Circulatory miRNAs as Correlates of Elevated Intra-Pancreatic Fat Deposition in a Mixed Ethnic Female Cohort: The TOFI_Asia Study.

Ectopic lipid accumulation, including intra-pancreatic fat deposition (IPFD), exacerbates type 2 diabetes risk in susceptible individuals. Dysregulated circulating microRNAs (miRNAs) have been identified as correlating with clinical measures of pancreatitis, pancreatic cancer and type 1 diabetes. The aim of the current study was therefore to examine the association between circulating abundances of candidate miRNAs, IPFD and liver fat deposition as quantified using magnetic resonance imaging (MRI) and spectroscopy (MRS). Asian Chinese (n = 34; BMI = 26.7 ± 4.2 kg/m2) and European Caucasian (n = 34; BMI = 28.0 ± 4.5 kg/m2) females from the TOFI_Asia cohort underwent MRI and MRS analysis of pancreas (MR-%IPFD) and liver fat (MR-%liver fat), respectively, to quantify ectopic lipid deposition. Plasma miRNA abundances of a subset of circulatory miRNAs associated with IPFD and liver fat deposition were quantified by qRT-PCR. miR-21-3p and miR-320a-5p correlated with MR-%IPFD, plasma insulin and HOMA2-IR, but not MR-%liver fat. MR-%IPFD remained associated with decreasing miR-21-3p abundance following multivariate regression analysis. miR-21-3p and miR-320a were demonstrated to be negatively correlated with MR-%IPFD, independent of ethnicity. For miR-21-3p, this relationship persists with the inclusion of MR-%liver fat in the model, suggesting the potential for a wider application as a specific circulatory correlate of IPFD.

Postprandial glycine as a biomarker of satiety: A dose-rising randomised control trial of whey protein in overweight women.

This study aimed to identify biomarkers of appetite response, modelled using a dose-rising whey protein preload intervention. Female participants (n = 24) with body mass index (BMI) between 23 and 40 kg/m2 consumed preload beverages (0 g protein water control, WC; 12.5 g low-dose protein, LP; or 50.0 g high-dose protein, HP) after an overnight fast, in a randomised cross over design. Repeated venous blood samples were collected to measure plasma biomarkers of appetite response, including glucose, glucoregulatory peptides, gut peptides, and amino acids (AAs). Appetite was assessed using Visual Analogue Scales (VAS) and ad libitum energy intake (EI). Dose-rising protein beverage significantly changed the postprandial trajectory of almost all biomarkers (treatment*time, p < 0.05), but did not suppress postprandial appetite (treatment*time, p > 0.05) or EI (ANOVA, p = 0.799). Circulating glycine had the strongest association with appetite response. Higher area under the curve (AUC0-240) glycine was associated with lower EI (p = 0.026, trend). Furthermore, circulating glycine was associated with decreased Hunger in all treatment groups, whereas the associations of glucose, alanine and amylin with appetite were dependent on treatment groups. Multivariate models, incorporating multiple biomarkers, improved the estimation of appetite response (marginal R2, range: 0.13-0.43). In conclusion, whilst glycine, both alone and within a multivariate model, can estimate appetite response to both water and whey protein beverage consumption, a large proportion of variance in appetite response remains unexplained. Most biomarkers, when assessed in isolation, are poor predictors of appetite response, and likely of utility only in combination with VAS and EI.

Untargeted metabolomics reveals plasma metabolites predictive of ectopic fat in pancreas and liver as assessed by magnetic resonance imaging: the TOFI_Asia study.

BACKGROUND: Excess visceral obesity and ectopic organ fat is associated with increased risk of cardiometabolic disease. However, circulating markers for early detection of ectopic fat, particularly pancreas and liver, are lacking. METHODS: Lipid storage in pancreas, liver, abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from 68 healthy or pre-diabetic Caucasian and Chinese women enroled in the TOFI_Asia study was assessed by magnetic resonance imaging/spectroscopy (MRI/S). Plasma metabolites were measured with untargeted liquid chromatography-mass spectroscopy (LC-MS). Multivariate partial least squares (PLS) regression identified metabolites predictive of VAT/SAT and ectopic fat; univariate linear regression adjusting for potential covariates identified individual metabolites associated with VAT/SAT and ectopic fat; linear regression adjusted for ethnicity identified clinical and anthropometric correlates for each fat depot. RESULTS: PLS identified 56, 64 and 31 metabolites which jointly predicted pancreatic fat (R2Y = 0.81, Q2 = 0.69), liver fat (RY2 = 0.8, Q2 = 0.66) and VAT/SAT ((R2Y = 0.7, Q2 = 0.62)) respectively. Among the PLS-identified metabolites, none of them remained significantly associated with pancreatic fat after adjusting for all covariates. Dihydrosphingomyelin (dhSM(d36:0)), 3 phosphatidylethanolamines, 5 diacylglycerols (DG) and 40 triacylglycerols (TG) were associated with liver fat independent of covariates. Three DGs and 12 TGs were associated with VAT/SAT independent of covariates. Notably, comparison with clinical correlates showed better predictivity of ectopic fat by these PLS-identified plasma metabolite markers. CONCLUSIONS: Untargeted metabolomics identified candidate markers of visceral and ectopic fat that improved fat level prediction over clinical markers. Several plasma metabolites were associated with level of liver fat and VAT/SAT ratio independent of age, total and visceral adiposity, whereas pancreatic fat deposition was only associated with increased sulfolithocholic acid independent of adiposity-related parameters, but not age.

Intra-pancreatic fat is associated with high circulating glucagon and GLP-1 concentrations following whey protein ingestion in overweight women with impaired fasting glucose: A randomised controlled trial.

AIM: Intra-pancreatic fat deposition (IPFD) while hypothesised to impair beta-cell function, its impact on alpha-cells remains unclear. We evaluated the association between IPFD and markers of pancreatic cells function using whey protein. METHODS: Twenty overweight women with impaired fasting glucose (IFG) and low or high IPFD (<4.66% vs ≥4.66%) consumed 3 beverage treatments: 0 g (water control), 12.5 g (low-dose) and 50.0 g (high-dose) whey protein, after an overnight fast, in randomised order. Blood glucose, insulin, C-peptide, glucagon, gastric-inhibitory polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and amylin were analysed postprandially over 4 h. Incremental area-under-the-curve (iAUC), incremental maximum concentration (iCmax), and time to maximum concentration (Tmax) for these were compared between IPFD groups using repeated measures linear mixed models, also controlled for age (pcov). RESULTS: iAUC and iCmax glucose and insulin while similar between the two IPFD groups, high IPFD and ageing contributed to higher postprandial glucagon (iAUC: p = 0.012; pcov = 0.004; iCmax: p = 0.069; pcov = 0.021) and GLP-1 (iAUC: p = 0.006; pcov = 0.064; iCmax: p = 0.011; pcov = 0.122) concentrations. CONCLUSION: In our cohort, there was no evidence that IPFD impaired protein-induced insulin secretion. Conversely, IPFD may be associated with increased protein-induced glucagon secretion, a novel observation which warrants further investigation into its relevance in the pathogenesis of dysglycaemia and type-2 diabetes.

No Evidence That Circulating GLP-1 or PYY Are Associated with Increased Satiety during Low Energy Diet-Induced Weight Loss: Modelling Biomarkers of Appetite.

Bariatric surgery and pharmacology treatments increase circulating glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), in turn promoting satiety and body weight (BW) loss. However, the utility of GLP-1 and PYY in predicting appetite response during dietary interventions remains unsubstantiated. This study investigated whether the decrease in hunger observed following low energy diet (LED)-induced weight loss was associated with increased circulating 'satiety peptides', and/or associated changes in glucose, glucoregulatory peptides or amino acids (AAs). In total, 121 women with obesity underwent an 8-week LED intervention, of which 32 completed an appetite assessment via a preload challenge at both Week 0 and Week 8, and are reported here. Visual analogue scales (VAS) were administered to assess appetite-related responses, and blood samples were collected over 210 min post-preload. The area under the curve (AUC0-210), incremental AUC (iAUC0-210), and change from Week 0 to Week 8 (∆) were calculated. Multiple linear regression was used to test the association between VAS-appetite responses and blood biomarkers. Mean (±SEM) BW loss was 8.4 ± 0.5 kg (-8%). Unexpectedly, the decrease in ∆AUC0-210 hunger was best associated with decreased ∆AUC0-210 GLP-1, GIP, and valine (p < 0.05, all), and increased ∆AUC0-210 glycine and proline (p < 0.05, both). The majority of associations remained significant after adjusting for BW and fat-free mass loss. There was no evidence that changes in circulating GLP-1 or PYY were predictive of changes in appetite-related responses. The modelling suggested that other putative blood biomarkers of appetite, such as AAs, should be further investigated in future larger longitudinal dietary studies.

Gut microbiota profiles in two New Zealand cohorts with overweight and prediabetes: a Tu Ora/PREVIEW comparative study.

Obesity-related metabolic diseases such as type 2 diabetes (T2D) are major global health issues, affecting hundreds of millions of people worldwide. The underlying factors are both diverse and complex, incorporating biological as well as cultural considerations. A role for ethnicity - a measure of self-perceived cultural affiliation which encompasses diet, lifestyle and genetic components - in susceptibility to metabolic diseases such as T2D is well established. For example, Asian populations may be disproportionally affected by the adverse 'TOFI' (Thin on the Outside, Fat on the Inside) profile, whereby outwardly lean individuals have increased susceptibility due to excess visceral and ectopic organ fat deposition. A potential link between the gut microbiota and metabolic disease has more recently come under consideration, yet our understanding of the interplay between ethnicity, the microbiota and T2D remains incomplete. We present here a 16S rRNA gene-based comparison of the fecal microbiota of European-ancestry and Chinese-ancestry cohorts with overweight and prediabetes, residing in New Zealand. The cohorts were matched for mean fasting plasma glucose (FPG: mean ± SD, European-ancestry: 6.1 ± 0.4; Chinese-ancestry: 6.0 ± 0.4 mmol/L), a consequence of which was a significantly higher mean body mass index in the European group (BMI: European-ancestry: 37.4 ± 6.8; Chinese-ancestry: 27.7 ± 4.0 kg/m2; p < 0.001). Our findings reveal significant microbiota differences between the two ethnicities, though we cannot determine the underpinning factors. In both cohorts Firmicutes was by far the dominant bacterial phylum (European-ancestry: 93.4 ± 5.5%; Chinese-ancestry: 79.6 ± 10.4% of 16S rRNA gene sequences), with Bacteroidetes and Actinobacteria the next most abundant. Among the more abundant (≥1% overall relative sequence abundance) genus-level taxa, four zero-radius operational taxonomic units (zOTUs) were significantly higher in the European-ancestry cohort, namely members of the Subdoligranulum, Blautia, Ruminoclostridium, and Dorea genera. Differential abundance analysis further identified a number of additional zOTUs to be disproportionately overrepresented across the two ethnicities, with the majority of taxa exhibiting a higher abundance in the Chinese-ancestry cohort. Our findings underscore a potential influence of ethnicity on gut microbiota composition in the context of individuals with overweight and prediabetes.

The landscape of potential health benefits of carotenoids as natural supportive therapeutics in protecting against Coronavirus infection.

The Coronavirus Disease-2019 (COVID-19) pandemic urges researching possibilities for prevention and management of the effects of the virus. Carotenoids are natural phytochemicals of anti-oxidant, anti-inflammatory and immunomodulatory properties and may exert potential in aiding in combatting the pandemic. This review presents the direct and indirect evidence of the health benefits of carotenoids and derivatives based on in vitro and in vivo studies, human clinical trials and epidemiological studies and proposes possible mechanisms of action via which carotenoids may have the capacity to protect against COVID-19 effects. The current evidence provides a rationale for considering carotenoids as natural supportive nutrients via antioxidant activities, including scavenging lipid-soluble radicals, reducing hypoxia-associated superoxide by activating antioxidant enzymes, or suppressing enzymes that produce reactive oxygen species (ROS). Carotenoids may regulate COVID-19 induced over-production of pro-inflammatory cytokines, chemokines, pro-inflammatory enzymes and adhesion molecules by nuclear factor kappa B (NF-κB), renin-angiotensin-aldosterone system (RAS) and interleukins-6- Janus kinase-signal transducer and activator of transcription (IL-6-JAK/STAT) pathways and suppress the polarization of pro-inflammatory M1 macrophage. Moreover, carotenoids may modulate the peroxisome proliferator-activated receptors γ by acting as agonists to alleviate COVID-19 symptoms. They also may potentially block the cellular receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human angiotensin-converting enzyme 2 (ACE2). These activities may reduce the severity of COVID-19 and flu-like diseases. Thus, carotenoid supplementation may aid in combatting the pandemic, as well as seasonal flu. However, further in vitro, in vivo and in particular long-term clinical trials in COVID-19 patients are needed to evaluate this hypothesis.

Pancreas Fat, an Early Marker of Metabolic Risk? A Magnetic Resonance Study of Chinese and Caucasian Women: TOFI_Asia Study.

Objective: Prevalence of type 2 diabetes (T2D) is disproportionately higher in younger outwardly lean Asian Chinese compared to matched Caucasians. Susceptibility to T2D is hypothesised due to dysfunctional adipose tissue expansion resulting in adverse abdominal visceral and organ fat accumulation. Impact on early risk, particularly in individuals characterised by the thin-on-the-outside-fat-on-the-inside (TOFI) phenotype, is undetermined. Methods: Sixty-eight women [34 Chinese, 34 Caucasian; 18-70 years; body mass index (BMI), 20-45 kg/m2] from the TOFI_Asia study underwent magnetic resonance imaging and spectroscopy to quantify visceral, pancreas, and liver fat. Total body fat was (TBF) assessed by dual-energy x-ray absorptiometry, and fasting blood biomarkers were measured. Ethnic comparisons, conducted using two-sample tests and multivariate regressions adjusted for age, % TBF and ethnicity, identified relationships between abdominal ectopic fat depots with fasting plasma glucose (FPG), insulin resistance (HOMA2-IR), and related metabolic clinical risk markers in all, and within ethnic groups. Results: Despite being younger and of lower bodyweight, Chinese women in the cohort had similar BMI and % TBF compared to their Caucasian counterparts. Protective high-density lipoprotein cholesterol, total- and high-molecular weight adiponectin were significantly lower, while glucoregulatory glucagon-like peptide-1 and glucagon significantly higher, in Chinese. There were no ethnic differences between % pancreas fat and % liver fat. However, at low BMI, % pancreas and % liver fat were ∼1 and ∼2% higher in Chinese compared to Caucasian women. In all women, % pancreas and visceral adipose tissue had the strongest correlation with FPG, independent of age and % TBF. Percentage (%) pancreas fat and age positively contributed to variance in FPG, whereas % TBF, amylin and C-peptide contributed to IR which was 0.3 units higher in Chinese. Conclusion: Pancreas fat accumulation may be an early adverse event, in TOFI individuals, with peptides highlighting pancreatic dysfunction as drivers of T2D susceptibility. Follow-up is warranted to explore causality.

Exploring the relationship between pancreatic fat and insulin secretion in overweight or obese women without type 2 diabetes mellitus: A preliminary investigation of the TOFI_Asia cohort.

OBJECTIVE: While there is an emerging role of pancreatic fat in the aetiology of type 2 diabetes mellitus (T2DM), its impact on the associated decrease in insulin secretion remains controversial. We aimed to determine whether pancreatic fat negatively affects ß-cell function and insulin secretion in women with overweight or obesity but without T2DM. METHODS: 20 women, with normo- or dysglycaemia based on fasting plasma glucose levels, and low (< 4.5%) vs high (≥ 4.5%) magnetic resonance (MR) quantified pancreatic fat, completed a 1-hr intravenous glucose tolerance test (ivGTT) which included two consecutive 30-min square-wave steps of hyperglycaemia generated by using 25% dextrose. Plasma glucose, insulin and C-peptide were measured, and insulin secretion rate (ISR) calculated using regularisation deconvolution method from C-peptide kinetics. Repeated measures linear mixed models, adjusted for ethnicity and baseline analyte concentrations, were used to compare changes during the ivGTT between high and low percentage pancreatic fat (PPF) groups. RESULTS: No ethnic differences in anthropomorphic variables, body composition, visceral adipose tissue (MR-VAT) or PPF were measured and hence data were combined. Nine women (47%) were identified as having high PPF values. PPF was significantly associated with baseline C-peptide (p = 0.04) and ISR (p = 0.04) in all. During the 1-hr ivGTT, plasma glucose (p<0.0001), insulin (p<0.0001) and ISR (p = 0.02) increased significantly from baseline in both high and low PPF groups but did not differ between the two groups at any given time during the test (PPF x time, p > 0.05). Notably, the incremental areas under the curves for both first and second phase ISR were 0.04 units lower in the high than low PPF groups, but this was not significant (p > 0.05). CONCLUSION: In women with overweight or obesity but without T2DM, PPF did not modify ß-cell function as determined by ivGTT-assessed ISR. However, the salient feature in biphasic insulin secretion in those with ≥4.5% PPF may be of clinical importance, particularly in early stages of dysglycaemia may warrant further investigation.

A higher-protein nut-based snack product suppresses glycaemia and decreases glycaemic response to co-ingested carbohydrate in an overweight prediabetic Asian Chinese cohort: the Tu Ora postprandial RCT.

Nut-based products may aid low-glycaemic dietary strategies that are important for diabetes prevention in populations at increased risk of dysglycaemia, such as Asian Chinese. This randomised cross-over trial assessed the postprandial glycaemic response (0-120 min) of a higher-protein nut-based (HP-NB) snack formulation, in bar format (1009 kJ, Nutrient Profiling Score, NPS, -2), when compared with an iso-energetic higher-carbohydrate (CHO) cereal-based bar (HC-CB, 985 kJ, NPS +3). It also assessed the ability to suppress glucose response to a typical CHO-rich food (white bread, WB), when co-ingested. Ten overweight prediabetic Chinese adults (mean, sd: age 47⋅9, 15⋅7 years; BMI 25⋅5, 1⋅6 kg/m2), with total body fat plus ectopic pancreas and liver fat quantified using dual-energy X-ray absorptiometry and magnetic resonance imaging and spectroscopy, received the five meal treatments in random order: HP-NB, HC-CB, HP-NB + WB (50 g available CHO), HC-CB + WB and WB only. Compared with HC-CB, HP-NB induced a significantly lower 30-120 min glucose response (P < 0⋅05), with an approximately 10-fold lower incremental area under the glucose curve (iAUC0-120; P < 0⋅001). HP-NB also attenuated glucose response by approximately 25 % when co-ingested with WB (P < 0⋅05). Half of the cohort had elevated pancreas and/or liver fat, with 13-21 % greater suppression of iAUC0-120 glucose in the low v. high organ fat subgroups across all five treatments. A nut-based snack product may be a healthier alternative to an energy equivalent cereal-based product with evidence of both a lower postprandial glycaemic response and modulation of CHO-induced hyperglycaemia even in high-risk, overweight, pre-diabetic adults.

Metabolomic signatures for visceral adiposity and dysglycaemia in Asian Chinese and Caucasian European adults: the cross-sectional TOFI_Asia study.

BACKGROUND: Asian Chinese are more susceptible to deposition of visceral adipose tissue (VAT) and type 2 diabetes (T2D) development than European Caucasians when matched for gender, age and body mass index (BMI). Our aims were: (i) characterise the ethnicity-specific metabolomic signature of visceral adiposity measured by dual energy X-ray absorptiometry (DXA) and fasting plasma glucose (FPG), and (ii) identify individuals susceptible to worse metabolic health outcomes. METHODS: Fasting plasma samples from normoglycaemic (n = 274) and prediabetic (n = 83) participants were analysed with liquid chromatography-mass spectrometry using untargeted metabolomics. Multiple linear regression adjusting for age, gender and BMI was performed to identify metabolites associated with FPG and VAT calculated as percentage of total body fat (%VATTBF) in each ethnic group. Metabolic risk groups in each ethnicity were stratified based on the joint metabolomic signature for FPG and %VATTBF and clinically characterised using partial least squares-discriminant analysis (PLS-DA) and t-tests. RESULTS: FPG was correlated with 40 and 110 metabolites in Caucasians and Chinese respectively, with diglyceride DG(38:5) (adjusted ß = 0.29, p = 3.00E-05) in Caucasians and triglyceride TG(54:4) (adjusted ß = 0.28, p = 2.02E-07) in Chinese being the most significantly correlated metabolite based on the p-value. %VATTBF was correlated with 85 and 119 metabolites in Caucasians and Chinese respectively, with TG(56:2) (adjusted ß = 0.3, p = 8.25E-09) in Caucasians and TG(58:3) (adjusted ß = 0.25, p = 2.34E-08) in Chinese being the most significantly correlated. 24 metabolites associated with FPG were common to both ethnicities including glycerolipid species. 67 metabolites associated with %VATTBF were common to both ethnicities including positive correlations with dihydroceramide, sphingomyelin, glycerolipid, phosphatidylcholine, phosphatidylethnolamine, and inverse correlations with ether-linked phosphatidylcholine. Participant re-stratification found greater total and central adiposity, worse clinical lipid profiles, higher serum glucoregulatory peptides and liver enzymes in normal fasting glucose (NFG) individuals with a prediabetic metabolomic profile than NFG individuals with a normoglycaemic metabolomic profile in both ethnicities. CONCLUSIONS: Untargeted metabolomics identified common and disparate metabolites associated with FPG and %VATTBF, with an ethnic-dimorphic signature for these metabolic traits. These signatures could improve risk stratification and identify NFG individuals with an adverse cardiometabolic and T2D risk profile.