The Mitochondrial Puzzle: Why Obesity Affects Insulin Sensitivity Differently in Black and White Women

Type 2 diabetes (T2D) is a global health issue, affecting more than 460 million people worldwide. However, the burden of the disease is not equally distributed across populations (1). For instance, non-Hispanic Black women (BW) are at a disproportionately higher risk of developing T2D and insulin resistance compared to their non-Hispanic White counterparts (WW) (2). Nevertheless, despite this well-established disparity, the underlying causes of such racial differences are poorly understood. Notably, traditional risk factors for T2D, such as visceral and hepatic adiposity, do not fully explain the higher prevalence of insulin resistance among BW. Research has shown that BW tend to have lower levels of visceral and hepatic fat compared to WW, types of adiposity that are closely related to insulin resistance (3). This paradox suggests that other nontraditional risk factors, such as differences in muscle physiology, mitochondrial function, or hormonal responses, contribute to the increased susceptibility of BW to T2D. In this context, the study of mitochondrial function in skeletal muscle becomes particularly relevant. Indeed, skeletal muscle plays a central role in glucose metabolism and insulin sensitivity, and any dysfunction in its mitochondrial respiration could contribute to the higher rates of T2D observed in BW (4). Thus, understanding these alternative pathways may help to address racial disparities in T2D and improve prevention and treatment strategies. The study by Mucinski and colleagues (5) published in The Journal of Clinical Endocrinology & Metabolism builds on previous work by the same group demonstrating lower skeletal muscle mitochondrial respiration and peripheral insulin sensitivity in BW without obesity with respect to WW (6). The more recent study extends the analysis to women with obesity, seeking to determine whether the observed racial differences persist or are exacerbated by increased body weight. Specifically, 64 women with and without obesity were recruited, with an equal distribution between BW and WW, and accurate comparisons were ensured by matching participants for body weight, body mass index, and age (5). To assess insulin sensitivity, researchers used the gold-standard hyperinsulinemic-euglycemic clamp, which provides precise insight into glucose metabolism. They also conducted skeletal muscle biopsies to measure mitochondrial respiration and thus explore how muscle mitochondrial function might influence insulin sensitivity. Additionally, the team examined mitochondrial DNA (mtDNA) haplogroups, which are maternally inherited and have been linked to mitochondrial function, cardiorespiratory fitness, and risk of T2D (5). The results revealed that BW exhibited 21% lower peripheral insulin sensitivity compared to WW, even when matched for obesity, with a 67% reduction in insulin sensitivity across the two groups overall. This reduced sensitivity was linked primarily to skeletal muscle insulin resistance, indicating that BW are more susceptible to peripheral insulin resistance, a key risk factor for T2D. Notably, hepatic insulin sensitivity did not differ significantly between the groups, suggesting that the racial disparities observed are specific to peripheral tissues like skeletal muscle (5). Furthermore, BW presented with lower skeletal muscle mitochondrial respiration than their WW counterparts, which may have contributed to their reduced peripheral insulin sensitivity. Specifically, mitochondrial content was lower in BW compared to WW (P = .013), with nonobese BW showing significantly lower content (3.7 ± 0.3%) than nonobese WW (4.8 ± 0.4%; P = .013). However, mitochondrial content was similar in BW and WW with obesity (BW: 4.5 ± 0.3% vs WW: 4.6 ± 0.3%; P = .766) (5). High-resolution respirometry revealed 71% lower maximal coupled respiration (state 3; P < .001) and 38% lower maximal uncoupled respiration (state U; P < .001) in women with obesity compared to those without obesity. BW exhibited 24% lower respiration in state 3 (P < .001) and 22% lower in state U (P < .001) with respect to WW, but no difference in basal respiration was apparent (state 4; P = .612). Mitochondrial function is crucial for energy metabolism, and when impaired can reduce the capacity for glucose oxidation and exacerbate insulin resistance. These findings align with prior research suggesting that mitochondrial dysfunction is an important factor in metabolic diseases, particularly among BW (7). The study also explored the effect of obesity on racial disparities in insulin sensitivity and mitochondrial function. While obesity increased insulin resistance both in BW and WW, differences between the groups remained significant. This indicates that racial disparities in metabolic health are not driven solely by obesity, but also involve additional physiological or genetic factors. Lastly, the exploratory analysis of mtDNA haplogroups provides new insights into genetic differences between BW and WW that may affect mitochondrial function and insulin sensitivity. The authors emphasize the need for further research to explore the roles of mtDNA and nuclear genetic ancestry in shaping metabolic health outcomes across different racial groups. Indeed, in a previous study of mitochondrial haplogroups in women with obesity, one BW without an African haplogroup displayed respiratory rates similar to WW and 73 ± 29% higher than other BW with L-type haplogroups (5). This suggests that differences between nuclear and mtDNA genetic ancestry can affect skeletal muscle respiration. The data align with previous studies in which African-origin haplogroups (L-type) were associated with lower mitochondrial respiration compared to European haplogroups (eg, H-type) (8). The results reported by Mucinski et al (5) provide important new knowledge about diabetes risk; they highlight that BW are more at risk than WW and underline the need for further investigation into the mechanisms contributing to this risk. However, as the authors note, their research has some limitations: i) While the correlation analysis identifies associations, it does not establish causality; thus, further studies are needed to explore whether skeletal muscle mitochondrial dysfunction affects insulin sensitivity directly; ii) age differences of approximately 10 years between groups were accounted for in the analysis, but their effect cannot be completely ruled out; iii) the small sample size, especially of obese women, may have led to small effect sizes; and iv) the lack of measurements of visceral and liver fat limits the understanding of racial differences in insulin resistance (5). Lastly, the study does not account for lifestyle factors such as diet and physical activity, which can also affect mitochondrial function and insulin sensitivity. Including these variables in future research would provide a more comprehensive understanding of the factors contributing to racial disparities in metabolic health. The authors thank Brian Normanly (University of Valencia/CIBERehd; [email protected]) for his editorial assistance. This work was supported by the European Regional Development Fund (ERDF “A way to build Europe”); Generalitat Valenciana (grant PROMETEO CIPROM/2022/32); and the Spanish Ministry of Science and Innovation (grants CIBERehd CB06/04/0071 and PI22/00424 from Carlos III Health Institute). T.V. is the recipient of a Miguel Servet contract (CP22/00153) from the Carlos III Health Institute. The authors have nothing to disclose. Data sharing is not applicable to this article because no data sets were generated or analyzed during the present study. non-Hispanic Black women mitochondrial DNA type 2 diabetes non-Hispanic White women