Subsequent fracture risk in Norwegians and immigrants with an index forearm fracture: a cohort study.

The current study investigated subsequent fracture risk following a forearm fracture in three country of birth categories: Norway, Europe and North America, and other countries. Subsequent fracture risk was modestly higher in Norwegian-born individuals compared to the two other groups. Secondary fracture prevention should be recommended regardless of country background. BACKGROUND: Fracture risk is higher in patients with a previous fracture, but whether subsequent fracture risk differs by origin of birth is unknown. This study explores subsequent fracture risk in patients with an index forearm fracture according to region of birth. METHODS: Nationwide data on forearm fractures in patients ≥ 18 years in 2008-2019 were obtained from the Norwegian Patient Registry and Statistics Norway. Index fractures were identified by ICD-10 code S52, whereas subsequent fractures included any ICD-10 fracture code. Data on country of birth were from Statistics Norway and included three regional categories: (1) Norway, (2) other Europe and North America and (3) other countries. Direct age standardization and Cox proportional hazard regression were used to analyse the data. RESULTS: Among 143,476 individuals with an index forearm fracture, 35,361 sustained a subsequent fracture. Norwegian-born forearm fracture patients had the highest subsequent fracture rates (516/10,000 person-years in women and 380 in men). People born outside Europe and North America had the lowest rates (278/10,000 person-years in women and 286 in men). Compared to Norwegian-born individuals, the hazard ratios (HRs) of subsequent fracture in individuals from Europe and North American were 0.93 (95% CI 0.88-0.98) in women and 0.85 (95% CI 0.79-0.92) in men. The corresponding HRs in individuals from other countries were 0.76 (95% CI 0.70-0.84) in women and 0.82 (95% CI 0.74-0.92) in men. CONCLUSION: Individuals born outside Norway had a lower subsequent fracture risk than Norwegian-born individuals; however, subsequent fracture risk increased with age in all groups. Our results indicate that secondary fracture prevention should be recommended regardless of region of origin.

Epidemiology of forearm fractures in women and men in Norway 2008-2019.

The purpose of this paper is to describe rates of forearm fractures in adults in Norway 2008-2019. Incidence rate of distal forearm fractures declined over time in both sexes. Forearm fracture constitute a significant health burden and prevention strategies are needed. PURPOSE: To assess age- and sex-specific incidence rates, and time trends for forearm fractures in Norway, and compare these with incidence rates in other Nordic countries. METHODS: Data on all patients aged 20-107 years with forearm fractures treated in Norwegian hospitals from 2008 to 2019 was retrieved from the Norwegian Patient Registry. Fractures were identified based on International Classification of Disease 10th revision code S52. Age- and sex-specific incidence rates and changes in incidence rates were calculated. RESULTS: We identified 181,784 forearm fractures in 45,628,418 person-years. Mean annual forearm fracture incidence rates per 100,000 person-years were 398 (95% CI 390-407) for all, 565 (95% CI 550-580) for women, and 231 (95% CI 228-234) for men above 20 years. Mean annual number of forearm fractures was 15,148 (95% CI 14,575-15,722). From 2008 to 2019, age-adjusted total incidence rates of forearm fractures S52 diagnoses declined by 3.5% (incidence rate ratio (IRR) of 0.997 (95% CI 0.994-0.999)) in men. The corresponding decline in women was not significant (IRR: 0.999 (95% CI 0.997-1.002)). In the same period, the age-adjusted incidence rates of distal forearm fractures declined by 7.0% in men (IRR = 0.930; 95% CI 0.886-0.965) and 4.7% in women (IRR = 0.953; 95% CI 0.919-0.976). The incidence rates of distal forearm fractures were similar to rates in Sweden and Finland. CONCLUSION: Age-adjusted incidence rates of distal forearm fractures in both sexes declined over time.

Liraglutide treatment for the prevention of glucose tolerance deterioration in women with prior gestational diabetes mellitus: A 52-week randomized controlled clinical trial.

AIM: We investigated the effect of 52-week treatment with liraglutide, a glucagon-like peptide 1 receptor agonist, on glucose tolerance and incretin effect in women with previous gestational diabetes mellitus (pGDM). MATERIALS AND METHODS: Women with overweight/obesity and pGDM were randomized to once daily subcutaneous liraglutide 1.8 mg or placebo for 52 weeks. Participants underwent oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion at baseline and at 52 weeks, and an additional OGTT after the drug wash-out. RESULTS: In total, 104 women [age: mean ± SD, 38 ± 5 years; fasting plasma glucose (FPG): 5.5 ± 0.4 mmol/L; glycated haemoglobin (HbA1c): 33 ± 4 mmol/mol, bodyweight: 88.2 ± 14.8 kg, body mass index: 31.1 ± 4.3 kg/m2 ] were assigned to liraglutide (n = 49) or placebo (n = 55). Estimated treatment difference (ETD) for area under curve during OGTT was -173 (95% confidence interval -250 to -97) mmol/L × min, p < .0001, but after wash-out the difference disappeared [ETD 58 (-30 to 146) mmol/L × min, p = .536]. Liraglutide reduced FPG [ETD -0.2 (-0.4 to -0.1) mmol/L, p = .018], HbA1c [-2.2 (-3.5 to -0.8) mmol/mol, p = .018] and bodyweight [-3.9 (-6.2 to -1.6) kg, p = .012]. No change in the incretin effect was observed. The number of women with prediabetes was reduced from 64% to 10% with liraglutide vs. 50% with placebo [adjusted odds ratio 0.10 (0.03-0.32), p = .002]. CONCLUSIONS: Treatment with liraglutide for 52 weeks improved glucose tolerance, FPG, HbA1c and bodyweight in women with overweight/obesity and pGDM. Progression to prediabetes while on drug was markedly reduced, but after a 1-week drug wash-out, the effect was lost.

Validation of forearm fracture diagnoses in administrative patient registers.

The validity of forearm fracture diagnoses recorded in five Norwegian hospitals was investigated using image reports and medical records as gold standard. A relatively high completeness and correctness of the diagnoses was found. Algorithms used to define forearm fractures in administrative data should depend on study purpose. PURPOSE: In Norway, forearm fractures are routinely recorded in the Norwegian Patient Registry (NPR). However, these data have not been validated. Data from patient administrative systems (PAS) at hospitals are sent unabridged to NPR. By using data from PAS, we aimed to examine (1) the validity of the forearm fracture diagnoses and (2) the usefulness of washout periods, follow-up codes, and procedure codes to define incident forearm fracture cases. METHODS: This hospital-based validation study included women and men aged ≥ 19 years referred to five hospitals for treatment of a forearm fracture during selected periods in 2015. Administrative data for the ICD-10 forearm fracture code S52 (with all subgroups) in PAS and the medical records were reviewed. X-ray and computed tomography (CT) reports from examinations of forearms were reviewed independently and linked to the data from PAS. Sensitivity and positive predictive values (PPVs) were calculated using image reports and/or review of medical records as gold standard. RESULTS: Among the 8482 reviewed image reports and medical records, 624 patients were identified with an incident forearm fracture during the study period. The sensitivity of PAS registrations was 90.4% (95% CI: 87.8-92.6). The PPV increased from 73.9% (95% CI: 70.6-77.0) in crude data to 90.5% (95% CI: 88.0-92.7) when using a washout period of 6 months. Using procedure codes and follow-up codes in addition to 6-months washout increased the PPV to 94.0%, but the sensitivity fell to 69.0%. CONCLUSION: A relatively high sensitivity of forearm fracture diagnoses was found in PAS. PPV varied depending on the algorithms used to define cases. Choice of algorithm should therefore depend on study purposes. The results give useful measures of forearm fracture diagnoses from administrative patient registers. Depending on local coding practices and treatment pathways, we infer that the findings are relevant to other fracture diagnoses and registers.

Cortical bone structure of the proximal femur and incident fractures.

PURPOSE: Fracture risk is most frequently assessed using Dual X-ray absorptiometry to measure areal bone mineral density (aBMD) and using the Fracture Risk Assessment Tool (FRAX). However, these approaches have limitations and additional bone measurements may enhance the predictive ability of these existing tools. Increased cortical porosity has been associated with incident fracture in some studies, but not in others. In this prospective study, we examined whether cortical bone structure of the proximal femur predicts incident fractures independent of aBMD and FRAX score. METHODS: We pooled 211 postmenopausal women with fractures aged 54-94 years at baseline and 232 fracture-free age-matched controls based on a prior nested case-control study from the Tromsø Study in Norway. We assessed baseline femoral neck (FN) aBMD, calculated FRAX 10-year probability of major osteoporotic fracture (MOF), and quantified femoral subtrochanteric cortical parameters: porosity, area, thickness, and volumetric BMD (vBMD) from CT images using the StrAx1.0 software. Associations between bone parameters and any incident fracture, MOF and hip fracture were determined using Cox's proportional hazard models to calculate hazard ratio (HR) with 95% confidence interval. RESULTS: During a median follow-up of 7.2 years, 114 (25.7%) of 443 women suffered one or more incident fracture. Cortical bone structure did not predict any incident fracture or MOF after adjustment for age, BMI, and previous fracture. Each SD higher total cortical porosity, thinner cortices, and lower cortical vBMD predicted hip fracture with increased risk of 46-62% (HRs ranging from 1.46 (1.01-2.11) to 1.62 (1.02-2.57)). After adjustment for FN aBMD or FRAX score no association remained significant. Both lower FN aBMD and higher FRAX score predicted any incident fracture, MOF and hip fractures with HRs ranging from 1.45-2.56. CONCLUSIONS: This study showed that cortical bone measurements using clinical CT did not add substantial insight into fracture risk beyond FN aBMD and FRAX. We infer from these results that fracture risk related to the deteriorated bone structure seems to be largely captured by a measurement of FN aBMD and the FRAX tool.

Estimated Glomerular Filtration Rate (eGFR) based on cystatin C was associated with increased risk of hip and proximal humerus fractures in women and decreased risk of hip fracture in men, whereas eGFR based on creatinine was not associated with fracture risk in both sexes: The Tromsø Study.

PURPOSE: Patients with end-stage kidney disease have an increased fracture risk. Whether mild to moderate reductions in kidney function is associated with increased fracture risk is uncertain. Results from previous studies may be confounded by muscle mass because of the use of creatinine-based estimates of the glomerular filtration rate (eGFRcre). We tested the hypothesis that lower eGFR within the normal range of kidney function based on serum cystatin C (eGFRcys) or both cystatin C and creatinine (eGFRcrecys) predict fractures better than eGFR based on creatinine (eGFRcre). METHODS: In the Tromsø Study 1994-95, a cohort of 3016 women and 2836 men aged 50-84 years had eGFRcre, eGFRcys and eGFRcrecys estimated using the Chronic Kidney Disease Epidemiology Collaboration equations. Hazard ratios (HRs) (95% confidence intervals) for fracture were calculated in Cox's proportional hazards models and adjusted for age, height, body mass index, bone mineral density, diastolic blood pressure, smoking, physical activity, previous fracture, diabetes and cardiovascular disease. RESULTS: During a median of 14.6 years follow-up, 232, 135 and 394 women and 118, 35 and 65 men suffered incident hip, proximal humerus and wrist fractures. In women, lower eGFRcre did not predict fracture, but the risk for hip and proximal humerus fracture increased per standard deviation (SD) lower eGFRcys (HRs 1.36 (1.16-1.60) and 1.33 (1.08-1.63)) and per SD lower eGFRcrecys (HRs 1.25 (1.08-1.45) and 1.30 (1.07-1.57)). In men, none of the eGFR estimates were related to increased fracture risk. In contrast, eGFRcys and eGFRcrecys were inversely associated with hip fracture risk (HRs 0.85 (0.73-0.99) and 0.82 (0.68-0.98)). CONCLUSIONS: In women, each SD lower eGFRcys and eGFRcrecys increased the risk of hip and proximal humerus fracture by 25-36%, whereas eGFRcre did not. In men, none of the estimates of eGFR were related to increased fracture risk, and each SD lower eGFRcys and eGFRcrecys decreased the risk of hip fracture by 15-18%. The findings particularly apply to a cohort of generally healthy individuals with a normal kidney function. In future studies, the association of measured GFR using the gold standard method of iohexol clearance with fractures risk should be examined for causal inference. More clinical research is needed before robust clinical inferences can be made.

One Year's Treatment with the Glucagon-Like Peptide 1 Receptor Agonist Liraglutide Decreases Hepatic Fat Content in Women with Nonalcoholic Fatty Liver Disease and Prior Gestational Diabetes Mellitus in a Randomized, Placebo-Controlled Trial.

Prior gestational diabetes mellitus (pGDM) is associated with increased risk of nonalcoholic fatty liver disease (NAFLD). Treatment with glucagon-like peptide 1 (GLP-1) receptor agonists has shown beneficial effects in NAFLD patients. We evaluated the effect of the GLP-1 analogue liraglutide on NAFLD features in women with pGDM. Eighty-two overweight/obese, nondiabetic women with pGDM were included. We performed abdominal ultrasound, transient elastography with controlled attenuation parameter (CAP), and blood sampling at baseline and after 1 year. Thirty-seven women were randomized to liraglutide (1.8 mg once-daily) and 45 to placebo. Based on the ultrasound scan, 18 women (22%) had ultrasound-verified NAFLD at baseline and of these, 10 (56%) received liraglutide treatment. After 1 year, eight participants no longer had steatosis, four in each treatment group. The number of participants who developed NAFLD was similar in the two treatment groups; five in the liraglutide group and six in the placebo group (p = 0.74). Compared to placebo, liraglutide reduced the CAP-assessed intrahepatic fat content (-28 (-44;-11) vs. 2 (-13;18) dB/m, p < 0.01) and body weight (-4.7 (-6.4;-2.9) vs. -1.4 (-3;0.3) kg, p < 0.01). One-year's liraglutide treatment had no effect on the presence of ultrasound-diagnosed NAFLD in overweight/obese nondiabetic women with pGDM, but reduced body weight and steatosis assessed by transient elastography with CAP.

Prevalence of gestational diabetes and pregnancy outcomes in Nordland and Troms counties 2004­15. / Prevalens av diabetes blant gravide og svangerskapsutfall i Nordland og Troms 2004­15.

BACKGROUND: The aim was to investigate the prevalence of gestational diabetes and pregnancy outcomes in women with gestational diabetes in Nordland and Troms counties. MATERIAL AND METHOD: We included all 1 067 women with type 1 diabetes, type 2 diabetes and gestational diabetes among 34 915 births at four hospitals in Nordland and Troms counties from 2004 to 2015. Prevalence of diabetes was calculated based on ICD-10 codes in patient records for women with diabetes in Nordland and Troms counties, and compared with national prevalence figures from the Medical Birth Registry of Norway. Prevalence of pre-eclampsia, macrosomia (birth weight > 4 500 grams) and caesarian section was calculated for all women with diabetes and all those giving birth in the same region. RESULTS: Prevalence of type 1 diabetes and type 2 diabetes remained stable. Prevalence of gestational diabetes increased from 1.0 % to 4.0 % in Nordland and Troms counties and from 1.0 % to 3.8 % nationally. Prevalence of pre-eclampsia among all women with diabetes fell from 18.8 % in 2004-06 to 12.4 % in 2013-15. In women with diabetes, the prevalence of pre-eclampsia was 4.6 times higher, that of macrosomia was 3.5 times higher, and the proportion of caesarian sections was 2.3 times higher than in the background population. INTERPRETATION: Prevalence of gestational diabetes increased in Nordland and Troms counties, as it did nationally. Prevalence of pre-eclampsia among pregnant women with diabetes fell, but prevalence of pre-eclampsia, macrosomia and caesarean section was higher than in the background population.

Post-fracture Risk Assessment: Target the Centrally Sited Fractures First! A Substudy of NoFRACT.

The location of osteoporotic fragility fractures adds crucial information to post-fracture risk estimation. Triaging patients according to fracture site for secondary fracture prevention can therefore be of interest to prioritize patients considering the high imminent fracture risk. The objectives of this cross-sectional study were therefore to explore potential differences between central (vertebral, hip, proximal humerus, pelvis) and peripheral (forearm, ankle, other) fractures. This substudy of the Norwegian Capture the Fracture Initiative (NoFRACT) included 495 women and 119 men ≥50 years with fragility fractures. They had bone mineral density (BMD) of the femoral neck, total hip, and lumbar spine assessed using dual-energy X-ray absorptiometry (DXA), trabecular bone score (TBS) calculated, concomitantly vertebral fracture assessment (VFA) with semiquantitative grading of vertebral fractures (SQ1-SQ3), and a questionnaire concerning risk factors for fractures was answered. Patients with central fractures exhibited lower BMD of the femoral neck (765 versus 827 mg/cm2 ), total hip (800 versus 876 mg/cm2 ), and lumbar spine (1024 versus 1062 mg/cm2 ); lower mean TBS (1.24 versus 1.28); and a higher proportion of SQ1-SQ3 fractures (52.0% versus 27.7%), SQ2-SQ3 fractures (36.8% versus 13.4%), and SQ3 fractures (21.5% versus 2.2%) than patients with peripheral fractures (all p < 0.05). All analyses were adjusted for sex, age, and body mass index (BMI); and the analyses of TBS and SQ1-SQ3 fracture prevalence was additionally adjusted for BMD). In conclusion, patients with central fragility fractures revealed lower femoral neck BMD, lower TBS, and higher prevalence of vertebral fractures on VFA than the patients with peripheral fractures. This suggests that patients with central fragility fractures exhibit more severe deterioration of bone structure, translating into a higher risk of subsequent fragility fractures and therefore they should get the highest priority in secondary fracture prevention, although attention to peripheral fractures should still not be diminished. © 2019 American Society for Bone and Mineral Research. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

High prevalence of vertebral fractures and low trabecular bone score in patients with fragility fractures: A cross-sectional sub-study of NoFRACT.

PURPOSE: Norway has among the highest incidence rates of fractures in the world. Vertebral fracture assessment (VFA) and trabecular bone score (TBS) provide information about fracture risk, but their importance have not been studied in Norwegian patients with fragility fractures. The objectives of this study were to examine the clinical characteristics of a cohort of women and men with fragility fractures, their prevalence of vertebral fractures using VFA and prevalence of low TBS, and explore the differences between the sexes and patients with and without vertebral fractures. METHODS: This cross-sectional sub-study of the Norwegian Capture the Fracture Initiative (NoFRACT) included 839 patients with fragility fractures. Of these, 804 patients had bone mineral density (BMD) of the total hip, femoral neck and/or spine assessed using dual energy x-ray absorptiometry, 679 underwent concomitant VFA, 771 had TBS calculated and 696 responded to a questionnaire. RESULTS: Mean age was 65.8 (SD 8.8) years and 80.5% were women. VFA revealed vertebral fractures in 34.8% of the patients and 34.0% had low TBS (≤ 1.23), with no differences between the sexes. In all patients with valid measures of both VFA and TBS, 53.8% had either vertebral fractures, low TBS, or both. In the patients with osteopenia at the femoral neck, 53.6% had either vertebral fractures, low TBS, or both. Femoral neck BMD T-score ≤ -2.5 was found in 13.8% of all patients, whereas the corresponding figure was 27.4% using the skeletal site with lowest T-score. Women exhibited lower BMD at all sites and lower TBS than men (1.27 vs. 1.29), (all p < 0.05). Patients with prevalent vertebral fractures were older (69.4 vs. 64.0 years), exhibited lower BMD at all sites and lower TBS (1.25 vs.1.29) than those without vertebral fractures (all p < 0.05). Before assessment, 8.2% were taking anti-osteoporotic drugs (AOD), and after assessment, the prescription rate increased to 56.2%. CONCLUSIONS: More than half of the patients with fragility fractures had vertebral fractures, low TBS or both. The prescription of AOD increased seven fold from before assessment to after assessment, emphasizing the importance of risk assessment after a fragility fracture.

Is glucagon-like peptide-1 fully protected by the dipeptidyl peptidase 4 inhibitor sitagliptin when administered to patients with type 2 diabetes?

AIM: To evaluate the relationship between plasma dipeptidyl-peptidase 4 (DPP-4) activity and its protection of glucagon-like peptide-1 (GLP-1) using the DPP-4 inhibitor sitagliptin. METHODS: On four separate days, patients with type 2 diabetes (T2D) (n = 8; age: 59.9 ±10.8 [mean ±SD] years; body mass index [BMI]: 28.8 ±4.6 kg/m2 ; glycated haemoglobin A1c [HbA1c]: 43.1 ±0.5 mmol/mol [6.6% ±1.7%]) received a 380-minute continuous intravenous infusion of GLP-1 (1.0 pmol × kg bodyweight-1 × minutes-1 ) and a double-blind, single-dose oral administration of sitagliptin in doses of 0 (placebo), 25, 100 and 200 mg. RESULTS: Plasma DPP-4 activity decreased compared to baseline (placebo) with increasing doses of sitagliptin (P < .01), reaching a maximal inhibition with the 100 mg dose. Levels of intact GLP-1 increased with increasing doses of sitagliptin from placebo to 100 mg (area under curve [AUC] 7.2 [95%, CI; 12.1, 16.4] [placebo], 10.7 [16.1, 21.4] [25 mg], 11.7 [17.8, 23.6] [100 mg] nmol/L × 360 minutes [P < .01]), but no further increase in intact GLP-1 levels was observed with 200 mg of sitagliptin (11.5 [17.6, 23.4] nmol/L × 360 minutes) (P = .80). CONCLUSION: Our findings suggest that the sitagliptin dose of 100 mg is sufficient to inhibit both plasma and membrane-bound DPP-4 activity, presumably also leading to complete protection of endogenous GLP-1 in patients with T2D.

Effect of a Fracture Liaison Service on the Rate of Subsequent Fracture Among Patients With a Fragility Fracture in the Norwegian Capture the Fracture Initiative (NoFRACT): A Trial Protocol.

Importance: Fragility fracture is a major health issue because of the accompanying morbidity, mortality, and financial cost. Despite the high cost to society and personal cost to affected individuals, secondary fracture prevention is suboptimal in Norway, mainly because most patients with osteoporotic fractures do not receive treatment with antiosteoporotic drugs after fracture repair. Objectives: To improve secondary fracture prevention by introducing a standardized intervention program and to investigate the effect of the program on the rate of subsequent fractures. Design, Setting, and Participants: Trial protocol of the Norwegian Capture the Fracture Initiative (NoFRACT), an ongoing, stepped wedge cluster randomized clinical trial in 7 hospitals in Norway. The participating hospitals were cluster randomized to an intervention starting date: May 1, 2015; September 1, 2015; and January 1, 2016. Follow-up is through December 31, 2019. The outcome data were merged from national registries of women and men 50 years and older with a recent fragility fracture treated at 1 of the 7 hospitals. Discussion: The NoFRACT trial is intended to enroll 82 000 patients (intervention period, 26 000 patients; control period, 56 000 patients), of whom 23 578 are currently enrolled by January 2018. Interventions include a standardized program for identification, assessment, and treatment of osteoporosis in patients with a fragility fracture that is led by a trained coordinating nurse. The primary outcome is rate of subsequent fracture (per 10 000 person-years) based on national registry data. Outcomes before (2008-2015; control period) and after (2015-2019; intervention period) the intervention will be compared, and each hospital will act as its own control. Use of outcomes from national registry data means that all patients are included in the analysis regardless of whether they are exposed to the intervention (intention to treat). A sensitivity analysis with a transition window will be performed to mitigate possible within-cluster contamination. Results: Results are planned to be disseminated through publications in peer-reviewed journals and presented at local, national, and international conferences. Conclusions: By introducing a standardized intervention program for assessment and treatment of osteoporosis in patients with fragility fractures, we expect to document reduced rates of subsequent fractures and fracture-related mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT02536898.

Women with prior gestational diabetes mellitus and prediabetes are characterised by a decreased incretin effect.

AIMS/HYPOTHESIS: We investigated whether a reduced incretin effect, as observed in patients with type 2 diabetes, can be detected in high-risk individuals, such as women with prior gestational diabetes mellitus (pGDM). METHODS: In this cross-sectional study, 102 women without diabetes with pGDM and 15 control participants without pGDM and with normal glucose tolerance (NGT) underwent a 4 h 75 g OGTT and an isoglycaemic i.v. glucose infusion (IIGI). Women with pGDM were classified as having NGT or prediabetes (impaired fasting glucose and/or impaired glucose tolerance). Insulin sensitivity was assessed using the Matsuda index and HOMA2-IR and the incretin effect was calculated from insulin responses during the study (100% × [AUCinsulin,OGTT - AUCinsulin,IIGI]/AUCinsulin,OGTT). RESULTS: Sixty-three of the 102 women with pGDM (62%) had prediabetes (median [interquartile range]: age, 38.3 [6.5] years; BMI, 32.1 [5.8] kg/m2) and 39 women (38%) had NGT (age, 39.5 [5.6] years; BMI, 31.0 [6.7] kg/m2). Control participants (n = 15) were not significantly different from the pGDM group with regards to age (39.2 [7.4] years) and BMI (28.8 [9.2] kg/m2). Compared with women with NGT and control participants, women with prediabetes had lower insulin sensitivity, as measured by the Matsuda index (3.0 [2.4] vs 5.0 [2.6] vs 1.5 [1.8], respectively; p < 0.001). The incretin effect was 55.3% [27.8], 73.8% [19.0] and 76.7% [24.6] in women with prediabetes, women with normal glucose tolerance and control participants, respectively (p < 0.01). CONCLUSION/INTERPRETATION: Prediabetes was highly prevalent in women with pGDM, and alterations in the incretin effect were detected in this group before the development of type 2 diabetes. TRIAL REGISTRATION: clinicaltrialsregister.eu 2012-001371-37-DK.

Nonalcoholic Fatty Liver Disease Is Prevalent in Women With Prior Gestational Diabetes Mellitus and Independently Associated With Insulin Resistance and Waist Circumference.

OBJECTIVE: Type 2 diabetes increases the risk of nonalcoholic fatty liver disease (NAFLD), which is a potentially reversible condition but is also associated with progressive fibrosis and cirrhosis. Women with prior gestational diabetes mellitus (pGDM) have a higher risk for NAFLD. RESEARCH DESIGN AND METHODS: One hundred women without diabetes who had pGDM (median [interquartile range]: age 38.6 [6.4] years; BMI 31.0 [6.2] kg/m2) and 11 healthy control subjects without NAFLD (age 37.9 [7.8] years; BMI 28.1 [0.8] kg/m2) underwent a 75-g oral glucose tolerance test (OGTT), DXA whole-body scan, and ultrasonic evaluation of hepatic steatosis. RESULTS: Twenty-four (24%) women with pGDM had NAFLD on the basis of the ultrasound scan. None had cirrhosis. Women with NAFLD had a higher BMI (P = 0.0002) and waist circumference (P = 0.0003), increased insulin resistance (P = 0.0004), and delayed suppression of glucagon after the OGTT (P < 0.0001), but NAFLD was not associated with the degree of glucose intolerance (P = 0.2196). Visceral fat mass differed among the three groups, with the NAFLD group having the highest amount of fat and the control subjects the lowest (P = 0.0003). By logistic regression analysis, insulin resistance (P = 0.0057) and waist circumference (P = 0.0109) were independently associated with NAFLD. CONCLUSIONS: NAFLD was prevalent in this cohort of relatively young and nonseverely obese women with pGDM who are considered healthy apart from their increased risk for diabetes. Insulin resistance and a larger waist circumference were independently associated with the presence of NAFLD, whereas glucose intolerance was not.

Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge.

Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)).

Gene-environment interactions and obesity--further aspects of genomewide association studies.

Advances in genotyping technologies have facilitated the advent of the genomewide association studies in large study populations and thereby led to the identification of an impressive-and still increasing-number of genetic variants with significant impact on the risk of widespread lifestyle health problems such as obesity, diabetes, and cardiovascular disease. Yet, the scientific community is a long way from reaching a comprehensive picture of the heritable components of these diseases and advancing from plain statistical significance into a biological understanding where the true contribution to a trait is recognized. Increasingly large study populations, denser single-nucleotide polymorphism mapping, deep sequencing, and raised awareness of the importance of structural variants may add to the known genetic variance underlying common complex disorders; however, genetic variance alone probably cannot account for disease susceptibility without the addition of pre- and postnatal environmental and/or behavioral factors. Moreover, an interaction between genetic and environmental factors may hinder the detection of genetic effects if not accounted for, e.g., in genomewide association studies, and prospective cohort studies have hence been proposed to surpass the classic case-control design. With a focus on obesity we describe some of the recently reported gene-environment interactions for polymorphisms identified in the FTO and INSIG2 genes. Ultimately, a thorough understanding of the gene-environment interactions underlying a common complex condition such as obesity may suggest novel treatment or intervention strategies to complement the harmful effect of detrimental genetic variation and thus may assist in improving the quality of life for affected individuals.

Studies of CTNNBL1 and FDFT1 variants and measures of obesity: analyses of quantitative traits and case-control studies in 18,014 Danes.

BACKGROUND: A genome-wide scan in unrelated US Caucasians identified rs7001819 upstream of farnesyl-diphosphate farnesyltransferase 1 (FDFT1) and multiple variants within catenin (cadherin-associated protein), beta-like 1 (CTNNBL1) to associate strongly with body mass index (BMI). The most significantly associating variants within CTNNBL1 including rs6013029 and rs6020846 were additionally confirmed to associate with morbid obesity in a French Caucasian case-control sample. The aim of this study was to investigate the impact of these three variants on obesity, through analyses of obesity-related quantitative traits, and case-control studies in large study samples of Danes. METHODS: The FDFT1 rs7001819, CTNNBL1 rs6013029 and rs6020846 were genotyped, using TaqMan allelic discrimination, in a combined study sample comprising 18,014 participants ascertained from; the population-based Inter99 cohort (n = 6,514), the ADDITION Denmark screening study cohort (n = 8,662), and a population-based sample (n = 680) and a type 2 diabetic patients group (n = 2,158) from Steno Diabetes Center. RESULTS: Both CTNNBL1 variants associated with body weight and height with per allele effect sizes of 1.0 [0.3-0.8] kg and 0.6 [0.2-0.9] cm, respectively, for the rs6020846 G-allele. No association was observed with BMI and waist circumference. In case-control studies neither of the CTNNBL1 variants showed association with overweight, obesity or morbid obesity (rs6013029: Odds Ratio (OR)(overweight) = 1.02 [0.90-1.16], OR(obesity) = 1.09 [0.95-1.25], OR(morbidobesity) = 1.26 [0.91-1.74]; rs6020846: OR(overweight) = 1.05 [0.93-1.18], OR(obesity) = 1.13 [1.00-1.28], OR(morbidobesity) = 1.17 [0.86-1.61]). However, in meta-analyses of the present and the previous study, both the rs6013029 T-allele and the rs6020846 G-allele increased the risk of developing morbid obesity (rs6013029: OR(combined) = 1.36 [1.12-1.64], p = 0.002; rs6020846: OR(combined) = 1.26 [1.06-1.51], p = 0.01), and obesity (rs6013029: OR(combined) = 1.17 [1.04-1.31], p = 0.007; rs6020846: OR(combined) = 1.17 [1.05-1.30], p = 0.004). The FDFT1 rs7001819 C-allele showed no association with obesity-related quantitative measures or dichotomous measures of overweight, obesity and morbid obesity. CONCLUSION: CTNNBL1 variants associated with body weight and height, and confer the risk of developing obesity in meta-analyses combining the present and a previous study. FDFT1 rs7001819 showed no association with obesity, neither when analysing quantitative traits nor when performing case-control studies of obesity.

Variation in the gene encoding Krüppel-like factor 7 influences body fat: studies of 14 818 Danes.

OBJECTIVE: KLF7 encodes Krüppel-like factor (KLF) 7, a member of the KLF family of transcription factors, initially shown to play important roles in cellular development and differentiation, and reported to be specifically involved in adipogenesis. Several single nucleotide polymorphisms (SNPs) have been identified in KLF7, of which the A-allele of rs2302870 has been associated with type 2 diabetes in a Japanese population; however, a possible association of KLF7 SNPs with obesity has not been investigated. We aimed to identify variation in the putative promoter region, the coding regions, exon/intron boundaries, and 3'-UTR of KLF7, and to examine identified variants in relation to obesity, type 2 diabetes, and related quantitative traits in Danish individuals. METHODS: Identified variants were investigated for association with type 2 diabetes in 8777 individuals and with obesity in 14 818 individuals. RESULTS: We identified four common SNPs in low pairwise linkage disequilibrium; three in the putative promoter region (-1119 G>A, -963 C>A (rs7568369), and -614 G>A) and IVS2+35092 A>C (rs2302870). We failed to confirm an association between rs2302870 and type 2 diabetes. Neither was rs7568369 associated with type 2 diabetes; however, the minor A-allele of rs7568369 protected against obesity (OR=0.90 (0.84-0.96), P=0.001) and in studies of quantitative traits (n=5,535) the variant associated with decreased body mass index (P=0.002) and waist circumference (P=0.003). The -1119 G>A and -614 G>A variants were not associated with obesity or type 2 diabetes. CONCLUSION: We identified a novel association between the minor A-allele of KLF7 rs7568369 and protection against obesity in the Danish population.

Variants near MC4R are associated with obesity and influence obesity-related quantitative traits in a population of middle-aged people: studies of 14,940 Danes.

OBJECTIVE: Variants downstream of the melanocortin-4 receptor gene (MC4R) have been reported to associate with obesity. We examined rs17782313, rs17700633, rs12970134, rs477181, rs502933, and rs4450508 near MC4R for association with obesity-related quantitative traits, obesity, and type 2 diabetes in Danish individuals. RESEARCH DESIGN AND METHODS: The variants were investigated for association with obesity-related quantitative traits in 5,807 population-based sampled individuals, obesity in 14,940 individuals, and type 2 diabetes in 8,821 individuals. RESULTS: The minor risk alleles of rs17782313, rs17700633, and rs12970134 were associated with BMI (effect per allele 0.25 kg/m2, P = 0.01; 0.23, P = 0.01; and 0.31, P = 7 x 10(-4), respectively), waist circumference (0.67 cm, P = 0.006; 0.53, P = 0.02; and 0.85, P = 3 x 10(-4)), and body weight (1.04 kg, P = 6 x 10(-4); 0.71, P = 0.01; and 1.16, P = 8 x 10(-5)). In case-control studies of obesity defined by BMI, the minor C-allele of rs17782313 was associated with overweight/obesity and obesity (odds ratio [OR] 1.09, P = 0.006 and OR 1.12, P = 0.003, respectively). Similarly, the minor A-allele of rs17700633 was associated with overweight/obesity and obesity (1.12, P = 8 x 10(-5) and 1.16, P = 2 x 10(-5)), and the minor A-allele of rs12970134 was also associated with overweight/obesity and obesity (1.13, P = 2 x 10(-5) and 1.15, P = 6 x 10(-5)). rs477181, rs502933, and rs4450508 were not significantly associated with obesity in the Danish population. The frequency of the minor risk alleles of rs17782313 and rs12970134 was higher among patients with type 2 diabetes than among glucose-tolerant individuals (OR 1.08, P = 0.08 and 1.08, P = 0.06, respectively); however, these borderline associations were abolished after adjustment for BMI. CONCLUSIONS: rs17782313, rs17700633, and rs12970134 near MC4R associate with measures of obesity in Danish individuals.

Lack of association between PKLR rs3020781 and NOS1AP rs7538490 and type 2 diabetes, overweight, obesity and related metabolic phenotypes in a Danish large-scale study: case-control studies and analyses of quantitative traits.

BACKGROUND: Several studies in multiple ethnicities have reported linkage to type 2 diabetes on chromosome 1q21-25. Both PKLR encoding the liver pyruvate kinase and NOS1AP encoding the nitric oxide synthase 1 (neuronal) adaptor protein (CAPON) are positioned within this chromosomal region and are thus positional candidates for the observed linkage peak. The C-allele of PKLR rs3020781 and the T-allele of NOS1AP rs7538490 are reported to strongly associate with type 2 diabetes in various European-descent populations comprising a total of 2,198 individuals with a combined odds ratio (OR) of 1.33 [1.16-1.54] and 1.53 [1.28-1.81], respectively. Our aim was to validate these findings by investigating the impact of the two variants on type 2 diabetes and related quantitative metabolic phenotypes in a large study sample of Danes. Further, we intended to expand the analyses by examining the effect of the variants in relation to overweight and obesity. METHODS: PKLR rs3020781 and NOS1AP rs7538490 were genotyped, using TaqMan allelic discrimination, in a combined study sample comprising a total of 16,801 and 16,913 individuals, respectively. The participants were ascertained from four different study groups; the population-based Inter99 cohort (nPKLR = 5,962, nNOS1AP = 6,008), a type 2 diabetic patient group (nPKLR = 1,873, nNOS1AP = 1,874) from Steno Diabetes Center, a population-based study sample (nPKLR = 599, nNOS1AP = 596) from Steno Diabetes Center and the ADDITION Denmark screening study cohort (nPKLR = 8,367, nNOS1AP = 8,435). RESULTS: In case-control studies we evaluated the potential association between rs3020781 and rs7538490 and type 2 diabetes and obesity. No significant associations were observed for type 2 diabetes (rs3020781: pAF = 0.49, OR = 1.02 [0.96-1.10]; rs7538490: pAF = 0.84, OR = 0.99 [0.93-1.06]). Neither did we show association with overweight or obesity. Additionally, the PKLR and the NOS1AP genotypes were demonstrated not to have a major influence on diabetes-related quantitative metabolic phenotypes. CONCLUSION: We failed to provide evidence of an association between PKLR rs3020781 and NOS1AP rs7538490 and type 2 diabetes, overweight, obesity or related quantitative metabolic phenotypes in large-scale studies of Danes.