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BACKGROUND: Single nucleotide polymorphisms (SNPs) in the promoter region of CRYAB gene have been associated with in multiple sclerosis. CRYAB gene, which encodes alpha B-crystallin (a member of small heat shock protein), was reported as a potential autoimmune target. In this study we investigated whether SNPs in the promoter region of CRYAB gene were also important in the etiology of Type 1 diabetes (T1D).

METHODS: Genotyping of SNPs in the promoter region of CRYAB gene was performed in a Swedish cohort containing 444 T1D patients and 350 healthy controls. Three SNPs were included in this study: CRYAB-652 A>G (rs762550), -650 C>G (rs2234702) and -249 C > G (rs14133). Two SNPs (CRYAB-652 and -650) were not included in previous genome wide association studies.

RESULTS: CRYAB-650 (rs2234702)*C allele was significantly more frequent in patients than in controls (OR = 1.48, Pc = 0.03). CRYAB-650*C allele was associated with IAA positivity (OR = 8.17, Pc < 0.0001) and IA-2A positivity (OR = 2.14, Pc = 0.005) in T1D patients. This association with IAA was amplified by high-risk HLA carrier state (OR = 10.6, P < 0.0001). No association was found between CRYAB-650 and other autoantibody positivity (GADA and ICA). CRYAB haplotypes were also associated with IAA and IA-2A positivity (highest OR = 2.07 and 2.11, respectively), these associations remain in high HLA-risk T1D patients.

CONCLUSIONS: CRYAB-650 was associated with T1D in the Swedish cohort we studied. CRYAB-650*C allele might confers susceptibility to the development of T1D. CRYAB-650 was also associated with the development of IAA-positivity in T1D patients, especially in those carrying T1D high-risk HLA haplotypes.

A case-referent study nested within a population-based health survey investigated the associations between psychosocial stress, such as work stress and low emotional support, and future development of type 2 diabetes among occupationally working middle-aged men and women. All participants in a health survey conducted during 1989-2000 (n=33,336) in Umeå in northern Sweden, were included. We identified 191 cases, who were not diabetic initially but were diagnosed with type 2 diabetes after 5.4+/-2.6 years. Two age- and sex-matched referents were selected for each case. Multivariate logistic regression analyses and interaction effects between variables were evaluated.

In women, passive or tense working situations were associated with future type 2 diabetes with odds ratios 3.6 (95% confidence interval 1.1-11.7) and 3.6 (1.0-13.3), respectively, and also low emotional support 3.0 (1.3-7.0). These associations were not seen in men. In women, they remained after adjustment for BMI, civil status and educational level, and there were also tendencies for interactions between work stress and low emotional support.

In conclusion, work stress and low emotional support may increase the risk of type 2 diabetes in women, but not in men. These findings contribute to our understanding of psychosocial stress as potential risk factors for type 2 diabetes in a Swedish population.

OBJECTIVE: To identify a screening model that predicts high risk of future type 2 diabetes and is useful in clinical practice. DESIGN AND METHODS: Incident case-referent study nested within a population-based health survey. We compared screening models with three risk criteria and calculated sensitivity, specificity, positive (PPV) and negative (NPV) predictive values and attributable proportion. We used fasting plasma glucose (FPG) alone or with an oral glucose tolerance test (OGTT), glycosylated haemoglobin A (HbA1c) (normal range 3.6-5.3%), body mass index (BMI), triglycerides and family history of diabetes (FHD). SETTING: Participants in a health survey at all primary care centres (n=33,336) and subjects with diagnosed type 2 diabetes in primary and hospital care (n=6088) in Umeå during 1989-2001. SUBJECTS: Each of the 164 subjects who developed clinically diagnosed type 2 diabetes (median time to diagnosis of 5.4 years) and 304 sex- and age-matched referents without diabetes diagnosis. RESULTS: Screening models with at least one criterion present had sensitivities of 0.90-0.96, specificities of 0.43-0.57 and PPVs of 8-9%. Combinations of the criteria, FPG>or=6.1 mmol L-1 (capillary plasma), HbA1c>or=4.7% and BMI>or=27 in men and BMI>or=30 in women, had sensitivities, specificities and PPVs of 0.66%, 0.93% and 32%, and 0.52%, 0.97% and 46% respectively. Using FHD as one of three risk criteria showed comparable results. Addition of triglycerides or OGTT did not improve the prediction. CONCLUSIONS: The combination of HbA1c, FPG and BMI are effective in screening for individuals at risk of future clinical diagnosis of type 2 diabetes. OGTT or FHD is not necessary.

Objective To evaluate the interplay between hyperglycaemia, insulin resistance, hormones and adipokines in patients with type 2 diabetes mellitus (T2DM). Design and methods Ten patients with T2DM with good glycaemic control (G), 10 with poor control (P) and 10 nondiabetic control subjects (C) were matched for sex (M/F 6/4), age and body mass index. A hyperinsulinaemic, euglycaemic clamp was performed and cytokines and endocrine functions, including cortisol axis activity were assessed. Results Patients with diabetes were more insulin resistant than group C, and group P exhibited the highest degree of insulin resistance ( P = 0·01, P vs C). Tumour necrosis factor (TNF)-alpha levels were elevated in patients with diabetes ( P = 0·05) and group P had the highest levels of fasting serum cortisol ( P = 0·05), nonesterified fatty acids (NEFA; P = 0·06) and C-reactive protein (CRP; P = 0·01). Adiponectin levels were lower in the P group. In partial correlation analyses, significant associations were found: glycaemic level (HbA1c) with insulin resistance, TNF-alpha, CRP and basal and ACTH-stimulated cortisol levels, insulin resistance with plasma NEFA, TNF-alpha and stimulated cortisol levels. Conclusion Poor glycaemic control in patients with T2DM was associated with insulin resistance and with elevated TNF-alpha, CRP and basal as well as stimulated cortisol levels. Inflammatory mediators, e.g. TNF-alpha, may contribute to insulin resistance in hyperglycaemic patients with T2DM and this might be a partial explanation for glucotoxicity.