Sex differences in adipose insulin resistance are linked to obesity, lipolysis and insulin receptor substrate 1.

BACKGROUND/OBJECTIVE: Insulin resistance is more prominent in men than women. If this involves adipose tissue is unknown and was presently examined. SUBJECTS/METHODS: AdipoIR (in vivo adipose insulin resistance index) was measured in 2344 women and 787 men. In 259 of the women and 54 of the men, insulin induced inhibition of lipolysis (acylglycerol breakdown) and stimulation of lipogenesis (glucose conversion to acylglycerols) were determined in subcutaneous adipocytes; in addition, basal (spontaneous) lipolysis was also determined in the fat cells. In 234 women and 115 men, RNAseq expression of canonical insulin signal genes were measured in subcutaneous adipose tissue. Messenger RNA transcripts of the most discriminant genes were quantified in 175 women and 109 men. RESULTS: Men had higher AdipoIR values than women but only when obesity (body mass index 30 kg/m2 or more) was present (p < 0.0001). The latter sex dimorphism was found among physically active and sedentary people, in those with and without cardiometabolic disease and in people using nicotine or not (p = 0.0003 or less). In obesity, adipocyte insulin sensitivity (half maximum effective hormone concentration) and maximal antilipolytic effect were tenfold and 10% lower, respectively, in men than women (p = 0.005 or less). Basal rate of lipolysis was two times higher in men than women (p > 0.0001). Sensitivity and maximum effect of insulin on lipogenesis were similar in both sexes (p = 0.26 and p = 0.18, respectively). When corrected for multiple comparison only RNAseq expression of insulin receptor substrate 1 (IRS1) was lower in men than women (p < 0.0001). The mRNA transcript for IRS1 was 60% higher in women than men (p < 0.0001). CONCLUSIONS: In obesity, adipose tissue insulin resistance is more pronounced in men than in women. The mechanism involves less efficient insulin-mediated inhibition of adipocyte lipolysis, increased basal rate of lipolysis and decreased adipose expression of a key element of insulin signaling, IRS1.

Reflections on the discovery GLP-1 as a satiety hormone: Implications for obesity therapy and future directions.

Scientists were chasing an incretin hormone, and when GLP-1 was finally discovered, we found that it had a pronounced satiety effect, slowed down gastric emptying, and actually reduced postprandial insulin response. These mechanisms are the basis for the highly efficacious GLP-1 analogues that today offer safe and effective treatment in millions of people living with obesity. Moreover, the combined GLP-1 mechanisms of weight loss and delayed carbohydrate absorption may also be the key drivers of remission of type 2 diabetes and reduced cardiovascular events found by GLP-1 analogues.

Social inequity in health among patients with severe obesity and multimorbidity.

INTRODUCTION: Obesity adversely affects the health of the individual and impacts society through increased healthcare costs and lost workdays. Individuals in lower socioeconomic groups are more severely affected. Here, we examined people living with severe obesity and comorbidities across educational levels. METHODS: Individuals with a BMI ≥ 35 kg/m2 and aged ≥ 16 years from the Danish National Health Survey 2021 were categorised into five educational levels and according to their number of obesity-related comorbidities (0, 1, 2 and ≥ 3). RESULTS: A total of 5.8% had a BMI ≥ 35 kg/m2, ranging from 2.2% to 10.7% in the 98 municipalities, and from 2.6% to 8.8% according to education level. Among individuals with a BMI ≥ 35 kg/m2 and the shortest education, 13.4% had no comorbidities, and 45.6% had ≥ 3 comorbidities. In contrast, among individuals with a BMI ≥ 35 kg/m2 and the longest education, 47.4% had no comorbidities, and 14.6% had ≥ 3 comorbidities. Among those with a BMI ≥ 35 kg/m2 and ≥ 3 comorbidities, 73.6% had elementary or vocational school as their highest education level, and 3.4% had a long higher education. CONCLUSIONS: The prevalence of individuals living with a BMI ≥ 35 kg/m2 differs by 3-5-fold depending on municipality and between the lowest and highest educational level. Additionally, the less educated group living with a BMI ≥ 35 kg/m2 was three times more likely to have ≥ 3 comorbidities than the most educated group. Hence, more research is warranted to understand the underlying causes and reduce social inequity in health. FUNDING: Novo Nordisk Fonden. TRIAL REGISTRATION: Not relevant.

Health-Related Quality of Life during 26-Week Intervention with the New Nordic Renal Diet.

The New Nordic Renal Diet (NNRD) is a whole-food approach, tailored to meet recommended guidelines in patients with moderate chronic kidney disease (stage 3b-4). The NNRD improved various metabolic and physiological endpoints during a 26-week randomized controlled study. Here, we examined the effect of dietary intervention on health-related quality of life (HRQoL). Sixty participants were recruited (NNRD group n = 30, control group n = 30) and 58 completed the study. During the intervention, the NNRD group received food boxes, and recipes once a week. The control group continued their habitual diet. HRQoL was examined at baseline and at the end of the intervention using the validated EuroQol-5D-5L, including a 5-point scale Likert questionnaire at the end of the intervention. Assessed by the EuroQol-5D-5L questionnaire, the NNRD group experienced a reduction in pain/discomfort during the intervention by 26% [-0.44 points (95% CI; -0.73, -0.16)], compared with no change in the control group [0.25 points (95% CI; -0.02, 0.53)] and a between-group difference of -0.70 points (95% CI; -1.03, -0.37, p < 0.001). A larger decrease of body fat mass was associated with a larger decrease in pain/discomfort (p = 0.014). In addition, the NNRD group reported an overall improvement in conducting usual daily activities by 23% [-0.30-point (95% CI; -0.50, -0.11)], while no change was seen in the control group [-0.02 points (95% CI; -0.21, 0.17)], with a between-group difference -0.28 points (95% CI; -0.51, -0.06, p = 0.014). A larger decrease in 24 h urine phosphorus excretion, used as a marker of compliance, was associated with a larger improvement in conducting usual daily activities (p = 0.036). The NNRD group had a clinically relevant improvement in various HRQoL outcomes.

Long-term trajectories of weight loss and health outcomes: protocol of the SCOOP-RNPC nationwide observational study.

INTRODUCTION: Behavioural weight loss programmes are generally accepted as being beneficial in reducing cardiometabolic risk and improving patient-reported outcomes. However, prospective data from large real-world cohorts are scarce concerning the mid-term and long-term impact of such interventions. The objective of this large prospective cohort study (n>10 000 participants) is to demonstrate the effectiveness of the standardised Nutritional and Psycho-Behavioural Rehabilitation programme (RNPC Programme) in reducing the percentage of subjects requiring insulin and/or other diabetes drug therapy, antihypertensive drugs, lipid-lowering therapies and continuous positive airway pressure therapy for obstructive sleep apnoea after the end of the intervention. The rate of remission of hypertension, type 2 diabetes and sleep apnoea will also be prospectively assessed. METHODS: This is a prospective multicentre observational study carried out in 92 RNPC centres in France. Participants will follow the standardised RNPC Programme. The prospective dataset will include clinical, anthropometric and biochemical data, comorbidities, medications, body composition, patient-reported outcome questionnaire responses, sleep study data with objective measurements of sleep apnoea severity and surrogate markers of cardiovascular risk (ie, blood pressure and arterial stiffness). About 10 000 overweight or obese participants will be included over 2 years with a follow-up duration of up to 5 years. ETHICS AND DISSEMINATION: Ethical approval for this study has been granted by the Ethics Committee (Comité de protection des personnes Sud-Est I) of Saint-Etienne University Hospital, France (SI number: 23.00174.000237). Results will be submitted for publication in peer-review journals, presented at conferences and inform the design of a future randomised controlled trial in the specific population identified as good responders to the RNPC Programme. TRIAL REGISTRATION NUMBER: NCT05857319.

Post-intervention Adherence to the New Nordic Renal Diet among patients with chronic kidney disease, stages 3 and 4.

The New Nordic Renal Diet (NNRD) is a meal pattern reduced in phosphorus, protein, and sodium for patients with moderate chronic kidney disease. The NNRD showed improvements in metabolic, and physiological outcomes after 26-weeks intervention. In the original study, participants were randomized to NNRD (n = 30), or control (habitual diet) (n = 30). The aim of this study was to explore adherence to the NNRD 3 months after cessation of intervention (follow-up). Fifty-seven participants completed the follow-up visit, which consisted of fasting blood samples and 24 h urine samples. At follow-up, there was no longer a significant reduction in 24 h urine phosphorus excretion in the NNRD group. From intervention to follow-up, 24 h urine phosphorus increased by 63 mg in the NNRD group, vs. -24.1 mg in the control group, between-group difference 87.1 mg (-10.1, 184.3, p = 0.08). Our findings show that more active intervention is needed to support adherence and maintain beneficial effects of the NNRD.

Weight Loss for Patients With Gout and Concomitant Obesity: A Proof-of-Concept Randomized Trial.

OBJECTIVE: Despite scarce evidence, guidelines recommend weight loss as a management strategy for patients with gout. We investigated the effect of an intensive dietary intervention on body weight and clinical measures of gout severity in individuals with obesity and gout. METHODS: We conducted a 16-week randomized nonmasked parallel-group trial in Denmark, randomly assigning (one-to-one) individuals with obesity and gout to a low-energy diet or a control diet. The primary outcome was change in body weight. Key secondary outcomes were changes in serum urate (SU) level and visual analog scale-assessed pain and fatigue. RESULTS: Between December 1, 2018, and June 1, 2019, 61 participants were included in the intention-to-treat population and randomly assigned to the intensive diet group (n = 29) or control diet group (n = 32). Participants had a mean age of 60.3 (SD 9.9) years and mean body mass index of 35.6 (SD 5.0), and 59 (97%) were men. After 16 weeks, there was a significant difference in change in body weight between the diet and control groups (-15.4 vs -7.7 kg; difference -7.7 kg [95% confidence interval -10.7 to -4.7], P < 0.001). Despite results being potentially in favor of a low-energy diet, we could not confirm differences in SU level changes and fatigue between groups. No differences in pain and gout flares were observed between groups. No serious adverse events or deaths occurred during the trial. CONCLUSION: An intensive dietary intervention was safe and effectively lowered body weight in people with obesity and gout, but the weight loss did not directly translate into effects on SU level, fatigue, and pain.

On the pathogenesis of obesity: causal models and missing pieces of the puzzle.

Application of the physical laws of energy and mass conservation at the whole-body level is not necessarily informative about causal mechanisms of weight gain and the development of obesity. The energy balance model (EBM) and the carbohydrate-insulin model (CIM) are two plausible theories, among several others, attempting to explain why obesity develops within an overall common physiological framework of regulation of human energy metabolism. These models have been used to explain the pathogenesis of obesity in individuals as well as the dramatic increases in the prevalence of obesity worldwide over the past half century. Here, we summarize outcomes of a recent workshop in Copenhagen that brought together obesity experts from around the world to discuss causal models of obesity pathogenesis. These discussions helped to operationally define commonly used terms; delineate the structure of each model, particularly focussing on areas of overlap and divergence; challenge ideas about the importance of purported causal factors for weight gain; and brainstorm on the key scientific questions that need to be answered. We hope that more experimental research in nutrition and other related fields, and more testing of the models and their predictions will pave the way and provide more answers about the pathogenesis of obesity than those currently available.

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications.

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Interaction of Diet/Lifestyle Intervention and TCF7L2 Genotype on Glycemic Control and Adiposity among Overweight or Obese Adults: Big Data from Seven Randomized Controlled Trials Worldwide.

Objective. The strongest locus which associated with type 2 diabetes (T2D) by the common variant rs7903146 is the transcription factor 7-like 2 gene (TCF7L2). We aimed to quantify the interaction of diet/lifestyle interventions and the genetic effect of TCF7L2 rs7903146 on glycemic traits, body weight, or waist circumference in overweight or obese adults in several randomized controlled trials (RCTs).Methods. From October 2016 to May 2018, a large collaborative analysis was performed by pooling individual-participant data from 7 RCTs. These RCTs reported changes in glycemic control and adiposity of the variant rs7903146 after dietary/lifestyle-related interventions in overweight or obese adults. Gene treatment interaction models which used the genetic effect encoded by the allele dose and common covariates were applicable to individual participant data in all studies.Results. In the joint analysis, a total of 7 eligible RCTs were included (n=4,114). Importantly, we observed a significant effect modification of diet/lifestyle-related interventions on the TCF7L2 variant rs7903146 and changes in fasting glucose. Compared with the control group, diet/lifestyle interventions were related to lower fasting glucose by -3.06 (95% CI, -5.77 to -0.36) mg/dL (test for heterogeneity and overall effect: I2=45.1%, p<0.05; z=2.20, p=0.028) per one copy of the TCF7L2 T risk allele. Furthermore, regardless of genetic risk, diet/lifestyle interventions were associated with lower waist circumference. However, there was no significant change for diet/lifestyle interventions in other glycemic control and adiposity traits per one copy of TCF7L2 risk allele.Conclusions. Our findings suggest that carrying the TCF7L2 T risk allele may have a modestly greater benefit for specific diet/lifestyle interventions to improve the control of fasting glucose in overweight or obese adults.