Exploring the determinants of ethnic differences in insulin clearance between men of Black African and White European ethnicity.

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.

ß-cell function in black South African women: exploratory associations with insulin clearance, visceral and ectopic fat.

The role of ectopic fat, insulin secretion and clearance in the preservation ofß-cell function in black African women with obesity who typically present with hyperinsulinaemia is not clear. We aim to examine the associations between disposition index (DI, an estimate of ß-cell function), insulin secretion and clearance and ectopic fat deposition. This is a cross-sectional study of 43 black South African women (age 20-35 years) with obesity (BMI 30-40 kg/m2) and without type 2 diabetes that measured the following: DI, insulin sensitivity (SI), acute insulin response (AIRg), insulin secretion rate (ISR), hepatic insulin extraction and peripheral insulin clearance (frequently sampled i.v. glucose tolerance test); pancreatic and hepatic fat, visceral adipose tissue (VAT) and abdominal s.c. adipose tissue (aSAT) volume (MRI), intra-myocellular (IMCL) and extra-myocellular fat content (EMCL) (magnetic resonance spectroscopy). DI correlated positively with peripheral insulin clearance (ß 55.80, P = 0.002). Higher DI was associated with lower VAT, pancreatic fat and soleus fat, but VAT explained most of the variance in DI (32%). Additionally, higher first phase ISR (P = 0.033) and lower hepatic insulin extraction (P = 0.022) were associated with lower VAT, independent from SI, rather than with ectopic fat. In conclusion, peripheral insulin clearance emerged as an important correlate of DI. However, VAT was the main determinant of a lower DI above ectopic fat depots. Importantly, VAT, but not ectopic fat, is associated with both lower insulin secretion and higher hepatic insulin extraction. Prevention of VAT accumulation in young black African women should, therefore, be an important target for beta cell preservation.

Ethnic differences in beta cell function occur independently of insulin sensitivity and pancreatic fat in black and white men.

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) × 103 vs 56.4 (95% CI 48.9 to 63.8) × 103 pmol/m2 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.

Adiponectin is associated with insulin sensitivity in white European men but not black African men.

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-α (TNF-α) 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-γ, IL-13, IL-1ß, 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-α with whole-body insulin sensitivity and TNF-α with adipose tissue insulin sensitivity (all pinteraction <0.05). Leptin significantly predicted whole-body insulin sensitivity in white European (R2  = 0.51) and black African (R2  = 0.29) men; however, adiponectin was a statistically significant predictor in only white European men (R2  = 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.

The Link between Obesity and Inflammatory Markers in the Development of Type 2 Diabetes in Men of Black African and White European Ethnicity.

In this study, we aimed to assess ethnic differences in visceral (VAT), deep subcutaneous (dSAT), and superficial subcutaneous (sSAT) adipose tissue and their relationships with inflammatory markers between white European (WE) and black West African (BWA) men with normal glucose tolerance (NGT) and type 2 diabetes (T2D). Forty-two WE (23 NGT/19 T2D) and 43 BWA (23 NGT/20 T2D) men underwent assessment of plasma inflammatory markers using immunoassays alongside Dixon magnetic resonance imaging to quantify L4-5 VAT, dSAT and sSAT. Despite no ethnic differences in sSAT and dSAT, BWA men exhibited lower VAT (p = 0.002) and dSAT:sSAT (p = 0.047) than WE men. Adiponectin was inversely associated with sSAT in WE (p = 0.041) but positively associated in BWA (p = 0.031) men with T2D. Interleukin-6 (IL-6) was associated with VAT in WE but not in BWA men with NGT (WE: p = 0.009, BWA: p = 0.137) and T2D (WE: p = 0.070, BWA: p = 0.175). IL-6 was associated with dSAT in only WE men with NGT (WE: p = 0.030, BWA: p = 0.833). The only significant ethnicity interaction present was for the relationship between adiponectin and sSAT (Pinteraction = 0.003). The favourable adipose tissue distribution and the weaker relationships between adiposity and inflammation in BWA men suggest that adipose tissue inflammation may play a lesser role in T2D in BWA than WE men.

Insulin clearance as the major player in the hyperinsulinaemia of black African men without diabetes.

AIM: To investigate relationships between insulin clearance, insulin secretion, hepatic fat accumulation and insulin sensitivity in black African (BA) and white European (WE) men. METHODS: Twenty-three BA and twenty-three WE men with normal glucose tolerance, matched for age and body mass index, underwent a hyperglycaemic clamp to measure insulin secretion and clearance, hyperinsulinaemic-euglycaemic clamp with stable glucose isotope infusion to measure whole-body and hepatic-specific insulin sensitivity, and magnetic resonance imaging to quantify intrahepatic lipid (IHL). RESULTS: BA men had higher glucose-stimulated peripheral insulin levels (48.1 [35.5, 65.2] × 103 vs. 29.9 [23.3, 38.4] × 103 pmol L-1 × min, P = .017) and lower endogeneous insulin clearance (771.6 [227.8] vs. 1381 [534.3] mL m-2 body surface area min -1 , P < .001) compared with WE men. There were no ethnic differences in beta-cell insulin secretion or beta-cell responsivity to glucose, even after adjustment for prevailing insulin sensitivity. In WE men, endogenous insulin clearance was correlated with whole-body insulin sensitivity (r = 0.691, P = .001) and inversely correlated with IHL (r = -0.674, P = .001). These associations were not found in BA men. CONCLUSIONS: While normally glucose-tolerant BA men have similar insulin secretory responses to their WE counterparts, they have markedly lower insulin clearance, which does not appear to be explained by either insulin resistance or hepatic fat accumulation. Low insulin clearance may be the primary mechanism of hyperinsulinaemia in populations of African origin.

Effect of exercise training on insulin sensitivity, hyperinsulinemia and ectopic fat in black South African women: a randomized controlled trial.

OBJECTIVE: We investigated the effects of a 12-week exercise intervention on insulin sensitivity (SI) and hyperinsulinemia and associated changes in regional and ectopic fat. RESEARCH DESIGN AND METHODS: Healthy, black South African women with obesity (mean age 23 ± 3.5 years) and of isiXhosa ancestry were randomised into a 12-week aerobic and resistance exercise training group (n = 23) and a no exercise group (control, n = 22). Pre and post-intervention testing included assessment of SI, insulin response to glucose (AIRg), insulin secretion rate (ISR), hepatic insulin extraction (FEL) and disposition index (DI) (AIRg × SI) (frequently sampled i.v. glucose tolerance test); fat mass and regional adiposity (dual-energy X-ray absorptiometry); hepatic, pancreatic and skeletal muscle fat content and abdominal s.c. and visceral adipose tissue volumes (MRI). RESULTS: Exercise training increased VO2peak (mean ± s.d.: 24.9 ± 2.42 to 27.6 ± 3.39 mL/kg/min, P < 0.001), SI (2.0 (1.2-2.8) to 2.2 (1.5-3.7) (mU/l)-1 min-1, P = 0.005) and DI (median (interquartile range): 6.1 (3.6-7.1) to 6.5 (5.6-9.2) × 103 arbitrary units, P = 0.028), and decreased gynoid fat mass (18.5 ± 1.7 to 18.2 ± 1.6%, P < 0.001) and body weight (84.1 ± 8.7 to 83.3 ± .9.7 kg, P = 0.038). None of these changes were observed in the control group, but body weight increased (P = 0.030). AIRg, ISR and FEL, VAT, SAT and ectopic fat were unaltered after exercise training. The increase in SI and DI were not associated with changes in regional or ectopic fat. CONCLUSION: Exercise training increased SI independent from changes in hyperinsulinemia and ectopic fat, suggesting that ectopic fat might not be a principal determinant of insulin resistance in this cohort.

Exercise training results in depot-specific adaptations to adipose tissue mitochondrial function.

We assessed differences in mitochondrial function in gluteal (gSAT) and abdominal subcutaneous adipose tissue (aSAT) at baseline and in response to 12-weeks of exercise training; and examined depot-specific associations with body fat distribution and insulin sensitivity (SI). Obese, black South African women (n = 45) were randomized into exercise (n = 23) or control (n = 22) groups. Exercise group completed 12-weeks of aerobic and resistance training (n = 20), while the control group (n = 15) continued usual behaviours. Mitochondrial function (high-resolution respirometry and fluorometry) in gSAT and aSAT, SI (frequently sampled intravenous glucose tolerance test), body composition (dual-energy X-ray absorptiometry), and ectopic fat (MRI) were assessed pre- and post-intervention. At baseline, gSAT had higher mitochondrial respiratory capacity and hydrogen peroxide (H2O2) production than aSAT (p < 0.05). Higher gSAT respiration was associated with higher gynoid fat (p < 0.05). Higher gSAT H2O2 production and lower aSAT mitochondrial respiration were independently associated with lower SI (p < 0.05). In response to training, SI improved and gynoid fat decreased (p < 0.05), while H2O2 production reduced in both depots, and mtDNA decreased in gSAT (p < 0.05). Mitochondrial respiration increased in aSAT and correlated with a decrease in body fat and an increase in soleus and hepatic fat content (p < 0.05). This study highlights the importance of understanding the differences in mitochondrial function in multiple SAT depots when investigating the pathophysiology of insulin resistance and associated risk factors such as body fat distribution and ectopic lipid deposition. Furthermore, we highlight the benefits of exercise training in stimulating positive adaptations in mitochondrial function in gluteal and abdominal SAT depots.

Ethnic distinctions in the pathophysiology of type 2 diabetes: a focus on black African-Caribbean populations.

Type 2 diabetes (T2D) is a global public health priority, particularly for populations of black African-Caribbean ethnicity, who suffer disproportionately high rates of the disease. While the mechanisms underlying the development of T2D are well documented, there is growing evidence describing distinctions among black African-Caribbean populations. In the present paper, we review the evidence describing the impact of black African-Caribbean ethnicity on T2D pathophysiology. Ethnic differences were first recognised through evidence that metabolic syndrome diagnostic criteria fail to detect T2D risk in black populations due to less central obesity and dyslipidaemia. Subsequently more detailed investigations have recognised other mechanistic differences, particularly lower visceral and hepatic fat accumulation and a distinctly hyperinsulinaemic response to glucose stimulation. While epidemiological studies have reported exaggerated insulin resistance in black populations, more detailed and direct measures of insulin sensitivity have provided evidence that insulin sensitivity is not markedly different to other ethnic groups and does not explain the hyperinsulinaemia that is exhibited. These findings lead us to hypothesise that ectopic fat does not play a pivotal role in driving insulin resistance in black populations. Furthermore, we hypothesise that hyperinsulinaemia is driven by lower rates of hepatic insulin clearance rather than heightened insulin resistance and is a primary defect rather than occurring in compensation for insulin resistance. These hypotheses are being investigated in our ongoing South London Diabetes and Ethnicity Phenotyping study, which will enable a more detailed understanding of ethnic distinctions in the pathophysiology of T2D between men of black African and white European ethnicity.

Differences in the link between insulin sensitivity and ectopic fat in men of Black African and White European ethnicity.

OBJECTIVES: In men of black west African (BAM) and white European (WEM) ethnicity, we aimed to (1) compare adipose tissue, peripheral and hepatic insulin sensitivity and (2) investigate associations between ectopic fat and insulin sensitivity by ethnicity. DESIGN AND METHODS: In overweight BAM (n = 21) and WEM (n = 23) with normal glucose tolerance, we performed a two-step hyperinsulinaemic-euglycaemic clamp with infusion of [6,6 2H2]-glucose and [2H5]-glycerol to measure whole body, peripheral, hepatic and adipose tissue insulin sensitivity (lipolysis). Visceral adipose tissue (VAT), intrahepatic lipids (IHL) and intramyocellular (IMCL) lipids were measured using MRI and spectroscopy. Associations between insulin sensitivity and ectopic fat were assessed using Pearson's correlation coefficient by ethnicity and regression analysis. RESULTS: There were no ethnic differences in whole body or tissue-specific insulin sensitivity (all P > 0.05). Suppression of lipolysis was inversely associated with VAT and IHL in WEM but not BAM (VAT: WEM r = -0.68, P < 0.01; BAM r = 0.07, P = 0.79. IHL: WEM r = -0.52, P = 0.01; BAM r = -0.12, P = 0.63). IMCL was inversely associated with skeletal muscle insulin sensitivity in WEM but not BAM (WEM r = -0.56, P < 0.01; BAM r = -0.09, P = 0.75) and IHL was inversely associated with hepatic insulin sensitivity in WEM but not BAM (WEM r = -0.53, P = 0.02; BAM r = -0.13, P = 0.62). CONCLUSIONS: Ectopic fat deposition may play a lesser role in reducing insulin sensitivity in men of black African ethnicity and may not be driven by lipolysis. Resistance to storing VAT, IHL and IMCL may enable men of black African ethnicity to maintain comparable insulin sensitivity to white Europeans.

Ethnic differences in hepatic, pancreatic, muscular and visceral fat deposition in healthy men of white European and black west African ethnicity.

AIMS: We aimed to assess ethnic differences in visceral adipose tissue (VAT), intrahepatic (IHL), intrapancreatic (IPL) and intramyocellular lipids (IMCL) between healthy white European (WE) and black west African (BWA) men. METHODS: 23 WE and 20 BWA men underwent Dixon-magnetic resonance imaging to quantify VAT, IHL and IPL; and proton-magnetic resonance spectroscopy to quantify IMCL. Insulin sensitivity and beta-cell function were determined using homeostasis model assessment (HOMA-2). RESULTS: BWA men exhibited significantly lower VAT (P = 0.021) and IHL (P = 0.044) than WE men, but comparable IPL (P = 0.92) and IMCL (P = 0.87). VAT was associated with IPL in both ethnicities (WE: P < 0.001; BWA: P = 0.001) but the relationship with IHL differed by ethnicity (Pinteraction = 0.018) and was only significant in WE men (WE: P < 0.001; BWA: P = 0.36). All ectopic fat depots inversely associated with insulin sensitivity and positively associated with beta-cell function in WE but not BWA men. CONCLUSIONS: Lower VAT and IHL, and their lack of interrelation, in BWA men suggests ethnic differences exist in the mechanisms of ectopic fat deposition. The lack of association between ectopic fat with insulin sensitivity and beta-cell function in BWA men may indicate a lesser role for ectopic fat in the development of type 2 diabetes mellitus in black populations.

Ethnic differences in intrahepatic lipid and its association with hepatic insulin sensitivity and insulin clearance between men of black and white ethnicity with early type 2 diabetes.

Intrahepatic lipid (IHL) is linked with reduced hepatic insulin sensitivity and insulin clearance. Despite their high risk for type 2 diabetes (T2D), there have been limited investigations of these relationships in black populations. We investigated these relationships in 18 white European (WE) and 18 black West African (BWA) men with T2D <5 years. They underwent magnetic resonance imaging to quantify IHL, a hyperinsulinemic euglycaemic clamp with [6,6 2 H2 ] glucose infusion to assess hepatic insulin sensitivity and a hyperglycaemic clamp to assess insulin clearance. BWA men had lower IHL than WE men (3.7 [5.3] vs 6.6 [10.6]%, P = 0.03). IHL was inversely associated with basal hepatic insulin sensitivity in WE but not BWA men (BWA: r = -0.01, P = 0.96; WE: r = -0.72, P = 0.006) with a significant interaction by ethnicity (Pinteraction = 0.05); however, IHL was not associated with % suppression of endogenous glucose production by insulin in either ethnicity. IHL showed a trend to an association with insulin clearance in BWA only (BWA: r = -0.42, P = 0.09; WE: r = -0.14, P = 0.58). The lack of association between IHL and hepatic insulin sensitivity in BWA men indicates IHL may play a lesser detrimental role in T2D in BWA men.

Black African men with early type 2 diabetes have similar muscle, liver and adipose tissue insulin sensitivity to white European men despite lower visceral fat.

AIMS/HYPOTHESIS: Type 2 diabetes is more prevalent in black African than white European populations although, paradoxically, black African individuals present with lower levels of visceral fat, which has a known association with insulin resistance. Insulin resistance occurs at a tissue-specific level; however, no study has simultaneously compared whole body, skeletal muscle, hepatic and adipose tissue insulin sensitivity between black and white men. We hypothesised that, in those with early type 2 diabetes, black (West) African men (BAM) have greater hepatic and adipose tissue insulin sensitivity, compared with white European men (WEM), because of their reduced visceral fat. METHODS: Eighteen BAM and 15 WEM with type 2 diabetes underwent a two-stage hyperinsulinaemic-euglycaemic clamp with stable glucose and glycerol isotope tracers to assess tissue-specific insulin sensitivity and a magnetic resonance imaging scan to assess body composition. RESULTS: We found no ethnic differences in whole body, skeletal muscle, hepatic or adipose tissue insulin sensitivity between BAM and WEM. This finding occurred in the presence of lower visceral fat in BAM (3.72 vs 5.68 kg [mean difference -1.96, 95% CI -3.30, 0.62]; p = 0.01). There was an association between skeletal muscle and adipose tissue insulin sensitivity in WEM that was not present in BAM (r = 0.78, p < 0.01 vs r = 0.25 p = 0.37). CONCLUSIONS/INTERPRETATION: Our data suggest that in type 2 diabetes there are no ethnic differences in whole body, skeletal muscle, hepatic and adipose tissue insulin sensitivity between black and white men, despite differences in visceral adipose tissue, and that impaired lipolysis may not be contributing to skeletal muscle insulin resistance in men of black African ethnicity.

Associations Between Pancreatic Lipids and ß-Cell Function in Black African and White European Men With Type 2 Diabetes.

CONTEXT: Intrapancreatic lipid (IPL) has been linked to ß-cell dysfunction. Black populations disproportionately develop type 2 diabetes (T2D) and show distinctions in ß-cell function compared with white populations. OBJECTIVE: We quantified IPL in white European (WE) and black West African (BWA) men with early T2D and investigated the relationships between IPL and ß-cell insulin secretory function (ISF). DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional assessment of 18 WE and 19 BWA middle-age men with early T2D as part of the South London Diabetes and Ethnicity Phenotyping study. MAIN OUTCOME MEASURES: The participants underwent Dixon MRI to determine IPL in the pancreatic head, body, and tail and subcutaneous and visceral adipose tissue volumes. Modeled first- and second-phase ISFs were comprehensively determined using C-peptide measurements during a 3-hour meal tolerance test and a 2-hour hyperglycemic clamp test. RESULTS: The WE men had greater mean IPL levels compared with BWA men (P = 0.029), mainly owing to greater IPL levels in the pancreatic head (P = 0.009). The mean IPL level was inversely associated with orally stimulated first-phase ISF in WE but not BWA men (WE, r = -0.554, P = 0.026; BWA, r = -0.183, P = 0.468). No association was found with orally stimulated second-phase ISF in either WE or BWA men. No associations were found between the mean IPL level and intravenously stimulated ISF. CONCLUSIONS: The IPL levels were lower in BWA than WE men with early T2D, and the lack of inverse association with first-phase ISF in BWA men indicates that IPL might be a less important determinant of the development of T2D in BWA than in WE men.