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Key features: 

• The Northern Sweden Health and Disease Study (NSHDS) was initiated in the mid-1980s. The NSHDS is a population-based prospective longitudinal cohort comprising >140 000 participants in the two northernmost regions in Sweden, Norrbotten and Västerbotten, with >240 000 blood samples and 1.5 million person-years of follow-up.
• The NSHDS includes three sub-cohorts: the Västerbotten Intervention Programme (VIP), the expanded Northern Sweden Monitoring of Trends and Determinants of Cardiovascular Disease (MONICA) Study, and the Mammography Screening Project (MSP). The VIP is both a community-based cardiometabolic intervention programme encouraging healthy lifestyle (targeting individuals 40, 50, and 60 years of age), and a corresponding research cohort. The MONICA is an observational study focusing on cardiovascular disease and its associated risk factors, recruiting individuals aged 25–74 years. The MSP recruited women attending mammography during 1995–2006. The NSHDS median participation age is 50 years (53% women).
• Most participants contribute data on health, lifestyle, anthropometric measures, blood pressure, blood lipids, and glucose tolerance, along with research blood samples that are fractionated, frozen within an hour of collection, and stored at –80°C. Linkage to registries, clinical cohorts, and biological tissue archives facilitates studies of well-characterized participants (often combined with intervention studies).
• Collaborations are encouraged. Additional information can be found at: info.brs@umu.se; https://www.umu.se/en/biobank

Aims: Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of the fibrinolytic system and is mainly secreted from adipose tissue. It is associated with cardiovascular disease and has also been considered a possible early risk marker for type 2 diabetes. Here, we present the results of a large prospective study investigating PAI-1 levels in relation to incident type 2 diabetes mellitus.

Methods: We conducted a prospective incident case-referent study within the Västerbotten Intervention Programme (VIP). Data on cardiovascular risk factors, fasting plasma glucose (FPG) and 2-hour plasma glucose (2-hPG) were collected at baseline health examination 1990–2005. Blood samples were collected and stored for future analyses. Participants were followed and 484 cases developed type 2 diabetes. Referents without type 2 diabetes were matched for sex, age, and year of participation, n = 484. Baseline plasma samples were analysed for PAI-1. Subgroup analysis was performed for 201 cases and 201 matched referents with normal baseline glucose levels (FPG < 6.1 and 2hPG < 8.9 mmol/L).

Results: Elevated baseline levels of PAI-1 were associated with incident type 2 diabetes after adjustments for BMI, family history of diabetes, smoking status, hypertension, FPG and 2hPG (PAI-1; OR = 1.87, 95% CI: 1.06–3.29). A similar result was shown in the subgroup analysis with 201 participants who had normal glucose levels at time of the health examination (PAI-1; OR = 2.68, 95% CI: 1.03–6.95).

Conclusions: Elevated PAI-1 levels in non-diabetic persons precede the manifestation of type 2 diabetes and can be detected before an elevation of FPG or 2-hPG is observed.

Background: Leisure-time physical activity decreases the risk of type 2 diabetes. Whether occupational physical activity affects the risk of type 2 diabetes is still not fully understood. The primary aim of this study was to investigate the association between occupational physical activity and 10-year diabetes incidence in a general adult population in Northern Sweden. The secondary aim was to explore the moderating role of BMI on this association.

Methods: This population-based, longitudinal cohort study included 16,282 diabetes-free individuals aged 28–52 years who participated in a cardiovascular intervention programme in Northern Sweden, and who reported the same occupational physical activity level at baseline and at 10-year follow-up. Incident type 2 diabetes was diagnosed based on oral glucose tolerance testing or a register-based diagnosis. Occupational physical activity was self-reported and categorized as: a) Low: ‘Sedentary or standing’ or ‘Light but partly physically active’, b) Moderate: ‘Light and physically active’, or c) High: Sometimes physically strenuous or ‘Physically strenuous most of the time’. Odds ratios (OR) and 95% confidence intervals (CI) for incident diabetes were calculated using multivariable logistic regression analysis, adjusting for age, sex, smoking, education level, family history of diabetes, country of birth, intake of fruits and vegetables, leisure-time physical activity, prediabetes and BMI. Potential interactions between BMI category and T2D were tested using interaction terms in the multivariable model.

Results: Six hundred twenty-four individuals developed type 2 diabetes in the 10 years between the first visit and the follow-up. A significant moderation effect of BMI on occupational physical activity was found (p = 0.01). Having a low level of occupational physical activity, compared with a moderate level of occupational physical activity, was associated with an increased risk of incident type 2 diabetes in overweight and obese individuals (OR 1.46, 95% CI 1.09–1.96), but not in those with normal weight (OR 0.80, 95% CI 0.52–1.23). High level of occupational physical activity was not associated with type 2 diabetes (OR 1.12, 95% CI 0.82–1.54).

Conclusions: Low occupational physical activity was associated with incident type 2 diabetes in overweight and obese individuals. Public-health efforts may benefit from encouraging less sitting and standing and more light physical activity during the workday.

Background: Individuals with type 2 diabetes (T2D) have an increased risk of cognitive symptoms and Alzheimer's disease (AD). Mis-metabolism with aggregation of amyloid-β peptides (Aβ) play a key role in AD pathophysiology. Therefore, human studies on Aβ metabolism and T2D are warranted.

Objective: The objective of this study was to examine whether acute hyperglycemia affects plasma Aβ1-40 and Aβ1-42 concentrations in individuals with T2D and matched controls.

Methods: Ten participants with T2D and 11 controls (median age, 69 years; range, 66-72 years) underwent hyperglycemic clamp and placebo clamp (saline infusion) in a randomized order, each lasting 4 hours. Aβ1-40, Aβ1-42, and insulin-degrading enzyme (IDE) plasma concentrations were measured in blood samples taken at 0 and 4 hours of each clamp. Linear mixed-effect regression models were used to evaluate the 4-hour changes in Aβ1-40 and Aβ1-42 concentrations, adjusting for body mass index, estimated glomerular filtration rate, and 4-hour change in insulin concentration.

Results: At baseline, Aβ1-40 and Aβ1-42 concentrations did not differ between the two groups. During the hyperglycemic clamp, Aβ decreased in the control group, compared to the placebo clamp (Aβ1-40: p = 0.034, Aβ1-42: p = 0.020), IDE increased (p = 0.016) during the hyperglycemic clamp, whereas no significant changes in either Aβ or IDE was noted in the T2D group.

Conclusions: Clamp-induced hyperglycemia was associated with increased IDE levels and enhanced Aβ40 and Aβ42 clearance in controls, but not in individuals with T2D. We hypothesize that insulin-degrading enzyme was inhibited during hyperglycemic conditions in people with T2D.

Background: Self-reported adherence to the Mediterranean diet has been modestly inversely associated with incidence of type 2 diabetes (T2D) in cohort studies. There is uncertainty about the validity and magnitude of this association due to subjective reporting of diet. The association has not been evaluated using an objectively measured biomarker of the Mediterranean diet.

Methods and findings: We derived a biomarker score based on 5 circulating carotenoids and 24 fatty acids that discriminated between the Mediterranean or habitual diet arms of a parallel design, 6-month partial-feeding randomised controlled trial (RCT) conducted between 2013 and 2014, the MedLey trial (128 participants out of 166 randomised). We applied this biomarker score in an observational study, the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, to assess the association of the score with T2D incidence over an average of 9.7 years of follow-up since the baseline (1991 to 1998). We included 22, 202 participants, of whom 9, 453 were T2D cases, with relevant biomarkers from an original case-cohort of 27, 779 participants sampled from a cohort of 340, 234 people. As a secondary measure of the Mediterranean diet, we used a score estimated from dietary-self report. Within the trial, the biomarker score discriminated well between the 2 arms; the cross-validated C-statistic was 0.88 (95% confidence interval (CI) 0.82 to 0.94). The score was inversely associated with incident T2D in EPIC-InterAct: the hazard ratio (HR) per standard deviation of the score was 0.71 (95% CI: 0.65 to 0.77) following adjustment for sociodemographic, lifestyle and medical factors, and adiposity. In comparison, the HR per standard deviation of the self-reported Mediterranean diet was 0.90 (95% CI: 0.86 to 0.95). Assuming the score was causally associated with T2D, higher adherence to the Mediterranean diet in Western European adults by 10 percentiles of the score was estimated to reduce the incidence of T2D by 11% (95% CI: 7% to 14%). The study limitations included potential measurement error in nutritional biomarkers, unclear specificity of the biomarker score to the Mediterranean diet, and possible residual confounding.

Conclusions: These findings suggest that objectively assessed adherence to the Mediterranean diet is associated with lower risk of T2D and that even modestly higher adherence may have the potential to reduce the population burden of T2D meaningfully.

Background: Despite decreasing mortality from cardiovascular disease (CVD), there are persistent inequities in mortality between socioeconomic groups. Primary preventative medications reduce mortality in CVD; thus, inequitable treatments will contribute to unequal outcomes. Physicians might contribute to inequality by prescribing preventative medication for CVD to themselves in a biased manner.

Aim: To determine whether primary medications for preventing CVD were prescribed inequitably between physicians and non-physicians.

Design and setting: This retrospective study retrieved registry data on prescribed medications for all physicians in Sweden aged 45–74 years, during 2013, and for reference non-physician individuals, matched by sex, age, residence, and level of education. The outcome was any medication for preventing CVD, received at least once during 2013.

Method: Age and the sex-specific prevalence of myocardial infarction (MI) among physicians and non-physicians were used as a proxy for the need for medication. Thereafter, to limit the analysis to preventative medication, we excluded individuals that were diagnosed with CVD or diabetes. To analyse differences in medication usage between physicians and matched non-physicians, we estimated odds ratios (ORs) with conditional logistic regression and adjusted for need and household income.

Results: MI prevalences were 5.7% for men and 2.3% for women, among physicians, and 5.4% for men and 1.8% for women, among non-physicians. We included 25,105 physicians and 44,366 non-physicians. The OR for physicians receiving any CVD preventative medication, compared to non-physicians, was 1.65 (95% confidence interval 1.59–1.72).

Conclusion: We found an inequity in prescribed preventative CVD medications, which favoured physicians over non-physicians.

Diabetic peripheral neuropathy (DPN) is a serious complication of diabetes, where skin biopsy assessing intraepi-dermal nerve fiber density (IENFD) plays an important diagnostic role. In vivo confocal microscopy (IVCM) of the corneal subbasal nerve plexus has been proposed as a noninvasive diagnostic modality for DPN. Direct compari-sons of skin biopsy and IVCM in controlled cohorts are lacking, as IVCM relies on subjective selection of images depicting only 0.2% of the nerve plexus. We compared these diagnostic modalities in a fixed-age cohort of 41 participants with type 2 diabetes and 36 healthy participants using machine algorithms to create wide-field image mosaics and quantify nerves in an area 37 times the size of prior studies to avoid human bias. In the same partici-pants, and at the same time point, no correlation between IENFD and corneal nerve density was found. Corneal nerve density did not correlate with clinical measures of DPN, including neuropathy symptom and disability scores, nerve conduction studies, or quantitative sensory tests. Our findings indicate that corneal and intraepidermal nerves likely mirror different aspects of nerve degeneration, where only intraepidermal nerves appear to reflect the clinical status of DPN, suggesting that scrutiny is warranted concerning methodologies of studies using corneal nerves to assess DPN.

Aims: To evaluate whether dog ownership from the time of type 2 diabetes diagnosis improved glycaemic control, increased achievement of major guideline treatment goals or reduced the risk of all-cause death.

Methods: Patients diagnosed with type 2 diabetes were followed by linkage of four Swedish national registers covering diabetes, dog ownership, socioeconomics, and mortality. Linear regression was used to estimate the mean yearly change in glycated haemoglobin (HbA1c). Cox survival analysis and logistic regression were used to analyse associations between dog ownership and all-cause death and achievement of treatment goals, respectively.

Results: Of 218,345 individuals included, 8,352 (3.8%) were dog-owners. Median follow-up was 5.2 years. Dog-owners had worse yearly change in HbA1c, and were less likely to reach HbA1c, low-density lipoprotein (LDL), and systolic blood pressure (SBP) treatment goals than non-dog-owners (adjusted odds ratios [95% CI] of 0.93 [0.88–0.97], 0.91 [0.86–0.95], and 0.95 [0.90–1.00], respectively). There was no difference in the risk of all-cause death (adjusted hazard ratio [95% CI] 0.92 [0.81–1.04], dog owners versus not).

Conclusion: Owning a dog when diagnosed with diabetes did not lead to better achievement of treatment goals or reduced mortality, but was in fact associated with a smaller reduction in HbA1c and reduced likelihood of achieving treatment goals.

Aims/hypothesis: Islet autoimmunity may progress to adult-onset diabetes. We investigated whether circulating odd-chain fatty acids (OCFA) 15:0 and 17:0, which are inversely associated with type 2 diabetes, interact with autoantibodies against GAD65 (GAD65Ab) on the incidence of adult-onset diabetes.

Methods: We used the European EPIC-InterAct case–cohort study including 11,124 incident adult-onset diabetes cases and a subcohort of 14,866 randomly selected individuals. Adjusted Prentice-weighted Cox regression estimated HRs and 95% CIs of diabetes in relation to 1 SD lower plasma phospholipid 15:0 and/or 17:0 concentrations or their main contributor, dairy intake, among GAD65Ab-negative and -positive individuals. Interactions between tertiles of OCFA and GAD65Ab status were estimated by proportion attributable to interaction (AP).

Results: Low concentrations of OCFA, particularly 17:0, were associated with a higher incidence of adult-onset diabetes in both GAD65Ab-negative (HR 1.55 [95% CI 1.48, 1.64]) and GAD65Ab-positive (HR 1.69 [95% CI 1.34, 2.13]) individuals. The combination of low 17:0 and high GAD65Ab positivity vs high 17:0 and GAD65Ab negativity conferred an HR of 7.51 (95% CI 4.83, 11.69), with evidence of additive interaction (AP 0.25 [95% CI 0.05, 0.45]). Low dairy intake was not associated with diabetes incidence in either GAD65Ab-negative (HR 0.98 [95% CI 0.94, 1.02]) or GAD65Ab-positive individuals (HR 0.97 [95% CI 0.79, 1.18]).

Conclusions/interpretation: Low plasma phospholipid 17:0 concentrations may promote the progression from GAD65Ab positivity to adult-onset diabetes. Graphical Abstract: [Figure not available: see fulltext.]

Background: Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways.

Methods: To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses.

Results: Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology.

Conclusions: Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.