INTRODUCTION:This narrative review explores the epidemiological evidence and potential underlying pathophysiological defects underlying the disproportionately greater risk of Type 2 diabetes (T2D) and cardiometabolic disease in people of South Asian and African Caribbean ancestry compared with White Europeans. Differences in (i) insulin dynamics, (ii) body composition and liver and pancreas triglyceride accumulation, and (iii) dysregulated fat metabolism likely contribute to this obesity-related susceptibility. INSULIN DYNAMICS:Insulin resistance and hyperinsulinemia are key pathophysiological defects in T2D, although the primary defect is uncertain. Many believe that insulin resistance precedes compensatory hyperinsulinemia; much data suggest that hyperinsulinemia precedes insulin resistance. Hyperinsulinemia, related to reduced hepatic insulin clearance, may represent the primary defect in people of African Caribbean ancestry. BODY COMPOSITION:Ectopic fat, particularly visceral, liver, and pancreatic fat, is associated with impairments in insulin action/secretion: Higher liver fat is specifically related to hepatic insulin resistance and higher pancreatic fat to impaired beta cell function. People of South Asian ancestry exhibit greater ectopic particularly liver fat, compared with White Europeans, and more severe insulin resistance, driving hyperinsulinemia. People of African Caribbean ancestry have lower visceral and liver fat and greater muscle mass. DYSREGULATED FAT METABOLISM:Dysregulated fat metabolism in adipose tissue/liver may increase serum fatty acids and triglyceride concentrations exposing non-adipose tissues to increased lipid. Differential T2D susceptibility likely reflects diverse but ethnic group-specific metabolic phenotypes representing genetic and environmentally mediated pathophysiological traits, consistent with the "palette" model of T2D.

AIM/HYPOTHESIS:Pilots with type 1 diabetes are required to perform capillary glucose monitoring regularly during flights. Continuous glucose monitoring (CGM) may be an effective and more practical alternative. This study aimed to assess the accuracy of CGM systems against self-monitoring of blood glucose (SMBG) during a hypobaric flight simulation. METHODS:Twelve insulin pump users with type 1 diabetes were studied using two simulation protocols. Protocol A consisted of a ground phase, ascent, a 190 min cruise with ingestion of a liquid meal, descent and then ground. Protocol B consisted of a ground phase, ascent, a 60 min cruise while fasting, descent, a 20 min ground phase, ascent, a second flight of 120 min with ingestion of a meal, followed by descent and ground. Insulin was administered with or before the meal according to the participants' carbohydrate-counting regimen during both protocols. In Protocol A, capillary, interstitial and plasma glucose were measured during flight and at ground, while in Protocol B, glucose and oxygen were measured. Measurements from three CGM brands and two SMBG devices were recorded during the flight simulations. Findings at cabin pressures during flight (550 mmHg) and ground (750 mmHg) were compared. Fasted and postprandial glucose measurements were analysed using Spearman's correlations and mean absolute relative differences (MARDs). RESULTS:Eleven men and one woman (n=6 men in Protocol A; n=5 men and n=1 woman in Protocol B) were studied. A total of 1533 data points were recorded. During flight vs ground level, Spearman's correlations for CGM system- and SMBG-derived glucose values were very strong in both Protocol A (r=0.96 during flight vs r=0.94 at ground) and Protocol B (r=0.85 during flight vs r=0.69 at ground). The differences in aggregated CGM MARDs during flight vs ground level were minimal across Protocol A (11.85%; 95% CI [9.78, 13.92] vs 9.08%; 95% CI [7.02, 11.14]) and Protocol B (12.01%; 95% CI [3.34, 20.69] vs 12.97%; 95% CI [4.30, 21.65]). CONCLUSIONS/INTERPRETATION:The performance of CGM systems and SMBG are comparable during flight-associated atmospheric pressure changes. All tested measurement devices for CGM and SMBG were suitable for diabetes-care-based decisions during flight simulation.

The impact of atmospheric pressure changes on glucose metabolism encountered in aviation on people with type 1 diabetes is controversial. A dual-isotope study was performed in a hypobaric chamber to simulate pressure changes experienced on commercial flights. The fasting and postprandial glucose kinetics of individuals with type 1 diabetes were evaluated across simulated in-flight cabin pressures (550mmHg; experimental arm) and ground level (750mmHg; control arm). The impact of ambient pressure on glucose disposal (Rd), endogenous glucose production (EGP), meal glucose appearance (Ra), and insulin concentrations were evaluated. Six male participants, aged 20-61 years, with a median BMI of 26.6 kg/m2 were studied. Baseline glucose Rd, EGP, and meal Ra were not affected by ambient pressure changes. Postprandial glucose Rd was higher in hypobaric conditions than ground, percent change in postprandial glucose concentration was lower but postprandial EGP and meal Ra were not affected. Insulin concentration between 120-180 min was higher in the hypobaric simulation. The observed increase in glucose Rd for individuals with type 1 diabetes on insulin pumps may be related to the hypoxia and pressure changes experienced during flight. Since glucose profiles were unaffected, there is no evidence that insulin pump therapy is a risk factor in flight.

AIMS:The primary objective of this cross-sectional study was to re-examine the liver fat thresholds associated with metabolic health and number of metabolic syndrome (MetS) traits. METHODS:In this cross-sectional study, 597 participants (99.7 % white European) underwent assessment of i) cardiometabolic health with individual MetS traits ii) alcohol consumption and iii) steatotic liver disease (SLD), defined by MRI-PDFF or proton spectroscopy (1H-MRS) liver fat ≥5.56 %. RESULTS:The median (IQR) liver fat was 0.4 % (0.9) in 30 subjects without MetS traits and 6.7 % (15.4) and 16.7 % (20.1) in 117 and 108 subjects with 3 and 5 MetS traits respectively. SLD was associated with each MetS trait (increased blood pressure, central obesity, dysglycaemia, high triglyceride and low HDL-C concentrations; all p < 0.001). There was an increase in liver fat (%) according to increasing number of MetS traits (p < 0.001). There was an increase in every MetS trait with liver fat categories below 5.56 % (i.e. ≥1 % and ≤1.85 %, >1.85 % and <5.56 %). CONCLUSIONS:Previously defined normal levels of liver fat are not associated with optimal metabolic health (no MetS traits). Small increments in liver fat, even within a pre-defined normal range, are associated with a progressive increase in the number of MetS traits.

Obesity causes dyslipidemia and is a major risk factor for cardiovascular disease. However, the mechanisms coupling weight gain and lipid metabolism are poorly understood. Brain melanocortin 4 receptors (MC4Rs) regulate body weight and lipid metabolism in mice, but the relevance of these findings to humans is unclear. Here we investigated lipid levels in men and women with obesity due to MC4R deficiency. Among 7,719 people from the Genetics of Obesity Study cohort, we identified 316 probands and 144 adult family members with loss-of-function (LoF) MC4R mutations. Adults with MC4R deficiency had lower levels of total and low-density lipoprotein (LDL)-cholesterol and triglycerides than 336,728 controls from the UK Biobank, after adjusting for adiposity. Carriers of LoF MC4R variants within the UK Biobank had lower lipid levels and a lower risk of cardiovascular disease, after accounting for body weight, compared to noncarriers. After a high-fat meal, the postprandial rise in triglyceride-rich lipoproteins and metabolomic markers of fatty acid oxidation were reduced in people with MC4R deficiency compared to controls, changes that favor triglyceride storage in adipose tissue. We concluded that central MC4Rs regulate lipid metabolism and cardiovascular disease risk in humans, highlighting potential therapeutic approaches for cardiovascular risk reduction.

People of Black African (BA) ancestry are disproportionately affected by type 2 diabetes when compared with people of White European (WE) descent, despite lower levels of ectopic fat. Impaired beta cell function is a key pathophysiological feature of type 2 diabetes. It remains to be determined whether an associative relationship exists between intrapancreatic lipid (IPL) accumulation and beta cell function, and whether this differs by ethnicity. Fifty-three BA (23 normal glucose tolerance, 11 impaired glucose tolerance and 19 type 2 diabetes) and 51 WE (23/13/15) men underwent a hyperglycaemic clamp and mixed-meal tolerance test to assess insulin secretion and beta cell function, a hyperinsulinaemic–euglycaemic clamp to measure insulin sensitivity and Dixon MRI to determine IPL. Associations between IPL and beta cell function were assessed using linear regression. IPL was lower in BA compared with WE men (mean ± SD; 7.6 ± 2.6

BACKGROUND AND OBJECTIVES:Very-low calorie diets (VLCD) achieve weight loss and remission of Type 2 diabetes (T2DM), but efficacy and acceptability in non-European populations is less clear. This feasibility study examines the impact of 10% weight loss through VLCD on metabolic and body composition outcomes in a multi-ethnic cohort of Aotearoa New Zealand (AoNZ) men with prediabetes/early T2DM, and VLCD tolerability/cultural acceptability.METHODS AND STUDY DESIGN:Participants followed a VLCD intervention (mean energy 3033kJ/day) until achievement of 10% weight loss. An oral glucose tolerance test (OGTT), hyperinsulinaemic isoglycaemic clamp with stable isotopes, hood calorimetry and dual-energy Xray absorptiometry (DXA) were undertaken before and after intervention. Qualitative data on VLCD tolerability/cultural acceptability were collected.RESULTS:Fifteen participants were enrolled; nine achieved 10% weight loss. In this group, mean HbA1c reduced by 4.8mmol/mol (2.4-7.1) and reverted to normoglycaemia in n=5/9; mean body weight reduced by 12.0 kg (11.0-13.1) and whole-body glucose disposal improved by 1.5 mg kgFFM-1 min-1 (0.7-2.2). Blood pressure and fasting triglycerides improved significantly. No changes in hepatic glu-cose metabolism were found. In all participants who attended completion testing, HbA1c reduced by 3.4mmol/mol (SD 3.5) and total weight by 9.0kg (SD 5.7). The intervention was highly tolerable/culturally acceptable however challenges with fulfilment of cultural obligations were described.CONCLUSIONS:Results support VLCD use in AoNZ however further work to investigate ethnic differences in physiological response to VLCDs and to optimise protocols for multi-ethnic populations are required.

Black African-Caribbean (BAC) populations are at greater risk of cardiometabolic disease than White Europeans (WE), despite exhibiting lower fasting triacylglycerol (TAG) concentrations. However, limited data exist regarding postprandial fatty acid metabolism in BAC populations. This study determined the ethnic differences in postprandial fatty acid metabolism between overweight and obese WE and BAC men. WE [n = 10, age 33.3 ± 1.7 yr; body mass index (BMI) = 26.8 (25.8-31.0) kg/m2] and BAC [n = 9, age 27.9 ± 1.0 yr; BMI = 27.5 (26.0-28.6) kg/m2] men consumed two consecutive (at 0 and 300 min) moderate-to-high-fat meals-the first labeled with [U-13C]palmitate. The plasma concentration and appearance of meal-derived fatty acids in very-low-density lipoprotein (VLDL)-TAG, chylomicron-TAG, and nonesterified fatty acid (NEFA) were determined over an 8-h postprandial period. Indirect calorimetry with 13CO2 enrichment determined total and meal-derived fatty acid oxidation rates, and plasma β-hydroxybutyrate (3-OHB) concentration was measured to assess ketogenesis. BAC exhibited lower postprandial TAG [area under the curve (AUC0-480) = 671 (563-802) vs. 469 (354-623) mmol/L/min, P = 0.022] and VLDL-TAG [AUC0-480 = 288 ± 30 vs. 145 ± 27 mmol/L/min, P = 0.003] concentrations than WE. The appearance of meal-derived fatty acids in VLDL-TAG was lower in BAC than in WE (AUC0-480 = 133 ± 12 vs. 78 ± 13 mmol/L/min, P = 0.007). Following the second meal, BAC showed a trend for lower chylomicron-TAG concentration [AUC300-480 = 69 (51-93) vs. 43 (28-67) mmol/L/min, P = 0.057]. There were no ethnic differences in the appearance of chylomicron-TAG, cumulative fatty acid oxidation, and the NEFA:3-OHB ratio (P > 0.05). In conclusion, BAC exhibit lower postprandial TAG concentrations compared with WE men, driven by lower VLDL-TAG concentrations and possibly lower chylomicron-TAG in the late postprandial period. These findings suggest that postprandial fatty acid trafficking may be a less important determinant of cardiometabolic risk in BAC than in WE men.NEW & NOTEWORTHY Postprandial TAG is lower in Black African-Caribbean men than in White European men, and this is likely driven by lower meal-derived VLDL-TAG in Black African-Caribbean men. This observation could suggest that fatty acid trafficking may be a less important determinant of cardiometabolic risk in Black Africans than in White European men.

AIM:To examine the hypothesis that there would be ethnic differences in the relationship between ectopic fat and tissue-specific insulin resistance (IR) across a spectrum of glucose tolerance in Black African (BA) and White European (WE) men. MATERIALS AND METHODS:Fifty-three WE men (23/10/20 normal glucose tolerance [NGT]/impaired glucose tolerance [IGT]/type 2 diabetes [T2D]) and 48 BA men (20/10/18, respectively) underwent a two-step hyperinsulinaemic-euglycaemic clamp with infusion of D-[6,6-2H2]-glucose and [2H5]-glycerol to assess hepatic, peripheral and adipose tissue IR. Magnetic resonance imaging was used to measure subcutaneous adipose tissue, visceral adipose tissue (VAT) and intrahepatic lipid (IHL). Associations between ectopic fat and IR were assessed using linear regression models. RESULTS:There were no differences in tissue-specific IR between ethnic groups at any stage of glucose tolerance. VAT level was consistently lower in the BA population; NGT (p = 0.013), IGT (p = 0.006) and T2D (p = 0.015). IHL was also lower in the BA compared with the WE men (p = 0.013). VAT and IHL levels were significantly associated with hepatic IR in the BA population (p = 0.001) and with peripheral IR in the WE population (p = 0.027). CONCLUSIONS:The present study suggests that BA and WE men exhibit the same degree of IR across a glucose tolerance continuum, but with lower VAT and IHL levels in the BA population, suggesting that IR may be driven by a mechanism other than increased ectopic fat accumulation in BA men.

BACKGROUND AND AIMS:Exercise is recommended for the management of metabolic dysfunction-associated steatotic liver disease (MASLD), yet effects on liver histology remain unknown, especially without significant weight loss. We aimed to examine changes in surrogate measures of liver histological response with exercise training. METHODS:We conducted a post hoc pooled analysis of three randomised controlled trials (duration: 12-20 weeks) comparing aerobic exercise interventions with controls. The primary outcome measure was a ≥30% relative reduction in (MRI-measured) liver fat, as a surrogate measure of liver histological response (the threshold necessary for fibrosis improvement). Secondary outcome measures were changes in other biomarkers of liver fibrosis, anthropometry, body composition and aerobic fitness. RESULTS:Eighty-eight adults (exercise: 54, control: 34; male: 67%) were included with mean (SD) age 51 (11) years and body mass index 33.3 (5.2) kg/m2. Following the intervention, exercise had ~5-fold (OR [95%CI]: 4.86 [1.72, 13.8], p = .002) greater odds of ≥30% relative reduction in MRI-measured liver fat compared with control. This paralleled the improvements in anthropometry (waist and hip circumference reduction), body composition (body fat, visceral and subcutaneous adipose tissue) and aerobic fitness (V̇O2peak, ventilatory threshold and exercise capacity). Importantly, these effects were independent of clinically significant body weight loss (<3% body weight). CONCLUSION:Exercise training led to clinically meaningful improvements in surrogate serum- and imaging-based measures of liver histological change, without clinically meaningful body weight reduction. These data reinforce the weight-neutral benefit of exercise training and suggest that aerobic training may improve liver fibrosis in patients with MASLD.

Objective This work aimed to investigate the effect of the SGLT(2) inhibitor, dapagliflozin (DAPA), on cardiac function and the metabolic and hormonal response to moderate exercise in people with type 2 diabetes. Methods This was a double-blind, placebo-controlled crossover study with a 4-week washout period. Nine participants were randomly assigned to receive either 4 weeks of DAPA or 4 weeks of placebo. After each treatment, they underwent an exercise protocol with 2 consecutive 10-minute stages at a constant load corresponding to 40% and 70% maximal oxygen consumption (VO2max), coupled with hormonal and metabolic analysis. A blinded transthoracic echocardiogram was performed 3 days later. Results During the exercise protocol, glucose and lactate were lower (P < .0001 and P < .05, respectively) and beta-hydroxybutyrate (BOBH) and growth hormone (GH) were higher (P < .0005 and P = .01) following DAPA treatment compared to placebo. There was a trend for lower insulin with DAPA. Adrenalin, noradrenalin, and glucagon were not different. Following DAPA participants demonstrated an increased mean peak diastolic mitral annular velocity (e') in comparison to placebo (P = .03). The indexed left atrial volume and right ventricular e" were reduced following DAPA compared with placebo (P = .045 and P = .042, respectively). Arterial stiffness was not different between treatments (DAPA 9.35 +/- 0.60 m/s; placebo 9.07 +/- 0.72 m/s). Conclusion During exercise, GH may be more important than catecholamines in driving the shift from glucose to fatty acid metabolism by SGLT(2) inhibitors. The 4-week crossover design showed changes in cardiac function were rapid in onset and reversible.

Objective. To investigate the mechanism for increased ketogenesis following treatment with SGLT2 inhibitor, dapagliflozin in people with type 2 diabetes. Research, Design & Methods. This was a double-blind placebo-controlled crossover study with a 4-week washout period. Participants received dapagliflozin or placebo in random order for 4 weeks. After each treatment, they ingested 30ml of olive oil containing [U-13C] palmitate to measure ketogenesis with blood sampling for 480 min. Stable isotopes of glucose and glycerol were infused to measure glucose flux and lipolysis respectively at 450-480 min. Results. Glucose excretion rate was higher and peripheral glucose uptake lower with dapagliflozin than placebo. Plasma beta-hydroxybutyrate (BOHB) concentrations and [13C2] BOHB concentrations were higher and glucose concentrations lower with dapagliflozin than placebo. Non-esterified fatty acids (NEFA) were higher with dapagliflozin at 300 and 420 min but lipolysis at 450-480 min was not different. Triacylglycerol (TAG) at all time points and endogenous glucose production rate at 450-480 min were not different between treatments. Conclusions. The increase in ketone enrichment from the ingested palmitic acid tracer suggests meal derived fatty acids contribute to the increase in ketones during treatment with dapagliflozin. The increase in BOHB concentration with dapagliflozin, occurred with only minimal changes in plasma NEFA concentration and no change in lipolysis. This suggests a metabolic switch to increase ketogenesis within the liver.

The objective of the study was to assess associations of the rs9939609 FTO allele to glucose tolerance, hepatic and total insulin sensitivity (IS) in individuals with obesity. From a low-dose hyperinsulinemic euglycemic clamp with glucose-tracer, hepatic IS was assessed by rates of basal and suppressed glucose appearance (Ra), a measure of endogenous glucose production (EGP), and the hepatic insulin resistance index (HIR). Total IS was assessed by rates of glucose infusion (GIR), disappearance (Rd), and metabolic clearance (MCR). From a meal test we assessed IS by the Matsuda index and glucose tolerance by glucose and insulin measurements in the fasted state and postprandially for 2.5 h. The meal test was performed in 97 healthy individuals with BMI ≥35 in similar-sized risk-allele groups (n = 32 T/T, 31 A/T, and 34 A/A), and 79 of them performed the clamp. We analyzed outcomes separately for males and females, and adjusted glucose Ra, Rd, MCR, GIR, and HIR for fat mass. We did not find genotype effects on EGP. Among males, genotype A/A was associated with a significantly lower glucose Rd, MCR, and Matsuda index score relative to genotype T/T. Glucose tolerance was significantly lower in males with genotype A/T vs. T/T and A/A. For females, there were no genotype effects on hepatic or total IS, or on glucose tolerance. Independently of genotypes, females displayed a significantly better hepatic and total IS, and better glucose tolerance than males. We conclude that in subjects with similar obesity we did not register any FTO risk-allele effect on hepatic IS. A FTO risk-allele effect on total IS was registered in males only, findings which need to be reproduced in further studies. Results confirm marked differences in IS between the biological sexes and extend present knowledge by demonstrating a lower endogenous glucose production in females vs. males in uniformly obese individuals.

Introduction The newer glucose-lowering therapies for type 2 diabetes (T2D), the glucagon-like peptide-1 receptor agonists (GLP1-RAs) and the sodium-glucose co-transporter 2 inhibitors (SGLT2i), have additional clinical benefits beyond improving glycaemic control; promoting weight loss, addressing associated cardiovascular risk factors and reducing macrovascular and microvascular complications. Considering their independent mechanisms of actions, there is a potential for significant synergy with combination therapy, yet limited data exist. This 32-week randomised, double-blind, placebo-controlled trial will gain mechanistic insight into the effects of coadministration of exenatide QW, a weekly subcutaneous GLP1-RA, with dapagliflozin, a once daily oral SGLT2i, on the dynamic, adaptive changes in energy balance, total, regional and organ-specific fat mass and multiorgan insulin sensitivity. Methods and analysis 110 obese patients with diagnosed T2D (glycated haemoglobin, HbA 1c ≥48 mmol/mol) will be treated for 32 weeks with dapagliflozin (10 mg once daily either alone or in combination with exenatide QW (2 mg once weekly); active treatments will be compared with a control group (placebo tablet and sham injection). The primary objective of the study is to compare the adjusted mean reduction in total body fat mass (determined by dual-energy X-ray absorptiometry, DEXA) from baseline following 32 weeks of treatment with exenatide QW and dapagliflozin versus dapagliflozin alone compared with control (placebo). Secondary outcome measures include changes in (1) energy balance (energy intake and energy expenditure measured by indirect calorimetry); (2) appetite (between and within meals) and satiety quotient; (3) body composition including visceral adipose tissue, subcutaneous adipose tissue, liver and pancreatic fat. Exploratory outcome measures include metabolic changes in hepatic and peripheral insulin sensitivity (using a two-stage hyperinsulinaemic, euglycaemic clamp), central nervous system responses to food images using blood oxygen level-dependent (BOLD) functional MRI (fMRI) and changes in cardiovascular function (using transthoracic echocardiography, cardiac MR and duplex ultrasonography). Ethics and dissemination This study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/1147) and is conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice. Results from the study will be published in peer-reviewed scientific and open access journals and/or presented at scientific conferences and summarised for distribution to the participants. Trial sponsor University of Liverpool. Trial registration number ISRCTN 52028580; EUDRACT number 2015-005242-60.

Aim People of Black African ancestry, who are known to be at disproportionately high risk of type 2 diabetes (T2D), typically exhibit lower hepatic insulin clearance compared with White Europeans. However, the mechanisms underlying this metabolic characteristic are poorly understood. We explored whether low insulin clearance in Black African (BA) men could be explained by insulin resistance, subclinical inflammation or adiponectin concentrations. Methods BA and White European (WE) men, categorised as either normal glucose tolerant (NGT) or with T2D, were recruited to undergo the following: a mixed meal tolerance test with C-peptide modelling to determine endogenous insulin clearance; fasting serum adiponectin and cytokine profiles; a hyperinsulinaemic–euglycaemic clamp to measure whole-body insulin sensitivity; and magnetic resonance imaging to quantify visceral adipose tissue. Results Forty BA (20 NGT and 20 T2D) and 41 WE (23 NGT and 18 T2D) men were studied. BA men had significantly lower insulin clearance ( P = 0.011) and lower plasma adiponectin ( P = 0.031) compared with WE men. In multiple regression analysis, ethnicity, insulin sensitivity and plasma adiponectin were independent predictors of insulin clearance, while age, visceral adiposity and tumour necrosis factor alpha (TNF- α ) did not significantly contribute to the variation. Conclusion These data suggest that adiponectin may play a direct role in the upregulation of insulin clearance beyond its insulin-sensitising properties.

Aims We aimed to assess ethnic differences in inflammatory markers and their relationships with insulin sensitivity and regional adiposity between white European and black African men. Methods A total of 53 white European and 53 black African men underwent assessment of inflammatory markers alongside Dixon-magnetic resonance imaging to quantify subcutaneous and visceral adipose tissue and intrahepatic lipid. A hyperinsulinaemic-euglycaemic clamp was used to measure whole-body and adipose tissue insulin sensitivity. To assess ethnic differences in relationships, the statistical significance of an interaction term between adipokines and ethnic group was tested in multivariable regression models. Results The black African men exhibited significantly lower adiponectin and tumour necrosis factor-alpha (TNF-alpha) and greater interleukin-10 (IL-10) compared to white European men (all p < 0.05). There were no statistically significant ethnic differences in leptin, resistin, IL-6, interferon-gamma, IL-13, IL-1 beta, IL-8 and vascular endothelial growth factor. Several relationships differed significantly by ethnicity such that they were stronger in white European than black African men including IL-6 with visceral adipose tissue; adiponectin with subcutaneous adipose tissue; leptin with intrahepatic lipid; adiponectin, IL-6 and TNF-alpha with whole-body insulin sensitivity and TNF-alpha with adipose tissue insulin sensitivity (all pinteraction <0.05). Leptin significantly predicted whole-body insulin sensitivity in white European (R-2 = 0.51) and black African (R-2 = 0.29) men; however, adiponectin was a statistically significant predictor in only white European men (R-2 = 0.22). Conclusions While adiponectin is lower in black African men, its insulin sensitising effects may be greater in white men suggesting that the role of adipokines in the development of type 2 diabetes may differ by ethnicity.

Introduction It is increasingly recognized that type 2 diabetes (T2D) is a heterogenous disease with ethnic variations. Differences in insulin secretion, insulin resistance and ectopic fat are thought to contribute to these variations. Therefore, we aimed to compare postprandial insulin secretion and the relationships between insulin secretion, insulin sensitivity and pancreatic fat in men of black West African (BA) and white European (WE) ancestry. Research design and methods A cross-sectional, observational study in which 23 WE and 23 BA men with normal glucose tolerance, matched for body mass index, underwent a mixed meal tolerance test with C peptide modeling to measure beta cell insulin secretion, an MRI to quantify intrapancreatic lipid (IPL), and a hyperinsulinemic-euglycemic clamp to measure whole-body insulin sensitivity. Results Postprandial insulin secretion was lower in BA versus WE men following adjustment for insulin sensitivity (estimated marginal means, BA vs WE: 40.5 (95% CI 31.8 to 49.2) × 10 3 vs 56.4 (95% CI 48.9 to 63.8) × 10 3 pmol/m 2 body surface area × 180 min, p=0.008). There was a significantly different relationship by ethnicity between IPL and insulin secretion, with a stronger relationship in WE than in BA (r=0.59 vs r=0.39, interaction p=0.036); however, IPL was not a predictor of insulin secretion in either ethnic group following adjustment for insulin sensitivity. Conclusions Ethnicity is an independent determinant of beta cell function in black and white men. In response to a meal, healthy BA men exhibit lower insulin secretion compared with their WE counterparts for their given insulin sensitivity. Ethnic differences in beta cell function may contribute to the greater risk of T2D in populations of African ancestry.

Using the power of stable isotope techniques, our study explored the physiological effects of the SGLT2 inhibitor dapagliflozin on glucose flux, lipolysis, and ketonebody concentration in people with acute absolute insulin withdrawal (1). The power of our study from the clinical perspective was the crossover design with each individual undergoing an identical insulin withdrawal protocol with the only difference being the presence or absence of an SGLT2 inhibitor. Bolli et al. (2) argue that wewould have seenagreatereffectonnonesterified fatty acids (NEFAs) and ketones at baseline (prior towithdrawalof insulin) if the insulin dose had been adjusted in the SGLT2 arm during the 7 days preceding the study. As this was a double-blind study, this wasn’t feasible. It is possible that adjusting the insulin dose would have resulted in a greater effect on NEFAs and ketones at baseline, but this is hypothetical. We agree that the extreme insulin deficiency in our study design is unlikely to occur in clinical practice, but it was designed to illustrate effect of SGLT2 inhibitors on ketone body physiology and worked well. Bolli et al. (2) argue that because this model generates maximal effects, it is difficult to observe enhanced lipolysis by SGLT2 that might occur with only amoderate decrease in insulin. This is speculative, and we would welcome experimental evidence to substantiate it. A 10–20% reduction in insulin, as suggested, may or may not have shown anything significant. Bolli et al. refer to a study by Miles et al. in 1980 (3), where patients with type 1 diabetes were withdrawn from insulin after a 2-h insulin infusion, exactly as in our current study. Wedemonstratedagradual rise in ketones as shown in the study by Miles et al., although the rise in ketones was considerably smaller. In the study by Miles et al., all patients (n57)werewithin95–110%of their ideal bodyweight but noBMI is given. In our study, BMI ranged from 19.8 to 34.5 and the ketone response was greater the lower theirBMI (seeSupplementaryFig.1). The lower ketone response in our study may have been simply a consequence of our subjects having much higher BMI than those studied by Miles et al. We believe our protocol has produced some informative physiological data and thank Bolli et al. for their comments and agree that a range of future different protocols may shed further light on this interesting field.

Scope Fructose exacerbates post‐prandial hypertriacylglycerolaemia; perhaps partly due to increased enterocyte de novo lipogenesis (DNL). It is unknown whether this is concentration‐dependent or if fructose has a greater effect on lipid synthesis than glucose. Dose‐dependent effects of fructose and glucose on DNL and de novo triacylglycerol (TAG)‐glycerol synthesis are investigated in a Caco‐2 cell model. Methods and Results Caco‐2 cells are treated for 96 h with 5, 25, or 50 mM fructose or glucose, or 12.5 mM fructose/12.5 mM glucose mix. DNL is measured following addition of [13C2]‐acetate to apical media. Separately, [13C6]‐fructose and [13C6]‐glucose are used to measure DNL and de novo TAG‐glycerol synthesis. DNL from [13C2]‐acetate is detected following all treatments, with greater amounts in intracellular than secreted (media) samples (all p < 0.05). DNL from [13C6]‐fructose and [13C6]‐glucose is also measurable. Intracellular synthesis is concentration‐dependent for both glucose (p = 0.003) and fructose (p = 0.034) tracers and is higher with 25 mM glucose than 25 mM fructose (p = 0.025). DNL from fructose and glucose is <1%, but up to 70% of de novo TAG‐glycerol is synthesized from glucose or fructose. Conclusion Fructose is not a major source of DNL in Caco‐2 cells but contributes substantially to de novo TAG‐glycerol synthesis.