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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.

Aims/hypothesis Serum sex hormone-binding globulin (SHBG) has been proposed to act as a hepatokine that contributes to the extrahepatic complications observed in non-alcoholic fatty liver disease (NAFLD). However, it remains uncertain whether serum SHBG mediates the association between intrahepatic lipids (IHL) and type 2 diabetes. Therefore, we studied whether, and to what extent, serum SHBG mediates the association between IHL content and type 2 diabetes. Methods We used cross-sectional data from the Maastricht Study (n=1554), a population-based cohort study with oversampling of individuals with type 2 diabetes. Type 2 diabetes status was assessed by oral glucose tolerance test, and IHL content was measured using 3T Dixon MRI. Mediation analyses were performed to assess the role of serum SHBG in mediating the association between IHL content and type 2 diabetes. Results IHL content was significantly associated with type 2 diabetes in women and men (OR 1.08 [95% CI 1.04, 1.14] and OR 1.12 [95% CI 1.08, 1.17], respectively). Serum SHBG significantly mediated the association between IHL content and type 2 diabetes. The contribution of serum SHBG was higher in women (OR 1.04 [95% CI 1.02, 1.07]; proportion mediated 50.9% [95% CI 26.7, 81.3]) than in men (OR 1.02 [95% CI 1.01, 1.03]; proportion mediated 17.2% [95% CI 9.6, 27.6]). Repeat analyses with proxies of type 2 diabetes and adjustment for covariates did not substantially affect the results. Conclusions/interpretation In this large-scale population-based cohort study, serum SHBG was found to be a mediator of the association between IHL content and type 2 diabetes. These findings extend our understanding of the potential mechanisms by which NAFLD is a risk factor for type 2 diabetes, and further elaborate on the role of SHBG as a hepatokine. Graphical abstract

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 (

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

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent among individuals with type 2 diabetes. Although epidemiological studies have shown that NAFLD is associated with cardiovascular disease (CVD), it remains unknown whether NAFLD is an active contributor or an innocent bystander. Plasma lipids, low-grade inflammation, impaired fibrinolysis and hepatokines are potential mediators of the relationship between NAFLD and CVD. The Mendelian randomisation approach can help to make causal inferences. Studies that used common variants in PNPLA3, TM6SF2 and GCKR as instruments to investigate the relationship between NAFLD and coronary artery disease (CAD) have reported contrasting results. Variants in PNPLA3 and TM6SF2 were found to protect against CAD, whereas variants in GCKR were positively associated with CAD. Since all three genes have been associated with non-alcoholic steatohepatitis, the second stage of NAFLD, the question of whether low-grade inflammation is an important mediator of the relationship between NAFLD and CAD arises. In contrast, the differential effects of these genes on plasma lipids (i.e. lipid-lowering for PNPLA3 and TM6SF2, and lipid-raising for GCKR) strongly suggest that plasma lipids account for their differential effects on CAD risk. This concept has recently been confirmed in an extended set of 12 NAFLD susceptibility genes. From these studies it appears that plasma lipids are an important mediator between NAFLD and CVD risk. These findings have important clinical implications, particularly for the design of anti-NAFLD drugs that also affect lipid metabolism.

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. ​

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.

Aims Limited knowledge exists on the preferences of people with Type 2 diabetes towards diabetes care. Consequently, these care preferences cannot yet be considered in the development of tailored diabetes care approaches. Therefore, this study aimed to assess care preferences and their determinants in people with Type 2 diabetes. Methods A discrete choice experiment was conducted to elicit people's preferences. People with Type 2 diabetes, treated in 30 Dutch primary care practices, were asked to choose repeatedly between two hypothetical diabetes care packages, which differed in six attributes: role division in daily diabetes care planning, lifestyle education method, type of medication management support, consultation frequency, emotional support and time spend on self‐management. A mixed‐logit model was used to estimate the relative importance of the included attributes. Preference heterogeneity among people with different person‐ and disease‐related characteristics was investigated. Results In total, 288 participants completed the experiment. They preferred to plan their daily diabetes care together with a healthcare provider, to receive individual lifestyle education, medication and emotional support from a healthcare provider, one consultation visit every 3 months and to spend less time on self‐management. Participants did not prefer to receive emotional support from a psychologist. Heterogeneity in preferences could partly be explained by differences in sex, education level and glucose‐lowering drug use. Conclusion People with Type 2 diabetes show a preference for traditional care models. Emotional support was identified by participants as the most important attribute. It is therefore important to adequately guide them when changes in diabetes care organization are implemented., What's new? There is increasing consensus that the preferences of people with Type 2 diabetes should be used to develop tailored diabetes care approaches.In this study, participants with Type 2 diabetes clearly indicated that they did not prefer to receive emotional support from a psychologist and preferred traditional care models, such as one consultation every 3 months.The information from this study can be used to tailor Type 2 diabetes care by identifying subgroups of people with Type 2 diabetes with varying preferences towards Type 2 diabetes care, and can potentially lead to more person‐centred care.

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.

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: 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)

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.

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.

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.

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

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.

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 …

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

stiffening leads to an increased velocity of the pulse wave that is generated during the cardiac contraction. An increased pulse wave velocity results in early wave reflections reaching the heart during the systole instead of diastole, which has important cardiac consequences [5]. First, cardiac hypertrophy develops because of increased cardiac afterload. Furthermore, cardiac perfusion decreases, as the coronary arteries are perfused during diastole [5].

Metformin-associated lactate acidosis is a rare, but life-threatening complication of a widely prescribed medication. We describe here a case of metformin-associated lactate acidosis that rapidly deteriorated probably as a consequence of concomitant glucose infusion that was initiated to correct sulphonylurea-induced hypoglycemia.

Item does not contain fulltext BACKGROUND AND AIMS: Two recent independent studies showed that patients with familial combined hyperlipidemia (FCHL) have elevated plasma levels of proprotein convertase subtilisin kexin type 9 (PCSK9) and markers of cholesterol synthesis. Both PCSK9 expression and cholesterol synthesis are downstream effects of hepatic activation of sterol regulatory element binding protein 2 (SREBP2). The present study was conducted to study the relationship between plasma PCSK9 and markers of cholesterol synthesis in FCHL. METHODS AND RESULTS: Markers of cholesterol synthesis (squalene, desmosterol, lathosterol), cholesterol absorption (campesterol, sitosterol, cholestanol) and PCSK9 were measured in plasma of FCHL patients (n = 103) and their normolipidemic relatives (NLR; n = 240). Plasma PCSK9, lathosterol and desmosterol levels were higher in FCHL patients than their NLR (p < 0.001, age and sex adjusted). Heritability calculations demonstrated that 35% of the variance in PCSK9 levels could be explained by additive genetic effects (p < 0.001). Significant age- and sex-adjusted correlations were observed for the relationship between PCSK9 and lathosterol, both unadjusted and adjusted for cholesterol, in the overall FCHL population (both p < 0.001). Multivariate regression analyses, with PCSK9 as the dependent variable, showed that the regression coefficient for FCHL status decreased by 25% (from 0.8 to 0.6) when lathosterol was included. Nevertheless, FCHL status remained an independent contributor to plasma PCSK9 (p < 0.001). CONCLUSIONS: The present study confirms the previously reported high and heritable PCSK9 levels in FCHL patients. Furthermore, we now show that high PCSK9 levels are, in part, explained by plasma lathosterol, suggesting that SREBP2 activation partly accounts for elevated PCSK9 levels in FCHL.

Background: Dysfunctional adipose tissue plays an important role in the etiology of the metabolic syndrome, type 2 diabetes, and dyslipidemia. However, the molecular mechanisms underlying adipocyte dysfunction are incompletely understood. Aim: The aim of the study was to identify differentially regulated pathways in sc adipocytes of dyslipidemic subjects. Methods: Whole-genome expression profiling was conducted on sc adipocytes from a discovery group of nine marginally overweight subjects with familial combined hyperlipidemia (FCHL) and nine controls of comparable body sizes as well as two independent confirmation groups. In this study, FCHL served as a model of familial insulin resistance and dyslipidemia, in the absence of frank obesity. Results: Functional analyses and gene set enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes or a custom pathway database identified the complement system and complement regulators as one of the top up-regulated pathways in FCHL [false discovery rate (FDR)

The existence of metformin-induced lactic acidosis has been questioned, in particular in the absence of specific risk factors such as impaired renal function. This report describes the presence of lactic acidosis in a patient with normal kidney function and normal doses of metformin. Subsequent positive rechallenge with metformin confirms causality.

Objective Type 2 diabetes mellitus (T2DM) is associated with elevated plasma apolipoprotein B and triglycerides levels, reduced HDL cholesterol and the presence of small-dense LDL particles. The present study was conducted to investigate the role of plasma proprotein convertase subtilisin kexin type 9 (PCSK9) levels, a regulator of LDL-receptor expression, in the occurrence of diabetic dyslipidemia. Methods Plasma PCSK9 was measured in a cohort of subjects with normal glucose metabolism (NGM; n = 288), impaired glucose metabolism (IGM; n = 121) and type 2 diabetes mellitus (T2DM; n = 139) to study whether its relation with plasma apolipoprotein B, triglycerides, total cholesterol, non-HDL cholesterol, LDL cholesterol and HDL cholesterol differed by levels of glucose metabolism status. Results Plasma PCSK9 levels were not different between the three groups (82, 82 and 80 ng/mL in NGM, IGM and T2DM, respectively). PCSK9 was positively associated with total cholesterol, non-HDL cholesterol, LDL cholesterol, apolipoprotein B and triglycerides levels in all subgroups. The regression slopes for the associations with non-HDL cholesterol were steeper among individuals with T2DM than with NGM ( β = 0.016 versus β = 0.009, p -interaction = 0.05). Similar results were obtained for the relation with apolipoprotein B ( β = 0.004 versus β = 0.002, p -interaction = 0.09). Conclusions Although glucose metabolism status per se is not associated with plasma PCSK9 levels, the presence of T2DM may modify the relation between plasma PCSK9 and non-HDL cholesterol and apolipoprotein B. These observations should be regarded as hypothesis generating for further studies aimed at elucidating the role of PCSK9 in the pathogenesis and treatment of diabetic dyslipidemia.

The role of ventricular–arterial hemodynamic interaction in the occurrence of arterial dissection and rupture in vascular Ehlers–Danlos syndrome (vEDS) is unknown. We recently introduced an ultrasound-based method to extract, from common carotid artery (CCA) diameter waveforms, central arterial properties and left ventricular (LV) systolic time intervals. We obtained CCA diameters, compliance and distensibility coefficients, and LV isovolumic contraction and ejection periods (ICP and EP) of 19 vEDS patients (aged 27–65 yrs) and 19 age-matched healthy controls. CCA distension and compliance tended to be lower in vEDS subjects (p = 0.062 and p = 0.073), especially in younger patients. ICP (−12 ms) and EP (−24 ms) were shorter (p < 0.001), while heart rate was increased (+10 bpm; p < 0.001) in vEDS. The ICP/EP ratio and estimated isovolumic dPLV/dt indicated increased LV contractility in vEDS. In conclusion, vascular EDS patients tend to have a lower CCA compliance but a normal pulse pressure, most likely reflecting reduced physical fitness.

ObjectiveAdipose tissue releases factors (adipokines) that influence local, peripheral as well as central processes. In the present study, we determined the relationship between plasma concentration of a recently identified adipokine, pigment epithelium-derived factor (SERPINF1), and human obesity, particularly specific adipose tissue depots, and other features of the metabolic syndrome.MethodsWe examined the plasma concentration of SERPINF1, anthropometric parameters, abdominal s.c. and visceral adipose tissue, lipid, glucose, insulin, and alanine aminotransferase level in a non-diabetic general Caucasian population (n=59).ResultsPlasma SERPINF1 level in males (6.2±2.1 μg/ml) was higher than in females (3.1±1.4 μg/ml; Pβ=0.361, P=0.010) and body mass index (β=0.288, P=0.008) were significant independent determinants of plasma SERPINF1 level, together with gender (β=−0.424, PConclusionsWe conclude that the plasma SERPINF1 level is strongly associated with body adiposity, in particular with the visceral fat depot in the non-diabetic general population. This association may (partly) explain the relationship between SERPINF1 and metabolic syndrome in this population.

AIMS: Low-density lipoprotein cholesterol (LDL-C) levels are often fairly normal in Type 2 diabetes mellitus (DM). We anticipated that a parabolic relation between plasma triglycerides and LDL-C, as previously demonstrated in familial combined hyperlipidaemia (FCHL), might account for this phenomenon. METHODS: Our hypothesis was tested in 1343 subjects derived from the general population who were studied on two occasions 6 years apart (the Hoorn study). Three groups were constructed depending on plasma triglycerides: group A (individuals with both measurements below 1.5 mmol/l), group B (one measurement below and one above 1.5 mmol/l) and group C (both measurements above 1.5 mmol/l). Diabetes status was ascertained by an oral glucose tolerance test. RESULTS: In a mixed linear model, a significant, positive relation between triglycerides and LDL-C was observed for males in group A (beta(a) = 0.5, P < 0.001) and group B (beta(b) = 0.2, P < 0.001), whereas a significant negative relation was found for males in group C (beta(c) = -0.2, P = 0.003). The regression slopes did not differ between diabetic and non-diabetic subjects. Similar results were obtained for women, with the exception that the relation was not significantly negative in group C (beta(c) = -0.1, P = 0.4). CONCLUSION: Plasma triglycerides and LDL-C are related in a parabolic fashion, not only in FCHL, but also in the general population and Type 2 DM. These findings aid our interpretation of typical dyslipidaemia and the effects of treatment that are frequently observed in hypertriglyceridaemic states.

Contains fulltext : 69040.pdf (Publisher’s version ) (Open Access) FCHL (familial combined hyperlipidaemia) is a highly prevalent genetic lipid disorder that accounts for a substantial number of premature cardiovascular events. To date, FCHL has been complicated by the different lipid phenotypes that are present within one family and one individual patient over time. In the present study, we hypothesized that a parabolic relationship between plasma triacylglycerols (triglycerides) and LDL (low-density lipoprotein)-cholesterol can explain this so-called 'multiple-type hyperlipidaemia' in FCHL. Our hypothesis was tested in two well-documented FCHL cohorts [Maastricht (n=145) and Nijmegen (n=299)] that were followed over a 5-year interval. Three groups were constructed depending on plasma triacylglycerols: group A (individuals with both measurements below 1.5 mmol/l), group B (one measurement below and one measurement above 1.5 mmol/l) and group C (both measurement above 1.5 mmol/l). In both male, but not female, cohorts, a significant positive relationship between plasma triacylglycerols and LDL-cholesterol was observed in group A (P=0.02 for Maastricht cohort and P=0.001 for the Nijmegen cohort), a significant negative relationship in group C (P=0.01 for Maastricht cohort and P=0.02 for the Nijmegen cohort), and a relationship intermediate to group A and C in group B. In contrast, both apoB (apolipoprotein B) levels and the prevalence of cardiovascular disease were related with plasma triacylglycerols in a more linear fashion. In conclusion, a parabolic relationship between plasma triacylglycerols and LDL-cholesterol explains the 'multiple-type hyperlipidaemia' in FCHL. In addition, the linear relationship between triacylglycerols and both apoB levels and the prevalence of cardiovascular disease substantiate the use of apoB instead of LDL-cholesterol in the diagnosis of FCHL and the prediction of cardiovascular disease.

Familial combined hyperlipidemia (FCHL) is a genetic form of dyslipidemia, which is characterized by an increased cardiovascular risk. The current study was conducted to investigate the relation of endothelial, inflammatory and fibrinolysis markers with the presence of hypertriglyceridemia and fatty liver in FCHL, in order to advance insight in their contribution to the cardiovascular risk profile.Key plasma markers of low-grade inflammation, endothelial dysfunction and fibrinolysis were measured in 38 hypertriglyceridemic FCHL patients and 38 age and sex-matched spouses. The presence of fatty liver was determined with ultrasound.hsCRP, vWF, PAI-1, tPA and tPA/PAI-1 complex levels were significantly higher in hypertriglyceridemic FCHL patients compared to spouses (p0.05). Subsequent analyses revealed that these increased levels were confined to FCHL patients with the fatty liver phenotype (n=25). Only PAI-1 and tPA levels were also elevated in the hypertriglyceridemic FCHL patients without fatty liver (n=13). Of interest, 11 hypertriglyceridemic non-FCHL patients with the E2/E2 genotype displayed significantly lower PAI-1 levels when compared to the overall FCHL population (p=0.001), implicating a role for apolipoprotein E in the relation of PAI-1 with plasma triglycerides.Markers of fibrinolysis were increased in all hypertriglyceridemic FCHL patients, whereas an increased state of endothelial dysfunction and inflammation was particularly observed in those hypertriglyceridemic FCHL patients who also have fatty liver. These results demonstrate the complex genesis of the unfavourable cardiovascular risk profile that is present in FCHL, and illustrate the potential risk of fatty liver above, and beyond hypertriglyceridemia per se.