Cytochrome P450, peroxisome proliferation, and cytoplasmic fatty acid-binding protein content in liver, heart and kidney of the diabetic rat

Diabetes mellitus generally results in an increased systemic fatty acid mobilization which can be associated with an increase in mitochondrial and peroxisomal beta-oxidation of fatty acids in selected tissues. The latter is usually accompanied by a concomitant increase in the tissue content of cytoplasmic fatty acid-binding protein (FABP) which functions in the intracellular translocation of fatty acids. It was previously found that in liver clofibrate-induced proliferation of peroxisomes and increase in FABP expression each are dependent on the induction by cytochrome P4504A1 -mediated (CYP4A1) formation of dicarboxylic acids. We studied whether peroxisome proliferation and an increase of FABP contents in liver, heart and kidney of streptozotocin-induced diabetic rats are also accompanied by an increase of CYP4A1 activity, as this would indicate a possible regulatory role for dicarboxylic acids in peroxisome proliferation and FABP induction in diabetic organs other than liver. In livers of the diabetic rat, a concomitant increase was observed of the activities of CYP4A1 and the peroxisomal key enzyme fatty acyl-CoA oxidase (FACO) and of the FABP content. In the diabetic heart FACO activity and FABP content also increased, but there was no induction of CYP4A1 activity. Conversely, in diabetic kidney there was no increase in FACO activity nor FABP content in spite of a marked induction of CYP4A1 activity. It is concluded that streptozotocin-induced diabetes leads to increased peroxisome proliferation and increased levels of FABP in both liver and heart, which only in liver is accompanied by an induction of the cytochrome P450 system. Consequently, it is not likely that dicarboxylic acids are involved in the induction of peroxisome proliferation in the heart

Study protocol: a randomised controlled trial on the clinical effects of levothyroxine treatment for subclinical hypothyroidism in people aged 80 years and over

Background: Subclinical hypothyroidism is common in older people and its contribution to health and disease needs to be elucidated further. Observational and clinical trial data on the clinical effects of subclinical hypothyroidism in persons aged 80 years and over is inconclusive, with some studies suggesting harm and some suggesting benefits, translating into equipoise whether levothyroxine therapy provides clinical benefits. This manuscript describes the study protocol for the Institute for Evidence-Based Medicine in Old Age (IEMO) 80-plus thyroid trial to generate the necessary evidence base. Methods: The IEMO 80-plus thyroid trial was explicitly designed as an ancillary experiment to the Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism randomised placebo controlled Trial (TRUST) with a near identical protocol and shared research infrastructure. Outcomes will be presented separately for the IEMO and TRUST 80-plus groups, as well as a pre-planned combined analysis of the 145 participants included in the IEMO trial and the 146 participants from the TRUST thyroid trial aged 80 years and over. The IEMO 80-plus thyroid trial is a multi-centre randomised double-blind placebo-controlled parallel group trial of levothyroxine treatment in community-dwelling participants aged 80 years and over with persistent subclinical hypothyroidism (TSH ≥4.6 and ≤ 19.9 mU/L and fT4 within laboratory reference ranges). Participants are randomised to levothyroxine 25 or 50 micrograms daily or matching placebo with dose titrations according to TSH levels, for a minimum follow-up of one and a maximum of three years. Primary study endpoints: hypothyroid physical symptoms and tiredness on the thyroid-related quality of life patient-reported outcome (ThyPRO) at one year. Secondary endpoints: generic quality of life, executive cognitive function, handgrip strength, functional ability, blood pressure, weight, body mass index, and mortality. Adverse events will be recorded with specific interest on cardiovascular endpoints such as atrial fibrillation and heart failure. Discussion: The combined analysis of participants in the IEMO 80-plus thyroid trial with the participants aged over 80 in the TRUST trial will provide the largest experimental evidence base on multimodal effects of levothyroxine treatment in 80-plus persons to date

A digitally enabled combined lifestyle intervention for weight loss: pilot study in a Dutch general population cohort

Background: Overweight and obesity rates among the general population of the Netherlands keep increasing. Combined lifestyle interventions (CLIs) focused on physical activity, nutrition, sleep, and stress management can be effective in reducing weight and improving health behaviors. Currently available CLIs for weight loss (CLI-WLs) in the Netherlands consist of face-to-face and community -based sessions, which face scalability challenges. A digitally enabled CLI-WL with digital and human components may provide a solution for this challenge; however, the feasibility of such an intervention has not yet been assessed in the Netherlands. Objective: The aim of this study was two -fold: (1) to determine how weight and other secondary cardiometabolic outcomes (lipids and blood pressure) change over time in a Dutch population with overweight or obesity and cardiometabolic risk participating in a pilot digitally enabled CLI-WL and (2) to collect feedback from participants to guide the further development of future iterations of the intervention. Methods: Participants followed a 16 -week digitally enabled lifestyle coaching program rooted in the Fogg Behavior Model, focused on nutrition, physical activity, and other health behaviors, from January 2020 to December 2021. Participants could access the digital app to register and track health behaviors, weight, and anthropometrics data at any time. We retrospectively analyzed changes in weight, blood pressure, and lipids for remeasured users. Surveys and semistructured interviews were conducted to assess critical positive and improvement points reported by participants and health care professionals. Results: Of the 420 participants evaluated at baseline, 53 participated in the pilot. Of these, 37 (70%) were classified as overweight and 16 (30%) had obesity. Mean weight loss of 4.2% occurred at a median of 10 months postintervention. The subpopulation with obesity (n=16) showed a 5.6% weight loss on average. Total cholesterol decreased by 10.2% and low -density lipoprotein cholesterol decreased by 12.9% on average. Systolic and diastolic blood pressure decreased by 3.5% and 7.5%, respectively. Participants identified the possibility of setting clear action plans to work toward and the multiple weekly touch points with coaches as two of the most positive and distinctive components of the digitally enabled intervention. Surveys and interviews demonstrated that the digital implementation of a CLI-WL is feasible and well -received by both participants and health care professionals. Conclusions: Albeit preliminary, these findings suggest that a behavioral lifestyle program with a digital component can achieve greater weight loss than reported for currently available offline CLI-WLs. Thus, a digitally enabled CLI-WL is feasible and may be a scalable alternative to offline CLI-WL programs. Evidence from future studies in a Dutch population may help elucidate the mechanisms behind the effectiveness of a digitally enabled CLI-WL.Public Health and primary carePrevention, Population and Disease management (PrePoD

A single site in human β-hexosaminidase A binds both 6-sulfate-groups on hexosamines and the sialic acid moiety of GM2 ganglioside

AbstractHuman β-hexosaminidase A (Hex A) (αβ) is composed of two subunits whose primary structures are ∼60% identical. Deficiency of either subunit results in severe neurological disease due to the storage of GM2 ganglioside; Tay–Sachs disease, α deficiency, and Sandhoff disease, β deficiency. Whereas both subunits contain active sites only the α-site can efficiently bind negatively charged 6-sulfated hexosamine substrates and GM2 ganglioside. We have recently identified the αArg424 as playing a critical role in the binding of 6-sulfate-containing substrates, and βAsp452 as actively inhibiting their binding. To determine if these same residues affect the binding of the sialic acid moiety of GM2 ganglioside, an αArg424Gln form of Hex A was expressed and its kinetics analyzed using the GM2 activator protein:[3H]-GM2 ganglioside complex as a substrate. The mutant showed a ∼3-fold increase in its Km for the complex. Next a form of Hex B (ββ) containing a double mutation, βAspLeu453AsnArg (duplicating the α-aligning sequences), was expressed. As compared to the wild type (WT), the mutant exhibited a >30-fold increase in its ability to hydrolyze a 6-sulfated substrate and was now able to hydrolyze GM2 ganglioside when the GM2 activator protein was replaced by sodium taurocholate. Thus, this α-site is critical for binding both types of negatively charge substrates

High prevalence of impaired awareness of hypoglycemia and severe hypoglycemia among people with insulin-treated type 2 diabetes: The Dutch Diabetes Pearl Cohort

Objective People with type 2 diabetes on insulin are at risk for hypoglycemia. Recurrent hypoglycemia can cause impaired awareness of hypoglycemia (IAH), and increase the risk for severe hypoglycemia. The aim of this study was to assess the prevalence and determinants of self-reported IAH and severe hypoglycemia in a Dutch nationwide cohort of people with insulin-treated type 2 diabetes. Research design and methods Observational study of The Dutch Diabetes Pearl, a cohort of people with type 2 diabetes treated in primary, secondary and tertiary diabetes care centers. The presence of IAH and the occurrence of severe hypoglycemia in the past year, defined as an event requiring external help to re