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1.  Insulin pump therapy, multiple daily injections, and cardiovascular mortality in 18 168 people with type 1 diabetes: observational study 
Objective To investigate the long term effects of continuous subcutaneous insulin infusion (insulin pump therapy) on cardiovascular diseases and mortality in people with type 1 diabetes.
Design Observational study.
Setting Swedish National Diabetes Register, Sweden 2005-12.
Participants 18 168 people with type 1 diabetes, 2441 using insulin pump therapy and 15 727 using multiple daily insulin injections.
Main outcome measures Cox regression analysis was used to estimate hazard ratios for the outcomes, with stratification of propensity scores including clinical characteristics, risk factors for cardiovascular disease, treatments, and previous diseases.
Results Follow-up was for a mean of 6.8 years until December 2012, with 114 135 person years. With multiple daily injections as reference, the adjusted hazard ratios for insulin pump treatment were significantly lower: 0.55 (95% confidence interval 0.36 to 0.83) for fatal coronary heart disease, 0.58 (0.40 to 0.85) for fatal cardiovascular disease (coronary heart disease or stroke), and 0.73 (0.58 to 0.92) for all cause mortality. Hazard ratios were lower, but not significantly so, for fatal or non-fatal coronary heart disease and fatal or non-fatal cardiovascular disease. Unadjusted absolute differences were 3.0 events of fatal coronary heart disease per 1000 person years; corresponding figures were 3.3 for fatal cardiovascular disease and 5.7 for all cause mortality. When lower body mass index and previous cardiovascular diseases were excluded, results of subgroup analyses were similar to the results from complete data. A sensitivity analysis of unmeasured confounders in all individuals showed that an unmeasured confounders with hazard ratio of 1.3 would have to be present in >80% of the individuals treated with multiple daily injections versus not presence in those treated with pump therapy to invalidate the significantly lower hazard ratios for fatal cardiovascular disease. Data on patient education and frequency of blood glucose monitoring were missing, which might have influenced the observed association.
Conclusion Among people with type 1 diabetes use of insulin pump therapy is associated with lower cardiovascular mortality than treatment with multiple daily insulin injections.
PMCID: PMC4476263  PMID: 26100640
2.  Impact of ethnicity on progress of glycaemic control in 131 935 newly diagnosed patients with type 2 diabetes: a nationwide observational study from the Swedish National Diabetes Register 
BMJ Open  2015;5(6):e007599.
Studies on ethnic disparities in glycaemic control have been contradictory, and compromised by excessively broad categories of ethnicity and inadequate adjustment for socioeconomic differences. We aimed to study the effect of ethnicity on glycaemic control in a large cohort of patients with type 2 diabetes.
We used nationwide data (mainly from primary care) from the Swedish National Diabetes Register (2002–2011) to identify patients with newly diagnosed (within 12 months) type 2 diabetes.
We included 131 935 patients (with 713 495 appointments), representing 10 ethnic groups, who were followed up to 10 years.
Primary and secondary outcome measures
Progress of glycated haemoglobin (HbA1c) for up to 10 years was examined. Mixed models were used to correlate ethnicity with HbA1c (mmol/mol). The effect of glycaemic disparities was examined by assessing the risk of developing albuminuria. The impact of ethnicity was compared to that of income, education and physical activity.
Immigrants, particularly those of non-Western origin, received glucose-lowering therapy earlier, had 30% more appointments but displayed poorer glycaemic control (2–5 mmol/mol higher HbA1c than native Swedes). Probability of therapy failure was 28–111% higher for non-Western groups than for native Swedes. High-income Western groups remained below the target-level of HbA1c for 4–5 years, whereas non-Western populations never reached the target level. These disparities translated into 51–92% higher risk of developing albuminuria. The impact of ethnicity was greater than the effect of income and education, and equal to the effect of physical activity.
Despite earlier pharmacological treatment and more frequent appointments, immigrants of non-Western origin display poorer glycaemic control and this is mirrored in a higher risk of developing albuminuria.
PMCID: PMC4458585  PMID: 26048210
3.  Durability of oral hypoglycemic agents in drug naïve patients with type 2 diabetes: report from the Swedish National Diabetes Register (NDR) 
To analyze the durability of monotherapy with different classes of oral hypoglycemic agents (OHAs) in drug naïve patients with type 2 diabetes mellitus (T2DM) in real life.
Men and women with T2DM, who were new users of OHA monotherapy and registered in the Swedish National Diabetes Register July 2005–December 2011, were available (n=17 309) and followed for up to 5.5 years. Time to monotherapy failure, defined as discontinuation of continuous use with the initial agent, switch to a new agent, or add-on treatment of a second agent, was analyzed as a measure of durability. Baseline characteristics were balanced by propensity score matching 1:5 between groups of sulfonylurea (SU) versus metformin (n=4303) and meglitinide versus metformin (n=1308). HRs with 95% CIs were calculated using Cox regression models.
SU and meglitinide, as compared with metformin, were associated with increased risk of monotherapy failure (HR 1.74; 95% CI 1.56 to 1.94 and 1.66; 1.37 to 2.00 for SU and meglitinide, respectively). When broken down by type of monotherapy failure, SU and meglitinide were associated with an increased risk of add-on treatment of a second agent (HR 3.14; 95% CI 2.66 to 3.69 and 2.52; 1.89 to 3.37 for SU and meglitinide, respectively) and of switch to a new agent (HR 2.81; 95% CI 2.01 to 3.92 and 3.78; 2.25 to 6.32 for SU and meglitinide, respectively). The risk of discontinuation did not differ significantly between the groups.
In this nationwide observational study reflecting clinical practice, SU and meglitinide showed substantially increased risk of switch to a new agent or add on of a second agent compared with metformin. These results indicate superior glycemic durability with metformin compared with SU and also meglitinide in real life.
PMCID: PMC4368982  PMID: 25815205
Pharmacoepidemiology; Oral Hypoglycaemic Agents; Type 2 Diabetes
4.  Obesity attenuates gender differences in cardiovascular mortality 
To estimate cardiovascular disease (CVD) mortality in relation to obesity and gender.
Data from 11 prospective cohorts from four European countries including 23 629 men and 21 965 women, aged 24 to 99 years, with a median follow-up of 7.9 years were analyzed. Hazards ratios (HR) for CVD mortality in relation to baseline body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) were estimated using Cox proportional hazards models with age as the timescale.
Men had higher CVD mortality than women in all four BMI categories (<25.0, 25.0-29.9, 30.0-34.9 and ≥35.0 kg/m2). Compared with the lowest BMI category in women, multivariable adjusted HRs (95% confidence intervals) for higher BMI categories are 1.0 (0.8-1.4), 1.6 (1.1-2.1) and 2.8 (2.0-3.8) in women and 2.8 (2.2-3.6), 3.1 (2.5-3.9), 3.8 (2.9-4.9) and 5.4 (3.8-7.7) in men, respectively. Similar findings were observed for abdominal obesity defined by WC, WHR or WHtR. The gender difference was slightly smaller in obese than in non-obese individuals; but the interaction was statistically significant only between gender and WC (p = 0.02), and WHtR (p = 0.01). None of the interaction terms was significant among non-diabetic individuals.
Men had higher CVD mortality than women across categories of anthropometric measures of obesity. The gender difference was attenuated in obese individuals, which warrants further investigation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-014-0144-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4212094  PMID: 25928355
Obesity; Gender; Cardiovascular disease mortality
5.  Evidence of a Causal Relationship Between Adiponectin Levels and Insulin Sensitivity 
Diabetes  2013;62(4):1338-1344.
The adipocyte-secreted protein adiponectin is associated with insulin sensitivity in observational studies. We aimed to evaluate whether this relationship is causal using a Mendelian randomization approach. In a sample of Swedish men aged 71 years (n = 942) from the Uppsala Longitudinal Study of Adult Men (ULSAM), insulin sensitivity (M/I ratio) was measured by the euglycemic insulin clamp. We used three genetic variants in the ADIPOQ locus as instrumental variables (IVs) to estimate the potential causal effect of adiponectin on insulin sensitivity and compared these with results from conventional linear regression. The three ADIPOQ variants, rs17300539, rs3774261, and rs6444175, were strongly associated with serum adiponectin levels (all P ≤ 5.3 × 10−9) and were also significantly associated with M/I ratio in the expected direction (all P ≤ 0.022). IV analysis confirmed that genetically determined adiponectin increased insulin sensitivity (β = 0.47–0.81, all P ≤ 0.014) comparable with observational estimates (β = 0.50, all Pdifference ≥ 0.136). Adjustment for BMI and waist circumference partly explained the association of both genetically determined and observed adiponectin levels with insulin sensitivity. The observed association between higher adiponectin levels and increased insulin sensitivity is likely to represent a causal relationship partly mediated by reduced adiposity.
PMCID: PMC3609596  PMID: 23274890
6.  Reducing the noise in signal detection of adverse drug reactions by standardizing the background: a pilot study on analyses of proportional reporting ratios-by-therapeutic area 
Disproportionality screening analysis is acknowledged as a tool for performing signal detection in databases of adverse drug reactions (ADRs), e.g., in the European Union (EU) Drug Authority setting. The purpose of this study was to explore the possibility of decreasing false-positive signals of disproportionate reporting (SDR) by calculating the proportional reporting ratio (PRR)-by-therapeutic area (TA), while still maintaining the ability to detect relevant SDRs.
In the EudraVigilance (EV) Database, output from PRR calculated with a restricted TA comparator background was compared in detail to output from conventional authority-setting PRR calculations for four drugs: bicalutamide, abiraterone, metformin, and vildagliptin, within the TAs of prostate gland disease and type 2 diabetes mellitus.
ADR reports per investigated drug ranged from 2,400 to 50,000. The PRR-TA’s ability to detect true-positive SDRs (as acknowledged in approved labeling) was increased compared to the conventional PRR, and performed 8–31 % better than a recently proposed stricter EU-SDR definition. The PRR-TA removed false SDRs confounded by disease or disease spill-over by up to 63 %, while retaining/increasing the number of unclassified SDRs relevant for manual validation, and thereby improving the ratio between confounded SDRs (i.e., noise) and unclassified SDRs for all investigated drugs (possible signals).
The performance of the PRR was improved by background restriction with the PRR-TA method; the number of false-positive SDRs decreased, and the ability to detect true-positive SDRs increased, improving the signal-to-noise ratio. Further development and validation of the method is needed within other TAs and databases, and for disproportionality analysis methods.
Electronic supplementary material
The online version of this article (doi:10.1007/s00228-014-1658-1) contains supplementary material, which is available to authorized users.
PMCID: PMC3978377  PMID: 24599513
PRR; Adverse drug reactions; ADR; Signal detection; Pharmacovigilance; Disproportionality analysis
7.  GDF-15 for Prognostication of Cardiovascular and Cancer Morbidity and Mortality in Men 
PLoS ONE  2013;8(12):e78797.
The objective was to evaluate the hypothesis that growth-differentiation factor 15 (GDF-15) is an independent marker of the long-term risk for both cardiovascular disease and cancer morbidity beyond clinical and biochemical risk factors. Plasma obtained at age 71 was available from 940 subjects in the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort. Complete mortality and morbidity data were obtained from public registries. At baseline there were independent associations between GDF-15 and current smoking, diabetes mellitus, biomarkers of cardiac (high-sensitivity troponin-T, NT-proBNP) and renal dysfunction (cystatin-C) and inflammatory activity (C-reactive protein), and previous cardiovascular disease (CVD). During 10 years follow-up there occurred 265 and 131 deaths, 115 and 46 cardiovascular deaths, and 185 and 86 events with coronary heart disease mortality or morbidity in the respective total cohort (n=940) and non-CVD (n=561) cohort. After adjustment for conventional cardiovascular risk factors, one SD increase in log GDF-15 were, in the respective total and non-CVD populations, associated with 48% (95%CI 26 to 73%, p<0.001) and 67% (95%CI 28 to 217%, p<0.001) incremental risk of cardiovascular mortality, 48% (95%CI 33 to 67%, p<0.001) and 61% (95%CI 38 to 89%, p<0.001) of total mortality and 36% (95%CI 19 to 56%, p<0.001) and 44% (95%CI 17 to 76%, p<0.001) of coronary heart disease morbidity and mortality. The corresponding incremental increase for cancer mortality in the respective total and non-cancer disease (n=882) population was 46% (95%CI 21 to 77%, p<0.001) and 38% (95%CI 12 to 70%, p<0.001) and for cancer morbidity and mortality in patients without previous cancer disease 30% (95%CI 12 to 51%, p<0.001). In conclusion, in elderly men, GDF-15 improves prognostication of both cardiovascular, cancer mortality and morbidity beyond established risk factors and biomarkers of cardiac, renal dysfunction and inflammation.
PMCID: PMC3846468  PMID: 24312445
8.  Circulating Levels of Phthalate Metabolites Are Associated With Prevalent Diabetes in the Elderly 
Diabetes Care  2012;35(7):1519-1524.
Phthalates are ubiquitous industrial high-volume chemicals known as ligands to peroxisome proliferator–activated receptors (PPARs). Because PPAR-γ agonists modulate insulin sensitivity and are used to treat type 2 diabetes, we investigated whether circulating levels of phthalate metabolites are related to prevalent type 2 diabetes.
A total of 1,016 subjects, aged 70 years, were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors Study. Four phthalate metabolites were detected in almost all participant sera by an API 4000 liquid chromatograph/tandem mass spectrometer. Type 2 diabetes was defined as the use of pharmacological hypoglycemic agents or a fasting plasma glucose >7.0 mmol/L.
A total of 114 subjects were shown to have diabetes. Following adjustment for sex, BMI, serum cholesterol and triglycerides, educational level, and smoking and exercise habits, high levels of the phthalate metabolites monomethyl phthalate (MMP) (P < 0.01), monoisobutyl phthalate (MiBP) (P < 0.05), and monoethyl phthalate (MEP) (P < 0.05), but not mono(2-ethylhexyl) phthalate, were associated with an increased prevalence of diabetes. Using the fasting proinsulin–to–insulin ratio as a marker of insulin secretion and the homeostasis model assessment-insulin resistance index as a marker of insulin resistance, MiBP was mainly related to poor insulin secretion, whereas MEP and MMP mainly were related to insulin resistance.
The findings in this cross-sectional study showed that several phthalate metabolites are related to diabetes prevalence, as well as to markers of insulin secretion and resistance. These findings support the view that these commonly used chemicals might influence major factors that are regulating glucose metabolism in humans at the level of exposure of phthalate metabolites seen in the general elderly population.
PMCID: PMC3379584  PMID: 22498808
9.  Platelet Counts and Liver Enzymes after Bariatric Surgery 
Journal of Obesity  2013;2013:567984.
Background. Obesity is characterized by liver steatosis, chronic inflammation, and increased liver enzymes, that is, gamma-glutamyltransferase (GGT) and alanine aminotransferase (ALT), markers for nonalcoholic fatty liver disease (NAFLD) and liver fat content. Increased platelet counts (PCs) are associated with inflammatory conditions and are a valuable biomarker of the degree of fibrosis in NAFLD. We investigated alterations in PC, GGT, and ALT after biliopancreatic diversion with duodenal switch (BPD-DS) and Roux-en-Y gastric bypass (RYGBP). Methods. Ten morbidly obese patients (body mass index, BMI: 53.5 ± 3.8 kg/m2) who underwent BPD-DS were evaluated preoperatively (baseline) and 1 year (1st followup) and 3 years (2nd followup) after surgery and compared with 21 morbidly obese patients (BMI: 42.3 ± 5.2 kg/m2) who underwent RYGBP. Results. Over the 3 years of followup, changes in BPD-DS and RYGBP patients (BPD-DS/RYGBP) were as follows: BMI (−44%/−24%), GGT (−63%/−52%), and ALT (−48%/−62%). PC decreased (−21%) statistically significantly only in BPD-DS patients. Conclusions. Morbidly obese patients treated by RYGBP or BPD-DS show sustained reductions in BMI, ALT, and GGT. The decrease in PC and liver enzymes after BPD-DS may reflect a more pronounced decrease of liver-fat-content-related inflammation and, as a result, a lowered secondary thrombocytosis.
PMCID: PMC3590647  PMID: 23509615
10.  Serum Glucose and Fructosamine in Relation to Risk of Cancer 
PLoS ONE  2013;8(1):e54944.
Impaired glucose metabolism has been linked with increased cancer risk, but the association between serum glucose and cancer risk remains unclear. We used repeated measurements of glucose and fructosamine to get more insight into the association between the glucose metabolism and risk of cancer.
We selected 11,998 persons (>20 years old) with four prospectively collected serum glucose and fructosamine measurements from the Apolipoprotein Mortality Risk (AMORIS) study. Multivariate Cox proportional hazards regression was used to assess standardized log of overall mean glucose and fructosamine in relation to cancer risk. Similar analyses were performed for tertiles of glucose and fructosamine and for different types of cancer.
A positive trend was observed between standardized log overall mean glucose and overall cancer risk (HR = 1.08; 95% CI: 1.02–1.14). Including standardized log fructosamine in the model resulted in a stronger association between glucose and cancer risk and aninverse association between fructosamine and cancer risk (HR = 1.17; 95% CI: 1.08–1.26 and HR: 0.89; 95% CI: 0.82–0.96, respectively). Cancer risks were highest among those in the highest tertile of glucose and lowest tertile of fructosamine. Similar findings were observed for prostate, lung, and colorectal cancer while none observed for breast cancer.
The contrasting effect between glucose, fructosamine, and cancer risk suggests the existence of distinct groups among those with impaired glucose metabolism, resulting in different cancer risks based on individual metabolic profiles. Further studies are needed to clarify whether glucose is a proxy of other lifestyle-related or metabolic factors.
PMCID: PMC3556075  PMID: 23372798
11.  Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes 
Strawbridge, Rona J. | Dupuis, Josée | Prokopenko, Inga | Barker, Adam | Ahlqvist, Emma | Rybin, Denis | Petrie, John R. | Travers, Mary E. | Bouatia-Naji, Nabila | Dimas, Antigone S. | Nica, Alexandra | Wheeler, Eleanor | Chen, Han | Voight, Benjamin F. | Taneera, Jalal | Kanoni, Stavroula | Peden, John F. | Turrini, Fabiola | Gustafsson, Stefan | Zabena, Carina | Almgren, Peter | Barker, David J.P. | Barnes, Daniel | Dennison, Elaine M. | Eriksson, Johan G. | Eriksson, Per | Eury, Elodie | Folkersen, Lasse | Fox, Caroline S. | Frayling, Timothy M. | Goel, Anuj | Gu, Harvest F. | Horikoshi, Momoko | Isomaa, Bo | Jackson, Anne U. | Jameson, Karen A. | Kajantie, Eero | Kerr-Conte, Julie | Kuulasmaa, Teemu | Kuusisto, Johanna | Loos, Ruth J.F. | Luan, Jian'an | Makrilakis, Konstantinos | Manning, Alisa K. | Martínez-Larrad, María Teresa | Narisu, Narisu | Nastase Mannila, Maria | Öhrvik, John | Osmond, Clive | Pascoe, Laura | Payne, Felicity | Sayer, Avan A. | Sennblad, Bengt | Silveira, Angela | Stančáková, Alena | Stirrups, Kathy | Swift, Amy J. | Syvänen, Ann-Christine | Tuomi, Tiinamaija | van 't Hooft, Ferdinand M. | Walker, Mark | Weedon, Michael N. | Xie, Weijia | Zethelius, Björn | Ongen, Halit | Mälarstig, Anders | Hopewell, Jemma C. | Saleheen, Danish | Chambers, John | Parish, Sarah | Danesh, John | Kooner, Jaspal | Östenson, Claes-Göran | Lind, Lars | Cooper, Cyrus C. | Serrano-Ríos, Manuel | Ferrannini, Ele | Forsen, Tom J. | Clarke, Robert | Franzosi, Maria Grazia | Seedorf, Udo | Watkins, Hugh | Froguel, Philippe | Johnson, Paul | Deloukas, Panos | Collins, Francis S. | Laakso, Markku | Dermitzakis, Emmanouil T. | Boehnke, Michael | McCarthy, Mark I. | Wareham, Nicholas J. | Groop, Leif | Pattou, François | Gloyn, Anna L. | Dedoussis, George V. | Lyssenko, Valeriya | Meigs, James B. | Barroso, Inês | Watanabe, Richard M. | Ingelsson, Erik | Langenberg, Claudia | Hamsten, Anders | Florez, Jose C.
Diabetes  2011;60(10):2624-2634.
Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.
We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.
Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.
We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.
PMCID: PMC3178302  PMID: 21873549
12.  Clinical Usefulness of Different Lipid Measures for Prediction of Coronary Heart Disease in Type 2 Diabetes 
Diabetes Care  2011;34(9):2095-2100.
We assessed the association between different blood lipid measures and risk of fatal/nonfatal coronary heart disease (CHD).
We conducted an observational study of patients with type 2 diabetes from the Swedish National Diabetes Register. Baseline LDL cholesterol, non-HDL cholesterol, ratio of non-HDL to HDL cholesterol (non-HDL:HDL), and ratio of triacylglycerol to HDL cholesterol (TG:HDL) was measured in 18,673 patients aged 30–70 years, followed for a mean of 4.8 years from 2003 to 2007.
Hazard ratios (HRs) for CHD per 1-SD increment in lipid measures were 1.23 with non-HDL:HDL, 1.20 with non-HDL cholesterol, 1.17 with LDL cholesterol, and 1.15 with TG:HDL (all P < 0.001 when adjusted for clinical characteristics and nonlipid risk factors). The best global model fit was found with non-HDL:HDL. When patients within the lowest tertile of a lipid measure were compared with those with all lipid measures within the highest tertile, the adjusted HR for CHD was 0.62 with non-HDL:HDL <3.5 mmol/L, 0.65 with non-HDL cholesterol <3.3 mmol/L, and 0.70 with LDL cholesterol <2.5 mmol/L (all P < 0.001). The lowest tertile of LDL and non-HDL cholesterol corresponded with treatment targets according to U.S. and European guidelines. HRs for CHD were 0.52, 0.62, and 0.66 with the lowest deciles of non-HDL:HDL, non-HDL cholesterol, and LDL cholesterol ≤1.8 mmol/L (all P < 0.001). Mean TG:HDL was considerably lower in patients within the lowest tertile of non-HDL:HDL, 0.82 ± 0.47, than in those within the lowest tertile of LDL cholesterol (<2.5 mmol/L), 1.49 ± 1.03.
Non-HDL:HDL had a stronger effect on CHD risk than LDL cholesterol, and low TG:HDL values were more often seen within the lowest non-HDL:HDL tertile than within the lowest LDL cholesterol tertile. LDL cholesterol was not the best predictor of CHD risk in type 2 diabetes.
PMCID: PMC3161275  PMID: 21775750
13.  Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register 
BMJ Open  2012;2(4):e001076.
To evaluate the effectiveness and safety of metformin use in clinical practice in a large sample of pharmacologically treated patients with type 2 diabetes and different levels of renal function.
Observational study between July 2004 and December 2010, mean follow-up 3.9 years.
Hospital outpatient clinics and primary care in Sweden.
51 675 men and women with type 2 diabetes, registered in the Swedish National Diabetes Register, and on continuous glucose-lowering treatment with oral hypoglycaemic agents (OHAs) or insulin.
Main outcome measures
Risks of cardiovascular disease (CVD), all-cause mortality and acidosis/serious infection, associated with each treatment regimens, were analysed in all patients and in subgroups with different estimated glomerular filtration rate (eGFR) intervals. Covariance adjustment and propensity scores were used to adjust for several baseline risk factors and characteristics at Cox regression.
Compared with metformin in monotherapy, HRs for fatal/non-fatal CVD and all-cause mortality with all other OHAs combined (approximately 80% sulphonylureas) in monotherapy were 1.02 (95% CI 0.93 to 1.12) and 1.13 (1.01 to 1.27), while 1.18 (1.07 to 1.29) and 1.34 (1.19 to 1.50) with insulin in monotherapy, adjusting using propensity scores. Metformin, compared with any other treatment, showed reduced risks of acidosis/serious infection (adjusted HR 0.85, 95% CI 0.74 to 0.97) and all-cause mortality (HR 0.87, 95% CI 0.77 to 0.99), in patients with eGFR 45–60 ml/min/1.73 m2, and no increased risks of all-cause mortality, acidosis/serious infection or CVD were found in patients with eGFR 30–45 ml/min/1.73 m2.
Metformin showed lower risk than insulin for CVD and all-cause mortality and slightly lower risk for all-cause mortality compared with other OHA, in these 51 675 patients followed for 4 years. Patients with renal impairment showed no increased risk of CVD, all-cause mortality or acidosis/serious infection. In clinical practice, the benefits of metformin use clearly outbalance the risk of severe side effects.
Article summary
Article focus
To evaluate the risks of CVD, acidosis/serious infection and mortality associated with metformin and other glucose-lowering treatments, in a cohort of 51 675 type 2 diabetes patients and in subgroups with different degrees of renal impairment.
Key messages
Metformin was associated with reduced risk of CVD, acidosis/serious infection and all-cause mortality compared with insulin and a reduced risk of all-cause mortality compared with other OHAs.
The effects were consistent in patients with renal impairment (eGFR 45–60 ml/min/1.73 m2), and there were no increased risk of acidosis/serious infection even in patients with low renal function (eGFR 30–45 ml/min/1.73 m2).
Strengths and limitations of this study
A large cohort with comprehensive data on patient characteristics was studied.
A composite end point including diagnosis of acidosis, shock, acute renal failure and serious infections was used to evaluate the occurrence of lactic acidosis.
PMCID: PMC3400073  PMID: 22798258
14.  HbA1C and Cancer Risk in Patients with Type 2 Diabetes – A Nationwide Population-Based Prospective Cohort Study in Sweden 
PLoS ONE  2012;7(6):e38784.
Diabetes is associated with increased cancer risk. The underlying mechanisms remain unclear. Hyperglycemia might be one risk factor. HbA1c is an indicator of the blood glucose level over the latest 1 to 3 months. This study aimed to investigate association between HbA1c level and cancer risks in patients with type 2 diabetes based on real life situations.
This is a cohort study on 25,476 patients with type 2 diabetes registered in the Swedish National Diabetes Register from 1997–1999 and followed until 2009. Follow-up for cancer was accomplished through register linkage. We calculated incidences of and hazard ratios (HR) for cancer in groups categorized by HbA1c ≤58 mmol/mol (7.5%) versus >58 mmol/mol, by quartiles of HbA1c, and by HbA1c continuously at Cox regression, with covariance adjustment for age, sex, diabetes duration, smoking and insulin treatment, or adjusting with a propensity score.
Comparing HbA1c >58 mmol/mol with ≤58 mmol/mol, adjusted HR for all cancer was 1.02 [95% CI 0.95–1.10] using baseline HbA1c, and 1.04 [95% CI 0.97–1.12] using updated mean HbA1c, and HRs were all non-significant for specific cancers of gastrointestinal, kidney and urinary organs, respiratory organs, female genital organs, breast or prostate. Similarly, no increased risks of all cancer or the specific types of cancer were found with higher quartiles of baseline or updated mean HbA1c, compared to the lowest quartile. HR for all cancer was 1.01 [0.98–1.04] per 1%-unit increase in HbA1c used as a continuous variable, with non-significant HRs also for the specific types of cancer per unit increase in HbA1c.
In this study there were no associations between HbA1c and risks for all cancers or specific types of cancer in patients with type 2 diabetes.
PMCID: PMC3375298  PMID: 22719946
15.  Seasonal variations of insulin sensitivity from a euglycemic insulin clamp in elderly men 
Seasonal variations in hemoglobin-A1c have been reported in diabetic patients, but the underlying mechanisms have not been elucidated.
To study if insulin sensitivity, insulin secretion, and fasting plasma glucose showed seasonal variations in a Swedish population-based cohort of elderly men.
Altogether 1117 men were investigated with a euglycemic insulin clamp and measurements of fasting plasma glucose and insulin secretion after an oral glucose tolerance test. Values were analyzed in linear regression models with an indicator variable for winter/summer season and outdoor temperature as predictors.
During winter, insulin sensitivity (M/I, unit = 100 × mg × min-1 × kg-1/(mU × L-1)) was 11.0% lower (4.84 versus 5.44, P = 0.0003), incremental area under the insulin curve was 16.4% higher (1167 versus 1003 mU/L, P = 0.007). Fasting plasma glucose was, however, not statistically significantly different (5.80 versus 5.71 mmol/L, P = 0.28) compared to the summer season. There was an association between outdoor temperature and M/I (0.57 units increase (95% CI 0.29–0.82, P < 0.0001) per 10°C increase of outdoor temperature) independent of winter/summer season. Adjustment for life-style factors, type 2 diabetes, and medication did not alter these results.
Insulin sensitivity showed seasonal variations with lower values during the winter and higher during the summer season. Inverse compensatory variations of insulin secretion resulted in only minor variations of fasting plasma glucose. Insulin sensitivity was associated with outdoor temperature. These phenomena should be further investigated in diabetic patients.
PMCID: PMC3282240  PMID: 22066936
Insulin secretion; insulin sensitivity; seasonal variation
16.  Changes in Erythrocyte Sedimentation Rate, White Blood Cell Count, Liver Enzymes, and Magnesium after Gastric Bypass Surgery 
Journal of Obesity  2011;2011:273105.
Background. Roux-en-Y gastric bypass (RYGBP) is an established method for treatment of obesity, a condition of chronic inflammation with liver steatosis, characterised by increased erythrocyte sedimentation rate (ESR), white blood cell count (WBC), liver enzymes, and decreased magnesium (Mg). We investigated alterations, if any, in ESR, WBC, alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), and Mg after RYGBP. Methods. 21 morbidly obese nondiabetic patients who underwent RYGBP surgery were evaluated preoperatively (baseline), then 1 year (1st followup) and 3.5 years (2nd followup) after RYGBP and compared to an untreated control group. Results. Body mass index, ESR, WBC, ALT, and GGT were all significantly reduced at 1 year in the RYGBP group (30%, 35%, 20%, 45%, and 57%, resp.) while Mg increased by 6%, compared to control group (P = 0.001−0.009). Conclusions. Obese patients treated by RYGBP show sustained reductions in ESR, WBC, ALT, and GGT possibly due to reduced liver steatosis and increased Mg.
PMCID: PMC3253464  PMID: 22235366
17.  Serum levels of selenium and smoking habits at age 50 influence long term prostate cancer risk; a 34 year ULSAM follow-up 
BMC Cancer  2011;11:431.
Serum selenium level (s-Se) has been associated with prostate cancer (PrCa) risk. We investigated the relation between s-Se, smoking and non-screening detected PrCa and explored if polymorphisms in two DNA repair genes: OGG1 and MnSOD, influenced any effect of s-Se.
ULSAM, a population based Swedish male cohort (n = 2322) investigated at age 50 for s-Se and s-Se influencing factors: serum cholesterol, erythrocyte sedimentation rate and smoking habits. At age 71 a subcohort, (n = 1005) was genotyped for OGG1 and MnSOD polymorphisms.
In a 34-year-follow-up, national registries identified 208 PrCa cases further confirmed in medical records. Participants with s-Se in the upper tertile had a non-significantly lower risk of PrCa. Smokers with s-Se in the two lower tertiles (≤80 μg/L) experienced a higher cumulative incidence of PrCa than smokers in the high selenium tertile (Hazard Ratio 2.39; 95% CI: 1.09-5.25). A high tertile selenium level in combination with non-wt rs125701 of the OGG1 gene in combination with smoking status or rs4880 related variation of MnSOD gene appeared to protect from PrCa.
S-Se levels and smoking habits influence long-term risk of PrCa. Smoking as a risk factor for PrCa in men with low s-Se is relevant to explore further. Exploratory analyses of variations in OGG1 and MnSOD genes indicate that hypotheses about patterns of exposure to selenium and smoking combined with data on genetic variation in genes involved in DNA repair can be valuable to pursue.
PMCID: PMC3199281  PMID: 21982398
18.  The metabolic syndrome and the risk of prostate cancer under competing risks of death from other causes 
Associations between Metabolic Syndrome (MetS) components and prostate cancer development have not been studied comprehensively; results have been divergent. Using the National Cholesterol Education Program Adult Treatment panel III (NCEP) and International Diabetes Federation (IDF) definitions of the MetS we investigated such associations taking competing risks of death into consideration.
In the prospective Uppsala Longitudinal Study of Adult Men (ULSAM) of 2322 Caucasian men with 34 years of follow-up baseline MetS-measurements at age 50 were used. Cumulative incidence of prostate cancer and death with/without the MetS were calculated. Competing risk of dying was taken into account by calculating the conditional probability of prostate cancer with/without the MetS.
Two-hundred-and- thirty-seven prostate cancers were identified. Prostate cancer probability by age 80 with baseline MetS compared to without the MetS was non-significantly higher, 5.2 percent-units (CI -0.8%-11.3%, (NCEP), 2.7 percent-units (CI -2.7%-8.0%) (IDF), cumulative incidence proportions of death was significantly higher, 19.3 percent-units (CI 13.4%-25.3%) (NCEP), 15.3 percent-units (CI 9.5%-21.1%) (IDF) and conditional probability of prostate cancer considering death from other causes was significantly higher, 7.3 percent-units (CI 0.2%-14.5%) odds ratio(OR) of 1.64 (CI 1.03-2.23). (NCEP), and non-significantly higher 5.0 percent-units (CI -1.6%-11.6%) OR 1.43 (CI 0.89-1.90). (IDF).
The MetS by the NCEP definition is associated with prostate cancer taking the competing risk of early death from other causes into account.
The results further highlight the public health impact of the increasing prevalence of MetS, and the importance of considering competing risks when studying risk factors for cancer.
PMCID: PMC2923431  PMID: 20647401
epidemiology; prostate cancer; metabolic syndrome; competing risk; risk factors
19.  Glycemic Control and Cardiovascular Disease in 7,454 Patients With Type 1 Diabetes 
Diabetes Care  2010;33(7):1640-1646.
We assessed the association between A1C and cardiovascular diseases (CVDs) in an observational study of patients with type 1 diabetes followed for 5 years.
A total of 7,454 patients were studied from the Swedish National Diabetes Register (aged 20–65 years, diabetes duration 1–35 years, followed from 2002 to 2007).
Hazard ratios (HRs) for fatal/nonfatal coronary heart disease (CHD) per 1% unit increase in baseline or updated mean A1C at Cox regression analysis were 1.31 and 1.34 and 1.26 and 1.32, respectively, for fatal/nonfatal CVD (all P < 0.001 after adjustment for age, sex, diabetes duration, blood pressure, total and LDL cholesterol, triglycerides, BMI, smoking, and history of CVD). HRs were only slightly lower for CHD (P = 0.002) and CVD (P = 0.002–0.007) after also adjusting for albuminuria. Adjusted 5-year event rates of CHD and CVD increased progressively with higher A1C, ranging from 5 to 12%, as well as when subgrouped by shorter (1–20 years) or longer (21–35 years) duration of diabetes. A group of 4,186 patients with A1C 5–7.9% (mean 7.2) at baseline showed risk reductions of 41% (95% confidence intervals: 15–60) (P = 0.005) for fatal/nonfatal CHD and 37% (12–55) (P = 0.008) for CVD, compared with 3,268 patients with A1C 8–11.9% (mean 9.0), fully adjusted also for albuminuria.
This observational study of patients in modern everyday clinical practice demonstrates progressively increasing risks for CHD and CVD with higher A1C, independently of traditional risk factors, with no J-shaped risk curves. A baseline mean A1C of 7.2% showed considerably reduced risks of CHD and CVD compared with A1C 9.0%, emphasizing A1C as a strong independent risk factor in type 1 diabetes.
PMCID: PMC2890374  PMID: 20424222
20.  Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans 
Diabetes  2010;59(5):1266-1275.
Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action.
We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084).
The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 × 10−71). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction.
Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.
PMCID: PMC2857908  PMID: 20185807
21.  Cytokine-mediated inflammation is independently associated with insulin sensitivity measured by the euglycemic insulin clamp in a community-based cohort of elderly men 
Both clinical and experimental studies suggest a close relation between an inflammatory state and insulin resistance. We investigated the association between cytokine-mediated inflammation (high sensitivity C reactive protein [hsCRP] and interleukin [IL] 6) and insulin sensitivity (insulin-mediated glucose disposal rate, assessed by the euglycemic insulin clamp) in a community-based cohort, with subgroup analyses of normal weight individuals without diabetes mellitus and metabolic syndrome (NCEP). hsCRP and IL-6 were inversely associated with insulin sensitivity (multivariable-adjusted regression coefficient for 1-SD increase of hsCRP -0.12 (-0.21-(-0.03), p=0.01) and of IL-6 -0.11 (-0.21-(-0.02), p=0.01) in models adjusting for age and components of the metabolic syndrome (systolic and diastolic blood pressure, antihypertensive drugs, HDL-cholesterol, triglycerides, fasting plasma glucose, waist circumference). The multivariable-adjusted association between hsCRP, IL-6 and insulin sensitivity were of a similar magnitude in normal weight individuals without diabetes and without the metabolic syndrome. Our data show that cytokine -mediated subclinical inflammation is independently associated with decreased insulin sensitivity also in apparently metabolically healthy normal weight individuals, indicating that the interplay between inflammatory processes and insulin resistance is present already in the early stages of the development of glucometabolic disease.
PMCID: PMC3113503  PMID: 21686140
Euglycemic insulin clamp; insulin sensitivity; inflammation; cytokines; metabolic syndrome; diabetes
22.  New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk 
Dupuis, Josée | Langenberg, Claudia | Prokopenko, Inga | Saxena, Richa | Soranzo, Nicole | Jackson, Anne U | Wheeler, Eleanor | Glazer, Nicole L | Bouatia-Naji, Nabila | Gloyn, Anna L | Lindgren, Cecilia M | Mägi, Reedik | Morris, Andrew P | Randall, Joshua | Johnson, Toby | Elliott, Paul | Rybin, Denis | Thorleifsson, Gudmar | Steinthorsdottir, Valgerdur | Henneman, Peter | Grallert, Harald | Dehghan, Abbas | Hottenga, Jouke Jan | Franklin, Christopher S | Navarro, Pau | Song, Kijoung | Goel, Anuj | Perry, John R B | Egan, Josephine M | Lajunen, Taina | Grarup, Niels | Sparsø, Thomas | Doney, Alex | Voight, Benjamin F | Stringham, Heather M | Li, Man | Kanoni, Stavroula | Shrader, Peter | Cavalcanti-Proença, Christine | Kumari, Meena | Qi, Lu | Timpson, Nicholas J | Gieger, Christian | Zabena, Carina | Rocheleau, Ghislain | Ingelsson, Erik | An, Ping | O’Connell, Jeffrey | Luan, Jian'an | Elliott, Amanda | McCarroll, Steven A | Payne, Felicity | Roccasecca, Rosa Maria | Pattou, François | Sethupathy, Praveen | Ardlie, Kristin | Ariyurek, Yavuz | Balkau, Beverley | Barter, Philip | Beilby, John P | Ben-Shlomo, Yoav | Benediktsson, Rafn | Bennett, Amanda J | Bergmann, Sven | Bochud, Murielle | Boerwinkle, Eric | Bonnefond, Amélie | Bonnycastle, Lori L | Borch-Johnsen, Knut | Böttcher, Yvonne | Brunner, Eric | Bumpstead, Suzannah J | Charpentier, Guillaume | Chen, Yii-Der Ida | Chines, Peter | Clarke, Robert | Coin, Lachlan J M | Cooper, Matthew N | Cornelis, Marilyn | Crawford, Gabe | Crisponi, Laura | Day, Ian N M | de Geus, Eco | Delplanque, Jerome | Dina, Christian | Erdos, Michael R | Fedson, Annette C | Fischer-Rosinsky, Antje | Forouhi, Nita G | Fox, Caroline S | Frants, Rune | Franzosi, Maria Grazia | Galan, Pilar | Goodarzi, Mark O | Graessler, Jürgen | Groves, Christopher J | Grundy, Scott | Gwilliam, Rhian | Gyllensten, Ulf | Hadjadj, Samy | Hallmans, Göran | Hammond, Naomi | Han, Xijing | Hartikainen, Anna-Liisa | Hassanali, Neelam | Hayward, Caroline | Heath, Simon C | Hercberg, Serge | Herder, Christian | Hicks, Andrew A | Hillman, David R | Hingorani, Aroon D | Hofman, Albert | Hui, Jennie | Hung, Joe | Isomaa, Bo | Johnson, Paul R V | Jørgensen, Torben | Jula, Antti | Kaakinen, Marika | Kaprio, Jaakko | Kesaniemi, Y Antero | Kivimaki, Mika | Knight, Beatrice | Koskinen, Seppo | Kovacs, Peter | Kyvik, Kirsten Ohm | Lathrop, G Mark | Lawlor, Debbie A | Le Bacquer, Olivier | Lecoeur, Cécile | Li, Yun | Lyssenko, Valeriya | Mahley, Robert | Mangino, Massimo | Manning, Alisa K | Martínez-Larrad, María Teresa | McAteer, Jarred B | McCulloch, Laura J | McPherson, Ruth | Meisinger, Christa | Melzer, David | Meyre, David | Mitchell, Braxton D | Morken, Mario A | Mukherjee, Sutapa | Naitza, Silvia | Narisu, Narisu | Neville, Matthew J | Oostra, Ben A | Orrù, Marco | Pakyz, Ruth | Palmer, Colin N A | Paolisso, Giuseppe | Pattaro, Cristian | Pearson, Daniel | Peden, John F | Pedersen, Nancy L. | Perola, Markus | Pfeiffer, Andreas F H | Pichler, Irene | Polasek, Ozren | Posthuma, Danielle | Potter, Simon C | Pouta, Anneli | Province, Michael A | Psaty, Bruce M | Rathmann, Wolfgang | Rayner, Nigel W | Rice, Kenneth | Ripatti, Samuli | Rivadeneira, Fernando | Roden, Michael | Rolandsson, Olov | Sandbaek, Annelli | Sandhu, Manjinder | Sanna, Serena | Sayer, Avan Aihie | Scheet, Paul | Scott, Laura J | Seedorf, Udo | Sharp, Stephen J | Shields, Beverley | Sigurðsson, Gunnar | Sijbrands, Erik J G | Silveira, Angela | Simpson, Laila | Singleton, Andrew | Smith, Nicholas L | Sovio, Ulla | Swift, Amy | Syddall, Holly | Syvänen, Ann-Christine | Tanaka, Toshiko | Thorand, Barbara | Tichet, Jean | Tönjes, Anke | Tuomi, Tiinamaija | Uitterlinden, André G | van Dijk, Ko Willems | van Hoek, Mandy | Varma, Dhiraj | Visvikis-Siest, Sophie | Vitart, Veronique | Vogelzangs, Nicole | Waeber, Gérard | Wagner, Peter J | Walley, Andrew | Walters, G Bragi | Ward, Kim L | Watkins, Hugh | Weedon, Michael N | Wild, Sarah H | Willemsen, Gonneke | Witteman, Jaqueline C M | Yarnell, John W G | Zeggini, Eleftheria | Zelenika, Diana | Zethelius, Björn | Zhai, Guangju | Zhao, Jing Hua | Zillikens, M Carola | Borecki, Ingrid B | Loos, Ruth J F | Meneton, Pierre | Magnusson, Patrik K E | Nathan, David M | Williams, Gordon H | Hattersley, Andrew T | Silander, Kaisa | Salomaa, Veikko | Smith, George Davey | Bornstein, Stefan R | Schwarz, Peter | Spranger, Joachim | Karpe, Fredrik | Shuldiner, Alan R | Cooper, Cyrus | Dedoussis, George V | Serrano-Ríos, Manuel | Morris, Andrew D | Lind, Lars | Palmer, Lyle J | Hu, Frank B. | Franks, Paul W | Ebrahim, Shah | Marmot, Michael | Kao, W H Linda | Pankow, James S | Sampson, Michael J | Kuusisto, Johanna | Laakso, Markku | Hansen, Torben | Pedersen, Oluf | Pramstaller, Peter Paul | Wichmann, H Erich | Illig, Thomas | Rudan, Igor | Wright, Alan F | Stumvoll, Michael | Campbell, Harry | Wilson, James F | Hamsten, Anders | Bergman, Richard N | Buchanan, Thomas A | Collins, Francis S | Mohlke, Karen L | Tuomilehto, Jaakko | Valle, Timo T | Altshuler, David | Rotter, Jerome I | Siscovick, David S | Penninx, Brenda W J H | Boomsma, Dorret | Deloukas, Panos | Spector, Timothy D | Frayling, Timothy M | Ferrucci, Luigi | Kong, Augustine | Thorsteinsdottir, Unnur | Stefansson, Kari | van Duijn, Cornelia M | Aulchenko, Yurii S | Cao, Antonio | Scuteri, Angelo | Schlessinger, David | Uda, Manuela | Ruokonen, Aimo | Jarvelin, Marjo-Riitta | Waterworth, Dawn M | Vollenweider, Peter | Peltonen, Leena | Mooser, Vincent | Abecasis, Goncalo R | Wareham, Nicholas J | Sladek, Robert | Froguel, Philippe | Watanabe, Richard M | Meigs, James B | Groop, Leif | Boehnke, Michael | McCarthy, Mark I | Florez, Jose C | Barroso, Inês
Nature genetics  2010;42(2):105-116.
Circulating glucose levels are tightly regulated. To identify novel glycemic loci, we performed meta-analyses of 21 genome-wide associations studies informative for fasting glucose (FG), fasting insulin (FI) and indices of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 non-diabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with FG/HOMA-B and two associated with FI/HOMA-IR. These include nine new FG loci (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and FAM148B) and one influencing FI/HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB/TMEM195 with type 2 diabetes (T2D). Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify T2D risk loci, as well as loci that elevate FG modestly, but do not cause overt diabetes.
PMCID: PMC3018764  PMID: 20081858
23.  Persistent ischaemic ECG abnormalities on repeated ECG examination have important prognostic value for cardiovascular disease beyond established risk factors: a population‐based study in middle‐aged men with up to 32 years of follow‐up 
Heart  2007;93(9):1104-1110.
To determine the effect of new, persistent or reverted ischaemic ECG abnormalities at ages 50 and 70 years on the risk of subsequent cardiovascular disease.
Design, setting and participants
A prospective community‐based observational cohort of 50‐year‐old men in Sweden, followed for 32 years. 2322 men of age 50 years participated in 1970–3, and 1221 subjects were re‐examined at the age of 70 years.
Main outcome measures
Myocardial infarction (MI), cardiovascular mortality and overall mortality.
At 50 years of age, after adjusting for established conventional risk factors, T wave abnormalities, ST segment depression, major Q/QS pattern and ECG‐left ventricular hypertrophy were all found to be independent risk factors for the main outcome measures during the 32 years of follow‐up. When ECG variables were re‐measured at 70 years of age, they were still found to be independent risk factors for the mortality outcomes, but lost in significance for prediction of MI. Regarding mortality, it was twice as dangerous to have persistent T wave abnormalities (HR 4.63; 95% CI 2.18 to 9.83) or ST segment depression (HR 5.66; 95% CI 1.77 to 18.1), as with new T wave abnormalities (HR 2.20; 95% CI 1.48 to 3.29) or ST segment depression (HR 2.55; 95% CI 1.74 to 3.75), developing between ages 50 and 70 years. The addition of “ECG indicating ischaemia” significantly increased the predictive power of the Framingham score (p<0.001).
It is worthwhile to obtain serial ECGs for proper risk assessment, since persistent ST‐T abnormalities carried twice as high a risk for future mortality compared with new or reverted abnormalities.
PMCID: PMC1955011  PMID: 17483125
24.  Age and follow‐up time affect the prognostic value of the ECG and conventional cardiovascular risk factors for stroke in adult men 
To explore whether the predictive power of mid‐life ECG abnormalities and conventional cardiovascular risk factors for future stroke change over a 30‐year follow‐up period, and whether a repeated examination improves their predictive power.
Design and setting
Longitudinal population‐based study.
2322 men aged 50 years, with a follow‐up period of 30 years. 1221 subjects were re‐examined at age 70 years
Main outcome measure
Risk for fatal and non‐fatal stroke during three decades of follow‐up. Investigations included resting ECG and traditional cardiovascular risk factors.
When measured at age 50 years, ST segment depression and T wave abnormalities, together with ECG‐left ventricular hypertrophy, were of importance only during the first 20 years, but regained importance when re‐measured at age 70 years. Blood pressure was a significant predictor for stroke over all three decades of follow‐up. In elderly people only, there is evidence that apolipoprotein A1 may protect from future stroke.
Mid‐life values for blood pressure and ECG abnormalities retain their predictive value over long follow‐up periods even though they improved in predictive power when re‐measured in elderly people. Despite lower prevalence, ECG abnormalities had greater impact at age 50 years than at age 70 years. By contrast, apolipoprotein A1 was protective for future stroke only at age 70 years.
PMCID: PMC2652998  PMID: 17630370
25.  Hyperglycemia and Stroke Mortality 
Diabetes Care  2009;32(2):348-354.
OBJECTIVE—We investigated stroke mortality in individuals in different categories of glycemia and compared hazard ratios (HRs) corresponding to a 1-SD increase in 2-h plasma glucose and fasting plasma glucose (FPG) criteria.
RESEARCH DESIGN AND METHODS—We examined data from 2-h 75-g oral glucose tolerance tests taken from 13 European cohorts comprising 11,844 (55%) men and 9,862 (45%) women who were followed up for a median of 10.5 years. A multivariate adjusted Cox proportional hazards model was used to estimate HRs for stroke mortality.
RESULTS—In men and women without a prior history of diabetes, multivariate adjusted HRs for stroke mortality corresponding to a 1-SD increase in FPG were 1.02 (95% CI 0.83–1.25) and 1.52 (1.22–1.88) and those in 2-h plasma glucose 1.21 (1.06–1.38) and 1.31 (1.06–1.61), respectively. Addition of 2-h plasma glucose to the model with FPG significantly improved prediction of stroke mortality in men (χ2 = 10.12; P = 0.001) but not in women (χ2 = 0.01; P = 0.94), whereas addition of FPG to 2-h plasma glucose improved stroke mortality in women (χ2 = 4.08; P = 0.04) but not in men (χ2 = 3.29; P = 0.07).
CONCLUSIONS—Diabetes defined by either FPG or 2-h plasma glucose increases the risk of stroke mortality. In individuals without a history of diabetes, elevated 2-h postchallenge glucose is a better predictor than elevated fasting glucose in men, whereas the latter is better than the former in women.
PMCID: PMC2628706  PMID: 19017775

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