetes. This raises the question of the relative importance of autoimmunity vis-à-vis insulin resistance for the etiology of LADA and whether etiology differs among patients with LADA. Support for etiological heterogeneity comes from the large UK Prospective Diabetes Study (UKPDS), in which only a minority of patients with the diagnosis of LADA, when defined solely as GAD antibody positivity, developed the need for insulin treatment during 6 years of follow-up (1). The heterogeneity of LADA is also evident when one compares phenotypes of patients with LADA in different studies (3–6).Heterogeneity of patients with LADA could be further elucidated by comparing phenotypes of insulin-treated patients with LADA with those not treated with insulin. However, several conditions have to be met for such comparisons to be valid. First, groups of diabetic subjects to be compared must be drawn from the same geographically defined population. A population-based study is necessary to avoid the possible biases incurred by studying referral patients or patients selected for inclusion in clinical intervention studies. Second, the perceived need for insulin treatment has to be unbiased by LADA classification, because it has been shown that insulin treatment is initiated earlier when prior knowledge of autoimmunity, measured as GAD antibodies, is available (7). Third, valid comparison groups of insulin-treated and non–insulin-treated type 2 diabetic patients from the same population must be at hand.We had the opportunity to study patients with LADA and type 2 diabetes fulfilling the above-mentioned conditions, who were identified and characterized in the Nord-Trøndelag (HUNT) study. The HUNT study was performed between 1995 and 1997. The study was open to all adult subjects (∼90,000) living in a geographically defined area and had a high attendance rate (70%). To our knowledge, the patients with LADA and type 2 diabetes defined in the HUNT study did not participate in any study at the time of diagnosis and initiation of treatment, thereby minimizing any deviation from standard clinical practice and obviating increased attentiveness for signs of insufficient metabolic control and insulin requirement. Further, autoantibodies, such as GAD antibodies, were not measured by doctors (general practitioners) responsible for treatment in the region as part of the diabetes workup before and at the time of assembling data in 1995–1997. Thus, patients with autoimmune diabetes not requiring insulin at time of diagnosis were regarded and treated as type 2 diabetic patients. This assumption provided a unique opportunity to use the need for insulin as clinically perceived as a parameter for subclassifying patients with LADA and to compare phenotypes of insulin-treated and non–insulin-treated patients with LADA with respective groups of type 2 diabetic patients. Specifically, we wished to assess the influence of autoimmunity and β-cell insufficiency vis-à-vis insulin resistance factors for the perceived need for insulin treatment in patients with LADA.     

大鼠急性肺栓塞模型中CA3和NHE1表达的变化

目的研究大鼠急性肺栓塞模型肺组织中与酸碱平衡相关的碳酸酐酶3（CA3）和Na+/H+交换器（NHE1）的表达变化。方法建立大鼠急性肺栓塞模型,分别在急性肺栓塞后1、8、24和48 h开胸取出肺组织,然后提取肺组织的总RNA和总蛋白,以正常组为对照,采取半定量RT-PCR的方法研究CA3和NHE1在mRNA水平表达的变化;采用western-b lot方法进一步验证CA3和NHE1在蛋白水平表达的变化;同时采用免疫组织化学的方法检测大鼠肺组织中NHE1在肺栓塞前后表达的变化。结果在大鼠急性肺栓塞后的不同时间点,CA3的mRNA水平和蛋白水平均逐渐降低,而NHE1在mRNA水平和蛋白水平的表达都出现逐渐升高现象。免疫组化研究表明NHE1主要分布在支气管黏膜上皮和细支气管黏膜上皮的胞浆内,急性肺栓塞后NHE1在上皮细胞内的表达明显升高。结论大鼠急性肺栓塞后肺组织内CA3的表达降低,NHE1的表达升高,这一现象可能与机体的酸碱平衡调节相关。     

Leptin and leptin receptor genes in Atlantic salmon: Cloning, phylogeny, tissue distribution and expression correlated to long-term feeding status

The present study reports the complete coding sequences for two paralogues for leptin (sLepA1 and sLepA2) and leptin receptor (sLepR) in Atlantic salmon. The deduced 171-amino acid (aa) sequence of sLepA1 and 175 aa sequence for sLepA2 shows 71.6% identity to each other and clusters phylogenetically with teleost Lep type A, with 22.4% and 24.1% identity to human Lep. Both sLep proteins are predicted to consist of four helixes showing strong conservation of tertiary structure with other vertebrates. The highest mRNA levels for sLepA1 in fed fish (satiation ration = 100%) were observed in the brain, white muscle, liver, and ovaries. In most tissues sLepA2 generally had a lower expression than sLepA1 except for the gastrointestinal tract (stomach and mid-gut) and kidney. Only one leptin receptor ortholog was identified and it shares 24.2% aa sequence similarity with human LepR, with stretches of highest sequence similarity corresponding to domains considered important for LepR signaling. The sLepR was abundantly expressed in the ovary, and was also high in the brain, pituitary, eye, gill, skin, visceral adipose tissue, belly flap, red muscle, kidney, and testis. Fish reared on a rationed feeding regime (60% of satiation) for 10 months grew less than control (100%) and tended to have a lower sLepA1 mRNA expression in the fat-depositing tissues visceral adipose tissue (p < 0.05) and white muscle (n.s.). sLepA2 mRNA levels was very low in these tissues and feeding regime tended to affect its expression in an opposite manner. Expression in liver differed from that of the other tissues with a higher sLepA2 mRNA in the feed-rationed group (p < 0.01). Plasma levels of sLep did not differ between fish fed restricted and full feeding regimes. No difference in brain sLepR mRNA levels was observed between fish fed reduced and full feeding regimes. This study in part supports that sLepA1 is involved in signaling the energy status in fat-depositing tissues in line with the mammalian model, whereas sLepA2 may possibly play important roles in the digestive tract and liver. At present, data on Lep in teleosts are too scarce to allow generalization about how the Lep system is influenced by tissue-specific energy status and, in turn, may regulate functions related to feed intake, growth, and adiposity in fish. In tetraploid species like Atlantic salmon, different Lep paralogues seems to serve different physiological roles.     

Syphilis epidemiology in Norway, 1992-2008: resurgence among men who have sex with men

Background  

In recent years, the number of syphilis cases has stabilised in many countries of Western Europe, however several countries have reported increases among men who have sex with men (MSM). The aim of this article was to describe the epidemiology of early syphilis in Norway in 1992-2008.     

大鼠急性肺栓塞血清差异表达蛋白的研究

目的研究急性肺栓塞（APE）大鼠血清和正常大鼠血清的差异蛋白表达变化。方法采用血栓颈静脉注入法制备大鼠APE模型,采用双向电泳技术找出差异蛋白,用MALDI-TOF技术和生物信息学技术鉴定差异蛋白,并对部分差异表达蛋白采用Western-blot技术作进一步验证。结果大鼠血清蛋白的2-DE胶银染可分离出1 400多个点,考染可达到1 200个点以上。经图像分析得到的24个差异表达蛋白中有12个蛋白得到鉴定。对部分差异蛋白采用Western-blot方法在蛋白水平的验证结果与2-DE结果基本相符。结论采用比较蛋白质组学的方法可以发现APE大鼠血清中的差异表达蛋白,这些差异表达蛋白分子将为我们寻找新的APE血清学标志物提供重要的线索和依据。     

Angiopoietin-2 and angiopoietin-like 4 protein provide prognostic information in patients with suspected acute coronary syndrome

Background

Plasma levels of angiopoietin-2 (ANGPT2) and angiopoietin-like 4 protein (ANGPTL4) reflect different pathophysiological aspects of cardiovascular disease. We evaluated their association with outcome in a hospitalized Norwegian patient cohort (n = 871) with suspected acute coronary syndrome (ACS) and validated our results in a similar Argentinean cohort (n = 982).

Methods

A cox regression model, adjusting for traditional cardiovascular risk factors, was fitted for ANGPT2 and ANGPTL4, respectively, with all-cause mortality and cardiac death within 24 months and all-cause mortality within 60 months as the dependent variables.

Results

At 24 months follow-up, 138 (15.8%) of the Norwegian and 119 (12.1%) of the Argentinian cohort had died, of which 86 and 66 deaths, respectively, were classified as cardiac. At 60 months, a total of 259 (29.7%) and 173 (17.6%) patients, respectively, had died. ANGPT2 was independently associated with all-cause mortality in both cohorts at 24 months [hazard ratio (HR) 1.27 (95% confidence interval (CI), 1.08–1.50) for Norway, and HR 1.57 (95% CI, 1.27–1.95) for Argentina], with similar results at 60 months [HR 1.19 (95% CI, 1.05–1.35) (Norway), and HR 1.56 (95% CI, 1.30–1.88) (Argentina)], and was also significantly associated with cardiac death [HR 1.51 (95% CI, 1.14–2.00)], in the Argentinean population. ANGPTL4 was significantly associated with all-cause mortality in the Argentinean cohort at 24 months [HR 1.39 (95% CI, 1.15–1.68)] and at 60 months [HR 1.43 (95% CI, 1.23–1.67)], enforcing trends in the Norwegian population.

Conclusions

ANGPT2 and ANGPTL4 were significantly associated with outcome in similar ACS patient cohorts recruited on two continents.

Clinical Trial Registration

ClinicalTrials.gov Identifier: NCT00521976. ClinicalTrials.gov Identifier: NCT01377402.

     

Serum TSH related to measures of body mass: longitudinal data from the HUNT Study, Norway

Objective Thyroid function and body mass are related, but the causal relationship remains unclear. Our objective was to investigate the longitudinal relationship between thyroid stimulating hormone (TSH) and body mass measures [body weight, body mass index (BMI), waist circumference (WC) and waist‐hip‐ratio (WHR)]. Design We used data from two waves of a population‐based study: HUNT 2 (1995–1997) and 3 (2006–2008). Average follow‐up time was 10·5 years. Multivariable general linear and logistic regression models were used to assess the relation between TSH and the body mass measures. Participants In total 9954 women and 5066 men without self‐reported thyroid disease and TSH within the reference range (0·5–3·5 mU/l) at baseline and <10 mU/l at follow‐up. Results For each mU/l increase in TSH among women, weight increased 0·9 kg (95% CI 0·8, 1·1), BMI 0·3 kg/m² (95% CI 0·3, 0·4) and WC 0·6 cm (95% CI 0·3, 0·8). In men, the corresponding figures were 0·8 kg (95% CI 0·5, 1·0), 0·2 kg/m² (95% CI 0·2, 0·3) and 0·5 cm (95% CI 0·2, 0·8). In line with this, a weight gain of more than 5 kg was associated with a TSH increase of 0·08 mU/l (95% CI 0·06, 0·11) in women and 0·15 mU/l (95% CI 0·12, 0·18) in men. Women who lost more than 5 kg decreased their TSH by 0·12 mU/l (95% CI 0·09, 0·16) and men by 0·03 mU/l (95% CI ?0.02, 0·09). Conclusion Weight gain is accompanied by increasing TSH, and weight loss in women is related to decreasing TSH.     

参麦注射液联合氢化可的松治疗老年脓毒性休克的临床研究

目的探索参麦注射液联合氢化可的松对老年脓毒性休克的治疗效果。方法选取2015年7月—2018年7月沧州市人民医院收治的脓毒性休克患者102例,随机分为对照组(51例)和治疗组(51例)。对照组静脉滴注注射用氢化可的松琥珀酸钠,200 mg加入生理盐水250 mL,1次/d;治疗组在对照组基础上静脉滴注参麦注射液,100 mL/次,1次/d。两组患者均持续治疗5天。观察两组患者临床疗效,同时比较治疗前后两组患者白细胞计数、APACHEⅡ评分、乳酸、降钙素原和脑钠肽水平及随访结果。结果治疗后,对照组和治疗组临床有效率分别为76.47%和86.27%,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者白细胞计数、C-反应蛋白水平及APACHEⅡ评分均明显降低(P0.05),且治疗组白细胞计数、C-反应蛋白水平及APACHEⅡ评分明显低于对照组(P0.05)。治疗后,两组患者乳酸、降钙素原和脑钠肽水平均显著降低(P0.05),且治疗组乳酸、降钙素原和脑钠肽水平明显低于对照组(P0.05)。治疗组ICU住院时间、14 d死亡率及28 d死亡率上均优于对照组,两组比较差异具有统计学意义(P0.05)。结论参麦注射液联合氢化可的松可明显改善老年脓毒性休克患者早期生理生化指标,提高整体生存率。