Effects of a Flavonoid-Rich Blackcurrant Beverage on Markers of the Gut-Brain Axis in Healthy Females: Secondary Findings From a 4-Week Randomized Crossover Control Trial.

The microbiota-gut-brain axis is a promising target to alleviate the growing burden of neurologic and mental health disorders. Dietary polyphenols act on multiple components of the microbiota-gut-brain axis, but this complex relationship requires further attention. This randomized, placebo-controlled, double-blind, crossover trial (ACTRN12622000850774) compared 4 wk of a commercially available flavonoid-rich blackcurrant beverage (FBB; 151 mg anthocyanins, 308 mg total polyphenols) with placebo in 40 healthy females (18-45 y). The primary outcome of stress reactivity was assessed by change in present feelings of stress, mood, and fatigue before and after completing a 20-min cognitive stressor [Purple multitasking framework (MTF)]. Secondary end points included cognitive performance (MTF), mood [profile of mood states (POMS)], sleep (Pittsburgh Sleep Quality Index), fecal microbiome composition and functional potential (shotgun sequencing), and blood biomarker concentrations (brain-derived neurotrophic factor, tryptophan, kynurenine, and interleukin 6). Statistical analyses were conducted on an intention-to-treat basis using linear mixed-effect models. Thirty-eight participants completed both intervention arms. There was no significant treatment effect on the primary outcome of stress reactivity. Compared with placebo, working memory (letter retrieval scores from MTF), and anxiety/tension and anger/hostility domains of the POMS improved with FBB supplementation (time × intervention interaction; P < 0.05). There were no treatment effects on gut microbiome composition or functional potential. Baseline abundances of Bifidobacterium genera and species (Bifidobacterium longum and Bifidobacterium bifidum) tended to be higher in participants with the greatest improvements in letter retrieval scores with FBB supplementation (nominally significant, P < 0.05). In conclusion, 4-wk FBB supplementation improved secondary outcomes of working memory performance during multitasking and mood outcomes in healthy adult females. These results should be confirmed in a larger cohort with a longer duration of follow-up.

Vitamin B and One-Carbon Metabolite Profiles Show Divergent Associations with Cardiometabolic Risk Markers but not Cognitive Function in Older New Zealand Adults: A Secondary Analysis of the REACH Study.

BACKGROUND: Vitamin B inadequacies and elevated homocysteine status have been associated with impaired cognitive and cardiometabolic health with aging. There is, however, a scarcity of research investigating integrated profiles of one-carbon (1C) metabolites in this context, including metabolites of interconnected folate, methionine, choline oxidation, and transsulfuration pathways. OBJECTIVES: The study aimed to examine associations between vitamins B and 1C metabolites with cardiometabolic health and cognitive function in healthy older adults, including the interactive effects of Apolipoprotein E-ε4 status. METHODS: Three hundred and thirteen healthy participants (65-74 y, 65% female) were analyzed. Vitamins B were estimated according to dietary intake (4-d food records) and biochemical status (serum folate and vitamin B12). Fasting plasma 1C metabolites were quantified by liquid chromatography with tandem mass spectrometry. Measures of cardiometabolic health included biochemical (lipid panel, blood glucose) and anthropometric markers. Cognitive function was assessed by the Computerized Mental Performance Assessment System (COMPASS) and Montreal Cognitive Assessment (MoCA). Associations were analyzed using multivariate linear (COMPASS, cardiometabolic health) and Poisson (MoCA) regression modeling. RESULTS: Over 90% of participants met dietary recommendations for riboflavin and vitamins B6 and B12, but only 78% of males and 67% of females achieved adequate folate intakes. Higher serum folate and plasma betaine and glycine concentrations were associated with favorable cardiometabolic markers, whereas higher plasma choline and homocysteine concentrations were associated with greater cardiometabolic risk based on body mass index and serum lipids concentration values (P< 0.05). Vitamins B and homocysteine were not associated with cognitive performance in this cohort, though higher glycine concentrations were associated with better global cognitive performance (P = 0.017), episodic memory (P = 0.016), and spatial memory (P = 0.027) scores. Apolipoprotein E-ε4 status did not modify the relationship between vitamins B or 1C metabolites with cognitive function in linear regression analyses. CONCLUSIONS: Vitamin B and 1C metabolite profiles showed divergent associations with cardiometabolic risk markers and limited associations with cognitive performance in this cohort of healthy older adults.

Adherence and eating experiences differ between participants following a flexitarian diet including red meat or a vegetarian diet including plant-based meat alternatives: findings from a 10-week randomised dietary intervention trial.

Background: Flexitarian, vegetarian and exclusively plant-based diets are increasingly popular, particularly amongst young adults. This is the first randomised dietary intervention to investigate the health, wellbeing, and behavioural implications of consuming a basal vegetarian diet that additionally includes low-to-moderate amounts of red meat (flexitarian) compared to one containing plant-based meat alternatives (PBMAs, vegetarian) in young adults (ClinicalTrials.gov NCT04869163). The objective for the current analysis is to measure adherence to the intervention, nutrition behaviours, and participants' experience with their allocated dietary group. Methods: Eighty healthy young adults participated in this 10-week dietary intervention as household pairs. Household pairs were randomised to receive either approximately three serves of red meat (average of 390 g cooked weight per individual, flexitarian group) or PBMAs (350-400 g per individual, vegetarian group) per week on top of a basal vegetarian diet. Participants were supported to adopt healthy eating behaviours, and this intervention was developed and implemented using a behaviour change framework. Adherence (eating allocated red meat or PBMA, abstaining from animal-based foods not provided by researchers) was continuously monitored, with total scores calculated at the end of the 10-week intervention period. Eating experiences were measured by the Positive Eating Scale and a purpose-designed exit survey, and a food frequency questionnaire measured dietary intake. Analyses used mixed effects modeling taking household clustering into account. Results: The total average adherence score was 91.5 (SD = 9.0) out of a possible 100, with participants in the flexitarian group scoring higher (96.1, SD = 4.6, compared to 86.7, SD = 10.0; p < 0.001). Those receiving red meat were generally more satisfied with this allocation compared to those receiving the PBMAs, even though a leading motivation for participants joining the study was an opportunity to try plant-based eating (35% expressed that their interest in taking part was related to trying plant-based eating). Participants in both intervention groups had increased vegetable intake (p < 0.001), and reported more positive eating experiences (p = 0.020) and satisfaction with eating (p = 0.021) at the end of the 10-week intervention relative to baseline values. Conclusion: Methods to encourage engagement with the trial were successful, as participants demonstrated excellent adherence to the intervention. Observed differences in participants' adherence and experiences between flexitarian and vegetarian groups holds implications for the adoption of healthy, sustainable dietary patterns beyond this study alone.

The acute postprandial response of homocysteine to multivitamin and mineral supplementation with a standard meal is not impaired in older compared to younger adults.

PURPOSE: B vitamins are required for the complex regulation of homocysteine and one-carbon (1C) metabolism. Nutritional supplements are frequently used by older adults to counter nutritional inadequacies. However, the postprandial use of B vitamins from supplements in 1C metabolism may be altered with age owing to impaired nutrient absorption and metabolic regulation. Despite implications for health and nutritional status, postprandial 1C metabolite responses have not been characterised in older adults. METHODS: Healthy older (n = 20, 65-76 years) and younger (n = 20, 19-30 years) participants were recruited through online and printed advertisements in Auckland, New Zealand. Participants consumed a multivitamin and mineral supplement with a standard breakfast meal. Blood samples were collected at baseline and hourly for 4 h following ingestion. Plasma 1C metabolites (betaine, choline, cysteine, dimethylglycine, glycine, methionine, serine) were quantified using liquid chromatography coupled with mass spectrometry. Serum homocysteine, folate and vitamin B12 were quantified on a Cobas e411 autoanalyzer. RESULTS: Older adults had higher fasting homocysteine concentrations (older: 14.0 ± 2.9 µmol/L; younger: 12.2 ± 2.5 µmol/L; p = 0.036) despite higher folate (older: 36.7 ± 17.4 nmol/L; younger: 21.6 ± 7.6 nmol/L; p < 0.001) and similar vitamin B12 concentrations (p = 0.143) to younger adults. However, a similar postprandial decline in homocysteine was found in older and younger subjects in response to the combined meal and supplement. Except for a faster decline of cystathionine in older adults (p = 0.003), the postprandial response of other 1C metabolites was similar between young and older adults. CONCLUSION: Healthy older adults appear to maintain postprandial responsiveness of 1C metabolism to younger adults, supported by a similar postprandial decline in homocysteine concentrations.

Nutritional supplementation alters associations between one-carbon metabolites and cardiometabolic risk profiles in older adults: a secondary analysis of the Vienna Active Ageing Study.

PURPOSE: Cardiovascular diseases and cognitive decline, predominant in ageing populations, share common features of dysregulated one-carbon (1C) and cardiometabolic homeostasis. However, few studies have addressed the impact of multifaceted lifestyle interventions in older adults that combine both nutritional supplementation and resistance training on the co-regulation of 1C metabolites and cardiometabolic markers. METHODS: 95 institutionalised older adults (83 ± 6 years, 88.4% female) were randomised to receive resistance training with or without nutritional supplementation (Fortifit), or cognitive training (control for socialisation) for 6 months. Fasting plasma 1C metabolite concentrations, analysed by liquid chromatography coupled with mass spectrometry, and cardiometabolic parameters were measured at baseline and the 3- and 6-month follow-ups. RESULTS: Regardless of the intervention group, choline was elevated after 3 months, while cysteine and methionine remained elevated after 6 months (mixed model time effects, p < 0.05). Elevated dimethylglycine and lower betaine concentrations were correlated with an unfavourable cardiometabolic profile at baseline (spearman correlations, p < 0.05). However, increasing choline and dimethylglycine concentrations were associated with improvements in lipid metabolism in those receiving supplementation (regression model interaction, p < 0.05). CONCLUSION: Choline metabolites, including choline, betaine and dimethylglycine, were central to the co-regulation of 1C metabolism and cardiometabolic health in older adults. Metabolites that indicate upregulated betaine-dependent homocysteine remethylation were elevated in those with the greatest cardiometabolic risk at baseline, but associated with improvements in lipid parameters following resistance training with nutritional supplementation. The relevance of how 1C metabolite status might be optimised to protect against cardiometabolic dysregulation requires further attention.

The Effect of Elevated Protein Intake on DNA Damage in Older People: Comparative Secondary Analysis of Two Randomized Controlled Trials.

A high protein intake at old age is important for muscle protein synthesis, however, this could also trigger protein oxidation with the potential risk for DNA damage. The aim of this study was to investigate whether an increased protein intake at recommended level or well above would affect DNA damage or change levels of reduced (GSH) and oxidised glutathione (GSSG) in community-dwelling elderly subjects. These analyses were performed in two randomized intervention studies, in Austria and in New Zealand. In both randomized control trials, the mean protein intake was increased with whole foods, in the New Zealand study (n = 29 males, 74.2 ± 3.6 years) to 1.7 g/kg body weight/d (10 weeks intervention; p < 0.001)) in the Austrian study (n = 119 males and females, 72.9 ± 4.8 years) to 1.54 g/kg body weight/d (6 weeks intervention; p < 0.001)). In both studies, single and double strand breaks and as formamidopyrimidine-DNA glycosylase-sensitive sites were investigated in peripheral blood mononuclear cells or whole blood. Further, resistance to H2O2 induced DNA damage, GSH, GSSG and CRP were measured. Increased dietary protein intake did not impact on DNA damage markers and GSH/GSSG levels. A seasonal-based time effect (p < 0.05), which led to a decrease in DNA damage and GSH was observed in the Austrian study. Therefore, increasing the protein intake to more than 20% of the total energy intake in community-dwelling seniors in Austria and New Zealand did not increase measures of DNA damage, change glutathione status or elevate plasma CRP.

Heat Treatment of Milk: A Rapid Review of the Impacts on Postprandial Protein and Lipid Kinetics in Human Adults.

Background: Most milk consumed by humans undergoes heat treatment to ensure microbiological safety and extend shelf life. Although heat treatment impacts the structure and physiochemical properties of milk, effects on nutrient absorption in humans are unclear. Therefore, a rapid review was performed to identify studies conducted on healthy human adult subjects that have assessed the impacts of heat treatment of milk on protein and fat digestion and metabolism in the postprandial period (up to 24 h). Methods: Relevant databases (Medline, EMBASE, Cochrane, Scopus) were systematically screened for intervention studies on healthy adult men and women that assessed the impact of consuming heat-treated milk on the postprandial kinetics or appearance in peripheral circulation or urine of ingested proteins and/or lipids. The risk-of-bias assessment tool 2 was used for quality assessment. Results: Of 511 unique database records, 4 studies were included encompassing 6 study treatments (n = 57 participants, 20-68 years). Three studies evaluated pasteurization, two evaluated ultra-high temperature (UHT) treatment, and one evaluated oven-heated milk. Protein and lipid appearances in peripheral blood were reported in two sets of two studies. None of the studies used the same heat treatments and outcome measures, limiting generalization of effects. Protein appearance (ng/mL or area under the curve) (as plasma amino acids - lysine) was reduced when milk was oven-heated for 5 h in one study (n = 7 participants), while the other study reported a reduced retention of dietary N with UHT milk (n = 25 participants). Overall plasma triacylglycerol responses were unaffected by milk heat treatments reported, but plasma fatty acid composition differed. The studies observed higher plasma myristic and palmitic acid abundance with successive heat treatment at 2 h (n = 11 participants; pasteurized) and 4 h (n = 14 participants; UHT) after ingestion; other differences were inconsistent. All studies had moderate-high risk of bias, which should be taken into consideration when interpreting findings. Discussion: This review identified few studies reporting the effects of milk heat treatment on postprandial nutrient responses in adults. Although the findings suggest that milk heat treatment likely affects postprandial protein and lipid dynamics, generalization of the findings is limited as treatments, outcomes, and methods differed across studies. Because of the study variability, and the acute post-prandial nature of the studies, it is also difficult to draw conclusions regarding potential long-term health outcomes. However, the possibility that altered digestive kinetics may influence postprandial protein retention and anabolic use of dietary N suggests heat treatment of milk may impact outcomes such as long-term maintenance of muscle mass.

Responsiveness of one-carbon metabolites to a high-protein diet in older men: Results from a 10-wk randomized controlled trial.

OBJECTIVES: Dietary strategies to promote successful aging are divergent. Higher-protein diets are recommended to preserve skeletal muscle mass and physical function. Conversely, increased B-vitamin intake, supporting one-carbon (1C) metabolism, reduces the risk of cognitive decline and cardiovascular disease. On the hypothesis that higher protein intake through animal-based sources will benefit 1C regulation by the supply of B vitamins (folate, riboflavin, and vitamins B6 and B12) and methyl donors (choline) despite higher methionine intake, this study explored the effect of a higher-protein diet on 1C metabolite status in older men compared to current protein recommendations. METHODS: Older men (age, 74 ± 3 y) were randomized to receive a diet for 10 wk containing either the recommended dietary allowance (RDA) of protein (0.8 g/kg body weight/d, n = 14), or double that amount (2RDA, n = 15), with differences in protein accounted for by modifying carbohydrate intake. Intervention diets were matched to each individual's energy requirements based on the Harris-Benedict equation and adjusted fortnightly as required depending on physical activity and satiety. Fasting plasma 1C metabolite concentrations were quantified by liquid chromatography coupled with mass spectrometry at baseline and after 10 wk of intervention. RESULTS: Plasma homocysteine concentrations were reduced from baseline to follow-up with both diets. Changes in metabolite ratios reflective of betaine-dependent homocysteine remethylation were specific to the RDA diet, with an increase in the betaine-to-choline ratio and a decrease in the dimethylglycine-to-betaine ratio. Comparatively, increasing folate intake was positively associated with a change in choline concentration and inversely with the betaine-to-choline ratio for the 2RDA group. CONCLUSIONS: Adding to the known benefits of higher protein intake in older people, this study supports a reduction of homocysteine with increased consumption of animal-based protein, although the health effects of differential response of choline metabolites to a higher-protein diet remain uncertain.

Protein Intake at Twice the RDA in Older Men Increases Circulatory Concentrations of the Microbiome Metabolite Trimethylamine-N-Oxide (TMAO).

Higher dietary protein intake is increasingly recommended for the elderly; however, high protein diets have also been linked to increased cardiovascular disease (CVD) risk. Trimethylamine-N-oxide (TMAO) is a bacterial metabolite derived from choline and carnitine abundant from animal protein-rich foods. TMAO may be a novel biomarker for heightened CVD risk. The purpose of this study was to assess the impact of a high protein diet on TMAO. Healthy men (74.2 ± 3.6 years, n = 29) were randomised to consume the recommended dietary allowance of protein (RDA: 0.8 g protein/kg bodyweight/day) or twice the RDA (2RDA) as part of a supplied diet for 10 weeks. Fasting blood samples were collected pre- and post-intervention for measurement of TMAO, blood lipids, glucose tolerance, insulin sensitivity, and inflammatory biomarkers. An oral glucose tolerance test was also performed. In comparison with RDA, the 2RDA diet increased circulatory TMAO (p = 0.002) but unexpectedly decreased renal excretion of TMAO (p = 0.003). LDL cholesterol was increased in 2RDA compared to RDA (p = 0.049), but no differences in other biomarkers of CVD risk and insulin sensitivity were evident between groups. In conclusion, circulatory TMAO is responsive to changes in dietary protein intake in older healthy males.

Derivation and validation of the prediabetes self-assessment screening score after acute pancreatitis (PERSEUS).

BACKGROUND AND AIM: Approximately 40% of patients develop abnormal glucose metabolism after a single episode of acute pancreatitis. This study aimed to develop and validate a prediabetes self-assessment screening score for patients after acute pancreatitis. METHODS: Data from non-overlapping training (n=82) and validation (n=80) cohorts were analysed. Univariate logistic and linear regression identified variables associated with prediabetes after acute pancreatitis. Multivariate logistic regression developed the score, ranging from 0 to 215. The area under the receiver-operating characteristic curve (AUROC), Hosmer-Lemeshow χ2 statistic, and calibration plots were used to assess model discrimination and calibration. The developed score was validated using data from the validation cohort. RESULTS: The score had an AUROC of 0.88 (95% CI, 0.80-0.97) and Hosmer-Lemeshow χ2 statistic of 5.75 (p=0.676). Patients with a score of ≥75 had a 94.1% probability of having prediabetes, and were 29 times more likely to have prediabetes than those with a score of <75. The AUROC in the validation cohort was 0.81 (95% CI, 0.70-0.92) and the Hosmer-Lemeshow χ2 statistic was 5.50 (p=0.599). Model calibration of the score showed good calibration in both cohorts. CONCLUSION: The developed and validated score, called PERSEUS, is the first instrument to identify individuals who are at high risk of developing abnormal glucose metabolism following an episode of acute pancreatitis.

Fasting levels of insulin and amylin after acute pancreatitis are associated with pro-inflammatory cytokines.

BACKGROUND: The prevalence of metabolic diseases continues to rise worldwide, with a growing recognition of metabolic dysregulation after acute inflammatory diseases such as acute pancreatitis (AP). Adipokines and cytokines play an important role in metabolism and the course of AP, but there is a paucity of research investigating their relationship with pancreatic hormones after AP. This study aimed to explore associations between pancreatic hormones and adipokines as well as cytokines to provide insights into the pathophysiology of altered pancreatic hormone secretion following AP [corrected]. METHODS: A total of 83 patients previously diagnosed with AP and no prior diabetes or pre-diabetes were recruited into this cross-sectional follow up study. Fasting venous blood samples were collected to analyse a panel of pancreatic hormones and derivatives (amylin, C-peptide, glucagon, insulin, pancreatic polypeptide, somatostatin), adipokines (adiponectin, leptin, retinol binding protein-4, and resistin), and cytokines (interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumour necrosis factor-α (TNF-α)). Linear regression analyses were used, and potential confounders were adjusted for in multivariate analyses. RESULTS: Insulin was significantly associated with IL-6 in both unadjusted and adjusted models (p = .029 and p = .040, respectively). Amylin was significantly associated with MCP-1 in the unadjusted model (p = .046), and TNF-α in unadjusted and adjusted models (p = .025 and p = .027, respectively). CONCLUSIONS: Insulin and amylin have a strong positive association with pro-inflammatory cytokines in patients following an episode of AP. These associations have possible relevance in the development of diabetes associated with diseases of the exocrine pancreas, providing the opportunity to develop novel treatment paradigms.

Glucose Variability Measures as Predictors of Oral Feeding Intolerance in Acute Pancreatitis: A Prospective Pilot Study.

BACKGROUND: Oral feeding intolerance (OFI) is a common complication in patients with acute pancreatitis (AP). Variations in blood glucose are associated with impaired gastrointestinal function but, to date, measures of glucose variability have not been investigated to predict OFI in patients with AP. AIM: To investigate the usefulness of several glucose variability measures in predicting the occurrence of OFI early in the course of AP. METHODS: In this prospective cohort study, six measures of glucose variability were calculated prior to the occurrence of OFI. Multivariate binary logistic regression analyses were conducted, and the diagnostic performance and accuracy of glucose variability measures were assessed. RESULTS: Of the 95 prospectively enrolled patients, 21 (22%) developed OFI. After adjusting for confounders, admission blood glucose concentration and mean blood glucose concentration were significantly associated with OFI [odds ratio 1.49 (95% confidence interval 1.01-2.20) and odds ratio 1.67 (95% confidence interval 1.07-2.61), respectively]. Both admission blood glucose and mean blood glucose had an area under the curve of 0.83 and positive likelihood ratios of 6.45 and 10.19, respectively. Blood glucose concentration before refeeding, standard deviation of blood glucose concentration, coefficient of variation, and mean amplitude of glycemic excursions were not significantly associated with OFI. CONCLUSION: In-hospital blood glucose concentrations are associated with subsequent development of OFI in patients with AP. In particular, admission blood glucose and mean blood glucose could be useful predictors of OFI in this setting.

Associations between circulating levels of adipocytokines and abdominal adiposity in patients after acute pancreatitis.

Adipocytokines are strongly associated with abdominal adiposity during the course of acute pancreatitis (AP). This study investigated associations between a panel of adipocytokines and abdominal adiposity in AP patients after hospital discharge, as well as the effect of several covariates. Fasting venous blood samples were collected to measure adiponectin, interleukin 6, leptin, monocyte chemoattractant protein 1, tumour necrosis factor α (TNFα), resistin, and retinol-binding protein 4. Waist circumference (WC), waist-hip ratio, and waist-height ratio (WheightR) were used as measures of abdominal adiposity. Generalised linear models were built, adjusting for age, sex, ethnicity, diabetes status, aetiology, duration since admission for AP, recurrence, and severity of AP. A total of 93 patients were studied, on average at 22 months after AP. Interleukin 6, TNFα, and leptin were significantly associated with WC in both the unadjusted and all the three adjusted models. Also, they were significantly associated with WheightR in both the unadjusted and the three adjusted models. Other studied adipocytokines did not show a consistent association or were not significantly associated with the abdominal adiposity indices. The results suggest that excess abdominal adiposity favours pro-inflammatory milieu in AP patients after hospital discharge, independent of diabetes and effect of other covariates.

Lipid metabolism in patients with chronic hyperglycemia after an episode of acute pancreatitis.

BACKGROUND: The importance of dyslipidemia is well recognized in the context of both risk factor for acute pancreatitis and prognostic factor for its in-hospital outcomes. With a growing appreciation of post-pancreatitis diabetes mellitus, there is a need to catalogue changes in lipid metabolism after hospitalization due to an acute pancreatitis attack and their associations with glucose metabolism. OBJECTIVE: To investigate lipid metabolism in patients with impaired glucose homeostasis following acute pancreatitis. METHODS: There were two study groups: newly diagnosed chronic hyperglycemia or normoglycemia after acute pancreatitis. During the fasting state, venous blood samples were collected to analyse markers of lipid metabolism (triglycerides, glycerol, low density lipoprotein, high density lipoprotein, total cholesterol, free fatty acids, and apolipoprotein-B) and glucose metabolism (HbA1c, insulin, index of adipose tissue insulin resistance (Adipo-IR), and HOMA-IR). Binary logistic and linear regression analyses were conducted, and potential confounders were adjusted for in multivariate analyses. RESULTS: The study included 64 patients with normoglycemia and 19 - with chronic hyperglycemia. Glycerol was significantly associated with the development of chronic hyperglycemia in both unadjusted (p=0.02) and adjusted (p=0.006) models. Triglycerides were significantly associated with the development of chronic hyperglycemia in adjusted (p=0.019) model. Other markers of lipid metabolism did not differ significantly between the two groups. None of the markers of lipid metabolism was significantly associated with Adipo-IR or HOMA-IR. CONCLUSION: Overall, patients with chronic hyperglycemia after acute pancreatitis appear to have a lipid profile indicative of an up-regulation of lipolysis, which is not significantly affected by either general or adipose tissue-specific insulin resistance.