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Funder: European Foundation for the Study of Diabetes (EFSD)/Sanofi; Id: http://dx.doi.org/10.13039/501100001648, Objective: Polycystic ovary syndrome (PCOS) has been associated with an increased risk of coronary artery disease (CAD). However, it remains uncertain whether this increased risk is the result of PCOS per se or, alternatively, is explained by obesity, a common feature of PCOS. The aim of this study was to assess the causal association between PCOS and CAD and the role of obesity herein. Design and Methods: We conducted two‐sample Mendelian randomisation analyses in large‐scale, female‐specific datasets to study the association between genetically predicted (1) risk of PCOS and risk of CAD, (2) body mass index (BMI) and risk of PCOS and (3) BMI and risk of CAD. Primary analyses were conducted with the inverse‐variance weighted (IVW) method. Simple median, penalized weighted median and contamination mixture analyses were performed to assess the robustness of the outcomes. Results: IVW analyses did not show a statistically significant association between PCOS and CAD (odds ratio [OR]: 0.99, 95% confidence interval [CI]: 0.89, 1.11). In contrast, genetically predicted BMI was statistically significantly associated with an increased odds of PCOS (OR: 3.21, 95% CI: 2.26, 4.56) and CAD (OR: 1.38, 95% CI: 1.14, 1.67). Similar results were obtained when secondary analyses were performed. Conclusion: These sex‐specific analyses show that the genetically predicted risk of PCOS is not associated with the risk of CAD. Instead, the genetically predicted risk of obesity (and its downstream metabolic effects) is the common denominator of both PCOS and CAD risk.

Inborn errors of metabolism (IEM) are a group of disorders that are often erroneously assumed to be the playing field of pediatricians only. This misconception combined with the rare nature of IEMs explains why there is often a serious delay in the diagnosis of an adult-onset IEM, which can have detrimental consequences. This review provides potential strategies to overcome this diagnostic delay. The most promising consists of stimulating critical clinical reasoning and creating awareness of the process that leads to the diagnosis of a rare disease. J Endocrinol Metab. 2021;11(3-4):65-68 doi: https://doi.org/10.14740/jem750

Aims CVD is the main cause of morbidity and mortality in individuals with diabetes. It is currently unclear whether daily glucose variability contributes to CVD. Therefore, we investigated whether glucose variability is associated with arterial measures that are considered important in CVD pathogenesis. Methods We included participants of The Maastricht Study, an observational population-based cohort, who underwent at least 48 h of continuous glucose monitoring (CGM) (n = 853; age: 59.9 ± 8.6 years; 49% women, 23% type 2 diabetes). We studied the cross-sectional associations of two glucose variability indices (CGM-assessed SD [SDCGM] and CGM-assessed CV [CVCGM]) and time in range (TIRCGM) with carotid–femoral pulse wave velocity (cf-PWV), carotid distensibility coefficient, carotid intima–media thickness, ankle–brachial index and circumferential wall stress via multiple linear regression. Results Higher SDCGM was associated with higher cf-PWV after adjusting for demographics, cardiovascular risk factors and lifestyle factors (regression coefficient [B] per 1 mmol/l SDCGM [and corresponding 95% CI]: 0.413 m/s [0.147, 0.679], p = 0.002). In the model additionally adjusted for CGM-assessed mean sensor glucose (MSGCGM), SDCGM and MSGCGM contributed similarly to cf-PWV (respective standardised regression coefficients [st.βs] and 95% CIs of 0.065 [−0.018, 0.167], p = 0.160; and 0.059 [−0.043, 0.164], p = 0.272). In the fully adjusted models, both higher CVCGM (B [95% CI] per 10% CVCGM: 0.303 m/s [0.046, 0.559], p = 0.021) and lower TIRCGM (B [95% CI] per 10% TIRCGM: −0.145 m/s [−0.252, −0.038] p = 0.008) were statistically significantly associated with higher cf-PWV. Such consistent associations were not observed for the other arterial measures. Conclusions Our findings show that greater daily glucose variability and lower TIRCGM are associated with greater aortic stiffness (cf-PWV) but not with other arterial measures. If corroborated in prospective studies, these results support the development of therapeutic agents that target both daily glucose variability and TIRCGM to prevent CVD. Graphical abstract

Background and objective: Methylmalonic acidemia (MMA) and propionic acidemia (PA) are inborn errors of metabolism. While survival of MMA and PA patients has improved in recent decades, long-term outcome is still unsatisfactory. A protein restricted diet is the mainstay for treatment. Additional amino acid mixtures (AAM) can be prescribed if natural protein is insufficient. It is unknown if dietary treatment can have an impact on outcome. Design: We performed a nationwide retrospective cohort study and evaluated both longitudinal dietary treatment and clinical course of Dutch MMA and PA patients. Protein prescription was compared to the recommended daily allowances (RDA); the safe level of protein intake as provided by the World Health Organization. The association of longitudinal dietary treatment with long-term outcome was evaluated. Results: The cohort included 76 patients with a median retrospective follow-up period of 15 years (min -max: 0-48 years) and a total of 1063 patient years on a protein restricted diet. Natural protein prescription exceeded the RDA in 37% (470/1287) of all prescriptions and due to AAM prescription, the total protein prescription exceeded RDA in 84% (1070/1277). Higher protein prescriptions were associated with adverse outcomes in severely affected patients. In PA early onset patients a higher natural protein prescription was associated with more frequent AMD. In MMA vitamin B12 unresponsive patients, both a higher total protein prescription and AAM protein prescription were associated with more mitochondrial complications. A higher AAM protein prescription was associated with an increased frequency of cognitive impairment in the entire. Conclusion: Protein intake in excess of recommendations is frequent and is associated with poor outcome. 0 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

OBJECTIVE: Obesity and liver fat are associated with decreased levels of serum sex hormone binding globulin (SHBG). Laboratory studies suggest that hepatic de novo lipogenesis (DNL) is involved in the downregulation of SHBG synthesis. The aim of the present study was to address the role of DNL on serum SHBG in humans. DESIGN: A cross-sectional study examining the association between DNL, measured by stable isotopes, and serum SHBG, stratified by sex. PARTICIPANTS: Healthy men (n = 34) and women (n = 21) were combined from two cross-sectional studies. Forty-two per cent of participants had hepatic steatosis, and the majority were overweight (62%) or obese (27%). RESULTS: DNL was inversely associated with SHBG in women (β: -0.015, 95% CI: -0.030; 0.000), but not in men (β: 0.007, 95% CI: -0.005; 0.019) (p for interaction = .068). Adjustment for study population, age and body mass index did not materially change these results, although statistical significance was lost after adjustment for serum insulin. CONCLUSIONS: An inverse association between DNL and SHBG may explain the decreased SHBG levels that are observed in obesity, at least in women. ispartof: CLINICAL ENDOCRINOLOGY vol:95 issue:1 pages:101-106 ispartof: location:England status: published

Background There is an ongoing debate on whether fructose plays a role in the development of nonalcoholic fatty liver disease. Objectives The aim of this study was to investigate the effects of fructose restriction on intrahepatic lipid (IHL) content in a double-blind randomized controlled trial using an isocaloric comparator. Methods Between March 2017 and October 2019, 44 adult overweight individuals with a fatty liver index ≥ 60 consumed a 6-wk fructose-restricted diet (

Background: Glucose variability (GV) measured by continuous glucose monitoring (CGM) has become an accepted marker of glycemic control. Nevertheless, several methodological aspects of GV assessment require further study. We, therefore, investigated the minimum number of days needed to reliably measure GV, assessed GV reference values, and studied the correlation of GV with established glycemic indices (i.e., HbA(1c), seven-point oral glucose tolerance test [OGTT]-derived indices). Methods: We used cross-sectional data from The Maastricht Study, an observational population-based cohort enriched with type 2 diabetes. Participants with more than 48 h of CGM (iPro2; Medtronic) were included for analysis (n = 851; age: 60 +/- 9years; 49% women; 23% type 2 diabetes). We used mean sensor glucose (MSG), standard deviation (SD), and coefficient of variation (CV) as CGM-derived indices (the latter two for GV quantification). We calculated reliability using the Spearman-Brown prophecy formula, established reference values by calculating 2.5th-97.5th percentiles, and studied correlations using Spearman's rho. Results: Sufficient reliability (R > 0.80) was achieved with two (MSG and SD), or three monitoring days (CV). The reference ranges, assessed in individuals with normal glucose metabolism (n = 470), were 90.5-120.6 mg/dL (MSG), 7.9-24.8 mg/dL (SD), and 7.74%-22.45% (CV). For MSG, the strongest correlation was found with fasting plasma glucose (rho = 0.65 [0.61; 0.69]); for SD, with the 1-h OGTT value (rho = 0.61 [0.56; 0.65]); and for CV, with both the incremental glucose peak (IGP) during the OGTT (rho = 0.50 [0.45; 0.55]) and the 1-h OGTT value (rho = 0.50 [0.45; 0.55]). Conclusions: The reliability findings and reference values are relevant for studies that aim to investigate CGM-measured GV. One-hour OGTT and IGP values can be used as GV indices when CGM is unavailable.

Evidence for effectiveness of newborn screening (NBS) for propionic acidemia (PA) and isolated methylmalonic acidemia (MMA) is scarce. Prior to implementation in the Netherlands, we aim to estimate the expected health gain of NBS for PA and MMA. In this national retrospective cohort study, the clinical course of 76/83 Dutch PA and MMA patients, diagnosed between January 1979 and July 2019, was evaluated. Five clinical outcome parameters were defined: adverse outcome of the first symptomatic phase, frequency of acute metabolic decompensations (AMD), cognitive function, mitochondrial complications, and treatment‐related complications. Outcomes of patients identified by family testing were compared with the outcomes of their index siblings. An adverse outcome due to the first symptomatic phase was recorded in 46% of the clinically diagnosed patients. Outcome of the first symptomatic phase was similar in 5/9 sibling pairs and better in 4/9 pairs. Based on the day of diagnosis of the clinically diagnosed patients and sibling pair analysis, a preliminary estimated reduction of adverse outcome due to the first symptomatic phase from 46% to 36%‐38% was calculated. Among the sibling pairs, AMD frequency, cognitive function, mitochondrial, and treatment‐related complications were comparable. These results suggest that the health gain of NBS for PA and MMA in overall outcome may be limited, as only a modest decrease of adverse outcomes due to the first symptomatic phase is expected. With current clinical practice, no reduced AMD frequency, improved cognitive function, or reduced frequency of mitochondrial or treatment‐related complications can be expected.

Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Hepatic saturated fatty acids (SFA) may be a marker of DNL and are suggested to be most detrimental in contributing to insulin resistance. Here, we show in a cross-sectional study design (ClinicalTrials.gov ID: NCT03211299) that we are able to distinguish the fractions of hepatic SFA, mono- and polyunsaturated fatty acids in healthy and metabolically compromised volunteers using proton magnetic resonance spectroscopy (1H-MRS). DNL is positively associated with SFA fraction and is elevated in patients with non-alcoholic fatty liver and type 2 diabetes. Intriguingly, SFA fraction shows a strong, negative correlation with hepatic insulin sensitivity. Our results show that the hepatic lipid composition, as determined by our 1H-MRS methodology, is a measure of DNL and suggest that specifically the SFA fraction may hamper hepatic insulin sensitivity., Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Here, the authors use 1H-MRS methodology to show hepatic SFA fraction is a measure of DNL and specifically may hamper hepatic insulin sensitivity.

Background and Aims Thiazolidinediones (TZDs) and glucagon-like peptide-1 (GLP-1) receptor agonists are potential pharmacological treatment options for patients at risk of NAFLD. Therefore, we examined the association between the risk of NAFLD and the use of TZDs and GLP-1 receptor agonists compared with the use of sulfonylureas (SUs) and insulins. Additionally, we calculated the incidence of HCC in users of TZDs and GLP-1 receptor agonists. Approach and Results We conducted a population-based cohort study using primary care data from the Clinical Practice Research Datalink database (2007-2018). All patients aged ≥18 with a prescription of an oral glucose-lowering agent or GLP-1 receptor agonist were included. The first prescription defined the start of follow-up. The primary outcome was a new diagnosis of NAFLD. Cox proportional hazards regression was used to estimate HRs and 95% CIs of the primary outcome. Incidence rates of HCC were determined per 1,000 person-years for all exposures. The study identified 207,367 adults with a prescription for a glucose-lowering agent. The risk of NAFLD was lower in patients prescribed a TZD than in those prescribed an SU (adjusted HR [aHR], 0.32; 95% CI, 0.20-0.51). No difference in risk of NAFLD was observed comparing GLP-1 receptor agonist use with insulin use (aHR, 1.22; 95% CI, 0.91-1.63). Conclusions Results of our study endorse the use of TZDs for selected patients at risk of NAFLD but do not support previous findings regarding the beneficial effect of GLP-1 receptor agonists. The low number of events in several subgroups may affect the generalizability of the current findings., Hepatology, 74 (5), ISSN:0270-9139, ISSN:1527-3350

ObjectiveDiabetic retinopathy in type 2 diabetes is preceded by retinal nerve fiber layer (RNFL) thinning, an index of neurodegeneration. We investigated whether glucose metabolism status (GMS), measures of glycemia, and daily glucose variability (GV) are associated with RNFL thickness over the entire range of glucose tolerance.Research design and methods We used cross-sectional data from The Maastricht Study (up to 5,455 participants, 48.9% men, mean age 59.5 years and 22.7% with type 2 diabetes) to investigate the associations of GMS, measures of glycemia (fasting plasma glucose [FPG], 2-hour post-load glucose [2-h PG], HbA1c, advanced glycation endproducts [AGEs] assessed as skin autofluorescence [SAF]) and indices of daily GV (incremental glucose peak [IGP] and continuous glucose monitoring [CGM]-assessed standard deviation [SD]) with mean RNFL thickness. We used linear regression analyses and, for GMS, P for trend analyses. We adjusted associations for demographic, cardiovascular risk and lifestyle factors, and, only for measures of GV, for indices of mean glycemia. Results After full adjustment, type 2 diabetes and prediabetes (versus normal glucose metabolism) were associated with lower RNFL thickness (standardized beta [95%CI], respectively -0.16[-0.25;-0.08]; -0.05[-0.13;0.03]; Ptrend=0.001). Greater FPG, 2-h PG, HbA1c, SAF, IGP and CGM-assessed SD were also associated with lower RNFL thickness (per SD, respectively -0.05 [-0.08; -0.01]; -0.06 [-0.09; -0.02]; -0.05 [-0.08; -0.02]; -0.04 [-0.07; -0.01]; -0.06 [-0.12; -0.01]; and -0.07 [-0.21; 0.07]).Conclusion In this population-based study, a more adverse GMS and, over the entire range of glucose tolerance, greater glycemia and daily GV were associated with lower RNFL thickness. Hence, early identification of individuals with hyperglycemia, early glucose-lowering treatment, and early monitoring of daily GV may contribute to the prevention of RNFL thinning, an index of neurodegeneration and precursor of diabetic retinopathy.

Context There is an ongoing debate about whether and how fructose is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A recent experimental study showed an increased intrahepatic triglyceride (IHTG) content in mice deficient for aldolase B (aldo B−/−), the enzyme that converts fructose-1-phosphate to triose phosphates. Objective To translate these experimental findings to the human situation. Design Case-control study. Setting Outpatient clinic for inborn errors of metabolism. Patients or Other Participants Patients with hereditary fructose intolerance, a rare inborn error of metabolism caused by a defect in aldolase B (n = 15), and healthy persons matched for age, sex, and body mass index (BMI) (n =15). Main Outcome Measure IHTG content, assessed by proton magnetic resonance spectroscopy. Results IHTG content was higher in aldo B−/− patients than controls (2.5% vs 0.6%; P = 0.001) on a background of lean body mass (median BMI, 20.4 and 21.8 kg/m2, respectively). Glucose excursions during an oral glucose load were higher in aldo B−/− patients (P = 0.043). Hypoglycosylated transferrin, a surrogate marker for hepatic fructose-1-phosphate concentrations, was more abundant in aldo B−/− patients than in controls (P < 0.001). Finally, plasma β-hydroxybutyrate, a biomarker of hepatic β-oxidation, was lower in aldo B−/− patients than controls (P = 0.009). Conclusions This study extends previous experimental findings by demonstrating that aldolase B deficiency also results in IHTG accumulation in humans. It suggests that the accumulation of fructose-1-phosphate and impairment of β-oxidation are involved in the pathogenesis.

Objective A recent Mendelian randomization study has suggested a causal role for sex hormone‐binding globulin (SHBG), total testosterone and free testosterone in the pathogenesis of polycystic ovary syndrome (PCOS). The aim of this study was to assess the relationships of SHBG, androstenedione, total and free testosterone with the individual metabolic and reproductive features of PCOS. Design Cross‐sectional data in PCOS patients (n=96) prospectively collected in a secondary/tertiary clinic for menstrual cycle disorders. Methods Multivariable regression analyses were conducted to study the associations between SHBG, androstenedione, total and free testosterone with metabolic (BMI, waist circumference, systolic and diastolic blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and homeostatic model assessment for insulin resistance [HOMA2‐IR]) and reproductive features (menstrual cycle length, antral follicle count, anti‐Müllerian hormone, luteinizing hormone, follicle‐stimulating hormone and Ferriman‐Gallwey score) of PCOS. Results Serum SHBG and free testosterone, but not total testosterone or androstenedione, were significantly associated with BMI, waist circumference, serum triglycerides, HDL cholesterol, LDL cholesterol and HOMA2‐IR. The strength of the associations with serum lipids was reduced after adjustment for BMI, but not for HOMA2‐IR. Total testosterone was significantly associated with antral follicle count. SHBG, total testosterone and androstenedione were significantly associated with serum AMH. Only the strength of the association for SHBG was reduced after adjustment for BMI. Conclusions Serum SHBG is associated with primarily metabolic features, whereas total testosterone and androstenedione are associated with reproductive features of PCOS. These results suggest a differential underlying pathophysiology for the metabolic and reproductive features of PCOS., Sex hormone‐binding globulin (SHBG), total testosterone, and free testosterone have been found to play a causal role in the pathogenesis of polycystic ovary syndrome (PCOS), but it remains uncertain how these androgen markers associate with individual features of PCOS. In this cross‐sectional study in a cohort of patients with PCOS, serum SHBG was primarily associated with metabolic features of PCOS, whereas total testosterone and androstenedione were associated with reproductive features of PCOS. These results suggest a differential underlying pathophysiology for the metabolic and reproductive features of PCOS. ​

In a response to a Formal Comment critiquing their model for classifying individualized glucose patterns into glucotypes, these authors stand by their results and conclusions, which can be reproduced using their publicly available data, and maintain that improved algorithms for analyzing CGM data will continue to emerge and enrich the field.

AimTo determine whether metformin's effects on carotid artery intima-media thickness (cIMT) in type 1 diabetes differ according to smoking status.MethodsRegression model effect estimates for the effect of metformin versus placebo (double-blind) on carotid IMT were calculated as a subgroup analysis of the REMOVAL trial.ResultsIn 428 randomized participants (227 never-smokers, 201 ever-smokers), averaged mean carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (−0.012 mm, 95% CI −0.021 to −0.002; p = .0137) but not in ever-smokers (0.003 mm, 95% CI −0.008 to 0.014; p = .5767); and similarly in non-current smokers (−0.008 mm, 95% CI −0.015 to −0.00001; p = .0497) but not in current smokers (0.013 mm, 95% CI −0.007 to 0.032; p = .1887). Three-way interaction terms (treatment*time*smoking status) were significant for never versus ever smoking (p = .0373, prespecified) and non-current versus current smoking (p = .0496, exploratory). Averaged maximal carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (−0.020 mm, 95% CI −0.034 to −0.006; p = .0067) but not in ever-smokers (−0.006 mm, 95% CI −0.020 to 0.008; p = .4067), although this analysis was not supported by a significant three-way interaction term.ConclusionsThis subgroup analysis of the REMOVAL trial provides additional support for a potentially wider role of adjunct metformin therapy in cardiovascular risk management in type 1 diabetes, particularly for individuals who have never smoked cigarettes.

Objective: Previous studies have shown that patients with hereditary fructose intolerance (HFI) are characterized by a greater intrahepatic triglyceride content, despite a fructose-restricted diet. The present study aimed to examine the long-term consequences of HFI on other aldolase-B-expressing organs, i.e. the kidney and vascular endothelium. Methods: Fifteen adult HFI patients were compared to healthy control individuals matched for age, sex and body mass index. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (cf-PWV) and endothelial function by peripheral arterial tonometry, skin laser doppler flowmetry and the endothelial function biomarkers soluble E-selectin [sE-selectin] and von Willebrand factor. Serum creatinine and cystatin C were measured to estimate the glomerular filtration rate (eGFR). Urinary glucose and amino acid excretion and the ratio of tubular maximum reabsorption of phosphate to GFR (TmP/GFR) were determined as measures of proximal tubular function. Results: Median systolic blood pressure was significantly higher in HFI patients (127 versus 122 mmHg, p = .045). Pulse pressure and cf-PWV did not differ between the groups (p = .37 and p = .49, respectively). Of all endothelial function markers, only sE-selectin was significantly higher in HFI patients (p = .004). eGFR was significantly higher in HFI patients than healthy controls (119 versus 104 ml/min/1.73m2, p = .001, respectively). All measurements of proximal tubular function did not differ significantly between the groups. Conclusions: Adult HFI patients treated with a fructose-restricted diet are characterized by a higher sE-selectin level and slightly higher systolic blood pressure, which in time could contribute to a greater cardiovascular risk. The exact cause and, hence, clinical consequences of the higher eGFR in HFI patients, deserves further study. ispartof: MOLECULAR GENETICS AND METABOLISM REPORTS vol:23 ispartof: location:United States status: published

Aims: In REMOVAL (NCT01483560), metformin attenuated decline in estimated glomerular filtration rate (eGFR) using the creatinine-based Modified Diet in Renal Disease (MDRD) equation in adults with T1D. We now report the effects of metformin vs. placebo on: (i) eGFR by CKD-EPI; and (ii) microalbuminuria (albumin: creatinine ratio, ACR). Methods: In 428 participants (mean age 55 years; HbA1c 8.0%; BP 130/72mmHg; eGFR 92 ml/min/1.73m2, 69% on ACE inhibitors/ARBs), CKD-EPI was derived separately from creatinine and cystatin C (annual). ACR was measured on annual first morning void. Treatment effects were compared by ANCOVA for continuous data (adjusted for baseline) and Cox Regression for incident microalbuminuria. Results: Mean baseline eGFR by CKD-EPI was 90 ml/min/1.73m2 by creatinine and 96 ml/min/1.73m2 by cystatin C. Decline in eGFR over 3 years was attenuated by metformin vs. placebo when CKD-EPI was derived from creatinine and cystatin C. There was no effect on ACR but confidence intervals were wide (Table). Conclusions: Deriving eGFR from other biomarkers/equations does not alter the conclusion that metformin has a potentially beneficial effect on eGFR in T1D; its effect on ACR requires further study. Disclosure J.G. Timmons: None. N. Greenlaw: None. C.D. Stehouwer: None. M. Brouwers: None. N. Chaturvedi: Consultant; Self; AstraZeneca. A.D. Hughes: Advisory Panel; Spouse/Partner; AstraZeneca. I. Hramiak: Consultant; Self; Medtronic, Novo Nordisk Inc. Research Support; Self; Eli Lilly and Company, PHRI Population Health Research Institute, Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim (Canada) Ltd., Merck & Co., Inc. Other Relationship; Self; AstraZeneca, Bristol-Myers Squibb, Insulet Corporation. A. Jenkins: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Sanofi-Aventis. P. Welsh: Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Roche Diagnostics. N. Sattar: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Sanofi. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. H.M. Colhoun: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Novo Nordisk Inc., Pfizer Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Speaker’s Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. Other Relationship; Self; Eli Lilly and Company, Sanofi. P. Rossing: Advisory Panel; Self; Sanofi. Consultant; Self; Astellas Pharma Inc., AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Eli Lilly and Company. Stock/Shareholder; Self; Novo Nordisk A/S. J.R. Petrie: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Advanced Clinical Intelligence, IQVIA. Research Support; Self; AstraZeneca, Janssen Pharmaceuticals, Inc. Speaker’s Bureau; Self; Merck KGaA, Novo Nordisk A/S.

We investigated the association between the current use of individual sulphonylureas and the risk of a first ever acute myocardial infarction (AMI) and all-cause mortality, in a population-based cohort study using primary care data from the Clinical Practice Research Datalink (CPRD) database (2004-2012). New users (N=121,869) with at least one prescription for a non-insulin antidiabetic agent, and aged ≥18 years were included. The first prescription defined start of follow-up. Time-dependent Cox proportional hazards models were used to estimate the risk of a first ever AMI and all-cause mortality associated with the use of individual sulphonylureas, and other non-insulin glucose-lowering drugs. No differences in risk of a first ever AMI (adjusted hazard ratio [HRadj]: 1.02, 95% Confidence Interval [CI]: 0.70-1.50) or all-cause mortality (HRadj: 0.97, 95% CI: 0.80-1.17) were observed comparing gliclazide use with non-gliclazide sulphonylurea use. Similar results were found for each individual sulphonylurea. As evidence is accumulating that gliclazide is no safer than other sulphonylureas, current guidelines suggesting superiority should be carefully evaluated.

AimTo identify, predict and validate distinct glycaemic trajectories among patients with newly diagnosed type 2 diabetes treated in primary care, as a first step towards more effective patient-centred care.MethodsWe conducted a retrospective study in two cohorts, using routinely collected individual patient data from primary care practices obtained from two large Dutch diabetes patient registries. Participants included adult patients newly diagnosed with type 2 diabetes between January 2006 and December 2014 (development cohort, n=10528; validation cohort, n=3777). Latent growth mixture modelling identified distinct glycaemic 5-year trajectories. Machine learning models were built to predict the trajectories using easily obtainable patient characteristics in daily clinical practice.ResultsThree different glycaemic trajectories were identified: (1) stable, adequate glycaemic control (76.5% of patients); (2) improved glycaemic control (21.3% of patients); and (3) deteriorated glycaemic control (2.2% of patients). Similar trajectories could be discerned in the validation cohort. Body mass index and glycated haemoglobin and triglyceride levels were the most important predictors of trajectory membership. The predictive model, trained on the development cohort, had a receiver-operating characteristic area under the curve of 0.96 in the validation cohort, indicating excellent accuracy.ConclusionsThe developed model can effectively explain heterogeneity in future glycaemic response of patients with type 2 diabetes. It can therefore be used in clinical practice as a quick and easy tool to provide tailored diabetes care.

AimTo identify which patient-related effect modifiers influence the outcomes of integrated care programs for type 2 diabetes in primary care.BackgroundIntegrated care is a widespread management strategy for the treatment of type 2 diabetes. However, most integrated care programs are not tailored to patients’ needs, preferences and abilities. There is increasing consensus that such a patient-centered approach could improve the management of type 2 diabetes. Thus far, it remains unclear which patient-related effect modifiers should guide such an approach.MethodsPubMed, CINAHL and EMBASE were searched for empirical studies published after 1998. A systematic literature review was conducted according to the PRISMA guidelines.FindingsIn total, 23 out of 1015 studies were included. A total of 21 studies measured the effects of integrated diabetes care programs on hemoglobin A1c (HbA1c) and three on low-density lipoprotein cholesterol, systolic blood pressure and health-care utilization. In total, 49 patient characteristics were assessed as potential effect modifiers with HbA1c as an outcome, of which 46 were person or health-related and only three were context-related. Younger age, insulin therapy and longer disease duration were associated with higher HbA1c levels in cross-sectional and longitudinal studies. Higher baseline HbA1c was associated with higher HbA1c at follow-up in longitudinal studies. Information on context- and person-related characteristics was limited, but is necessary to help identify the care needs of individual patients and implement an effective integrated type 2 diabetes tailored care program.

Contains fulltext : 182572.pdf (Publisher’s version ) (Open Access) Cognitive and mental health problems in individuals with the inherited metabolic disorder phenylketonuria (PKU) have often been associated with metabolic control and its history. For the present study executive functioning (EF) was assessed in 21 PKU patients during childhood (T1, mean age 10.4 years, SD = 2.0) and again in adulthood (T2, mean age 25.8 years, SD = 2.3). At T2 additional assessments of EF in daily life and mental health were performed. Childhood (i.e. 0-12 years) blood phenylalanine was significantly related to cognitive flexibility, executive motor control, EF in daily life and mental health in adulthood (i.e. at T2). Patients with a greater increase in phenylalanine levels after the age of 12 performed more poorly on EF-tasks at T2. Group-based analyses showed that patients with phenylalanine /=360 micromol/L from age 13 onwards (n = 11) had better cognitive flexibility and executive motor control than those who had phenylalanine >/=360 micromol/L throughout life (n = 7), supporting the notion that phenylalanine should be below the recommended upper treatment target of 360 micromol/L during childhood for better outcome in adulthood. Despite some results indicating additional influence of phenylalanine levels between 13 and 17 years of age, evidence for a continued influence of phenylalanine levels after childhood on adult outcomes was largely lacking. This may be explained by the fact that the patients in the present study had relatively low phenylalanine levels during childhood (mean: 330 micromol/L, range: 219-581 micromol/L) and thereafter (mean Index of Dietary Control at T2: 464 micromol/L, range: 276-743 micromol/L), which may have buffered against transitory periods of poor metabolic control during adolescence and early adulthood.

Background & Aims: Plasma soluble E-selectin (sE-selectin) is a frequently used biomarker of systemic endothelial dysfunction. The present study explored the relationship between nonalcoholic fatty liver disease (NAFLD) and plasma sE-selectin levels. Methods: Expression of E-selectin in liver, visceral adipose tissue (VAT) and muscle was studied in relation to plasma sE-selectin in severely obese individuals (n = 74). The course of hepatic E-selectin expression in relation to hepatic steatosis and inflammation was examined in C57BL/6J LDLR−/− mice on a Western-type diet. The relationship between biomarkers of NAFLD, that is, plasma aminotransferase (ALT) and NAFLD susceptibility genes (rs738409 [PNPLA3] and rs1260326 [GCKR]), and plasma sE-selectin was studied in the combined CODAM (n = 571) and Hoorn (n = 694) studies. Results: E-selectin expression in liver, not VAT or muscle, was associated with plasma sE-selectin in severely obese individuals (β = 0.26; 95% CI: 0.05-0.47). NAFLD severity was associated with hepatic E-selectin expression (P =.02) and plasma sE-selectin (P =.003). LDLR−/− mice on a Western-type diet displayed increased hepatic E-selectin expression that followed the same course as hepatic inflammation, but not steatosis. In the CODAM study, plasma ALT was associated with plasma sE-selectin, independent of potential confounders (β = 0.25; 95% CI: 0.16-0.34). Both rs738409 and rs1260326 were associated with higher plasma sE-selectin in the combined CODAM and Hoorn studies (P =.01 and P =.004 respectively). Conclusions: NAFLD and related markers are associated with higher expression of hepatic E-selectin and higher levels of plasma sE-selectin. Further studies are required to investigate the role of E-selectin in the pathogenesis of NAFLD and the applicability of sE-selectin as a plasma biomarker of NAFLD/NASH.

ObjectiveFamilial combined hyperlipidemia (FCHL) is common among survivors of a premature myocardial infarction. FCHL patients are characterized by visceral obesity, fatty liver, and insulin resistance. The aim of the present study was to determine the incidence and determinants of type 2 diabetes (T2D) in a longitudinal cohort of FCHL pedigrees.Research design and methodsFCHL patients, their unaffected relatives and spouses included in our baseline cohort in 1998–2005 (n=596) were re-invited to determine the incidence of self-reported T2D (that was confirmed by medical records), used as the primary outcome measure. The Fatty Liver Index (FLI) and Homeostasis Model Assessment Insulin Resistance (HOMA2-IR) were used as markers of fatty liver and insulin resistance, respectively. A subset of the original cohort underwent ultrasound of the liver, and subcutaneous and visceral fat in 2002–2005 (n=275; ‘ultrasound subcohort’).ResultsFollow-up data (median: 15 years) was acquired for 76%. The incidence rate of T2D was significantly higher in FCHL patients compared with spouses (19.2 per 1000 person-years vs 2.8 per 1000 person-years; HR : 6.3, 95% CI: 2.4 to 16.8), whereas no differences were observed between unaffected relatives and spouses (HR: 0.9, 95% CI: 0.3 to 2.6). Cox’s proportional hazard regression analyses showed that baseline HOMA2-IR and FLI≥60, but not waist circumference, BMI, or the FCHL affected state, were independently associated with incident T2D. Similar results were obtained in the ultrasound subcohort (median follow-up: 11 years), in which baseline HOMA2-IR and fatty liver (assessed by ultrasound) were independently associated with incident T2D.ConclusionThis study further corroborates the suggestion that the liver plays a central role in the pathogenesis of cardiometabolic complications in FCHL. It supports periodical screening for T2D in this high-risk population.

Background Daily glucose variability may contribute to vascular complication development irrespective of mean glucose values. The incremental glucose peak (IGP) during an oral glucose tolerance test (OGTT) can be used as a proxy of glucose variability. We investigated the association of IGP with arterial stiffness, arterial remodeling, and microvascular function, independent of HbA1c and other confounders. Methods IGP was calculated as the peak minus baseline plasma glucose value during a seven-point OGTT in 2758 participants (age: 60 ± 8 years; 48% women) of The Maastricht Study, an observational population-based cohort. We assessed the cross-sectional associations between IGP and arterial stiffness (carotid-femoral pulse wave velocity [cf-PWV], carotid distensibility coefficient [carDC]), arterial remodeling (carotid intima-media thickness [cIMT]; mean [CWSmean] and pulsatile [CWSpuls] circumferential wall stress), and microvascular function (retinal arteriolar average dilatation; heat-induced skin hyperemia) via multiple linear regression with adjustment for age, sex, HbA1c, cardiovascular risk factors, lifestyle factors, and medication use. Results Higher IGP was independently associated with higher cf-PWV (regression coefficient [B]: 0.054 m/s [0.020; 0.089]) and with higher CWSmean (B: 0.227 kPa [0.008; 0.446]). IGP was not independently associated with carDC (B: − 0.026 10−3/kPa [− 0.112; 0.060]), cIMT (B: − 2.745 µm [− 5.736; 0.245]), CWSpuls (B: 0.108 kPa [− 0.054; 0.270]), retinal arteriolar average dilatation (B: − 0.022% [− 0.087; 0.043]), or heat-induced skin hyperemia (B: − 1.380% [− 22.273; 19.513]). Conclusions IGP was independently associated with aortic stiffness and maladaptive carotid remodeling, but not with carotid stiffness, cIMT, and microvascular function measures. Future studies should investigate whether glucose variability is associated with cardiovascular disease.

Background Recently, there has been growing interest in providing more tailored, patient-centered care for the treatment of type 2 diabetes mellitus (T2DM). Yet it remains unclear which patient characteristics should be determined to guide such an approach. Therefore, the opinions of healthcare providers (HCP) and people with T2DM about relevant patient characteristics for estimating healthcare needs of people with T2DM were assessed and compared. Methods Two separate online Delphi studies were conducted according to the RAND-UCLA Appropriateness Method: one with HCPs (n = 22) from Dutch primary and secondary care and one with people with T2DM treated in Dutch primary care (n = 46). The relevance of patient characteristics for estimating healthcare needs, defined as the number of yearly consultations, was assessed on a 5-point Likert scale. Characteristics with a median of 4 or 5 and an interquartile range ≤ 1.5 were considered relevant with consensus. Participants were also asked to select the top 5 of most relevant patient characteristics. To determine the overall top 5, the mean relative importance score of each characteristic was calculated. Results In two Delphi rounds, 28 and 15 patient characteristics were rated by HCPs and people with T2DM, respectively. Both HCPs and people with T2DM found health-related characteristics relevant for estimating healthcare needs of people with T2DM. However, HCPs preferred to estimate healthcare needs using person- and context-related characteristics. They ranked self-efficacy as the most relevant estimator. In contrast, people with T2DM were more in favor of health-related characteristics and ranked HbA1c as the most relevant estimator. Conclusions The findings show that there is discrepancy in opinions on relevant patient characteristics for estimating healthcare needs between HCPs and people with T2DM. To achieve more tailored, patient-centered care, it is important that both groups agree on the topics to be discussed during patient consultations. Electronic supplementary material The online version of this article (10.1186/s12913-019-4371-z) contains supplementary material, which is available to authorized users.

Background: In REMOVAL (NCT01483560), adjunct metformin treatment in adults with type 1 diabetes reduced body weight and LDL cholesterol (secondary outcomes) and progression of averaged maximal carotid intima-media thickness (tertiary outcome). Here, we report effects of metformin on tissue plasminogen activator antigen (tPA), soluble E-selectin (sE-selectin) and soluble intracellular-adhesion molecule 1 (sICAM-1) (tertiary outcomes) as well as other exploratory biomarkers. Methods: Samples were available at 0, 12, 24 and 36 months from 428 men and women with type 1 diabetes randomly assigned to metformin 1000 mg or matching placebo twice daily for three years: (mean±SD) age 55±8·5 years, HbA1c 8·0±0·82%, BMI 28·4±4·3 kg/m2, duration of diabetes 34±10·8 years, 82% on statin therapy. Commercial ELISA kits were used for tPA, sE-selectin, and sICAM-1 and automated platforms for apolipoproteins (Apo) A-1 and B, C-reactive protein (CRP), and high sensitivity cardiac troponin T (cTnT). Results: Metformin reduced tPA (22.2%, p Conclusion: The reductions in tPA and CRP observed with metformin in type 1 diabetes indicate modest antithrombotic and anti-inflammatory effects consistent with previous studies in type 2 diabetes. Disclosure P. Welsh: Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH. N. Greenlaw: None. H. Colhoun: Advisory Panel; Self; Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Sanofi-Aventis. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Regeneron Pharmaceuticals, Roche Pharma, Sanofi-Aventis. Speaker's Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. N. Chaturvedi: Advisory Panel; Self; AstraZeneca. I. Ford: None. I. Hramiak: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Insulet Corporation, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; Merck & Co., Inc. A.D. Hughes: Advisory Panel; Spouse/Partner; AstraZeneca. A. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. B.E.K. Klein: None. R. Klein: None. M. Brouwers: None. P. Rossing: Advisory Panel; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp. Other Relationship; Self; Novartis AG, Novo Nordisk A/S. C.D. Stehouwer: None. N. Sattar: Advisory Panel; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. Consultant; Self; NAPP Pharmaceuticals Limited. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Amgen Inc., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Roche Diagnostics France, Sanofi. J.R. Petrie: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Itamar Medical Ltd., Merck KGaA. Other Relationship; Self; Applied Clinical Intelligence, LLC, Boehringer Ingelheim International GmbH, Diabetes UK, Quintiles. Funding JDRF (17-2011-272)

Although movement disorders (MDs) are known complications, the exact frequency and severity remains uncertain in patients with classical galactosemia, especially in children. We determined the frequency, classification and severity of MDs in a cohort of pediatric and adult galactosemia patients, and assessed the association with nonmotor neuropsychological symptoms and daily functioning. Patients from seven centers in the United Kingdom and the Netherlands with a confirmed galactosemia diagnosis were invited to participate. A videotaped neurological examination was performed and an expert panel scored the presence, classification and severity of MDs. Disease characteristics, nonmotor neuropsychological symptoms, and daily functioning were evaluated with structured interviews and validated questionnaires (Achenbach, Vineland, Health Assessment Questionnaire, SIP68). We recruited 37 patients; 19 adults (mean age 32.6 years) and 18 children (mean age 10.7 years). Subjective self-reports revealed motor symptoms in 19/37 (51.4%), similar to the objective (video) assessment, with MDs in 18/37 patients (48.6%). The objective severity scores were moderate to severe in one third (6/37). Dystonia was the overall major feature, with additional tremor in adults, and myoclonus in children. Behavioral or psychiatric problems were present in 47.2%, mostly internalizing problems, and associated with MDs. Daily functioning was significantly impaired in the majority of patients. Only one patient received symptomatic treatment for MDs. We show that MDs and nonmotor neuropsychological symptoms are frequent in both children and adults with classical galactosemia.

Hereditary fructose intolerance (HFI) is a rare inborn disease characterized by a deficiency in aldolase B, which catalyzes the cleavage of fructose 1,6-bisphosphate and fructose 1-phosphate (Fru 1P) to triose molecules. In patients with HFI, ingestion of fructose results in accumulation of Fru 1P and depletion of ATP, which are believed to cause symptoms, such as nausea, vomiting, hypoglycemia, and liver and kidney failure. These sequelae can be prevented by a fructose-restricted diet. Recent studies in aldolase B-deficient mice and HFI patients have provided more insight into the pathogenesis of HFI, in particular the liver phenotype. Both aldolase B-deficient mice (fed a very low fructose diet) and HFI patients (treated with a fructose-restricted diet) displayed greater intrahepatic fat content when compared to controls. The liver phenotype in aldolase B-deficient mice was prevented by reduction in intrahepatic Fru 1P concentrations by crossing these mice with mice deficient for ketohexokinase, the enzyme that catalyzes the synthesis of Fru 1P. These new findings not only provide a potential novel treatment for HFI, but lend insight into the pathogenesis of fructose-induced non-alcoholic fatty liver disease (NAFLD), which has raised to epidemic proportions in Western society. This narrative review summarizes the most recent advances in the pathogenesis of HFI and discusses the implications for the understanding and treatment of fructose-induced NAFLD.

Contains fulltext : 171523.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Early treatment of phenylketonuria (ET-PKU) prevents mental retardation, but many patients still show cognitive and mood problems. In this study, it was investigated whether ET-PKU-patients have specific phenylalanine (Phe-)related problems with respect to social-cognitive functioning and social skills. METHODS: Ninety five PKU-patients (mean age 21.6 +/- 10.2 years) and 95 healthy controls (mean age 19.6 +/- 8.7 years) were compared on performance of computerized and paper-and-pencil tasks measuring social-cognitive abilities and on parent- and self-reported social skills, using multivariate analyses of variance, and controlling for general cognitive ability (IQ-estimate). Further comparisons were made between patients using tetrahydrobiopterin (BH4, N = 30) and patients not using BH4. Associations with Phe-levels on the day of testing, during childhood, during adolescence and throughout life were examined. RESULTS: PKU-patients showed poorer social-cognitive functioning and reportedly had poorer social skills than controls (regardless of general cognitive abilities). Quality of social-cognitive functioning was negatively related to recent Phe-levels and Phe-levels between 8 and 12 years for adolescents with PKU. Quality of social skills was negatively related to lifetime phenylalanine levels in adult patients, and specifically to Phe-levels between 0 and 7, and between 8 and 12 years. There were no differences with respect to social outcome measures between the BH4 and non-BH4 groups. CONCLUSION: PKU-patients have Phe-related difficulties with social-cognitive functioning and social skills. Problems seem to be more evident among adolescents and adults with PKU. High Phe-levels during childhood and early adolescence seem to be of greater influence than current and recent Phe-levels for these patients.

Background and aims: Familial combined hyperlipidemia (FCHL) is a complex dyslipidemia associated with premature cardiovascular disease (CVD). The present study was conducted to 1) determine the incidence of CVD in FCHL in this era of protocolled, primary prevention; and 2) examine whether cardiovascular risk estimation based on the Systemic Coronary Risk Estimation (SCORE) chart, as proposed in the 2016 ESC/EAS guidelines for the management of dyslipidemia, is justified in FCHL.Methods: FCHL patients, their normolipidemic (NL) relatives and spouses originally included in our baseline cohort in 1998-2005 (n = 596) were invited for a follow-up visit to determine the incidence of CVD, defined as (non-) fatal coronary artery disease, ischemic stroke and peripheral artery disease requiring invasive treatment.Results: Follow-up data (median: 15 years) was acquired for 85% of the original cohort. The cumulative incidence of CVD was significantly higher in FCHL patients than in spouses (23.6% versus 4.7%; hazard ratio (HR): 5.4, 95% CI: 2.0-14.6; HR after adjustment for risk factors included in SCORE: 4.7, 95% CI: 1.6-13.8), but not in NL relatives compared to spouses (5.8% versus 4.7%). The SCORE chart tended to overestimate CVD risk in the spouses (observed [O]/expected [E] ratio: 0.2, p = 0.01), but not in FCHL patients (O/E: 1.3, p = 0.50).Conclusions: Risk of primary CVD is still substantially increased in FCHL patients, despite preventive measures. The overestimation of CVD risk by the SCORE chart -a nowadays frequently observed phenomenon thanks to improved primary prevention - was not seen in FCHL. These results suggest that more aggressive treatment is justified to avoid excessive CVD in FCHL.

Hepatology communications 3(4), 587-596 (2019). doi:10.1002/hep4.1319, Published by Wiley, Hoboken, NJ

Context: Hepatokines have emerged as potential mediators of obesity-associated comorbidities, such as type 2 diabetes, cardiovascular disease, fractures, and central hypogonadism.Objective: To assess whether weight loss-induced changes in hepatokines are mediated by intrahepatic triglyceride (IHTG) content.Design: Cross-sectional study and randomized controlled trial.Setting: General community.Participants: Metabolically healthy, lean men (waistIntervention: Men with abdominal obesity were randomized to 8-week dietary weight loss or no weight loss.Main Outcome Measures: IHTG and serum hepatokines, that is, serum IGF1, IGF binding protein 1 (IGFBP1), SHBG, fibroblast growth factor 21 (FGF21), fetuin A, and plasma fetuin B.Results: All hepatokines, except for fetuin B, were significantly different between lean men and men with obesity. After the weight-loss intervention (-10.3 kg; 95% CI, -11.4 to-9.2), serum IGF1, IGFBP1, SHBG, and fetuin A approached the values observed in lean men. Cross-sectional associations were observed between IHTG and IGF1 (beta = -0.51; 95% CI, -0.82 to -0.20), IGFBP1 (beta = -4.2; 95% CI, -7.7 to -0.7), and FGF21 (beta = 2.1; 95% CI, 1.3 to 2.9) in lean men and men with abdominal obesity combined. Weight loss resulted in a reduction of IHTG (treatment effect, -2.2%; 95% CI, -3.4% to -1.2%) that was associated with a change in IGF1 (beta = -0.9; 95% CI, -1.3 to -0.4), IGFBP1 (beta = -0.17; 95% CI, -0.31 to -0.03), and SHBG levels (beta = -0.18; 95% CI, -0.29 to -0.07). Mediation analyses showed that only the weight loss-induced change in serum IGF1 was mediated by IHTG (mediated effect, 32.7%; 95% CI, 4.6% to 79.2%).Conclusions: Dietary weight loss has differential effects on hepatokines. This study shows that the change in serum IGF1 levels after dietary weight loss is mediated by the change in IHTG content.

Introduction: Currently, around the world, the majority of patients with type 2 diabetes mellitus T2DM receives standardized care, based on evidence-based, disease-specific guidelines. Calls to step away from this ‘one-size-fits-all’ approach have been increasing and are supported by a growing body of scientific evidence showing its inherent limitations. Although a large proportion of diabetes care is based on self-management, limited knowledge exists on the care preferences of patients with T2DM. Consequently, patients’ care preferences cannot be considered in the development of tailored diabetes care approaches. The objective of this study was therefore to assess preferences of patients with T2DM towards diabetes care using a discrete choice experiment DCE. Methods: In this DCE, adult patients diagnosed with T2DM less than 5 years ago and treated in Dutch primary care were asked to choose repeatedly between two hypothetical diabetes care packages, which differed in six attributes identified through patient focus groups: role division in daily diabetes care planning, lifestyle education method, type of medication management support, consultation frequency, emotional support approach, and time spend on self-management. A mixed-logit model was used to estimate the relative importance of the included attributes. Results: Preliminary results based on data from193 patients with T2DM who completed the DCE survey 20.3% of the total research sample showed that 59.1% is male with a mean age of 68.2 years [SD 10.2]. Except for the estimate of the medication management support attribute, all other attribute estimates were statistically significant, indicating that they are important for patients with T2DM when choosing a diabetes care package. Frequency of consultations, emotional support approach, and lifestyle education method were the most important attributes with a relative importance of 25, 24 and 23%, respectively. Overall, patients preferred shorter consultation intervals three monthly instead of annually or six monthly and to receive emotional support from their general practitioner, practice nurse or diabetes nurse, rather than no support or support from a psychologist. They also preferred to receive lifestyle education individually instead of in a group or digitally. Discussion: The results of this study give insight into the care preferences of patients with T2DM. Care providers can use this information to develop tailored treatment plans for their patients. Conclusion: The most important aspects of diabetes care for patients with T2DM are frequency of consultations, emotional support approach, and lifestyle education method. Lessons learned: It is important to take into account patients’ care preferences in the development of tailored diabetes treatment plans. Limitations: Choices made in a DCE are hypothetical choices. It is unclear to which extent these choices reflect actual choices made in real life. Suggestions for future research: This is an ongoing study. In further research, subgroup analyses of patient preferences will be conducted based on patients’ glycemic control status. The influence of psychosocial characteristics, such as self-efficacy, educational level and quality of life, on patients’ care preferences will also be determined.

Objectives: Despite early and continuous treatment many patients with phenylketonuria (PKU) still experience neurocognitive problems. Most problems have been observed in the domain of executive functioning (EF). For regular monitoring of EF, the use of the Behavior Rating Inventory of Executive Function (BRIEF) has been proposed. The aim of this study was to investigate whether the BRIEF is indeed a useful screening instrument in monitoring of adults with PKU.Study design: Adult PKU patients (n = 55; mean age 28.3 +/- 6.2 years) filled out the BRIEF-A (higher scores = poorer EF) and performed computerized tasks measuring executive functions (inhibition, cognitive flexibility, and working memory). The outcome of the BRIEF-A questionnaire was compared with the neurocognitive outcome as measured by three tasks from the Amsterdam Neuropsychological Tasks (ANT).Results: Forty-two percent of the PKU patients scored in the borderline/clinical range of the BRIEF-A. Six of the 55 patients (11%) scored >1 SD above the normative mean, mostly on the Metacognition Index. With respect to ANT measurements, patients mainly showed deficits in inhibitory control (34-36%) and cognitive flexibility (31-40%) as compared to the general Dutch population. No significant correlations between the two methods were found, which was confirmed with the Bland-Altman approach where no agreement between the two methods was observed. Only with respect to inhibitory control, patients scored significantly worse on both BRIEF-A and ANT classifications. No other associations between classification according to the BRIEF-A and classifications according to the ANT tasks were found.Conclusions: Patients reporting EF problems in daily life are not necessarily those that present with core EF deficits. The results of this study suggest that regular self-administration of the BRIEF-A is not a sufficient way to monitor EF in adult PKU patients. (C) 2014 Elsevier Inc. All rights reserved.

The continuous search for drugs targeting type 2 diabetes mellitus (T2DM) has led to the identification of small molecules that disrupt the binding between glucokinase and glucokinase regulatory protein (GKRP). Although mice studies are encouraging, it will take years before these disruptors can be introduced to T2DM patients. Recently, genome-wide association studies (GWASs) have shown that variants in the gene encoding GKRP protect against T2DM and kidney disease but predispose to gout, nonalcoholic fatty liver disease, and dyslipidemia. These genetic data, together with previous experience with systemic and hepatospecific glucokinase activators, provide insight into the anticipated efficacy and safety of small-molecule disruptors in humans. Interestingly, they suggest that the opposite - enhanced GKRP-glucokinase binding - could be beneficial in selected patients.

BACKGROUND:\ud \ud Metformin might reduce insulin requirement and improve glycaemia in patients with type 1 diabetes, but whether it has cardiovascular benefits is unknown. We aimed to investigate whether metformin treatment (added to titrated insulin therapy) reduced atherosclerosis, as measured by progression of common carotid artery intima-media thickness (cIMT), in adults with type 1 diabetes at increased risk for cardiovascular disease.\ud \ud METHODS:\ud \ud REMOVAL was a double-blind, placebo-controlled trial undertaken at 23 hospital diabetes clinics in five countries (Australia, Canada, Denmark, the Netherlands, and the UK). Adults aged 40 years and older with type 1 diabetes of at least 5 years' duration and at least three of ten specific cardiovascular risk factors were randomly assigned (via an interactive voice response system) to oral metformin 1000 mg twice daily or placebo. Participants and site staff were masked to treatment allocation. The primary outcome was averaged mean far-wall cIMT, quantified annually for 3 years, analysed in a modified intention-to-treat population (all randomly assigned participants with post-randomisation data available for the outcome of interest at any given timepoint, irrespective of subsequent adherence or study participation), using repeated measures regression. Secondary outcomes were HbA1c, LDL cholesterol, estimated glomerular filtration rate (eGFR), incident microalbuminuria (not reported), incident retinopathy, bodyweight, insulin dose, and endothelial function, also analysed in all participants with post-randomisation data available for the outcome of interest at any given timepoint. This trial is registered with ClinicalTrials.gov, number NCT01483560.\ud \ud FINDINGS:\ud \ud Between Dec 14, 2011, and June 24, 2014, 493 participants entered a 3 month run-in to optimise risk factor and glycaemic control (single-blind placebo in the final month). Of 428 randomly assigned patients, 219 were allocated to metformin and 209 to placebo. Progression of mean cIMT was not significantly reduced with metformin (-0·005 mm per year, 95% CI -0·012 to 0·002; p=0·1664), although maximal cIMT (a prespecified tertiary outcome) was significantly reduced (-0·013 mm per year, -0·024 to -0·003; p=0·0093). HbA1c (mean 8·1% [SD 0·9] for metformin and 8·0% [0·8] for placebo at baseline) was reduced on average over 3 years by metformin (-0·13%, 95% CI -0·22 to -0·037; p=0·0060), but this was accounted for by a reduction at the 3-month timepoint (-0·24%, -0·34 to -0·13; p

We read with interest the Article in The Lancet Diabetes and Endocrinology by Dalong Zhu and colleagues, in which dorzagliatin, a dual-acting, allosteric glucokinase activator, showed a beneficial effect on glycaemic control in a phase 2 trial. Although the introduction of a new class of glucose-lowering drugs with a different mode of action is always welcome, particularly in this era of precision medicine, it is important to question the metabolic consequences of the dorzagliatin-induced reduction in plasma glucose.

Objectives The prognostic value of lactate in the setting of an emergency department (ED) has not been studied extensively. The goal of this study was to assess 28-day mortality in ED patients in whom lactate was elevated (≥4.0 mmol/L)

This article presents a new Dutch multicenter study ("PKU-COBESO") into cognitive and behavioral sequelae of early and continuously treated Phenylketonuria (PKU) patients. Part of the study sample will consist of young adult PKU patients who have participated in a large neuropsychological study approximately 10 years ago, when they were 7-to-15-year-olds (Huijbregts et al., 2002 [1]). Their neurocognitive development will be mapped in association with their earlier and continued metabolic history, taking into account possible changes in, for instance, medication.A second part of the sample will consist of PKU patients between the ages of 7 and approximately 40 years (i.e., born in or after 1974, when neonatal screening was introduced in The Netherlands), who have not participated in the earlier neuropsychological study. Again, their cognitive functioning will be related to their metabolic history. With respect to aspects of cognition, there will be an emphasis on executive functioning. The concept of executive functioning will however be extended with further emphasis on the impact of cognitive deficits on the daily lives of PKU patients, aspects of social cognition, social functioning, and behavior/mental health (i.e., COgnition, BEhavior, SOcial functioning: COBESO).In addition to a description of the PKU-COBESO study, some preliminary results with respect to mental health and social functioning will be presented in this article. Thirty adult PKU patients (mean age 27.8, SD 6.4) and 23 PKU patients under the age of 18 years (mean age 11.0, SD 33) were compared to 14 (mean age 26.9 years, SD 5.9) and 7 matched controls (mean age 10.5, SD 2.6) respectively, with respect to their scores on the Adult Self-Report or Child Behavior Checklist (measuring mental health problems) and the Social Skills Checklist or Social Skills Rating System (measuring social skills).Whereas there were very few significant group differences (except for mental health problems in the internalizing spectrum for adult PKU patients), possibly due to the small control groups, several significant associations between mental health problems and Phe levels were observed for the PKU patients. Childhood Phe levels and internalizing problems for adult PKU patients were related; concurrent Phe was associated with both internalizing and externalizing behavioral problems for those under the age of 18. These preliminary results underline the importance of early dietary adherence. (C) 2013 Elsevier Inc. All rights reserved.

OBJECTIVE Small molecules that disrupt the binding between glucokinase and glucokinase regulatory protein (GKRP) are potential new glucose-lowering targets. They stimulate hepatic glucose disposal by increasing glucokinase activity in the liver. It can, however, be anticipated that increased hepatic glucokinase activity might be accompanied by the development of hypertriglyceridemia, particularly in type 2 diabetes. We examined whether the strength of association between rs1260326, a common, functional gene variant in GKRP, and plasma lipids is affected by glucose metabolism. RESEARCH DESIGN AND METHODS rs1260326 was genotyped in subjects with normal glucose metabolism (n = 497), subjects with impaired glucose metabolism (n = 256), and patients with type 2 diabetes (n = 351) in the combined Hoorn and Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) studies. RESULTS The strength of association between the rs1260326 minor T allele and plasma triglycerides increased from normal glucose metabolism to impaired glucose metabolism to type 2 diabetes (P for interaction = 0.002). The inverse relation between rs1260326 and plasma HDL cholesterol was again most prominent in type 2 diabetes (P for interaction = 0.004). Similar trends were observed when the Hoorn and CODAM cohorts were analyzed separately. Comparable results were obtained when glucose metabolism strata were replaced by continuous indices of glucose metabolism, i.e., HbA1c and fasting plasma glucose. CONCLUSIONS These findings illustrate that common gene variants, such as rs1260326, can have substantial effect sizes when they are studied in specific populations, such as type 2 diabetes. Moreover, our results shed light on potential side effects of small molecule disruptors of the GKRP-glucokinase complex, especially when glucose control is suboptimal.

Objective To determine the association between use of sulphonylureas and risk of hypoglycaemia in relation to renal function and sulphonylurea metabolic group compared with use of metformin. Design Population based cohort study using routinely collected data from general practices in England. Setting Clinical Practice Research Datalink (CPRD) database, 2004-12. Participants 120 803 new users of a non-insulin antidiabetic agent with at least one prescription and aged 18 years or more. The first prescription defined start of follow-up. Patients were followed until the end of data collection, a record for hypoglycaemia, or a blood glucose level of less than 3.0 mmol/L. Main outcome measures Associations between sulphonylurea dose, renal impairment, type of sulphonylurea used, and risk of hypoglycaemia, were determined using Cox proportional hazard models. Adjustments were made for age, sex, lifestyle, comorbidity, and drug use. Results The risk of hypoglycaemia in current users of sulphonylureas only was significantly increased compared with current users of metformin only (adjusted hazard ratio 2.50, 95% confidence interval 2.23 to 2.82). The higher risk in current users of sulphonylureas only was further increased in patients with an estimated glomerular filtration rate of less than 30 mL/min/1.73 m 2 (4.96, 3.76 to 6.55). The risk of hypoglycaemia was also significantly higher in patients with a high sulphonylurea dose (3.12, 2.68 to 3.62) and in current users of glibenclamide (7.48, 4.89 to 11.44). Gliclazide, the sulphonylurea of first choice, showed a similar risk of hypoglycaemia compared with other sulphonylureas. Conclusions Sulphonylurea treatment in patients with a renal function of less than 30 mL/min/1.73 m 2 should be considered with caution. Moreover, an increased risk of hypoglycaemic events was observed among all users of sulphonylureas. This contrasts with several guidelines that recommend gliclazide as first choice sulphonylurea, and therefore requires further investigation.

The aim of the present study was to investigate the relationship between circulating PCSK9 (proprotein convertase subtilisin kexin type 9) and FCHL (familial combined hyperlipidaemia) and, when positive, to determine the strength of its heritability. Plasma PCSK9 levels were measured in FCHL patients (n=45), NL (normolipidaemic) relatives (n=139) and their spouses (n=72). In addition, 11 FCHL patients were treated with atorvastatin to study the response in PCSK9 levels. PCSK9 levels were higher in FCHL patients compared with NL relatives and spouses: 96.1 compared with 78.7 and 82.0 ng/ml (P=0.004 and P=0.002 respectively). PCSK9 was significantly associated with both TAG (triacylglycerol) and apolipoprotein B levels (P

OBJECTIVE: The current study was conducted to investigate whether greater arterial stiffening is already present in normolipidemic relatives of patients with familial combined hyperlipidemia (FCHL), as compared with healthy controls, and to establish the factors that are associated with arterial stiffness in comparison with markers of atherosclerosis. METHODS: Seventy-seven FCHL patients, 121 normolipidemic relatives and 72 spouses (controls) underwent ultrasound examination of the common carotid artery to determine the presence of plaques and the degree of arterial stiffness, expressed as stiffness index alpha. RESULTS: Age-adjusted and sex-adjusted analyses revealed that the arterial stiffness index alpha and prevalence of plaques were higher in normolipidemic relatives when compared with spouses, but lower than in FCHL patients (P

FCHL (familial combined hyperlipidaemia), an entity with many features of the metabolic syndrome, is characterized by changes in cholesterol and triacylglycerol (triglyceride) phenotype over time. The present study was conducted to investigate the relationship of ALT (alanine aminotransferase) levels, used as a surrogate marker for the amount of hepatic fat, with the switch in triacylglycerol phenotype and the increased susceptibility to develop hypertriglyceridaemia in FCHL. BMI (body mass index), waist circumference and plasma triacylglycerols, insulin and ALT levels were measured in 145 FCHL family members and 54 spouses at baseline and after a 5-year follow-up. A switch from normotriglyceridaemia to hypertriglyceridaemia or vice versa, as observed in 22 of 145 FCHL family members, was associated with changes in plasma ALT levels (P=0.001), but not with insulin levels or waist circumference. At 5 years of follow-up, an intra-individual relationship was observed between waist circumference and plasma triacylglycerols, insulin and ALT levels. For each waist circumference, FCHL patients, but not their NL (normolipidaemic) relatives, exhibited higher triacylglycerol and insulin levels than spouses (P

Glycogenic hepatopathy is a rare but probably underdiagnosed feature of poorly controlled diabetes, in particular type 1 diabetes. It is characterized by excessive hepatic glycogen storage as first described in 1930 by Mauriac as a part of a syndrome comprising growth retardation, delayed puberty, and Cushingoid features in young patients with type 1 diabetes (1). Recent case reports have demonstrated that glycogenic hepatopathy can be the sole presenting feature of Mauriac syndrome (reviewed in ref. 2). Here, we describe four strikingly similar cases of young adults with poorly controlled type 1 diabetes who presented with excess hepatic glycogen storage and increased plasma lactate levels. The combination of these metabolic abnormalities led to the initial presumption …

VLDL overproduction, a process that is driven by an excess amount of hepatic fat, is a well-documented feature of familial combined hyperlipidemia (FCHL). The aims of this study were to investigate whether fatty liver, measured with ultrasound and as plasma alanine aminotransferase (ALT) levels, develops against a genetic background in FCHL and to identify chromosomal loci that are linked to these traits. In total, 157 FCHL family members and 20 spouses participated in this study. Radiological evidence of fatty liver was more prevalent not only in FCHL probands (40%) but also in their relatives (35%) compared with spouses (15%) (P < 0.05). Heritability calculations revealed that 20-36% of the variability in ALT levels could be attributed to genetic factors. Nonparametric quantitative trait locus (QTL) analysis revealed three significant (P < 0.001) loci with either the ultrasound or the ALT trait in the male sample: 1q42.3, 7p12-21, and 22p13-q11; none was found in the female sample or the entire group. Of these QTLs, the 7p region was consistent over time, because reanalysis with ALT levels that were determined during a visit 5 years earlier yielded similar results. This study shows that fatty liver is a heritable aspect of FCHL. Replication of particularly the 7p region is awaited.

Homozygous carriers of the apolipoprotein 62 allele are at risk of type III hyperlipidaemia, but do not necessarily develop this lipid disorder. In the present study, we have investigated the role of circulating PCSK9 (pro-protein convertase subtilisin kexin type 9), an important regulator of LDL (low-density lipoprotein) receptor expression, in the development of this hyperlipidaemic phenotype. In an observational study, plasma PCSK9 was measured in homozygous carriers of apolipoprotein epsilon 2 (epsilon 2/epsilon 2; n=12), normal controls (n = 72) and hypertriglyceridaemic patients with FCHL (familial combined hyperlipidaemia; n = 38), who served as a hyperlipidaemic reference group. Cholesterol, triacylglycerols (triglycerides) and apolipoprotein B content in VLDL (very-low-density lipoprotein) and LDL particles was determined by ultracentrifugation in epsilon 2/epsilon 2 and FCHL patients. Median circulating PCSK9 levels did not differ between epsilon 2/epsilon 2 carriers compared with controls and hypertriglyceridaemic FCHL patients (84.5 compared with 82.0 and 84.9 ng/ml; P = 0.2 and 0.6 respectively). Circulating PCSK9 was associated with total cholesterol and triacylglycerols levels in epsilon 2/epsilon 2 carriers (P