Metformin and carotid intima-media thickness in never-smokers with type 1 diabetes: the REMOVAL trial

Aim: To determine whether metformin's effects on carotid artery intima‐media thickness (cIMT) in type 1 diabetes differ according to smoking status. Methods: Regression 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. Results: In 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. Conclusions: This 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

Preferred conversation topics with respect to treatment decisions among individuals with type 2 diabetes.

Purpose Greater knowledge of individuals' needs and preferences can enhance shared decision-making, which is associated with improved quality of decisions and increased satisfaction. This study aimed to identify and prioritize the attributes (ie conversation topics) that individuals with type 2 diabetes find it most important to discuss with their healthcare provider regarding treatment decisions. Patients and methods First, small group interviews were organized with adults with type 2 diabetes (N=8) treated in primary care to identify the attributes that they find important to discuss regarding treatment decisions. A five-step nominal group technique was applied during the interviews. An object best-worst scaling (BWS) survey was subsequently distributed to individuals with self-reported diabetes participating in the Dutch Health Care Consumer Panel of the Netherlands Institute for Health Services Research (N=600) to determine the relative importance score (RIS) of the identified attributes. A higher RIS indicates a higher level of perceived importance. Subgroup and latent class analyses were performed to explore whether individuals' demographic and disease characteristics influenced their attribute preferences. Results A total of 21 attributes were identified during three small group interviews with individuals with type 2 diabetes. Respondents in the BWS survey (N=285) viewed "quality of life" (RIS=11.97), "clinical outcomes" (RIS=10.40), "long-term diabetes complications" (RIS=9.83) and "short-term adverse medication" (RIS=7.72) as the most important in the decision-making process for the treatment of type 2 diabetes. Some differences in attribute preferences were identified according to demographic and disease characteristics. Conclusion In general, individuals with type 2 diabetes not only want to discuss the biological effects of treatments, but also the impact of treatment on their quality of life. Healthcare providers should be aware that attributes are viewed differently by different individuals. This emphasizes the need for tailor-made healthcare decisions, which means eliciting and responding to individual preferences in the decision-making process

Effects of fructose added to an oral glucose tolerance test on plasma glucose excursions in healthy adults

Background and objective: Previous experimental studies have shown that fructose interacts with glucose metabolism by increasing hepatic glucose uptake. However, human studies investigating the effects of small (‘catalytic’) amounts of fructose, added to an oral glucose load, on plasma glucose levels remain inconclusive. The aim of this study, therefore, was to repeat and extend these previous studies by examining the plasma glucose response during a 75 g oral glucose tolerance test (OGTT) with the addition of different doses of fructose. Methods: Healthy adults (n = 13) received an OGTT without addition of fructose and OGTTs with addition of different doses of fructose (1, 2, 5, 7.5 and 15 g) in a random order, on six separate occasions. Plasma glucose levels were measured every 15 min for 120 min during the study. Findings: The plasma glucose incremental area under the curve (iAUC) of the OGTT without addition of fructose was not significantly different from any OGTT with fructose (p ≥ 0.2 for all fructose doses). Similar results were observed when these data were clustered with data from a similar, previous study (pooled mean difference: 10.6; 95%CI: 45.0; 23.8 for plasma glucose iAUC of the OGTT without addition of fructose versus an OGTT with 5 g fructose; fixed-effect meta-analysis, n = 38). Of interest, serum fructose increased from 4.8 μmol/L (interquartile range: 4.1–5.9) at baseline to 5.3 μmol/L (interquartile range: 4.8–7.5) at T = 60 min during an OGTT without addition of fructose (p = 0.002). Conclusion: Low doses of fructose added to an OGTT do not affect plasma glucose levels in healthy adults. The role of endogenous fructose production, as a potential explanation of these null-findings, deserves further investigation

Thiazolidinediones and Glucagon-Like Peptide-1 Receptor Agonists and the Risk of Nonalcoholic Fatty Liver Disease: A Cohort Study

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

Hepatic glucokinase regulatory protein and carbohydrate response element binding protein attenuation reduce de novo lipogenesis but do not mitigate intrahepatic triglyceride accumulation in Aldob deficiency

Objective: Stable isotope studies have shown that hepatic de novo lipogenesis (DNL) plays an important role in the pathogenesis of intrahepatic lipid (IHL) deposition. Furthermore, previous research has demonstrated that fructose 1-phosphate (F1P) not only serves as a substrate for DNL, but also acts as a signalling metabolite that stimulates DNL from glucose. The aim of this study was to elucidate the mediators of F1P-stimulated DNL, with special focus on two key regulators of intrahepatic glucose metabolism, i.e., glucokinase regulatory protein (GKRP) and carbohydrate response element binding protein (ChREBP). Methods: Aldolase B deficient mice (Aldob−/−), characterized by hepatocellular F1P accumulation, enhanced DNL, and hepatic steatosis, were either crossed with GKRP deficient mice (Gckr−/−) or treated with short hairpin RNAs directed against hepatic ChREBP. Results: Aldob−/− mice showed higher rates of de novo palmitate synthesis from glucose when compared to wildtype mice (p < 0.001). Gckr knockout reduced de novo palmitate synthesis in Aldob−/− mice (p = 0.017), without affecting the hepatic mRNA expression of enzymes involved in DNL. In contrast, hepatic ChREBP knockdown normalized the hepatic mRNA expression levels of enzymes involved in DNL and reduced fractional DNL in Aldob−/− mice (p < 0.05). Of interest, despite downregulation of DNL in response to Gckr and ChREBP attenuation, no reduction in intrahepatic triglyceride levels was observed. Conclusions: Both GKRP and ChREBP mediate F1P-stimulated DNL in aldolase B deficient mice. Further studies are needed to unravel the role of GKRP and hepatic ChREBP in regulating IHL accumulation in aldolase B deficiency

Thiazolidinediones and Glucagon-Like Peptide-1 Receptor Agonists and the Risk of Nonalcoholic Fatty Liver Disease:A Cohort Study

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

Traditional lifestyle factors partly mediate the association of socioeconomic position with intrahepatic lipid content:The Maastricht study

Background &amp; Aims: Recent studies have unveiled an association between socioeconomic position (SEP) and intrahepatic lipid (IHL) content. The aim of this study was to examine to what extent traditional lifestyle factors mediate the relationship between SEP and IHL content, independent of aetiology, and non-alcoholic fatty liver disease (NAFLD). Methods: We used cross-sectional data derived from The Maastricht Study (N = 4,001; mean age: 60 years, 49% women, 32% low education level, 21% diabetes, 21% NAFLD). Education, income, and occupation were used as indicators of SEP. Physical activity (accelerometer), intake of total energy, alcohol, saturated fat, protein, vitamin E, dietary fibre, and fructose from sugar-sweetened beverages (SSBs) and fruit juice (food frequency questionnaires) were potential mediators. IHL content was quantified by magnetic resonance imaging. Age, sex, and type 2 diabetes were covariates. Multiple parallel mediation analyses (bootstraps = 10,000) were performed. Results: Individuals with a low education level had a 1.056-fold higher IHL content (95% CI: 1.03–1.08) and a 44% greater NAFLD risk (OR:1.44; 95% CI:1.18–1.77) compared with those with higher education levels. Approximately 8.9% of educational disparity in risk of IHL content was attributable to moderate-to-vigorous physical activity; 6.3% to fructose intake from SSBs; 5.5% to dietary fibre; and -23% to alcohol. Approximately 8.7% of educational disparity in risk of NAFLD was attributable to moderate-to-vigorous physical activity; and 7.7% to fructose intake from SSBs. However, the indirect effect of these mediators was small (0.998 for IHL content and 1.045 for NAFLD) in comparison to the total effect. Similar results were found when income and occupation were used as SEP indicators. Conclusions: Societal measures may alleviate the burden of NAFLD and further studies that identify mediators other than traditional lifestyle factors are warranted to define the relationship underlying SEP and IHL content. Impact and implications: Individuals with a low or medium level of education, income, or occupational status had more fat accumulation in their livers than individuals with a higher education, income, or occupational status. This difference may be attributed to the influence of unhealthy lifestyle factors, such as reduced physical activity and a higher intake of sugar-sweetened beverages among individuals with lower socioeconomic position. Nevertheless, other yet unknown factors may also play a role

The impact of metabolic control and tetrahydrobiopterin treatment on health related quality of life of patients with early-treated phenylketonuria: A PKU-COBESO study

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