The determinants of β-cell function, a critical factor in the pathogenesis of T2D, are incompletely understood, especially in black African populations who present with a phenotype of low SI, hyperinsulinemia and low ectopic fat deposition. Our study extend existing evidence by demonstrating that DI was positively associated with CLp. Notably, the major determinant of AIRg was ISRfirst phase, above insulin clearance. VAT emerged as the strongest determinant of DI, above and independent of pancreatic fat and soleus fat. Additionally, we showed that a lower VAT also associated with a higher ISRfirst phase and lower FEL. Thus, our findings suggest that VAT is a more important determinant of a lower DI than ectopic fat in this cohort, not only through its association with a lower SI, but also through its relation with the AIRg downstream components, ISR and FEL.
Our study, not only distinguishes between FEL and CLp, which has only been done in a few studies in adults without T2D [5,6,26], but we also demonstrated for the first time a positive association between DI and CLp. The reason for this relationship is unclear. Nevertheless, considering DI is based on the product of SI and AIRg, we can postulate two scenarios. Firstly, a higher DI may be due to a hyperinsulinemia relative to the the level of SI. However, hyperinsulinemia has been associated with lower insulin clearance in both adipose tissue [27] and muscle [28], due to reduced affinity of insulin receptors at these sites, and is therefore an unlikely explanation for our finding of a higher CLp relative to higher DI. Secondly, a higher DI could be due to a greater SI in relation to the level of AIRg. In this scenario, a higher CLp may be due to enhanced binding of insulin to insulin receptors in peripheral tissues. Although a positive association has been demonstrated between SI and hepatic insulin clearance [29], no association between insulin internalization, a measure of insulin clearance, and SI was observed in rat adipocytes [27], whereas the association between SI and insulin clearance in muscle is unknown. However, in support of the second scenario, we showed that those with the highest DI and CLp were also more insulin sensitive, but only exhibited a slightly higher AIRg compared to those with lower DI and CLp. Nevertheless, CLp was not associated with SI in our study, but rather with the insulin secretory component. Further, we may also consider that the observed association between DI and CLp is in compensation for a lower FEL, but this association remained independent of FEL. We also evaluated the associations of CLp with ectopic fat deposition as possible explanation for the association with DI, but found that CLp was not associated with skeletal muscle fat. Skeletal muscle fat has been associated with reduced SI [30], which may also affect CLp in the muscle. Further study is justified to evaluate the relationship between CLp and SI in the muscle, considering that the muscle is only secondary to the kidney in the proportion of insulin cleared in the periphery [31]. Of note, CLp in our study is much higher compared to another study conducted in black American women [5]. However, the acute insulin response in our cohort was twice as high as that observed in Piccinini et al, and may contribute to this discrepancy.
Preservation of β-cell function is critical for delaying the onset of T2D. We, therefore, investigated, firstly, whether ectopic fat accumulation may explain the variance in DI and secondly, we assessed the associations of ectopic fat with the components of DI. Our study demonstrated that a higher DI was associated with a lower pancreatic and soleus fat and a tendency towards a lower hepatic fat, but these associations were not independent from VAT. A similar observation was found in overweight African American and Hispanic adolescents (13 to 25 years old) without T2D [32]. In contrast a positive association between DI and pancreatic fat, adjusted for BMI and VAT, was shown in black African American women [11]. However, this study included participants with and without T2D, which may explain the incongruent findings. Our study extends the literature by showing that pancreatic fat was not associated with ISRfirst phase or with FEL in black Africans. Notably, a positive association was found between pancreatic fat and VAT in our study. Our findings therefore suggest that pancreatic fat may only be a marker of VAT accumulation and is not detrimental to β-cell function in this cohort.
The ability to maintain β-cell function and prevent deteriorating glucose tolerance depends on the balance between AIRg and SI [1]. However, there is no consensus on the mechanism of maintaining a higher AIRg, which is frequently observed in black African populations [2,3]. Some studies reported that a lower hepatic insulin clearance alone is responsible for a higher AIRg [33,34], while others showed that both lower hepatic insulin clearance and higher ISR contribute towards a higher AIRg [3,5]. Notably, AIRg may be out of proportion for the level of SI, and to assess the relative contribution of ISRfirst phase and insulin clearance to AIRg in this context, we need to adjust for SI. Accordingly, a lower FEL and higher ISRfirst phase were the main independent contributors towards a higher AIRg, but ISRfirst phase explained more of the variance in AIRg. Lowering hepatic insulin clearance is an important compensatory mechanism to reduce the strain on the pancreatic β-cells, which has been shown in canines [35]. However, we have shown that a higher ISR associates with AIRg, independently of lower FEL and SI, suggesting that despite a lower FEL, pancreatic β-cells may continue to secrete insulin at a higher rate, which may be detrimental to the longevity of the β-cell in this cohort.
The current study further examined the associations between the components of AIRg and ectopic fat. Previously, reduced hepatic insulin clearance and increased insulin secretion, have been associated with hepatic fat accumulation [36]. An association between fasting hepatic insulin clearance and hepatic fat was studied in African American women [13], but the association between stimulated hepatic insulin clearance, which is a more physiological response, and hepatic fat has not been previously investigated in black African populations without T2D . We showed that hepatic fat was not associated with FEL and ISR in obese black South African women. Therefore, in black African populations, hepatic fat may not be an important determinant of hepatic insulin clearance and insulin secretion prior to T2D, and also not in those with early T2D [37]. Instead, we found that a lower ISRfirst phase and higher FEL was associated with higher VAT. This highlights a novel mechanism to explain the association between AIRg and VAT since to the best of our knowledge, no previous study has evaluated the effect of central fat depots on FEL. In addition, evidence on the associations between central fat depots and ISR, determined by C-peptide deconvolution are also limited in black African populations [9]. We add to the literature by showing a negative association between VAT and ISRfirst phase, independent of SI, in premenopausal black South African women. Interestingly, black African women have lower VAT compared to other ethnicities [2,3], but they have a greater propensity to increase VAT over time, with the greatest increase occurring in the 20-29-year age group [38]. However, further studies are needed to confirm the effect of VAT on ISR in this cohort.
We also assessed the association between SI and ectopic fat and found no association between SI and skeletal muscle or hepatic fat. These findings suggest that these ectopic fat depots are not important contributors to SI in our study. However, we should consider that we measured whole body SI, which could have diluted the associations with hepatic and soleus fat. Indeed, a small South African study found that in black South African women, hepatic fat was associated with hepatic SI but not peripheral SI [12]. Furthermore, total soleus fat and soleus IMCL were associated with peripheral SI, but not hepatic SI [12]. Nevertheless, lower SI was associated with higher VAT which may contribute to the observed inverse association between DI and VAT in this cohort.
A major strength of this study is that ISR and both hepatic and peripheral clearance were determined using mathematical modelling, which has never been done before in an African cohort. Further we assessed pancreatic, hepatic and skeletal muscle ectopic fat depots, as well as VAT and aSAT volumes using MRI. However, limitations of this study were that we did not determine glucose tolerance, and we did not distinguish between hepatic and peripheral SI. In addition, these findings are applicable to premenopausal, obese black South African women and may not be extrapolated to men or other races.
In conclusion, an original finding from this study was that DI was associated with CLp, independent from FEL. Further, while both FEL and ISRfirst phase independently contributed towards hyperinsulinemia, ISRfirst phase was more important. Ectopic fat was not an important independent determinant of DI and its components. Rather, a key finding was that higher VAT was the principal determinant of a lower DI, above other ectopic fat depots. Additionally, the associations of higher VAT on the downstream components of DI, a lower ISRfirst phase and higher FEL may contribute to lower DI prior to T2D onset but requires further elucidation. Accordingly, the prevention of VAT accumulation, especially in young black African women should be an important target for β-cell preservation.