Aldose reductase gene polymorphisms and peripheral nerve function in patients with type 2 diabetes

OBJECTIVE: We screened the human aldose reductase (ALR) gene for DNA sequence variants in type 2 diabetic and nondiabetic subjects and investigated whether the previously reported and novel polymorphisms were associated with neurophysiologic deterioration and clinical peripheral neuropathy. RESEARCH DESIGN AND METHODS: The study population included 85 Finnish type 2 diabetic and 126 nondiabetic subjects. The genetic analyses were performed using the PCR, single-strand conformation polymorphism, restriction fragment-length polymorphism, and automated laser fluorescence scanning analyses. A detailed neurologic examination and neurophysiologic analyses were performed at the time of diagnosis and at the 10-year examination. RESULTS: The genetic screening identified four polymorphisms: C-106T, C-11G, A11370G, and C19739A. The C and Z-2 alleles of the C-106T polymorphism and the previously reported (CA)(n) repeat marker were more frequent in type 2 diabetic subjects than in nondiabetic subjects. At baseline, the diabetic subjects with the T allele of the C-106T polymorphism had lower sensory response amplitude values in the peroneal (P = 0.025), sural (P = 0.007), and radial (P = 0.057) nerves and, during follow-up, a greater decrease in the conduction velocity of the motor peroneal nerve than those with the C-106C genotype. No associations were found between the polymorphisms examined and clinical polyneuropathy. CONCLUSIONS: The C-106T polymorphism of the ALR gene may contribute to an early development of neurophysiologic deterioration in type 2 diabetic patients.     

Role of angiogenic growth factors in transplant coronary artery disease

Transplant coronary artery disease (TxCAD) as a manifestation of chronic rejection is a major limitation to long-term survival of heart transplant recipients. Although the exact molecular and cellular mechanisms contributing to neointimal formation are unknown, it has been generally believed that smooth muscle cells (SMC) of donor origin migrate from the media into the subendothelial layer of the vascular wall, where SMC proliferate and synthesize extracellular matrix resulting in intimal thickening. However, recent observations indicate that hematopoietic and vascular progenitor cells derived from recipient bone marrow may contribute to the arteriosclerotic lesion formation in the coronary arteries of the transplant. On the other hand, studies on postnatal hematopoiesis indicate that angiogenic growth factors such as vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1) may regulate the recruitment of these cells into distant organs. Furthermore, embryonic VEGFR-2 /CD34+ stem cells may serve as vascular progenitor cells and their differentiation into endothelial cells and SMC may be regulated by VEGF and platelet-derived growth factor (PDGF), respectively. In this review, we discuss the role of angiogenic growth factors such as VEGF, Ang, and PDGF in the recruitment of hematopoietic and vascular progenitor cells in TxCAD and suggest novel therapies targeted at homing, differentiation and proliferation of these cells in the allograft.     

Long-term use of probucol in the multifactorial primary prevention of vascular disease

Over 1,200 middle-aged men with no apparent vascular disease participated in a 5-year multifactorial primary prevention trial, in which 612 received dietetic, hygienic and—when indicated—pharmacologic treatment for the following risk factors: hyperlipidemia, hypertension, smoking, obesity and abnormal glucose tolerance. Pharmacologic therapy included hypolipidemic agents (mainly probucol and clofibrate) and antihypertensive drugs (mainly diuretics and β blockers). At the end of the 5 years, results in these men were compared with findings in 610 high risk and 593 low risk control subjects, none of whom had received treatment. Although intervention decreased the mean risk factor status of the treated men by 33%, their 5-year coronary incidence exceeded that of the high risk control subjects (3.1 % vs 1.5%). Stroke incidence, however, was markedly reduced in the treated subjects (0% vs 1.3%). Multivariate analysis showed that the coronary events occurred in patients taking β blockers or clofibrate, while few occurred in those receiving probucol or the diuretics. The decrease in mean serum cholesterol was 15% in men receiving only probucol, and ranged from 0% to 13% in those receiving different drug combinations, including clofibrate plus probucol (11%). Probucol also markedly decreased high density lipoprotein cholesterol levels, especially when combined with clofibrate.

It is possible that adverse drug effects offset the probable benefit of an improved risk profile in the treated men, thereby explaining the greater than expected occurrence of cardiac events in this group. The probucol data, however, suggest that it may not be harmful to lower the high density lipoprotein cholesterol level when there is a significant decrease in total cholesterol as well.     

Unemployment, depressiveness and disability retirement: a follow-up study of the Finnish HeSSup population sample

Background  

Disability retirement because of depression is increasingly common in Finland. The rise of such retirement coincided with the rise of unemployment in the second half of the 1990s. In this study we sought potential connections between these two epidemics. We assumed that depressiveness incurs a higher risk of disability retirement among the unemployed than among the employed population.     

Gender differences in brain serotonin transporter availability in panic disorder

The role of the serotonin (5-HT) system in the neurobiology and treatment of panic disorder (PD) remains unproven. Previously we detected lower brain 5-HT transporter (SERT) availability in PD, but the findings were preliminary and mainly limited to female patients. The aim of this study was to assess non-displaceable brain SERT binding potential (BP (ND)) in male and female patients with PD. The SERT BP (ND) was measured in groups of patients with PD (five males and six females) and matched healthy control subjects (12 males and 12 females) using positron emission tomography (PET) and [11C]MADAM tracer. SERT BP (ND) were significantly higher in 13 of 20 studied brain regions, including several cortical and raphe areas, but lower in the hippocampus in males with PD as compared with healthy males. No significant differences in SERT BP (ND) were observed between female patients and controls. The results suggest gender-dependent regional differences in brain SERT availability and converge with previous PET findings of reduced 5-HT(1A) receptor binding in similar brain areas in PD. Distinctive functioning of the 5-HT system in males and females may underlie certain gender-dependent differences in expressions of PD.     

The cytoplasmic tail of hantavirus Gn glycoprotein interacts with RNA

We recently characterized the interaction between the intraviral domains of envelope glycoproteins (Gn and Gc) and ribonucleoprotein (RNP) of Puumala and Tula hantaviruses (genus Hantavirus, family Bunyaviridae). Herein we report a direct interaction between spike-forming glycoprotein and nucleic acid. We show that the envelope glycoprotein Gn of hantaviruses binds genomic RNA through its cytoplasmic tail (CT). The nucleic acid binding of Gn-CT is unspecific, as demonstrated by interactions with unrelated RNA and with single-stranded DNA. Peptide scan and protein deletions of Gn-CT mapped the nucleic acid binding to regions that overlap with the previously characterized N protein binding sites and demonstrated the carboxyl-terminal part of Gn-CT to be the most potent nucleic acid-binding site. We conclude that recognition of the RNP complex by the Gn-CT could be mediated by interactions with both genomic RNA and the N protein. This would provide the required selectivity for the genome packaging of hantaviruses.     

Association of 18 Confirmed Susceptibility Loci for Type 2 Diabetes With Indices of Insulin Release, Proinsulin Conversion, and Insulin Sensitivity in 5,327 Nondiabetic Finnish Men

OBJECTIVE

We investigated the effects of 18 confirmed type 2 diabetes risk single nucleotide polymorphisms (SNPs) on insulin sensitivity, insulin secretion, and conversion of proinsulin to insulin.

RESEARCH DESIGN AND METHODS

A total of 5,327 nondiabetic men (age 58 ± 7 years, BMI 27.0 ± 3.8 kg/m²) from a large population-based cohort were included. Oral glucose tolerance tests and genotyping of SNPs in or near PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, LOC387761, CDKN2B, IGF2BP2, CDKAL1, HNF1B, WFS1, JAZF1, CDC123, TSPAN8, THADA, ADAMTS9, NOTCH2, KCNQ1, and MTNR1B were performed. HNF1B rs757210 was excluded because of failure to achieve Hardy-Weinberg equilibrium.

RESULTS

Six SNPs (TCF7L2, SLC30A8, HHEX, CDKN2B, CDKAL1, and MTNR1B) were significantly (P < 6.9 × 10⁻⁴) and two SNPs (KCNJ11 and IGF2BP2) were nominally (P < 0.05) associated with early-phase insulin release (InsAUC_0–30/GluAUC_0–30), adjusted for age, BMI, and insulin sensitivity (Matsuda ISI). Combined effects of these eight SNPs reached −32% reduction in InsAUC_0–30/GluAUC_0–30 in carriers of ≥11 vs. ≤3 weighted risk alleles. Four SNPs (SLC30A8, HHEX, CDKAL1, and TCF7L2) were significantly or nominally associated with indexes of proinsulin conversion. Three SNPs (KCNJ11, HHEX, and TSPAN8) were nominally associated with Matsuda ISI (adjusted for age and BMI). The effect of HHEX on Matsuda ISI became significant after additional adjustment for InsAUC_0–30/GluAUC_0–30. Nine SNPs did not show any associations with examined traits.

CONCLUSIONS

Eight type 2 diabetes–related loci were significantly or nominally associated with impaired early-phase insulin release. Effects of SLC30A8, HHEX, CDKAL1, and TCF7L2 on insulin release could be partially explained by impaired proinsulin conversion. HHEX might influence both insulin release and insulin sensitivity.Impaired insulin secretion and insulin resistance, two main pathophysiological mechanisms leading to type 2 diabetes, have a significant genetic component (1). Recent studies have confirmed 20 genetic loci reproducibly associated with type 2 diabetes (2–13). Three were previously known (PPARG, KCNJ11, and TCF7L2), whereas 17 loci were recently discovered either by genome-wide association studies (SLC30A8, HHEX-IDE, LOC387761, CDKN2A/2B, IGF2BP2, CDKAL1, FTO, JAZF1, CDC123/CAMK1D, TSPAN8/LGR5, THADA, ADAMTS9, NOTCH2, KCNQ1, and MTNR1B), or candidate gene approach (WFS1 and HNF1B). The mechanisms by which these genes contribute to the development of type 2 diabetes are not fully understood.PPARG is the only gene from the 20 confirmed loci previously associated with insulin sensitivity (14,15). Association with impaired β-cell function has been reported for 14 loci (KCNJ11, SLC30A8, HHEX-IDE, CDKN2A/2B, IGF2BP2, CDKAL1, TCF7L2, WFS1, HNF1B, JAZF1, CDC123/CAMK1D, TSPAN8/LGR5, KCNQ1, and MTNR1B) (6,12,13,16–38). Although associations of variants in HHEX (16–22), CDKAL1 (6,21–26), TCF7L2 (22,27–30), and MTNR1B (13,31,32) with impaired insulin secretion seem to be consistent across different studies, information concerning other genes is limited (12,18–25,27,33–38). The mechanisms by which variants in these genes affect insulin secretion are unknown. However, a few recent studies suggested that variants in TCF7L2 (22,39–42), SLC30A8 (22), CDKAL1 (22), and MTNR1B (31) might influence insulin secretion by affecting the conversion of proinsulin to insulin. Variants of FTO have been shown to confer risk for type 2 diabetes through their association with obesity (7,16) and therefore were not included in this study.Large population-based studies can help to elucidate the underlying mechanisms by which single nucleotide polymorphisms (SNPs) of different risk genes predispose to type 2 diabetes. Therefore, we investigated confirmed type 2 diabetes–related loci for their associations with insulin sensitivity, insulin secretion, and conversion of proinsulin to insulin in a population-based sample of 5,327 nondiabetic Finnish men.     

Effort-reward imbalance and relational injustice at work predict sickness absence: the Whitehall II study

OBJECTIVES: Sickness absence is a major occupational health problem, but evidence for associations between potentially modifiable psychosocial work factors and sickness absence is still scarce. We studied the impact of relational justice and effort-reward imbalance on subsequent rates of sickness absence. METHODS: The Whitehall II prospective cohort study of British civil servants, 10,308 men and women, was established between 1985 and 1988. Indicators of effort-reward imbalance and the relational component of organizational justice were constructed from questions included at baseline. Participants were classified into three groups (low, intermediate, and high) for both effort-reward imbalance and relational justice. Short (< or =7 days) and long (>7 days) spells of sickness absence during 1985-1989 and 1991-1995 were used to study immediate and longer term effects of work characteristics. RESULTS: After adjustment for age, employment grade, and baseline health, men and women with low relational justice had increased risks of long spells of sickness absence of 14% and 28% in comparison to men and women experiencing high levels of justice. Similar effect sizes (25% and 21%) were found for high vs. low effort-reward imbalance. Both work measures also predicted short spells of sickness absence. Effort-reward imbalance (men and women) and relational justice (women only) each predicted long spells of sickness absence independently of the other. CONCLUSIONS: Both relational justice and effort-reward imbalance are important determinants of sickness absence. Workplace interventions to improve these aspects of working conditions have the potential to reduce levels of sickness absence.